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- Venugopalan, Shankar R., et al.
(författare)
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Novel expression and transcriptional regulation of FoxJ1 during oro-facial morphogenesis
- 2008
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 17:23, s. 3643-3654
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Tidskriftsartikel (refereegranskat)abstract
- Axenfeld-Rieger syndrome (ARS) patients with PITX2 point mutations exhibit a wide range of clinical features including mild craniofacial dysmorphism and dental anomalies. Identifying new PITX2 targets and transcriptional mechanisms are important to understand the molecular basis of these anomalies. Chromatin immunoprecipitation assays demonstrate PITX2 binding to the FoxJ1 promoter and PITX2C transgenic mouse fibroblasts and PITX2-transfected cells have increased endogenous FoxJ1 expression. FoxJ1 is expressed at embryonic day 14.5 (E14.5) in early tooth germs, then down-regulated from E15.5-E17.5 and re-expressed in the inner enamel epithelium, oral epithelium, tongue epithelium, sub-mandibular salivary gland and hair follicles during E18.5 and neonate day 1. FoxJ1 and Pitx2 exhibit overlapping expression patterns in the dental and oral epithelium. PITX2 activates the FoxJ1 promoter and, Lef-1 and beta-catenin interact with PITX2 to synergistically regulate the FoxJ1 promoter. FoxJ1 physically interacts with the PITX2 homeodomain to synergistically regulate FoxJ1, providing a positive feedback mechanism for FoxJ1 expression. Furthermore, FoxJ1, PITX2, Lef-1 and beta-catenin act in concert to activate the FoxJ1 promoter. The PITX2 T68P ARS mutant protein physically interacts with FoxJ1; however, it cannot activate the FoxJ1 promoter. These data indicate a mechanism for the activity of the ARS mutant proteins in specific cell types and provides a basis for craniofacial/ tooth anomalies observed in these patients. These data reveal novel transcriptional mechanisms of FoxJ1 and demonstrate a new role of FoxJ1 in oro-facial morphogenesis.
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- Touraine, Philippe, et al.
(författare)
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Lipoatrophy in GH deficient patients treated with a long-acting pegylated GH
- 2009
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Ingår i: European Journal of Endocrinology. - 0804-4643 .- 1479-683X. ; 161, s. 533-540
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Changes observed during adult GH deficiency (GHD) are most often reversed with the administration of recombinant human GH (rhGH). To avoid daily injections, a long-acting GH molecule has been obtained by covalent binding of polyethylene glycol (PEG) with rhGH (PEG–GH), allowing weekly s.c. injections. This study was designed to assess its efficacy and safety, in adult GHD subjects. Design and methods: This was a randomized, double-blind, placebo-controlled, multiple-dose, parallel group study. Subjects were recruited from 34 centers. A total of 105 subjects with GHD were assigned a treatment. They received 6 weekly injections of either PEG–GH or placebo. Subjects were randomized into one out of four treatment groups (Groups A–D) or placebo (Group E). Groups A, B, and C received 1, 3, and 4 mg PEG–GH respectively, for the first 3 weeks followed by 2, 6, and 8 mg PEG–GH respectively, for the remaining 3 weeks. Group D received 4 mg PEG–GH for 6 weeks. Group E received placebo. The study was suspended because of the development of lipoatrophy in certain subjects and restarted with an injection rotation plan, before being terminated due to further subjects developing lipoatrophy. Results: A total of 13 cases of injection-site lipoatrophy were reported, of which ten were in females and three occurred after the first injection; all cases were independent of PEG–GH dose or IGF1 levels, either basal or under treatment. Conclusion: The unpredictable occurrence of injection-site lipoatrophy with weekly long-acting pegylated GH molecules may be a limiting factor for their development.
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