Publications by authors named "Matti Kiupel"

187 Publications

Correlation Between KIT Expression and Mutations in 2 Subtypes of Canine Oral Melanocytic Neoplasms.

Vet Pathol 2021 Apr 29:3009858211009784. Epub 2021 Apr 29.

3078Michigan State University, Lansing, MI, USA.

mutations have been reported in 15% to 40% of certain human melanoma subtypes, including those histologically similar to canine oral malignant melanomas. Therapeutic response to tyrosine kinase inhibitors has been demonstrated in those human patients. As canine oral malignant melanomas tend to have a poor prognosis despite aggressive surgical removal, evaluation of KIT expression and identification of mutations in canine oral melanocytic neoplasms was performed to determine if there is any indication that tyrosine kinase inhibitor drugs might effectively treat any of these cases. This study evaluated 27 canine oral malignant melanomas and 12 canine histologically well-differentiated oral melanocytic neoplasms for activating mutations, determined differences in immunohistochemical expression of KIT and mutation status, and determined if KIT expression could predict mutation status. Among samples that contained intraepithelial nests of neoplastic melanocytes in the KIT-labeled sections, KIT was expressed within cells in these nests in 22/23 (96%) malignant melanomas and 5/7 histologically well-differentiated neoplasms. KIT was expressed in 10% to 30% of neoplastic melanocytes in the lamina propria in 3/24 (13%) malignant melanomas, but 0/9 (0%) histologically well-differentiated neoplasms. Next-generation sequencing identified 85 variants in , including 9 nonsynonymous mutations that resulted in amino acid changes predicted to affect protein function. mutations with predicted deleterious protein effects were more common in malignant melanomas (8/27 [30%] vs 1/12 [8%]). There was no apparent relationship between detected mutations and KIT expression. These results do not support the use of therapies that target .
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http://dx.doi.org/10.1177/03009858211009784DOI Listing
April 2021

Dwarfism in Tibetan Terrier dogs with an mutation.

J Vet Diagn Invest 2021 Apr 23:10406387211007526. Epub 2021 Apr 23.

Veterinary Diagnostic Laboratory, Lansing, MI, USA.

Canine pituitary dwarfism in German Shepherd and related dog breeds has been reported to be associated with a 7-bp deletion mutation in intron 5 of the gene. This mutation is transmitted as an autosomal recessive trait that results in dwarf dogs with significantly smaller stature and abnormal haircoat, and potentially early death. Phenotypically, affected adult dogs are proportionally dwarfs. These dwarfs also have a soft, woolly puppy coat that fails to transition into the typical adult hair coat, and marked hair loss occurs in some dogs. We report a similar manifestation of dwarfism in Tibetan Terriers with the same mutation. Dwarf Tibetan Terrier puppies were born physically normal but failed to gain weight or to grow at the same rate as their normal littermates. The 7-bp deletion mutation of the gene was identified in both alleles of 3 Tibetan Terrier dwarfs from 3 litters, which were biologically related. All parents of these dogs are carriers, confirming transmission of dwarfism in an autosomal recessive manner. Recognition and detection of this mutation will help in guiding future breeding plans to eventually eliminate this trait from Tibetan Terriers.
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http://dx.doi.org/10.1177/10406387211007526DOI Listing
April 2021

Eastern Equine Encephalitis Virus in Mexican Wolf Pups at Zoo, Michigan, USA.

Emerg Infect Dis 2021 ;27(4):1173-1176

During the 2019 Eastern equine encephalitis virus (EEEV) outbreak in Michigan, two 2-month old Mexican wolf pups experienced neurologic signs, lymphohistiocytic neutrophilic meningoencephalitis with neuronal necrosis and neuronophagia, and acute death. We identified EEEV by reverse transcription real-time PCR and in situ hybridization. Vector mosquitoes were trapped at the zoo.
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http://dx.doi.org/10.3201/eid2704.202400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007284PMC
January 2021

Chronic Wasting Disease Diagnostic Discrepancies: The Importance of Testing Both Medial Retropharyngeal Lymph Nodes.

J Wildl Dis 2021 Jan;57(1):194-198

Michigan Department of Natural Resources, Wildlife Disease Laboratory, 4125 Beaumont Road, Lansing, Michigan 48910, USA.

Chronic wasting disease (CWD) of white-tailed deer (Odocoileus virginianus) is a fatal neurologic disease that is spreading across North America. A common surveillance protocol for CWD currently involves screening with an enzyme-linked immunosorbent assay (ELISA) followed by confirmatory testing with immunohistochemistry (IHC). Medial retropharyngeal lymph nodes (MRPLN) are the tissue of choice to diagnose CWD in free-ranging white-tailed deer. We examined left and right MRPLN from 101 ELISA-positive deer harvested from 2015 to 2019 to determine the prevalence of cases in which prion protein was not detected by IHC as well as differences in IHC labeling between contralateral lymph nodes. Prion protein was not detected using IHC in either MRPLN in 5.9% (6/101) of cases. There was a significant but weak positive relationship between the number of IHC-positive follicles and ELISA optical density values (R2=0.08, P=0.039). Mean optical density values in IHC-positive MRPLN were higher than in IHC-negative MRPLN; however, this was not statistically significant (P=0.260). Failure to confirm ELISA diagnoses with IHC may have been because the methods tested different areas of MRPLN, or that there were differences in test sensitivity or antibody affinity. An additional 5.9% (6/101) of cases had one IHC-positive MRPLN, whereas the contralateral MRPLN was IHC negative. Therefore, testing a single MRPLN for CWD may lead to false-negative results, regardless of methodology, which highlights the importance of collecting and testing both MRPLN.
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http://dx.doi.org/10.7589/JWD-D-20-00007DOI Listing
January 2021

Safety and Efficacy of Felid Herpesvirus-1 Deletion Mutants in Cats.

