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  • DKFZ Publication Database  (1,743)
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  • Articles  (4)
  • DKFZ Publication Database  (1,743)
Keywords
  • 1
    Keywords: Germany ; RISK ; COLORECTAL-CANCER ; VALIDITY ; PREDICTORS ; INEQUALITIES ; PROGRAM ; ENGLAND ; CANCER SCREENING PARTICIPATION
    Abstract: We aimed to describe the utilization of colonoscopy and its association with sociodemographic characteristics within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Heidelberg cohort study. We included 15 014 study participants (43% men) of the EPIC-Heidelberg cohort recruited between 1994 and 1998. At baseline recruitment, as well as in the 3-yearly follow-up surveys, study participants completed questionnaires on lifestyle, socioeconomic background variables, health status, and use of medications and medical services, including colonoscopy examinations. The present analyses focused on participants who completed the question on colonoscopy examination in all follow-up rounds. Our results show that by the end of the fourth follow-up round, more than half of all participants of the EPIC-Heidelberg cohort had had a colonoscopy. Colonoscopy was associated with some socioeconomic and demographic characteristics: a positive association with vocational training level as well as overall socioeconomic status level [International Standard Classification of Education (ISCED) classification]. A negative association was found for household size and employment status. Colonoscopy usage increased steeply within the subgroup of participants older than 55 years of age and decreased again within the subgroup of participants older than 75 years of age. Organized colorectal cancer screening should include a written invitation system, to overcome the problem of sociodemographic-related differential awareness of and attendance at colonoscopy examinations. Also, the high proportion of prescreened individuals should be taken into account to avoid unnecessary re-examinations.
    Type of Publication: Journal article published
    PubMed ID: 25244156
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  • 2
    Keywords: carcinoma ; RISK ; GENOME ; DISCOVERY ; smoking ; COLORECTAL-CANCER ; molecular epidemiology ; HETEROGENEITY ; SCIENCE ; ENVIRONMENTAL-FACTORS
    Abstract: Cancer research is drawing on the human genome project to develop new molecular-targeted treatments. This is an exciting but insufficient response to the growing, global burden of cancer, particularly as the projected increase in new cases in the coming decades is increasingly falling on developing countries. The world is not able to treat its way out of the cancer problem. However, the mechanistic insights from basic science can be harnessed to better understand cancer causes and prevention, thus underpinning a complementary public health approach to cancer control. This manuscript focuses on how new knowledge about the molecular and cellular basis of cancer, and the associated high-throughput laboratory technologies for studying those pathways, can be applied to population-based epidemiological studies, particularly in the context of large prospective cohorts with associated biobanks to provide an evidence base for cancer prevention. This integrated approach should allow a more rapid and informed translation of the research into educational and policy interventions aimed at risk reduction across a population.
    Type of Publication: Journal article published
    PubMed ID: 25515230
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  • 3
  • 4
    Keywords: DISEASE ; POPULATION ; RISK ; POLYMORPHISMS ; IDENTIFICATION ; METAANALYSIS ; telomere length ; LOCI ; GENOME-WIDE ASSOCIATION ; 5P15.33
    Abstract: A small number of common susceptibility loci have been identified for pancreatic cancer, one of which is marked by rs401681 in the TERT-CLPTM1L gene region on chromosome 5p15.33. Because this region is characterized by low linkage disequilibrium, we sought to identify whether additional single nucleotide polymorphisms (SNPs) could be related to pancreatic cancer risk, independently of rs401681. We performed an in-depth analysis of genetic variability of the telomerase reverse transcriptase (TERT) and the telomerase RNA component (TERC) genes, in 5,550 subjects with pancreatic cancer and 7,585 controls from the PANcreatic Disease ReseArch (PANDoRA) and the PanScan consortia. We identified a significant association between a variant in TERT and pancreatic cancer risk (rs2853677, odds ratio = 0.85; 95% confidence interval = 0.80-0.90, p = 8.3 x 10(-8)). Additional analysis adjusting rs2853677 for rs401681 indicated that the two SNPs are independently associated with pancreatic cancer risk, as suggested by the low linkage disequilibrium between them (r(2) = 0.07, D = 0.28). Three additional SNPs in TERT reached statistical significance after correction for multiple testing: rs2736100 (p = 3.0 x 10(-5)), rs4583925 (p = 4.0 x 10(-5)) and rs2735948 (p = 5.0 x 10(-5)). In conclusion, we confirmed that the TERT locus is associated with pancreatic cancer risk, possibly through several independent variants. What's new? Most pancreatic cancer patients do not survive long after diagnosis, and, so far, there are not many genetic markers to help screen for the disease. In search of genetic predictors of pancreatic cancer, the authors zoomed in on a region linked to susceptibility to the disease. They measured the frequency of different variants of two genes, telomerase reverse transcriptase and telomerase RNA component, among thousands of pancreatic cancer patients and controls. They identified several variants of the TERT gene that indicate a boosted pancreatic cancer risk, and which may develop into useful prognostic tools.
    Type of Publication: Journal article published
    PubMed ID: 25940397
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  • 5
    Keywords: CANCER ; EXPOSURE ; RISK ; POLYMORPHISMS ; SUSCEPTIBILITY ; REPAIR ; MARKERS ; LYMPHOCYTES ; DNA-DAMAGE ; GSTT1
    Abstract: Nonspecific chromosomal aberrations (CAs) are found in about 1% of lymphocytes drawn from healthy individuals. They include chromosome-type aberrations (CSAs), which are increased in exposure to ionizing radiation, and chromatid-type aberrations (CTAs) which in experimental systems are formed by DNA binding carcinogens and mutagens. The frequency of CAs is associated with the risk of cancer, but the causes of CAs in general population are unknown. Here, we want to test whether variants in metabolic genes associate with CAs in healthy volunteers. Cases were considered those whose total CA (CAtot) frequency was 〉2% and for CSA and CTA the limit was 〉1%. Controls had lower frequencies of CAs. Functional polymorphisms in seven genes were selected for analysis: cytochrome P450 1B1 (CYP1B1), epoxide hydrolase 1 (EPHX1), NAD(P)H:quinone oxidoreductase 1 (NQO1), each coding for phase 1 enzymes, and glutathione S-transferase P1 (GSTP1), glutathione S-transferases M1 (GSTM1) and T1 (GSTT1), coding for enzymes which conjugate reactive metabolites, that is, phase 2 enzymes. The number of volunteers genotyped for each gene varied from 550 to 1,500. Only EPHX1 was individually associated with CAtot; high activity genotypes decreased CAtot. A total of six significant (P 〈 0.01) pair-wise interactions were observed, most including a GST variant as one of the pair. In all genotype combinations with significant odds ratios for CAs a GST variant was involved. The present data provide evidence that variants in genes coding for metabolic enzymes, which individually have small effects, interact and are associated with CA frequencies in peripheral lymphocytes of healthy volunteers. (c) 2015 Wiley Periodicals, Inc.
    Type of Publication: Journal article published
    PubMed ID: 25622915
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  • 6
    Keywords: DIAGNOSIS ; MORTALITY ; RISK ; TRIAL ; DATABASE ; NATURAL-HISTORY ; PARTICIPANTS ; ENDOSCOPY ; sigmoidoscopy
    Abstract: Aim: Endoscopy based screening programmes for colorectal cancer (CRC) are being implemented in an increasing number of countries. In Germany, screening colonoscopy at age 55 or older has been offered since the end of 2002. We aimed to estimate the long-term impact of this offer on CRC prevention. Methods: We estimated numbers of prevented CRC cases by expected age and year of their (prevented) occurrence over four decades (2005-2045) by four state Markov models (non-advanced adenoma, advanced adenoma, preclinical CRC, clinically manifest CRC). Estimates are based on screening colonoscopies reported to the German screening colonoscopy registry in 2003-2012 (N = 4,407,971), transition rates between the four states and general population mortality rates. Results: Numbers of prevented clinically manifest CRC cases are projected to increase from 〈100 in 2005 to approximately 6500 in 2015, 12,600 in 2025, 15,400 in 2035 and 16,000 in 2045, compared to approximately 58,000 incident cases observed in 2003. The annual number of prevented cases is expected to be higher among men than among women and to strongly vary by age. The vast majority of prevented cases would have occurred at age 75 or older. Conclusions: Despite modest participation rates, the German screening colonoscopy programme will lead to substantial reductions in the CRC burden. The reductions will be fully disclosed in the long run only and predominantly affect numbers of incident cases above 75 years of age. Screening offers would need to start at younger ages in order to achieve more effective CRC prevention at younger ages.
