Biocompatible dextran-coated gadolinium-doped cerium oxide nanoparticles as MRI contrast agents with high T1 relaxivity and selective cytotoxicity to cancer cells.

Gd-based complexes are widely used as magnetic resonance imaging (MRI) contrast agents. The safety of previously approved contrast agents is questionable and is being re-assessed. The main causes of concern are possible gadolinium deposition in the brain and the development of systemic nephrogenic fibrosis after repeated use of MRI contrasts. Thus, there is an urgent need to develop a new generation of MRI contrasts that are safe and that have high selectivity in tissue accumulation with improved local contrast. Here, we report on a new type of theranostic MRI contrast, namely dextran stabilised, gadolinium doped cerium dioxide nanoparticles. These ultra-small (4-6 nm) Ce0.9Gd0.1O1.95 nanoparticles have been shown to possess excellent colloidal stability and high r1-relaxivity (3.6 mM-1 s-1). They are effectively internalised by human normal and cancer cells and demonstrate dose-dependent selective cytotoxicity to cancer cells.

Evaluation of Migration Radiological Equivalence for Dual Component Nuclear Waste in a Deep Geological Repository.

ABSTRACT: The paper is concerned with the issue of achieving the radiological equivalence (the equivalence of radiation risks) of radioactive waste of nuclear reactors and corresponding mass of natural uranium, taking into account the different migration ability of radionuclides in geological formations and soil. This migration radiological equivalence is being investigated for the deep burial of radioactive waste in the case of the development of a two-component nuclear power system with the concurrent use of thermal neutron reactors and fast neutron reactors. Calculations were performed of radiation doses and radiation risks of cancer death arising from consumption of drinking water from a well above a disposal site. The radiation risk relating to a two-component nuclear power system is lower than that from natural uranium; i.e., after reaching the radiological equivalence (100 y of storage) over the timescale of 109 y, the principle of migration radiological equivalence is satisfied. It would take 106 y after radioactive waste disposal to reach the migration radiological equivalence if only thermal reactors were operated. As regards consumption of well drinking water, the radiation risk does not exceed 10-5 y-1 for a two-component nuclear power system, while being 10-3 y-1 (socially unacceptable level) for a power system using only thermal reactors. Radionuclides 241Am, 239Pu, and 240Pu in drinking water make the main contribution to the doses and radiation risks of people for 104 y after the disposal of radioactive waste.

Ceria-Containing Hybrid Multilayered Microcapsules for Enhanced Cellular Internalisation with High Radioprotection Efficiency.

Cerium oxide nanoparticles (nanoceria) are believed to be the most versatile nanozyme, showing great promise for biomedical applications. At the same time, the controlled intracellular delivery of nanoceria remains an unresolved problem. Here, we have demonstrated the radioprotective effect of polyelectrolyte microcapsules modified with cerium oxide nanoparticles, which provide controlled loading and intracellular release. The optimal (both safe and uptake efficient) concentrations of ceria-containing microcapsules for human mesenchymal stem cells range from 1:10 to 1:20 cell-to-capsules ratio. We have revealed the molecular mechanisms of nanoceria radioprotective action on mesenchymal stem cells by assessing the level of intracellular reactive oxygen species (ROS), as well as by a detailed 96-genes expression analysis, featuring genes responsible for oxidative stress, mitochondrial metabolism, apoptosis, inflammation etc. Hybrid ceria-containing microcapsules have been shown to provide an indirect genoprotective effect, reducing the number of cytogenetic damages in irradiated cells. These findings give new insight into cerium oxide nanoparticles' protective action for living beings against ionising radiation.

Nanoceria-curcumin conjugate: Synthesis and selective cytotoxicity against cancer cells under oxidative stress conditions.

