Publications by authors named "Henk J van Kranen"

30 Publications

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Optimising SME Potential in Modern Healthcare Systems: Challenges, Opportunities and Policy Recommendations.

Public Health Genomics 2018 24;21(1-2):1-17. Epub 2018 Aug 24.

Institute for Public Health Genomics, Department of Genetics and Cell Biology, Research Institute GROW, Faculty of Health, Medicine and Life Sciences, University of Maastricht, Maastricht, The Netherlands.

The expansion of European small and medium-sized enterprises (SMEs) into the healthcare innovation arena suggests that this should be an important EU policy priority that can significantly benefit the economy, society and citizens, including patients. Deepening and widening of Europe's SMEs' growth and activities is part of the EU objectives as set out by the European Commission in its Communications "Small Business Act" for Europe [1] and "Small Business, Big World" [2]. However, innovative healthcare SMEs have struggled to get traction despite the sector being worth more than EUR 250 billion. The 1991 Maastricht Treaty gave the Union new competences in public health and more scope for cross-border cooperation in this area [3]. Nevertheless, health initiatives here have tripped over each other, due to the fact that the delivery of healthcare is a national competence [4]. As such, EU healthcare-driven policy has never truly found its footing as a singular policy area despite the fact that a tenth of the EU's GDP is spent on healthcare and more than 17 million people are employed in Europe in this sector [5]. Taking into account the necessity of bringing innovation into healthcare, and the willingness of SMEs to undertake the risk to be at the forefront of it, there is a need for a renewed effort to support SMEs so as to provide solutions for citizens and patients throughout the bloc in different healthcare settings [6]. This policy paper brings together two separate strands of analysis: firstly, a policy review of the main challenges and opportunities; secondly, a proposal for policy recommendations.
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http://dx.doi.org/10.1159/000492809DOI Listing
April 2019

MECP2 variation in Rett syndrome-An overview of current coverage of genetic and phenotype data within existing databases.

Hum Mutat 2018 07 21;39(7):914-924. Epub 2018 May 21.

Rett Expertise Centre Netherlands - GKC, Maastricht University Medical Center, Maastricht, The Netherlands.

Rett syndrome (RTT) is a monogenic rare disorder that causes severe neurological problems. In most cases, it results from a loss-of-function mutation in the gene encoding methyl-CPG-binding protein 2 (MECP2). Currently, about 900 unique MECP2 variations (benign and pathogenic) have been identified and it is suspected that the different mutations contribute to different levels of disease severity. For researchers and clinicians, it is important that genotype-phenotype information is available to identify disease-causing mutations for diagnosis, to aid in clinical management of the disorder, and to provide counseling for parents. In this study, 13 genotype-phenotype databases were surveyed for their general functionality and availability of RTT-specific MECP2 variation data. For each database, we investigated findability and interoperability alongside practical user functionality, and type and amount of genetic and phenotype data. The main conclusions are that, as well as being challenging to find these databases and specific MECP2 variants held within, interoperability is as yet poorly developed and requires effort to search across databases. Nevertheless, we found several thousand online database entries for MECP2 variations and their associated phenotypes, diagnosis, or predicted variant effects, which is a good starting point for researchers and clinicians who want to provide, annotate, and use the data.
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http://dx.doi.org/10.1002/humu.23542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6033003PMC
July 2018

Circulating concentrations of vitamin D in relation to pancreatic cancer risk in European populations.

Int J Cancer 2018 03 22;142(6):1189-1201. Epub 2017 Nov 22.

Dipartimento di medicina clinica e chirurgia, Federico II university, Naples, Italy.

Evidence from in vivo, in vitro and ecological studies are suggestive of a protective effect of vitamin D against pancreatic cancer (PC). However, this has not been confirmed by analytical epidemiological studies. We aimed to examine the association between pre-diagnostic circulating vitamin D concentrations and PC incidence in European populations. We conducted a pooled nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) and the Nord-Trøndelag Health Study's second survey (HUNT2) cohorts. In total, 738 primary incident PC cases (EPIC n = 626; HUNT2 n = 112; median follow-up = 6.9 years) were matched to 738 controls. Vitamin D [25(OH)D and 25(OH)D combined] concentrations were determined using isotope-dilution liquid chromatography-tandem mass spectrometry. Conditional logistic regression models with adjustments for body mass index and smoking habits were used to estimate incidence rate ratios (IRRs) and 95% confidence intervals (95%CI). Compared with a reference category of >50 to 75 nmol/L vitamin D, the IRRs (95% CIs) were 0.71 (0.42-1.20); 0.94 (0.72-1.22); 1.12 (0.82-1.53) and 1.26 (0.79-2.01) for clinically pre-defined categories of ≤25; >25 to 50; >75 to 100; and >100 nmol/L vitamin D, respectively (p for trend = 0.09). Corresponding analyses by quintiles of season-standardized vitamin D concentrations also did not reveal associations with PC risk (p for trend = 0.23). Although these findings among participants from the largest combination of European cohort studies to date show increasing effect estimates of PC risk with increasing pre-diagnostic concentrations of vitamin D, they are not statistically significant.
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http://dx.doi.org/10.1002/ijc.31146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5813219PMC
March 2018

Policy Making in Newborn Screening Needs a Structured and Transparent Approach.

Front Public Health 2017 21;5:53. Epub 2017 Mar 21.

Section Community Genetics, Department of Clinical Genetics, Amsterdam Public Health Research Institute , Amsterdam , Netherlands.

Purpose: Newborn bloodspot screening (NBS) programs have expanded significantly in the past years and are expected to expand further with the emergence of genetic technologies. Historically, NBS expansion has often occurred following consideration of conditions, instead of a structured and transparent approach. In this review, we explore issues pertinent to NBS policy making, through the lens of the policy cycle: (a) agenda setting, (b) policy advice, (c) policy decision, (d) implementation, and (e) evaluation.

Methods: A literature search was conducted to gather information on the elements specific to NBS and its policy making process.

Results: The review highlighted two approaches to nominate a condition: a structured approach through horizon scanning; and an process. For assessment of a condition, there was unanimous support for a robust process based on criteria. While the need to assess harms and benefits was a repeated theme in the articles, there is no agreed-upon threshold for benefit in decision-making. Furthermore, the literature was consistent in its recommendation for an overarching, independent, multidisciplinary group providing recommendations to government. An implementation plan focusing on the different levels on which NBS operates and the information needed on each level is essential for successful implementation. Continuously monitoring, and improving a program is vital, particularly following the implementation of screening for a new condition. An advisory committee could advise on implementation, development, review, modification, and cessation of (parts of) NBS.

