Slow accumulation of mutations in Xpc-/- mice upon induction of oxidative stress.

XPC is one of the key DNA damage recognition proteins in the global genome repair route of the nucleotide excision repair (NER) pathway. Previously, we demonstrated that NER-deficient mouse models Xpa(-/-) and Xpc(-/-) exhibit a divergent spontaneous tumor spectrum and proposed that XPC might be functionally involved in the defense against oxidative DNA damage. Others have mechanistically dissected several functionalities of XPC to oxidative DNA damage sensitivity using in vitro studies.

Life spanning murine gene expression profiles in relation to chronological and pathological aging in multiple organs.

Aging and age-related pathology is a result of a still incompletely understood intricate web of molecular and cellular processes. We present a C57BL/6J female mice in vivo aging study of five organs (liver, kidney, spleen, lung, and brain), in which we compare genome-wide gene expression profiles during chronological aging with pathological changes throughout the entire murine life span (13, 26, 52, 78, 104, and 130 weeks). Relating gene expression changes to chronological aging revealed many differentially expressed genes (DEGs), and altered gene sets (AGSs) were found in most organs, indicative of intraorgan generic aging processes.

Detection of genotoxic and non-genotoxic carcinogens in Xpc(-/-)p53(+/-) mice.

An accurate assessment of the carcinogenic potential of chemicals and pharmaceutical drugs is essential to protect humans and the environment. Therefore, substances are extensively tested before they are marketed to the public. Currently, the rodent two-year bioassay is still routinely used to assess the carcinogenic potential of substances.

Broad segmental progeroid changes in short-lived Ercc1(-/Δ7) mice.

Genome maintenance is considered a prime longevity assurance mechanism as apparent from many progeroid human syndromes that are caused by genome maintenance defects. The ERCC1 protein is involved in three genome maintenance systems: nucleotide excision repair, interstrand cross-link repair, and homologous recombination. Here we describe in-life and post-mortem observations for a hypomorphic Ercc1 variant, Ercc1(-/Δ7), which is hemizygous for a single truncated Ercc1 allele, encoding a protein lacking the last seven amino acids.

DNA repair-deficient Xpa/p53 knockout mice are sensitive to the non-genotoxic carcinogen cyclosporine A: escape of initiated cells from immunosurveillance?

The DNA repair-deficient Xpa(-/-)p53(+/-) (Xpa/p53) mouse is a potent model for carcinogenicity testing, representing increased sensitivity toward genotoxic but surprisingly also toward true human non-genotoxic carcinogens. The mechanism of this increased sensitivity in Xpa/p53 mice toward non-genotoxic carcinogens is still unknown. Here, we investigated the mechanism of the human non-genotoxic carcinogen cyclosporine A (CsA) in the Xpa/p53 mouse model.

Tissue response to partially in vitro predegraded poly-L-lactide implants.

The in vivo local reaction of as-polymerized poly-L-lactide composed of 96% L-lactide and 4% D-lactide (PLA96) was investigated by histology at 2, 13 and 26 weeks after subcutaneous implantation in rats. In order to simulate possible end stage reactions the PLA96 was also predegraded in vitro until approximately 50% weight loss. The local reaction of predegraded PLA (PLA96(168)) was compared to the local reaction of polyethylene (PE) and non-predegraded PLA (PLA96).