Protracted Exposure to a Sub-background Radiation Environment Negatively Impacts the Anhydrobiotic Recovery of Desiccated Yeast Sentinels.

ABSTRACT: Experiments that examine the impacts of subnatural background radiation exposure provide a unique approach to studying the biological effects of low-dose radiation. These experiments often need to be conducted in deep underground laboratories in order to filter surface-level cosmic radiation. This presents some logistical challenges in experimental design and necessitates a model organism with minimal maintenance. As such, desiccated yeast ( Saccharomyces cerevisiae ) is an ideal model system for these investigations. This study aimed to determine the impact of prolonged sub-background radiation exposure in anhydrobiotic (desiccated) yeast at SNOLAB in Sudbury, Ontario, Canada. Two yeast strains were used: a normal wild type and an isogenic recombinational repair-deficient rad51 knockout strain ( rad51 Δ). Desiccated yeast samples were stored in the normal background surface control laboratory (68.0 nGy h -1 ) and in the sub-background environment within SNOLAB (10.1 nGy h -1 ) for up to 48 wk. Post-rehydration survival, growth rate, and metabolic activity were assessed at multiple time points. Survival in the sub-background environment was significantly reduced by a factor of 1.39 and 2.67 in the wild type and rad51 ∆ strains, respectively. Post-rehydration metabolic activity measured via alamarBlue reduction remained unchanged in the wild type strain but was 26% lower in the sub-background rad51 ∆ strain. These results demonstrate that removing natural background radiation negatively impacts the survival and metabolism of desiccated yeast, highlighting the potential importance of natural radiation exposure in maintaining homeostasis of living organisms.

Acute Impacts of Ionizing Radiation Exposure on the Gastrointestinal Tract and Gut Microbiome in Mice.

Radiation therapy for abdominopelvic malignancies often results in damage to the gastrointestinal tract (GIT) and permanent changes in bowel function. An overlooked component of the pathophysiology of radiation-induced bowel injury is the role of the gut microbiome. The goal of this research was to identify the impacts of acute radiation exposure on the GIT and gut microbiome. C57BL/6 mice exposed to whole-body X-rays (0.1-3 Gy) were assessed for histological and microbiome changes 48 h post-radiation exposure. Within the ileum, a dose of 3 Gy significantly decreased crypt depth as well as the number of goblet cells, but increased overall goblet cell size. Overall, radiation altered the microbial distribution within each of the main phyla in a dose- and tissue-dependent manner. Within the Firmicutes phylum, high dose irradiation resulted in significant alterations in bacteria from the class Bacilli within the small bowels, and from the class Clostridia in the large bowels. The 3 Gy radiation also significantly increased the abundance of bacterial families from the Bacteroidetes phylum in the colon and feces. Overall, we identified various alterations in microbiome composition following acute radiation exposure, which could potentially lead to novel biomarkers for tracking patient toxicities or could be used as targets for mitigation strategies against radiation damage.

Impact of and interplay between proton arc therapy and range uncertainties in proton therapy for head-and-neck cancer.

Objective. Proton therapy reduces the integral dose to the patient compared to conventional photon treatments. However,in vivoproton range uncertainties remain a considerable hurdle. Range uncertainty reduction benefits depend on clinical practices. During intensity-modulated proton therapy (IMPT), the target is irradiated from only a few directions, but proton arc therapy (PAT), for which the target is irradiated from dozens of angles, may see clinical implementation by the time considerable range uncertainty reductions are achieved. It is therefore crucial to determine the impact of PAT on range uncertainty reduction benefits.Approach. For twenty head-and-neck cancer patients, four different treatment plans were created: an IMPT and a PAT treatment plan assuming current clinical range uncertainties of 3.5% (IMPT3.5%and PAT3.5%), and an IMPT and a PAT treatment plan assuming that range uncertainties can be reduced to 1% (IMPT1%and PAT1%). Plans were evaluated with respect to target coverage and organ-at-risk doses as well as normal tissue complication probabilities (NTCPs) for parotid glands (endpoint: parotid gland flow <25%) and larynx (endpoint: larynx edema).Main results. Implementation of PAT (IMPT3.5%-PAT3.5%) reduced mean NTCPs in the nominal and worst-case scenario by 3.2 percentage points (pp) and 4.2 pp, respectively. Reducing range uncertainties from 3.5% to 1% during use of IMPT (IMPT3.5%-IMPT1%) reduced evaluated NTCPs by 0.9 pp and 2.0 pp. Benefits of range uncertainty reductions subsequently to PAT implementation (PAT3.5%-PAT1%) were 0.2 pp and 1.0 pp, with considerably higher benefits in bilateral compared to unilateral cases.Significance. The mean clinical benefit of implementing PAT was more than twice as high as the benefit of a 3.5%-1% range uncertainty reduction. Range uncertainty reductions are expected to remain beneficial even after PAT implementation, especially in cases with target positions allowing for full leveraging of the higher number of gantry angles during PAT.

