ABSTRACT
Decreased mitochondrial oxidative metabolism is a hallmark bioenergetic characteristic of malignancy that may have an adaptive role in carcinogenesis. By stimulating proton leak, mitochondrial uncoupling proteins (UCP1-3) increase mitochondrial respiration and may thereby oppose cancer development. To test this idea, we generated a mouse model that expresses an epidermal-targeted keratin-5-UCP3 (K5-UCP3) transgene and exhibits significantly increased cutaneous mitochondrial respiration compared with wild type (FVB/N). Remarkably, we observed that mitochondrial uncoupling drove keratinocyte/epidermal differentiation both in vitro and in vivo. This increase in epidermal differentiation corresponded to the loss of markers of the quiescent bulge stem cell population, and an increase in epidermal turnover measured using a bromodeoxyuridine (BrdU)-based transit assay. Interestingly, these changes in K5-UCP3 skin were associated with a nearly complete resistance to chemically-mediated multistage skin carcinogenesis. These data suggest that targeting mitochondrial respiration is a promising novel avenue for cancer prevention and treatment.
Subject(s)
Cell Differentiation , Cell Transformation, Neoplastic/metabolism , Ion Channels/metabolism , Keratinocytes/cytology , Keratinocytes/metabolism , Mitochondria/metabolism , Mitochondrial Proteins/metabolism , Animals , Cell Transformation, Neoplastic/chemically induced , Epidermis/metabolism , Gene Expression , Ion Channels/genetics , Mice , Mitochondrial Proteins/genetics , Oxygen Consumption/physiology , Resting Phase, Cell Cycle/genetics , Skin/metabolism , Skin/pathology , Stem Cells/cytology , Stem Cells/metabolism , Uncoupling Protein 3ABSTRACT
BACKGROUND: The current legal system for prosecuting medical malpractice claims has bred widespread discontent. It has increased costs, jeopardized the delivery of necessary medical services, and corroded the physician-patient relationship with mistrust and poor morale. METHODS: Analysis of fairness of compensation awards and deterrence of substandard medical services under the current system. RESULTS: Compensation awards are inconsistent and unfairly contingent on irrational, adventitious factors. The current system does not seem to have had a significant effect on detering poor medical practice or on improving medical practice in general. CONCLUSIONS: An alternative to the current litigation-oriented medical malpractice system should be established and centered around a four-member Medical Malpractice Tribunal composed of a general physician, an expert physician in the specialty area of the claim, an attorney, and a lay person. This tribunal would be empowered to investigate malpractice claims by gathering evidence and taking testimony from parties, experts, and witnesses. The tribunal could employ a table of treatment-related injuries in making findings as to physician liability and victim compensation. Such a system, through predictability, would likely increase malpractice prevention while decreasing legal costs and also costs associated with defensive medicine. Deterrence could be served by giving the tribunal power to recommend sanctions against substandard providers to appropriate licensing and disciplinary bodies and by requiring those found guilty of malpractice to contribute subsidies to a compensation fund.