    Type of Publication: Journal article published
    PubMed ID: 25908273
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  • 7
    Keywords: RISK ; HEALTH ; OBESITY ; COUNTRIES ; VALIDITY ; QUESTIONNAIRE ; CARDIOVASCULAR-DISEASE ; PARTICIPANTS ; LIFE EXPECTANCY ; COLLEGE
    Abstract: BACKGROUND: The higher risk of death resulting from excess adiposity may be attenuated by physical activity (PA). However, the theoretical number of deaths reduced by eliminating physical inactivity compared with overall and abdominal obesity remains unclear. OBJECTIVE: We examined whether overall and abdominal adiposity modified the association between PA and all-cause mortality and estimated the population attributable fraction (PAF) and the years of life gained for these exposures. DESIGN: This was a cohort study in 334,161 European men and women. The mean follow-up time was 12.4 y, corresponding to 4,154,915 person-years. Height, weight, and waist circumference (WC) were measured in the clinic. PA was assessed with a validated self-report instrument. The combined associations between PA, BMI, and WC with mortality were examined with Cox proportional hazards models, stratified by center and age group, and adjusted for sex, education, smoking, and alcohol intake. Center-specific PAF associated with inactivity, body mass index (BMI; in kg/m(2)) (〉30), and WC (〉/=102 cm for men, 〉/=88 cm for women) were calculated and combined in random-effects meta-analysis. Life-tables analyses were used to estimate gains in life expectancy for the exposures. RESULTS: Significant interactions (PA x BMI and PA x WC) were observed, so HRs were estimated within BMI and WC strata. The hazards of all-cause mortality were reduced by 16-30% in moderately inactive individuals compared with those categorized as inactive in different strata of BMI and WC. Avoiding all inactivity would theoretically reduce all-cause mortality by 7.35% (95% CI: 5.88%, 8.83%). Corresponding estimates for avoiding obesity (BMI 〉30) were 3.66% (95% CI: 2.30%, 5.01%). The estimates for avoiding high WC were similar to those for physical inactivity. CONCLUSION: The greatest reductions in mortality risk were observed between the 2 lowest activity groups across levels of general and abdominal adiposity, which suggests that efforts to encourage even small increases in activity in inactive individuals may be beneficial to public health.
    Type of Publication: Journal article published
    PubMed ID: 25733647
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  • 8
    Keywords: RISK ; BRCA1 ; OVARIAN-CANCER ; METAANALYSIS ; ESTROGEN ; ALLELES ; CHEK2-ASTERISK-1100DELC ; CONFER SUSCEPTIBILITY ; COMMON VARIANTS ; GENOTYPE IMPUTATION
    Abstract: Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining approximately 14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS, comprising 15,748 breast cancer cases and 18,084 controls together with 46,785 cases and 42,892 controls from 41 studies genotyped on a 211,155-marker custom array (iCOGS). Analyses were restricted to women of European ancestry. We generated genotypes for more than 11 million SNPs by imputation using the 1000 Genomes Project reference panel, and we identified 15 new loci associated with breast cancer at P 〈 5 x 10(-8). Combining association analysis with ChIP-seq chromatin binding data in mammary cell lines and ChIA-PET chromatin interaction data from ENCODE, we identified likely target genes in two regions: SETBP1 at 18q12.3 and RNF115 and PDZK1 at 1q21.1. One association appears to be driven by an amino acid substitution encoded in EXO1.
    Type of Publication: Journal article published
    PubMed ID: 25751625
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  • 9
    Keywords: DISEASE ; RISK ; PROTEIN ; POLYMORPHISMS ; PATHOGENESIS ; CLINICAL-FEATURES ; GENETIC SUSCEPTIBILITY ; MANIFESTATIONS ; AICARDI-GOUTIERES SYNDROME ; TRIM39
    Abstract: Cutaneous lupus erythematosus (CLE) is a chronic autoimmune disease of the skin with typical clinical manifestations. Here, we genotyped 906 600 single nucleotide polymorphisms (SNPs) in 183 CLE cases and 1288 controls of Central European ancestry. Replication was performed for 13 SNPs in 219 case subjects and 262 controls from Finland. Association was particularly pronounced at 4 loci, all with genomewide significance (P 〈 5 x 10(-8) ): rs2187668 (PGWAS = 1.4 x 10(-12) ), rs9267531 (PGWAS = 4.7 x 10(-10) ), rs4410767 (PGWAS = 1.0 x 10(-9) ) and rs3094084 (PGWAS = 1.1 x 10(-9) ). All mentioned SNPs are located within the major histocompatibility complex (MHC) region of chromosome 6 and near genes of known immune functions or associations with other autoimmune diseases such as HLA-DQ alpha chain 1 (HLA-DQA1), MICA, MICB, MSH5, TRIM39 and RPP21. For example, TRIM39/RPP21 read through transcript is a known mediator of the interferon response, a central pathway involved in the pathogenesis of CLE and systemic lupus erythematosus (SLE). Taken together, this genomewide analysis of disease association of CLE identified candidate genes and genomic regions that may contribute to pathogenic mechanisms in CLE via dysregulated antigen presentation (HLA-DQA1), apoptosis regulation, RNA processing and interferon response (MICA, MICB, MSH5, TRIM39 and RPP21).
    Type of Publication: Journal article published
    PubMed ID: 25827949
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  • 10
    Keywords: CANCER ; RISK ; IMPACT ; CIGARETTE-SMOKING ; MEN ; SMOKERS ; PRODUCTS ; SMOKING-CESSATION ; 4 COUNTRY SURVEY
    Abstract: OBJECTIVES: To examine if exclusive Roll-Your-Own (RYO) tobacco use relative to factory-made (FM) cigarette use has been rising over time, to determine the extent to which economic motives and perceptions that RYO cigarettes are less harmful act as primary motivations for use, and to examine the association of income and education with the level of RYO tobacco use among smokers in four European countries. METHODS: Data were obtained from the International Tobacco Control (ITC) Europe Surveys, and a cohort sample of 7070 smokers from the Netherlands, Germany, France and UK were interviewed between June 2006 and December 2012. Generalised estimating equations (GEE) were used to assess trends in RYO use, and whether RYO consumption varied by socioeconomic variables. RESULTS: Exclusive RYO use over the study period has increased significantly in the UK from 26.4% in 2007 to 32.7% in 2010 (p〈0.001); France from 12.2% in 2006 to 19.1% in 2012 (p〈0.001); and Germany from 12.7% in 2007 to 18.6% in 2011 (p=0.031), with increased borderline significantly in the Netherlands (31.7% to 34.3%, p=0.052), from 2008 to 2010. Over three-quarters of users in each of the study countries indicated that lower price was a reason why they smoked RYO. Just over a fourth of smokers in the UK, less than a fifth in France, and around a tenth in Germany and the Netherlands believed that RYO is healthier. Compared with exclusive FM users, exclusive RYO users were more likely to have lower incomes and lower education. CONCLUSIONS: Effective tobacco tax regulation is needed in the European Union and elsewhere to eliminate or reduce the price advantage of RYO tobacco. Additional health messages are also required to correct the misperception that RYO tobacco is healthier than FM cigarettes.
    Type of Publication: Journal article published
    PubMed ID: 26101043
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  • 11
    Keywords: RISK ; AGE ; WOMEN ; PROSPECTIVE COHORT ; PREVALENCE ; PROJECT ; LIFE-STYLE ; MELLITUS ; ALL-CAUSE MORTALITY ; PREMATURE
    Abstract: STUDY QUESTION: Do women who have diabetes before menopause have their menopause at an earlier age compared with women without diabetes? SUMMARY ANSWER: Although there was no overall association between diabetes and age at menopause, our study suggests that early-onset diabetes may accelerate menopause. WHAT IS KNOWN ALREADY: Today, more women of childbearing age are being diagnosed with diabetes, but little is known about the impact of diabetes on reproductive health. STUDY DESIGN, SIZE, DURATION: We investigated the impact of diabetes on age at natural menopause (ANM) in 258 898 women from the European Prospective Investigation into Cancer and Nutrition (EPIC), enrolled between 1992 and 2000. PARTICIPANTS/MATERIALS, SETTING, METHODS: Determinant and outcome information was obtained through questionnaires. Time-dependent Cox regression analyses were used to estimate the associations of diabetes and age at diabetes diagnosis with ANM, stratified by center and adjusted for age, smoking, reproductive and diabetes risk factors and with age from birth to menopause or censoring as the underlying time scale. MAIN RESULTS AND THE ROLE OF CHANCE: Overall, no association between diabetes and ANM was found (hazard ratio (HR) = 0.94; 95% confidence interval (CI) 0.89-1.01). However, women with diabetes before the age of 20 years had an earlier menopause (10-20 years: HR = 1.43; 95% CI 1.02-2.01, 〈10 years: HR = 1.59; 95% CI 1.03-2.43) compared with non-diabetic women, whereas women with diabetes at age 50 years and older had a later menopause (HR = 0.81; 95% CI 0.70-0.95). None of the other age groups were associated with ANM. LIMITATIONS, REASONS FOR CAUTION: Strengths of the study include the large sample size and the broad set of potential confounders measured. However, results may have been underestimated due to survival bias. We cannot be sure about the sequence of the events in women with a late age at diabetes, as both events then occur in a short period. We could not distinguish between type 1 and type 2 diabetes. WIDER IMPLICATIONS OF THE FINDINGS: Based on the literature, an accelerating effect of early-onset diabetes on ANM might be plausible. A delaying effect of late-onset diabetes on ANM has not been reported before, and is not in agreement with recent studies suggesting the opposite association. STUDY FUNDING/COMPETING INTERESTS: The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Generale de l'Education Nationale, Institut National de la Sante et de la Recherche Medicale (INSERM) (France); German Cancer Aid, German Cancer Research Center (DKFZ) and Federal Ministry of Education and Research (BMMF) (Germany); Ministry of Health and Social Solidarity, Stavros Niarchos Foundation and Hellenic Health Foundation (Greece); Italian Association for Research on Cancer (AIRC) and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); ERC-2009-AdG 232997 and Nordforsk, Nordic Centre of Excellence programme on Food, Nutrition and Health (Norway); Health Research Fund (FIS), Regional Governments of Andalucia, Asturias, Basque Country, Murcia (no. 6236) and Navarra, ISCIII RETIC (RD06/0020) (Spain); Swedish Cancer Society, Swedish Scientific Council and Regional Government of Skane and Vasterbotten (Sweden); Cancer Research UK, Medical Research Council, Stroke Association, British Heart Foundation, Department of Health, Food Standards Agency, and Wellcome Trust (UK). None of the authors reported a conflict of interest.