Phenotypic and transcriptional changes in lens epithelial cells following acute and fractionated ionizing radiation exposure.

PURPOSE: Exposure to ionizing radiation is one of the known risk factors for the development of lens opacities. It is believed that radiation interactions with lens epithelial cells (LEC) are the underlying cause of cataract development, however, the exact mechanisms have yet to be identified. The aim of this study was to investigate how different radiation dose and fractionation impact normal LEC function. MATERIALS AND METHODS: A human derived LEC cell line (HLE-B3) was exposed to a single acute x-ray dose (0.25 Gy) and 6 fractionated doses (total dose of 0.05, 0.1, 0.25, 0.5, 1, and 2 Gy divided over 5 equal fractions). LEC were examined for proliferation using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and migration using a Boyden chamber assay at various time points (0.25, 0.5, 1, 2, 4, 7, 9, 11, and 14 d) post-irradiation. Transcriptomic analysis through RNA sequencing was also performed to identify differentially expressed genes and regulatory networks in cells following 4 different acute exposures and 1 fractionated exposure. RESULTS: Exposure to an acute dose of 0.25 Gy significantly increased proliferation and migration rates, peaking at 7 d post irradiation (20% and 240% greater than controls, respectively), before returning to baseline levels by day 14. Fractionated exposures had minimal effects up to a dose of 0.5 Gy, but significantly reduced proliferation and migration after 1 and 2 Gy by up to 50%. The largest transcriptional response occurred 12 h after an acute 0.25 Gy dose, with 362 genes up-regulated and 288 genes down-regulated. A unique panel of differentially expressed genes was observed between moderate versus high dose exposures, suggesting a dose-dependent transcriptional response in LEC that is more pronounced at lower doses. Gene ontology and upstream regulator analysis identified multiple biological processes and molecular functions implicated in the radiation response, in particular differentiation, motility, receptor/ligand binding, cell signaling and epithelial-mesenchymal cell transition. CONCLUSIONS: Overall, this research provides novel insights into the dose and fractionation effects on functional changes and transcriptional regulatory networks in LEC, furthering our understanding of the mechanisms behind radiation induced cataracts.

Reconstruction of organ doses for patients undergoing computed tomography examinations in Canada 1992-2019.

We derived the first comprehensive organ dose library for Canadian pediatric and adult patients who underwent computed tomography (CT) scans between 1992 and 2019 to support epidemiological analysis of radiation risk. We calculated organ absorbed doses for Canadian CT patients in two steps. First, we modeled Computed Tomography Dose Index (CTDI) values by patient age, scan body part, and scan year for the scan period between 1992 and 2019 using national survey data conducted in Canada and partially the United Kingdom survey data as surrogates. Second, we converted CTDI values to organ absorbed doses using a library of organ dose conversion coefficients built in an organ dose calculation program, the National Cancer Institute dosimetry system for CT. In result, we created a library of doses delivered to 33 organs and tissues by different patient ages and genders, scan body parts and scan years. In the scan period before 2000, the organs receiving the greatest dose in the head, chest and abdomen-pelvis scans were the active marrow (3.7-15.2 mGy), lungs (54.7-62.8 mGy) and colon (54.9-68.5 mGy), respectively. We observed organ doses reduced by 24% (pediatric head and torso scans, and adult head scans) and 55% (adult torso scans) after 2000. The organ dose library will be used to analyse the risk of radiation exposure from CT scans in the Canadian CT patient cohort.

Assessment of Cataract Risk after Diagnostic Head CT Scan Radiation Exposure in Ontario, Canada.

