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1.
PLoS Comput Biol ; 19(1): e1010831, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36689547

RESUMO

Colorectal adenoma are precursor lesions on the pathway to cancer. Their removal in screening colonoscopies has markedly reduced rates of cancer incidence and death. Generic models of adenoma growth and transition to cancer can guide the implementation of screening strategies. But adenoma shape has rarely featured as a relevant risk factor. Against this backdrop we aim to demonstrate that shape influences growth dynamics and cancer risk. Stochastic cell-based models are applied to a data set of 197,347 Bavarian outpatients who had colonoscopies from 2006-2009, 50,649 patients were reported with adenoma and 296 patients had cancer. For multi-stage clonal expansion (MSCE) models with up to three initiating stages parameters were estimated by fits to data sets of all shapes combined, and of sessile (70% of all adenoma), peduncular (17%) and flat (13%) adenoma separately for both sexes. Pertinent features of adenoma growth present themselves in contrast to previous assumptions. Stem cells with initial molecular changes residing in early adenoma predominantly multiply within two-dimensional structures such as crypts. For these cells mutation and division rates decrease with age. The absolute number of initiated cells in an adenoma of size 1 cm is small around 103, related to all bulk cells they constitute a share of about 10-5. The notion of very few proliferating stem cells with age-decreasing division rates is supported by cell marker experiments. The probability for adenoma transiting to cancer increases with squared linear size and shows a shape dependence. Compared to peduncular and flat adenoma, it is twice as high for sessile adenoma of the same size. We present a simple mathematical expression for the hazard ratio of interval cancers which provides a mechanistic understanding of this important quality indicator. We conclude that adenoma shape deserves closer consideration in screening strategies and as risk factor for transition to cancer.


Assuntos
Adenoma , Neoplasias Colorretais , Masculino , Feminino , Humanos , Neoplasias Colorretais/patologia , Colonoscopia/métodos , Fatores de Risco , Incidência , Adenoma/diagnóstico
2.
Radiat Environ Biophys ; 62(1): 1-15, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36633666

RESUMO

The probability that an observed cancer was caused by radiation exposure is usually estimated using cancer rates and risk models from radioepidemiological cohorts and is called assigned share (AS). This definition implicitly assumes that an ongoing carcinogenic process is unaffected by the studied radiation exposure. However, there is strong evidence that radiation can also accelerate an existing clonal development towards cancer. In this work, we define different association measures that an observed cancer was newly induced, accelerated, or retarded. The measures were quantified exemplarily by Monte Carlo simulations that track the development of individual cells. Three biologically based two-stage clonal expansion (TSCE) models were applied. In the first model, radiation initiates cancer development, while in the other two, radiation has a promoting effect, i.e. radiation accelerates the clonal expansion of pre-cancerous cells. The parameters of the TSCE models were derived from breast cancer data from the atomic bomb survivors of Hiroshima and Nagasaki. For exposure at age 30, all three models resulted in similar estimates of AS at age 60. For the initiation model, estimates of association were nearly identical to AS. However, for the promotion models, the cancerous clonal development was frequently accelerated towards younger ages, resulting in associations substantially higher than AS. This work shows that the association between a given cancer and exposure in an affected person depends on the underlying biological mechanism and can be substantially larger than the AS derived from classic radioepidemiology.


Assuntos
Neoplasias Induzidas por Radiação , Guerra Nuclear , Humanos , Adulto , Pessoa de Meia-Idade , Neoplasias Induzidas por Radiação/epidemiologia , Neoplasias Induzidas por Radiação/etiologia , Modelos Biológicos , Carcinogênese , Radiação Ionizante , Japão
3.
Am J Epidemiol ; 191(10): 1766-1775, 2022 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-35231928

