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The article reports on a study, which examines the levels of urine Biopyrrins in experimental peritonitis of mice. Urine samples from cecal ligation and puncture (CLP) model of mice were measured at intervals. The levels of urine Biopyrrins were measured by the enzyme linked immunosorbent assay method using the homemade antibilirubin monoclonal antibody. In the group of CLP model, at 2 h after treatment, the level of Biopyrrins began to increase, resulting to reach the peak at 10 h. It is conceivable that, under the condition of increased oxidative stress such as severe peritonitis, the host may accelerate the productivify of bilirubin.

The T cell aging process can be modified by genotoxic factors, including ionizing radiation, and metabolic controls, such as caloric restriction; the former accelerates and the latter retards the process. However, the mechanisms by which these systemic factors interact to cause T cell aging remain unclear. This study investigated the naïve T-cell pool, thymic cellularity, and transcriptome in mice irradiated with 3.8 Gy at 5 weeks of age and treated 13 months later with 30 mM spermidine (SPD), a metabolism regulator. The number of conventional naïve CD4 and CD8 T cells in the peripheral blood decreased 14 months after irradiation whereas the number of virtual memory naïve T cells, which increased with age, further increased by irradiation. However, these radiation-related changes were not significant in similarly irradiated mice that were subsequently treated with SPD. The numbers of total, double-positive, and single-positive thymocytes were decreased by irradiation, whereas none were decreased in the irradiated mice treated with SPD. RNA sequencing of thymus cells revealed 803 upregulated genes in irradiated mice compared with those in non-irradiated control mice, with these genes enriched in leukocyte activation and inflammatory cytokine production. However, only 22 genes were upregulated in irradiated and SPD-treated mice, suggesting a reversal of many radiation-induced gene expression changes. These findings suggest that SPD may alleviate radiation-induced acceleration of T-cell aging, particularly by mitigating reduced thymopoiesis and inflammation. Further research is warranted to explore the rejuvenating potential of SPD and its mechanisms of action in accelerated T-cell aging., (Copyright © 2024. Published by Elsevier Inc.)

In estimating radiation-related risk of cancer and other diseases based on the RERF Life Span Study (LSS), joint analyses can be performed where multiple health outcome endpoints are combined in the same model, allowing some parameters to be estimated in common among all endpoints with possible increase in precision of radiation risk and other model parameter estimates. Using as a basis excess relative risk (ERR) and excess absolute risk (EAR) models of the type commonly used in analysis of LSS data at RERF, we use maximum likelihood theory to compute the asymptotic relative standard error of endpoint-specific radiation effect and other parameter estimates using joint analyses as compared to traditional independent analysis. We show that some gains in precision of endpoint-specific radiation risk parameter estimates can be achieved by sharing effect modifier and other model parameters, but only small or negligible gains in precision are achieved for endpoint-specific background modifying or effect modifying parameters when other model parameters are shared. The magnitude of the precision gain for radiation risk estimates depends on the number of endpoints, the baseline incidence rate of the endpoint, and the type of model being used., (© 2024. The Author(s).)