Ionizing radiation is one of the known risk factors for cataract development, however, there is still debate regarding the level of risk after low dose exposures. One of the largest sources of radiation exposure to the lens of the eye is diagnostic CT scans. The aim of this study was to examine whether ionizing radiation associated with head CT scans increases cataract risk in residents of Ontario, Canada. Data were collected from January 1, 1994 to December 31, 2015 (22 years) from anonymized Ontario Health Insurance Plan (OHIP) medical records for over 16 million subjects. A lens dose was estimated for each CT scan using the National Cancer Institute dosimetry system for CT (NCICT) program combined with Canada-specific CTDIvol data. Multivariate Cox proportional hazards analysis was performed with cataract extraction surgery as the primary outcome and lens dose as the main variable of interest, with inclusion of various medical and demographic covariates. Lag periods of 3, 5 and 7 years were incorporated. When lens dose was treated as a continuous variable, hazard ratios (per 100 mGy) ranged from 0.82 (0.80-0.84) to 1.10 (1.09-1.11) depending on the lag period. As a secondary analysis, when individuals were binned based on their total cumulative dose, no significant dose response pattern was observed in the low dose region. Overall, within the bounds of this study, the data do not support an increased risk of vision impairing cataracts after diagnostic head CT scan radiation exposure.

Overexpression of FRA1 (FOSL1) Leads to Global Transcriptional Perturbations, Reduced Cellular Adhesion and Altered Cell Cycle Progression.

FRA1 (FOSL1) is a transcription factor and a member of the activator protein-1 superfamily. FRA1 is expressed in most tissues at low levels, and its expression is robustly induced in response to extracellular signals, leading to downstream cellular processes. However, abnormal FRA1 overexpression has been reported in various pathological states, including tumor progression and inflammation. To date, the molecular effects of FRA1 overexpression are still not understood. Therefore, the aim of this study was to investigate the transcriptional and functional effects of FRA1 overexpression using the CGL1 human hybrid cell line. FRA1-overexpressing CGL1 cells were generated using stably integrated CRISPR-mediated transcriptional activation, resulting in a 2-3 fold increase in FRA1 mRNA and protein levels. RNA-sequencing identified 298 differentially expressed genes with FRA1 overexpression. Gene ontology analysis showed numerous molecular networks enriched with FRA1 overexpression, including transcription-factor binding, regulation of the extracellular matrix and adhesion, and a variety of signaling processes, including protein kinase activity and chemokine signaling. In addition, cell functional assays demonstrated reduced cell adherence to fibronectin and collagen with FRA1 overexpression and altered cell cycle progression. Taken together, this study unravels the transcriptional response mediated by FRA1 overexpression and establishes the role of FRA1 in adhesion and cell cycle progression.

Genomic Loss and Epigenetic Silencing of the FOSL1 Tumor Suppressor Gene in Radiation-induced Neoplastic Transformation of Human CGL1 Cells Alters the Tumorigenic Phenotype In Vitro and In Vivo.

The CGL1 human hybrid cell system has been utilized for many decades as an excellent cellular tool for investigating neoplastic transformation. Substantial work has been done previously implicating genetic factors related to chromosome 11 to the alteration of tumorigenic phenotype in CGL1 cells. This includes candidate tumor suppressor gene FOSL1, a member of the AP-1 transcription factor complex which encodes for protein FRA1. Here we present novel evidence supporting the role of FOSL1 in the suppression of tumorigenicity in segregants of the CGL1 system. Gamma-induced mutant (GIM) and control (CON) cells were isolated from 7 Gy gamma-irradiated CGL1s. Western, Southern and Northern blot analysis were utilized to assess FOSL1/FRA1 expression as well as methylation studies. GIMs were transfected to re-express FRA1 and in vivo tumorigenicity studies were conducted. Global transcriptomic microarray and RT-qPCR analysis were used to further characterize these unique cell segregants. GIMs were found to be tumorigenic in vivo when injected into nude mice whereas CON cells were not. GIMs show loss of Fosl/FRA1 expression as confirmed by Western blot. Southern and Northern blot analysis further reveals that FRA1 reduction in tumorigenic CGL1 segregants is likely due to transcriptional suppression. Results suggest that radiation-induced neoplastic transformation of CGL1 is in part due to silencing of the FOSL1 tumor suppressor gene promoter by methylation. The radiation-induced tumorigenic GIMs transfected to re-express FRA1 resulted in suppression of subcutaneous tumor growth in nude mice in vivo. Global microarray analysis and RT-qPCR validation elucidated several hundred differentially expressed genes. Downstream analysis reveals a significant number of altered pathways and enriched Gene Ontology terms genes related to cellular adhesion, proliferation, and migration. Together these findings provide strong evidence that FRA1 is a tumor suppressor gene deleted and epigenetically silenced after ionizing radiation-induced neoplastic transformation in the CGL1 human hybrid cell system.

