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Burd C.E.,University of North Carolina at Chapel Hill | Sorrentino J.A.,University of North Carolina at Chapel Hill | Clark K.S.,University of North Carolina at Chapel Hill | Darr D.B.,University of North Carolina at Chapel Hill | And 6 more authors.
Cell | Year: 2013

Monitoring cancer and aging in vivo remains experimentally challenging. Here, we describe a luciferase knockin mouse (p16LUC), which faithfully reports expression of p16INK4a, a tumor suppressor and aging biomarker. Lifelong assessment of luminescence in p16+/LUC mice revealed an exponential increase with aging, which was highly variable in a cohort of contemporaneously housed, syngeneic mice. Expression of p16 INK4a with aging did not predict cancer development, suggesting that the accumulation of senescent cells is not a principal determinant of cancer-related death. In 14 of 14 tested tumor models, expression of p16 LUC was focally activated by early neoplastic events, enabling visualization of tumors with sensitivity exceeding other imaging modalities. Activation of p16INK4a was noted in the emerging neoplasm and surrounding stromal cells. This work suggests that p16INK4a activation is a characteristic of all emerging cancers, making the p16 LUC allele a sensitive, unbiased reporter of neoplastic transformation. © 2013 Elsevier Inc.

Bertoletti A.,National University of Singapore | Bertoletti A.,Agency for Science, Technology and Research Singapore | Kennedy P.T.,Blizard Institute
Cellular and Molecular Immunology | Year: 2015

Chronic hepatitis B virus (HBV) infection progresses through distinct disease phases that are strongly associated with patient age. The so-called immune tolerant (IT) phase represents the classical early phase of infection; it is associated with high levels of HBV replication and lack of clinical signs of liver Inflammation. Whether this phase of HBV infection is also associated with immunological features of "tolerance' has recently been challenged. Here, we review the data that dispute this concept of immune tolerance and then propose an alternative interpretation of the immunopathological events that take place during this early phase of CHB infection. © 2015 CSI and USTC.

Wright N.A.,Blizard Institute
Journal of Pathology | Year: 2012

Recently, a dispute has arisen concerning the operational definition and identification of epithelial stem cells. There is a current view which considers that epithelial stem cell identification depends solely on the in vitro isolation and expansion of cells from the putative stem cell. This article argues strongly that this is a perverse and erroneous view, and that lineage labelling, using genetic markers, remains the gold standard for identifying epithelial stem cells and for analysing their behaviour: in vitro methods show, at best, clonogenic potential but not fate, and constitute ancillary support for conclusions drawn from lineage analysis. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Otto W.R.,Cancer Research UK Research Institute | Wright N.A.,Blizard Institute
Fibrogenesis and Tissue Repair | Year: 2011

There is currently much interest in adult mesenchymal stem cells (MSCs) and their ability to differentiate into other cell types, and to partake in the anatomy and physiology of remote organs. It is now clear these cells may be purified from several organs in the body besides bone marrow. MSCs take part in wound healing by contributing to myofibroblast and possibly fibroblast populations, and may be involved in epithelial tissue regeneration in certain organs, although this remains more controversial. In this review, we examine the ability of MSCs to modulate liver, kidney, heart and intestinal repair, and we update their opposing qualities of being less immunogenic and therefore tolerated in a transplant situation, yet being able to contribute to xenograft models of human tumour formation in other contexts. However, such observations have not been replicated in the clinic. Recent studies showing the clinical safety of MSC in several pathologies are discussed. The possible opposing powers of MSC need careful understanding and control if their clinical potential is to be realised with long-term safety for patients. © 2011 Otto and Wright; licensee BioMed Central Ltd.

Dobson R.,Blizard Institute
Multiple Sclerosis and Related Disorders | Year: 2012

There remains a need for sensitive and reliable biomarkers that can be used longitudinally in multiple sclerosis. Whilst both CSF and MRI have been extensively studied, they remain invasive and expensive methods of investigation. On the contrary, urine provides a valuable fluid which is readily available for serial sampling. Some work has been done on urinary biomarkers in multiple sclerosis; however, urinary biomarkers have not been extensively studied and validated for use in routine clinical practice, and urine remains understudied and underutilised. In this review the use of neopterin, urinary free light chains, nitric oxide metabolites and urinary myelin basic protein-like protein as potential biomarkers that have been identified in urine are discussed, and avenues for future study are raised. © 2012 Elsevier B.V.

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