RESUMO

Mathematical models are able to reflect biological processes and to capture epidemiologic data. Thus, they may help elucidate roles of risk factors in disease progression. We propose to account for smoking, hypertension, and dyslipidemia in a previously published process-oriented model that describes the development of atherosclerotic lesions resulting in myocardial infarction (MI). The model is sex-specific and incorporates individual heterogeneity. It was applied to population-based individual risk factors and MI rates (Cooperative Health Research in the Region of Augsburg (KORA) study) together with subclinical atherosclerotic lesion data (Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study). Different model variants were evaluated, testing the association of risk factors with different disease processes. Best fits were obtained for smoking affecting a late-stage disease process, suggesting a thrombogenic role. Hypertension was mainly related to complicated, vulnerable lesions. Dyslipidemia was consistent with increasing the number of initial lesions. By accounting for heterogeneity, individual hazard ratios differ from the population average. The mean individual hazard ratio for smoking was twice the population-based hazard ratio for men and even more for women. Atherosclerotic lesion progression and MI incidence data can be related in a mathematical model to illuminate how risk factors affect different phases of this pathological process.


Assuntos
Aterosclerose , Dislipidemias , Hipertensão , Infarto do Miocárdio , Adolescente , Aterosclerose/epidemiologia , Aterosclerose/etiologia , Feminino , Humanos , Hipertensão/complicações , Hipertensão/epidemiologia , Masculino , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/etiologia , Fatores de Risco
4.
Eur Respir J ; 60(1)2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-34887322

RESUMO

BACKGROUND: Survival after curative resection of early-stage lung adenocarcinoma (LUAD) varies and prognostic biomarkers are urgently needed. METHODS: Large-format tissue samples from a prospective cohort of 200 patients with resected LUAD were immunophenotyped for cancer hallmarks TP53, NF1, CD45, PD-1, PCNA, TUNEL and FVIII, and were followed for a median of 2.34 (95% CI 1.71-3.49) years. RESULTS: Unsupervised hierarchical clustering revealed two patient subgroups with similar clinicopathological features and genotype, but with markedly different survival: "proliferative" patients (60%) with elevated TP53, NF1, CD45 and PCNA expression had 50% 5-year overall survival, while "apoptotic" patients (40%) with high TUNEL had 70% 5-year survival (hazard ratio 2.23, 95% CI 1.33-3.80; p=0.0069). Cox regression and machine learning algorithms including random forests built clinically useful models: a score to predict overall survival and a formula and nomogram to predict tumour phenotype. The distinct LUAD phenotypes were validated in The Cancer Genome Atlas and KMplotter data, and showed prognostic power supplementary to International Association for the Study of Lung Cancer tumour-node-metastasis stage and World Health Organization histologic classification. CONCLUSIONS: Two molecular subtypes of LUAD exist and their identification provides important prognostic information.


Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Humanos , Neoplasias Pulmonares/patologia , Fenótipo , Prognóstico , Antígeno Nuclear de Célula em Proliferação/genética , Estudos Prospectivos
5.
Stat Med ; 40(14): 3299-3312, 2021 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-34008245

RESUMO

Analyzing epidemiological data with simplified mathematical models of disease development provides a link between the time-course of incidence and the underlying biological processes. Here we point out that considerable modeling flexibility is gained if the model is solved by simulation only. To this aim, a model of atherosclerosis is proposed: a Markov Chain with continuous state space which represents the coronary artery intimal surface area involved with atherosclerotic lesions of increasing severity. Myocardial infarction rates are assumed to be proportional to the area of most severe lesions. The model can be fitted simultaneously to infarction incidence rates observed in the KORA registry, and to the age-dependent prevalence and extent of atherosclerotic lesions in the PDAY study. Moreover, the simulation approach allows for non-linear transition rates, and to consider at the same time randomness and inter-individual heterogeneity. Interestingly, the fit revealed significant age dependence of parameters in females around the age of menopause, qualitatively reproducing the known vascular effects of female sex hormones. For males, the incidence curve flattens for higher ages. According to the model, frailty explains this flattening only partially, and saturation of the disease process plays also an important role. This study shows the feasibility of simulating subclinical and epidemiological data with the same mathematical model. The approach is very general and may be extended to investigate the effects of risk factors or interventions. Moreover, it offers an interface to integrate quantitative individual health data as assessed, for example, by imaging.