The Planning and Acting Network for Low Dose Radiation Research in Japan (PLANET) was established in 2017 in response to the need for an all-Japan network of experts. It serves as an academic platform to propose strategies and facilitate collaboration to improve quantitative estimation of health risks from ionizing radiation at low-doses and low-dose-rates. PLANET established Working Group 1 (Dose-Rate Effects in Animal Experiments) to consolidate findings from animal experiments on dose-rate effects in carcinogenesis. Considering international trends in this field as well as the situation in Japan, PLANET updated its priority research areas for Japanese low-dose radiation research in 2023 to include (i) characterization of low-dose and low-dose-rate radiation risk, (ii) factors to be considered for individualization of radiation risk, (iii) biological mechanisms of low-dose and low-dose-rate radiation effects and (iv) integration of epidemiology and biology. In this context, PLANET established Working Group 2 (Dose and Dose-Rate Mapping for Radiation Risk Studies) to identify the range of doses and dose rates at which observable effects on different endpoints have been reported; Working Group 3 (Species- and Organ-Specific Dose-Rate Effects) to consider the relevance of stem cell dynamics in radiation carcinogenesis of different species and organs; and Working Group 4 (Research Mapping for Radiation-Related Carcinogenesis) to sort out relevant studies, including those on non-mutagenic effects, and to identify priority research areas. These PLANET activities will be used to improve the risk assessment and to contribute to the revision of the next main recommendations of the International Commission on Radiological Protection., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Hypertension is an uncommon manifestation of Behcet's disease, which is also an uncommon cause of renovascular hypertension. We herein report a case of malignant hypertension associated with unilateral renal artery stenosis due to vascular Behcet's disease. A 19-year-old man, who had no significant medical history, was referred to ophthalmology at our hospital because he was suspected to have uveitis and Vogt-Koyanagi-Harada syndrome. In addition to poor eyesight, he had been aware of a fever, loss of appetite, and weight loss for a month. He was admitted with markedly elevated blood pressure (222/140 mmHg), hypertensive retinopathy, and acute kidney injury, who was diagnosed with malignant hypertension. Laboratory findings showed high plasma renin activity and plasma aldosterone concentration, hypokalemia, and elevated inflammatory response. Computed tomography showed an atrophic right kidney and a compensatorily enlarged left kidney. Renal computed tomography angiography revealed severe and diffuse stenosis of the right renal artery, and stenosis of the ostium of celiac artery. Since he was suspected to have uveitis and his inflammatory responses were elevated on admission, we listed Behcet's disease as a differential diagnosis. Medical interview and examination focusing on Behcet's disease revealed that the patient had recurrent oral aphthous lesions and folliculitis, and a positive pathergy test, which led to the patient being diagnosed with vascular Behcet's disease. After admission, his blood pressure was well controlled with multiple antihypertensive drugs including an angiotensin receptor/neprilysin inhibitor, and his oral aphthous lesions and skin lesion were improved with colchicine. When young men who are at a higher risk for vascular Behcet's disease show renovascular hypertension with an elevated inflammatory reaction, vascular Behcet's disease should be considered as a differential diagnosis., (© 2024. The Author(s), under exclusive licence to Japanese Society of Nephrology.)

The numbers of naive T cells that react to novel pathogens not yet encountered by an immune system, decrease during aging, mainly due to age-associated involution of the thymus. CD45RA+ naive CD4 T cells consist of heterogeneous populations, including highly CXCR3-expressing cells that appear during the homeostatic proliferation of naive T cells and exhibit enhanced type-1 inflammatory phenotypes. Based on previous evidence of radiation-associated reductions in thymic function and peripheral blood naive CD4 T cells, we hypothesized that the homeostatic proliferation of naive CD4 T cells compensates for deficits in peripheral T-cell populations after radiation injury, which may increase the proportion of CXCR3high cells in naive CD4 T cells and enhance inflammation. The statistical models employed in this study revealed positive associations between the number of CXCR3high naive CD4 T cells and age as well as radiation dose among 580 Hiroshima atomic bomb survivors. In addition, the CXCR3high cells in these survivors increased not only with the levels of homeostatic cytokines, IL6 and IL7, but also with those of inflammatory indicators, CXCL10 and CRP. These results suggest that thymic T-cell production deficiency due to radiation and aging results in enhanced homeostatic proliferation that drives the appearance of CXCR3high naive CD4 T cells poised for an inflammatory response. Molecular mechanisms and clinical relevance of increasing CXCR3high cells in naive CD4 T populations should be further investigated in the context of inflammatory disease development long after radiation exposure., (© 2024 by Radiation Research Society.)

Although some adverse effects on neurocognitive function have been reported in children and adolescents irradiated prenatally during the atomic bombings and the Chernobyl nuclear accident, little information is available for effects on the elderly. Here we evaluate the effects of prenatal exposure to atomic bomb radiation on subjective neurocognitive function in aged survivors. To evaluate neurocognitive impairment, we mailed the Neurocognitive Questionnaire (NCQ), a self-administered scale, to prenatally exposed survivors, including clinic visitors and non-visitors at the time of the 2011 and 2013 Adult Health Study (AHS) examinations. We received replies from 444 individuals (mean age, 66.9 ± 0.6 years). After adjusting for sex, city, and educational background, we found no significant effects of radiation, clinic visit, or interaction between radiation and clinic visit on the scores of the 4 NCQ factors of metacognition, emotional regulation, motivation/organization, and processing speed. Even in analyses considering gestational age at the time of the bombings, none of the 4 NCQ factor scores was related to maternal uterine dose. There remains the limitation that this study consisted of healthy survivors, but we found no significant radiation effect on late-life cognition in people prenatally exposed to atomic bomb radiation., (©2023 by Radiation Research Society. All rights of reproduction in any form reserved.)

