Here we report that a 1-week exposure to oligonucleotide homologous to the telomere 3 -overhang sequence TTAGGG (T-oligo) similarly specifically induces a senescent phenotype in cultured human fibroblasts, mimicking serial passage or ectopic expression of a dominant negative form of the telomeric repeat binding factor, TRF2 DN . We propose that exposure of the 3 overhang due to telomere loop disruption may occur with critical telomere shortening or extensive acute DNA damage and that the exposed TTAGGG tandem repeat sequence then triggers DNA-damage responses. We further demonstrate that these responses can be induced by treatment with oligonucleotides homologous to the overhang in the absence of telomere disruption, a phenomenon of potential therapeutic importance.DNA damage ͉ aging

Telomere shortening induces a nonproliferative senescent phenotype, believed to reduce cancer risk, and telomeres are involved in a poorly understood manner in responses to DNA damage. Although telomere disruption induces p53 and triggers apoptosis or cell cycle arrest, the features of the disrupted telomere that trigger this response and the precise mechanism involved are poorly understood. Using human cells, we show that DNA oligonucleotides homologous to the telomere 3' overhang sequence specifically induce and activate p53 and activate an S phase checkpoint by modifying the Nijmegen breakage syndrome protein, known to mediate the S phase checkpoint after DNA damage. These responses are mediated, at least in part, by the ATM kinase and are not attributable to disruption of cellular telomeres. Based on these and earlier data, we propose that these oligonucleotides mimic a physiological signal, exposure of the telomere 3' overhang due to opening of the normal telomere loop structure, and hence evoke these protective antiproliferative responses in the absence of DNA damage or telomere disruption.

Conservative treatment of humeral shaft fractures has a higher rate of nonunion, while operative treatment is associated with a low incidence of iatrogenic nerve palsy but higher rates of infection.

Background: Several classification systems exist for sacral fractures; however, these systems are primarily descriptive, are not uniformly used, have not been validated, and have not been associated with a treatment algorithm or prognosis. The goal of the present study was to demonstrate the reliability of the AOSpine Sacral Classification System among a group of international spine and trauma surgeons. Methods: A total of 38 sacral fractures were reviewed independently by 18 surgeons selected from an expert panel of AOSpine and AOTrauma members. Each case was graded by each surgeon on 2 separate occasions, 4 weeks apart. Intrarater reproducibility and interrater agreement were analyzed with use of the kappa statistic (κ) for fracture severity (i.e., A, B, and C) and fracture subtype (e.g., A1, A2, and A3). Results: Seventeen reviewers were included in the final analysis, and a total of 1,292 assessments were performed (646 assessments performed twice). Overall intrarater reproducibility was excellent (κ = 0.83) for fracture severity and substantial (κ = 0.71) for all fracture subtypes. When comparing fracture severity, overall interrater agreement was substantial (κ = 0.75), with the highest agreement for type-A fractures (κ = 0.95) and the lowest for type-C fractures (κ = 0.70). Overall interrater agreement was moderate (κ = 0.58) when comparing fracture subtype, with the highest agreement seen for A2 subtypes (κ = 0.81) and the lowest for A1 subtypes (κ = 0.20). Conclusions: To our knowledge, the present study is the first to describe the reliability of the AOSpine Sacral Classification System among a worldwide group of expert spine and trauma surgeons, with substantial to excellent intrarater reproducibility and moderate to substantial interrater agreement for the majority of fracture subtypes. These results suggest that this classification system can be reliably applied to sacral injuries, providing an important step toward standardization of treatment.