Distinct effects of ionizing radiation on in vivo murine kidney and brain normal tissue gene expression.

PURPOSE: There is a growing awareness that radiation-induced normal tissue injury in late-responding organs, such as the brain, kidney, and lung, involves complex and dynamic responses between multiple cell types that not only lead to targeted cell death but also acute and chronic alterations in cell function. The specific genes involved in the acute and chronic responses of these late-responding normal tissues remain ill defined; understanding these changes is critical to understanding the mechanism of organ damage. As such, the aim of the present study was to identify candidate genes involved in the development of radiation injury in the murine kidney and brain using microarray analysis. EXPERIMENTAL DESIGN: A multimodality experimental approach combined with a comprehensive expression analysis was done to determine changes in normal murine tissue gene expression at 8 and 24 hours after irradiation. RESULTS: A comparison of the gene expression patterns in normal mouse kidney and brain was strikingly different. This observation was surprising because it has been long assumed that the changes in irradiation-induced gene expression in normal tissues are preprogrammed genetic changes that are not affected by tissue-specific origin. CONCLUSIONS: This study shows the potential of microarray analysis to identify gene expression changes in irradiated normal tissue cells and suggests how normal cells respond to the damaging effects of ionizing radiation is complex and markedly different in cells of differing origin.

Education and training for radiation scientists: radiation research program and American Society of Therapeutic Radiology and Oncology Workshop, Bethesda, Maryland, May 12-14, 2003.

Current and potential shortfalls in the number of radiation scientists stand in sharp contrast to the emerging scientific opportunities and the need for new knowledge to address issues of cancer survivorship and radiological and nuclear terrorism. In response to these challenges, workshops organized by the Radiation Research Program (RRP), National Cancer Institute (NCI) (Radiat. Res. 157, 204-223, 2002; Radiat. Res. 159, 812-834, 2003), and National Institute of Allergy and Infectious Diseases (NIAID) (Nature, 421, 787, 2003) have engaged experts from a range of federal agencies, academia and industry. This workshop, Education and Training for Radiation Scientists, addressed the need to establish a sustainable pool of expertise and talent for a wide range of activities and careers related to radiation biology, oncology and epidemiology. Although fundamental radiation chemistry and physics are also critical to radiation sciences, this workshop did not address workforce needs in these areas. The recommendations include: (1) Establish a National Council of Radiation Sciences to develop a strategy for increasing the number of radiation scientists. The strategy includes NIH training grants, interagency cooperation, interinstitutional collaboration among universities, and active involvement of all stakeholders. (2) Create new and expanded training programs with sustained funding. These may take the form of regional Centers of Excellence for Radiation Sciences. (3) Continue and broaden educational efforts of the American Society for Therapeutic Radiology and Oncology (ASTRO), the American Association for Cancer Research (AACR), the Radiological Society of North America (RSNA), and the Radiation Research Society (RRS). (4) Foster education and training in the radiation sciences for the range of career opportunities including radiation oncology, radiation biology, radiation epidemiology, radiation safety, health/government policy, and industrial research. (5) Educate other scientists and the general public on the quantitative, basic, molecular, translational and applied aspects of radiation sciences.

Problems with the assessment of dietary fat in prostate cancer studies.

The authors conducted a detailed review of studies on the association between prostate cancer and total dietary fat along with specific fatty acids. Overall, the 29 studies reporting actual dietary fat levels in grams of fat were heterogeneous, suggesting that pooling of the relative risks may be inappropriate. Heterogeneity was also seen by study design. More specifically, although the pooled estimate for prostate cancer and an increase of 45 g in total fat consumption per day was small (relative risk = 1.2), heterogeneity between studies was large, and the association was not supported by specific fatty acids. The strongest association was found among the five extremely inconsistent studies of alpha-linolenic fatty acid. The associations with advanced prostate cancer were more homogeneous and suggest a relation with total and saturated fat but none with specific fatty acids. This review highlights the inconsistent way in which total dietary fat and specific fatty acids have been measured and reported across epidemiologic studies of prostate cancer. The heterogeneity between studies was large, possibly because of the variation in the dietary instruments used and the corresponding databases (nondifferential misclassification), recall bias, differing case definitions, residual confounding, or potential selection bias in different studies.

Activation of matrix metalloproteinase-2 by overexpression of manganese superoxide dismutase in human breast cancer MCF-7 cells involves reactive oxygen species.

Matrix metalloproteinases (MMPs) participate in cell migration and remodeling processes by affecting the extracellular matrix. MMP-2 is thought to be involved in cancer cell invasiveness. It has been proposed that the activity of MMP-2 can be modulated by intracellular reactive oxygen species (ROS)/reactive nitrogen species. We hypothesized that manganese superoxide dismutase (MnSOD) could mediate MMP-2 activity by changing the intracellular ROS level and that nitric oxide ((.)NO) may be involved in this process. Human breast cancer MCF-7 cells were stably transfected with plasmids containing MnSOD cDNA. A 2-30-fold increase of MnSOD protein and activity was observed in four clones. Our data demonstrated that overexpression of MnSOD stimulated the activation of MMP-2 with a corresponding elevation of ROS. A decrease in ROS by ebselen, a glutathione peroxidase mimetic, or by transduction of adenovirus containing human catalase or glutathione peroxidase cDNA abolished the effect of MnSOD on MMP-2 activation. Treatment of MCF-7 cells with antimycin A or rotenone increased intracellular ROS production and MMP-2 activation simultaneously. Our data also showed a suppression of endothelial nitric-oxide synthase expression that was accompanied by decreased (.)NO production in MnSOD-overexpressing cells. However, the changes in endothelial nitric-oxide synthase and (.)NO did not correlate with the MnSOD activity. Corresponding changes of MMP-2 activity after the addition of a NOS inhibitor (N(G)-amino-l-arginine) or a (.)NO donor ((Z)-1-[(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate) to the cells suggested the possibility that (.)NO may be involved in the MnSOD-mediated MMP-2 activation pathway. These results indicate that MnSOD induces MMP-2 activity by regulation of intracellular ROS and imply that signaling pathways involving (.)NO may also be involved in the MnSOD mediation of MMP-2 activity.

Evaluation of the quantitative capability of a high-resolution positron emission tomography scanner for small animal imaging.

OBJECTIVE: The quantitative capability of a positron emission tomography scanner for small animal imaging was evaluated in this study. METHODS: The microPET P4 (Concorde Microsystems, Knoxville, TN) scanner's capability for dynamic imaging and corrections for radioactive decay, dead time, and attenuation were evaluated. Rat brain and heart studies with and without attenuation correction were compared. A calibration approach to convert the data to nanocuries per milliliter was implemented. Calibration factors were determined using calibration phantoms of 2 sizes with and without attenuation correction. Quantitation was validated using the MiniPhantom (Data Spectrum, Chapel Hill, NC) with hot features (5:1 ratio) of different sizes (4, 6.4, 8, 13, and 16 mm). RESULTS: The microPET P4 scanner's ability to acquire dynamic studies and to correct for decay, dead time, and attenuation was demonstrated. The microPET P4 scanner provided accurate quantitation to within 6% for features larger than 10 mm. Sixty percent of object contrast was retained for features as small as 4 mm. CONCLUSIONS: The microPET P4 scanner can provide accurate quantitation.