ARTS mediates apoptosis and regeneration of the intestinal stem cell niche

Stem cells (SCs) play a pivotal role in fueling homeostasis and regeneration. While much focus has been given to self-renewal and differentiation pathways regulating SC fate, little is known regarding the specific mechanisms utilized for their elimination. Here, we report that the pro-apoptotic protein ARTS (a Septin4 isoform) is highly expressed in cells comprising the intestinal SC niche and that its deletion protects Lgr5(+) and Paneth cells from undergoing apoptotic cell death. As a result, the Sept4/ARTS(-/-) crypt displays augmented proliferation and, in culture, generates massive cystic-like organoids due to enhanced Wnt/β-catenin signaling. Importantly, Sept4/ARTS(-/-) mice exhibit resistance against intestinal damage in a manner dependent upon Lgr5(+) SCs. Finally, we show that ARTS interacts with XIAP in intestinal crypt cells and that deletion of XIAP can abrogate Sept4/ARTS(-/-)-dependent phenotypes. Our results indicate that intestinal SCs utilize specific apoptotic proteins for their elimination, representing a unique target for regenerative medicine

Definition of vaginal doses in intrauterine high-dose-rate brachytherapy

PubMed ID: 15374542The aim of this study was to evaluate dosimetric aspects of high-dose-rate (HDR) intrauterine brachytherapy applications and to discuss a possible definition of vaginal points for dose reporting.HDR brachytherapy was performed using a "Fletcher-like" applicator. Doses to the vaginal mucosa were assessed using 2 sets of points for each ovoid. Fifty treated patients were chosen for the analysis. Repeatability and reproducibility were analyzed. Total doses for the whole treatment at the vaginal points were calculated for each patient. The average dose for both ovoids was determined and the ratio of this dose to the dose at point "A" was calculated. The correlation between delivered doses and vaginal complications was tested statistically.Repeatability and reproducibility were found to be less than 1% compared with patient-to-patient variations (> 99%) for all points. The number of fractions and the number of patients in which the middle ovoid point was "representative" were calculated for the lateral and upper surfaces, respectively. The calculated vaginal-average to point "A" dose ratio was found to be 175% and 130% for the 20 and 25 mm ovoids, respectively. A correlation between delivered doses and the rate of complications was not found.The proposed method has been validated and allows calculations of vaginal doses. The vaginal-to-point "A" dose ratios allow a fast estimation of the vaginal dose for 20 and 25mm ovoids. The doses delivered to our patients were below vaginal tolerance. © 2004 American Brachytherapy Society. All rights reserved