    Type of Publication: Journal article published
    PubMed ID: 25779698
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  • 12
    Keywords: HISTORY ; RISK ; radiation ; SUSCEPTIBILITY ; COLORECTAL-CANCER ; SURVEILLANCE ; CHILDHOOD ; NERVOUS-SYSTEM TUMORS ; COLLECTION ; AMERICAN SOCIETY
    Abstract: Public perception and anxiety of familial cancer have increased demands for clinical counseling, which may be well equipped for gene testing but less prepared for counseling of the large domain of familial cancer with unknown genetic background. The aim of the present study was to highlight the full scope of familial cancer and the variable levels of risk that need to be considered. Data on the 25 most common cancers were obtained from the Swedish Family Cancer Database and a Poisson regression model was applied to estimate relative risks (RR) distinguishing between family histories of single or multiple affected first-degree relatives and their diagnostic ages. For all cancers, individual risks were significantly increased if a parent or a sibling had a concordant cancer. While the RRs were around 2.00 for most cancers, risks were up to 10-fold increased for some cancers. Familial risks were even higher when multiple relatives were affected. Although familial risks were highest at ages below 60 years, most familial cases were diagnosed at older ages. The results emphasized the value of a detailed family history as a readily available tool for individualized counseling and its preventive potential for a large domain of non-syndromatic familial cancers.
    Type of Publication: Journal article published
    PubMed ID: 26256549
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  • 13
    Keywords: POPULATION ; RISK ; HEALTH ; HYPERTENSION ; PREVALENCE ; MANAGEMENT ; GUIDELINES ; MELLITUS ; CARDIOVASCULAR-DISEASE ; PULSE PRESSURE
    Abstract: BACKGROUND: Hypertension is a very common comorbidity and major risk factor for cardiovascular complications, especially in people with Type 2 Diabetes (T2D). Nevertheless, studies in the past have shown that blood pressure is often insufficiently controlled in medical practice. For the DIAB-CARE study, we used longitudinal data based on the German DIAB-CORE Consortium to assess whether health care regarding hypertension has improved during the last decade in our participants. METHODS: Data of the three regional population-based studies CARLA (baseline 2002-2006 and follow-up 2007-2010), KORA (baseline 1999-2001 and follow-up 2006-2008) and SHIP (baseline 1997-2001 and follow-up 2002-2006) were pooled. Stratified by T2D status we analysed changes in frequencies, degrees of awareness, treatment and control. Linear mixed models were conducted to assess the influence of sex, age, study, and T2D status on changes of systolic blood pressure between the baseline and follow-up examinations (mean observation time 5.7 years). We included 4,683 participants aged 45 to 74 years with complete data and accounted for 1,256 participants who were lost to follow-up by inverse probability weighting. RESULTS: Mean systolic blood pressure decreased in all groups from baseline to follow-up (e.g. - 8.5 mmHg in those with incident T2D). Pulse pressure (PP) was markedly higher in persons with T2D than in persons without T2D (64.14 mmHg in prevalent T2D compared to 52.87 mmHg in non-T2D at baseline) and did not change much between the two examinations. Awareness, treatment and control increased considerably in all subgroups however, the percentage of those with insufficiently controlled hypertension remained high (at about 50% of those with hypertension) especially in prevalent T2D. Particularly elderly people with T2D often had both, high blood pressure 〉/=140/90 mmHg and a PP of 〉/=60 mmHg. Blood pressure in men had improved more than in women at follow-up, however, men still had higher mean SBP than women at follow-up. CONCLUSION: Blood pressure management has developed positively during past years in Germany. While hypertension prevalence, awareness and treatment were substantially higher in participants with T2D than in those without T2D at follow-up, hypertension control was achieved only in about half the number of people in each T2D group leaving much room for further improvement.
    Type of Publication: Journal article published
    PubMed ID: 26221962
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  • 14
    Keywords: carcinoma ; RISK ; SAMPLES ; INFECTION ; antibodies ; LYMPHOMA ; CANCERS ; EPILYMPH ; MCPYV
    Abstract: Merkel cell polyomavirus (MCPyV) has been suspected to cause chronic lymphocytic leukaemia (CLL) but previous data are inconsistent. We measured seroreactivities of nine polyomaviruses (MCPyV, BKPyV, JCPyV, LPyV, KIPyV, WUPyV, HPyV-6, HPyV-7 and TSPyV) in 359 CLL cases and 370 controls using bead-based multiplex serology technology. We additionally tested two herpesviruses (HSV-1 and CMV). Associations between disease and viral seroreactivities were assessed using logistic regression. All human viruses showed high seroprevalences (69-99 %) against structural proteins in controls but significantly lower viral seroprevalences in cases (58-94 %; OR range = 0.21-0.70, P value 〈 0.05), except for MCPyV (OR = 0.79, 95 % CI = 0.54-1.16). Lower seroreactivity levels were observed among CLL subjects, with significant differences already observed at early stages of disease, unrelated to treatment status. Seroreactivities against polyomavirus related oncoproteins were almost null. Our data suggest no association for MCPyV polyomavirus with CLL development and an unlikely association for other polyomaviruses tested.
    Type of Publication: Journal article published
    PubMed ID: 25920529
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  • 15
    Keywords: DIAGNOSIS ; RISK ; PERFORMANCE ; COLORECTAL-CANCER ; BONE-MARROW-TRANSPLANTATION ; VERSUS-HOST-DISEASE ; IMMUNE FUNCTION ; BENEFITS ; COMORBIDITY INDEX ; MULTIMODAL INTERVENTION
    Abstract: Observational studies have suggested that physical activity may be associated with improved survival after cancer treatment. However, data from controlled clinical trials are required. We analyzed survival data of 103 patients from a previously published randomized controlled trial in allogeneic stem cell transplant patients who were randomized to either an exercise intervention (EX) or to a social contact control group. EX patients trained prior to hospital admission, during inpatient treatment, and for 6-8 weeks after discharge. Survival analyses were used to compare both total mortality (TM) and non-relapse mortality (NRM) after discharge and transplantation during an observation period of 2 years after transplantation. Analyses were corroborated with Cox and Fine & Gray regression models adjusting for potential confounders. After discharge, EX patients had a significantly lower TM rate than controls (12.0 vs. 28.3%, p = 0.030) and a numerically lower NRM rate (4.0 vs. 13.5%, p = 0.086). When the inpatient period was included, absolute risk reductions were similar but not significantly different (TM: 34.0 vs. 50.9%, p = 0.112; NRM: 26.0 vs. 36.5%, p = 0.293). The number needed to treat (NNT) to prevent one death with EX was about 6. Furthermore, regression analyses revealed that baseline fitness was protective against mortality. The data suggest that exercise might improve survival in patients undergoing allo-HCT. However, the results should be interpreted with caution as the study was not designed to detect differences in survival rates, and as no stratification on relevant prognostic factors was carried out.
    Type of Publication: Journal article published
    PubMed ID: 26061092
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  • 16
    Keywords: MODELS ; RISK ; DIETARY ; meat ; CALIBRATION ; CORONARY-HEART-DISEASE ; METAANALYSIS ; CONTAMINANTS ; DANISH ADULTS ; FISHERMEN
    Abstract: Fish is a source of important nutrients and may play a role in preventing heart diseases and other health outcomes. However, studies of overall mortality and cause-specific mortality related to fish consumption are inconclusive. We examined the rate of overall mortality, as well as mortality from ischaemic heart disease and cancer in relation to the intake of total fish, lean fish, and fatty fish in a large prospective cohort including ten European countries. More than 500,000 men and women completed a dietary questionnaire in 1992-1999 and were followed up for mortality until the end of 2010. 32,587 persons were reported dead since enrolment. Hazard ratios and their 99 % confidence interval were estimated using Cox proportional hazard regression models. Fish consumption was examined using quintiles based on reported consumption, using moderate fish consumption (third quintile) as reference, and as continuous variables, using increments of 10 g/day. All analyses were adjusted for possible confounders. No association was seen for fish consumption and overall or cause-specific mortality for both the categorical and the continuous analyses, but there seemed to be a U-shaped trend (p 〈 0.000) with fatty fish consumption and total mortality and with total fish consumption and cancer mortality (p = 0.046).
