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Modern hormone replacement therapy for endocrine disorders cannot reproduce the complex interactions of hormones. Cell transplantation is a more physiological approach to the treatment of endocrine gland dysfunction. The data obtained indicate the effectiveness of the stem cells (SCs) use for the treatment of endocrine diseases and, first of all, type 1 diabetes. SCs are cells with clonogenic potential that can repair themselves and differentiate into different types of cells. They are responsible for the regeneration and development of organs and tissues. SCs provide many opportunities for regenerative medicine and serve as a promising model system for studying the early stages of human embryo development. Many molecular mechanisms underlying SCs self-repair and carcinogenesis have been elucidated. The main signaling pathways involved in SCs are JAK/STAT (Janus kinase/signal transducer and activator of transcription), Notch, MAPK/ERK, PI3K/Akt, NF-κB, Wnt, Hedgehog (Hh), TGF-β (transforming growth factor beta) and Hippo, and analysis of their status and sequence of activation, suppression and interaction is important in the context of SCs functioning. The differentiation process of a pluripotent cell in vitro has a low efficiency. Many differentiated cells are characterized by dysregulated signaling pathways, and molecular markers for each stage of the differentiation process have not yet been identified. The development of protocols for the differentiation of pluripotent cells into β-cells that produce insulin in vitro, and their transplantation, engraftment in the body requires a clear understanding of the involvement and cross-interaction of a range of cell signaling systems. Studies of the signaling network required to maintain stemness have identified a strong correlation of these pathways with cancer signaling pathways, as well as the general cellular properties of embryonic SCs and cancer cells, which cannot be dismissed as coincidence. Studying these parallels will inevitably affect both clinical and fundamental sciences. Key words: stem cells, signaling pathways.

This study revised the thyroid doses for 2582 Ukrainian in utero cohort members exposed to Chornobyl fallout (the Ukrainian in utero cohort) based on revision of: (i) 131I thyroid activity measured in the Ukrainian population, (ii) thyroid dosimetry system for entire Ukraine, and (iii) 131I ground deposition densities in Ukraine. Other major improvements included: (i) assessment of uncertainties in the thyroid doses considering shared and unshared error, and (ii) accounting for intake of short-lived radioisotopes of tellurium and iodine (132Te+132I and 133I). Intake of 131I was the major pathway for thyroid exposure, its median contribution to the thyroid dose was 97.4%. The mean prenatal and postnatal thyroid dose from 131I was 87 mGy (median = 17 mGy), higher than previous deterministic dose of 72 mGy (median = 12 mGy). For 39 individuals (1.5%) the dose exceeded 1.0 Gy, while the highest dose among the cohort members was 2.7 Gy. The geometric standard deviation (GSD) of 1000 individual stochastic doses varied from 1.9 to 5.2 with a mean of 3.1 and a median of 3.2. The lowest uncertainty (mean GSD = 2.3, median GSD = 2.2) was found for the subjects whose mothers were measured for 131I thyroid activity, while for individuals, whose mothers were not measured, the mean and median GSDs were 3.4. Uncertainties in thyroid doses were driven by shared errors associated with the parameters of the ecological model.

Thyroid doses from intake of radioiodine isotopes (131I, 132Te+132I, and 133I) and associated uncertainties were revised for the 13,204 Ukrainian-American cohort members exposed in childhood and adolescence to fallout from the Chornobyl nuclear power plant accident. The main changes related to the revision of the 131I thyroid activity measured in cohort members, the use of thyroid-mass values specific to the Ukrainian population, and the revision of the 131I ground deposition densities in Ukraine. Uncertainties in doses were assessed considering shared and unshared errors in the parameters of the dosimetry model. Using a Monte-Carlo simulation procedure, 1,000 individual stochastic thyroid doses were calculated for each cohort member. The arithmetic mean of thyroid doses from intake of 131I, 132Te+132I, and 133I for the entire cohort was 0.60 Gy (median = 0.22 Gy). For 9,474 subjects (71.6% of the total), the thyroid doses were less than 0.5 Gy. Thyroid doses for 42 cohort members (0.3% of the total) exceeded 10 Gy while the highest dose was 35 Gy. Intake of 131I contributed around 95% to internal thyroid exposure from radioiodine isotopes. The geometric standard deviation of individual stochastic thyroid doses varied among cohort members from 1.4 to 4.3 with an arithmetic mean of 1.6 and a median of 1.4. It was shown that the contribution of shared errors to the dose uncertainty was small. The revised thyroid doses resulted, in average, in around 40% decrease for cohort members from Zhytomyr Oblast and an increase of around 24% and 35% for the cohort members from Kyiv and Chernihiv Oblast, respectively. Arithmetic mean of TD20 doses for the cohort was around 8% less than that estimated in TD10, 0.60 Gy vs. 0.65 Gy, respectively; however, global median of TD20 doses somewhat increased compared to TD10: 0.22 Gy vs. 0.19 Gy, respectively. The difference between TD10 and TD20 was mainly due to a revision of the individual 131I thyroid activity measured in the cohort members.