Assuntos
Aterosclerose , Infarto do Miocárdio , Feminino , Humanos , Incidência , Masculino , Sistema de Registros , Fatores de Risco
6.
Radiat Environ Biophys ; 59(1): 63-78, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31781840

RESUMO

Recent analyses of the Canadian fluoroscopy cohort study reported significantly increased radiation risks of mortality from ischemic heart diseases (IHD) with a linear dose-response adjusted for dose fractionation. This cohort includes 63,707 tuberculosis patients from Canada who were exposed to low-to-moderate dose fractionated X-rays in 1930s-1950s and were followed-up for death from non-cancer causes during 1950-1987. In the current analysis, we scrutinized the assumption of linearity by analyzing a series of radio-biologically motivated nonlinear dose-response models to get a better understanding of the impact of radiation damage on IHD. The models were weighted according to their quality of fit and were then mathematically superposed applying the multi-model inference (MMI) technique. Our results indicated an essentially linear dose-response relationship for IHD mortality at low and medium doses and a supra-linear relationship at higher doses (> 1.5 Gy). At 5 Gy, the estimated radiation risks were fivefold higher compared to the linear no-threshold (LNT) model. This is the largest study of patients exposed to fractionated low-to-moderate doses of radiation. Our analyses confirm previously reported significantly increased radiation risks of IHD from doses similar to those from diagnostic radiation procedures.


Assuntos
Fluoroscopia/efeitos adversos , Isquemia Miocárdica/mortalidade , Lesões por Radiação/mortalidade , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Canadá , Criança , Pré-Escolar , Estudos de Coortes , Relação Dose-Resposta à Radiação , Humanos , Lactente , Recém-Nascido , Pessoa de Meia-Idade , Fatores de Risco , Tuberculose/diagnóstico por imagem , Adulto Jovem
7.
Radiat Environ Biophys ; 59(4): 601-629, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32851496

RESUMO

ProZES is a software tool for estimating the probability that a given cancer was caused by preceding exposure to ionising radiation. ProZES calculates this probability, the assigned share, for solid cancers and hematopoietic malignant diseases, in cases of exposures to low-LET radiation, and for lung cancer in cases of exposure to radon. User-specified inputs include birth year, sex, type of diagnosed cancer, age at diagnosis, radiation exposure history and characteristics, and smoking behaviour for lung cancer. Cancer risk models are an essential part of ProZES. Linking disease and exposure to radiation involves several methodological aspects, and assessment of uncertainties received particular attention. ProZES systematically uses the principle of multi-model inference. Models of radiation risk were either newly developed or critically re-evaluated for ProZES, including dedicated models for frequent types of cancer and, for less common diseases, models for groups of functionally similar cancer sites. The low-LET models originate mostly from the study of atomic bomb survivors in Hiroshima and Nagasaki. Risks predicted by these models are adjusted to be applicable to the population of Germany and to different time periods. Adjustment factors for low dose rates and for a reduced risk during the minimum latency time between exposure and cancer are also applied. The development of the methodology and software was initiated and supported by the German Federal Ministry for the Environment, Nature Conservation and Nuclear Safety (BMU) taking up advice by the German Commission on Radiological Protection (SSK, Strahlenschutzkommission). These provide the scientific basis to support decision making on compensation claims regarding malignancies following occupational exposure to radiation in Germany.


Assuntos
Modelos Teóricos , Neoplasias Induzidas por Radiação/etiologia , Exposição à Radiação/efeitos adversos , Software , Alemanha , Humanos , Probabilidade , Medição de Risco
8.
Carcinogenesis ; 40(10): 1240-1250, 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-30915466