A water- and alcohol-soluble cerium oxide-curcumin conjugate was obtained by co-evaporation with poly(N-vinylpyrrolidone) (PVP). A nanocomposite consisting of hybrid organic-inorganic particles was stable in a wide range of pH values. Its properties were evaluated using nine cell lines: normal (MDBK, ST, Vero) and malignant (L929, T98G, HEp-2, A549, RIN-m5F, Hep G2). PVP-stabilised nanoceria was shown to inhibit autoxidation of curcumin, to enhance curcumin photostability, to promote bioaccumulation and to affect curcumin cytotoxicity and photocytotoxicity, depending on cell type, being more toxic to cancer cells in a selective manner. Under the conditions of UVA/UVC or H2O2-induced oxidative stress, the nanoceria-PVP-curcumin (NPC) conjugate was found to possess a selective cytotoxicity: it caused drastic inhibition of metabolic activity or a decrease in the total number of tumour cells, while in non-transformed cultures under the same conditions, the nanoceria-PVP-curcumin conjugate protected cells from these damaging factors. The NPC-conjugate, unlike curcumin itself, demonstrated a photosensitising effect in tumour cell cultures, while protecting non-transformed cultures from the damaging effects of UV radiation or oxidative stress. Based on the results obtained, we strongly believe that this novel hybrid material has enhanced characteristics compared to other curcumin formulations, and can be considered as a potent drug for biomedical applications, including cancer therapy.

Relationship between follow-up periods and the low-dose ranges with statistically significant radiation-induced risk of all solid cancers in the Russian cohort of Chernobyl emergency workers.

Radiation-induced risks for all solid cancer incidence and mortality were studied in the cohort of Russian Chernobyl emergency workers. The cohort included 69,440 persons with documented individual radiation dose accrued over the time of working in the Chernobyl zone. The mean age at entry into the zone of recovery operations was 33.9 years and accumulated radiation dose was 132.9 mGy. A total of 6981 solid cancer incident cases and 4272 deaths occurred in this cohort from 1992 to 2017. Three follow-up periods were studied: 1992-2009, 1992-2013, and 1992-2017. For each follow-up period, the lowest dose range with statistically significant (p < 0.05) radiation-induced risk of all solid cancer incidence and mortality were obtained. For the incidence of all solid cancer during the follow-up period 1992-2009, this lowest dose range was estimated to be 0-250 mGy with an excess relative risk per dose of ERR Gy-1 = 0.51 and 95% confidence interval (CI) (0.02; 1.05) Gy-1. For the period 1992-2013, the lowest dose range was 0-175 mGy with ERR Gy-1 = 0.85 (95% CI 0.03; 1.78), while for the whole follow-up period 1992-2017, it was 0-175 mGy with ERR Gy-1 = 0.81 (95% CI 0.08; 1.62). For mortality from all solid cancers during the follow-up period 1992-2009, the lowest dose range with statistically significant radiation-induced risk was estimated to be 0-225 mGy with ERR Gy-1 = 1.07 (95% CI 0.31; 0.97). For the period 1992-2013, the lowest dose range was 0-225 mGy with ERR Gy-1 = 0.86 (95% CI 0.23; 1.58), while for the whole follow-up period 1992-2017, the lowest dose range was 0-200 mGy with ERR Gy-1 = 0.82 (95% CI 0.10; 1.65). Thus, it was found that the minimal level of significant exposure (Dmin), for which a statistically significant radiation-induced risk of all solid cancers was obtained for Russian emergency workers (with individual doses of 0 - Dmin), decreases with increasing duration of cohort observation, both for cancer incidence and mortality.

Radiation Risk of Cardiovascular Diseases in the Cohort of Russian Emergency Workers of the Chernobyl Accident.

This paper continues a series of publications that analyze the impact of radiation on incidence of circulatory system diseases in the cohort of Russian recovery operation workers (liquidators) and presents the results of the analysis of cardiovascular disease (CVD) incidence. The studied cohort consists of 53,772 liquidators who arrived in the Chernobyl accident zone within the first year after the accident (26 April 1986 to 26 April 1987). The individual doses varied from 0.0001 Gy to 1.42 Gy, and the mean external whole body dose in the cohort was 0.161 Gy. A total of 27,456 cases of CVD were diagnosed during the follow-up period 1986-2012 as a result of annual health examinations. A Poisson regression model was applied to estimate radiation risks and other risk factors associated with CVD. The following factors were identified as risk factors for CVD: the dose, duration of the liquidators' work in the Chernobyl zone, and concomitant diseases (diabetes mellitus, hypertension, overweight, and alcohol dependence). The baseline incidence of CVD is statistically significantly (p < 0.001) associated with all studied concomitant diseases. The incidence of CVD has revealed a statistically significant dose response with the lack of a latent period and with the average ERR Gy = 0.47, 95% CI = 0.31, 0.63, p < 0.001. Radiation risks of CVD statistically significantly (p = 0.01) varied with the duration of liquidators' stay in the Chernobyl zone; for those who stayed in the Chernobyl zone less than 6 wk, ERR/Gy = 0.80, 95% CI = 0.53; 1.08, p < 0.001.