Background: In case-cohort studies with binary outcomes, ordinary logistic regression analyses have been widely used because of their computational simplicity. However, the resultant odds ratio estimates cannot be interpreted as relative risk measures unless the event rate is low. The risk ratio and risk difference are more favorable outcome measures that are directly interpreted as effect measures without the rare disease assumption., Methods: We provide pseudo-Poisson and pseudo-normal linear regression methods for estimating risk ratios and risk differences in analyses of case-cohort studies. These multivariate regression models are fitted by weighting the inverses of sampling probabilities. Also, the precisions of the risk ratio and risk difference estimators can be improved using auxiliary variable information, specifically by adapting the calibrated or estimated weights, which are readily measured on all samples from the whole cohort. Finally, we provide computational code in R (R Foundation for Statistical Computing, Vienna, Austria) that can easily perform these methods., Results: Through numerical analyses of artificially simulated data and the National Wilms Tumor Study data, accurate risk ratio and risk difference estimates were obtained using the pseudo-Poisson and pseudo-normal linear regression methods. Also, using the auxiliary variable information from the whole cohort, precisions of these estimators were markedly improved., Conclusion: The ordinary logistic regression analyses may provide uninterpretable effect measure estimates, and the risk ratio and risk difference estimation methods are effective alternative approaches for case-cohort studies. These methods are especially recommended under situations in which the event rate is not low.

Female sex in patients with atrial fibrillation (AF) is a controversial and paradoxical risk factor for stroke-controversial because it increases the risk of stroke only among older women of some ethnicities and paradoxical because it appears to contradict male predominance in cardiovascular diseases. However, the underlying mechanism remains unclear. We conducted simulations to examine the hypothesis that this sex difference is generated non-causally through left truncation due to competing risks (CR) such as coronary artery diseases, which occur more frequently among men than among women and share common unobserved causes with stroke. We modeled the hazards of stroke and CR with correlated heterogeneous risk. We assumed that some people died of CR before AF diagnosis and calculated the hazard ratio of female sex in the left-truncated AF population. In this situation, female sex became a risk factor for stroke in the absence of causal roles. The hazard ratio was attenuated in young populations without left truncation and in populations with low CR and high stroke incidence, which is consistent with real-world observations. This study demonstrated that spurious risk factors can be identified through left truncation due to correlated CR. Female sex in patients with AF may be a paradoxical risk factor for stroke.

We describe two patients with primary diffuse large B-cell lymphoma of the central nervous system (PCNS-DLBCL). The first patient (case 1) was a woman in her late 70s who presented with a tumor in the left frontal lobe, whereas the second patient (case 2) was a man in his early 70s who presented with a left frontal lobe tumor associated with intratumoral hemorrhage. The histopathology of the tumor specimen disclosed the proliferation of large cells with centroblastic (case 1) or immunoblastic/plasmablastic (case 2) cytomorphology and an accumulation of the tumor cells within the perivascular space. The cells in both cases were positive for CD20, CD79a, BCL6, IRF4/MUM1, MYC, and BCL2 and negative for CD5 and CD10. G-banding revealed t(8;14)(q24;q32) in case 1, and the tetraploid-range karyotype including two or three copies of der(3)t(3;14)(q27;q32) and der(14)t(3;14)(q27;q32) in case 2. Fluorescence in situ hybridization applied to metaphase spreads confirmed colocalization of MYC and IGH (case 1) and BCL6 and IGH (case 2) hybridization signals on the relevant derivative chromosomes. Case 1 carried the MYD88 L265P mutation. This case report provides clear evidence for the occurrence of t(8;14)(q24;q32) and t(3;14)(q27;q32) in PCNS-DLBCL using metaphase-based cytogenetic analysis.