The REPAIR Project, a Deep-Underground Radiobiology Experiment Investigating the Biological Effects of Natural Background Radiation: The First 6 Years.

In 2017, a special edition of Radiation Research was published [Oct; Vol. 188 4.2 (https://bioone.org/journals/radiation-research/volume-188/issue-4.2)] which focused on a recently established radiobiology project within SNOLAB, a unique deep-underground research facility. This special edition included original articles, reviews and commentaries relevant to the research goals of this new project which was titled Researching the Effects of the Presence and Absence of Ionizing Radiation (REPAIR). These research goals were founded in understanding the biological effects of terrestrial and cosmic natural background radiation (NBR). Since 2017, REPAIR has evolved into a sub-NBR radiobiology research program which investigates these effects using multiple model systems and various biological endpoints. This paper summarizes the evolution of the REPAIR project over the first 6-years including its experimental scope and capabilities as well as research accomplishments.

Low-Dose Hemibody Radiation, a Treatment Option for Recurrent Prostate Cancer: A Phase 2 Single-Arm Trial.

Purpose: Nontargeted low-dose ionizing radiation has been proposed as a cancer therapeutic for several decades; however, questions remain about the duration of hematological changes and optimal dosing regimen. Early studies delivering fractionated low doses of radiation to patients with cancer used varying doses and schedules, which make it difficult to standardize a successful dose and scheduling system for widespread use. The aim of this phase 2 two-stage trial was to determine whether low-dose radiation therapy (LD-RT) reduced prostate-specific antigen (PSA) in patients with recurrent prostate cancer in efforts to delay initiation of conventional therapies that are known to decrease quality of life. The primary study outcome was reduction in PSA levels by at least 50%. Methods and Materials: Sixteen patients with recurrent prostate cancer were recruited and received 2 doses of 150 mGy of nontargeted radiation per week, for 5 consecutive weeks, with 15 participants completing the study. Results: A maximal response of 40.5% decrease in PSA at 3 months was observed. A total of 8 participants remained off any additional interventions, of whom 3 had minor fluctuations in PSA for at least 1 year after treatment. The most common adverse event reported was mild fatigue during active treatment (n = 4), which did not persist in the follow-up period. No participants withdrew due to safety concerns or hematological abnormalities (ie, platelet ≤50 × 109/L, leukocyte ≤3 × 109/L, granulocyte ≤2 × 109/L). Conclusions: Our study did not meet the primary objective; however, LD-RT may be a potential therapy for some patients with recurrent prostate cancer by stalling rising PSA. This study also demonstrates that low-dose radiation is well tolerated by participants with minimal toxicities and no change in quality of life.

Identification of Radiation-Induced miRNA Biomarkers Using the CGL1 Cell Model System.

MicroRNAs (miRNAs) have emerged as a potential class of biomolecules for diagnostic biomarker applications. miRNAs are small non-coding RNA molecules, produced and released by cells in response to various stimuli, that demonstrate remarkable stability in a wide range of biological fluids, in extreme pH fluctuations, and after multiple freeze-thaw cycles. Given these advantages, identification of miRNA-based biomarkers for radiation exposures can contribute to the development of reliable biological dosimetry methods, especially for low-dose radiation (LDR) exposures. In this study, an miRNAome next-generation sequencing (NGS) approach was utilized to identify novel radiation-induced miRNA gene changes within the CGL1 human cell line. Here, irradiations of 10, 100, and 1000 mGy were performed and the samples were collected 1, 6, and 24 h post-irradiation. Corroboration of the miRNAome results with RT-qPCR verification confirmed the identification of numerous radiation-induced miRNA expression changes at all doses assessed. Further evaluation of select radiation-induced miRNAs, including miR-1228-3p and miR-758-5p, as well as their downstream mRNA targets, Ube2d2, Ppp2r2d, and Id2, demonstrated significantly dysregulated reciprocal expression patterns. Further evaluation is needed to determine whether the candidate miRNA biomarkers identified in this study can serve as suitable targets for radiation biodosimetry applications.

