- Book Review: Mouse Models of Cancer: A Laboratory Manual 25 febbraio 2015
Knoblaugh, S. E.
- Frontiers in Nonclinical Drug Development: Biosimilars 25 febbraio 2015
Ryan, A. M.
Biopharmaceuticals, produced by recombinant DNA technology, are generally more complicated to produce than small molecule drugs. As patents around the development and manufacturing of these biopharmaceuticals expire, biosimilars are being developed as comparable and more affordable alternatives to improve patient access and market competition. This commentary explains what a biosimilar is; it compares and contrasts biosimilar production with that of small molecule, generic, and other biological drugs; and it describes basic principles of the nonclinical development program for monoclonal antibody biosimilars.
- In Memoriam: William "Bill" John Hartley, OAM, RCVS, FRCVS, MVSc, FRC Path., DSc, FACVSc, 1922-2014 25 febbraio 2015
- The Common Marmoset as a Model for the Study of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis 25 febbraio 2015
Kramer, J. A., Grindley, J., Crowell, A. M., Makaron, L., Kohli, R., Kirby, M., Mansfield, K. G., Wachtman, L. M.
Nonalcoholic fatty liver disease (NAFLD) is considered the hepatic manifestation of metabolic syndrome. The more clinically concerning form of the disease, nonalcoholic steatohepatitis (NASH), is characterized by steatosis, lobular inflammation, and ballooning degeneration. Here we describe a naturally occurring syndrome in the common marmoset that recapitulates the pathologic findings associated with NAFLD/NASH in humans. Hepatomegaly determined to result from NAFLD was observed in 33 of 183 marmosets. A comprehensive histopathologic assessment performed in 31 marmosets demonstrated that NAFLD was characterized by variably sized, Oil Red O staining cytoplasmic vacuoles and observed primarily in animals with evidence of obesity and insulin resistance. A subset of marmosets (16 of 31) also demonstrated evidence of NASH characterized by multifocal inflammation combined with ballooning hepatocellular degeneration. Marmosets with NASH demonstrated an increase in immunostaining with an antibody targeted against the human leukocyte antigens (HLA)–DP, HLA-DQ, and HLA-DR compared with marmosets without NASH (38.89 cells/10x field vs 12.05 cells/10x field, P = .05). In addition, marmosets with NASH demonstrated increased Ki-67 immunopositive cellular proliferation compared with those without (5.95 cells/10x field vs 1.53 cells/10x field, P = .0002). Finally, animals with NASH demonstrated significantly increased mean circulating serum iron levels (160.47 μg/dl, P = .008) and an increase in numbers of Prussian blue–positive Kupffer cells (9.28 cells/40x field, P = .005) relative to marmosets without NASH (97.75 μg/dl and 1.87 cells/40x, respectively). This study further characterizes the histopathology of NAFLD/NASH and suggests that the marmoset may be a valuable animal model with which to investigate the host and environmental factors contributing to the progression of NAFLD/ NASH.
- Ultrastructural Abnormalities of the Trabecular Meshwork Extracellular Matrix in Cyp1b1-Deficient Mice 25 febbraio 2015
Teixeira, L. B. C., Zhao, Y., Dubielzig, R. R., Sorenson, C. M., Sheibani, N.
Cytochrome P450 1B1 (CYP1B1) is highly expressed in human and murine ocular tissues during development. Mutations in this gene are implicated in the development of primary congenital glaucoma (PCG) in humans. Mice deficient in Cyp1b1 (Cyp1b1–/– ) present developmental abnormalities similar to human primary congenital glaucoma. The present work describes the ultrastructural morphology of the iridocorneal angle of 21 eyes from 1-week-old to 8-month-old Cyp1b1–/– mice. Morphometric and semiquantitative analysis of the data revealed that 3-week-old Cyp1b1–/– mice present a significantly (P < .005) decreased amount of trabecular meshwork (TM) collagen and higher TM endothelial cell and collagen lesion scores (P < .005) than age-matched controls. Collagen loss and lesion scores were progressively increased in older animals, with 8-month-old animals presenting severe atrophy of the TM. Our findings advance the understanding of the effects of CYP1B1 mutations in TM development and primary congenital glaucoma, as well as suggest a link between TM morphologic alterations and increased intraocular pressure.
- Immunohistochemical Characterization and Morphometric Analysis of Macrophages in Rat Mammary Tumors 25 febbraio 2015
Ong, C. B., Brandenberger, C., Kiupel, M., Kariagina, A., Langohr, I. M.