    Type of Publication: Journal article published
    PubMed ID: 25377533
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  • 17
    Keywords: CELLS ; RISK ; INFECTION ; LESIONS ; CERVICAL-CANCER ; intraepithelial neoplasia ; METAANALYSIS ; HIV ; VULVA ; GENOTYPE ATTRIBUTION
    Abstract: Knowledge about human papillomaviruses (HPV) types involved in anal cancers in some world regions is scanty. Here, we describe the HPV DNA prevalence and type distribution in a series of invasive anal cancers and anal intraepithelial neoplasias (AIN) grades 2/3 from 24 countries. We analyzed 43 AIN 2/3 cases and 496 anal cancers diagnosed from 1986 to 2011. After histopathological evaluation of formalin-fixed paraffin-embedded samples, HPV DNA detection and genotyping was performed using SPF-10/DEIA/LiPA25 system (version 1). A subset of 116 cancers was further tested for p16(INK4a) expression, a cellular surrogate marker for HPV-associated transformation. Prevalence ratios were estimated using multivariate Poisson regression with robust variance in the anal cancer data set. HPV DNA was detected in 88.3% of anal cancers (95% confidence interval [CI]: 85.1-91.0%) and in 95.3% of AIN 2/3 (95% CI: 84.2-99.4%). Among cancers, the highest prevalence was observed in warty-basaloid subtype of squamous cell carcinomas, in younger patients and in North American geographical region. There were no statistically significant differences in prevalence by gender. HPV16 was the most frequent HPV type detected in both cancers (80.7%) and AIN 2/3 lesions (75.4%). HPV18 was the second most common type in invasive cancers (3.6%). p16(INK4a) overexpression was found in 95% of HPV DNA-positive anal cancers. In view of the results of HPV DNA and high proportion of p16(INK4a) overexpression, infection by HPV is most likely to be a necessary cause for anal cancers in both men and women. The large contribution of HPV16 reinforces the potential impact of HPV vaccines in the prevention of these lesions.
    Type of Publication: Journal article published
    PubMed ID: 24817381
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  • 18
  • 19
    Keywords: FOLLOW-UP ; MORTALITY ; RISK ; BIOMARKERS ; C-REACTIVE PROTEIN ; PREDICTION ; PROGNOSTIC VALUE ; FAILURE ; GENERAL-POPULATION ; CARDIOVASCULAR EVENTS
    Abstract: Objective To assess the prognostic value of 12-months N-Terminal Pro-Brain Natriuretic Peptide (NT-proBNP) levels on adverse cardiovascular events in patients with stable coronary heart disease. Methods NT-proBNP concentrations were measured at baseline and at 12-months follow-up in participants of cardiac rehabilitation (median follow-up 8.96 years). Cox-proportional hazards models evaluated the prognostic value of log-transformed NT-proBNP levels, and of 12-months NT-proBNP relative changes on adverse cardiovascular events adjusting for established risk factors measured at baseline. Results Among 798 participants (84.7% men, mean age 59 years) there were 114 adverse cardiovascular events. 12-months NT-proBNP levels were higher than baseline levels in 60 patients (7.5%) and numerically more strongly associated with the outcome in multivariable analysis (HR 1.65 [95% CI 1.33-2.05] vs. HR 1.41 [95% CI 1.12-1.78], with a net reclassification improvement (NRI) of 0.098 [95% CI 0.002-0.194] compared to NRI of 0.047 [95% CI -0.0004-0.133] for baseline NT-proBNP levels. A 12-month 10% increment of NTproBNP was associated with a HR of 1.35 [95% CI 1.12-1.63] for the onset of an adverse cardiovascular event. Subjects with a 12-month increment of NT-proBNP had a HR of 2.56 [95% CI 1.10-5.95] compared to those with the highest 12-months reduction. Conclusions Twelve-months NT-proBNP levels after an acute cardiovascular event are strongly associated with a subsequent event and may provide numerically better reclassification of patients at risk for an adverse cardiovascular event compared to NT-proBNP baseline levels after adjustment for established risk factors.
    Type of Publication: Journal article published
    PubMed ID: 25629613
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  • 20
    Keywords: RISK ; BREAST-CANCER ; METAANALYSIS ; GENOME-WIDE ASSOCIATION ; GENETIC-VARIATION ; myopodin ; COMMON VARIANTS ; BRCA2 MUTATION CARRIERS ; ABO BLOOD-GROUP ; HUMAN ELG1
    Abstract: Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P 〈 5 x 10(-8). Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.
    Type of Publication: Journal article published
    PubMed ID: 25581431
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  • 21
    Keywords: RISK ; HEALTH ; POSTMENOPAUSAL WOMEN ; REGRESSION ; CANCER INCIDENCE ; fractional polynomials ; US ADULTS ; DIETARY CALCIUM ; SERUM 25-HYDROXYVITAMIN D ; DOSE-RESPONSE ANALYSES
    Abstract: Non-linearity is a likely phenomenon in bone metabolism, but is often ignored in pertinent epidemiological studies. Using NHANES III data on calcium intake and bone mineral density, the most important non-linear methods are introduced and discussed. The results should motivate researchers to consider non-linearity in this field more frequently. Introduction Many relationships in bone metabolism and homeostasis are likely to follow non-linear patterns. Detailed dose-response analyses allowing for non-linear associations nonetheless remain scarce in this field. Methods A detailed analysis of NHANES III data on dietary calcium intake and bone mineral density was used to demonstrate the application and some of the challenges of the most important dose-response methods, including LOESS, categorical analysis, fractional polynomials, restricted cubic splines, and segmented regression. Results The spline estimate suggested increasing bone mineral density up to a calcium intake of about 1 g/day and a plateau thereafter. In segmented regression, the break-point marking the beginning of the plateau was placed at an intake of 0.58 (95 % confidence interval, 0.33 to 0.82) g/day. Sensitivity analyses suggested a less curved dose-response in women. Conclusions Knowing about the possibilities and limitations of non-linear dose-response approaches should encourage researchers to consider these methods more frequently in studies on bone health and disease. The example analysis suggested bone mineral density to reach a plateau slightly below current calcium intake recommendations, with fairly pronounced differences of the dose-response shape by sex and menopausal status.
    Type of Publication: Journal article published
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  • 22
    Keywords: TOOL ; RISK ; ANTIGEN ; IDENTIFICATION ; DUAL ROLE ; TRANSLATION ; ANTIANGIOGENIC ACTIVITY ; susceptibility loci ; MICRORNA EXPRESSION ; VAMP8
    Abstract: Prostate cancer is the second most common malignancy among men worldwide. Genome-wide association studies have identified 100 risk variants for prostate cancer, which can explain approximately 33% of the familial risk of the disease. We hypothesized that a comprehensive analysis of genetic variations found within the 3' untranslated region of genes predicted to affect miRNA binding (miRSNP) can identify additional prostate cancer risk variants. We investigated the association between 2,169 miRSNPs and prostate cancer risk in a large-scale analysis of 22,301 cases and 22,320 controls of European ancestry from 23 participating studies. Twenty-two miRSNPs were associated (P 〈 2.3 x 10(-5)) with risk of prostate cancer, 10 of which were within 7 genes previously not mapped by GWAS studies. Further, using miRNA mimics and reporter gene assays, we showed that miR-3162-5p has specific affinity for the KLK3 rs1058205 miRSNP T-allele, whereas miR-370 has greater affinity for the VAMP8 rs1010 miRSNP A-allele, validating their functional role. SIGNIFICANCE: Findings from this large association study suggest that a focus on miRSNPs, including functional evaluation, can identify candidate risk loci below currently accepted statistical levels of genome-wide significance. Studies of miRNAs and their interactions with SNPs could provide further insights into the mechanisms of prostate cancer risk.
    Type of Publication: Journal article published
    PubMed ID: 25691096
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  • 23
    Keywords: MORTALITY ; RISK ; HEART ; ASSOCIATION ; ARTERY-DISEASE ; CREATININE ; CKD ; CHRONIC KIDNEY-DISEASE ; EQUATION ; CYSTATIN C
    Abstract: Background The usefulness of estimated glomerular filtration rate (eGFR) and albuminuria for prediction of cardiovascular outcomes is controversial. We aimed to assess the addition of creatinine-based eGFR and albuminuria to traditional risk factors for prediction of cardiovascular risk with a meta-analytic approach. Methods We meta-analysed individual-level data for 637 315 individuals without a history of cardiovascular disease from 24 cohorts (median follow-up 4.2-19.0 years) included in the Chronic Kidney Disease Prognosis Consortium. We assessed C statistic difference and reclassification improvement for cardiovascular mortality and fatal and non-fatal cases of coronary heart disease, stroke, and heart failure in a 5 year timeframe, contrasting prediction models for traditional risk factors with and without creatinine-based eGFR, albuminuria (either albumin-to-creatinine ratio [ACR] or semi-quantitative dipstick proteinuria), or both. Findings The addition of eGFR and ACR significantly improved the discrimination of cardiovascular outcomes beyond traditional risk factors in general populations, but the improvement was greater with ACR than with eGFR, and more evident for cardiovascular mortality (C statistic difference 0.0139 [95% CI 0.0105- 0.0174] for ACR and 0.0065 [0.0042-0.0088] for eGFR) and heart failure (0.0196 [0.0108-0.0284] and 0.0109 [0.0059-0.0159]) than for coronary disease (0.0048 [0.0029-0.0067] and 0.0036 [0.0019-0.0054]) and stroke (0.0105 [0.0058-0.0151]and 0.0036 [0.0004-0.0069]). Dipstick proteinuria showed smaller improvement than ACR. The discrimination improvement with eGFR or ACR was especially evident in individuals with diabetes or hypertension, but remained significant with ACR for cardiovascular mortality and heart failure in those without either of these disorders. In individuals with chronic kidney disease, the combination of eGFR and ACR for risk discrimination outperformed most single traditional predictors; the C statistic for cardiovascular mortality fell by 0.0227 (0.0158-0.0296) after omission of eGFR and ACR compared with less than 0.007 for any single modifiable traditional predictor. Interpretation Creatinine-based eGFR and albuminuria should be taken into account for cardiovascular prediction, especially when these measures are already assessed for clinical purpose or if cardiovascular mortality and heart failure are outcomes of interest. ACR could have particularly broad implications for cardiovascular prediction. In populations with chronic kidney disease, the simultaneous assessment of eGFR and ACR could facilitate improved classification of cardiovascular risk, supporting current guidelines for chronic kidney disease. Our results lend some support to also incorporating eGFR and ACR into assessments of cardiovascular risk in the general population.
