Publications by authors named "Krista M D La Perle"

34 Publications

Cotton Rat Placenta Anatomy and Fc Receptor Expression and Their Roles in Maternal Antibody Transfer.

Comp Med 2020 Dec 29;70(6):510-519. Epub 2020 Oct 29.

Department of Veterinary Biosciences, Ohio State University, Columbus, Ohio; Comparative Pathology and Mouse Phenotyping Shared Resource, Ohio State University, Columbus, Ohio.

Respiratory syncytial virus (RSV) is the leading cause of bronchiolitis and viral pneumonia in infants and young children worldwide. Currently no vaccine is available to prevent RSV infection, but virus-neutralizing monoclonal antibodies can be given prophylactically, emphasizing the protective potential of antibodies. One concept of RSV vaccinology is mothers' immunization to induce high antibody titers, leading to passive transfer of high levels of maternal antibody to the fetus through the placenta and to the neonate through colostrum. Cotton rats are an excellent small animal model for RSV infection and have been used to test maternal immunization. To mechanistically understand antibody transfer in the cotton rat model, we characterized the cotton rat placenta and Fc receptor localization. Placentas from cotton rats at midgestation (approximately day 14) and at late gestation (approximately day 25) and neonatal (younger than 1 wk) gastrointestinal tracts were collected for light microscopy, immunohistochemistry, and transmission electron microscopy. The cotton rat placenta is hemotrichorial and has 5 distinct layers: decidua, junctional zone, labyrinth, chorionic plate, and yolk sac. Consistent with the transfer of maternal antibodies, the majority of the Fc receptors are present in the yolk sac endoderm and fetal capillary endothelium of the chorionic plate, involving 10% of the cells within the labyrinth. In addition, Fc receptors are present on duodenal and jejunal enterocytes in cotton rats, similar to humans, mice, and rats. These findings provide the structural basis for the pre- and postnatal transfer of maternal antibodies described in cotton rats.
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http://dx.doi.org/10.30802/AALAS-CM-20-000040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754198PMC
December 2020

Cause and Treatment of Exophthalmos in Aged Cotton Rats ().

Comp Med 2020 06 13;70(3):291-299. Epub 2020 May 13.

Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio; Comparative Pathology and Mouse Phenotyping, The Ohio State University, Columbus, Ohio;, Email:

Aged cotton rats () from an established breeding colony displayed signs of spontaneous exophthalmos. Of a total of 118 colony animals that were older than 6 mo of age, 37 (31%) displayed signs of exophthalmos. These rats were clinically healthy and had no other signs of disease. Ophthalmic exams, molecular and microbiologic testing, and histopa- thology were performed to determine the cause of the exophthalmos and to provide appropriate treatment. Environmental monitoring records were also reviewed for vivarium rooms in which the cotton rats were housed. Histopathology findings supported that the exophthalmos in these cotton rats was secondary to retro-orbital thrombosis associated with cardiomyopathy. The exophthalmic eyes were treated by either removal of the affected eye (enucleation) or surgical closure of the eyelids (temporary tarsorraphy). Enucleation of the exophthalmic eye was the best intervention for these aged cotton rats. These findings demonstrate the potential for a high incidence of ocular problems occurring secondary to cardiomyopathy in aged cotton rats. Enucleation as a therapeutic intervention for exophthalmic eyes in aged cotton rats prolongs the morbidity-free time span during which these aged animals can be used experimentally.
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http://dx.doi.org/10.30802/AALAS-CM-19-000107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7287388PMC
June 2020

Tagging enhances histochemical and biochemical detection of Ran Binding Protein 9 in vivo and reveals its interaction with Nucleolin.

Sci Rep 2020 04 28;10(1):7138. Epub 2020 Apr 28.

Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University and Arthur G. James Comprehensive Cancer Center, Columbus, USA.

The lack of tools to reliably detect RanBP9 in vivo has significantly hampered progress in understanding the biological functions of this scaffold protein. We report here the generation of a novel mouse strain, RanBP9-TT, in which the endogenous protein is fused with a double (V5-HA) epitope tag at the C-terminus. We show that the double tag does not interfere with the essential functions of RanBP9. In contrast to RanBP9 constitutive knock-out animals, RanBP9-TT mice are viable, fertile and do not show any obvious phenotype. The V5-HA tag allows unequivocal detection of RanBP9 both by IHC and WB. Importantly, immunoprecipitation and mass spectrometry analyses reveal that the tagged protein pulls down known interactors of wild type RanBP9. Thanks to the increased detection power, we are also unveiling a previously unknown interaction with Nucleolin, a protein proposed as an ideal target for cancer treatment. In summary, we report the generation of a new mouse line in which RanBP9 expression and interactions can be reliably studied by the use of commercially available αtag antibodies. The use of this line will help to overcome some of the existing limitations in the study of RanBP9 and potentially unveil unknown functions of this protein in vivo such as those linked to Nucleolin.
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http://dx.doi.org/10.1038/s41598-020-64047-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188826PMC
April 2020

Machine Learning and Veterinary Pathology: Be Not Afraid!

Vet Pathol 2019 07;56(4):506-507

1 Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, USA.

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http://dx.doi.org/10.1177/0300985819848504DOI Listing
July 2019

MAPK- and AKT-activated thyroid cancers are sensitive to group I PAK inhibition.

Endocr Relat Cancer 2019 08;26(8):699-712

Division of Endocrinology, Diabetes, and Metabolism, The Ohio State University Wexner Medical Center and Arthur G. James Comprehensive Cancer Center, Columbus, Ohio, USA.

