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Ward J.M.,Global VetPathology | Ward J.M.,U.S. National Institutes of Health | Rehg J.E.,St Jude Childrens Research Hospital
Veterinary Pathology | Year: 2014

Immunohistochemistry (IHC) is a common adjunct in pathology for morphologic diagnosis, research pathology, and studying the pathogenesis of the disease. Proper technique and interpretation of an immunohistochemistry assay is of utmost importance. A variety of problems, including the presence of artifacts (nonspecific background or other staining problems) and the differentiation between nonspecific and specific staining, commonly occur. It is essential that antibody quality and IHC technique be optimized. We review the histologic patterns of specific and nonspecific staining after using IHC techniques, as well as basic troubleshooting procedures, and provide some examples of nonspecific staining and other artifacts especially in formalin-fixed, paraffin-embedded tissues (FFPE) of mice. © The Author(s) 2013. Source


Schofield P.N.,University of Cambridge | Schofield P.N.,The Jackson Laboratory | Dubus P.,University and Hospital of Bordeaux | Klein L.,Canceropole Grand Sud Ouest | And 4 more authors.
Toxicologic Pathology | Year: 2011

The fifth in a series of European workshops for veterinary and human pathologists, "Pathology of the Laboratory Mouse: An International Workshop on Challenges for High Throughput Phenotyping," was held in Bordeaux, France, from September 30 to October 1, 2010. In this report we outline the rationale for setting up this workshop series, summarize our experience, and suggest approaches for optimizing histopathology phenotyping for gene function discovery. © 2011 by The Author(s). Source


Cullen J.M.,North Carolina State University | Ward J.M.,Global VetPathology | Thompson C.M.,ToxStrategies Inc.
Toxicologic Pathology | Year: 2016

Thirteen-week and 2-year drinking water studies conducted by the National Toxicology Program (NTP) reported that hexavalent chromium (Cr(VI)) induced diffuse epithelial hyperplasia in the duodenum of B6C3F1 mice but not F344 rats. In the 2-year study, Cr(VI) exposure was additionally associated with duodenal adenomas and carcinomas in mice only. Subsequent 13-week Cr(VI) studies conducted by another group demonstrated non-neoplastic duodenal lesions in B6C3F1 mice similar to those of the NTP study as well as mild duodenal hyperplasia in F344 rats. Because intestinal lesions in mice are the basis for proposed safety standards for Cr(VI), and the histopathology data are relevant to the mode of action, consistency (an important Hill criterion for causality) was assessed across the aforementioned studies. Two veterinary pathologists applied uniform diagnostic criteria to the duodenal lesions in rats and mice from the 4 repeated-dose studies. Comparable non-neoplastic intestinal lesions were evident in mice and rats from all 4 studies; however, the incidence and severity of intestinal lesions were greater in mice than rats. These findings demonstrate consistency across studies and species and highlight the importance of standardized nomenclature for intestinal pathology. The differences in the severity of non-neoplastic lesions also likely contribute to the differential tumor response. © The Author(s) 2015. Source


Schofield P.N.,University of Cambridge | Schofield P.N.,The Jackson Laboratory | Ward J.M.,Global VetPathology | Sundberg J.P.,The Jackson Laboratory
DMM Disease Models and Mechanisms | Year: 2016

Reproducibility of data from experimental investigations using animal models is increasingly under scrutiny because of the potentially negative impact of poor reproducibility on the translation of basic research. Histopathology is a key tool in biomedical research, in particular for the phenotyping of animal models to provide insights into the pathobiology of diseases. Failure to disclose and share crucial histopathological experimental details compromises the validity of the review process and reliability of the conclusions. We discuss factors that affect the interpretation and validation of histopathology data in publications and the importance of making these data accessible to promote replicability in research. © 2016. Published by The Company of Biologists Ltd. Source


Qu A.,U.S. National Cancer Institute | Jiang C.,U.S. National Cancer Institute | Cai Y.,U.S. National Cancer Institute | Kim J.-H.,U.S. National Cancer Institute | And 5 more authors.
Journal of Hepatology | Year: 2014

Background & Aims Myc is involved in cell growth, proliferation, apoptosis, energy metabolism, and differentiation. Whether it is essential for hepatocellular proliferation and carcinogenesis is unclear due to a lack of an efficient hepatocyte-specific Myc disruption model. This study used a novel genetic model to investigate the involvement of Myc in hepatocellular proliferation and hepatocarcinogenesis in mice. Methods Temporal hepatocyte-specific Myc disruption was achieved by use of the tamoxifen-inducible Cre-ERT2 recombinase system under control of the serum albumin promoter. Hepatocyte proliferation was assessed by administering peroxisome proliferator-activated receptor α (PPARα) agonist Wy-14,643. A diethylnitrosamine-induced liver cancer model was used to evaluate the role of Myc in hepatocarcinogenesis. Results Tamoxifen administration induced recombination of Myc specifically in hepatocytes of Myc fl/fl,ERT2-Cre mice. When treated with a known hepatocellular proliferative stimulus Wy-14,643, Mycfl/fl,ERT2-Cre mice showed a lower liver/body weight ratio and suppressed hepatocyte proliferation as compared to Mycfl/fl mice. Hepatic expression of cell cycle control genes, DNA repair genes, and Myc target gene miRNAs were upregulated in Wy-14,643-treated Mycfl/fl mouse livers, but not in Wy-14,643-treated Mycfl/fl,ERT2-Cre livers. However, no differences were observed in the lipid-lowering effect of Wy-14,643 between Mycfl/fl,ERT2-Cre and Mycfl/fl mice, consistent with no differences in the expression of several PPARα target genes involved in fatty acid β-oxidation. Moreover, when subjected to the diethylnitrosamine liver cancer bioassay, Mycfl/fl,ERT2-Cre mice exhibited a markedly lower incidence of tumor formation compared with Mycfl/fl mice. Conclusions Myc plays an essential role in hepatocellular proliferation and liver tumorigenesis. Source

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