Genetic ablation of caveolin-1 drives estrogen-hypersensitivity and the development of DCIS-like mammary lesions.

Caveolin-1 (Cav-1) loss-of-function mutations are exclusively associated with estrogen receptor-positive (ER(+)) human breast cancers. To dissect the role of Cav-1 loss-of-function in the pathogenesis of human breast cancers, we used Cav-1(-/-) null mice as a model system. First, we demonstrated that Cav-1(-/-) mammary epithelia overexpress two well-established ER co-activator genes, CAPER and Foxa1, in addition to ER-alpha. Thus, the functional loss of Cav-1 may be sufficient to confer estrogen-hypersensitivity in the mammary gland. To test this hypothesis directly, we subjected Cav-1(-/-) mice to ovariectomy and estrogen supplementation. As predicted, Cav-1(-/-) mammary glands were hyper-responsive to estrogen and developed dysplastic mammary lesions with adjacent stromal angiogenesis that resemble human ductal carcinoma in situ. Based on an extensive biomarker analysis, these Cav-1(-/-) mammary lesions contain cells that are hyperproliferative and stain positively with nucleolar (B23/nucleophosmin) and stem/progenitor cell markers (SPRR1A and beta-catenin). Genome-wide transcriptional profiling identified many estrogen-related genes that were over-expressed in Cav-1(-/-) mammary glands, including CAPER--an ER co-activator gene and putative stem/progenitor cell marker. Analysis of human breast cancer samples revealed that CAPER is overexpressed and undergoes a cytoplasmic-to-nuclear shift during the transition from pre-malignancy to ductal carcinoma in situ. Thus, Cav-1(-/-) null mice are a new preclinical model for studying the molecular paradigm of estrogen hypersensitivity and the development of estrogen-dependent ductal carcinoma in situ lesions.

The hermes transposon of Musca domestica is an efficient tool for the mutagenesis of Schizosaccharomyces pombe.

Currently, no transposon-based method for the mutagenesis of Schizosaccharomyces pombe exists. We have developed such a system based on the introduction of the hermes transposon from the housefly into S. pombe. This system efficiently disrupts open reading frames and allows the insertion sites to be readily identified.

Retrospective Review of Limitations of Care for Inpatients at a Free-Standing, Tertiary Care Children's Hospital.

Limited studies exist regarding the timing, location, or physicians involved in do-not-resuscitate (DNR) order placement in pediatrics. Prior pediatric studies have noted great variations in practice during end-of-life (EOL) care. This study aims to analyze the timing, location, physician specialties, and demographic factors influencing EOL care in pediatrics. We examined the time preceding and following the implementation of a pediatric palliative care team (PCT) via a 5-year, retrospective chart review of all deceased patients previously admitted to inpatient services. Thirty-five percent (167/471) of the patients in our study died with a DNR order in place. Sixty-two percent of patients died in an ICU following DNR order placement. A difference was noted in DNR order timing between patients on general inpatient units and those discharged to home compared with those in the ICUs (p = 0.02). The overall DNR order rate increased following the initiation of the PCT from 30.8% to 39.2% (p = 0.05), but no change was noted in the rate of death in the ICUs. Our study demonstrates a variation in the timing of death following DNR order placement when comparing ICUs and general pediatric floors. Following the initiation of the PCT, we saw increased DNR frequency but no change in the interval between a DNR order and death.