Conclusion: The results highlight that there are a wave of issues facing NBS programs that policy makers must take into account when developing policy processes. What conditions to screen, and the technologies used in NBS, are both up for debate.
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http://dx.doi.org/10.3389/fpubh.2017.00053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5359248PMC
March 2017

The impact of personalized medicine of Type 2 diabetes mellitus in the global health context.

Per Med 2016 Jul 22;13(4):381-393. Epub 2016 Jun 22.

Institute for Public Health Genomics, Department of Genetics & CellBiology, School for Oncology & Developmental Biology (GROW), Faculty of Health, Medicine & LifeSciences, Maastricht University, Maastricht 6200 MD, The Netherlands.

Advances in the fields of genomic sciences have given rise to personalized medicine. This new paradigm draws upon a patient's genetic and metabolic makeup in order to tailor diagnostics and treatment. Personalized medicine holds remarkable promises to improve prevention and management of chronic diseases of global relevance, such as Type 2 diabetes mellitus (T2DM). This review article aims at summarizing the evidence from genome-based sciences on T2DM risk and management in different populations and in the Global Health context. Opinions from leading experts in the field were also included. Based on these findings, strengths and weaknesses of personalized approach to T2DM in a global context are delineated. Implications for future research and implementation on that subject are discussed.
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http://dx.doi.org/10.2217/pme-2016-0029DOI Listing
July 2016

Specific polymorphisms in the vitamin D metabolism pathway are not associated with susceptibility to Chlamydia trachomatis infection in humans.

Pathog Dis 2016 Apr 10;74(3). Epub 2016 Feb 10.

Laboratory of Immunogenetics, Department of Medical Microbiology and Infection Control, VU University Medical Center, Amsterdam 1081 BT, the Netherlands Institute for Public Health Genomics, Department of Genetics and Cell Biology, School for Oncology and Developmental Biology (GROW), Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht 6200 MD, the Netherlands.

Chlamydia trachomatis is the most common sexually transmitted bacterium worldwide. Its often asymptomatic course of infection increases chances of transmission, and increases risk of late complications. Genetic variations in the host immune system are known to impact the course of infections. Recent studies have shown a positive impact of vitamin D on the regulation of the immune system. This study assesses the impact of eight polymorphisms in five genes [VDR (rs1544410 G > A, rs2228570 C > T), CYP27B1 (rs10877012 G > T), DHCR7 (rs7944926 G > A, rs3829251 G > A), GC (rs3755967) and CYP2R1 (rs10741657 G > A, rs2060793 G > A)] on susceptibility to Chlamydia infections in humans. These polymorphisms could influence protein expression or function, and thus influence the immune system. Samples of women visiting the STD outpatient clinic in South Limburg were genotyped using the Roche Lightcycler 480. In this study, we did not observe statistically significant differences between the genotype distributions of these polymorphisms in women with or without a Chlamydia infection. This suggests that VDR, CYP27B1, DHCR7, GC and CYP2R1 do not affect the susceptibility to Chlamydia infections. However, due to its pleiotropic nature in the immune system a role for the vitamin D pathway may not be excluded from the whole clinical course of Chlamydia infections (e.g. late complications), and further research is required.
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http://dx.doi.org/10.1093/femspd/ftw010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5975236PMC
April 2016

Preferences for genetic testing for colorectal cancer within a population-based screening program: a discrete choice experiment.

Eur J Hum Genet 2016 Mar 3;24(3):361-6. Epub 2015 Jun 3.

Centre for Nutrition, Prevention and Health Services, National Institute for Public Health and the Environment, Bilthoven, The Netherlands.

This study explored individuals' preferences for genetic testing for colorectal cancer (CRC) in a screening situation and their willingness to participate in genetic testing for Lynch syndrome, familial adenomatous polyposis (FAP), and familial colorectal cancer (FCC). For that purpose, 532 respondents aged 55-65 years completed a Discrete Choice Experiment. Using panel latent class models, the preferences for two screening situation characteristics (the probability of being genetically predisposed and the probability of developing CRC) and screening test characteristics (the frequency of preventive colonoscopies and CRC survival) were estimated. Based on these preferences, respondents' willingness to participate in the three screening initiatives was estimated. Lower-educated respondents and respondents who express serious anxiety and worries found colonoscopy frequency and the probability of developing CRC relatively more important and survival relatively less important compared with higher-educated respondents and respondents who express no anxiety and worries. These differences in preferences resulted in opposite preferences for participation in FCC and FAP screening. In conclusion, the general population is willing to participate in genetic screening for CRC. If individuals are suspected of genetic or familial CRC, they should at least be informed about their increased risk of being genetically predisposed and about the importance of participating in all preventive follow-up colonoscopies in order to maximize survival.
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http://dx.doi.org/10.1038/ejhg.2015.117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4755369PMC
March 2016

Rett Syndrome as a Rare Disease: A European Perspective.

Public Health Genomics 2015 14;18(4):233-6. Epub 2015 Apr 14.

Rett Expertise Centre - Governor Kremers Centre (GKC), Maastricht University Medical Centre, Maastricht, The Netherlands.

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http://dx.doi.org/10.1159/000381139DOI Listing
October 2015

Dietary fat intake and development of specific breast cancer subtypes.

J Natl Cancer Inst 2014 Apr 9;106(5). Epub 2014 Apr 9.

Affiliations of authors: Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy (SS, CA, VP, FB, SG, VK); Medical Statistics Unit, Second University of Naples, Naples, Italy (PC); Hellenic Health Foundation, Athens, Greece (ATr); Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, Athens, Greece (VB, EV); Escuela Andaluza de Salud Pública, Granada, Spain (M-JS); CIBER de Epidemiología y Salud Pública, Madrid, Spain (M-JS, M-DC, PA, EA); Instituto de Investigación Biosanitaria de Granada, Granada, Spain (M-JS); Department of Epidemiology, Murcia Health Authority, Murcia, Spain (M-DC); Public Health Division of Gipuzkoa, BioDonostia Research Institute, Health Department of Basque Region, San Sebastian, Spain (PA); Health Information Unit, Public Health and Health Planning Directorate, Asturias, Spain (JRQ); Navarre Public Health Institute, Pamplona, Spain (EA); Unit of Nutrition, Environment and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology, Barcelona, Spain (GB); Molecular and Nutritional Epidemiology Unit, ISPO-Cancer Research and Prevention Institute, Florence, Italy (GM); Department of Clinical and Experimental Medicine, University of Naples Federico II, Naples, Italy (SP); Center for Cancer Prevention, Turin, Italy (CS); Human Genetics Foundation, Turin, Italy (CS); Department of Oncology, Histopathology Unit (RT), and Cancer Registry (RT), Ospedale Civile "M.P. Arezzo," Ragusa, Italy; INSERM, Centre for Research in Epidemiology and Population Health, U1018, Nutrition, Hormones and Women's Health team, F-94805, Villejuif, France (MC-BR); Univ Paris Sud, UMRS 1018, F-94805, Villejuif, France (FC-C); IGR, F-94805, Villejuif, France (GF); Department of Epidemiology, Julius Center for Health Sciences and Primary Care (PHMP, CHvG), and Department of Gastroenterology and Hepatology (HBB-d-M), University Medical Center Utrecht, Utrecht, the Netherlands;

