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To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ydbio.2010.08.030 Byline: Kryn Stankunas, Gene K. Ma, Frank J. Kuhnert, Calvin J. Kuo, Ching-Pin Chang Keywords: VEGF; Heart valve development; Endocardial-mesenchymal transformation; Endocardial cushions; Outflow tract; Atrioventricular canal; Mitral valve; NFATc1; miR-126 Abstract: Heart valve malformations are one of the most common types of birth defects, illustrating the complex nature of valve development. Vascular endothelial growth factor (VEGF) signaling is one pathway implicated in valve formation, however its specific spatial and temporal roles remain poorly defined. To decipher these contributions, we use two inducible dominant negative approaches in mice to disrupt VEGF signaling at different stages of embryogenesis. At an early step in valve development, VEGF signals are required for the full transformation of endocardial cells to mesenchymal cells (EMT) at the outflow tract (OFT) but not atrioventricular canal (AVC) endocardial cushions. This role likely involves signaling mediated by VEGF receptor 1 (VEGFR1), which is highly expressed in early cushion endocardium before becoming downregulated after EMT. In contrast, VEGFR2 does not exhibit robust cushion endocardium expression until after EMT is complete. At this point, VEGF signaling acts through VEGFR2 to direct the morphogenesis of the AVC cushions into mature, elongated valve leaflets. This latter role of VEGF requires the VEGF-modulating microRNA, miR-126. Thus, VEGF roles in the developing valves are dynamic, transitioning from a differentiation role directed by VEGFR1 in the OFT to a morphogenetic role through VEGFR2 primarily in the AVC-derived valves. Article History: Received 8 April 2010; Revised 25 August 2010; Accepted 26 August 2010

Transcriptional control by [beta]-catenin and lymphoid enhancer-binding factor 1 (LEF1)/T cell factor regulates proliferation in stem cells and tumorigenesis. Here we provide evidence that transcriptional corepressor homeodomain interacting protein kinase 2 (HIPK2) controls the number of stem and progenitor cells in the skin and the susceptibility to develop squamous cell carcinoma. Loss of HIPK2 leads to increased proliferative potential, more rapid [G.sub.1]-S transition in cell cycle, and expansion of the epidermal stem cell compartment. Among the critical regulators of [G.sub.1]-S transition in the cell cycle, only cyclin D1 is selectively up-regulated in cells lacking HIPK2. Conversely, overexpression of HIPK2 suppresses LEF1/[beta]-catenin-mediated transcriptional activation of cyclin D1 expression. However, deletion of the C-terminal YH domain of HIPK2 completely abolishes its ability to recruit another transcriptional corepressor CtBP and suppress LEF1/ [beta]-catenin-mediated transcription. To determine whether loss of HIPK2 leads to increased susceptibility to tumorigenesis, we treat wild-type, Hipk[2.sup.+/-], and Hipk[2.sup.-/-] mice with the two-stage carcinogenesis protocol. Our results indicate that more skin tumors are induced in Hipk[2.sup.+/-] and Hipk[2.sup.-/-] mutants, with most of the tumors showing shortened incubation time and malignant progression. Together, our results indicate that HIPK2 is a tumor suppressor that controls proliferation by antagonizing LEF1/[beta]-catenin-mediated transcription. Loss of HIPK2 synergizes with activation of H-ras to induce tumorigenesis. cell cycle | proliferation | Wnt | corepressor

Introduction. Orthotopic liver transplantation anastomotic biliary strictures (OLT ABS) are managed with endoscopic biliary stent therapy but the recurrence rate is substantial. Our aims were to retrospectively determine the recurrence rates of OLT ABS after initial successful stent therapy, characterize the management of recurrences and identify associated variables. Materials and methods. Clinical data from 943 patients receiving non-living donor OLT at our institution from 2005-2012 were reviewed, and 123 OLT ABS patients receiving stent therapy were identified. Features of their endoscopic stent therapy and other pertinent clinical information were evaluated. Results. ABS recurred in 25.5% of patients (24/94) after an initial successful course of stent therapy. Recurrences were received a second course of endoscopic stent therapy and 67% of patients (16/24) achieved long-term remediation of ABS. Six patients underwent a third course of endoscopic stent therapy with 4 patients achieving remediation. Overall remediation rate among ABS recurrences was 83.3% (20/24). A bivariate comparison demonstrated HCV infection, age, median months of maximal stenting and a lower maximum cumulative stent diameter were risk factors for ABS recurrence. Using a Cox regression model, only HCV status proved to be a risk factor for recurrence. Discussion. In conclusion repeat stent therapy achieved high stricture remediation rates. Recurrence after the first or even second course of stenting should not imply failure of endoscopic therapy. A positive HCV status may be associated with higher stricture recurrence rates and this association should be further investigated. [ABSTRACT FROM AUTHOR]

Transcriptional control by β-catenin and lymphoid enhancer-binding factor 1 (LEF1)/T cell factor regulates proliferation in stem cells and tumorigenesis. Here we provide evidence that transcriptional corepressor homeodomain interacting protein kinase 2 (HIPK2) controls the number of stem and progenitor cells in the skin and the susceptibility to develop squamous cell carcinoma. Loss of HIPK2 leads to increased proliferative potential, more rapid G1-S transition in cell cycle, and expansion of the epidermal stem cell compartment. Among the critical regulators of G1-S transition in the cell cycle, only cyclin D1 is selectively up-regulated in cells lacking HIPK2. Conversely, overexpression of HIPK2 suppresses LEF1/β-catenin-mediated transcriptional activation of cyclin D1 expression. However, deletion of the C-terminal YH domain of HIPK2 completely abolishes its ability to recruit another transcriptional corepressor CtBP and suppress LEF1/β-catenin-mediated transcription. To determine whether loss of HIPK2 leads to increased susceptibility to tumorigenesis, we treat wild-type, Hipk2+/-, and Hipk2-/- mice with the two-stage carcinogenesis protocol. Our results indicate that more skin tumors are induced in Hipk2+/- and Hipk2-/- mutants, with most of the tumors showing shortened incubation time and malignant progression. Together, our results indicate that HIPK2 is a tumor suppressor that controls proliferation by antagonizing LEF1/β-catenin-mediated transcription. Loss of HIPK2 synergizes with activation of H-ras to induce tumorigenesis. [ABSTRACT FROM AUTHOR]

An editorial is presented which discusses on the use of biodegradable endoprosthetic stents, as a new technological medical surgery device in the treatment of the benign esophageal strictures.