    Type of Publication: Journal article published
    PubMed ID: 26028594
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  • 24
    Keywords: RISK ; cancer prevention ; C-REACTIVE PROTEIN ; CARDIOVASCULAR-DISEASE ; ALL-CAUSE MORTALITY ; OLDER-ADULTS ; GENERAL-POPULATION ; D DEFICIENCY ; SERUM 25-HYDROXYVITAMIN D ; HILLS CRITERIA
    Abstract: There is debate on whether vitamin D deficiency is a risk factor for major chronic diseases and premature death or whether observed associations were just confounded by general health status. Here, we review recent results from the Epidemiologische Studie zu Chancen der Verhutung, Fruherkennung und optimierten Therapie chronischer Erkrankungen in der alteren Bevolkerung (ESTHER) cohort study and the Consortium on Heatlh and Ageing: Network of Cohorts from Europe and the United States (CHANCES) that suggest that vitamin D deficiency may not be a risk factor for the development of cardiovascular diseases and cancer but may be a risk factor for fatal instances of these diseases. Furthermore, analyses comprehensively adjusted for the health status showed that the association of vitamin D and mortality was very likely not confounded by general health status. These results suggest that vitamin D could be a marker of resilience to fatality of potentially fatal diseases. Sufficient vitamin D serum concentrations may be needed to regulate the response of the immune system when it is challenged by severe diseases to prevent a fatal course of the disease. If this hypothesis can be verified through basic research studies and adequately designed randomized controlled trials, it could have important public health implications because vitamin D deficiency is very common worldwide, and interventions could be implemented easily.
    Type of Publication: Journal article published
    PubMed ID: 25954901
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  • 25
    Keywords: CLASSIFICATION ; RISK ; VARIANTS ; PREVALENCE ; BRCA2 MUTATIONS ; YOUNG-WOMEN ; PALB2 ; next-generation ; SEQUENCING DATA ; UNCERTAIN SIGNIFICANCE
    Abstract: PURPOSE: Recent advances in DNA sequencing have led to the development of breast cancer susceptibility gene panels for germline genetic testing of patients. We assessed the frequency of mutations in 17 predisposition genes, including BRCA1 and BRCA2, in a large cohort of patients with triple-negative breast cancer (TNBC) unselected for family history of breast or ovarian cancer to determine the utility of germline genetic testing for those with TNBC. PATIENTS AND METHODS: Patients with TNBC (N = 1,824) unselected for family history of breast or ovarian cancer were recruited through 12 studies, and germline DNA was sequenced to identify mutations. RESULTS: Deleterious mutations were identified in 14.6% of all patients. Of these, 11.2% had mutations in the BRCA1 (8.5%) and BRCA2 (2.7%) genes. Deleterious mutations in 15 other predisposition genes were detected in 3.7% of patients, with the majority observed in genes involved in homologous recombination, including PALB2 (1.2%) and BARD1, RAD51D, RAD51C, and BRIP1 (0.3% to 0.5%). Patients with TNBC with mutations were diagnosed at an earlier age (P 〈 .001) and had higher-grade tumors (P = .01) than those without mutations. CONCLUSION: Deleterious mutations in predisposition genes are present at high frequency in patients with TNBC unselected for family history of cancer. Mutation prevalence estimates suggest that patients with TNBC, regardless of age at diagnosis or family history of cancer, should be considered for germline genetic testing of BRCA1 and BRCA2. Although mutations in other predisposition genes are observed among patients with TNBC, better cancer risk estimates are needed before these mutations are used for clinical risk assessment in relatives.
    Type of Publication: Journal article published
    PubMed ID: 25452441
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  • 26
    Keywords: MODEL ; RISK ; ACTIVATION ; TARGET ; STEM-CELLS ; DIABETES-MELLITUS ; ARREST ; DUCTAL ADENOCARCINOMA ; METAANALYSIS ; TO-MESENCHYMAL TRANSITION
    Abstract: Metformin treatment is associated with a decreased risk and better prognosis of pancreatic cancer (PC) in patients with type 2 diabetes, but the mechanism of metformin's PC growth inhibition in the context of a prediabetic state is unknown. We used a Panc02 pancreatic tumor cell transplant model in diet-induced obese (DIO) C57BL/6 mice to compare the effects of metformin and the direct mammalian target of rapamycin (mTOR) inhibitor rapamycin on PC growth, glucose regulation, mTOR pathway signaling, and candidate microRNA (miR) expression. In DIO/prediabetic mice, metformin and rapamycin significantly reduced pancreatic tumor growth and mTOR-related signaling. The rapamycin effects centered on decreased mTOR-regulated growth and survival signaling, including increased expression of let-7b and cell cycle-regulating miRs. Metformin (but not rapamycin) reduced glucose and insulin levels and expression of miR-34a and its direct targets Notch, Slug, and Snail. Metformin also reduced the number and size of Panc02 tumor spheres in vitro and inhibited the expression of Notch in spheroids. Our results suggest that metformin and rapamycin can both inhibit pancreatic tumor growth in obese, prediabetic mice through shared and distinct mechanisms. Metformin and direct mTOR inhibitors, alone or possibly in combination, represent promising intervention strategies for breaking the diabetes-PC link.
    Type of Publication: Journal article published
    PubMed ID: 25576058
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  • 27
    Keywords: RISK ; INFECTION ; ASSOCIATION ; antibodies ; PREDICTION ; AUTOANTIBODIES ; Myocarditis ; BETA-CELL AUTOIMMUNITY ; SUSPENSION ARRAY ; PICORNAVIRIDAE
    Abstract: Exposure to Ljungan virus (LV) is implicated in the risk of autoimmune (type 1) diabetes but possible contribution by other parechoviruses is not ruled out. The aim was to compare children diagnosed with type 1 diabetes in 2005-2011 (n = 69) with healthy controls (n = 294), all from the Jamtland County in Sweden, using an exploratory suspension multiplex immunoassay for IgM and IgG against 26 peptides of LV, human parechoviruses (HPeV), Aichi virus and poliovirus in relation to a radiobinding assay (RBA) for antibodies against LV and InfluenzaA/H1N1pdm09. Islet autoantibodies and HLA-DQ genotypes were also determined. 1) All five LV-peptide antibodies correlated to each other (P 〈 0.001) in the suspension multiplex IgM- and IgG-antibody assay; 2) The LV-VP1_31-60-IgG correlated with insulin autoantibodies alone (P = 0.007) and in combination with HLA-DQ8 overall (P = 0.022) as well as with HLA-DQ 8/8 and 8/X subjects (P = 0.013); 3) RBA detected LV antibodies correlated with young age at diagnosis (P 〈 0.001) and with insulin autoantibodies (P 〈 0.001) especially in young HLA-DQ8 subjects (P = 0.004); 4) LV-peptide-VP1_31-60-IgG correlated to RBA LV antibodies (P = 0.009); 5) HPeV3-peptide-IgM and -IgG showed inter-peptide correlations (P 〈 0.001) but only HPeV3-VP1_1-30-IgG (P 〈 0.001) and VP1_95-124-IgG (P = 0.009) were related to RBA LV antibodies without relation to insulin autoantibody positivity (P = 0.072 and P = 0.486, respectively). Both exploratory suspension multiplex IgG to LV-peptide VP1_31-60 and RBA detected LV antibodies correlated with insulin autoantibodies and HLA-DQ8 suggesting possible role in type 1 diabetes. It remains to be determined if cross-reactivity or concomitant exposure to LV and HPeV3 contributes to the seroprevalence. J. Med. Virol. 87:1130-1140, 2015. (c) 2015 Wiley Periodicals, Inc.
    Type of Publication: Journal article published
    PubMed ID: 25873230
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  • 28
    Keywords: COHORT ; POPULATION ; RISK ; METAANALYSIS ; GTPASE-ACTIVATING PROTEIN ; BASE-LINE CHARACTERISTICS ; GENOME-WIDE ASSOCIATION ; SEQUENCE VARIANTS ; GLEASON SCORE ; LINKAGE SCAN
    Abstract: Most men diagnosed with prostate cancer will experience indolent disease; hence, discovering genetic variants that distinguish aggressive from nonaggressive prostate cancer is of critical clinical importance for disease prevention and treatment. In a multistage, case-only genome-wide association study of 12,518 prostate cancer cases, we identify two loci associated with Gleason score, a pathological measure of disease aggressiveness: rs35148638 at 5q14.3 (RASA1, P=6.49 x 10(-9)) and rs78943174 at 3q26.31 (NAALADL2, P=4.18 x 10(-8)). In a stratified case-control analysis, the SNP at 5q14.3 appears specific for aggressive prostate cancer (P=8.85 x 10(-5)) with no association for nonaggressive prostate cancer compared with controls (P=0.57). The proximity of these loci to genes involved in vascular disease suggests potential biological mechanisms worthy of further investigation.