The review of the literature summarizes and analyzes the material on inflammatory processes accompanying cardiovascular complications in diabetes mellitus. The role of endothelial dysfunction is shown leading to an increase in the permeability of the endothelium, accumulation of lipoproteins in the vessel wall, their modification, formation and secretion of cell adhesion molecules, which in turn leads to involvement of monocytes and their differentiation into inflammatory macrophages. The role of scavenger receptors in the deposition of cholesterol and the formation of foam cells was noted. The mechanisms of the inflammatory process initiation and the formation of inflammasоmes are considered in detail. The scheme of transduction of proinflammatory signals in the cell and participation of the key factor NF-κB integrating all incoming information and controlling the transactivation of genes involved in inflammation are described. It is shown that inflammation is key process in the development of vascular diseases in diabetes mellitus, and the suppression of these processes inhibits the progression of the disease reducing arterial damage and contributing to their healing.

Наведені історичні факти становлення медицини як науки з акцентом на розвиток ендокринології. В історичному плані з’ясована роль досліджень іноземних і вітчизняних учених та їхній внесок у розвиток хімії гормонів. З’ясована роль навчальних закладів, академій у формуванні світогляду майбутніх науковців, просуванні передового досвіду. Показано, як поступово накопичувалися знання з медицини: опис клінічних проявів, визначення лабораторних відмінностей. Можливість надання людині з ендокринним захворюванням патогенетично обґрунтованого лікування з’явилась у більшості випадків тільки після розвитку промислового синтезу гормональних препаратів. Праці багатьох учених відзначені Нобелівською премією за досягнення в галузі медицини та фізіології. Наведено визначення поняття «гормон», класифікацію, місця біосинтезу, особливості секреції, промисловий синтез деяких гормонів і сфери використання. Особлива увага приділяється опису нових методів синтезу тироксину, флутафарму та інших речовин.

The article describes the current understanding of the pathogenesis of different types of thyroid nodules. An algorithm for the diagnosis of thyroid diseases, which is aimed at verifying the morphological structure of goiter before the start of treatment, is presented in order to make the right decision on the indications for surgical treatment and its scope. The main methods for both conservative and surgical treatment of thyroid nodules are considered. The features of the treatment of pregnant women with thyroid nodules have been determined.

Background: A significant increase in the incidence of papillary thyroid carcinoma (PTC) in subjects exposed to radiation at a young age is a well-documented health consequence of the Chernobyl accident. The ongoing Thyroid Ultrasound Examination (TUE) program in children and adolescents of Fukushima Prefecture in Japan also indicated a high prevalence of PTC although its attribution to radiation exposure is a subject of debate. The objective of this study was to perform histopathological analysis of tumor architecture and invasive properties in (i) radiogenic post-Chernobyl and sporadic PTCs from Ukraine, and (ii) PTCs in patients from Fukushima and other Prefectures of Japan of comparable age groups. Methods: The Ukrainian radiogenic PTCs included 245 PTCs from patients who resided in three highly 131I-contaminated regions and 165 sporadic PTCs diagnosed in residents of the same regions who were born after the accident and therefore not exposed to radioiodine. The Japanese series included 115 PTCs detected during the preliminary and the first full-scale surveys of the TUE in Fukushima and 223 PTCs from patients resident in other Prefectures. All of the subjects were included in the main statistical analysis. Three additional analyses were performed limiting the subjects to children, adolescents, and adults. Results: Ukrainian radiogenic PTC was characterized by the higher frequency of tumors with a dominant solid-trabecular growth pattern and higher invasiveness, more frequent extrathyroidal extension, lymphatic/vascular invasion, regional and distant metastases when compared with sporadic Ukrainian PTC. The integrative "invasiveness score," based on five cancer characteristics, was also higher in the radiogenic group. The differences were most pronounced in children. In contrast, no significant differences in tumor morphology or invasiveness were observed between the two Japanese groups or the three age subgroups. The only statistically significant findings were the higher proportion of male patients, smaller mean tumor size, and higher frequency of T1b tumors in the Fukushima group. Conclusions: The difference in morphological features that indicate biological behavior of PTC between the radiation-related and sporadic groups from Ukraine, together with the lack of such in the two groups from Japan, strongly suggest a nonradiogenic etiology of PTC from Fukushima and other Prefectures.

Background The radiation-related risk of breast cancer among women following the Chornobyl accident remains uncertain. During pregnancy, there is rapid cell proliferation in the breast while radioactive iodine from fallout exposure can concentrate in lactating breast tissues. Methods We conducted a standardized incidence ratio (SIR) analysis of breast cancer in a cohort of 2,631 women who were lactating and/or pregnant at any time during the two-month period of radioiodine fallout (April 26, 1986 - June 30, 1986). There were 37,151 person-years of follow-up, and 26 incident breast cancers were identified through linkage with the National Cancer Registry of Ukraine. Breast cancer rates among pregnant or lactating women were compared to the general population rates, and SIRs were adjusted for oblast, urban/rural, age, and calendar year. Results The SIR was non-significantly elevated for women lactating at the time of accident (SIR = 1.30, 95% CI: 0.40; 3.01), but not for women initiating lactation within the two months of the accident (SIR = 0.82, 95% CI: 0.32; 1.65) or women pregnant at the time of the accident (SIR = 0.75, 95% CI: 0.44; 1.18). Conclusions The increased SIR for breast cancer among lactating women is consistent with the results of a similar study in Belarus and indicates the need to quantify the radiation risk of breast cancer in a larger study of women lactating during the period of fallout exposure.

