Genetic Abolishment of Hepatocyte Proliferation Activates Hepatic Stem Cells

Quiescent hepatic stem cells (HSCs) can be activated when hepatocyte proliferation is compromised. Chemical injury rodent models have been widely used to study the localization, biomarkers, and signaling pathways in HSCs, but these models usually exhibit severe promiscuous toxicity and fail to distinguish damaged and non-damaged cells. Our goal is to establish new animal models to overcome these limitations, thereby providing new insights into HSC biology and application. We generated mutant mice with constitutive or inducible deletion of Damaged DNA Binding protein 1 (DDB1), an E3 ubiquitin ligase, in hepatocytes. We characterized the molecular mechanism underlying the compensatory activation and the properties of oval cells (OCs) by methods of mouse genetics, immuno-staining, cell transplantation and gene expression profiling. We show that deletion of DDB1 abolishes self-renewal capacity of mouse hepatocytes in vivo, leading to compensatory activation and proliferation of DDB1-expressing OCs. Partially restoring proliferation of DDB1-deficient hepatocytes by ablation of p21, a substrate of DDB1 E3 ligase, alleviates OC proliferation. Purified OCs express both hepatocyte and cholangiocyte markers, form colonies in vitro, and differentiate to hepatocytes after transplantation. Importantly, the DDB1 mutant mice exhibit very minor liver damage, compared to a chemical injury model. Microarray analysis reveals several previously unrecognized markers, including Reelin, enriched in oval cells. Here we report a genetic model in which irreversible inhibition of hepatocyte duplication results in HSC-driven liver regeneration. The DDB1 mutant mice can be broadly applied to studies of HSC differentiation, HSC niche and HSCs as origin of liver cancer

Apremilast for the Treatment of Moderate to Severe Plaque Psoriasis : A Critique of the Evidence

As part of the National Institute for Health and Care Excellence's (NICE) single technology appraisal (STA) process, apremilast was assessed to determine the clinical and cost effectiveness of its use in the treatment of moderate to severe plaque psoriasis in two patient populations, differentiated by the severity of the patient's Psoriasis Area Severity Index (PASI) score. The Centre for Reviews and Dissemination (CRD) and the Centre for Health Economics (CHE) Technology Appraisal Group at the University of York was commissioned to act as the evidence review group (ERG). This article provides a summary of the company's submission, the ERG report and NICE's subsequent guidance. In the company's initial submission, a sequence of treatments including apremilast was found to be both more effective and cheaper than a comparator sequence without it in both populations considered. However, this result was found to be highly sensitive to a series of assumptions made by the company, primarily reflecting the costs of best supportive care once no further treatments are available, and the source of utility estimates. A re-estimation of the cost effectiveness of apremilast by the ERG suggested that the apremilast sequence in the two populations was more effective, but due to high additional costs was not indicative of a cost-effective use of NHS resources. As such, in the final appraisal decision NICE concluded that apremilast was not cost effective in either population