Radiation-Induced Alterations in Proliferation, Migration, and Adhesion in Lens Epithelial Cells and Implications for Cataract Development.

The lens of the eye is one of the most radiosensitive tissues. Although the exact mechanism of radiation-induced cataract development remains unknown, altered proliferation, migration, and adhesion have been proposed as factors. Lens epithelial cells were exposed to X-rays (0.1-2 Gy) and radiation effects were examined after 12 h and 7 day. Proliferation was quantified using an MTT assay, migration was measured using a Boyden chamber and wound-healing assay, and adhesion was assessed on three extracellular matrices. Transcriptional changes were also examined using RT-qPCR for a panel of genes related to these processes. In general, a nonlinear radiation response was observed, with the greatest effects occurring at a dose of 0.25 Gy. At this dose, a reduction in proliferation occurred 12 h post irradiation (82.06 ± 2.66%), followed by an increase at 7 day (116.16 ± 3.64%). Cell migration was increased at 0.25 Gy, with rates 121.66 ± 6.49% and 232.78 ± 22.22% greater than controls at 12 h and 7 day respectively. Cell adhesion was consistently reduced above doses of 0.25 Gy. Transcriptional alterations were identified at these same doses in multiple genes related to proliferation, migration, and adhesion. Overall, this research began to elucidate the functional changes that occur in lens cells following radiation exposure, thereby providing a better mechanistic understanding of radiation-induced cataract development.

Hematological Changes Following Low Dose Radiation Therapy and Comparison to Current Standard of Care Cancer Treatments.

Cancer is the second leading cause of mortality worldwide accounting for almost 10 million deaths in 2020. Current standard of care treatment varies depending on the type and stage of disease, but commonly includes surgery, chemotherapy, and/or radiation therapy. There is evidence that whole- and half-body exposure to low dose ionizing radiation can also be an effective therapeutic due to its stimulation of anti-cancer immunity. One of the limiting factors for past clinical trials using low dose radiation therapy has been adverse hematological events. However, similar hematological changes are also frequently reported following standard of care treatments in oncology. This review summarizes the effects of various cancer therapies on hematologic toxicity through the evaluation of complete blood count reports. The reviewed literature elucidates hematological trends in patients undergoing chemotherapy, and both high and low dose radiation therapy. In general, high dose radiation and chemotherapy can result in widespread changes in blood counts, with the most severe effects related to leukopenia. Overall, compared to standard of care treatments, low dose radiation results in similar, yet more mild hematological changes. Taken together, hematological toxicities should not be a limiting factor in the applicability of low dose radiation as a cancer therapeutic.

DOSIMETRIC CHARACTERISATION OF A SUB-NATURAL BACKGROUND RADIATION ENVIRONMENT FOR RADIOBIOLOGY INVESTIGATIONS.

Living systems have evolved in the presence of naturally occurring ionising radiation. REPAIR is a research project investigating the biological effects of sub-natural background radiation exposure in SNOLAB, a deep-underground laboratory. Biological systems are being cultured within a sub-background environment as well as two control locations (underground and surface). A comprehensive dosimetric analysis was performed. GEANT4 simulation was used to characterise the contribution from gamma, muons and neutrons. Additionally, dose rates from radon, 40K and 14C were calculated based on measured activity concentrations. The total absorbed dose rate in the sub-background environment was 27 times lower than the surface control, at 2.48 ± 0.20 nGy hr-1, including a >400-fold reduction in the high linear energy transfer components. This modelling quantitatively confirms that the environment within SNOLAB provides a substantially reduced background radiation dose rate, thereby setting the stage for future sub-background biological studies using a variety of model organisms.

A novel specialized tissue culture incubator designed and engineered for radiobiology experiments in a sub-natural background radiation research environment.