The radiation-related risk of breast cancer among women following the Chornobyl accident remains uncertain. During pregnancy, there is rapid cell proliferation in the breast while radioactive iodine from fallout exposure can concentrate in lactating breast tissues. We conducted a standardized incidence ratio (SIR) analysis of breast cancer in a cohort of 2,631 women who were lactating and/or pregnant at any time during the 2-month period of radioiodine fallout (April 26, 1986-June 30, 1986). There were 37,151 person-years of follow-up, and 26 incident breast cancers were identified through linkage with the National Cancer Registry of Ukraine. Breast cancer rates among pregnant or lactating women were compared to the general population rates, and SIRs were adjusted for oblast, urban/rural, age, and calendar year. The SIR was not significant for women pregnant at the time of the accident (SIR = 0.75; 95% CI 0.44, 1.18) or for women lactating anytime within 2 months of the accident (SIR = 0.96; 95% CI 0.48, 1.68). However, there was a non-significantly elevated risk for women lactating at the time of accident (SIR = 1.30, 95% CI 0.40, 3.01). The increased SIR for breast cancer among lactating women is consistent with the results of a similar study in Belarus and indicates the need to quantify the radiation risk of breast cancer in a larger study of women lactating during the period of fallout exposure.

Histopathological changes in the fusion oncogene-driven papillary thyroid carcinomas (PTCs) from children and adolescents exposed to Chernobyl fallout have been extensively studied. However, characteristics of the radiogenic BRAFV600E-positive PTCs, whose proportion is growing with time, are not well described yet. We analyzed the relationship between the BRAFV600E status (determined immunohistochemically with the VE1 antibody) and the clinicopathological features of 247 radiogenic and 138 sporadic PTCs from young Ukrainian patients aged ≤28 years. The frequency of BRAFV600E was increasing with patient age, consistently remaining lower in radiogenic PTCs. In both etiopathogenic groups, the BRAFV600E-positive PTCs more frequently had a dominant papillary growth pattern, smaller tumor size, higher Ki67 labeling index, and a frequency of the major indicators of tumor invasiveness that is lower than or equal to that of the BRAFV600E-negative tumors. Comparison of the BRAFV600E-positive PTCs across the groups found a virtual absence of differences. In contrast, the BRAFV600E-negative radiogenic PTCs displayed less frequent dominant papillary and more frequent solid growth patterns, lower Ki67 labeling index, and higher invasiveness than the BRAFV600E-negative sporadic tumors. Thus, BRAFV600E is not associated with a more aggressive course of PTC in young patients regardless of etiology. The major clinicopathological differences between the radiogenic and sporadic PTCs are observed among the BRAFV600E-negative tumors., Cancers, 13(23), art. no. 6038; 2021

Simple Summary Analysis of the groups of young Ukrainian patients (aged ≤28 years) with radiogenic and sporadic papillary thyroid carcinomas (PTCs) showed that the frequency of BRAFV600E was increasing with patient age, consistently remaining lower in radiogenic PTCs. In both etiopathogenic groups, the BRAFV600E-positive PTCs more frequently had a dominant papillary growth pattern, smaller tumor size, higher Ki67 labeling index, and a frequency of the major indicators of tumor invasiveness that is lower than or equal to that of the BRAFV600E-negative tumors. Comparison of the BRAFV600E-positive PTCs across the groups found a virtual absence of differences, while the BRAFV600E-negative tumors differed markedly and displayed a higher frequency of invasive tumor features in the radiogenic PTCs. Hence, there is evidence that BRAFV600E does not confer a more aggressive course of PTC in young patients regardless of tumor etiology. Abstract Histopathological changes in the fusion oncogene-driven papillary thyroid carcinomas (PTCs) from children and adolescents exposed to Chernobyl fallout have been extensively studied. However, characteristics of the radiogenic BRAFV600E-positive PTCs, whose proportion is growing with time, are not well described yet. We analyzed the relationship between the BRAFV600E status (determined immunohistochemically with the VE1 antibody) and the clinicopathological features of 247 radiogenic and 138 sporadic PTCs from young Ukrainian patients aged ≤28 years. The frequency of BRAFV600E was increasing with patient age, consistently remaining lower in radiogenic PTCs. In both etiopathogenic groups, the BRAFV600E-positive PTCs more frequently had a dominant papillary growth pattern, smaller tumor size, higher Ki67 labeling index, and a frequency of the major indicators of tumor invasiveness that is lower than or equal to that of the BRAFV600E-negative tumors. Comparison of the BRAFV600E-positive PTCs across the groups found a virtual absence of differences. In contrast, the BRAFV600E-negative radiogenic PTCs displayed less frequent dominant papillary and more frequent solid growth patterns, lower Ki67 labeling index, and higher invasiveness than the BRAFV600E-negative sporadic tumors. Thus, BRAFV600E is not associated with a more aggressive course of PTC in young patients regardless of etiology. The major clinicopathological differences between the radiogenic and sporadic PTCs are observed among the BRAFV600E-negative tumors.

An observational study was conducted in Ukraine to determine the independent mortality risks among adult inpatients with COVID-19. The results of treatment of COVID-19 inpatients ( n = 367) are presented, and waist circumference (WC) was measured. Logistic regression analysis was applied to evaluate the effects of factors on the risk of mortality. Odds ratios and 95% CIs for the association were calculated. One hundred and three of 367 subjects had fasting plasma glucose level that met the diabetes mellitus criteria (≥7.0 mmol/L), in 53 patients, diabetes mellitus was previously known. Two hundred and eleven patients did not have diabetes or hyperglycemia. Diabetes mellitus/hyperglycemia odds ratio 2.5 (CI 1.0–6.1), p = 0.045 loses statistical significance after standardization by age, waist circumference or fasting plasma glucose. No effect on gender, body mass index-determined obesity, or hypertension was found. The fasting plasma glucose (>8.5 mmol/L), age (≥61 years), and waist circumference (>105 cm) categories were associated with ORs 6.34 (CI 2.60–15.4); 4.12 (CI 1.37–12.4); 8.93 (CI 3.26–24.5), respectively. The optimal model of mortality risk with AUC 0.86 (CI 0.81–0.91) included the diabetes/heperglycemia and age categories as well as waist circumference as a continued variable. Waist circumference is an independent risk factor for mortality of inpatients with COVID-19.