The number of individuals who succumb to thyroid cancer has been increasing and those who are refractory to standard care have limited therapeutic options, highlighting the importance of developing new treatments for patients with aggressive forms of the disease. Mutational activation of MAPK signaling, through BRAF and RAS mutations and/or gene rearrangements, and activation of PI3K signaling, through mutational activation of PIK3CA or loss of PTEN, are well described in aggressive thyroid cancer. We previously reported overactivation and overexpression of p21-activated kinases (PAKs) in aggressive human thyroid cancer invasive fronts and determined that PAK1 functionally regulated thyroid cancer cell migration. We reported mechanistic crosstalk between the MAPK and PAK pathways that are BRAF-dependent but MEK independent, suggesting that PAK and MEK inhibition might be synergistic. In the present study, we tested this hypothesis. Pharmacologic inhibition of group I PAKs using two PAK kinase inhibitors, G-5555 or FRAX1036, reduced thyroid cancer cell viability, cell cycle progression and migration and invasion, with greater potency for G-5555. Combination of G-5555 with vemurafenib was synergistic in BRAFV600E-mutated thyroid cancer cell lines. Finally, G-5555 restrained thyroid size of BRAFV600E-driven murine papillary thyroid cancer by >50% (P < 0.0001) and reduced carcinoma formation (P = 0.0167), despite maintenance of MAPK activity. Taken together, these findings suggest both that group I PAKs may be a new therapeutic target for thyroid cancer and that PAK activation is functionally important for BRAFV600E-mediated thyroid cancer development.
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http://dx.doi.org/10.1530/ERC-19-0188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7062234PMC
August 2019

Pathology Principles and Practices for Analysis of Animal Models.

ILAR J 2018 12;59(1):40-50

Department of Veterinary Biosciences, and Comparative Pathology & Mouse Phenotyping Shared Resource, The Ohio State University, Columbus, Ohio.

Over 60% of NIH extramural funding involves animal models, and approximately 80% to 90% of these are mouse models of human disease. It is critical to translational research that animal models are accurately characterized and validated as models of human disease. Pathology analysis, including histopathology, is essential to animal model studies by providing morphologic context to in vivo, molecular, and biochemical data; however, there are many considerations when incorporating pathology endpoints into an animal study. Mice, and in particular genetically modified models, present unique considerations because these modifications are affected by background strain genetics, husbandry, and experimental conditions. Comparative pathologists recognize normal pathobiology and unique phenotypes that animals, including genetically modified models, may present. Beyond pathology, comparative pathologists with research experience offer expertise in animal model development, experimental design, optimal specimen collection and handling, data interpretation, and reporting. Critical pathology considerations in the design and use of translational studies involving animals are discussed, with an emphasis on mouse models.
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http://dx.doi.org/10.1093/ilar/ilz001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927822PMC
December 2018

Pathology of wild Norway rats in Vancouver, Canada.

J Vet Diagn Invest 2019 Mar;31(2):184-199

Department of Pathobiology, Ontario Veterinary College, University of Guelph and Canadian Wildlife Health Cooperative (CWHC; Ontario-Nunavut Region), Guelph, ON, Canada (Rothenburger, Nemeth, Jardine).

To achieve a contemporary understanding of the common and rare lesions that affect wild, urban Norway rats ( Rattus norvegicus), we conducted a detailed pathology analysis of 672 rats from Vancouver, British Columbia, Canada. Grossly evident lesions, such as wounds, abscesses, and neoplasms, were present in 71 of 672 rats (11%) and tended to be severe. The most common and significant lesions were infectious and inflammatory, most often affecting the respiratory tract and associated with bite wounds. We assessed a subset of rats (up to n = 406 per tissue) for the presence of microscopic lesions in a variety of organ systems. The most frequent lesions that could impact individual rat health included cardiomyopathy (128 of 406; 32%), chronic respiratory tract infections as indicated by pulmonary inducible bronchus-associated lymphoid tissue (270 of 403; 67%), tracheitis (192 of 372; 52%), and thyroid follicular hyperplasia (142 of 279; 51%). We isolated 21 bacterial species from purulent lesions in rats with bacterial infections, the most frequent of which were Escherichia coli, Enterococcus sp., and Staphylococcus aureus. Parasitic diseases in rats resulted from infection with several invasive nematodes: Capillaria hepatica in the liver (242 of 672; 36%), Eucoleus sp. in the upper gastrointestinal tract (164 of 399; 41%), and Trichosomoides crassicauda in the urinary bladder (59 of 194; 30%). Neoplastic, congenital, and degenerative lesions were rare, which likely reflects their adverse effect on survival in the urban environment. Our results establish a baseline of expected lesions in wild urban rats, which may have implications for urban rat and zoonotic pathogen ecology, as well as rat control in cities worldwide.
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http://dx.doi.org/10.1177/1040638719833436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6838826PMC
March 2019

Comparative Pathologists: Ultimate Control Freaks Seeking Validation!

Vet Pathol 2019 Jan 28;56(1):19-23. Epub 2018 Oct 28.

1 Department of Veterinary Biosciences, Comparative Pathology & Mouse Phenotyping Shared Resource, The Ohio State University, Columbus, OH, USA.

Definable, reproducible, and meaningful are elemental features of grading/scoring systems, while thoroughness, accuracy, and consistency are quality indicators of pathology reports. The expertise of pathologists is significantly underutilized when it is limited to rendering diagnoses. The opportunity to provide guidance on animal model development, experimental design, optimal sample collection, and data interpretation not only contributes to job satisfaction but also, more importantly, promotes validation of the pathology data. Keys to validation include standard operating procedures, experimental controls, and standardized nomenclature applied throughout the experimental design and execution, tissue sampling, and slide preparation, as well as the creation or adaptation and application of semiquantitative grading/scoring systems. Diagnostic drift, thresholds, mental noise, and various diurnal fluctuations strongly influence the repeatability of grading/scoring systems used by the same or different pathologists. Quantitative image analyses are not plagued by the visual and cognitive traps that affect manual semiquantitative grading schemes but may still be affected by technical variables associated with necropsy, tissue sampling, and slide preparation. The validity of a grading scheme is ultimately assessed by its repeatability and biologic relevance, so it is important to correlate scores with comprehensive pathobiology data such as results of antemortem imaging, clinical pathology data, body and organ weights, and histopathologic evaluation of full tissue sets.
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http://dx.doi.org/10.1177/0300985818806047DOI Listing
January 2019

Alterations in Sod2-Induced Oxidative Stress Affect Endocrine Cancer Progression.

J Clin Endocrinol Metab 2018 11;103(11):4135-4145

Department of Cancer Biology and Genetics, The Ohio State University, Columbus, Ohio.

Context: Although important advances have been made in understanding the genetics of endocrine tumors, cellular physiology is relatively understudied as a determinant of tumor behavior. Oxidative stress and reactive oxygen species are metabolic factors that may affect tumor behavior, and these are, in part, controlled by manganese-dependent superoxide dismutase (MnSod), the mitochondrial superoxide dismutase (encoded by SOD2).