Experimental Study of the Effects of Nanodispersed Ceria on Wound Repair.

We studied the effects of nanodispersed ceria on wound healing in vitro and in vivo. It was found that cerium dioxide stimulated wound healing, which manifested in shrinkage of burn wound area (by 1.5 times) and intensification (by 2.4 times) marginal epithelialization.

[Non-Parametric Analysis of Radiation Risks of Mortality among Chernobyl Clean-Up Workers].

Analysis of the relationship between dose and mortality from cancer and circulation diseases in the cohort of Chernobyl clean-up workers based on the data from the National Radiation and Epidemiological Registry was performed. Medical and dosimetry information on the clean-up workers, males, who got radiation doses from April 26, 1986 to April 26, 1987, which was accumulated from 1992 to 2012, was used for the analysis. The total size of the cohort was 42929 people, 12731 deaths were registered in the cohort, among them 1893 deaths from solid cancers and 5230 deaths were from circulation diseases. An average age of the workers was 39 years in 1992 and the mean dose was 164 mGy. The dose-effect relationship was estimated with the use of non-parametric analysis of survival with regard to concurrence of risks of mortality. The risks were estimated in 6 dose groups of similar size (1-70, 70-130, 130-190, 190-210, 210-230 and.230-1000 mGy). The group "1-70 mGy" was used as control. Estimated dose-effect relationship related to cancers and circulation diseases is described approximately with a linear model, coefficient of determination (the proportion of variability explained by the linear model) for cancers was 23-25% and for circulation diseases - 2-13%. The slope coefficient of the dose-effect relationship normalized to 1 Gy for the ratio of risks for cancers in the linear model was 0.47 (95% CI: -0.77, 1.71), and for circulation diseases it was 0.22 (95% CI: -0.58, 1.02). Risks coefficient (slope coefficient of excess mortality at a dose of 1 Gy) for solid cancers was 1.94 (95% CI: - 3.10, 7.00) x 10(-2) and for circulation diseases it was 0.67 (95% CI: -9.61, 11.00) x 10(-2). 137 deaths from radiation-induced cancers and 47 deaths from circulation diseases were registered during a follow up period.

Radiation-epidemiological Study of Cerebrovascular Diseases in the Cohort of Russian Recovery Operation Workers of the Chernobyl Accident.

The paper presents an analysis of the incidence of cerebrovascular diseases (CeVD) in the cohort of Russian workers involved in recovery tasks after the Chernobyl accident. The studied cohort consists of 53,772 recovery operation workers (liquidators) who arrived in the zone of the Chernobyl accident within the first year after this accident (26 April 1986-26 April 1987). The mean external whole body dose in the cohort was 0.161 Gy, while individual doses varied from 0.0001 Gy to 1.42 Gy. During the follow-up period 1986-2012, a total of 23,264 cases of CeVD were diagnosed as a result of annual health examinations. A Poisson regression model was applied for estimation of radiation risks and for an assessment of other risk factors of CeVD. The following factors were considered as risk factors for CeVD: the dose, duration of the liquidators' work in the Chernobyl zone, and the concomitant diseases (hypertension, ischemic heart disease, atherosclerosis, and diabetes). The baseline incidence of CeVD is statistically significantly (p < 0.001) associated with all studied concomitant diseases. The incidence of CeVD has revealed a statistically significant dose response with the lack of a latent period and with the average ERR/Gy = 0.45, 95% CI: (0.28, 0.62), p < 0.001. Radiation risks of CeVD statistically significantly (p = 0.03) varied with the duration of liquidators' stay in the Chernobyl zone; for those who stayed in the Chernobyl zone less than 6 wk, ERR/Gy = 0.64, 95% CI = (0.38; 0.93), p < 0.001. Among studied concomitant diseases, diabetes mellitus statistically significantly (p = 0.002) increases the radiation risk of CeVD: for liquidators with diagnosed diabetes, ERR/Gy = 1.29.

