Morphological features of pulmonary fibrosis in workers occupationally exposed to alpha radiation.

Purpose: The article reports on a comparative analysis of biological specimens of lung tissues collected from workers with pulmonary fibrosis induced by internal exposure to plutonium alpha-particles (plutonium-induced pulmonary fibrosis [PuPF]) and with etiologically different pulmonary fibrosis (non-PuPF) that developed as an outcome of a chronic obstructive pulmonary disease (COPD).Materials and methods: To perform histological examinations, lung tissues were sampled during autopsy. Six samples of various lung regions (the apical region, the lingula of the left lung and the inferior lobe) were collected from each donor. The resected tissue samples were fixed in 10% neutral-buffered formalin during 24 h and embedded into paraffin blocks (FFPE). FFPE blocks with lung tissue specimens collected from 56 workers with PuPF, 34 workers with non-PuPF and 35 workers without any lung disease were used in the study. To perform microscopic examination, lung tissue specimens were hematoxylin and eosin stained. To examine the connective-tissue scaffold of lung stroma and identify foci of pulmonary fibrosis, the cut sections of paraffin blocks were stained by Van Gizon's method (to assess the total volume of fibrosis-affected tissues), Gomori's technique (to define the reticular scaffold of lung stroma) and Weigert's technique (to examine elastic fibers). Morphological patterns of all biological specimens were studied using immunohistochemistry. To fit the empirical data, the Weibull's model was used.Results and conclusions: The study found qualitative and quantitative morphological features specific for PuPF compared to non-PuPF. The study demonstrated that hyper-production of collagen type V plays a key role in PuPF. The collagen type V content in fibrotic foci in lung tissue specimens from workers with PuPF was found to be increased.

Somatic mutation signatures in primary liver tumors of workers exposed to ionizing radiation.

Liver cancer is associated with genetic mutations caused by environmental exposures, including occupational exposure to alpha radiation emitted by plutonium. We used whole exome sequencing (WES) to characterize somatic mutations in 3 histologically distinct primary liver tumors (angiosarcoma of the liver (ASL), cholangiocarcinoma (CCA) and hepatocellular carcinoma (HCC)) from Mayak worker subjects occupationally exposed to ionizing radiation (IR) to investigate the contribution of IR to the mutational landscape of liver cancer. DNA sequence analysis revealed these tumors harbor an excess of deletions, with a deletions:substitutions ratio similar to that previously reported in radiation-associated tumors. These tumors were also enriched for clustered mutations, a signature of radiation exposure. Multiple tumors displayed similarities in abrogated gene pathways including actin cytoskeletal signaling and DNA double-strand break (DSB) repair. WES identified novel candidate driver genes in ASL involved in angiogenesis and PIK3CA/AKT/mTOR signaling. We confirmed known driver genes of CCA, and identified candidate driver genes involved in chromatin remodeling. In HCC tumors we validated known driver genes, and identified novel putative driver genes involved in Wnt/ß-catenin signaling, chromatin remodeling, PIK3CA/AKT/mTOR signaling, and angiogenesis. This pilot study identifies several novel candidate driver mutations that are likely to be caused by IR exposure, and provides the first data on the mutational landscape of liver cancer after IR exposure.

The Russian Human Radiobiological Tissue Repository: A Unique Resource for Studies of Plutonium-Exposed Workers.

The Russian Radiobiological Human Tissue Repository (RHTR) at the Southern Urals Biophysics Institute in Ozyorsk, Russia, was established to collect and store biospecimens supporting research on health consequences of chronic, low-dose radiation exposures. The purpose of this paper is to describe the RHTR resources and the availability of high-quality biological specimens. RHTR has enrolled two groups of subjects from 1951 to the present time: exposed workers at the Mayak Production Association facilities and residents of Ozyorsk who were never occupationally exposed to ionizing radiation (controls). Biospecimens are collected with informed consent of participants and are annotated with demographic, occupational, dosimetry and medical information. To date, 900 individuals have provided surgical tissues and 1000 have provided autopsy tissues. Blood samples are also collected and stored. Familial DNA is available from parent-offspring triads. Biospecimens and annotated data are available to interested scientists worldwide, via the RHTR website.

A repository of bio-specimens from Mayak workers exposed to protracted radiation.

A repository of bio-specimens that includes organs from 700 deceased workers employed at the first nuclear weapons facility "Mayak" and donations of blood, buccal cells, and tissues removed at the time of surgery and/or biopsy from the members of the Mayak cohort undergoing medical treatment or diagnostic procedures has been established at the Southern Ural Biophysics Institute, in Ozyorsk, Russian Federation. The autopsied tissues include formaline-preserved organs, paraffin blocks, and histology slides. For all, occupational, dosimetry, and detailed medical information is available. For 359 individuals, information on malignant tumors, i.e., lung (171), stomach (51), liver (28), and intestine (19), as well as 32 cases of leukemia, are available. External gamma exposures are known for 95% of the 700 autopsies, of whom 560 were exposed to protracted doses exceeding 0.5 Gy, with known maximum annual doses ranging from 0.01-0.5 Gy for about 46%, and annual doses exceeding 0.5 Gy for 48%. Plutonium body burden is known for 73%, of which 40% had body burden greater than 1.5 kBq, and 15% of individuals had body burdens greater than 11.85 kBq. Newly collected specimens include frozen lymphocytes, EBV-immortalized B-cells, frozen erythrocytes, and DNA as well as frozen tumors. Donations were obtained to date from more than 1,600 individuals. For these donors external doses of exposure exceeded 0.5 Gy for 83%, and plutonium body burden exceeded 1.48 kBq for 30%. A Web site describing the Repository that also includes forms for tissue requests can be accessed at http://www.subi.ru/RHTR.