Objective: We sought to understand the role of MnSod in the prognosis of aggressive human endocrine cancers and directly assessed the effect of MnSod under- or overexpression on tumor behavior, using established mouse thyroid cancer models.

Methods: We performed transcriptome analysis of human and mouse models of endocrine cancer. To address the role of Sod2 in endocrine tumors, we introduced a Sod2 null allele or a transgenic Sod2 overexpression allele into mouse models of benign thyroid follicular neoplasia or aggressive, metastatic follicular thyroid cancer (FTC) and monitored phenotypic changes in tumor initiation and progression.

Results: In the thyroid, SOD2/Sod2 was downregulated in FTC but not papillary thyroid cancer. Reduced expression of SOD2 was correlated with poorer survival of patients with aggressive thyroid or adrenal cancers. In mice with benign thyroid tumors, Sod2 overexpression increased tumor burden. In contrast, in mice with aggressive FTC, overexpression of Sod2 reduced tumor proliferation and improved mortality rates, whereas its deficiency enhanced tumor growth.

Conclusion: Overall, our results indicate that SOD2 has dichotomous roles in cancer progression and acts in a context-specific manner.
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http://dx.doi.org/10.1210/jc.2018-01039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6194813PMC
November 2018

Characterization of Cotton Rat () Eosinophils, Including Their Response to Respiratory Syncytial Virus Infection.

Comp Med 2018 02;68(1):31-40

Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio;, Email:

Eosinophils have been postulated to play a protective role against infection with respiratory syncytial virus (RSV), increase the severity of allergic asthma during respiratory viral infection, and drive vaccine-enhanced disease. To address these questions in the cotton rat model of RSV infection, we characterized cotton rat eosinophils by electron microscopy as well as by bronchoalveolar lavage and histology of lung sections. Using these methods, we demonstrated that eosinophils comprise approximately half of all cells in the bronchoalveolar lavage fluids from cotton rats. The function of these cells was comparable to that of eosinophils of other species. Ex vivo, eosinophils stimulated with calcium ionophores secreted eosinophil peroxidase. In vivo, treatment with house dust mite antigen increased eosinophil numbers in lung. Infection with Staphylococcus aureus lead to a marked increase in neutrophils without an increase in eosinophils, and eosinophil numbers were not influenced by infection with influenza virus or measles virus. Similarly, infection with RSV did not result in an increase in eosinophils. Lastly, RSV infection did not increase eosinophil recruitment into the lung after challenge with house dust mite antigen, but it did increase eosinophil recruitment into the lungs of cotton rats previously immunized with formalin-inactivated RSV vaccine, thus contributing to vaccine-enhanced disease.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5824137PMC
February 2018

Role of Wild-type and Recombinant Human T-cell Leukemia Viruses in Lymphoproliferative Disease in Humanized NSG Mice.

Comp Med 2018 02;68(1):4-14

Department of Veterinary Biosciences, Center for Retrovirus Research, College of Veterinary Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, OH;, Email:

Chronic infection with human T-cell leukemia virus type 1 (HTLV1) can lead to adult T-cell leukemia (ATL). In contrast, infection with HTLV2 does not lead to leukemia, potentially because of distinct virus-host interactions and an active immune response that controls virus replication and, therefore, leukemia development. We created a humanized mouse model by injecting human umbilical-cord stem cells into the livers of immunodeficient neonatal NSG mice, resulting in the development of human lymphocytes that cannot mount an adaptive immune response. We used these mice to compare the ability of molecular clones of HTLV1, HTLV2, and select recombinant viruses to induce leukemia-lymphoma in vivo. Infection with HTLV1 strongly stimulated the proliferation of CD4+ T cells, whereas HTLV2 preferentially stimulated the proliferation of CD8+ T cells; both HTLV1 and HTLV2 induced lymphoproliferative disease. Uninfected and HTLV-infected humanized mice both showed granulomatous inflammation as a background lesion. Similarly, recombinant viruses that expressed the HTLV1 envelope protein (Env) on an HTLV2 background (HTLV2-Env1) or Env2 on an HTLV1 background (HTLV1-Env2) induced lymphoproliferative disease. HTLV2-Env1 stimulated the proliferation of CD4+ T cells, whereas HTLV1-Env2 stimulated both CD4+ and CD8+ T-cell subsets. Our results show that T-cell transformation in vivo is guided by the Env protein of the virus. Furthermore, our humanized mouse model is useful for exploring the preferred T-cell tropisms of HTLV1 and HTLV2.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5824134PMC
February 2018

Safety Profile of Good Manufacturing Practice Manufactured Interferon γ-Primed Mesenchymal Stem/Stromal Cells for Clinical Trials.

Stem Cells Transl Med 2017 10 9;6(10):1868-1879. Epub 2017 Sep 9.

Nationwide Children's Hospital, The Ohio State University, Columbus, Ohio, USA.

Mesenchymal stem/stromal cells (MSCs) are widely studied by both academia and industry for a broad array of clinical indications. The collective body of data provides compelling evidence of the clinical safety of MSC therapy. However, generally accepted proof of therapeutic efficacy has not yet been reported. In an effort to generate a more effective therapeutic cell product, investigators are focused on modifying MSC processing protocols to enhance the intrinsic biologic activity. Here, we report a Good Manufacturing Practice-compliant two-step MSC manufacturing protocol to generate MSCs or interferon γ (IFNγ) primed MSCs which allows freshly expanded cells to be infused in patients on a predetermined schedule. This protocol eliminates the need to infuse cryopreserved, just thawed cells which may reduce the immune modulatory activity. Moreover, using (IFNγ) as a prototypic cytokine, we demonstrate the feasibility of priming the cells with any biologic agent. We then characterized MSCs and IFNγ primed MSCs prepared with our protocol, by karyotype, in vitro potential for malignant transformation, biodistribution, effect on engraftment of transplanted hematopoietic cells, and in vivo toxicity in immune deficient mice including a complete post-mortem examination. We found no evidence of toxicity attributable to the MSC or IFNγ primed MSCs. Our data suggest that the clinical risk of infusing MSCs or IFNγ primed MSCs produced by our two-step protocol is not greater than MSCs currently in practice. While actual proof of safety requires phase I clinical trials, our data support the use of either cell product in new clinical studies. Stem Cells Translational Medicine 2017;6:1868-1879.
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http://dx.doi.org/10.1002/sctm.16-0485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6430053PMC
October 2017

Spontaneous reproductive pathology in female guinea pigs.