Glycoside hydrolase family 12 endocellulase (GH family12) plays a key role in the degradation of β-glucan and cellulose. Hyperthermostable GH family 12 endocellulase from the archaeon Pyrococcus furiosus (EGPf) catalyzes the hydrolysis of β(1 → 4) glucosidic linkages in cellulose and β-glucan containing β(1 → 3),(1 → 4) mixed-linkages. Therefore, in the combination with the hyperthermophilic β-glucosidase from P. furiosus (BGLPf), non-crystalline cellulose and β-glucan can be degraded to glucose completely by EGPf at high temperature. X-ray crystallography and protein engineering were used to reveal how the β(1 → 4) and β(1 → 3) linkages in β-glucan substrates are recognized by the enzyme. Structural and functional analyses clarified that the active site of EGPf consists of six subsites: the reducing end subsites (+1 and + 2) recognize both β(1 → 4) and β(1 → 3) linkages of various substrates in a productive binding mode, and recognition is controlled by Trp121 and Gln208 located at subsite +2. It was also revealed that the deep cleft in subsite -4 can accommodate the torsion angles of substrates consisting of β(1 → 3),(1 → 4) mixed-linkages due to the changing tilt of the Trp62 side chain. From the structural similarity, it is proposed that the substrate specificity of family 12 endocellulases towards β(1 → 3),(1 → 4) mixed-linkage substrates are controlled by the subsites (+1, +2, and -4). Furthermore, the function of family 12 endocellulase could be improved by protein engineering method using the information of the analysis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Clonal hematopoiesis (CH) is prevalent in the elderly and associates with hematologic malignancy and cardiovascular disease. Although the risk of developing these diseases increases with radiation doses in atomic-bomb survivors, the causal relationship between radiation exposure and CH is unclear. This study investigated whether radiation exposure induces CH in mice 12-18 months after 3-Gy whole-body irradiation. We found radiation-associated increases in peripheral blood myeloid cells and red blood cell distribution width (RDW). Deep sequencing of bone marrow and non-hematopoietic tissue cells revealed recurrent somatic mutations specifically in the hematopoietic system in 11 of 12 irradiated mice but none in 6 non-irradiated mice. The irradiated mice possessed mutations with variant allele frequencies (VAFs) of > 0.02 on an average of 5.8 per mouse; mutations with VAFs of > 0.1 and/or deletion were prevalent. Examining hematopoietic stem/progenitor cells in two irradiated mice revealed several mutations co-existing in the same clones and multiple independent clones that deliver 60-80% of bone marrow nuclear cells. Our results indicate development of massive CH due to radiation exposure. Moreover, we have characterized mutations in radiation-induced CH., (© 2022. The Author(s).)

A new species and an already known species of the genus Anchistrocheles Brady & Norman, 1889 from the Pacific coast of Japan, are described in detail using scanning electron microscopy of the carapaces and soft-part anatomy of the appendages. The new species, Anchistrocheles hayatotanakai sp. nov., is only the second to be described in the genus Anchistrocheles from Japan, and this study is also the first to describe the appendages of A. yamaguchii Yajima, 1987, previously only known as a fossil from Pleistocene strata of the Atsumi Formation in central Japan. The two species are considered to be closely related because they share many common characters in their appendages, but they are distinguishable from each other based on the male and female copulatory organs, furcal chaetotaxy, brush-shaped organs, number of lateral pore systems, and outlines of the carapaces in dorsal view. Ontogenetic changes of carapace sizes were compared between three interstitial species (Anchistrocheles hayatotanakai sp. nov., A. yamaguchii, and Neonesidea sp. I) and an epifaunal species (N. sp. S). The reduction in carapace width was found to be the primary reason for the reduction in the cross-sectional area and is probably related to the adaptation to interstitial environments. The brush-shaped organs located between the 6th pair of limbs are also shown. This study is the first to report the anatomically precise position of these organs.

High-dose radiation in childhood such as is used in radiation therapy causes cognitive decline, but there is insufficient research on the cognitive effects of low- to medium-dose radiation. We aimed to reveal the association between atomic bomb radiation exposure in childhood and late-life neurocognitive function. In 2011 and 2013, we mailed the Neurocognitive Questionnaire (NCQ) to subjects who were 12 years old or younger at the time of the atomic bombing. We converted the four NCQ subscales (metacognition, emotional regulation, motivation/organization, and processing speed) to T scores and defined the highest 10% of the controls (exposure dose < 5 mGy) as impaired. We used a generalized linear mixed model to evaluate the effect of radiation exposure on T scores and percentage impaired. We enrolled 859 participants. At the time of the bombing, the mean (SD) age was 6.7 (3.8) years for the control (N = 390) and 6.1 (3.8) years for the exposed (N = 469). At the time of replying to the questionnaire, the mean age of all the participants was 73.7 (3.8) years of age. After adjusting for cofactors, older age was related to the decline of all neurocognitive subscales. Sex and education level had relevance to some of the subscales. For neurocognitive function, exposure dose was not related except to percentage impaired, motivation/organization. Late-life neurocognitive function in atomic bomb survivors exposed as children was associated with age, but not clearly with radiation dose. More studies are needed to evaluate the effect of low-dose radiation during childhood on long-term neurocognitive function., (©2022 by Radiation Research Society. All rights of reproduction in any form reserved.)

