cAMP Response Element Binding Protein Is Required for Differentiation of Respiratory Epithelium during Murine Development

The cAMP response element binding protein 1 (Creb1) transcription factor regulates cellular gene expression in response to elevated levels of intracellular cAMP. Creb1−/− fetal mice are phenotypically smaller than wildtype littermates, predominantly die in utero and do not survive after birth due to respiratory failure. We have further investigated the respiratory defect of Creb1−/− fetal mice during development. Lungs of Creb1−/− fetal mice were pale in colour and smaller than wildtype controls in proportion to their reduced body size. Creb1−/− lungs also did not mature morphologically beyond E16.5 with little or no expansion of airway luminal spaces, a phenotype also observed with the Creb1−/− lung on a Crem−/− genetic background. Creb1 was highly expressed throughout the lung at all stages examined, however activation of Creb1 was detected primarily in distal lung epithelium. Cell differentiation of E17.5 Creb1−/− lung distal epithelium was analysed by electron microscopy and showed markedly reduced numbers of type-I and type-II alveolar epithelial cells. Furthermore, immunomarkers for specific lineages of proximal epithelium including ciliated, non-ciliated (Clara), and neuroendocrine cells showed delayed onset of expression in the Creb1−/− lung. Finally, gene expression analyses of the E17.5 Creb1−/− lung using whole genome microarray and qPCR collectively identified respiratory marker gene profiles and provide potential novel Creb1-regulated genes. Together, these results demonstrate a crucial role for Creb1 activity for the development and differentiation of the conducting and distal lung epithelium

Radical perineal prostatectomy and early continence: outcomes after 120 cases

PURPOSE: Evaluate the results of urinary continence on patients who had undergone radical perineal prostatectomy (RPP) for clinically localized prostate cancer. MATERIALS AND METHODS: We analyzed the continence data of 120 patients with pathology of cT1-cT2N0M0 prostate cancer and who had undergone RPP. Continence was assessed on the day of catheter removal, at the end of the first and third month, and the first year postoperatively. The patients who were continent immediately after catheter removal were classified in the group of “immediately continent” while the patients who became continent during the 3 postoperative months were classified as “early continent.” RESULTS: Mean duration of catheterization was 10 (10-25) days. Of 120 patients, 44 (36.7%) were immediately continent. At the end of the first and third months, 65 (54.1%) and 87 (72.5%), respectively, were early continent. At the one-year follow-up, 95.3% of 107 cases whose one-year follow-up data were available were continent. When the relationship between patients’ age and continence was analyzed, it was found that the early continence rates were 77.7% (7/9), 73.3% (33/45), 73.4% (36/49), and 64.7% (11/17) in the groups of = 49, 50-59, 60-69, and = 70 years, respectively (p = 0.68). CONCLUSIONS: The majority of patients who underwent RPP rapidly regained continence within 3 months. RPP is an exceptional alternative approach for radical surgery in the treatment of localized prostate cancer

Zfp148 Deficiency Causes Lung Maturation Defects and Lethality in Newborn Mice That Are Rescued by Deletion of p53 or Antioxidant Treatment

The transcription factor Zfp148 (Zbp-89, BFCOL, BERF1, htβ) interacts physically with the tumor suppressor p53 and is implicated in cell cycle control, but the physiological role of Zfp148 remains unknown. Here we show that Zfp148 deficiency leads to respiratory distress and lethality in newborn mice. Zfp148 deficiency prevented structural maturation of the prenatal lung without affecting type II cell differentiation or surfactant production. BrdU analyses revealed that Zfp148 deficiency caused proliferation arrest of pulmonary cells at E18.5–19.5. Similarly, Zfp148-deficient fibroblasts exhibited proliferative arrest that was dependent on p53, raising the possibility that cell stress is part of the underlying mechanism. Indeed, Zfp148 deficiency lowered the threshold for activation of p53 under oxidative conditions. Moreover, both in vivo and cellular phenotypes were rescued on Trp53 (+/−) or Trp53 (−/−) backgrounds and by antioxidant treatment. Thus, Zfp148 prevents respiratory distress and lethality in newborn mice by attenuating oxidative stress–dependent p53-activity during the saccular stage of lung development. Our results establish Zfp148 as a novel player in mammalian lung maturation and demonstrate that Zfp148 is critical for cell cycle progression in vivo