VADER: a variable dose-rate external Cs irradiator for internal emitter and low dose rate studies.

In the long term, Cs is probably the most biologically important agent released in many accidental (or malicious) radiation disasters. It can enter the food chain, and be consumed, or, if present in the environment (e.g.

Effects of High- and Low-LET Radiation on Human Hematopoietic System Reconstituted in Immunodeficient Mice.

Over the last 50 years, a number of important physiological changes in humans who have traveled on spaceflights have been catalogued. Of major concern are the short- and long-term radiation-induced injuries to the hematopoietic system that may be induced by high-energy galactic cosmic rays encountered on interplanetary space missions. To collect data on the effects of space radiation on the human hematopoietic system in vivo, we used a humanized mouse model.

Candidate protein markers for radiation biodosimetry in the hematopoietically humanized mouse model.

After a radiological incident, there is an urgent need for fast and reliable bioassays to identify radiation-exposed individuals within the first week post exposure. This study aimed to identify candidate radiation-responsive protein biomarkers in human lymphocytes in vivo using humanized NOD scid gamma (Hu-NSG) mouse model. Three days after X-irradiation (0-2 Gy, 88 cGy/min), human CD45+ lymphocytes were collected from the Hu-NSG mouse spleen and quantitative changes in the proteome of the human lymphocytes were analysed by mass spectrometry.

In vitro RABiT measurement of dose rate effects on radiation induction of micronuclei in human peripheral blood lymphocytes.

Developing new methods for radiation biodosimetry has been identified as a high-priority need in case of a radiological accident or nuclear terrorist attacks. A large-scale radiological incident would result in an immediate critical need to assess the radiation doses received by thousands of individuals. Casualties will be exposed to different doses and dose rates due to their geographical position and sheltering conditions, and dose rate is one of the principal factors that determine the biological consequences of a given absorbed dose.

Radiation Dose-Rate Effects on Gene Expression in a Mouse Biodosimetry Model.

In the event of a nuclear accident or radiological terrorist attack, there will be a pressing need for biodosimetry to triage a large, potentially exposed population and to assign individuals to appropriate treatment. Exposures from fallout are likely, resulting in protracted dose delivery that would, in turn, impact the extent of injury. Biodosimetry approaches that can distinguish such low-dose-rate (LDR) exposures from acute exposures have not yet been developed.

Radiation dose-rate effects on gene expression for human biodosimetry.

Background: The effects of dose-rate and its implications on radiation biodosimetry methods are not well studied in the context of large-scale radiological scenarios. There are significant health risks to individuals exposed to an acute dose, but a realistic scenario would include exposure to both high and low dose-rates, from both external and internal radioactivity. It is important therefore, to understand the biological response to prolonged exposure; and further, discover biomarkers that can be used to estimate damage from low-dose rate exposures and propose appropriate clinical treatment.

The effect of low dose rate on metabolomic response to radiation in mice.

Metabolomics has been shown to have utility in assessing responses to exposure by ionizing radiation (IR) in easily accessible biofluids such as urine. Most studies to date from our laboratory and others have employed γ-irradiation at relatively high dose rates (HDR), but many environmental exposure scenarios will probably be at relatively low dose rates (LDR). There are well-documented differences in the biologic responses to LDR compared to HDR, so an important question is to assess LDR effects at the metabolomics level.

Potential reduction of contralateral second breast-cancer risks by prophylactic mammary irradiation: validation in a breast-cancer-prone mouse model.

Background: Long-term breast-cancer survivors have a highly elevated risk (1 in 6 at 20 years) of contralateral second breast cancer. This high risk is associated with the presence of multiple pre-malignant cell clones in the contralateral breast at the time of primary breast cancer diagnosis. Mechanistic analyses suggest that a moderate dose of X-rays to the contralateral breast can kill these pre-malignant clones such that, at an appropriate Prophylactic Mammary Irradiation (PMI) dose, the long-term contralateral breast cancer risk in breast cancer survivors would be considerably decreased.

Widespread decreased expression of immune function genes in human peripheral blood following radiation exposure.

We report a large-scale reduced expression of genes in pathways related to cell-type specific immunity functions that emerges from microarray analysis 48 h after ex vivo γ-ray irradiation (0, 0.5, 2, 5, 8 Gy) of human peripheral blood from five donors. This response is similar to that seen in patients at 24 h after the start of total-body irradiation and strengthens the rationale for the ex vivo model as an adjunct to human in vivo studies.

Single-cell responses to ionizing radiation.

While gene expression studies have proved extremely important in understanding cellular processes, it is becoming more apparent that there may be differences in individual cells that are missed by studying the population as a whole. We have developed a qRT-PCR protocol that allows us to assay multiple gene products in small samples, starting at 100 cells and going down to a single cell, and have used it to study radiation responses at the single-cell level. Since the accuracy of qRT-PCR depends greatly on the choice of "housekeeping" genes used for normalization, initial studies concentrated on determining the optimal panel of such genes.

Combined haploinsufficiency and genetic control of the G2/M checkpoint in irradiated cells.

When cells are exposed to a dose of radiation large enough to cause chromosome aberrations, they become arrested at the G(2)/M checkpoint, facilitating DNA repair. Defects in checkpoint control genes can impart radiosensitivity. Arrest kinetics were monitored in mouse embryo fibroblasts at doses ranging from 10 mGy to 5.

Proton radiation-induced miRNA signatures in mouse blood: characterization and comparison with 56Fe-ion and gamma radiation.