    Type of Publication: Journal article published
    PubMed ID: 25939597
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  • 29
    Keywords: RISK ; OVARIAN-CANCER ; BRCA2 ; ANEMIA GENES
    Type of Publication: Journal article published
    PubMed ID: 26067930
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  • 30
    Keywords: POPULATION ; RISK ; HEART ; RENAL-FUNCTION ; CARDIOVASCULAR-DISEASE ; PARATHYROID-HORMONE ; LEFT-VENTRICULAR HYPERTROPHY ; CHRONIC KIDNEY-DISEASE ; FGF23 ; DIETARY PHOSPHORUS
    Abstract: BACKGROUND: Increased fibroblast growth factor 23 (FGF23), a bone-derived hormone involved in the regulation of phosphate and vitamin D metabolism, has been related to the development of cardiovascular disease (CVD) in chronic kidney disease patients and in the general population. However, what determines higher FGF23 levels is still unclear. Also, little is known about the influence of diet on FGF23. The aim of this study was therefore to identify demographic, clinical and dietary correlates of high FGF23 concentrations in the general population. METHODS: We performed a cross-sectional analysis within a randomly selected subcohort of the European Prospective Investigation into Cancer and Nutrition (EPIC)-Germany comprising 2134 middle-aged men and women. The Human FGF23 (C-Terminal) ELISA kit was used to measure FGF23 in citrate plasma. Dietary data were obtained at baseline via validated food frequency questionnaires including up to 148 food items. RESULTS: Multivariable adjusted logistic regression showed that men had a 66% lower and smokers a 64% higher probability of having higher FGF23 (〉/= 90 RU/mL) levels compared, respectively, with women and nonsmokers. Each doubling in parathyroid hormone, creatinine, and C-reactive protein was related to higher FGF23. Among the dietary factors, each doubling in calcium and total energy intake was related, respectively, to a 1.75 and to a 4.41 fold increased probability of having higher FGF23. Finally, each doubling in the intake of iron was related to an 82% lower probability of having higher FGF23 levels. Results did not substantially change after exclusion of participants with lower kidney function. CONCLUSIONS: In middle-aged men and women traditional and non-traditional CVD risk factors were related to higher FGF23 concentrations. These findings may contribute to the understanding of the potential mechanisms linking increased FGF23 to increased CVD risk.
    Type of Publication: Journal article published
    PubMed ID: 26193703
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  • 31
    Keywords: EXPRESSION ; VISUALIZATION ; RISK ; CANCER PATIENTS ; centrosome ; MOLECULAR CLASSIFICATION ; MONOCLONAL GAMMOPATHY ; UNDETERMINED SIGNIFICANCE ; BLOOD STEM-CELLS ; DATA SETS
    Abstract: Here we perform the first genome-wide association study (GWAS) of multiple myeloma (MM) survival. In a meta-analysis of 306 MM patients treated at UCSF and 239 patients treated at the Mayo clinic, we find a significant association between SNPs near the gene FOPNL on chromosome 16p13 and survival (rs72773978; P=6 x 10(-10)). Patients with the minor allele are at increased risk for mortality (HR: 2.65; 95% CI: 1.94-3.58) relative to patients homozygous for the major allele. We replicate the association in the IMMEnSE cohort including 772 patients, and a University of Utah cohort including 318 patients (rs72773978 P=0.044). Using publicly available data, we find that the minor allele was associated with increased expression of FOPNL and increased expression of FOPNL was associated with higher expression of centrosomal genes and with shorter survival. Polymorphisms at the FOPNL locus are associated with survival among MM patients.
    Type of Publication: Journal article published
    PubMed ID: 26198393
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  • 32
    Keywords: RISK ; HEALTH ; CONSUMPTION ; POSTMENOPAUSAL WOMEN ; DRINKING ; PREMENOPAUSAL WOMEN ; HORMONE-RECEPTOR STATUS ; ESTROGEN-RECEPTORS
    Abstract: Alcohol intake has been associated to breast cancer in pre and postmenopausal women; however results are inconclusive regarding tumor hormonal receptor status, and potential modifying factors like age at start drinking. Therefore, we investigated the relation between alcohol intake and the risk of breast cancer using prospective observational data from the European Prospective Investigation into Cancer and Nutrition (EPIC). Up to 334,850 women, aged 35-70 years at baseline, were recruited in ten European countries and followed up an average of 11 years. Alcohol intake at baseline and average lifetime alcohol intake were calculated from country-specific dietary and lifestyle questionnaires. The study outcomes were the Hazard ratios (HR) of developing breast cancer according to hormonal receptor status. During 3,670,439 person-years, 11,576 incident breast cancer cases were diagnosed. Alcohol intake was significantly related to breast cancer risk, for each 10 g/day increase in alcohol intake the HR increased by 4.2% (95% CI: 2.7-5.8%). Taking 0 to 5 g/day as reference, alcohol intake of 〉5 to 15 g/day was related to a 5.9% increase in breast cancer risk (95% CI: 1-11%). Significant increasing trends were observed between alcohol intake and ER+/PR+, ER-/PR-, HER2- and ER-/PR-HER2- tumors. Breast cancer risk was stronger among women who started drinking prior to first full-time pregnancy. Overall, our results confirm the association between alcohol intake and both hormone receptor positive and hormone receptor negative breast tumors, suggesting that timing of exposure to alcohol drinking may affect the risk. Therefore, women should be advised to control their alcohol consumption.
    Type of Publication: Journal article published
    PubMed ID: 25677034
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  • 33
    Keywords: FOLLOW-UP ; RISK ; HEALTH ; WOMEN ; OBESITY ; ADULTS ; PHYSICAL-ACTIVITY ; BODY-MASS INDEX ; JAPANESE MEN ; WEIGHT CHANGE
    Abstract: Our objective was to investigate the association of change of anthropometric measurements and the incidence of type 2 diabetes mellitus (T2DM) within a pooled sample of 2 population-based cohorts.A final sample of 1324 women and 1278 men aged 31 to 83 years from 2 prospective cohorts in Germany, the CARLA (Cardiovascular Disease - Living and Ageing in Halle) and the SHIP study (Study of Health in Pomerania), were pooled. The association of change of body weight and waist circumference (WC) with incidence of T2DM was assessed by calculating sex-specific hazard ratios (HRs). We investigated the absolute change of markers of obesity as well as change relative to the baseline value and estimated crude and adjusted HRs. Furthermore, we conducted the analyses stratified by obesity status and age (〈60 vs 〉/=60 years) at baseline.Associations were found for both change of body weight and WC and incidence of T2DM in the crude and adjusted analyses. In the stratified study sample, those participants with a body mass index of 〈30 kg/m at baseline showed considerably lower HRs compared with obese women and men for both weight and WC. In the age-stratified analysis, we still found associations between change of weight and WC and incident T2DM with only marginal differences between the age groups.Our study showed associations of change of weight and WC as markers of obesity with incidence of T2DM. Keeping a healthy and primarily stable weight should be the goal for preventing the development of T2DM.
    Type of Publication: Journal article published
    PubMed ID: 26313783
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  • 34
    Keywords: POPULATION ; RISK ; HEREDITARY ; QUESTIONNAIRE ; PARTICIPATION
    Abstract: BACKGROUND: Although the risk of developing colorectal cancer (CRC) is 2-4 times higher in case of a positive family history, risk-adapted screening programs for family members related to CRC- patients do not exist in the German health care system. CRC screening recommendations for persons under 55 years of age that have a family predisposition have been published in several guidelines. The primary aim of this study is to determine the frequency of positive family history of CRC (1(st) degree relatives with CRC) among 40-54 year old persons in a general practitioner (GP) setting in Germany. Secondary aims are to detect the frequency of occurrence of colorectal neoplasms (CRC and advanced adenomas) in 1(st) degree relatives of CRC patients and to identify the variables (e.g. demographic, genetic, epigenetic and proteomic characteristics) that are associated with it. This study also explores whether evidence-based information contributes to informed decisions and how screening participation correlates with anxiety and (anticipated) regret. METHODS/DESIGN: Prior to the beginning of the study, the GP team (GP and one health care assistant) in around 50 practices will be trained, and about 8,750 persons that are registered with them will be asked to complete the "Network against colorectal cancer" questionnaire. The 10 % who are expected to have a positive family history will then be invited to give their informed consent to participate in the study. All individuals with positive family history will be provided with evidence-based information and prevention strategies. We plan to examine each participant's family history of CRC in detail and to collect information on further variables (e.g. demographics) associated with increased risk. Additional stool and blood samples will be collected from study-participants who decide to undergo a colonoscopy (n 350) and then analyzed at the German Cancer Research Center (DKFZ) Heidelberg to see whether further relevant variables are associated with an increased risk of CRC. One screening list and four questionnaires will be used to collect the data, and a detailed statistical analysis plan will be provided before the database is closed (expected to be June 30, 2015). DISCUSSION: It is anticipated that when persons with a family history of colorectal cancer have been provided with professional advice by the practice team, there will be an increase in the availability of valid information on the frequency of affected individuals and an increase in the number of persons making informed decisions. We also expect to identify further variables that are associated with colorectal cancer. This study therefore has translational relevance from lab to practice. TRIAL REGISTRATION: German Clinical Trials Register DRKS00006277.