Extensive research has been conducted investigating the effects of ionizing radiation on biological systems, including specific focus at low doses. However, at the surface of the planet, there is the ubiquitous presence of ionizing natural background radiation (NBR) from sources both terrestrial and cosmic. We are currently conducting radiobiological experiments examining the impacts of sub-NBR exposure within SNOLAB. SNOLAB is a deep underground research laboratory in Sudbury, Ontario, Canada located 2 km beneath the surface of the planet. At this depth, significant shielding of NBR components is provided by the rock overburden. Here, we describe a Specialized Tissue Culture Incubator (STCI) that was engineered to significantly reduce background ionizing radiation levels. The STCI was installed 2 km deep underground within SNOLAB. It was designed to allow precise control of experimental variables such as temperature, atmospheric gas composition and humidity. More importantly, the STCI was designed to reduce radiological contaminants present within the underground laboratory. Quantitative measurements validated the STCI is capable of maintaining an appropriate experimental environment for sub-NBR experiments. This included reduction of sub-surface radiological contaminants, most notably radon gas. The STCI presents a truly novel piece of infrastructure enabling future research into the effects of sub-NBR exposure in a highly unique laboratory setting.

Modifying effects of a cobble substrate on thermal environments and implications for embryonic development in lake whitefish (Coregonus clupeaformis).

A laboratory flume was constructed to examine substrate effects on aquatic development. The flume was designed as a once-through system with a submerged cobble-filled corebox. Lake whitefish (Coregonus clupeaformis) embryos and temperature probes were deployed at multiple sites within the cobble and in the open water channel. Embryos were incubated in the flume for two different experimental periods: one to examine substrate impacts during natural lake cooling (37 days: 5 December 2016 to 10 January 2017) and the second to investigate substrate effects while administering a twice weekly 1 h heat shock (51 days: 11 January to 2 March 2017). During incubation, no significant difference was found in the average temperature between locations; however, temperatures were more stable within the cobble. Following both incubation periods, embryos retrieved from the cobble were significantly smaller in both dry mass and body length by up to 20%. These results demonstrate differences between embryos submerged in a cobble substrate and in the open water column, highlighting the need to consider the physical influences from the incubation environment when assessing development effects as part of any scientific study or environmental assessment.

Cataract Formation and Low-Dose Radiation Exposure from Head Computed Tomography (CT) Scans in Ontario, Canada, 1994-2015.

Ionizing radiation exposure to the lens of the eye is a known cause of cataractogenesis. Administrative data from the Ontario Health Insurance Program was used to examine the association between low-dose radiation exposure from head CT scans and cataract extraction surgery for 16 million Ontarians over a 22-year period (1994-2015). Subjects were grouped based on the number of head CT scans they received, and a Cox proportional hazards analysis was used to determine if there was a correlation with cataract surgery. Covariates included in the analysis were age, sex, diabetes, hypertension and prior history of intraocular surgery. To account for the potentially long latency period between radiation exposure and cataract formation, the data were analyzed incorporating a 5- and 10-year lag between head CT scan exposure and cataract surgery. Both the 5- and 10-year lagged models followed a similar trend, where only the first three head CT scans significantly increased the risk of cataract surgery by 3-8%. Individuals receiving four or more head CT scans did not have an increased cataract risk and in several cases the risk was reduced. Overall, no positive dose-response relationship was seen between the number of head CT scans received and the risk of cataract surgery. Due to the nature of the data extracted from medical records, several uncertainties exist in the analysis related to dosimetry, ultraviolet light exposure and smoking status. Nonetheless, these results do not support an association between ionizing radiation from repeated head CT scans and cataract formation.

Transcriptomic profiling of gamma ray induced mutants from the CGL1 human hybrid cell system reveals novel insights into the mechanisms of radiation-induced carcinogenesis.