We prospectively evaluated fat intake as predictor of developing breast cancer (BC) subtypes defined by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor 2 receptor (HER2), in a large (n = 337327) heterogeneous cohort of women, with 10062 BC case patients after 11.5 years, estimating BC hazard ratios (HRs) by Cox proportional hazard modeling. High total and saturated fat were associated with greater risk of ER(+)PR(+) disease (HR = 1.20, 95% confidence interval [CI] = 1.00 to 1.45; HR = 1.28, 95% CI = 1.09 to 1.52; highest vs lowest quintiles) but not ER(-)PR(-) disease. High saturated fat was statistically significantly associated with greater risk of HER2(-) disease. High saturated fat intake particularly increases risk of receptor-positive disease, suggesting saturated fat involvement in the etiology of this BC subtype.
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http://dx.doi.org/10.1093/jnci/dju068DOI Listing
April 2014

Hepatocellular carcinoma risk factors and disease burden in a European cohort: a nested case-control study.

J Natl Cancer Inst 2011 Nov 21;103(22):1686-95. Epub 2011 Oct 21.

Department of Epidemiology, Harvard School of Public Health, 677 Huntington Avenue, Boston, MA 02115, USA.

Background: To date, no attempt has been made to systematically determine the apportionment of the hepatocellular carcinoma burden in Europe or North America among established risk factors.

Methods: Using data collected from 1992 to 2006, which included 4,409,809 person-years in the European Prospective Investigation into Cancer and nutrition (EPIC), we identified 125 case patients with hepatocellular carcinoma, of whom 115 were matched to 229 control subjects. We calculated odds ratios (ORs) for the association of documented risk factors for hepatocellular carcinoma with incidence of this disease and estimated their importance in this European cohort.

Results: Chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (OR = 9.10, 95% confidence interval [CI] = 2.10 to 39.50 and OR = 13.36, 95% CI = 4.11 to 43.45, respectively), obesity (OR = 2.13, 95% CI = 1.06 to 4.29), former or current smoking (OR = 1.98, 95% CI = 0.90 to 4.39 and OR = 4.55, 95% CI = 1.90 to 10.91, respectively), and heavy alcohol intake (OR = 1.77, 95% CI = 0.73 to 4.27) were associated with hepatocellular carcinoma. Smoking contributed to almost half of all hepatocellular carcinomas (47.6%), whereas 13.2% and 20.9% were attributable to chronic HBV and HCV infection, respectively. Obesity and heavy alcohol intake contributed 16.1% and 10.2%, respectively. Almost two-thirds (65.7%, 95% CI = 50.6% to 79.3%) of hepatocellular carcinomas can be accounted for by exposure to at least one of these documented risk factors.

Conclusions: Smoking contributed to more hepatocellular carcinomas in this Europe-wide cohort than chronic HBV and HCV infections. Heavy alcohol consumption and obesity also contributed to sizeable fractions of this disease burden. These contributions may be underestimates because EPIC volunteers are likely to be more health conscious than the general population.
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http://dx.doi.org/10.1093/jnci/djr395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3216968PMC
November 2011

Endogenous sex steroids and risk of cervical carcinoma: results from the EPIC study.

Cancer Epidemiol Biomarkers Prev 2011 Dec 12;20(12):2532-40. Epub 2011 Oct 12.

International Agency for Research on Cancer, Lyon, France.

Background: Epidemiologic data and animal models suggest that, despite the predominant role of human papillomavirus infection, sex steroid hormones are also involved in the etiology of invasive cervical carcinoma (ICC).

Methods: Ninety-nine ICC cases, 121 cervical intraepithelial neoplasia grade 3 (CIN3) cases and 2 control women matched with each case for center, age, menopausal status and blood collection-related variables, were identified in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Circulating levels of testosterone (T) and estradiol (E(2)); dehydroepiandrosterone sulfate (DHEAS); progesterone (premenopausal women); and sex hormone-binding globulin (SHBG) were measured using immunoassays. Levels of free (f) T and E(2) were calculated from absolute concentrations of T, E(2), and SHBG. Odds ratios (ORs) and 95% confidence intervals (CI) were computed using regularized conditional logistic regression.

Results: Among premenopausal women, associations with ICC were observed for fT (OR for highest vs. lowest tertile = 5.16, 95% CI, 1.50-20.1). SHBG level was associated with a significant downward trend in ICC risk. T, E(2), fE(2), and DHEAS showed nonsignificant positive association with ICC. Progesterone was uninfluential. Among postmenopausal women, associations with ICC were found for T (OR = 3.14; 95% CI, 1.21-9.37), whereas E(2) and fT showed nonsignificant positive association. SHBG level was unrelated to ICC risk in postmenopausal women. No associations between any hormone and CIN3 were detected in either pre- or postmenopausal women.

Conclusions: Our findings suggest for the first time that T and possibly E(2) may be involved in the etiology of ICC.

Impact: The responsiveness of cervical tumors to hormone modulators is worth exploring.
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http://dx.doi.org/10.1158/1055-9965.EPI-11-0753DOI Listing
December 2011

Costs and health effects of adding functional foods containing phytosterols/-stanols to statin therapy in the prevention of cardiovascular disease.

Eur J Pharmacol 2011 Sep 27;668 Suppl 1:S91-100. Epub 2011 Jul 27.

National Institute for Public Health and the Environment (RIVM), PO Box 1, 3720 BA Bilthoven, The Netherlands.