A previous study of peripheral blood lymphocyte translocations around age 40 among atomic-bomb survivors exposed in utero revealed no overall association with radiation dose-despite a clear association between translocations and dose among their mothers-but the data suggested an increase at doses below 100 mGy with a definite peak. That analysis of the in utero-exposed survivors did not adjust for their subsequent smoking behavior, an established cause of chromosomal aberrations, or their subsequent exposures to medical irradiation, a potential mediator. In addition, atomic-bomb survivor radiation dose estimates have subsequently been updated and refined. We therefore re-estimated the dose response using the latest DS02R1 dose estimates and adjusting for smoking as well as for city and proximal-distal location at the time of exposure to the atomic bomb. Sex of the survivor, mother's age around the time of conception, and approximate trimester of gestation at the time of exposure were also considered as explanatory variables and modifiers. Precision of the estimated dose response was slightly lower due to greater variability near zero in the updated dose estimates, but there was little change in evidence of a low-dose increase and still no suggestion of an overall increase across the entire dose range. Adjustment for smoking behavior led to a decline in background number of translocations (the dose-response intercept), but smoking did not interact with dose overall (across the entire dose range). Adjustment for medical irradiation did not alter the association between dose and translocation frequency. Sex, mother's age, and trimester were not associated with number of translocations, nor did they interact with dose overall. Interactions with dose in the low-dose range could not be evaluated because of numerical instability., (© 2022. The Author(s).)

Norovirus continues to evolve, adjusting its pathogenesis and transmissibility. In the present study, we systematically collected datasets on Norovirus outbreaks in Japan from 2005 to 2019 and analyzed time-dependent changes in the asymptomatic ratio, the probability of virus detection, and the probability of infection given exposure. Reports of 1,728 outbreaks were published, and feces from all involved individuals, including those with asymptomatic infection, were tested for virus in 434 outbreaks. We found that the outbreak size did not markedly change over this period, but the variance in outbreak size increased during the winter (November-April). Assuming that natural history parameters did not vary over time, the asymptomatic ratio, the probability of virus detection, and the probability of infection given exposure were estimated to be 18.6%, 63.3% and 84.5%, respectively. However, a model with time-varying natural history parameters yielded better goodness-of-fit and suggested that the asymptomatic ratio varied by year. The asymptomatic ratio was as high as 25.8% for outbreaks caused by genotype GII.4 noroviruses. We conclude that Norovirus transmissibility has not changed markedly since 2005, and that yearly variation in the asymptomatic ratio could potentially be explained by the circulating dominant genotype., Competing Interests: Hiroshi Nishiura is an Academic Editor for PeerJ. Otherwise the authors declare that they have no competing interests., (© 2021 Misumi and Nishiura.)

Past reports indicated that total-body irradiation at low to moderate doses could be responsible for cardiovascular disease risks, but the mechanism remains unclear. The purpose of this study was to investigate the association between radiation exposure and atherosclerosis, an underlying pathology of cardiovascular diseases, in the Japanese atomic bomb survivors. We performed a cross-sectional study measuring 14 clinical-physiological atherosclerosis indicators during clinical exams from 2010 to 2014 in 3274 participants of the Adult Health Study cohort. Multivariable analyses were performed by using a structural equation model with latent factors representing underlying atherosclerotic pathologies: (1) arterial stiffness, (2) calcification, and (3) plaque　as measured with indicators chosen a priori on the basis of clinical-physiological knowledge. Radiation was linearly associated with calcification (standardized coefficient per Gy 0.15, 95 % confidence interval: CI [0.070, 0.23]) and plaque (0.11, 95 % CI [0.029, 0.20]), small associations that were comparable to about 2 years of aging per Gy of radiation exposure, but not with arterial stiffness (0.036, 95 % CI [- 0.025, 0.095]). The model fitted better and had narrower confidence intervals than separate ordinary regression models explaining individual indicators independently. The associations were less evident when the dose range was restricted to a maximum of 2 or 1 Gy. By combining individual clinical-physiological indicators that are correlated because of common, underlying atherosclerotic pathologies, we found a small, but significant association of radiation with atherosclerosis.