Thyroid ultrasound screening of young residents in Fukushima Prefecture, Japan, showed a high detection rate of papillary thyroid carcinoma (PTC). Detailed morphological analysis of these tumors was not presented to date. This study sets out to evaluate changes in histopathological and invasive characteristics of Fukushima PTC with time after the nuclear accident of March 2011 in all available cases and in different age subgroups. Histological specimens of 115 PTCs from patients aged 18 years or younger at the time of the Fukushima Dai‐ichi Nuclear Power Plant accident, who underwent surgical resection at Fukushima Medical University during 2012‐2016, were reviewed. Patients were divided into those treated during the first 4 years after the accident (n = 78, shorter‐onset) or later (n = 37, longer‐onset). The whole group and 3 age subgroups: children (aged less than 15 years), adolescents (aged from 15 to less than 19 years), and young adults (aged from 19 years) at surgery were analyzed. No statistically significant time‐related changes in tumor structure or invasiveness were found in the whole group or in age‐matched subgroups. Statistically significant age‐related downtrend was observed for intrathyroid spread in the whole group of patients. The absence of temporal changes in tumor morphological characteristics and tumor invasiveness strongly suggests common etiology of the shorter‐ and longer‐onset Fukushima PTCs, which are unlikely related to the effect of exposure to very low doses of radiation.

Genomics of radiation-induced damage The potential adverse effects of exposures to radioactivity from nuclear accidents can include acute consequences such as radiation sickness, as well as long-term sequelae such as increased risk of cancer. There have been a few studies examining transgenerational risks of radiation exposure but the results have been inconclusive. Morton et al. analyzed papillary thyroid tumors, normal thyroid tissue, and blood from hundreds of survivors of the Chernobyl nuclear accident and compared them against those of unexposed patients. The findings offer insight into the process of radiation-induced carcinogenesis and characteristic patterns of DNA damage associated with environmental radiation exposure. In a separate study, Yeager et al. analyzed the genomes of 130 children and parents from families in which one or both parents had experienced gonadal radiation exposure related to the Chernobyl accident and the children were conceived between 1987 and 2002. Reassuringly, the authors did not find an increase in new germline mutations in this population. Science , this issue p. eabg2538 , p. 725

BACKGROUND: Children and adolescents exposed to radioactive iodine-131 (I-131) in fallout from the 1986 Chernobyl nuclear accident appear to be at increased risk of thyroid cancer and benign thyroid nodules. The prenatal period is also considered radiosensitive, and the fetal thyroid can absorb I-131 from the maternal circulation. OBJECTIVES: We aimed to estimate the risk of malignant and benign thyroid nodules in individuals exposed prenatally. METHODS: We studied a cohort of 2582 subjects in Ukraine with estimates of I-131 prenatal thyroid dose (mean = 72.6 mGy), who underwent two standardized thyroid screening examinations. To evaluate the dose-response relationship, we estimated the excess OR (EOR) using logistic regression. RESULTS: Based on a combined total of eight cases diagnosed at screenings from 2003 to 2006 and 2012 to 2015, we found a markedly elevated, albeit not statistically significant, dose-related risk of thyroid cancer (EOR/Gy = 3.91, 95% CI: –1.49, 65.66). At cycle 2 (n = 1,786), there was a strong and significant association between I-131 thyroid dose and screen-detected large benign nodules (≥10 mm) (EOR/Gy = 4.19, 95% CI: 0.68, 11.62; P = 0.009), but no significant increase in risk for small nodules (

To evaluate risk of thyroid neoplasia nearly 30 years following exposure to radioactive iodine (I-131) from the 1986 Chernobyl nuclear accident, we conducted a fifth cycle of thyroid screening of the Ukrainian-American cohort during 2012-2015, following four previous screening cycles started in 1998. We identified 47 thyroid cancers (TC) and 33 follicular adenomas (FA) among 10,073 individuals who were

This study set out to compare structural and invasive characteristics of sporadic papillary thyroid carcinoma (PTC) in age-matched groups of children and adolescents of Japan and Ukraine to provide detailed histopathological analysis of tumors from different geographical areas with different iodine intake. A total of 348 (160 Japanese and 188 Ukrainian) PTCs from patients without radiation history were analyzed initially as a combined pediatric group and then subdivided into childhood (aged ≤14 years) and adolescent (aged from 15 to ≤18 years) age series. On multivariate comparison, the Japanese pediatric PTC was characterized by a higher sex ratio (p=1.504E-4), and a higher frequency of microcarcinoma (p=0.039), papillary dominant growth pattern (p=0.024), focal oxyphilic cell metaplasia (p=7.644E-6), intrathyroid spread (p=0.010), lymphatic/vascular invasion (p=0.01) and regional lymph node metastases (p=3.540E-6). In the Ukrainian group, multifocal (p=0.004) and non-encapsulated tumors with the solid-trabecular growth pattern (p=0.05) were more frequent. Childhood Japanese PTCs differed from Ukrainian PTCs by more pronounced invasive properties such as lymphatic/vascular invasion and nodal disease, but did not differ by the dominant growth pattern. In adolescents, the differences were detected not only for lymph node metastases, but also for a higher frequency of the papillary dominant pattern in Japanese PTC. Overall, significantly higher frequencies of oxyphilic cell metaplasia and more pronounced invasive features observed in the Japanese PTC in both age-matched series represent the major differences between the tumors from two geographical areas.