The present modelling study aimed to evaluate if and by how much functional foods containing phytosterols/-stanols add to the benefits of statins in the prevention of cardiovascular disease in terms of cost-effectiveness. Long-term health effects, measured as quality-adjusted life-years gained, and costs for scenarios with additional phytosterol/-stanol use were compared to scenarios without extra use. Phytosterols/-stanols were given only to persons who were eligible for use according to their 10-year absolute risk of fatal cardiovascular disease (SCORE-risk). Intake levels and discontinuation rates as observed in daily practice were included in the model. Two situations were compared: 1) A real-life situation in which persons at high SCORE-risk were identified through clinical case-finding and, 2) A theoretical maximum situation where universal screening was implemented resulting in known SCORE-risks for the whole Dutch population aged 35-75 years (8.4 million people). Sensitivity analyses were performed for variations in the cholesterol-lowering effect and intake level of phytosterols/-stanols, indirect health care costs, time horizon and discount rates. At the model's start year, a total of 1.0 (real-life situation) to 3.3 (maximum situation) million persons qualified for phytosterol/-stanol use based on their SCORE-risk (both statin users and statin non-users). Over the model's time horizon, this resulted in a gain of 2700 to 16,300 quality-adjusted life-years, and yielded cost-effectiveness ratios that ranged between €92,000 and €203,000 per quality-adjusted life-year. This simulation study showed that the cost-effectiveness of phytosterols/-stanols as monotherapy and as add-on to statins is above thresholds for cost-effectiveness, generally ranging between €20,000 and €50,000, and is thus a non-cost-effective strategy to reduce cardiovascular disease.
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http://dx.doi.org/10.1016/j.ejphar.2011.05.081DOI Listing
September 2011

Functional foods and dietary supplements: products at the interface between pharma and nutrition.

Eur J Pharmacol 2011 Sep 27;668 Suppl 1:S2-9. Epub 2011 Jul 27.

National Institute for Public Health and the Environment (RIVM), PO Box 1, 3720 BA Bilthoven, The Netherlands.

It is increasingly recognized that most chronic diseases of concern today are multifactorial in origin. To combat such diseases and adverse health conditions, a treatment approach where medicines and nutrition complement each other may prove to be the most successful. Within nutrition, apart from (disease-related) dietetic regimes, an increasing number of functional foods and dietary supplements, each with their own health claim, are marketed. These food items are considered to be positioned between traditional foods and medicines at the so-called 'Pharma-Nutrition Interface'. This paper encompasses aspects related to the regulatory framework and health claims of functional foods and dietary supplements. The use of functional foods or dietary supplements may offer opportunities to reduce health risk factors and risk of diseases, both as monotherapy and in combination with prescription drugs. Nevertheless, the potential caveats of these products should not be overlooked. These caveats include the increased risk for food-drug interactions due to the elevated amounts of specific functional ingredients in the diet, and the stimulation of self-medication potentially resulting in lower adherence to drug therapy. Health technology assessments should be used more to compare the cost-effectiveness and benefit-risk ratios of drugs, functional foods and dietary supplements, and to evaluate the added value of functional foods or dietary supplements to drug therapy.
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http://dx.doi.org/10.1016/j.ejphar.2011.07.008DOI Listing
September 2011

Influence of the use of functional foods enriched with phytosterols/-stanols on adherence to statin therapy.

Pharmacoepidemiol Drug Saf 2011 Aug 7;20(8):830-7. Epub 2011 Jun 7.

Utrecht Institute for Pharmaceutical Sciences, Utrecht, The Netherlands.

Purpose: Subjects using functional foods with approved health claims may be more likely to be non-adherent with prescribed drug therapy. This study aimed to assess the influence of the use of phytosterol/-stanol-enriched functional foods on adherence to statin therapy among patients initiating treatment.

Methods: We used data from the statin intervention research project, a randomized controlled trial aimed at improving adherence to statins. In the trial, new statin users were randomized to receive either usual care or extensive pharmaceutical care consisting of five individual counseling sessions. Customary use of phytosterol/-stanol-enriched products was identified by questionnaires filled out by all participants. Automated pharmacy-dispensing records were used to assess adherence in terms of discontinuation of therapy and the medication possession ratio. Analyses were performed for the overall population, as well as stratified for receiving pharmaceutical or usual care.

Results: The use of functional foods enriched with phytosterols/-stanols was not related to discontinuation of statin therapy, neither in the overall population (overall population adjusted hazard rate ratio (HR(adj)): 0.80 [95%CI: 0.59-1.08]), nor when stratified by randomization arm (pharmaceutical care HR(adj): 0.77 [95%CI: 0.49-1.23]); usual care HR(adj): 0.81 [95%CI: 0.54-1.21]). The median medication possession ratio was significantly lower in users of phytosterols/-stanols in the usual care group, but the difference was not clinically relevant.

Conclusions: Customary use of phytosterol/-stanol-enriched functional foods did not affect adherence to statins in new users that are well informed on the beneficial effects of statin therapy. In daily medical practice, general practitioners and pharmacists should urge subjects not to take phytosterol/-stanol-enriched functional foods as replacement for their prescribed medication.
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http://dx.doi.org/10.1002/pds.2168DOI Listing
August 2011

Genetic variability of the fatty acid synthase pathway is not associated with prostate cancer risk in the European Prospective Investigation on Cancer (EPIC).

Eur J Cancer 2011 Feb 19;47(3):420-7. Epub 2010 Oct 19.

German Cancer Research Center, DKFZ, Heidelberg, Germany.

A western lifestyle, characterised by low rates of energy expenditure and a high-energy diet rich in animal protein, saturated fats and refined carbohydrates, is associated with high incidence of prostate cancer in men. A high-energy nutritional status results in insulin/IGF signalling in cells, which in turn stimulates synthesis of fatty acids. We investigated whether the genetic variability of the genes belonging to the fatty acid synthesis pathway is related to prostate cancer risk in 815 prostate cancer cases and 1266 controls from the European Prospective Investigation on Cancer (EPIC). Using a tagging approach and selecting 252 SNPs in 22 genes, we covered all the common genetic variation of this pathway. None of the SNPs reached statistical significance after adjusting for multiple comparisons. Common SNPs in the fatty acid synthase pathway are not major contributors to prostate cancer risk.
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http://dx.doi.org/10.1016/j.ejca.2010.09.029DOI Listing
February 2011

Planning the human variome project: the Spain report.

Hum Mutat 2009 Apr;30(4):496-510

Division of Personalised Nutrition and Medicine, FDA/National Center for Toxicological Research, Jefferson, Arkansas 72079, USA.

