Description: Background: Prostate morphogenesis initiates in the urogenital sinus (UGS) with epithelial bud development. Sulfatase-1 (SULF1) inhibits bud development by reducing extracellular heparan sulfate (HS) 6- O sulfation and impairing FGF10 signaling via the ERK1/2 mitogen activated kinases. Results: We characterized the expression patterns of HS 6- O sulfation modifying enzymes in the developing prostate by in situ hybridization and showed that Sulf1 and Hs6st1 had overlapping but distinct expression domains. Notably, Hs6st1 was present while Sulf1 was excluded from the tips of elongating epithelial buds. This predicted relatively high HS 6- O sulfation at the tips of elongating epithelial buds that was confirmed by immunohistochemistry. The pattern of Sulf1 expression in the peri-mesenchymal epithelium matched predicted locations of BMP signaling. Exogenous BMP4 and BMP7 induced Sulf1 expression in the UGS, decreased epithelial HS 6- O sulfation, and reduced ERK1/2 activation in response to FGF10. Conclusions: These data suggest that BMPs limit FGF10 action in the developing prostate at least in part by inducing Sulf1.

Description: BACKGROUND: This study sought to determine if preoperative image-guided intensity-modulated radiotherapy (IG-IMRT) can reduce morbidity, including wound complications, by minimizing dose to uninvolved tissues in adults with lower extremity soft tissue sarcoma. METHODS: The primary endpoint was the development of an acute wound complication (WC). IG-IMRT was used to conform volumes to avoid normal tissues (skin flaps for wound closure, bone, or other uninvolved soft tissues). From July 2005 to June 2009, 70 adults were enrolled; 59 were evaluable for the primary endpoint. Median tumor size was 9.5 cm; 55 tumors (93%) were high-grade and 58 (98%) were deep to fascia. RESULTS: Eighteen (30.5%) patients developed WCs. This was not statistically significantly different from the result of the National Cancer Institute of Canada SR2 trial ( P = .2); however, primary closure technique was possible more often (55 of 59 patients [93.2%] versus 50 of 70 patients [71.4%]; P = .002), and secondary operations for WCs were somewhat reduced (6 of 18 patients [33%] versus 13 of 30 patients [43%]; P = .55). Moderate edema, skin, subcutaneous, and joint toxicity was present in 6 (11.1%), 1 (1.9%), 5 (9.3%), and 3 (5.6%) patients, respectively, but there were no bone fractures. Four local recurrences (6.8%, none near the flaps) occurred with median follow-up of 49 months. CONCLUSIONS: The 30.5% incidence of WCs was numerically lower than the 43% risk derived from the National Cancer Institute of Canada SR2 trial, but did not reach statistical significance. Preoperative IG-IMRT significantly diminished the need for tissue transfer. RT chronic morbidities and the need for subsequent secondary operations for WCs were lowered, although not significantly, whereas good limb function was maintained. Cancer 2013;. © 2013 American Cancer Society.

Description: BACKGROUND In vivo ectopic gene expression is a common approach for prostate research through the use of transgenes in germline transgenic mice. For some other organs, somatic transgenesis with the Sleeping Beauty transposon system has allowed in vivo ectopic gene expression with higher throughput and lower cost than germline transgenic approaches. METHODS Mouse e16 urogenital sinuses (UGSs) were co-injected with plasmids expressing the Sleeping Beauty transposase and plasmids with control or activated BRAF expressing transposons. Following electroporation, the transduced UGSs were grown as allografts in mouse hosts for 8 weeks, and the resulting allografts were evaluated for several endpoints. RESULTS Transposon-transduced UGS allografts developed into prostatic tissue with normal tissue structure and cellular differentiation. Integration of transposon vectors into the genomes of transduced allografts was confirmed using linker-mediated PCR, sequencing, and in situ PCR. Transduction of UGS allografts with transposons expressing activated BRAF resulted in ectopic BRAF expression that was detectable at both the mRNA and protein levels. Prostatic ducts over-expressing activated BRAF also had ectopic activation of the ERK1/2 mitogen activated kinases and increased epithelial cell proliferation. CONCLUSIONS The Sleeping Beauty transposon system can be used to achieve somatic transgenesis of prostatic allografts. This new method for achieving ectopic gene expression in the prostate will complement other existing approaches such as ectopic gene expression in cell lines and in germline transgenic mice. Advantages of this new approach include preservation of stromal–epithelial interactions not possible with cell lines, and higher throughput and lower cost than traditional germline transgenic approaches. Prostate © 2014 Wiley Periodicals, Inc.

Description: Mangaia hosts the most radiogenic Pb-isotopic compositions observed in ocean island basalts and represents the HIMU (high μ = 238 U/ 204 Pb) mantle end-member, thought to result from recycled oceanic crust. Complete geochemical characterization of the HIMU mantle end-member has been inhibited due to a lack of deep submarine glass samples from HIMU localities. We homogenized olivine-hosted melt inclusions separated from Mangaia lavas and the resulting glassy inclusions made possible the first volatile abundances to be obtained from the HIMU mantle end-member. We also report major and trace element abundances and Pb-isotopic ratios on the inclusions, which have HIMU isotopic fingerprints. We evaluate the samples for processes that could modify the volatile and trace element abundances post-mantle melting, including diffusive Fe and H 2 O-loss, degassing, and assimilation. H 2 O/Ce ratios vary from 119 to 245 in the most pristine Mangaia inclusions; excluding an inclusion that shows evidence for assimilation, the primary magmatic H 2 O/Ce ratios vary up to ~200, and are consistent with significant dehydration of oceanic crust during subduction and long-term storage in the mantle. CO 2 concentrations range up to 2346 ppm CO 2 in the inclusions. Relatively high CO 2 in the inclusions, combined with previous observations of carbonate blebs in other Mangaia melt inclusions, highlight the importance of CO 2 for the generation of the HIMU mantle. F/Nd ratios in the inclusions (30 ± 9; 2σ standard deviation) are higher than the canonical ratio observed in oceanic lavas, and Cl/K ratios (0.079 ± 0.028) fall in the range of pristine mantle (0.02-0.08).