BACKGROUND: Somatic cell hybrid systems generated by combining cancerous with non-cancerous cells provide useful model systems to study neoplastic transformation. Combined with recent advances in omics-based technologies, novel molecular signatures that drive radiation-induced carcinogenesis can be analyzed at an exceptional global level. METHODS: Here, we present a complete whole-transcriptome analysis of gamma-induced mutants (GIM) and gamma irradiated control (CON) segregants isolated from the CGL1 (HeLa x normal fibroblast) human hybrid cell-system exposed to high doses of radiation. Using the Human Transcriptome Array 2.0 microarray technology and conservative discrimination parameters, we have elucidated 1067 differentially expressed genes (DEGs) between tumorigenic and non-tumorigenic cells. RESULTS: Gene ontology enrichment analysis revealed that tumorigenic cells demonstrated shifts in extracellular matrix (ECM) and cellular adhesion profiles, dysregulation of cyclic AMP (cAMP) signaling, and alterations in nutrient transport and cellular energetics. Furthermore, putative upstream master regulator analysis demonstrated that loss of TGFß1 signaling due to reduced SMAD3 expression is involved in radiation-induced carcinogenesis. CONCLUSIONS: Taken together, this study presents novel insights into specific gene expression and pathway level differences that contribute to radiation-induced carcinogenesis in a human cell-based model. This global transcriptomic analysis and our published tumor suppressor gene deletion loci analyses will allow us to identify and functionally test candidate nexus upstream tumor suppressor genes that are deleted or silenced after exposure to radiation.

Physical and chemical characterization of McIntyre Powder: An aluminum dust inhaled by miners to combat silicosis.

McIntyre Powder (MP) is a finely ground aluminum powder that was used between 1943 and 1979 as a prophylaxis for silicosis. Silicosis is a chronic lung disease caused by the inhalation of crystalline silica dust and was prevalent in the Canadian mining industry during this time period. The McIntyre Research Foundation developed, patented, and produced the MP and distributed it to licensees in Canada, the United States, Mexico, Chile, Belgian Congo, and Western Australia. In the province of Ontario, Canada it is estimated that at least 27,500 miners between 1943 and 1979 were exposed to MP. The present study was undertaken to examine the chemical and physical characteristics of two variations of MP (light grey and black). Chemical analyses (using X-ray Fluorescence and Inductively Coupled Plasma approaches) indicate that the black MP contains significantly higher concentrations of aluminum and metal impurities than the light grey MP (p < 0.001). X-ray diffractometry shows that while aluminum hydroxide dominates the aluminum speciation in both variations, the higher total aluminum content in the black MP is attributable to a greater proportion of elemental aluminum. Physical characterization (using electron microscopy, light microscopy, and dynamic light scattering) indicates that the light grey MP consists of particles ranging from 5 nm to 5 µm in diameter. Atomic Force Microscopy shows that the light grey MP particles in the nanoparticle range (<100 nm) have a mode between 5 and 10 nm. Consequently, it is possible that inhaled smaller MP nanoparticles may be transported via blood and lymph fluid circulation to many different organs including the brain. It is also possible for inhaled larger MP particles to deposit onto lung tissue and for potential health effects to arise from inflammatory responses through immune activation. This MP characterization will provide crucial data to help inform future toxicological, epidemiological, and biological studies of any long-term effects related to the inhalation of aluminum dust and nanomaterials.

The influence of changing dose rate patterns from inhaled beta-gamma emitting radionuclide on lung cancer.

PURPOSE: Dose and dose rate are both appropriate for estimating risk from internally deposited radioactive materials. We investigated the role of dose rate on lung cancer induction in Beagle dogs following a single inhalation of strontium-90 (90Sr), cerium-144 (144Ce), yttrium-91 (91Y), or yttrium-90 (90Y). As retention of the radionuclide is dependent on biological clearance and physical half-life a representative quantity to describe this complex changing dose rate is needed. MATERIALS AND METHODS: Data were obtained from Beagle dog experiments from the Inhalation Toxicology Research Institute. The authors selected the dose rate at the effective half-life of each radionuclide (DRef). RESULTS: Dogs exposed to DRef (1-100 Gy/day) died within the first year after exposure from acute lung disease. Dogs exposed at lower DRef (0.1-10 Gy/day) died of lung cancer. As DRef decreased further (<0.1 Gy/day 90Sr, <0.5 Gy/day 144Ce, <0.9 Gy/day 91Y, <8 Gy/day 90Y), survival and lung cancer frequency were not significantly different from control dogs. CONCLUSION: Radiation exposures resulting from inhalation of beta-gamma emitting radionuclides that decay at different rates based on their effective half-life, leading to different rates of decrease in dose rate and cumulative dose, is less effective in causing cancer than acute low linear energy transfer exposures of the lung.