The remarkable progress in characterizing the human genome sequence, exemplified by the Human Genome Project and the HapMap Consortium, has led to the perception that knowledge and the tools (e.g., microarrays) are sufficient for many if not most biomedical research efforts. A large amount of data from diverse studies proves this perception inaccurate at best, and at worst, an impediment for further efforts to characterize the variation in the human genome. Because variation in genotype and environment are the fundamental basis to understand phenotypic variability and heritability at the population level, identifying the range of human genetic variation is crucial to the development of personalized nutrition and medicine. The Human Variome Project (HVP; http://www.humanvariomeproject.org/) was proposed initially to systematically collect mutations that cause human disease and create a cyber infrastructure to link locus specific databases (LSDB). We report here the discussions and recommendations from the 2008 HVP planning meeting held in San Feliu de Guixols, Spain, in May 2008.
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http://dx.doi.org/10.1002/humu.20972DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5879779PMC
April 2009

Estimated number of new cancer cases attributable to infection in the Netherlands in 2003.

Cancer Lett 2008 Dec 26;272(2):226-31. Epub 2008 Aug 26.

National Institute for Public Health and the Environment (RIVM), Centre for Infectious Disease Control, Postbox 1 (internal postbox 75), 3720 BA Bilthoven, The Netherlands.

Several infectious diseases are considered to play a causal role in cancer aetiology. It is estimated that in 2003 in the Netherlands at maximum 2553 new cancer cases (3.5% of all new cancer cases) were attributable to infection. This is considerably lower than globally (17.8%) and in developed countries in general (7.7%), as previously estimated by Parkin. Most likely the explanation is that the prevalence of infections in the Netherlands is lower. Infectious agents that cause the highest number of cancer cases in the Netherlands, as well as globally, are Helicobacter pylori (stomach cancer) and the human papilloma virus (mainly cervical cancer).
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http://dx.doi.org/10.1016/j.canlet.2008.07.007DOI Listing
December 2008

Opposing associations of serum n-3 and n-6 polyunsaturated fatty acids with colorectal adenoma risk: an endoscopy-based case-control study.

Int J Cancer 2008 Oct;123(8):1974-7

Division of Human Nutrition, Wageningen University, Wageningen, The Netherlands.

Several human and animal studies have shown that n-3 polyunsaturated fatty acids (PUFA) might be associated with a decreased risk, whereas other studies showed that n-6 PUFA may be associated with an increased risk of colorectal cancer. However, results from these studies are not consistent. We evaluated the associations between serum n-3 and n-6 PUFA levels and colorectal adenoma risk in an endoscopy-based case-control study, conducted in The Netherlands between 1997 and 2002. We included 363 cases of colorectal adenomas and 498 adenoma-free controls. Serum fatty acids were measured in cholesteryl esters. Logistic regression models were used to calculate odds ratios (OR), which were adjusted for age, gender and alcohol intake. Total serum n-3 PUFA levels were inversely associated with colorectal adenoma risk, the OR comparing the third tertile with the first tertile was 0.67 [95% confidence interval (CI) 0.46-0.96, p for trend = 0.03]. Serum eicosapentaenoic acid (EPA; C20:5n-3) and docosahexaenoic acid (DHA; C22:6n-3) and the n-3/n-6 ratio were inversely associated with colorectal adenoma risk, but these were not statistically significant. In contrast, the risk of colorectal adenomas was increased by total n-6 PUFA with an OR of 1.68 (95% CI, 1.17-2.42, p for trend = 0.006) and by linoleic acid (LA; C18:2n-6) with an OR of 1.65 (95% CI, 1.15-2.38, p for trend = 0.007). This is the first observational study that simultaneously finds an inverse association of serum n-3 PUFA and a positive association of n-6 PUFA with colorectal adenoma risk.
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http://dx.doi.org/10.1002/ijc.23729DOI Listing
October 2008

Comparative gene expression profiling in two congenic mouse strains following Bordetella pertussis infection.

BMC Microbiol 2007 Oct 12;7:88. Epub 2007 Oct 12.

Laboratory for Infectious Diseases and Screening, National Institute of Public Health and the Environment (RIVM), PO Box 1, 3720 BA Bilthoven, The Netherlands.

Background: Susceptibility to Bordetella pertussis infection varies widely. These differences can partly be explained by genetic host factors. HcB-28 mice are more resistant to B. pertussis infection than C3H mice, which could partially be ascribed to the B. pertussis susceptibility locus-1 (Bps1) on chromosome 12. The presence of C57BL/10 genome on this locus instead of C3H genome resulted in a decreased number of bacteria in the lung. To further elucidate the role of host genetic factors, in particular in the Bps1 locus, in B. pertussis infection, and to identify candidate genes within in this region, we compared expression profiles in the lungs of the C3H and HcB-28 mouse strains following B. pertussis inoculation. Twelve and a half percent of the genomes of these mice are from a different genetic background.

Results: Upon B. pertussis inoculation 2,353 genes were differentially expressed in the lungs of both mouse strains. Two hundred and six genes were differentially expressed between the two mouse strains, but, remarkably, none of these were up- or down-regulated upon B. pertussis infection. Of these 206 genes, 17 were located in the Bps1 region. Eight of these genes, which showed a strong difference in gene expression between the two mouse strains, map to the immunoglobulin heavy chain complex (Igh).

Conclusion: Gene expression changes upon B. pertussis infection are highly identical between the two mouse strains despite the differences in the course of B. pertussis infection. Because the genes that were differentially regulated between the mouse strains only showed differences in expression before infection, it appears likely that such intrinsic differences in gene regulation are involved in determining differences in susceptibility to B. pertussis infection. Alternatively, such genetic differences in susceptibility may be explained by genes that are not differentially regulated between these two mouse strains. Genes in the Igh complex, among which Igh-1a/b, are likely candidates to explain differences in susceptibility to B. pertussis. Thus, by microarray analysis we significantly reduced the number of candidate susceptibility genes within the Bps1 locus. Further work should establish the role of the Igh complex in B. pertussis infection.
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http://dx.doi.org/10.1186/1471-2180-7-88DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2174938PMC
October 2007

Induction of nevi and skin tumors in Ink4a/Arf Xpa knockout mice by neonatal, intermittent, or chronic UVB exposures.

Cancer Res 2006 Mar;66(5):2608-15

Dermatology Department, University Medical Centre Utrecht, Utrecht, the Netherlands.

