The gastrointestinal (GI) epithelium is a rapidly renewing tissue in which apoptosis represents part of the overall homeostatic process. Regulation of apoptosis in the GI epithelium is complex with a precise relationship between cell position and apoptosis. Apoptosis occurs spontaneously and in response to radiation and cytotoxic drugs at the base of the crypts. By contrast, the villus epithelial cells are extremely resistant to apoptosis. The molecular mechanism underlying this loss of function of villus epithelial cells to undergo apoptosis shortly after their exit from the crypt is unknown. In this study we demonstrate for the first time, that deletion of two homologous actin-binding proteins, villin and gelsolin renders villus epithelial cells extremely sensitive to apoptosis. Ultrastructural analysis of the villin-gelsolin À/À double-knockout mice shows an abnormal accumulation of damaged mitochondria demonstrating that villin and gelsolin function on an early step in the apoptotic signaling at the level of the mitochondria. A characterization of functional and ligand-binding mutants demonstrate that regulated changes in actin dynamics determined by the actin severing activities of villin and gelsolin are required to maintain cellular homeostasis. Our study provides a molecular basis for the regulation of apoptosis in the GI epithelium and identifies cell biological mechanisms that couple changes in actin dynamics to apoptotic cell death.
Purpose: Radiation‐induced normal‐tissue toxicity is heterogeneous in nature and manifests in a wide range of severities across women who undergo breast‐cancer radiotherapy (RT). Numerous studies have investigated the relationship between acute and late toxicity based on patient‐and physician‐conducted assessments, and the results have been conflicting. We carried out a prospective longitudinal study to examine whether acute toxicity can predict late toxicity in breast‐cancer RT using quantitative ultrasound Nakagami imaging. Methods: Twenty‐two patients were enrolled following lumpectomy and all participants received whole‐breast external‐beam RT (50Gy plus a 10Gy boost). Each participant received up to 6 ultrasound scans. A baseline ultrasound scan was performed 1 week prior to RT and followed by a scan at week 6 of RT. Four additional scans were taken post‐RT at 6‐week, 3‐month, 6‐month, and 1‐year follow‐ups. Patients were imaged on both breasts with a 10‐MHz ultrasound. Nakagami shape parameter was used as a surrogate for acute and late toxicity. A Nakagami shape parameter ratio (NSPR) was generated using measurements from the irradiated breast over the contralateral breast. Clinical assessment of normal‐tissue toxicity was conducted by a radiation oncologist using RTOG toxicity scheme. A linear regression model was used to examine the relationship between acute and late toxicity. Results: The NSRP measurements correlated with RTOG toxicity. For most patients, NSPR increased during RT and up to 3 months post RT, reached the highest value between 3 and 6 months, and then started to recover. The linearregression model indicates the NSPR during RT are correlated with NSPR measured at 3‐month, 6‐month and 1‐year post‐RT (p<0.05). Conclusion: Our results based on ultrasound Nakagami imaging suggest that acute normal‐tissue toxicity predicts late toxicity (up to 1 year) following breast RT. Therefore, interventions designed to limit acute toxicity may Result in less late toxicity and improved quality‐of‐life of breast‐cancer survivors.
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