    Type of Publication: Journal article published
    PubMed ID: 26314581
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  • 35
    Keywords: IN-VITRO ; MORTALITY ; RISK ; GENE ; TIME ; IMPACT ; protein expression ; CELL-GROWTH ; ESTROGEN ; HORMONE-THERAPY
    Abstract: BACKGROUND: Observational studies have reported a modest association between obesity and risk of ovarian cancer; however, whether it is also associated with survival and whether this association varies for the different histologic subtypes are not clear. We undertook an international collaborative analysis to assess the association between body mass index (BMI), assessed shortly before diagnosis, progression-free survival (PFS), ovarian cancer-specific survival and overall survival (OS) among women with invasive ovarian cancer. METHODS: We used original data from 21 studies, which included 12 390 women with ovarian carcinoma. We combined study-specific adjusted hazard ratios (HRs) using random-effects models to estimate pooled HRs (pHR). We further explored associations by histologic subtype. RESULTS: Overall, 6715 (54%) deaths occurred during follow-up. A significant OS disadvantage was observed for women who were obese (BMI: 30-34.9, pHR: 1.10 (95% confidence intervals (CIs): 0.99-1.23); BMI: 35, pHR: 1.12 (95% CI: 1.01-1.25)). Results were similar for PFS and ovarian cancer-specific survival. In analyses stratified by histologic subtype, associations were strongest for women with low-grade serous (pHR: 1.12 per 5 kg m(-2)) and endometrioid subtypes (pHR: 1.08 per 5 kg m(-2)), and more modest for the high-grade serous (pHR: 1.04 per 5 kg m(-2)) subtype, but only the association with high-grade serous cancers was significant. CONCLUSIONS: Higher BMI is associated with adverse survival among the majority of women with ovarian cancer.
    Type of Publication: Journal article published
    PubMed ID: 26151456
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  • 36
    Keywords: RISK
    Abstract: Dairy cattle meat and milk factors are proposed as risks for colon and breast cancers. Several novel small circular DNAs that are genetically active in human cells have been isolated from bovine sera and milk. Such agents have also been detected in two lesions of multiple sclerosis. A unifying concept is presented putatively explaining the risks for these diseases that are associated with these factors.
    Type of Publication: Journal article published
    PubMed ID: 26370607
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  • 37
    Keywords: DISEASE ; RISK ; SUSCEPTIBILITY ; FAMILY-CANCER DATABASE ; COMPLEX TRAITS ; GENETIC-VARIATION ; WIDE ASSOCIATION ; MISSING HERITABILITY ; COMMON SNPS ; THRESHOLD-MODEL
    Abstract: Genome-wide association studies (GWASs) have identified several single-nucleotide polymorphisms (SNPs) influencing the risk of Hodgkin's lymphoma (HL) and demonstrated the association of common genetic variation for this type of cancer. Such evidence for inherited genetic risk is also provided by the family history and the very high concordance between monozygotic twins. However, little is known about the genetic and environmental contributions. A common measure for describing the phenotypic variation due to genetics is the heritability. Using GWAS data on 906 HL cases by considering all typed SNPs simultaneously, we have calculated that the common variance explained by SNPs accounts for 〉35% of the total variation on the liability scale in HL (95% confidence interval 6-62%). These findings are consistent with similar heritability estimates of approximately 0.40 (95% confidence interval 0.17-0.58) based on Swedish population data. Our estimates support the underlying polygenic basis for susceptibility to HL, and show that heritability based on the population data is somehow larger than heritability based on the genomic data because of the possibility of some missing heritability in the GWAS data. Besides that there is still major evidence for multiple loci causing HL on chromosomes other than chromosome 6 that need to be detected. Because of limited findings in prior GWASs, it seems worth checking for more loci causing susceptibility to HL.European Journal of Human Genetics advance online publication, 17 September 2014; doi:10.1038/ejhg.2014.184.
    Type of Publication: Journal article published
    PubMed ID: 25227146
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  • 38
    Keywords: DEATH ; MORTALITY ; RISK ; ASSOCIATION ; SERUM CREATININE ; CARDIOVASCULAR EVENTS ; GLOMERULAR-FILTRATION-RATE ; STAGE RENAL-DISEASE ; CHRONIC KIDNEY-DISEASE ; CREATININE RATIO
    Abstract: Background: Despite standard laboratory quality control, drift and day-to-day variability in cystatin C measurements can be observed. We investigated whether correction for drift and day-to-day variation in cystatin C measurements improves the association of estimated glomerular filtration rate (eGFR) with chronic kidney disease (CKD) risk factors and prognosis. Methods: Plasma samples of the PREVEND study (Dutch cohort study, n = 8592) were used to measure cystatin C (Gentian assay) on 243 random days. A correction factor was calculated for each measurement day. GFR was estimated with CKD-EPI equation using routinely measured cystatin C (eGFR(cysC)) and corrected cystatin C (eGFR(cysC corr)). Participants were categorized in six categories of eGFR(cysC) and eGFR(cysC corr) : 〉= 120, 90-119, 75-89, 60-74, 45-59 and 〈 45 mL/min/1.73m(2). Independent replication was performed in the ESTHER study (German cohort study, n = 9949). Results: Compared to non-reclassified participants, participants re-classified upward had significantly lower age, body mass index, blood pressure, cholesterol, glucose and albuminuria, whereas the opposite was true for participants reclassified downward. CKD risk factors explained more variance in eGFR cysC corr than in eGFR cysC (p 〈 0.001). Compared to non-reclassified participants, risk of incident cardiovascular events (n = 789, follow-up 9.3 +/- 2.7 years) tended to be higher in downward reclassified and lower in upward reclassified participants. Net reclassification improvement for incident cardiovascular events using eGFR(cysC corr) was positive (0.102, p = 0.019). The ESTHER study showed similar results. Conclusions: Correction for drift and day-to-day variation in cystatin C measurement improves eGFR using cystatin C for its association with CKD risk factors and incident cardiovascular events.
    Type of Publication: Journal article published
    PubMed ID: 25415637
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    Keywords: CANCER ; RISK ; HUMANS ; DAMAGE ; PERIPHERAL-BLOOD ; TRANSLOCATIONS
    Type of Publication: Journal article published
    PubMed ID: 25428887
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    Keywords: PATHWAY ; THERAPY ; MORTALITY ; RISK ; prognosis ; PROSPECTIVE COHORT ; microsatellite instability ; colonoscopy ; DRUGS ; BETA-BLOCKER USE
    Abstract: Background: Statins have been associated with moderate reductions in mortality among colorectal cancer (CRC) patients, but these studies lacked adjustment for some potentially relevant factors associated with statin use. We aimed to provide more detailed results on this association from a population-based patient cohort study. Methods: Use of statins and other risk or protective factors were assessed in standardized interviews with 2697 patients from southern Germany with a diagnosis of incident CRC between 2003 and 2009 (Darmkrebs: Chancen der Verhutung durch Screening [DACHS] study). Follow-up included assessment of therapy details, recurrence, vital status, and cause of death. Information about molecular pathological subtypes of CRC was available for 1209 patients. Cox proportional hazard regression models were used to estimate adjusted hazard ratios (HRs) and their 95% confidence intervals (CIs). All statistical tests were two-sided. Results: Patients were age 68 years on average, 412 used statins (15%), and 769 died during follow-up (29%). After a median follow-up time of 3.4 years, use of statins was not associated with overall (HR = 1.10, 95% CI = 0.85 to 1.41), CRC-specific (HR = 1.11, 95% CI = 0.82 to 1.50), or recurrence-free survival (HR = 0.90, 95% CI = 0.63 to 1.27). Analyses in relevant subgroups also showed no association of statin use with overall and CRC-specific survival, and no associations were observed after stratifying for major pathological subtypes. Among stage I and II patients, statin use was associated with better recurrence-free but not with better CRC-specific survival. Conclusions: Statin use was not associated with reduced mortality among CRC patients. Effects reported in previous studies might reflect incomplete control for stage at diagnosis and other factors associated with the use of statins.
    Type of Publication: Journal article published
    PubMed ID: 25770147
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    Keywords: EXPRESSION ; BLOOD ; DIAGNOSIS ; RISK ; ASSOCIATION ; CIGARETTE-SMOKING ; adenocarcinoma ; biomarker ; DIFFERENTIAL DNA METHYLATION ; ACTIVATED RECEPTOR 4
    Abstract: Smoking accounts for a large share of lung cancer. F2RL3 methylation was recently identified as a biomarker closely reflecting both current and past smoking exposure. We aimed to assess the associations of F2RL3 methylation with lung cancer incidence and mortality. In a large population-based cohort study, F2RL3 methylation was measured in baseline blood samples of 4,987 participants by MassARRAY. Associations of F2RL3 methylation and smoking with lung cancer incidence/mortality during a median follow-up of 10.9 years were assessed by Cox regression, controlling for potential confounders. The ability of F2RL3 methylation to predict lung cancer was examined by Harrell's C statistics. Hypomethylation at F2RL3 was strongly associated with both lung cancer incidence and mortality, with age- and sex-adjusted hazard ratios (HR; 95% CI) of 9.99 (5.61-17.79) and 16.86 (8.53-33.34), respectively, for participants whose methylation intensity were 0.54 compared with whose methylation intensity were 0.75. Strongly elevated HRs of 2.88 (1.42-5.84) and 5.17 (2.28-11.70) persisted even after controlling for multiple covariates including smoking status and pack-years. With fully adjusted HRs of 9.92 (2.88-34.12) and 16.48 (4.10-66.15), the associations between methylation and the two outcomes were particularly strong among participants65 years. Combination of F2RL3 methylation and pack-years predicted lung cancer incidence with high accuracy (optimism-corrected Harrell's C statistics=0.86 for participants65 years). These findings suggested that F2RL3 methylation is a very strong predictor of lung cancer risk and mortality, particularly at older age. The potential implications of F2RL3 methylation for early detection, risk stratification and prevention of lung cancer warrant further exploration. What's new? Methylation of F2RL3 is linked to both current and lifetime smoking exposure, making it a potentially valuable marker for the assessment of lung cancer risk. This population-based prospective cohort study strengthens that potential, showing that F2RL3 hypomethylation, as measured in blood samples, is strongly predictive of lung cancer incidence and mortality. The association was significant regardless of whether F2RL3 methylation was considered alone or in combination with smoking status or pack-years. It was particularly strong in individuals aged 65 or older.