Nevi and melanomas correlate to childhood and intermittent solar UV exposure, xeroderma pigmentosum patients run increased risk, and p16(Ink4a) expression is often lost in malignant progression. To ascertain the effect of these risk factors, pigmented hairless Ink4a/Arf-, Xpa- knockout mice were subjected to various combinations of neonatal [7,12-dimethylbenz(a)anthracene (DMBA) or UVB exposure] and adult treatments (12-O-tetradecanoylphorbol-13-acetate or subacute daily UVB exposure or intermittent overexposure). Nevi occurred earliest, grew largest, and were most numerous in mice exposed to DMBA followed by intermittent UVB overexposure [effect of six minimal edemal doses (MED), 1 x /2 weeks > 4 MED 1 x /wk]. Neonatal UV exposure enhanced nevus induction but lost its effect after 200 days. The Xpa(-/-) mice proved exquisitely sensitive to UV-driven nevus induction, indicating the involvement of pyrimidine dimer DNA lesions, but Xpa(+/+) mice developed many more nevi (>40 per mouse) at high UV dosages not tolerated by Xpa(-/-) mice. Ink4a/Arf(-/-) mice developed most skin tumors faster, but surprisingly developed nevi slower than their heterozygous counterparts especially after neonatal UV exposure. Despite raising >1,600 nevi, only six melanomas arose in our experiments with Ink4a/Arf knockout mice (five of which in Xpa(+/+) mice at high UV dosages). In contrast to human nevi, these nevi lacked hotspot mutations in Braf or Ras genes, possibly explaining the lack of malignant progression in the Ink4a/Arf(-/-) mice. Hence, although our experiments did not effectively emulate human melanoma, they provided clear evidence that intermittent UV overexposure strongly stimulates and the Ink4a/Arf(-/-) genotype may actually impair nevus development.
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http://dx.doi.org/10.1158/0008-5472.CAN-05-2476DOI Listing
March 2006

Polymorphisms in the genes involved in the arachidonic acid-pathway, fish consumption and the risk of colorectal cancer.

Int J Cancer 2006 Jul;119(2):297-303

Department of Toxicology, Pathology and Genetics, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.

The objective of this study on colorectal cancer was to investigate the associations between SNPs in the genes involved in the arachidonic acid (AA)-pathway, their haplotypes and colorectal cancer. Moreover, interactions between SNPs and fish consumption were considered. In this study, a total of 508 cases and 772 controls were included, originating from 2 prospective cohorts, the Monitoring Project on Cardiovascular Disease Risk Factors (PPHV) and Diagnostisch Onderzoek Mammacarcinoom (DOM). Genotypes of 23 SNPs in 7 candidate genes were determined and the modifying effect of fish consumption was considered. A protective effect of the minor allele of SNP V102V in PTGS2 was observed (odds ratio (OR), 0.37; 95% confidence intervals (CI), 0.16-0.87). The haplotype representing this allele showed a weaker inverse association, indicating that 2 alleles are necessary to obtain this protective effect. Fish consumption data was available for 209 cases and 418 controls. Increased fish consumption was inversely associated with cancer, although not significant (OR, 0.83; 95% CI, 0.57-1.20). Despite the substantial reductions in cancer risk for some genotypes in combination with high fish intake, no significant interactions between any SNP studied and fish consumption were observed. We have previously described an association between colorectal adenomas and SNP V102V in PTGS2 and have now confirmed this association for colorectal adenocarcinomas. Fish consumption of once a week or more might protect against colorectal cancer, but no significant interactions with SNPs in the genes involved in the AA-pathway could be detected within the study.
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http://dx.doi.org/10.1002/ijc.21858DOI Listing
July 2006

Protective effect of nonsteroidal anti-inflammatory drugs on colorectal adenomas is modified by a polymorphism in peroxisome proliferator-activated receptor delta.

Pharmacogenet Genomics 2006 Jan;16(1):43-50

Department of Toxicology Pathology and Genetics, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.

Objective: Nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with a decreased risk of colorectal tumors. Single nucleotide polymorphisms (SNPs) in target genes of NSAID action, and their haplotypes, might modulate this protective effect.

Methods: A case-control study including 724 cases and 682 controls was used to evaluate the effect of NSAIDs on colorectal adenoma risk in The Netherlands, a country in which NSAID use is relatively low. Cases and controls were classified according to presence or absence of endoscopy-proven, pathology-confirmed colorectal adenomas, ever in their lives. Thirteen SNPs in four genes (PPARdelta, PPARgamma, PTGS1 and PTGS2) were genotyped in 787 subjects (384 cases and 403 controls).

Results: Compared to non-regular users (< 12 times/year), regular users of NSAIDs (> or = 12 times/year) had a lower risk of colorectal adenomas (odds ratio (OR): 0.75, 95% confidence interval (CI): 0.56-0.99). The results were similar for aspirin only. We found an interaction between SNP c.-789C>T in PPARdelta and NSAID use (P=0.03). The protective effect of NSAIDs was strengthened for regular users with the PPARdelta CT or TT genotypes (OR: 0.35, 95%CI: 0.11-1.13), whereas a positive association was observed for non-regular users with these genotypes (OR: 2.24, 95%CI: 1.06-4.73) as compared to non-regular users with the CC genotype. Also, a statistically significant interaction between a major haplotype containing the minor allele of this SNP and NSAID use was observed.

Conclusions: This study confirms the protective effect of NSAIDs and suggests a modulating effect of a SNP in the promoter of PPARdelta.
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http://dx.doi.org/10.1097/01.fpc.0000182778.03180.f3DOI Listing
January 2006

Relationship between UV-induced mutant p53 patches and skin tumours, analysed by mutation spectra and by induction kinetics in various DNA-repair-deficient mice.

Carcinogenesis 2005 Dec 28;26(12):2123-30. Epub 2005 Jul 28.

Department of Dermatology, Leiden University Medical Centre, Sylvius Laboratory, Leiden, The Netherlands.

Clusters of p53 immunopositive epidermal keratinocytes (so-called p53 patches, clones or foci) are found in sun or ultraviolet (UV) light-exposed skin. We investigated to what extent these p53 patches are genuine precursors of skin carcinomas in chronically irradiated hairless (SKH1) mice. The mutation spectra of exons 5-8 of the p53 gene of laser-micro-dissected mutant p53 patches and carcinomas were therefore compared. The mutations we found were mainly UV-signature mutations (C-->T and CC-->TT at dipyrimidine sites) located at known hotspots. No significant differences were found between both spectra, indicating that all p53 patches harbour mutations with which they could progress to carcinomas. To examine whether these p53 patches can be used as tumour risk indicators, we made an extensive comparison of the induction kinetics of these patches and carcinomas in genetically modified mice with various defects in nucleotide excision repair (NER), i.e. xeroderma pigmentosum A (Xpa), Xpc and Cockayne syndrome B (Csb) and wild-type mice. In this aforementioned order, the mouse strains developed both p53 patches and carcinomas in the course of daily exposure to 40 J/m(2) UV. Hence, the order in which the NER-deficient mice developed patches was predictive of the order in which they developed tumours. The induction kinetics of the patches in Xpc-deficient mice differed notably from the others: there was a stationary phase (days 13-41) where the numbers were limited to 5-10 patches per mouse before an explosive increase which ran parallel to the other groups. The chance that a p53 patch progresses to carcinoma is relatively small (estimated at 1 out of 8300-40,000/individual when the first tumour appears), but our results are strongly indicative of a causal relationship between p53 patches and carcinomas.
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http://dx.doi.org/10.1093/carcin/bgi198DOI Listing
December 2005

Transcription-coupled repair: impact on UV-induced mutagenesis in cultured rodent cells and mouse skin tumors.