This chapter analyzes histopathological characteristics of papillary thyroid carcinoma (PTC) in subjects of Ukraine who were children and adolescents at the time of the Chernobyl accident. Tumor architecture and invasive properties significantly changed with patients’ age at surgery increasing from 4 to 48 years and with the time elapsed after the accident extending to 30 years. Two major linear trends, the age- and time-related, were revealed for most pathological characteristics; some of them were ascending and some descending. “Radiogenic” PTC in subjects aged ≤4 years at the time of exposure who resided in three regions most contaminated by 131I differed from “sporadic” PTC in age-matched groups of patients from the same regions in terms of both tumor histoarchitectonics and invasiveness. “Radiogenic” PTC displayed a higher frequency of invasive features especially pronounced in children and adolescents. Changes in histopathological characteristics suggest that the phenotype of both “radiogenic” and “sporadic” PTCs becomes less invasive at older patients’ ages. The frequency of intermediate pathological diagnoses of thyroid tumors according to the WHO Classification of Tumours of Endocrine Organs, 4th edition, in the Ukrainian cases included in the Chernobyl Tissue Bank appeared to be not more than 3%.

AIM To compare the frequency of main histopathological characteristics, 131І thyroid radiation doses, invasive properties and post-operative follow-up of patients of different age groups with potentially radiogenic papillary thyroid carcinoma (PTC) with the presence and absence of oncocytic changes in tumor cells. MATERIALS AND METHODS PTC removed in 483 patients from high risk age-group for radiogenic thyroid cancer development (children and adolescents at the time of Chornobyl accident who lived in the northern regions of Ukraine: Kyiv, Zhytomyr, and Chernihiv regions) have been studied microscopically. RESULTS The frequency of PTC with the presence of oncocytic changes (OCh) in tumor cells increased significantly with increasing of patients' age at the time of surgery: from 8.3% in children 4-14 years old to 54.3% in adults 39-48 years old (ptrend < 0.0001). The presence of such changes is associated with papillary and solid-trabecular dominant tumor growth pattern in more than 90% of cases in each age group. The mean 131І thyroid dose in the whole series of PTC patients with OCh was significantly lower compared to the same index in PTC patients without OCh (493.7 mGy and 765.8 mGy, respectively, p < 0.0001). In addition, regional metastases recurrences were revealed more frequently in patients with OCh in primary PTC compared with patients without OCh in primary tumor (7.2% vs 1.5%, p = 0.0022). CONCLUSIONS Significantly increasing age-trend of OCh in PTC of patients affected by the Chornobyl fallout and operated at age from 4 to 48 years, as well as opposite decreasing linear age-trend of 131І thyroid dose may reflect a gradual increase of sporadic PTCs frequency in the potentially radiogenic series with time elapsed since accident. The frequency of oncocytic insensitive to radioiodine therapy of lymph node metastases recurrences also increased with patients age and OCh availability in primary PTC.

Materials and methods. Based on clinical and immunological studies, in this study, we present data on the establishment of mechanisms that are responsible for the development of early and late pre-clinical stages of the type 1 diabetes (T1D), obtained by studying diabetes-associated autoantibodies (DAAb) and the levels of basal and postprandial glycemia, and C-peptide secretion at the preclinical stage of T1D development in children and adolescents. Results. As a result we were able to form a group of marker-positive children with a genetic predisposition and an increased predicted risk of developing the diease. A total of 474 practically healthy normoglycemic children and adolescents aged 7 to 18 years were examined. An elevated titre of DAAb, mainly GADA and IA-2A was found in 94 (25.68 %) of 366 children with a genetic predisposition for at least of two determinants of DAAb, and the clinical onset of T1D manifesting in 68 (72.34 %) of them from 6 months to 15 years (30.9 ± 3.2 months). The formula of combined occurrence and values of simultaneously elevated titres of DAAb against islet autoantigens, namely, IA-2A + GADA, which is a predictor of the duration of the preclinical stage of T1D, was determined. Conclusions. It was established that the early preclinical development of T1D in DAAb + children was characterized by the presence of dysglycemia in the form of elevated glycemia 2 hours after the glucose tolerance test and a steady decrease in the secretion of stimulated C-peptide; additionally, dysglycemia was jointed as impaired fasting glycemia, and there was a decrease in both basal and stimulated secretions of C peptide, indicating the depletion of the potential of pancreatic beta-cells. Key words: type 1 diabetes (T1D), children and adolescents, diabetes-associated autoantibodies (DAAb), autoantibodies against glutamic acid decarboxylase (GADA), autoantibodies against tyrosine phosphatase (IA-2A), basal and postprandial glycemia, basal and stimulated C-peptide. For citation: Tronko MD, Mankovskyi BM, Popova VV, Zak KP. Concentration of diabetes-associated autoantibodies against islet autoantigens (IA-2A, GADA, IAA), levels of basal and postprandial glycemia, and secretory state of basal and stimulated C-peptide in the preclinical period of type 1 diabetes development in children and adolescents as immunological, metabolic and hormonal predictors of the clinical onset of the disease. Journal of the National Academy of Medical Sciences of Ukraine. 2019;25(3):285–95