J Vet Diagn Invest 2016 Nov 3;28(6):656-661. Epub 2016 Oct 3.

Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, TN (Veiga-Parga, Newman)Department of Veterinary Biosciences and the Comparative Pathology and Mouse Phenotyping Shared Resource, The Ohio State University, Columbus, OH (La Perle)

Reproductive pathology of domestic guinea pigs is underreported to date. To provide a comprehensive review of uterine disease in guinea pigs, we performed a retrospective study of the pathology archives of the University of Tennessee, College of Veterinary Medicine. By histology, 13 of 37 uterine lesions in 23 animals were neoplastic; the other 24 nonneoplastic lesions included cystic endometrial hyperplasia (16 of 24), endometrial hemorrhage (3 of 24), pyometra (2 of 24), polyp (2 of 24), and mucometra (1 of 24). The most common guinea pig uterine neoplasms were uterine leiomyomas (6 of 13), followed by adenomas (3 of 13) and leiomyosarcomas (1 of 13). Other neoplasms included anaplastic tumors of unknown origin (2 of 13) and choriocarcinoma (1 of 13). Both anaplastic tumors and the choriocarcinoma were positive for vimentin. The choriocarcinoma was positive for HSD83B1, indicating a trophoblastic origin and its final diagnosis. All were negative for cytokeratin and smooth muscle. In multiple animals, more than 1 tumor or lesion was reported. Estrogen receptor and progesterone receptor expression was nearly 100% in uterine neoplasms. Nearly all animals for which data were available had cystic rete ovarii (18 of 19); the animal with no cystic rete ovarii had paraovarian cysts. In our study, female pet guinea pigs had a tendency to develop cystic endometrial hyperplasia and uterine neoplasia. Factors for the development of these lesions could be cystic rete ovarii, hormone dysregulation, and/or age. Other factors could contribute to the development of uterine lesions. As in other species, early ovariohysterectomy could decrease the prevalence of uterine lesions.
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http://dx.doi.org/10.1177/1040638716665429DOI Listing
November 2016

Noncatalytic PTEN missense mutation predisposes to organ-selective cancer development in vivo.

Genes Dev 2015 Aug;29(16):1707-20

Solid Tumor Biology Program, James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA; Department of Molecular Genetics, College of Arts and Sciences, The Ohio State University, Columbus, Ohio 43210, USA; Department of Molecular Virology, Immunology, and Medical Genetics, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA;

Inactivation of phosphatase and tensin homology deleted on chromosome 10 (PTEN) is linked to increased PI3K-AKT signaling, enhanced organismal growth, and cancer development. Here we generated and analyzed Pten knock-in mice harboring a C2 domain missense mutation at phenylalanine 341 (Pten(FV)), found in human cancer. Despite having reduced levels of PTEN protein, homozygous Pten(FV/FV) embryos have intact AKT signaling, develop normally, and are carried to term. Heterozygous Pten(FV/+) mice develop carcinoma in the thymus, stomach, adrenal medulla, and mammary gland but not in other organs typically sensitive to Pten deficiency, including the thyroid, prostate, and uterus. Progression to carcinoma in sensitive organs ensues in the absence of overt AKT activation. Carcinoma in the uterus, a cancer-resistant organ, requires a second clonal event associated with the spontaneous activation of AKT and downstream signaling. In summary, this PTEN noncatalytic missense mutation exposes a core tumor suppressor function distinct from inhibition of canonical AKT signaling that predisposes to organ-selective cancer development in vivo.
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http://dx.doi.org/10.1101/gad.262568.115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4561480PMC
August 2015

Trophoblast deportation to the lungs of cotton rats (Sigmodon hispidus).

Comp Med 2014 Dec;64(6):448-55

Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio, USA.

Cotton rats (Sigmodon hispidus) have been used to study a variety of infectious agents, particularly human respiratory viral pathogens. During the course of comprehensive pathologic evaluations of aging breeders from our breeding colony, 6 of 22 (27%) female cotton rats had histologic evidence, limited to the lungs, of embolized cells that were confirmed to be trophoblastic in origin by HSD3B1 immunoreactivity. When pulmonary trophoblast emboli were numerous, they usually were associated with additional histologic findings in the lungs, including pulmonary edema and hemorrhage, endothelial hypertrophy, fibrinoid vascular necrosis, and abundant alveolar macrophages containing fresh fibrin and hemolyzing erythrocytes. Of the 6 cotton rats with pulmonary trophoblast emboli, 5 (83%) were at 8 to 18 d of the 27-d gestation period, with the greatest number of emboli per lung present between days 10 through 14. The remaining cotton rat had a focal pulmonary trophoblast embolus and was not pregnant but had delivered a litter 3 mo previously. Three other cotton rats in either the early or late stages of gestation showed no histologic evidence of pulmonary trophoblast deportation. This report is the first to document pulmonary trophoblast emboli in cotton rats. This finding suggests that cotton rats may be an alternative animal model for the study of normal and aberrant trophoblast deportation in routine pregnancies and gestational pathologic conditions in women.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4275080PMC
December 2014

Extra-prostatic transgene-associated neoplastic lesions in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice.

Toxicol Pathol 2015 Feb 17;43(2):186-97. Epub 2014 Apr 17.

Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, USA Comparative Pathology and Mouse Phenotyping Shared Resource, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA.

Male transgenic adenocarcinoma of the mouse prostate (TRAMP) mice are frequently used in prostate cancer research because their prostates consistently develop a series of preneoplastic and neoplastic lesions. Disease progression in TRAMP mouse prostates culminates in metastatic, poorly differentiated carcinomas with neuroendocrine features. The androgen dependence of the rat probasin promoter largely limits transgene expression to the prostatic epithelium. However, extra-prostatic transgene-positive lesions have been described in TRAMP mice, including renal tubuloacinar carcinomas, neuroendocrine carcinomas of the urethra, and phyllodes-like tumors of the seminal vesicle. Here, we describe the histologic and immunohistochemical features of 2 novel extra-prostatic lesions in TRAMP mice: primary anaplastic tumors of uncertain cell origin in the midbrain and poorly differentiated adenocarcinomas of the submandibular salivary gland. These newly characterized tumors apparently result from transgene expression in extra-prostatic locations rather than representing metastatic prostate neoplasms because lesions were identified in both male and female mice and in male TRAMP mice without histologically apparent prostate tumors. In this article, we also calculate the incidences of the urethral carcinomas and renal tubuloacinar carcinomas, further elucidate the biological behavior of the urethral carcinomas, and demonstrate the critical importance of complete necropsies even when evaluating presumably well characterized phenotypes in genetically engineered mice.
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http://dx.doi.org/10.1177/0192623314531351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4201646PMC
February 2015

Follicular thyroid cancers demonstrate dual activation of PKA and mTOR as modeled by thyroid-specific deletion of Prkar1a and Pten in mice.