Mutat Res 2005 Sep;577(1-2):170-8

Department of Toxicogenetics, Leiden University Medical Center, Wassenaarseweg 72, 2333 AL Leiden, The Netherlands.

UV-induced cyclobutane pyrimidine dimers (CPDs) are removed with accelerated speed from the transcribed strand of expressed genes in cultured mammalian cells by a process called transcription-coupled repair (TCR). It has been previously shown that this phenomenon has consequences for the molecular nature of the mutations induced by UV-light. Here, we review these data and show that TCR has not only a clear impact on UV-induced mutations in cultured mammalian cells but also on genes involved in tumor formation in the skin of UV-exposed mice. Mutations observed in the p53 gene in UV-induced squamous cell carcinoma are predominantly found at sites of dipyrimidines in the non-transcribed strand. In contrast, in UVC-irradiated Csb(-/-) Chinese hamster cells and in UVB-induced tumors in the Csb(-/-) mouse, almost all mutations are at positions of dipyrimidine sites in the transcribed strand of the mutated gene. Csb(-/-) mice appear to be susceptible to UVB-induced skin cancer in contrast to the human CSB patients. We speculate that the UVB-induced cancer susceptibility of Csb(-/-) mice is related to the absence of TCR as well as to a lack of a compensating global genome repair system for CPDs in mice.
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http://dx.doi.org/10.1016/j.mrfmmm.2005.03.018DOI Listing
September 2005

Dose-dependent effects of UVB-induced skin carcinogenesis in hairless p53 knockout mice.

Mutat Res 2005 Apr;571(1-2):81-90

National Institute of Public Health and Environment, Laboratory of Toxicology, Pathology and Genetics, Department of Carcinogenesis Mutagenesis and Aging, Bilthoven, The Netherlands.

Exposure to (solar) UVB radiation gives rise to mutations in the p53 tumor suppressor gene that appear to contribute to the earliest steps in the molecular cascade towards human and murine skin cancer. To examine in more detail the role of p53, we studied UVB-induced carcinogenesis in hairless p53 knock-out mice. The early onset of lymphomas as well as early wasting of mice interfered with the development of skin tumors in p53 null-mice. The induction of skin tumors in the hairless p53+/- mice was accomplished by daily exposure to two different UV-doses of approximately 450 J/m2 and 900 J/m2 from F40 lamps corresponding to a fraction of about 0.4 and 0.8 of the minimal edemal dose. Marked differences in skin carcinogenesis were observed between the p53+/- mice and their wild type littermates. Firstly, at 900 J/m2, tumors developed significantly faster in the heterozygotes than in wild types, whereas at 450 J/m2 there was hardly any difference, suggesting that only at higher damage levels loss of one functional p53 allele is important. Secondly, a large portion (25%) of skin tumors in the heterozygotes were of a more malignant, poorly differentiated variety of squamous cell carcinomas, i.e. spindle cell carcinomas, a tumor type that was rarely observed in daily UV exposed wild type hairless mice. Thirdly, the p53 mutation spectrum in skin tumors in heterozygotes is quite different from that in wild types. Together these results support the notion that a point mutation in the p53 gene impacts skin carcinogenesis quite differently than allelic loss: the former is generally selected for in early stages of skin tumors in wild type mice, whereas the latter enhances tumor development only at high exposure levels (where apoptosis becomes more prevalent) and appears to increase progression (to a higher grade of malignancy) of skin tumors.
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http://dx.doi.org/10.1016/j.mrfmmm.2004.07.018DOI Listing
April 2005

Effects of soy-derived isoflavones and a high-fat diet on spontaneous mammary tumor development in Tg.NK (MMTV/c-neu) mice.

Nutr Cancer 2004 ;50(1):46-54

Laboratory of Toxicology, Pathology and Genetics, National Institute for Public Health and the Environment, Bilthoven, The Netherlands.

Phytoestrogens such as isoflavonoids and lignans have been postulated as breast cancer protective constituents in soy and whole-grain cereals. We investigated the ability of isoflavones (IFs) and flaxseed to modulate spontaneous mammary tumor development in female heterozygous Tg.NK (MMTV/c-neu) mice. Two different exposure protocols were applied, either from 4 wk of age onward (postweaning) or during gestation and lactation (perinatal). In the postweaning exposure study, mice were fed IFs or flaxseed in a high-fat diet. In addition, flaxseed in a low-fat diet was tested. Postweaning exposure to IFs and flaxseed tended to accelerate the onset of mammary adenocarcinoma development, although tumor burden at necropsy was not changed significantly. Perinatal IF exposure resulted in enhanced mammary gland differentiation, but palpable mammary tumor onset was not affected. However, tumor burden at necropsy in the perinatal exposure study was significantly increased in the medium- and high-IF dose groups. Comparison of both exposure scenarios revealed a strongly accelerated onset of tumor growth after perinatal high-fat diet exposure compared with the low-fat diet. This study shows that breast cancer-modulating effects of phytoestrogens are dependent both on the background diet and on the timing of exposure in the life cycle.
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http://dx.doi.org/10.1207/s15327914nc5001_7DOI Listing
April 2005

Colorectal adenoma risk is modified by the interplay between polymorphisms in arachidonic acid pathway genes and fish consumption.

Carcinogenesis 2005 Feb 18;26(2):449-57. Epub 2004 Nov 18.

Department of Toxicology, Pathology and Genetics, National Institute for Public Health and the Environment, Bilthoven, The Netherlands.