Incidence and mortality of solid cancer among emergency workers of the Chernobyl accident: assessment of radiation risks for the follow-up period of 1992-2009.

This paper presents the results of a retrospective cohort study of cancer incidence and mortality among emergency workers of the Chernobyl accident, for the follow-up period 1992-2009. The cohort selected for analysis consists of 67,568 emergency workers who worked in the Chernobyl exclusion zone in 1986-1987. External radiation whole-body absorbed dose varied from 0.0001 gray (Gy) to 1.24 Gy, with a median of 0.102 Gy. Over the follow-up period 1992-2009, a total of 4,002 solid cancers of different sites were identified as the result of annual compulsory health examination, and a total of 2,442 deaths from all solid cancers in the study cohort were reported. Poisson regression was applied for the analysis of cancer incidence and mortality. The analysis of the standardized incidence ratio (SIR) has shown a statistically significant increase in cancer incidence in the cohort as compared with baseline cancer incidence among males of Russia. The average excess over the entire follow-up period is 18 % [SIR = 1.18, 95 % confidence interval (CI) 1.15; 1.22]. In contrast, however, no increase in the mortality from all cancers among the emergency workers as compared to the baseline mortality in Russian men was found. Values of excess relative risk of cancer incidence and mortality per 1 Gy (ERR Gy(-1)) are 0.47 (95 % CI 0.03; 0.96, p value = 0.034) and 0.58 (95 % CI 0.002; 1.25, p value = 0.049), respectively. These values are statistically significant.

Estimating the lifetime risk of cancer associated with multiple CT scans.

Multiple CT scans are often done on the same patient resulting in an increased risk of cancer. Prior publications have estimated risks on a population basis and often using an effective dose. Simply adding up the risks from single scans does not correctly account for the survival function. A methodology for estimating personal radiation risks attributed to multiple CT imaging using organ doses is presented in this article. The estimated magnitude of the attributable risk fraction for the possible development of radiation-induced cancer indicates the necessity for strong clinical justification when ordering multiple CT scans.

Panthenol-stabilized cerium dioxide nanoparticles for cosmeceutic formulations against ROS-induced and UV-induced damage.

A method of panthenol-stabilized cerium dioxide nanoparticles synthesis was developed and their effect on the survival rate of human epidermoid cancer cells HEp-2 and diploid epithelial swine testicular cell line (ST-cells) under oxidative stress conditions induced by hydrogen peroxide introduction and UV irradiation was studied. The results obtained indicate that the use of panthenol as a stabilizer supposedly provides a substantial increase in the efficiency of protection. The degree of protection is determined by panthenol-to-ceria molar ratio. The combination of panthenol and nano-ceria protects biological objects under study from reactive oxygen species (ROS) and UV-irradiation more effectively than individual panthenol or ceria. The protective action of panthenol-stabilized cerium dioxide nanoparticles depends strongly on their composition and the means of their application.

[Evaluation of intestinal viability on a simulation model of a small ileus based on determination of dielectric parameters].

Interrelationship between dielectric parameters and level of ATPH before and during ischemia, as well as with indices of survival after elimination of strangulation, was estimated on a simulation model of strangulation ileus in rats. The data obtained permit to suppose, that parameter tg δm may be used as effective noninvasive criterion of diagnosis in real time for estimation of the intestinal wall state in strangulation. Resection of the infringed intestine without elimination of strangulation is necessary in tg δm less than 2.20, in tg δm more than 2.36 the elimination of infringement is indicated, because there exist possibility to restore intestinal function after ischemic-reperfusion injury. Tactics of treatment in intermediate meanings of tg δm is not determined, but its measurement before reperfusion may help in estimation of a small intestine viability and choice of surgical tactics in its ischemia.

[Thyroid cancer: lessons of chernobyl and prognosis for Fukushima].

Results of epidemiological studies of thyroid cancer incidence in Russia following the Chernobyl accident are presented in the article. Child population in territories contaminated with radionuclides who got thyroid dose from incorporated (131)I above 100-150 mGy, should be referred to a group at radiation risk. Prognostic estimates of increase in thyroid cancer incidence among the population living in close vicinity of the Fukushima Daiichi NPP were made with account for the Chernobyl data and recommendations of the International Commission on Radiological Protection.

Estimation of risk from medical radiation exposure based on effective and organ dose: how much difference is there?