J Clin Endocrinol Metab 2014 May 10;99(5):E804-12. Epub 2014 Feb 10.

Departments of Molecular, Virology, Immunology, and Medical Genetics (D.R.P., P.K.M., A.A.L., J.M.K., L.S.K.) and Veterinary Biosciences (K.M.D.L.P.), Center for Biostatistics (L.Y., X.Z., D.J.), and Division of Endocrinology, Diabetes, and Metabolism (M.S., M.D.R., L.S.K.), The Ohio State University, Columbus, Ohio 43210; Department of Pediatrics (V.V.V.), Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814; and National Hormone and Peptide Program (A.F.P.), Harbor-UCLA Medical Center, Torrance, California 90509.

Context: Thyroid cancer is the most common form of endocrine cancer, and it is a disease whose incidence is rapidly rising. Well-differentiated epithelial thyroid cancer can be divided into papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC). Although FTC is less common, patients with this condition have more frequent metastasis and a poorer prognosis than those with PTC.

Objective: The objective of this study was to characterize the molecular mechanisms contributing to the development and metastasis of FTC.

Design: We developed and characterized mice carrying thyroid-specific double knockout of the Prkar1a and Pten tumor suppressor genes and compared signaling alterations observed in the mouse FTC to the corresponding human tumors.

Setting: The study was conducted at an academic research laboratory. Human samples were obtained from academic hospitals.

Patients: Deidentified, formalin-fixed, paraffin-embedded (FFPE) samples were analyzed from 10 control thyroids, 30 PTC cases, five follicular variant PTC cases, and 10 FTC cases.

Interventions: There were no interventions.

Main Outcome Measures: Mouse and patient samples were analyzed for expression of activated cAMP response element binding protein, AKT, ERK, and mammalian target of rapamycin (mTOR). Murine FTCs were analyzed for differential gene expression to identify genes associated with metastatic progression.

Results: Double Prkar1a-Pten thyroid knockout mice develop FTC and recapitulate the histology and metastatic phenotype of the human disease. Analysis of signaling pathways in FTC showed that both human and mouse tumors exhibited strong activation of protein kinase A and mTOR. The development of metastatic disease was associated with the overexpression of genes required for cell movement.

Conclusions: These data imply that the protein kinase A and mTOR signaling cascades are important for the development of follicular thyroid carcinogenesis and may suggest new targets for therapeutic intervention. Mouse models paralleling the development of the stages of human FTC should provide important new tools for understanding the mechanisms of FTC development and progression and for evaluating new therapeutics.
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http://dx.doi.org/10.1210/jc.2013-3101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4010710PMC
May 2014

Histopathological analysis of Salmonella chronic carriage in the mouse hepatopancreatobiliary system.

PLoS One 2013 12;8(12):e84058. Epub 2013 Dec 12.

Departments of Microbiology and Microbial Infection and Immunity, Center for Microbial Interface Biology, The Ohio State University, Columbus, Ohio, United States of America.

Salmonella Typhi asymptomatic chronic carriage represents a challenge for the diagnosis and prevention of typhoid fever in endemic areas. Such carriers are thought to be reservoirs for further spread of the disease. Gallbladder carriage has been demonstrated to be mediated by biofilm formation on gallstones and by intracellular persistence in the gallbladder epithelium of mice. In addition, both gallstones and chronic carriage have been associated with chronic inflammation and the development of gallbladder carcinoma. However, the pathogenic relationship between typhoid carriage and the development of pre-malignant and/or malignant lesions in the hepatopancreatobiliary system as well as the host-pathogen interactions occurring during chronic carriage remains unclear. In this study, we monitored the histopathological features of chronic carriage up to 1 year post-infection. Chronic cholecystitis and hepatitis ranging from mild to severe were present in infected mice regardless of the presence of gallstones. Biliary epithelial hyperplasia was observed more commonly in the gallbladder of mice with gallstones (uninfected or infected). However, pre-malignant lesions, atypical hyperplasia and metaplasia of the gallbladder and exocrine pancreas, respectively, were only associated with chronic Salmonella carriage. This study has implications regarding the role of Salmonella chronic infection and inflammation in the development of pre-malignant lesions in the epithelium of the gallbladder and pancreas that could lead to oncogenesis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0084058PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3861519PMC
September 2014

Modulation of sodium/iodide symporter expression in the salivary gland.

Thyroid 2013 Aug 17;23(8):1029-36. Epub 2013 Jul 17.

Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio, USA.

Background: Physiologic iodide-uptake, mediated by the sodium/iodide symporter (NIS), in the salivary gland confers its susceptibility to radioactive iodine-induced damage following (131)I treatment of thyroid cancer. Subsequent quality of life for thyroid cancer survivors can be decreased due to recurrent sialoadenitis and persistent xerostomia. NIS expression at the three principal salivary duct components in various pathological conditions was examined to better our understanding of NIS modulation in the salivary gland.

Methods: NIS expression was evaluated by immunohistochemistry in human salivary gland tissue microarrays constructed of normal, inflamed, and neoplastic salivary tissue cores. Cumulative (123)I radioactivity reflecting the combination of NIS activity with clearance of saliva secretion in submandibular and parotid salivary glands was evaluated by single-photon emission computed tomography/computed tomography imaging 24 hours after (123)I administration in 50 thyroid cancer patients.

Results: NIS is highly expressed in the basolateral membranes of the majority of striated ducts, yet weakly expressed in few intercalated and excretory duct cells. The ratio of (123)I accumulation between parotid and submandibular glands is 2.38±0.19. However, the corresponding ratio of (123)I accumulation normalized by volume of interest is 1.19±0.06. The percentage of NIS-positive striated duct cells in submandibular salivary glands was statistically greater than in parotid salivary glands, suggesting a higher clearance rate of saliva secretion in submandibular salivary glands. NIS expression in striated ducts was heterogeneously decreased or absent in sialoadenitis. Most ductal salivary gland tumors did not express NIS. However, Warthin's tumors of striated duct origin exhibited consistent and intense NIS staining, corresponding with radioactive iodine uptake.