The 1986 Chernobyl nuclear power plant accident increased papillary thyroid cancer (PTC) incidence in surrounding regions, particularly for 131I-exposed children. To investigate the contribution of environmental radiation to PTC characteristics and improve understanding of radiation-induced carcinogenesis, we analyzed genomic, transcriptomic, and epigenomic characteristics of 440 pathologically-confirmed fresh-frozen PTCs from Ukraine (359 with estimated childhood or in utero 131I exposure and 81 from unexposed children born after March 1987) and matched normal tissue (non-tumor thyroid tissue and/or blood). Mean age at PTC was 28.0 years (range: 10.0-45.6). Among 131I-exposed individuals, mean radiation dose was 250 mGy (range: 11.0-8,800). In multivariable models adjusted for age at PTC and sex, we observed radiation dose-dependent enrichment of fusion drivers (P=6.6 × 10−8), nearly all occurring in the MAPK pathway, as well as increases in small deletions (P=8.0 × 10−9) and simple/balanced structural variants (P=1.2 × 10−14). Further analyses demonstrated even stronger associations for those small deletions and simple/balanced structural variants that were clonal and bore hallmarks of non-homologous end-joining repair (deletions: P=4.9 × 10−31; simple/balanced structural variants: P=5.5 × 10−19). In contrast, radiation dose was not associated with subclonal small deletions (P=0.82) or subclonal simple/balanced structural variants (P=0.91). Additionally, radiation dose was not associated with TINS (locally templated insertions), which are characteristic of alt-end-joining repair (P=0.69). The effects of radiation on genomic alterations with more pronounced for those younger at exposure. Analyses generally were consistent with a linear radiation dose-response for all molecular characteristics except clonal small deletions. Analyses of transcriptomic and epigenomic features demonstrated strong associations with the PTC driver gene but not radiation dose. Our results point to DNA double-strand breaks as early carcinogenic events that subsequently enable PTC growth following environmental radiation exposure. Citation Format: Lindsay M. Morton, Danielle Karyadi, Chip Stewart, Tetiana Bogdanova, Eric Dawson, Mia Steinberg, Jieqiong Dai, Stephen Hartley, Sara Schonfeld, Joshua Sampson, Yosi Maruvka, Vidushi Kapoor, Dale Ramsden, Juan Carvajal-Garcia, Chuck Perou, Joel Parker, Marko Krznaric, Meredith Yeager, Joseph Boland, Amy Hutchinson, Belynda Hicks, Casey Dagnall, Julie Gastier-Foster, Jay Bowen, Olivia Lee, Mitchell Machiela, Elizabeth Cahoon, Alina Brenner, Kiyohiko Mabuchi, Vladimir Drozdovitch, Sergii Masiuk, Mykola Chepurny, Liudmyla Yu Zurnadzhy, Maureen Hatch, Amy Berrington de Gonzalez, Gerry Thomas, Mykola Tronko, Gad Getz, Stephen Chanock. Molecular characterization of papillary thyroid cancer in relation to ionizing radiation dose following the Chernobyl accident [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-055.

International audience; [No abstract available]

Background: The issue of whether radiation-induced thyroid cancer is pathologically different from sporadic remains not fully answered. This study compared structural characteristics and invasive features of papillary thyroid carcinoma (PTC) in two age-matched groups: patients who were children (≤4 years old) at the time of the Chernobyl accident and who lived in three regions of Ukraine most contaminated by radioactive iodine (131)I (“radiogenic” cancer), and those who lived in the same regions but who were born after 1987 and were not exposed to (131)I (“sporadic” cancer). Further, the histopathologic features of PTC were analyzed in relation to age and individual (131)I thyroid dose. Methods: The study included 301 radiogenic and 194 sporadic PTCs. According to age at surgery, patients were subdivided into children (≤14 years old), adolescents (15–18 years old), and adults (19–28 years old). Statistical analyses included univariate tests and multivariable logistic regression within and across the age subgroups. Analyses of morphological features related to (131)I doses were conducted among exposed patients on categorical and continuous scales controlling for sex and age. Results: Among children, radiogenic PTC displayed a significantly higher frequency of tumors with a dominant solid growth pattern, intrathyroidal spread, extrathyroidal extension, lymphatic/vascular invasion, and distant metastases. Exposed adolescents more frequently displayed extrathyroidal extension, lymphatic/vascular invasion, and distant metastases. Exposed adults more frequently had intrathyroidal spread and extrathyroidal extension. The frequency of PTC with dominant papillary pattern and oxyphilic cell metaplasia was significantly lower in radiogenic compared to sporadic tumors for all age groups. Manifestations of tumor aggressiveness were most frequent in children compared to adolescents and adults regardless of etiology. Conclusions: Radiogenic PTC is less likely to demonstrate a dominant papillary growth pattern and more likely to display more aggressive tumor behavior than sporadic PTC. Histopathologic tumor aggressiveness declines with patient age in both radiogenic and sporadic cases.

Summary This study showed a clear dose-response relationship for the CLIP2 radiation marker in post-Chernobyl papillary thyroid carcinoma cohorts for young patients and hints to different molecular mechanisms in tumors induced at low doses compared to moderate/high doses., A previous study on papillary thyroid carcinomas (PTC) in young patients who were exposed to 131iodine 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.