RESUMO

KRAS mutations of lung adenocarcinoma (LADC) are associated with smoking but little is known on other exposure-oncogene associations. Hypothesizing that different inciting agents may cause different driver mutations, we aimed to identify distinct molecular pathways to LADC, applying two entirely different approaches. First, we examined clinicopathologic features and genomic signatures of environmental exposures in the large LADC Campbell data set. Second, we designed a molecular mechanistic risk model of LADC (M3LADC) that links environmental exposure to incidence risk by mathematically emulating the disease process. This model was applied to incidence data of Japanese atom-bomb survivors which contains information on radiation and smoking exposure. Grouping the clinical data by driver mutations revealed two main distinct molecular pathways to LADC: one unique to transmembrane receptor-mutant patients that displayed robust signatures of radiation exposure and one shared between submembrane transducer-mutant patients and patients with no evident driver mutation that carried the signature of smoking. Consistently, best fit of the incidence data was achieved with a M3LADC with two pathways: in one LADC risk increased with radiation exposure and in the other with cigarette consumption. We conclude there are two main molecular pathways to LADC associated with different environmental exposures. Future molecular measurements in lung cancer tissue of atom-bomb survivors may allow to further test quantitatively the M3LADC-predicted link of radiation to transmembrane receptor mutations. Moreover, the developed molecular mechanistic model showed that for low doses, as relevant e.g. for medical imaging, smokers have the same radiation risk compared with never smokers.


Assuntos
Adenocarcinoma de Pulmão/etiologia , Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/etiologia , Neoplasias Induzidas por Radiação/etiologia , Exposição à Radiação/efeitos adversos , Fumar/efeitos adversos , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias Induzidas por Radiação/genética , Neoplasias Induzidas por Radiação/patologia , Armas Nucleares/estatística & dados numéricos , Prognóstico , Fatores de Risco , Transdução de Sinais , Fumar/genética , Taxa de Sobrevida , Sobreviventes/estatística & dados numéricos
9.
Radiat Environ Biophys ; 58(3): 305-319, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31006050

RESUMO

The problem of expressing cumulative detrimental effect of radiation exposure is revisited. All conventionally used and computationally complex lifetime or time-integrated risks are based on current population and health statistical data, with unknown future secular trends, that are projected far into the future. It is shown that application of conventionally used lifetime or time-integrated attributable risks (LAR, AR) should be limited to exposures under 1 Gy. More general quantities, such as excess lifetime risk (ELR) and, to a lesser extent, risk of exposure-induced death (REID), are free of dose constraints, but are even more computationally complex than LAR and AR and rely on the unknown total radiation effect on demographic and health statistical data. Appropriate assessment of time-integrated risk of a specific outcome following high-dose (more than 1 Gy) exposure requires consideration of competing risks for other radiation-attributed outcomes and the resulting ELR estimate has an essentially non-linear dose response. Limitations caused by basing conventionally applied time-integrated risks on current population and health statistical data are that they are: (a) not well suited for risk estimates for atypical groups of exposed persons not readily represented by the general population; and (b) not optimal for risk projections decades into the future due to large uncertainties in developments of the future secular trends in the population-specific disease rates. Alternative disease-specific quantities, baseline and attributable survival fractions, based on reduction of survival chances are considered here and are shown to be very useful in circumventing most aspects of these limitations. Another main quantity, named as radiation-attributed decrease of survival (RADS), is recommended here to represent cumulative radiation risk conditional on survival until a certain age. RADS, historically known in statistical literature as "cumulative risk", is only based on the radiation-attributed hazard and is insensitive to competing risks. Therefore, RADS is eminently suitable for risk projections in emergency situations and for estimating radiation risks for persons exposed after therapeutic or interventional medical applications of radiation or in other highly atypical groups of exposed persons, such as astronauts.


Assuntos
Exposição à Radiação/análise , Exposição à Radiação/prevenção & controle , Proteção Radiológica , Medição de Risco/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Medicina , Pessoa de Meia-Idade , Modelos Estatísticos , Prognóstico , Lesões por Radiação/diagnóstico , Lesões por Radiação/epidemiologia , Radiobiologia , Análise de Sobrevida , Adulto Jovem
10.
Radiat Environ Biophys ; 58(3): 321-336, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31218403

