ABSTRACT
One of the major challenges in prostate cancer (PCa) research is the identification of key players that control the progression of primary cancers to invasive and metastatic disease. The majority of metastatic PCa express wild-type p53, whereas loss of p63 expression, a p53 family member, is a common event. Here we identify inhibitor of apoptosis-stimulating protein of p53 (iASPP), a common cellular regulator of p53 and p63, as an important player of PCa progression. Detailed analysis of the prostate epithelium of iASPP transgenic mice, iASPP(Δ8/Δ8) mice, revealed that iASPP deficiency resulted in a reduction in the number of p63 expressing basal epithelial cells compared with that seen in wild-type mice. Nuclear and cytoplasmic iASPP expression was greater in PCa samples compared with benign epithelium. Importantly nuclear iASPP associated with p53 accumulation in vitro and in vivo. A pair of isogenic primary and metastatic PCa cell lines revealed that nuclear iASPP is enriched in the highly metastatic PCa cells. Nuclear iASPP is often detected in PCa cells located at the invasive leading edge in vivo. Increased iASPP expression associated with metastatic disease and PCa-specific death in a clinical cohort with long-term follow-up. These results suggest that iASPP function is required to maintain the expression of p63 in normal basal prostate epithelium, and nuclear iASPP may inactivate p53 function and facilitate PCa progression. Thus iASPP expression may act as a predictive marker of PCa progression.
Subject(s)
Cell Nucleus/metabolism , Disease Progression , Intracellular Signaling Peptides and Proteins/metabolism , Prostatic Neoplasms/pathology , Repressor Proteins/metabolism , Adult , Aged , Animals , Biomarkers, Tumor/metabolism , Cell Differentiation , Cell Line, Tumor , Coculture Techniques , Cohort Studies , Epithelium/metabolism , Epithelium/pathology , Humans , Male , Mice , Middle Aged , Multivariate Analysis , Neoplasm Invasiveness , Phenotype , Phosphorylation , Prognosis , Prostate/metabolism , Prostatic Neoplasms/surgery , Tumor Suppressor Proteins/metabolismSubject(s)
Accidents , Aged , Female , Hospital Units , Hospitalization , Humans , Long-Term Care , Male , Middle AgedABSTRACT
All falls which occurred in a geriatric hospital in period of one year were carefully recorded by nursing staff. Falls occurred most often in admission wards, less in rehabilitation wards and even less in long-stay wards. The incidence of falls was very much lower when patients were confined to bed as a result of industrial action by staff. Very few falls resulted in bone injury. The completion of accident reports by nurses after non-injurious falls is unproductive.