BackgroundSerum thyroglobulin (Tg) is associated with the presence of thyroid disease and has been proposed as a biomarker of iodine status. Few studies have examined factors related to serum Tg in populations environmentally exposed to ionizing radiation and living in regions with endemic mild-to-moderate iodine deficiency.MethodsWe screened 10,430 individuals who were living in Ukraine and under 18 years of age at the time of the 1986 Chernobyl Nuclear Power Plant accident for thyroid disease from 2001 to 2003. We estimated the percent change (PC) in serum Tg associated with demographic factors, iodine-131 thyroid dose, and indicators of thyroid structure and function using linear regression. We also examined these relationships for individuals with and without indications of thyroid abnormality.ResultsMean and median serum Tg levels were higher among participants with abnormal thyroid structure/function. Percent change in serum Tg increased among females, smokers and with older age (p-values

Iodine 131 (I-131), the principal component of nuclear fallout from the Chernobyl accident, concentrates in the thyroid gland and may pose risks to fetal development. To evaluate this, neonatal outcomes following the accident in April of 1986 were investigated in a cohort of 2582 in utero-exposed individuals from northern Ukraine for whom estimates of fetal thyroid I-131 dose were available. We carried out a retrospective review of cohort members’ prenatal, delivery and newborn records. The relationships of dose with neonatal anthropometrics and gestational length were modeled via linear regression with adjustment for potentially confounding variables. We found similar, statistically significant dose-dependent reductions in both head circumference (−1.0 cm/Gy, P = 0.005) and chest circumference (−0.9 cm/Gy, P = 0.023), as well as a similar but non-significant reduction in neonatal length (−0.6 cm/Gy, P = 0.169). Gestational length was significantly increased with increasing fetal dose (0.5 wks/Gy, P = 0.007). There was no significant (P > 0.1) effect of fetal dose on birth weight. The observed associations of radioiodine exposure with decreased head and chest circumference are consistent with those observed in the Japanese in utero-exposed atomic bomb survivors.

Background Exposure to ionizing radiation during childhood is a well-established risk factor for thyroid cancer. However, the genetic mechanisms of radiation-associated carcinogenesis remain not fully understood. Methods In this study, we used targeted next-generation sequencing and RNA-Seq to study 65 papillary thyroid cancers (PTCs) from patients in the Ukrainian-American cohort with measurement-based iodine-131 (I-131) thyroid doses received as a result of the Chernobyl accident. We fitted linear regression models to evaluate differences in distribution of risk factors for PTC according to type of genetic alteration and logistic regression models to evaluate the I-131 dose response. All statistical tests were two-sided. Results Driver mutations were identified in 96.9% of these thyroid cancers, including point mutations in 26.2% and gene fusions in 70.8% of cases. Novel driver fusions such as POR-BRAF, as well as STRN-ALK fusions that have not been implicated in radiation-associated cancer before, were found. The mean I-131 dose in cases with point mutations was 0.2 Gy (range = 0.013-1.05 Gy), statistically significantly lower than 1.4 Gy (range = 0.009-6.15 Gy) for cases with fusions (P < .001). No driver point mutations were found in tumors from individuals who received more than 1.1 Gy of radiation. Relative to tumors with point mutations, the proportion of tumors with gene fusions increased with radiation dose, reaching 87.8% among individuals exposed to 0.3 Gy or higher. With a limited study sample size, the estimated odds ratio at 1 Gy was 20.01 (95% confidence interval = 2.57 to 653.02, P < .001). In addition, after controlling for I-131 dose, we found higher odds ratios for gene fusion-positive PTCs associated with several specific demographic and geographic features. Conclusions Our data provide support for a link between I-131 thyroid dose and generation of carcinogenic gene fusions, the predominant mechanism of thyroid cancer associated with radiation exposure from the Chernobyl accident.

The Ukrainian–American (UkrAm) thyroid study is a cohort study of thyroid cancer and other thyroid pathologies in Ukrainian individuals exposed as children or adolescents to radioactive fallout from the Chernobyl accident. The 13,243 cohort members with direct thyroid radioactivity measurements taken in May–June 1986 were first screened in 1998–2000. During the period 2001–07, three additional biennial cycles of thyroid screening examinations were carried out. A fifth screening was conducted between 2012 and 2015, with 76.4% of the original cohort coming for examinations. As a result of this latest screening, 47 new pathologically confirmed thyroid cancers were diagnosed by the end of 2015. Preliminary analyses of the fifth cycle data show a statistically significant excess of radiation-related thyroid cancer 26–30 years after I-131 exposure. Further follow-up of the UkrAm cohort would help clarify the dose dependence and long-term temporal pattern of risk. In addition, pooling of data from the UkrAm and parallel Belarusian cohort (BelAm) could improve the precision of risk assessment of thyroid disease after exposure at young ages to I-131 in Chernobyl fallout.

The incidence and pathological characteristics of thyroid cancer in subjects from Ukraine who were children and adolescents at the time of the Chernobyl accident, but reached adulthood at the time of surgery, were analyzed. A significant increase in thyroid cancer incidence in this age group persists up to 2014, and the incidence rate in the six most contaminated regions by 131I exceeded that in 21 less contaminated regions. Pathological analysis of 2634 thyroid carcinomas of the adults aged from 19 to 46 years at the time of surgery showed that papillary thyroid carcinoma (PTC) was the most prevalent type of thyroid cancer in all studied periods. With increasing time after the accident, PTCs with dominant papillary growth pattern have more pronounced invasive properties, but generally the tumors clearly become less aggressive, which is important and favorable for the postoperative prognosis.