RESUMO

Exposure-lag-response associations shed light on the duration of pathogenesis for radiation-induced diseases. To investigate such relations for lung cancer mortality in the German uranium miners of the Wismut company, we apply distributed lag non-linear models (DLNMs) which offer a flexible description of the lagged risk response to protracted radon exposure. Exposure-lag functions are implemented with B-Splines in Cox models of proportional hazards. The DLNM approach yielded good agreement of exposure-lag-response surfaces for the German cohort and for the previously studied cohort of American Colorado miners. For both cohorts, a minimum lag of about 2 year for the onset of risk after first exposure explained the data well, but possibly with large uncertainty. Risk estimates from DLNMs were directly compared with estimates from both standard radio-epidemiological models and biologically based mechanistic models. For age > 45 year, all models predict decreasing estimates of the Excess Relative Risk (ERR). However, at younger age, marked differences appear as DLNMs exhibit ERR peaks, which are not detected by the other models. After comparing exposure-responses for biological processes in mechanistic risk models with exposure-responses for hazard ratios in DLNMs, we propose a typical period of 15 year for radon-related lung carcinogenesis. The period covers the onset of radiation-induced inflammation of lung tissue until cancer death. The DLNM framework provides a view on age-risk patterns supplemental to the standard radio-epidemiological approach and to biologically based modeling.


Assuntos
Poluentes Ocupacionais do Ar/análise , Poluentes Radioativos do Ar/análise , Neoplasias Pulmonares/mortalidade , Exposição Ocupacional/estatística & dados numéricos , Radônio , Adulto , Carcinogênese , Estudos de Coortes , Alemanha/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Risco , Fatores de Tempo , Urânio
11.
Radiat Environ Biophys ; 58(4): 539-552, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31346699

RESUMO

Current radiological emergency response recommendations have been provided by the International Commission on Radiological Protection and adopted by the International Atomic Energy Agency in comprehensive Safety Standards. These standards provide dose-based guidance for decision making (e.g., on sheltering or relocation) via generic criteria in terms of effective dose in the range from 20 mSv per year, during transition from emergency to existing exposure situation, to 100 mSv, acute or annual, in the urgent phase of a nuclear accident. The purpose of this paper was to examine how such dose reference levels directly translate into radiation-related risks of the main stochastic detrimental health effects (cancer). Methodologies, provided by the World Health Organization after the Fukushima accident, for calculating the lifetime and 20 year cancer risks and for attributing relevant organ doses from effective doses, have been applied here for this purpose with new software, designed to be available for use immediately after a nuclear accident. A new feature in this software is a comprehensive accounting for uncertainty via simulation technique, so that the risks may now be presented with realistic confidence intervals. The types of cancer risks considered here are time-integrated over lifetime and the first 20 years after exposure for all solid cancers and either the most radiation-sensitive types of cancer, i.e., leukaemia and female breast cancer, or the most radiation-relevant type of cancer occurring early in life, i.e., thyroid. It is demonstrated here how reference dose levels translate differently into specific cancer risk levels (with varying confidence interval sizes), depending on age at exposure, gender, time-frame at-risk and type of cancer considered. This demonstration applies German population data and considers external exposures. Further work is required to comprehensively extend this methodology to internal exposures that are likely to be important in the early stages of a nuclear accident. A discussion is provided here on the potential for such risk-based information to be used by decision makers, in the urgent and transition phases of nuclear emergencies, to identify protective measures (e.g., sheltering, evacuation) in a differential way (i.e., for particularly susceptible sub-groups of a population).


Assuntos
Emergências , Proteção Radiológica/métodos , Humanos , Agências Internacionais , Doses de Radiação , Monitoramento de Radiação , Fatores de Risco
12.
Radiat Environ Biophys ; 58(2): 303, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30799522

RESUMO

The article Dose-responses for mortality from cerebrovascular and heart diseases in atomic bomb survivors: 1950-2003, written by Helmut Schöllnberger.