Conclusions: NIS expression is tightly modulated during the transition of intercalated to striated ducts and striated to excretory ducts in salivary ductal cells. NIS expression in salivary glands is decreased during inflammation and tumor formation. Further investigation may identify molecular targets and/or pharmacologic agents that allow selective inhibition of NIS expression/activity in salivary glands during radioactive iodine treatment.
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http://dx.doi.org/10.1089/thy.2012.0571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3752512PMC
August 2013

Thyroid-specific ablation of the Carney complex gene, PRKAR1A, results in hyperthyroidism and follicular thyroid cancer.

Endocr Relat Cancer 2012 Jun 24;19(3):435-46. Epub 2012 May 24.

Department of Molecular, Virology, Immunology, and Medical Genetics, The Ohio State University, 420 West 12th Avenue, Tzagournis Research Facility 544, Columbus, Ohio 43210, USA.

Thyroid cancer is the most common endocrine malignancy in the population, and the incidence of this cancer is increasing at a rapid rate. Although genetic analysis of papillary thyroid cancer (PTC) has identified mutations in a large percentage of patients, the genetic basis of follicular thyroid cancer (FTC) is less certain. Thyroid cancer, including both PTC and FTC, has been observed in patients with the inherited tumor predisposition Carney complex, caused by mutations in PRKAR1A. In order to investigate the role of loss of PRKAR1A in thyroid cancer, we generated a tissue-specific knockout of Prkar1a in the thyroid. We report that the resulting mice are hyperthyroid and developed follicular thyroid neoplasms by 1 year of age, including FTC in over 40% of animals. These thyroid tumors showed a signature of pathway activation different from that observed in other models of thyroid cancer. In vitro cultures of the tumor cells indicated that Prkar1a-null thyrocytes exhibited growth factor independence and suggested possible new therapeutic targets. Overall, this work represents the first report of a genetic mutation known to cause human FTC that exhibits a similar phenotype when modeled in the mouse. In addition to our knowledge of the mechanisms of human follicular thyroid tumorigenesis, this model is highly reproducible and may provide a viable mechanism for the further clinical development of therapies aimed at FTC.
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http://dx.doi.org/10.1530/ERC-11-0306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3667702PMC
June 2012

Preclinical validation of AR42, a novel histone deacetylase inhibitor, as treatment for vestibular schwannomas.

Laryngoscope 2012 Jan 22;122(1):174-89. Epub 2011 Nov 22.

Department of Surgery, Division of Otolaryngology, University of Arizona, Tucson, Arizona 85724, USA.

Objectives/hypothesis: Recent studies indicate that vestibular schwannomas (VSs) rely on phosphatidylinositol 3-kinase/AKT activation to promote cell proliferation and survival; therefore, targeting AKT may provide new therapeutic options. We have previously shown that AR42, a novel histone deacetylase inhibitor, potently suppresses VS growth in vitro at doses correlating with AKT inactivation. The objectives of the current study were translational: 1) to examine the end biologic effects of AR42 on tumor growth in vivo, 2) to validate AKT as its in vivo molecular target, 3) to determine whether AR42 penetrates the blood-brain barrier (BBB), and 4) to study the pharmacotoxicity profile of AR42.

Study Design: In vivo mouse studies.

Methods: AR42 was dosed orally in murine schwannoma allografts and human VS xenografts. Magnetic resonance imaging was used to quantify changes in tumor volume, and intracellular molecular targets were analyzed using immunohistochemistry. BBB penetration was assayed, and both blood-chemistry measurements and histology studies were used to evaluate toxicity.

Results: Growth of schwannoma implants was dramatically decreased by AR42 at doses correlating with AKT dephosphorylation, cell cycle arrest, and apoptosis. AR42 penetrated the BBB, and wild-type mice fed AR42 for 6 months behaved normally and gained weight appropriately. Blood-chemistry studies and organ histology performed after 3 and 6 months of AR42 treatment demonstrated no clinically significant abnormalities.

Conclusions: AR42 suppresses schwannoma growth at doses correlating with AKT pathway inhibition. This orally bioavailable drug penetrates the BBB, is well tolerated, and represents a novel candidate for translation to human VS clinical trials.
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http://dx.doi.org/10.1002/lary.22392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3384504PMC
January 2012

Cox-2 expression, PGE(2) and cytokines production are inhibited by endogenously synthesized n-3 PUFAs in inflamed colon of fat-1 mice.

J Nutr Biochem 2011 Apr 23;22(4):360-5. Epub 2010 Jul 23.

Division of Gastroenterology and Hepatology, Department of Medicine, Weill Medical College of Cornell University, New York, NY 10065, USA.

There is great interest in the role of polyunsaturated fatty acids (PUFAs) in promoting (n-6 class) or inhibiting (n-3 class) inflammation. Mammalian cells are devoid of desaturase that converts n-6 to n-3 PUFAs. Consequently, essential n-3 fatty acids must be supplied with the diet. We have studied the effect of endogenously produced n-3 PUFAs on colitis development in fat-1 transgenic mice carrying the Caenorhabditis elegans fat-1 gene encoding n-3 desaturase. Colonic cell lipid profile was measured by capillary gas chromatography in fat-1 and wild-type (WT) littermates fed standard diet supplemented with 10% (w/w) safflower oil rich (76%) in n-6 polyunsaturated linoleic acid (LA). Experimental colitis was induced by administrating 3% dextran sodium sulphate (DSS). Colitis was scored by histopatological analysis. Cyclooxygenase-2 (Cox-2) expression was evaluated by real time polymerase chain reaction. Prostaglandin E(2) (PGE(2)) levels and cytokine production were determined by enzyme and microsphere-based immunoassays, respectively. The n-6/n-3 PUFA ratios in colonic cells of fat-1 mice were markedly lower (9.83±2.62) compared to WT (54.5±9.24, P<.001). Results also showed an attenuation of colonic acute and chronic inflammation in fat-1 mice with significant decreases in PGE(2) production (P<.01) and Cox-2 expression (P<.01). High levels of colitis-induced proinflammatory cytokines, interleukin (IL)-18, IL-1α, IL-1β, IL-6, monocytes chemotactic proteins 1, 2 and 3 (MCP 1,2,3), matrix metalloproteinase 9 and tumor necrosis factor α (TNF-α) were down-regulated in DSS acutely and chronically treated fat-1 mice. The expression of fat-1 gene in the colon was associated with endogenous n-3 PUFAs production, decreased Cox-2 expression, increased PGE(2) and cytokine production.
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http://dx.doi.org/10.1016/j.jnutbio.2010.03.003DOI Listing
April 2011

Targeted deletion of Kcne2 causes gastritis cystica profunda and gastric neoplasia.