Macrophages are an important leukocyte component of the microenvironment of neoplasms. Macrophages have classically been subdivided into M1 and M2, depending on their roles in immune response, wound healing, and promotion or inhibition of tumor growth. In human breast cancer, increased presence of M2 macrophages has been associated with poor prognosis. The authors hypothesized that rat mammary carcinomas have increased macrophage influx compared to benign mammary proliferative lesions and normal mammary glands as well. In humans, both M1 and M2 macrophages express CD68, while CD163 is expressed primarily by M2 macrophages. Based on a single immunolabeling protocol with anti-CD68 and anti-CD163 antibodies, the extent of macrophage influx was investigated by morphometry to quantitate the immunopositive cells in normal rat mammary glands, benign mammary proliferative lesions, and mammary carcinomas. In mammary carcinomas, there was significantly higher percentage of CD68+ cells compared to benign mammary proliferative lesions and normal mammary glands. There was also higher percentage of CD163+ cells in mammary carcinomas compared to benign mammary proliferative lesions. Thus, increase in CD68+ and CD163+ macrophages corresponded to increased malignancy of rat mammary tumors in this study.
- Primary Intestinal and Vertebral Chordomas in Laboratory Zebrafish (Danio rerio) 25 febbraio 2015
Cooper, T. K., Murray, K. N., Spagnoli, S., Spitsbergen, J. M.
Chordomas are uncommon neoplasms arising from notochord remnants, most commonly occurring in the axial skeleton. Extraskeletal soft tissue chordomas are rare primary tumors, and primary alimentary tract chordomas have not been reported. Herein we report 24 cases of spontaneous primary intestinal chordomas in zebrafish, as well as 9 spontaneous vertebral chordomas. Both intestinal and vertebral tumors showed invasive behavior, although more commonly in the latter. In all cases of primary intestinal chordomas, there was no axial or peripheral skeletal or other nonvisceral involvement. Although uncommon, intestinal chordomas represent a unique background lesion in aged zebrafish.
- Fatal Parastrongylus dujardini Infection in Captive Callitrichids 25 febbraio 2015
Graille, M., Ferte, H., Petit, T., Courtois, F. O., Gauchot, J.- Y., Nougaillon, J.- L., Vitaud, C., Wardzynski, C., Lemberger, K.
Intravascular nematodes were considered the cause of death of 14 captive callitrichids. All animals were captive born at zoos in France and died with little or no premonitory signs of disease. No consistent gross lesions were observed at necropsy, although in certain cases intracardiac adult parasites were noted. The most significant histologic findings were verminous pneumonia and pulmonary endarteritis. In all cases except one, intravascular adult nematodes were observed with eggs and larvae in the lungs. Adult nematodes were obtained from 8 animals and in all cases were identified as Parastrongylus dujardini. To the authors’ knowledge, this is the first report of intravascular angiostrongylosis with primary cardiopulmonary location in callitrichids in France.
- Nonregenerative Anemia: Mechanisms of Decreased or Ineffective Erythropoiesis 25 febbraio 2015
Grimes, C. N., Fry, M. M.
In veterinary medicine, anemia without an appropriate compensatory hematopoietic response is termed nonregenerative. Nonregenerative anemia is a common clinical entity, occurring as a result of diminished or ineffective erythropoiesis in association with many types of pathology. This article reviews nonregenerative anemia in domestic animals, emphasizing mechanisms of disease, and also covers other conditions associated with nonregenerative anemia in people. Many aspects of nonregenerative anemia in animals are worthy of further investigation, from molecular mechanisms of disease to epidemiologic impacts.
- Mycobacterium Fortuitum Lipoid Pneumonia in a Dog 25 febbraio 2015
Leissinger, M. K., Garber, J. B., Fowlkes, N., Grooters, A. M., Royal, A. B., Gaunt, S. D.
A 1-year old female spayed German Shepherd dog was evaluated for acute onset of dyspnea. Pyogranulomatous inflammation and green globoid structures were present on aspirates of the affected lung. Impression smears and histopathology confirmed pyogranulomatous pneumonia, with large amounts of lipid corresponding to the green structures noted cytologically, and identified poorly staining bacterial rods within lipid vacuoles. Special stains confirmed the presence of acid-fast bacterial rods, and polymerase chain reaction and DNA sequencing identified the organism as Mycobacterium fortuitum. M. fortuitum pneumonia is well described in humans and has previously been reported in 4 dogs and 1 cat. Lipid was a prominent cytologic and histologic feature, as is often described in humans and in the single feline case report. Additionally, this case highlights the variable cytologic appearance of lipid, as well as Mycobacterium spp, which are classically nonstaining with Wright-Giemsa.