Associations between polymorphisms in genes (SNPs) involved in the arachidonic acid (AA) pathway and colorectal adenomas have been investigated in a Dutch case control study including 384 cases and 403 polyp-free controls. Twenty-one polymorphisms in seven candidate genes were studied and a potential modifying effect of fish consumption was considered. A protective effect on colorectal adenomas was found for the CT genotype of SNP H477H in PPARgamma and the GC genotype of SNP V102V in COX-2 (OR 0.63, 95% CI 0.45-0.89 and OR 0.65, 95% CI 0.46-0.92, respectively) compared with the homozygous major genotypes. An increase in adenoma risk was observed for the TC genotype of SNP c.2242T-->C in COX-2 (OR 1.47, 95% CI 1.07-2.00) compared with the TT genotype. Analysis with estimated haplotypes confirmed these associations and revealed three additional associations with COX-2, sPLA(2) and 15LOX haplotypes. Fish consumption modified the associations with COX-2 and PPARdelta genotypes. For SNP c.-789C-->T in PPARdelta the major genotype showed a decrease in adenoma risk for those in the highest tertile of fish consumption (T3), as compared with the lowest tertile (T1) (OR 0.65, 95% CI 0.41-1.02). Protective effects were also observed for SNPs V102V and c.2242T-->C in COX-2 and high fish intake. The interaction between fish consumption and c.2242T-->C was statistically significant, with an OR for the TT genotype and high fish consumption of 0.52 (95% CI 0.27-1.01) as compared with low fish intake. These results indicate that SNPs in genes involved in the AA pathway are associated with colorectal adenoma risk. Some of these associations are modified by fish consumption.
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http://dx.doi.org/10.1093/carcin/bgh336DOI Listing
February 2005

UV exposure, genetic targets in melanocytic tumors and transgenic mouse models.

Photochem Photobiol 2005 Jan-Feb;81(1):52-64

Department of Dermatology, Leiden University Medical Center/LUMC, Sylvius Labs, Room 3038, Wassenaarseweg 72, NL-2333 AL Leiden, The Netherlands.

The genetic changes and corruption of kinase activity in melanomas appear to revolve around a central axis: mitogenic signaling along the RAS pathway down to transcription regulation by pRB. Epidemiological studies point to the importance of ultraviolet (UV) radiation in the etiology of melanoma, but where and how UV radiation is targeted to contribute to the oncogenic signaling remains obscure. Animal models of melanoma genesis could serve to clarify this issue, but many of these models are not responsive to UV exposure. Most interesting advances have been made by using transgenic mice that carry genetic defects that are known to be relevant to human melanoma: specifically, dysfunction in the tumor suppressive action of p16INK4a or a receptor tyrosine kinase/RAS pathway, that is constitutively activated in melanocytes. The latter types of mice appear to be most responsive to (neonatal) UV exposure. Whether this is due to a general increase in target cells by melanocytosis and a paucity or complete lack of pigment, or a possible UV-induced response of the promoter-enhancer of the transgene or a genuinely independent and additional genetic alteration caused by UV exposure needs to be established. Importantly, the full effect of UV radiation needs to be ascertained in mice with different pigmentation by varying the wavelengths, UV-B versus UV-A1, and the exposure schedules, i.e. neonatal versus adult and chronic versus intermittent overexposure. Intermittent UV-B overexposure deserves special attention because it most strongly evokes proliferative responses in melanocytes.
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http://dx.doi.org/10.1562/2004-09-26-IR-328DOI Listing
June 2005

Mismatch repair protein Msh2 contributes to UVB-induced cell cycle arrest in epidermal and cultured mouse keratinocytes.

DNA Repair (Amst) 2005 Jan;4(1):81-9

Department of Toxicogenetics, Leiden University Medical Center, Wassenaarseweg 72, 2333 AL Leiden, The Netherlands.

Nucleotide excision repair (NER), cell cycle regulation and apoptosis are major defence mechanisms against the carcinogenic effects of UVB radiation. NER eliminates UVB-induced DNA photolesions via two subpathways: global genome repair (GGR) and transcription-coupled repair (TCR). In a previous study, we found UVB-induced accumulation of tetraploid (4N) keratinocytes in the epidermis of Xpc(-/-) mice (no GGR), but not in Xpa(-/-) (no TCR and no GGR) or in wild-type (WT) mice. We inferred that this arrest in Xpc(-/-) mice is caused by erroneous replication past photolesions, leading to 'compound lesions' known to be recognised by mismatch repair (MMR). MMR-induced futile cycles of breakage and resynthesis at sites of compound lesions may then sustain a cell cycle arrest. The present experiments with Xpc(-/-)Msh2(-/-) mice and derived keratinocytes show that the MMR protein Msh2 indeed plays a role in the generation of the UVB-induced arrested cells: a Msh2-deficiency lowered significantly the percentage of arrested cells in vivo (40-50%) and in vitro (30-40%). Analysis of calyculin A (CA)-induced premature chromosome condensation (PCC) of cultured Xpc(-/-) keratinocytes showed that the delayed arrest occurred in late S phase rather than in G(2)-phase. Taken together, the results indicate that in mouse epidermis and cultured keratinocytes, the MMR protein Msh2 plays a role in the UVB-induced S-phase arrest. This indicates that MMR plays a role in the UVB-induced S-phase arrest. Alternatively, Msh2 may have a more direct signalling function.
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http://dx.doi.org/10.1016/j.dnarep.2004.08.008DOI Listing
January 2005

Lignan precursors from flaxseed or rye bran do not protect against the development of intestinal neoplasia in ApcMin mice.

Nutr Cancer 2003 ;45(2):203-10

Laboratory of Health Effects Research, Department of Carcinogenesis, Mutagenesis & Genetics, Laboratory of Pathology, National Institute of Public Health and Environment, PO Box 1, 3720 BA Bilthoven, The Netherlands.

Phytoestrogens, like isoflavonoids and lignans, have been postulated as possible colorectal cancer protective constituents. To investigate this hypothesis, two high-fiber sources rich in lignan precursors, i.e., rye bran and flaxseed, were tested for their ability to modulate intestinal tumor development in ApcMin mice. Test diets consisted of a control diet (a Western-style diet, adjusted for fiber and/or phytate content) supplemented with 5% flaxseed or 30% rye bran. Chemical analysis of diets and blood samples confirmed the enhanced systemic exposure of mice fed the test diets to the major lignan precursors, i.e., secoisolariciresinol and matairesinol. No statistically significant difference was observed in the incidence and multiplicity of small intestinal and colon tumors at terminal sacrifice between mice fed the control diet or the diet supplemented with 5% flaxseed. With the rye bran diet a statistically significant enhancement of the number of small intestinal tumors in female mice was observed. The number of colon tumors, however, was comparable between the control and rye bran-fed mice of either sex. Furthermore, no activating point mutations in the K-ras oncogene nor positive immunohistochemical staining for the p53 gene were observed in a set of 48 colon tumors. In conclusion, our results demonstrate that increased intake of lignan precursors from flaxseed or rye bran, administered in a Western-style diet, does not protect against intestinal tumor development in an appropriate animal model for intestinal neoplasia such as the ApcMin mice.
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http://dx.doi.org/10.1207/S15327914NC4502_10DOI Listing
February 2004