Ultrastructural Insights into the Biological Significance of Persisting DNA Damage Foci after Low Doses of Ionizing Radiation.

Purpose: Intensity-modulated radiotherapy (IMRT) enables the delivery of high doses to target volume while sparing surrounding nontargeted tissues. IMRT treatment, however, substantially increases the normal tissue volume receiving low-dose irradiation, but the biologic consequences are unclear.

Experimental Design: Using mouse strains that varied in genetic DNA repair capacity, we investigated the DNA damage response of cortical neurons during daily low-dose irradiation (0.

Nanoscale analysis of clustered DNA damage after high-LET irradiation by quantitative electron microscopy--the heavy burden to repair.

Low- and high-linear energy transfer (LET) ionising radiation are effective cancer therapies, but produce structurally different forms of DNA damage. Isolated DNA damage is repaired efficiently; however, clustered lesions may be more difficult to repair, and are considered as significant biological endpoints. We investigated the formation and repair of DNA double-strand breaks (DSBs) and clustered lesions in human fibroblasts after exposure to sparsely (low-LET; delivered by photons) and densely (high-LET; delivered by carbon ions) ionising radiation.

Even low doses of radiation lead to DNA damage accumulation in lung tissue according to the genetically-defined DNA repair capacity.

Background And Purpose: Intensity-modulated radiation therapy for thoracic malignancies increases the exposure of healthy lung tissue to low-dose radiation. The biological impact of repetitive low-dose radiation on the radiosensitive lung is unclear.

Materials And Methods: In the present study, using mouse strains with different genetic DNA repair capacities, we monitored the extent of DNA damage in lung parenchyma after 2, 4, 6, 8, and 10weeks of daily low-dose 100-mGy radiation.

Accumulation of DNA damage in complex normal tissues after protracted low-dose radiation.

The biological consequences of low levels of radiation exposure and their effects on human health are unclear. Ionizing radiation induces a variety of lesions of which DNA double-strand breaks (DSBs) are the most biologically significant, because unrepaired or misrepaired DSBs can lead to genomic instability and cell death. Using repair-proficient mice as an in vivo system we monitored the accumulation of DNA damage in normal tissues exposed to daily low-dose radiation of 100mGy or 10mGy.

Beyond repair foci: DNA double-strand break repair in euchromatic and heterochromatic compartments analyzed by transmission electron microscopy.

Purpose: DNA double-strand breaks (DSBs) generated by ionizing radiation pose a serious threat to the preservation of genetic and epigenetic information. The known importance of local chromatin configuration in DSB repair raises the question of whether breaks in different chromatin environments are recognized and repaired by the same repair machinery and with similar efficiency. An essential step in DSB processing by non-homologous end joining is the high-affinity binding of Ku70-Ku80 and DNA-PKcs to double-stranded DNA ends that holds the ends in physical proximity for subsequent repair.

DNA repair in the context of chromatin: new molecular insights by the nanoscale detection of DNA repair complexes using transmission electron microscopy.

The recognition and repair of DNA double-strand breaks (DSBs) occurs in the context of highly structured chromatin. Here, we established a transmission electron microscopy (TEM) approach to localize gold-labeled DSB repair components in different chromatin environments within the intact nuclear architecture of cells in irradiated mouse tissues. The ultra-high resolution of TEM offers the intriguing possibility of detecting core components of the DNA repair machinery at the single-molecule level and visualizing their molecular interactions with specific histone modifications.

Tumor refractoriness to anti-VEGF treatment is mediated by CD11b+Gr1+ myeloid cells.

Vascular endothelial growth factor (VEGF) is an essential regulator of normal and abnormal blood vessel growth. A monoclonal antibody (mAb) that targets VEGF suppresses tumor growth in murine cancer models and human patients. We investigated cellular and molecular events that mediate refractoriness of tumors to anti-angiogenic therapy.