13.
Radiat Environ Biophys ; 57(1): 17-29, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29222678

RESUMO

The scientific community faces important discussions on the validity of the linear no-threshold (LNT) model for radiation-associated cardiovascular diseases at low and moderate doses. In the present study, mortalities from cerebrovascular diseases (CeVD) and heart diseases from the latest data on atomic bomb survivors were analyzed. The analysis was performed with several radio-biologically motivated linear and nonlinear dose-response models. For each detrimental health outcome one set of models was identified that all fitted the data about equally well. This set was used for multi-model inference (MMI), a statistical method of superposing different models to allow risk estimates to be based on several plausible dose-response models rather than just relying on a single model of choice. MMI provides a more accurate determination of the dose response and a more comprehensive characterization of uncertainties. It was found that for CeVD, the dose-response curve from MMI is located below the linear no-threshold model at low and medium doses (0-1.4 Gy). At higher doses MMI predicts a higher risk compared to the LNT model. A sublinear dose-response was also found for heart diseases (0-3 Gy). The analyses provide no conclusive answer to the question whether there is a radiation risk below 0.75 Gy for CeVD and 2.6 Gy for heart diseases. MMI suggests that the dose-response curves for CeVD and heart diseases in the Lifespan Study are sublinear at low and moderate doses. This has relevance for radiotherapy treatment planning and for international radiation protection practices in general.


Assuntos
Transtornos Cerebrovasculares/mortalidade , Cardiopatias/mortalidade , Armas Nucleares , Lesões por Radiação/mortalidade , Sobreviventes/estatística & dados numéricos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Transtornos Cerebrovasculares/etiologia , Criança , Relação Dose-Resposta à Radiação , Cardiopatias/etiologia , Humanos , Pessoa de Meia-Idade , Lesões por Radiação/etiologia , Adulto Jovem
15.
Carcinogenesis ; 37(12): 1152-1160, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27729373

RESUMO

Strong evidence for the statistical association between radiation exposure and disease has been produced for thyroid cancer by epidemiological studies after the Chernobyl accident. However, limitations of the epidemiological approach in order to explore health risks especially at low doses of radiation appear obvious. Statistical fluctuations due to small case numbers dominate the uncertainty of risk estimates. Molecular radiation markers have been searched extensively to separate radiation-induced cancer cases from sporadic cases. The overexpression of the CLIP2 gene is the most promising of these markers. It was found in the majority of papillary thyroid cancers (PTCs) from young patients included in the Chernobyl tissue bank. Motivated by the CLIP2 findings we propose a mechanistic model which describes PTC development as a sequence of rate-limiting events in two distinct paths of CLIP2-associated and multistage carcinogenesis. It integrates molecular measurements of the dichotomous CLIP2 marker from 141 patients into the epidemiological risk analysis for about 13 000 subjects from the Ukrainian-American cohort which were exposed below age 19 years and were put under enhanced medical surveillance since 1998. For the first time, a radiation risk has been estimated solely from marker measurements. Cross checking with epidemiological estimates and model validation suggests that CLIP2 is a marker of high precision. CLIP2 leaves an imprint in the epidemiological incidence data which is typical for a driver gene. With the mechanistic model, we explore the impact of radiation on the molecular landscape of PTC. The model constitutes a unique interface between molecular biology and radiation epidemiology.


Assuntos
Biomarcadores Tumorais/biossíntese , Carcinoma/genética , Proteínas Associadas aos Microtúbulos/biossíntese , Neoplasias Induzidas por Radiação/genética , Neoplasias da Glândula Tireoide/genética , Adolescente , Adulto , Biomarcadores Tumorais/genética , Carcinoma/epidemiologia , Carcinoma/patologia , Carcinoma Papilar , Acidente Nuclear de Chernobyl , Criança , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Humanos , Masculino , Proteínas Associadas aos Microtúbulos/genética , Neoplasias Induzidas por Radiação/epidemiologia , Neoplasias Induzidas por Radiação/patologia , Câncer Papilífero da Tireoide , Glândula Tireoide/patologia , Glândula Tireoide/efeitos da radiação , Neoplasias da Glândula Tireoide/epidemiologia , Neoplasias da Glândula Tireoide/patologia
16.
Carcinogenesis ; 36(7): 748-56, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25957251