    Type of Publication: Journal article published
    PubMed ID: 25821117
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    Keywords: RISK ; prognosis ; PROGRESSION ; CYCLOPHOSPHAMIDE ; METAANALYSIS ; SINGLE-NUCLEOTIDE POLYMORPHISMS ; EPIRUBICIN ; LOCI ; GENOME-WIDE ASSOCIATION ; GENOTYPE IMPUTATION
    Abstract: Background: Survival after a diagnosis of breast cancer varies considerably between patients, and some of this variation may be because of germline genetic variation. We aimed to identify genetic markers associated with breast cancer-specific survival. Methods: We conducted a large meta-analysis of studies in populations of European ancestry, including 37 954 patients with 2900 deaths from breast cancer. Each study had been genotyped for between 200 000 and 900 000 single nucleotide polymorphisms (SNPs) across the genome; genotypes for nine million common variants were imputed using a common reference panel from the 1000 Genomes Project. We also carried out subtype-specific analyses based on 6881 estrogen receptor (ER)-negative patients (920 events) and 23 059 ER-positive patients (1333 events). All statistical tests were two-sided. Results: We identified one new locus (rs2059614 at 11q24.2) associated with survival in ER-negative breast cancer cases (hazard ratio [HR] = 1.95, 95% confidence interval [CI] = 1.55 to 2.47, P = 1.91 x 10(-8)). Genotyping a subset of 2113 case patients, of which 300 were ER negative, provided supporting evidence for the quality of the imputation. The association in this set of case patients was stronger for the observed genotypes than for the imputed genotypes. A second locus (rs148760487 at 2q24.2) was associated at genome-wide statistical significance in initial analyses; the association was similar in ER-positive and ER-negative case patients. Here the results of genotyping suggested that the finding was less robust. Conclusions: This is currently the largest study investigating genetic variation associated with breast cancer survival. Our results have potential clinical implications, as they confirm that germline genotype can provide prognostic information in addition to standard tumor prognostic factors.
    Type of Publication: Journal article published
    PubMed ID: 25890600
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    Keywords: RISK ; HUMAN-PAPILLOMAVIRUS ; POLYMERASE-CHAIN-REACTION ; adenocarcinoma ; NASOPHARYNGEAL CARCINOMA ; HELICOBACTER-PYLORI INFECTION ; EBV ; CLINICOPATHOLOGICAL FEATURES ; GASTRODUODENAL DISEASES ; IN-SITU DETECTION
    Abstract: Epstein-Barr virus (EBV) infection is found in a subset of gastric cancers. Previous reviews have exclusively focused on EBV-encoded small RNA (EBER) positivity in gastric cancer tissues, but a comprehensive evaluation of other type of studies is lacking. We searched the PubMed database up to September, 2014, and performed a systematic review. We considered studies comparing EBV nucleic acids positivity in gastric cancer tissue with positivity in either adjacent non-tumor tissue of cancer patients or non-tumor mucosa from healthy individuals, patients with benign gastric diseases, or deceased individuals. We also considered studies comparing EBV antibodies in serum from cancer patients and healthy controls. Selection of potentially eligible studies and data extraction were performed by 2 independent reviewers. Due to the heterogeneity of studies, we did not perform formal meta-analysis. Forty-seven studies (8069 cases and 1840 controls) were identified. EBER positivity determined by in situ hybridization (ISH) was significantly higher in cancer tissues (range 5.0%-17.9%) than in adjacent mucosa from the same patients or biopsies from all control groups (almost 0%). High EBV nuclear antigen-1 (EBNA-1) positivity by PCR was found in gastric cancer tissues, but most were not validated by ISH or adjusted for inflammatory severity and lymphocyte infiltration. Only 4 studies tested for EBV antibodies, with large variation in the seropositivities of different antibodies in both cases and controls, and did not find an association between EBV seropositivity and gastric cancer. In summary, tissue-based ISH methods strongly suggest an association between EBV infection and gastric cancer, but PCR method alone is invalid to confirm such association. Very limited evidence from serological studies and the lack of novel antibodies warrant further investigations to identify potential risk factors of EBV for gastric cancer.
    Type of Publication: Journal article published
    PubMed ID: 25997049
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    Keywords: RISK ; PERFORMANCE ; SURVEILLANCE ; MULTICENTER ; ENDOSCOPY ; POLYPECTOMY ; QUALITY INDICATORS ; COLORECTAL-CANCER INCIDENCE ; SOCIETY TASK-FORCE ; TANDEM COLONOSCOPY
    Abstract: BACKGROUND & AIMS: The adenoma detection rate (ADR) is an important quality indicator of screening colonoscopy; it is inversely associated with risk of interval cancers and colorectal cancer mortality. We assessed trends in the ADR in the first 10 years of the German screening colonoscopy program. METHODS: We calculated age-adjusted and age-specific detection rates of nonadvanced adenomas and advanced adenomas for each calendar year based on 4.4 million screening colonoscopies conducted from 2003 through 2012 and reported to the German screening colonoscopy registry. RESULTS: We observed a steady and strong increase in rate of detection of nonadvanced adenomas in both sexes and all age groups. Age-adjusted rates of detection of nonadvanced adenomas increased from 13.3% to 22.3% among men and from 8.4% to 14.9% among women. This increase was mostly due to an increase in detection rates of adenomas 〈0.5 cm, and it is partly explained by an innovation effect (higher ADRs among incoming colonoscopists than among leaving colonoscopists, and relatively stable ADRs among continuing colonoscopists). Only modest increases were observed in detection rates of advanced adenomas (from 7.4% to 9.0% among men, and from 4.4% to 5.2% among women) and colorectal cancer. In 2012, overall ADR reached 31.3% and 20.1% in men and women, respectively. CONCLUSIONS: We observed a strong increase in ADRs from 2003 through 2012 in Germany. Although we cannot exclude the effects of secular trends in colorectal neoplasm prevalence, the observed increase was mainly the result of a steady increase in detection of nonadvanced adenomas (especially adenomas 〈0.5 cm). Further research should address potential implications for defining screening and surveillance intervals.
    Type of Publication: Journal article published
    PubMed ID: 25911510
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    Keywords: RECEPTOR ; RISK ; POLYMORPHISMS ; SUSCEPTIBILITY LOCUS ; VARIANTS ; IDENTIFICATION ; GENOME-WIDE ASSOCIATION ; PROGESTERONE ; GENOTYPE IMPUTATION ; GRANULOSA-CELL TUMOR
    Abstract: Rabbit hemorrhagic disease virus (RHDV) is a member of the Caliciviridae family (Lagovirus genus). RHDV is highly contagious and attaches to epithelial cells in the digestive or respiratory tract, leading to massive lesions with high mortality rates. A new variant of RHDV (termed RHDVb) recently has emerged, and previously vaccinated rabbits appear to have little protection against this new strain. Similar to human norovirus (Caliciviridae, Norovirus genus), RHDV binds histo-blood group antigens (HBGAs), and this is thought to be important for infection. Here, we report the HBGA binding site on the RHDVb capsid-protruding domain (P domain) using X-ray crystallography. The HBGA binding pocket was located in a negatively charged patch on the side of the P domain and at a dimeric interface. Residues from both monomers contributed to the HBGA binding and involved a network of direct hydrogen bonds and water-mediated interactions. An amino acid sequence alignment of different RHDV strains indicated that the residues directly interacting with the ABH-fucose of the HBGAs (Asp472, Asn474, and Ser479) were highly conserved. This result suggested that different RHDV strains also could bind HBGAs at the equivalent pocket. Moreover, several HBGA binding characteristics between RHDVb and human genogroup II norovirus were similar, which indicated a possible convergent evolution of HBGA binding interactions. Further structural studies with other RHDV strains are needed in order to better understand the HBGA binding mechanisms among the diverse RHDV strains. IMPORTANCE: We identified, for the first time, the HBGA binding site on an RHDVb P domain using X-ray crystallography. Our results showed that RHDVb and human genogroup II noroviruses had similar HBGA binding interactions. Recently, it was discovered that synthetic HBGAs or HBGA-expressing enteric bacteria could enhance human genogroup II norovirus infection in B cells. Considering that RHDVb and genogroup II norovirus similarly interacted with HBGAs, it may be possible that a comparable cell culture system also could work with RHDVb. Taken together, these new findings will extend our understanding of calicivirus HBGA interactions and may help to elucidate the specific roles of HBGAs in calicivirus infections.
    Type of Publication: Journal article published
    PubMed ID: 25505081
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