PLoS One 2010 Jul 6;5(7):e11451. Epub 2010 Jul 6.

Department of Pharmacology, Weill Medical College of Cornell University, New York, New York, United States of America.

Gastric cancer is the second leading cause of cancer death worldwide. Predisposing factors include achlorhydria, Helicobacter pylori infection, oxyntic atrophy and TFF2-expressing metaplasia. In parietal cells, apical potassium channels comprising the KCNQ1 alpha subunit and the KCNE2 beta subunit provide a K(+) efflux current to facilitate gastric acid secretion by the apical H(+)K(+)ATPase. Accordingly, genetic deletion of murine Kcnq1 or Kcne2 impairs gastric acid secretion. Other evidence has suggested a role for KCNE2 in human gastric cancer cell proliferation, independent of its role in gastric acidification. Here, we demonstrate that 1-year-old Kcne2(-/-) mice in a pathogen-free environment all exhibit a severe gastric preneoplastic phenotype comprising gastritis cystica profunda, 6-fold increased stomach mass, increased Ki67 and nuclear Cyclin D1 expression, and TFF2- and cytokeratin 7-expressing metaplasia. Some Kcne2(-/-) mice also exhibited pyloric polypoid adenomas extending into the duodenum, and neoplastic invasion of thin walled vessels in the sub-mucosa. Finally, analysis of human gastric cancer tissue indicated reduced parietal cell KCNE2 expression. Together with previous findings, the results suggest KCNE2 disruption as a possible risk factor for gastric neoplasia.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0011451PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2897890PMC
July 2010

Neural crest-specific loss of Prkar1a causes perinatal lethality resulting from defects in intramembranous ossification.

Mol Endocrinol 2010 Aug 9;24(8):1559-68. Epub 2010 Jun 9.

Department of Molecular Virology, The Ohio State University, Columbus, Ohio 43210, USA.

The cranial neural crest (CNC) undergoes complex molecular and morphological changes during embryogenesis in order to form the vertebrate skull, and nearly three quarters of all birth defects result from defects in craniofacial development. The molecular events leading to CNC differentiation have been extensively studied; however, the role of the cAMP-dependent protein kinase [protein kinase A (PKA)] during craniofacial development has only been described in palate formation. Here, we provide evidence that strict PKA regulation in postmigratory CNC cells is essential during craniofacial bone development. Selective inactivation of Prkar1a, a regulatory subunit of the PKA holoenzyme, in the CNC results in perinatal lethality caused by dysmorphic craniofacial development and subsequent asphyxiation. Additionally, aberrant differentiation of CNC mesenchymal cells results in anomalous intramembranous ossification characterized by formation of cartilaginous islands in some areas and osteolysis of bony trabeculae with fibrous connective tissue stabilization in others. Genetic interaction studies revealed that genetic reduction of the PKA catalytic subunit C(alpha) was able to rescue the phenotype, whereas reduction in Cbeta had no effect. Overall, these observations provide evidence of the essential role of proper regulation of PKA during the ossification of the bones of the skull. This knowledge may have implications for the understanding and treatment of craniofacial birth defects.
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http://dx.doi.org/10.1210/me.2009-0439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2940464PMC
August 2010

Double knockout Nme1/Nme2 mouse model suggests a critical role for NDP kinases in erythroid development.

Mol Cell Biochem 2009 Sep 21;329(1-2):45-50. Epub 2009 Apr 21.

Laboratory of Biochemistry and Molecular Biology, Department of Pediatrics, Robert Wood Johnson Medical School/UMDNJ, New Brunswick, NJ, USA.

Nm23/NDP kinases A and B encoded by the Nme1/Nme2 genes are multifunctional enzymes responsible for the majority of NDP kinase activity in mammals. This review summarizes recent studies on their physiological roles using a mouse model in which both Nme1 and Nme2 genes have been deleted. The double knockout mice are stunted in growth and die perinatally. Additionally, these mice display hematologic phenotypes, including severe anemia, abnormal erythroid cell development, loss of the iron transport receptor molecule TfR1, and reduced iron uptake by Nme1 ( -/- ) /Nme2 ( -/- ) erythroid cells. We hypothesize that Nm23/NDP kinases regulate TfR1 gene expression in erythroid cells in some manner, and that defective iron transport into these cells is responsible for the anemia and death. This Nme1/Nme2 mouse model also links nucleotide metabolism with erythropoiesis, suggesting alternative or additional mechanisms that may explain the observed phenomena.
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http://dx.doi.org/10.1007/s11010-009-0110-9DOI Listing
September 2009

Targeted deletion of Nm23/nucleoside diphosphate kinase A and B reveals their requirement for definitive erythropoiesis in the mouse embryo.

Dev Dyn 2009 Mar;238(3):775-87

Laboratory of Biochemistry and Molecular Biology, Department of Pediatrics, Robert Wood Johnson Medical School/UMDNJ and Cancer Institute of New Jersey, Medical Education Building, New Brunswick, New Jersey 08903-0019, USA.