Red blood cell distribution width (RDW), which generally increases with age, is a risk marker for morbidity and mortality in various diseases. We investigated the association between elevated RDW and prior radiation exposure by examining longitudinal RDW changes in 4204 atomic-bomb survivors over 15 years. A positive association was found between RDW and radiation dose, wherein RDW increased by 0·18%/Gy. This radiation-associated effect increased as the participants aged. Elevated RDW was also associated with higher all-cause mortality. The biological mechanisms underlying these observed associations merit further investigation., (© 2020 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

We examined the mortality risks among 2463 individuals who were exposed in utero to atomic bomb radiation in Hiroshima or Nagasaki in August 1945 and were followed from October 1950 through 2012. Individual estimates of mother's weighted absorbed uterine dose (DS02R1) were used. Poisson regression method was used to estimate the radiation-associated excess relative risk per Gy (ERR/Gy) and 95% confidence intervals (CI) for cause-specific mortality. Head size, birth weight, and parents' survival status were evaluated as potential mediators of radiation effect. There were 339 deaths (216 males and 123 females) including deaths from solid cancer (n = 137), lymphohematopoietic cancer (n = 8), noncancer disease (n = 134), external cause (n = 56), and unknown cause (n = 4). Among males, the unadjusted ERR/Gy (95% CI) was increased for noncancer disease mortality (1.22, 0.10-3.14), but not for solid cancer mortality (- 0.18, < - 0.77-0.95); the unadjusted ERR/Gy for external cause mortality was not statistically significant (0.28, < - 0.60-2.36). Among females, the unadjusted ERRs/Gy were increased for solid cancer (2.24, 0.44-5.58), noncancer (2.86, 0.56-7.64), and external cause mortality (2.57, 0.20-9.19). The ERRs/Gy adjusted for potential mediators did not change appreciably for solid cancer mortality, but decreased notably for noncancer mortality (0.39, < - 0.43-1.91 for males; 1.48, - 0.046-4.55 for females) and external cause mortality (0.10, < - 0.57-1.96 for males; 1.38, < - 0.46-5.95 for females). In conclusion, antenatal radiation exposure is a consistent risk factor for increased solid cancer mortality among females, but not among males. The effect of exposure to atomic bomb radiation on noncancer disease and external cause mortality among individuals exposed in utero was mediated through small head size, low birth weight, and parental loss.

Purpose: Thyroid cancer of papillary histology (PTC) is the dominant type in radio-epidemiological cohorts established after nuclear accidents or warfare. Studies on post-Chernobyl PTC and on thyroid cancer in the life span study (LSS) of Japanese a-bomb survivors consistently revealed high radiation risk after exposure during childhood and adolescence. For post-Chernobyl risk assessment overexpression of the CLIP2 gene was proposed as molecular biomarker to separate radiogenic from sporadic PTC. Based on such binary marker a biologically-based risk model of PTC carcinogenesis has been developed for observational Chernobyl data. The model featured two independent molecular pathways of disease development, of which one was associated with radiation exposure. To gain credibility the concept for a mechanistic risk model must be based on general biological features which transcend findings in a single cohort. The purpose of the present study is therefore to demonstrate portability of the model concept by application to PTC incidence data in the LSS. By exploiting the molecular two-path concept we improve the determination of the probability of radiation causing cancer (POC)., Materials and Methods: The current analysis uses thyroid cancer incidence data of the LSS with thyroid cancer diagnoses and papillary histology ( n  = 292) from the follow-up period between 1958 and 2005. Risk analysis was performed with both descriptive and biologically-based models., Results: Judged by goodness-of-fit all applied models described the data almost equally well. They yielded similar risk estimates in cohorts post-Chernobyl and LSS. The preferred mechanistic model was selected by biological plausibility. It reflected important features of an imperfect radiation marker which are not easily addressed by descriptive models. Precise model predictions of marker prevalence in strata of epidemiological covariables can be tested by molecular measurements. Application of the radiation-related molecular pathway from our preferred model in retrospective risk assessment decreases the threshold dose for 50% POC from 0.33 (95% confidence interval (CI) 0.18; 0.64) Gy to 0.04 (95% CI 0.01; 0.19) Gy for females and from 0.43 (95% CI 0.17; 1.84) Gy to 0.19 (95% CI 0.05; 1.00) Gy for males. These improvements are still not sufficient to separate radiation-induced from sporadic PTC cases at very low doses <0.015 Gy typical for the Fukushima accident., Conclusions: Successful application of our preferred mechanistic model to LSS incidence data confirms and improves the biological two-path concept of radiation-induced PTC. Model predictions suggest further molecular validation studies to consolidate the basis of biologically-based risk estimation.