Geographic differences have been reported to affect the morphological and molecular features of papillary thyroid carcinomas (PTCs). The area around Chernobyl is well-known to be iodine-deficient in contrast to Japan, an iodine-rich country. We reviewed histological differences in adult PTC between Ukraine and Japan. In total, 112 PTCs from age- and sex-matched adults (Ukraine 56, Japan 56) were evaluated histologically for several factors including tumor size, capsulation, tumor components (papillary, follicular, solid, trabecular), lymph node metastasis, extrathyroid invasion, lymphocytic infiltration, oxyphilic metaplasia, and MIB-1 index. We demonstrated that tumors were smaller (1.56 vs. 2.13 cm, p

Background Our previous analysis of papillary thyroid carcinomas (PTC) from the Ukrainian-American cohort exposed to 131I from the Chernobyl accident found RET/PTC rearrangements and other driver mutations in 60% of tumors.

Background: A strong, consistent association between childhood irradiation and subsequent thyroid cancer provides an excellent model for studying radiation carcinogenesis. Methods: We evaluated gene expression in 63 paired RNA specimens from frozen normal and tumour thyroid tissues with individual iodine-131 (I-131) doses (0.008–8.6 Gy, no unirradiated controls) received from Chernobyl fallout during childhood (Ukrainian-American cohort). Approximately half of these randomly selected samples (32 tumour/normal tissue RNA specimens) were hybridised on 64 whole-genome microarrays (Agilent, 4 × 44 K). Associations between I-131 dose and gene expression were assessed separately in normal and tumour tissues using Kruskal−Wallis and linear trend tests. Of 155 genes significantly associated with I-131 after Bonferroni correction and with ⩾2-fold increase per dose category, we selected 95 genes. On the remaining 31 RNA samples these genes were used for validation purposes using qRT−PCR. Results: Expression of eight genes (ABCC3, C1orf9, C6orf62, FGFR1OP2, HEY2, NDOR1, STAT3, and UCP3) in normal tissue and six genes (ANKRD46, CD47, HNRNPH1, NDOR1, SCEL, and SERPINA1) in tumour tissue was significantly associated with I-131. PANTHER/DAVID pathway analyses demonstrated significant over-representation of genes coding for nucleic acid binding in normal and tumour tissues, and for p53, EGF, and FGF signalling pathways in tumour tissue. Conclusion: The multistep process of radiation carcinogenesis begins in histologically normal thyroid tissue and may involve dose-dependent gene expression changes.

BACKGROUND: Childhood exposure to iodine-131 from the 1986 nuclear accident in Chernobyl, Ukraine, led to a sharp increase in papillary thyroid carcinoma (PTC) incidence in regions surrounding the reactor. Data concerning the association between genetic mutations in PTCs and individual radiation doses are limited. METHODS: Mutational analysis was performed on 62 PTCs diagnosed in a Ukrainian cohort of patients who were < 18 years old in 1986 and received 0.008 to 8.6 Gy of 131I to the thyroid. Associations between mutation types and 131I dose and other characteristics were explored. RESULTS: RET/PTC (ret proto-oncogene/papillary thyroid carcinoma) rearrangements were most common (35%), followed by BRAF (15%) and RAS (8%) point mutations. Two tumors carrying PAX8/PPARγ (paired box 8/peroxisome proliferator-activated receptor gamma) rearrangement were identified. A significant negative association with 131I dose for BRAF and RAS point mutations and a significant concave association with 131I dose, with an inflection point at 1.6 Gy and odds ratio of 2.1, based on a linear-quadratic model for RET/PTC and PAX8/PPARγ rearrangements were found. The trends with dose were significantly different between tumors with point mutations and rearrangements. Compared with point mutations, rearrangements were associated with residence in the relatively iodine-deficient Zhytomyr region, younger age at exposure or surgery, and male sex. CONCLUSIONS: These results provide the first demonstration of PAX8/PPARγ rearrangements in post-Chernobyl tumors and show different associations for point mutations and chromosomal rearrangements with 131I dose and other factors. These data support the relationship between chromosomal rearrangements, but not point mutations, and 131I exposure and point to a possible role of iodine deficiency in generation of RET/PTC rearrangements in these patients. Cancer 2013. © 2013 American Cancer Society.

For the purpose of improving retrospective internal thyroid dose estimations for children and adolescents following the Chernobyl accident, age- and gender-dependent thyroid masses have been estimated for the children of Kiev and Zhytomyr oblasts, which are two of the most contaminated regions of Northern Ukraine. For children ages 6-16 y, the thyroid masses were based on the measurements by ultrasound of the thyroid volumes of about 60,000 children performed by the Sasakawa Memorial Health Foundation in the 1990s. For children aged 0 to 36 mo, because thyroid mass values for Ukrainian children were not found in the literature, autopsies were performed for the specific purpose of this paper. Thyroid mass values for children aged 3-5 and 17-18 y were either interpolated or extrapolated from the measured data sets. The results for children aged 6-16 y indicate that the thyroid masses of rural children are, on average, slightly higher (by about 8%) than the thyroid masses of urban children. The geometric means of the thyroid masses were estimated as 5.2 g, 9.0 g, and 15.8 g for boys and 5.2 g, 9.4 g, and 16.0 g for girls aged 5, 10, and 15 y, respectively. Those values are greater than the reference values that ICRP recommends for iodine-sufficient populations, thus reflecting the fact that the northern part of Ukraine is iodine-deficient.