The authors compare radiation risks of potential cancer following diagnostic radiation exposure evaluated with the use of organ and effective doses. Lifetime attributable risk values of CT scanning are estimated with the use of ICRP (Publication 103) risk models and Russian national medical statistics data. For populations under the age of 50, the risk evaluated using organ doses usually differs from that using effective doses by <30 %. In older populations, the difference can be up to a factor of 3. Calculated values of lifetime attributable cancer risk for particular organs are presented as well.

[Prevention of eventration in diffuse suppurative processes in small pelvis].

The study was devoted to the problem of postoperative eventrations in gynaecological practice. Coaptation removable sutures were applied in order to prevent similar complications. Operations were performed in the cases of desolate condition of purulent disease of the uterus and uterine appendages with diffuse suppurative peritonitis. An advanced operative technique of suturing through all layers of abdominal wall demonstrated its high efficacy. No one patient (from 39) had the eventration or wound abscess.

Formation of potential radiation risk groups to render timely targeted medical care: lessons of Chernobyl.

The paper discusses technology for establishing potential cancer risk groups, based on methods of molecular and radiation epidemiology. Assay of gene mutations at the T-cell receptor (TCR) locus as the method of molecular epidemiology was used for measuring the frequency of TCR-mutations in 320 nuclear workers of the Institute of Physics and Power Engineering (IPPE). The method of radiation epidemiology was applied to the estimation of attributable risk fraction (ARF) for solid cancers in these groups. The main estimates of radiation risk after the Chernobyl accident are in close agreement with the International Commission on Radiological Protection (ICRP) Publication, 103 models published in 2007. In nuclear workers of the IPPE with ARF ≥ 10%, the increased level of TCR-mutations occurs more often (risk ratio=9.7; 95% CI: 2.9; 32.1).

Radiation-epidemiological studies of thyroid cancer incidence in Russia after the Chernobyl accident (estimation of radiation risks, 1991-2008 follow-up period).

This study presents an analysis of the thyroid cancer incidence in the population of the most contaminated territories of Bryansk, Kaluga, Oryol and Tula oblasts affected by the Chernobyl accident. The follow-up period is 1991-2008, and the cohort size is 309 130 people. For that period 978 thyroid cancer cases were detected. The excess relative risk per 1 Gy (ERR/Gy) is found to be statistically significant for children and adolescents (0-17 y of age) at the time of the Chernobyl accident (ERR/Gy=3.22; 95 % confidence interval (1.56; 5.81). In boys, the ERR/Gy was higher than in girls -6.54 and 2.24, respectively. A statistically significant decrease in ERR/Gy with time since exposure, by a factor of 0.37 per 10 y, was observed for the whole cohort and for boys separately, but not for girls. No radiation risks of a thyroid cancer among people of 18 y of age at exposure and older were found.

Leukemia incidence in the Russian cohort of Chernobyl emergency workers.

Of all potentially radiogenic cancers, leukemia, a type of cancer of the blood, has the highest risk attributable to ionizing radiation. Despite this, the quantitative estimation of radiation risk of a leukemia demands studying very large exposed cohorts, because of the very low level of this disease in unexposed populations and because of the tendency for its radiation risk to decrease with time. At present, the Japanese cohort of atomic bomb survivors is still the primary source of data that allows analysis of radiation-induced leukemia and the underlying dose-response relationship. The second large cohort that would allow to study radiation-induced leukemia is comprised of individuals who were exposed due to the accident of the Chernobyl nuclear power plant in 1986. The objective of the present study was to estimate radiation risks of leukemia incidence among the Russian cohort of Chernobyl emergency workers, for different time periods after the accident. Twenty-five years after the Chernobyl accident and based on the results of the present study, one can conclude that the radiation risk of leukemia incidence derived from the Russian cohort of Chernobyl emergency workers is similar to that derived from the cohort of atomic bomb survivors: The time-averaged excess relative risk per Gray (ERR Gy(-1)) equals 4.98 for the Russian cohort and 3.9 for the life span study (LSS) cohort; excess absolute risk decreases with time after exposure at an annual rate of 9% for the Russian cohort, and of 6.5% for the LSS cohort. Thus, the excess in risk of leukemia incidence in a population due to a single exposure is restricted in time after exposure by the period of about 15 years.