The ubiquitously expressed nucleoside diphosphate kinases (Nm23/NDPK/Awd) are a large family of multifunctional enzymes implicated in nucleic acid metabolism and in normal and abnormal development. Here, we describe the generation and characterization of NDPK A- and B-deficient (Nme1(-/-)/Nme2(-/-)) mice in which >95% of the enzyme activity is eliminated. These mice are undersized, die perinatally, and exhibit a spectrum of hematological phenotypes including severe anemia, impaired maturation of erythrocytes, and abnormal hematopoiesis in the liver and bone marrow. Flow cytometric analysis of developing Nme1(-/-)/Nme2(-/-) erythroid cells indicated that the major iron transport receptor molecule TfR1 is attenuated concomitant with a reduction of intracellular iron, suggesting that TfR1 is a downstream target of NDPKs and that reduced iron in Nme1(-/-)/Nme2(-/-) erythroblasts is inhibiting their development. We conclude that Nm23/NDPKs play critical roles in definitive erythroid development. Our novel mouse model also links erythropoiesis and nucleotide metabolism.
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http://dx.doi.org/10.1002/dvdy.21887DOI Listing
March 2009

Pancreaticoduodenal arterial rupture and hemoabdomen in ACI/SegHsd rats with polyarteritis nodosa.

Comp Med 2007 Aug;57(4):370-6

Tri-Institutional Training Program in Laboratory Animal Medicine and Science, Memorial Sloan-Kettering Cancer Center, Rockefeller University, New York, NY, USA.

Many lesions associated with aging have been well-characterized in various strains of rats. Although documented in Sprague-Dawley and spontaneously hypertensive rats, polyarteritis nodosa has not previously been reported in ACI/SegHsd rats. ACII SegHsd rats were maintained on high-fat (40.5%), low-fat (11.6%), and high-fat to low-fat dietary protocols to examine the correlation between dietary fat and the regulation of prostate 5alpha-reductase gene expression and prostate cancer. Seven rats died unexpectedly with hemoabdomen and rupture of the pancreaticoduodenal artery secondary to polyarteritis nodosa (PAN). The purpose of this study was to analyze the pathologic findings in these and the remaining ACI/SegHsd rats and to correlate the level of dietary fat with the presence of PAN, arterial rupture, and hemoabdomen. Approximately 65% of the rats had evidence of PAN by histopathology, with a 24% incidence of arterial rupture. Additional lesions noted included an 88% incidence of chronic progressive nephropathy (CPN) and a 32% incidence of cartilaginous foci in the aortic valve. We found no association between the percentage of dietary fat and incidence of PAN, CPN, or cardiac cartilage. Although arterial rupture is a known complication of polyarteritis nodosa in humans, this case series is the first to document arterial rupture and hemoabdomen in rats with PAN.
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August 2007

In vivo-restricted and reversible malignancy induced by human herpesvirus-8 KSHV: a cell and animal model of virally induced Kaposi's sarcoma.

Cancer Cell 2007 Mar;11(3):245-58

Laboratory of Viral Oncogenesis, Division of Hematology-Oncology, Department of Medicine, Weill Medical College of Cornell University, New York, NY 10021, USA.

Transfection of a Kaposi's sarcoma (KS) herpesvirus (KSHV) Bacterial Artificial Chromosome (KSHVBac36) into mouse bone marrow endothelial-lineage cells generates a cell (mECK36) that forms KS-like tumors in mice. mECK36 expressed most KSHV genes and were angiogenic, but they didn't form colonies in soft agar. In nude mice, mECK36 formed KSHV-harboring vascularized spindle cell sarcomas that were LANA+/podoplanin+, overexpressed VEGF and Angiopoietin ligands and receptors, and displayed KSHV and host transcriptomes reminiscent of KS. mECK36 that lost the KSHV episome reverted to nontumorigenicity. siRNA suppression of KSHV vGPCR, an angiogenic gene upregulated in mECK36 tumors, inhibited angiogenicity and tumorigenicity. These results show that KSHV malignancy is in vivo growth restricted and reversible, defining mECK36 as a biologically sensitive animal model of KSHV-dependent KS.
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http://dx.doi.org/10.1016/j.ccr.2007.01.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2180156PMC
March 2007

Reduced STAT3 activity in mice mimics clinical disease syndromes.

Biochem Biophys Res Commun 2005 Apr;330(1):305-9

Laboratory of Molecular Cell Biology, The Rockefeller University, New York 10021, USA.

Phosphorylation on Y705 is obligatory for STAT3 activation, but full transcriptional activity of this widely expressed protein also requires phosphorylation on S727. We described earlier the STAT3 SA/- mice (SA, S727A allele) on a Black 6 (Bl6) background that showed 75% perinatal lethality and early growth retardation presumably due to the decreased transcription supported by STAT3 S727A. We now report additional analyses of long-term surviving SA/- animals which show no important tissue abnormalities. However, we have found a much greater susceptibility to doxorubicin-induced heart failure in the SA/- mice. Also we introduced the SA allele into strain 129 and found the SA/- mice showed greater susceptibility to LPS-induced toxicity. These results suggest a continued need for normal STAT3 transcriptional activity to resist two different noxious challenges that mimic the conditions necessary to induce adult diseases.
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http://dx.doi.org/10.1016/j.bbrc.2005.02.154DOI Listing
April 2005

Cardiac arrest/cardiopulmonary resuscitation increases anxiety-like behavior and decreases social interaction.

J Cereb Blood Flow Metab 2004 Apr;24(4):372-82

Department of Psychology, The Ohio State University, Columbus 43210, USA.

Advances in medical technology have increased the number of individuals who survive cardiac arrest/cardiopulmonary resuscitation (CPR). This increased incidence of survival has created a population of patients with behavioral and physiologic impairments. We used temperature manipulations to characterize the contribution of central nervous system damage to behavioral deficits elicited by 8 minutes of cardiac arrest/CPR in a mouse model. Once sensorimotor deficits were resolved, we examined anxiety-like behavior with the elevated plus maze and social interaction with an ovariectomized female. We hypothesized that anxiety-like behavior would increase and social interaction would decrease in mice subjected to cardiac arrest/CPR and that these changes would be attributable to central nervous system damage rather than damage to peripheral organs or changes orchestrated by the administration of epinephrine. Mice that were subjected to cardiac arrest/CPR while the peripheral organs, but not the brain, were protected by hypothermia exhibited increased anxiety-like behavior and decreased social interaction, whereas mice with hypothermic brains and peripheral organs during cardiac arrest/CPR did not exhibit behavioral impairments. The present study demonstrates that central nervous system damage from cardiac arrest/CPR results in increased anxiety and decreased social interaction and that these behavioral changes are not attributed to underlying sensorimotor deficits, dynamics of arrest and CPR, or peripheral organ damage.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1363744PMC
http://dx.doi.org/10.1097/00004647-200404000-00002DOI Listing
April 2004