Ionizing radiation causes DNA damage and is a mainstay for cancer treatment, but understanding of its genomic impact is limited. We analyzed mutational spectra following radiotherapy in 190 paired ...primary and recurrent gliomas from the Glioma Longitudinal Analysis Consortium and 3,693 post-treatment metastatic tumors from the Hartwig Medical Foundation. We identified radiotherapy-associated significant increases in the burden of small deletions (5-15 bp) and large deletions (20+ bp to chromosome-arm length). Small deletions were characterized by a larger span size, lacking breakpoint microhomology and were genomically more dispersed when compared to pre-existing deletions and deletions in non-irradiated tumors. Mutational signature analysis implicated classical non-homologous end-joining-mediated DNA damage repair and APOBEC mutagenesis following radiotherapy. A high radiation-associated deletion burden was associated with worse clinical outcomes, suggesting that effective repair of radiation-induced DNA damage is detrimental to patient survival. These results may be leveraged to predict sensitivity to radiation therapy in recurrent cancer.
Caloric restriction (CR), without malnutrition, delays aging and extends life span in diverse species; however, its effect on resistance to illness and mortality in primates has not been clearly ...established. We report findings of a 20-year longitudinal adult-onset CR study in rhesus monkeys aimed at filling this critical gap in aging research. In a population of rhesus macaques maintained at the Wisconsin National Primate Research Center, moderate CR lowered the incidence of aging-related deaths. At the time point reported, 50% of control fed animals survived as compared with 80% of the CR animals. Furthermore, CR delayed the onset of age-associated pathologies. Specifically, CR reduced the incidence of diabetes, cancer, cardiovascular disease, and brain atrophy. These data demonstrate that CR slows aging in a primate species.
We have decided to use the -opioid receptor (372 residues) as a model system to develop methods for the total chemical synthesis of G protein-coupled receptors. The most important feature of this ...receptor from a chemical synthesis perspective is the wealth of cysteines spread throughout its sequence, which are required for native chemical ligation. A total of 13 cysteines are located in the the -opioid receptor polypetide chain in both loop and putative transmembrane (TM) regions. We envisioned a synthesis of the polypeptide that would make use of peptide-thioesters ranging from 37 to 63 residues in length. Here, we report data from an exploratory synthesis of such a set of peptide-thioesters. For all seven peptides, the crude material 30 residues into the synthesis was sufficiently homogeneous to make isolation and purification straightforward. Extension of the peptides to between 40 and 50 residues in length generally produced a significant decrease in the quality of the crude products, although in most cases, we judged that high purity peptides could probably be isolated. By 60 residues, however, the crude peptide product mixtures are probably too heterogeneous to purify to homogeneity by reversed-phase HPLC. In general, -opioid receptor peptides with a single predicted TM domain were sufficiently soluble to handle postcleavage and to analyze by reversed-phase HPLC, whereas 1.5 TM domains rendered the peptides too hydrophobic to handle or analyze by standard protocols. Given the challenges of chain assembly, handling, and purification of these peptides, a synthetic strategy that uses 12 or 13 shorter peptide segments of 20-40 residues each is probably a more feasible approach.
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