RESUMO

A previous study on papillary thyroid carcinomas (PTC) in young patients who were exposed to (131)iodine from the Chernobyl fallout revealed an exclusive gain of chromosomal band 7q11.23 in exposed cases compared to an age-matched control cohort. CLIP2, a gene located within band 7q11.23 was shown to be differentially expressed between exposed and non-exposed cases at messenger RNA and protein level. Therefore, a standardized procedure for CLIP2 typing of PTCs has been developed in a follow-up study. Here we used CLIP2 typing data on 117 post-Chernobyl PTCs from two cohorts of exposed patients with individual dose estimates and 24 non-exposed controls to investigate a possible quantitative dose-response relationship of the CLIP2 marker. The 'Genrisk-T' cohort consisted of 45 PTCs and the 'UkrAm' cohort of 72 PTCs. Both cohorts differed in mean dose (0.59 Gy Genrisk-T, 1.2 Gy UkrAm) and mean age at exposure (AaE) (2 years Genrisk-T, 8 years UkrAm), whilst the median latency (16 years Genrisk-T, 18 years UkrAm) was comparable. We analyzed the association between the binary CLIP2 typing and continuous thyroid dose with logistic regression. A clear positive dose-response relationship was found for young PTC cases [age at operation (AaO) < 20 years, AaE < 5 years]. In the elder age group a higher proportion of sporadic tumors is assumed due to a negligible dose response, suggesting different molecular mechanisms in sporadic and radiation-induced cases. This is further supported by the association of elder patients (AaO > 20 years) with positivity for BRAF V600E mutation.


Assuntos
Carcinoma/metabolismo , Relação Dose-Resposta à Radiação , Proteínas Associadas aos Microtúbulos/metabolismo , Neoplasias da Glândula Tireoide/metabolismo , Adolescente , Adulto , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma/etiologia , Carcinoma/cirurgia , Carcinoma Papilar , Acidente Nuclear de Chernobyl , Criança , Pré-Escolar , Estudos de Coortes , Humanos , Radioisótopos do Iodo/administração & dosagem , Modelos Logísticos , Proteínas Associadas aos Microtúbulos/genética , Neoplasias Induzidas por Radiação/metabolismo , Neoplasias Induzidas por Radiação/cirurgia , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide/etiologia , Neoplasias da Glândula Tireoide/cirurgia , Adulto Jovem
18.
Radiat Environ Biophys ; 53(2): 391-401, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24398917

RESUMO

Thyroid cancer is one of the major health concerns after the accident in the Fukushima Dai-ichi nuclear power station (NPS). Currently, ultrasonography surveys are being performed for persons residing in the Fukushima Prefecture at the time of the accident with an age of up to 18 years. Here, the expected thyroid cancer prevalence in the Fukushima Prefecture is assessed based on an ultrasonography survey of Ukrainians, who were exposed at an age of up to 18 years to (131)I released during the Chernobyl NPS accident, and on differences in equipment and study protocol in the two surveys. Radiation risk of thyroid cancer incidence among survivors of the atomic bombings of Hiroshima and Nagasaki and preliminary estimates of thyroid dose due to the Fukushima accident were used for the prediction of baseline and radiation-related thyroid cancer risks. We estimate a prevalence of thyroid cancer of 0.027 % (95 % CI 0.010 %; 0.050 %) for the first screening campaign in the Fukushima Prefecture. Compared with the incidence rate in Japan in 2007, the ultrasonography survey is predicted to increase baseline thyroid cancer incidence by a factor of 7.4 (95 % CI 0.95; 17.3). Under the condition of continued screening, thyroid cancer during the first fifty years after the accident is predicted to be detected for about 2 % of the screened population. The prediction of radiation-related thyroid cancer in the most exposed fraction (a few ten thousand persons) of the screened population of the Fukushima Prefecture has a large uncertainty with the best estimates of the average risk of 0.1-0.3 %, depending on average dose.