Purpose: Previously, we showed that microRNA (miRNA) signatures derived from the peripheral blood of mice are highly specific for both radiation energy (γ-rays or high linear energy transfer [LET] (56)Fe ions) and radiation dose. Here, we investigate to what extent miRNA expression signatures derived from mouse blood can be used as biomarkers for exposure to 600 MeV proton radiation.

Materials And Methods: We exposed mice to 600 MeV protons, using doses of 0.

Impedance-based surveillance of transient permeability changes in coronary endothelial monolayers after exposure to ionizing radiation.

The relative radiation sensitivities of the various compartments of the heart are poorly characterized. Cardiac fibrosis is a common side effect of radiotherapy, suggesting that endothelial barrier function is an important factor in radiation-induced pathology. We employed Electric Cell Substrate Impedance Sensing (ECIS) to assess cytoskeletal rearrangement, permeability changes and endothelial barrier function changes in response to radiation in studies of human coronary arterial endothelial cells (HCAECs).

Mechanisms of increased risk of tumorigenesis in Atm and Brca1 double heterozygosity.

Background: Both epidemiological and experimental studies suggest that heterozygosity for a single gene is linked with tumorigenesis and heterozygosity for two genes increases the risk of tumor incidence. Our previous work has demonstrated that Atm/Brca1 double heterozygosity leads to higher cell transformation rate than single heterozygosity. However, the underlying mechanisms have not been fully understood yet.

Radiation-induced micro-RNA expression changes in peripheral blood cells of radiotherapy patients.

Purpose: MicroRNAs (miRNAs), a class of noncoding small RNAs that regulate gene expression, are involved in numerous physiologic processes in normal and malignant cells. Our in vivo study measured miRNA and gene expression changes in human blood cells in response to ionizing radiation, to develop miRNA signatures that can be used as biomarkers for radiation exposure.

Methods And Materials: Blood from 8 radiotherapy patients in complete remission 1 or 2 was collected immediately before and 4 hours after total body irradiation with 1.

Whole mouse blood microRNA as biomarkers for exposure to γ-rays and (56)Fe ion.

Purpose: Biomarkers of ionising radiation exposure are useful in a variety of scenarios, such as medical diagnostic imaging, occupational exposures, and spaceflight. This study investigates to what extent microRNA (miRNA) expression signatures in mouse peripheral blood can be used as biomarkers for exposures to radiation with low and high linear energy transfers.

Materials And Methods: Mice were irradiated with doses of 0.

Hemizygosity for Atm and Brca1 influence the balance between cell transformation and apoptosis.

Background: In recent years data from both mouse models and human tumors suggest that loss of one allele of genes involved in DNA repair pathways may play a central role in genomic instability and carcinogenesis. Additionally several examples in mouse models confirmed that loss of one allele of two functionally related genes may have an additive effect on tumor development. To understand some of the mechanisms involved, we examined the role of monoallelic loss or Atm and Brca1 on cell transformation and apoptosis induced by radiation.

Mrad9 and atm haploinsufficiency enhance spontaneous and X-ray-induced cataractogenesis in mice.

Rad9 and Atm regulate multiple cellular responses to DNA damage, including cell cycle checkpoints, DNA repair and apoptosis. However, the impact of dual heterozygosity for Atm and Rad9 is unknown. Using 50 cGy of X rays as an environmental insult and cataractogenesis as an end point, this study examined the effect of heterozygosity for one or both genes in mice.

New insight into intrachromosomal deletions induced by chrysotile in the gpt delta transgenic mutation assay.

Background: Genotoxicity is often a prerequisite to the development of malignancy. Considerable evidence has shown that exposure to asbestos fibers results in the generation of chromosomal aberrations and multilocus mutations using various in vitro approaches. However, there is less evidence to demonstrate the contribution of deletions to the mutagenicity of asbestos fibers in vivo.

Tumor development: haploinsufficiency and local network assembly.

According to the current models, tumor development is a continuous process of mutation accumulation, leading to several intermediate phenotypes and final phases of autonomy, unlimited growth and metastasis. One of the most important events in that process is the initial destabilization of cellular pathways that subsequently allow mutations to accumulate. The mechanisms involved in that stage are not clear.

Ionizing radiation induces DNA double-strand breaks in bystander primary human fibroblasts.

That irradiated cells affect their unirradiated 'bystander' neighbors is evidenced by reports of increased clonogenic mortality, genomic instability, and expression of DNA-repair genes in the bystander cell populations. The mechanisms underlying the bystander effect are obscure, but genomic instability suggests DNA double-strand breaks (DSBs) may be involved. Formation of DSBs induces the phosphorylation of the tumor suppressor protein, histone H2AX and this phosphorylated form, named gamma-H2AX, forms foci at DSB sites.

Combined haploinsufficiency for ATM and RAD9 as a factor in cell transformation, apoptosis, and DNA lesion repair dynamics.

Loss of function of oncogenes, tumor suppressor genes and DNA damage processing genes has been implicated in the development of many types of cancer, but for the vast majority of cases, there is no link to specific germ line mutations. In the last several years, heterozygosity leading to haploinsufficiency for proteins involved in DNA repair pathways was shown to play a role in genomic instability and carcinogenesis after DNA damage is induced. Because the effect of haploinsufficiency for one protein is relatively small, we hypothesize that predisposition to cancer could be a result of the additive effect of heterozygosity for two or more genes, critical for pathways that control DNA damage signaling, repair or apoptosis.