Assuntos
Coleta de Dados , Acidente Nuclear de Fukushima , Neoplasias Induzidas por Radiação/diagnóstico por imagem , Neoplasias Induzidas por Radiação/epidemiologia , Neoplasias da Glândula Tireoide/diagnóstico por imagem , Neoplasias da Glândula Tireoide/epidemiologia , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Incidência , Lactente , Japão/epidemiologia , Masculino , Risco , Ultrassonografia
19.
Int J Radiat Biol ; 100(7): 982-995, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38718325

RESUMO

PURPOSE: The Organisation for Economic Co-operation and Development (OECD) Adverse Outcome Pathway (AOP) Development Programme is being explored in the radiation field, as an overarching framework to identify and prioritize research needs that best support strengthening of radiation risk assessment and risk management strategies. To advance the use of AOPs, an international horizon-style exercise (HSE) was initiated through the Radiation/Chemical AOP Joint Topical Group (JTG) formed by the OECD Nuclear Energy Agency (NEA) High-Level Group on Low Dose Research (HLG-LDR) under the auspices of the Committee on Radiological Protection and Public Health (CRPPH). The intent of the HSE was to identify key research questions for consideration in AOP development that would help to reduce uncertainties in estimating the health risks following exposures to low dose and low dose-rate ionizing radiation. The HSE was conducted in several phases involving the solicitation of relevant questions, a collaborative review of open-ended candidate questions and an elimination exercise that led to the selection of 25 highest priority questions for the stated purpose. These questions were further ranked by over 100 respondents through an international survey. This final set of questions was judged to provide insights into how the OECD's AOP approach can be put into practice to meet the needs of hazard and risk assessors, regulators, and researchers. This paper examines the 25 priority questions in the context of hazard/risk assessment framework for ionizing radiation. CONCLUSION: By addressing the 25 priority questions, it is anticipated that constructed AOPs will have a high level of specificity, making them valuable tools for simplifying and prioritizing complex biological processes for use in developing revised radiation hazard and risk assessment strategies.


Assuntos
Rotas de Resultados Adversos , Humanos , Medição de Risco , Proteção Radiológica/métodos , Internacionalidade , Lesões por Radiação/prevenção & controle , Lesões por Radiação/etiologia
20.
Radiat Environ Biophys ; 52(1): 17-27, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23124826

RESUMO

A recent analysis of leukaemia mortality in Japanese A-bomb survivors has applied descriptive models, collected together from previous studies, to derive a joint excess relative risk estimate (ERR) by multi-model inference (MMI) (Walsh and Kaiser in Radiat Environ Biophys 50:21-35, 2011). The models use a linear-quadratic dose response with differing dose effect modifiers. In the present study, a set of more than 40 models has been submitted to a rigorous statistical selection procedure which fosters the parsimonious deployment of model parameters based on pairwise likelihood ratio tests. Nested models were consequently excluded from risk assessment. The set comprises models of the excess absolute risk (EAR) and two types of non-standard ERR models with sigmoidal responses or two line spline functions with a changing slope at a break point. Due to clearly higher values of the Akaike Information Criterion, none of the EAR models has been selected, but two non-standard ERR models qualified for MMI. The preferred ERR model applies a purely quadratic dose response which is slightly damped by an exponential factor at high doses and modified by a power function for attained age. Compared to the previous analysis, the present study reports similar point estimates and confidence intervals (CI) of the ERR from MMI for doses between 0.5 and 2.5 Sv. However, at lower doses, the point estimates are markedly reduced by factors between two and five, although the reduction was not statistically significant. The 2.5 % percentiles of the ERR from the preferred quadratic-exponential model did not fall below zero risk in exposure scenarios for children, adolescents and adults at very low doses down to 10 mSv. Yet, MMI produced risk estimates with a positive 2.5 % percentile only above doses of some 300 mSv. Compared to CI from a single model of choice, CI from MMI are broadened in cohort strata with low statistical power by a combination of risk extrapolations from several models. Reverting to MMI can relieve the dilemma of needing to choose between models with largely different consequences for risk assessment in public health.


Assuntos
Leucemia/mortalidade , Modelos Teóricos , Neoplasias Induzidas por Radiação/mortalidade , Armas Nucleares , Adolescente , Adulto , Povo Asiático , Criança , Pré-Escolar , Feminino , Humanos , Japão/epidemiologia , Leucemia/etiologia , Masculino , Pessoa de Meia-Idade , Neoplasias Induzidas por Radiação/etiologia , Risco , Medição de Risco , Sobreviventes , Adulto Jovem
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