Viruses 2021 01 22;13(2). Epub 2021 Jan 22.

Department of Pathobiology and Diagnostic Investigation, College of Veterinary Medicine, Michigan State University, 784 Wilson Road, East Lansing, MI 48824, USA.

Felid herpesvirus-1 (FeHV-1) is an important respiratory and ocular pathogen of cats and current vaccines are limited in duration and efficacy because they do not prevent infection, viral nasal shedding and latency. To address these shortcomings, we have constructed FeHV-1 gE-TK- and FeHV-1 PK- deletion mutants (gE-TK- and PK-) using bacterial artificial chromosome (BAC) mutagenesis and shown safety and immunogenicity in vitro. Here, we compare the safety and efficacy of a prime boost FeHV-1 gE-TK- and FeHV-1 PK- vaccination regimen with commercial vaccination in cats. Cats in the vaccination groups were vaccinated at 3-week intervals and all cats were challenge infected 3 weeks after the last vaccination. Evaluations included clinical signs, nasal shedding, virus neutralizing antibodies (VN), cytokine mRNA gene expression, post-mortem histology and detection of latency establishment. Vaccination with gE-TK- and PK- mutants was safe and resulted in significantly reduced clinical disease scores, pathological changes, viral nasal shedding, and viral DNA in the trigeminal ganglia (the site of latency) following infection. Both mutants induced VN antibodies and interferons after immunization. In addition, after challenge infection, we observed a reduction of IL-1β expression, and modulation of TNFα, TGFβ and IL10 expression. In conclusion, this study shows the merits of using FeHV-1 deletion mutants for prevention of FeHV-1 infection in cats.
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http://dx.doi.org/10.3390/v13020163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7911815PMC
January 2021

Disseminated Haemophagocytic Histiocytic Sarcoma in an African Pygmy Hedgehog (Atelerix albiventris).

J Comp Pathol 2021 Jan 9;182:54-57. Epub 2021 Jan 9.

Department of Preclinic and Animal Science, Faculty of Veterinary Science, Mahidol University, Salaya, Nakhon Pathom, Thailand. Electronic address:

A 3-year-old intact male African pygmy hedgehog (Atelerix albiventris) was found dead shortly after clinical onset of screaming, aerophagia and lethargy. On gross examination, the spleen was dark red and friable, and the liver was markedly enlarged with a prominent lobular pattern and multiple white nodules. Histopathological examination of liver and spleen revealed dense infiltrates of highly pleomorphic neoplastic, round to polyhedral cells with overt erythrophagocytosis. Similar neoplastic cells were found in the sinuses of the abdominal lymph nodes and in blood vessels in the heart, lung, brain and kidneys. Immunolabelling for CD204 confirmed the histiocytic origin of the neoplastic cells. To our knowledge, this is the first report of a disseminated haemophagocytic histiocytic sarcoma in a hedgehog.
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http://dx.doi.org/10.1016/j.jcpa.2020.12.003DOI Listing
January 2021

Host-specific preference of some Flavobacterium psychrophilum multilocus sequence typing genotypes determines their ability to cause bacterial coldwater disease in coho salmon (Oncorhynchus kisutch).

J Fish Dis 2021 May 21;44(5):521-531. Epub 2021 Jan 21.

Department of Fisheries and Wildlife, College of Agriculture and Natural Resources, Michigan State University, East Lansing, MI, USA.

Flavobacterium psychrophilum causes bacterial coldwater disease (BCWD) in salmonids, resulting in significant losses worldwide. Several serotyping and genetic studies of F. psychrophilum have suggested some geno-/serotypes may be either host-specific or generalistic in nature; however, this association has not been adequately explored in vivo using more natural exposure routes. Herein, F. psychrophilum isolate US19-COS, originally recovered from coho salmon (Oncorhynchus kisutch) and belonging to multilocus sequence typing clonal complex (CC) CC-ST9, and isolate US53-RBT, recovered from rainbow trout (Oncorhynchus mykiss) and belonging to CC-ST10, were serotyped via PCR, evaluated for proteolytic activity and utilized to determine their median lethal dose in immersion-challenged coho salmon fingerlings. US19-COS belonged to serotype 0, hydrolysed casein and gelatin but not elastin, led to fulminant multiorgan infections and elicited severe gross and microscopic pathology. In contrast, US53-RBT, belonging to serotype 2, hydrolysed all three substrates, but did not lead to detectable infections, disease signs or mortality in any exposed coho salmon despite proving virulent to rainbow trout in previous experiments. This study provides in vivo evidence for potential host specificity of some F. psychrophilum genotypes that can also be serologically distinct, a matter of importance towards better understanding F. psychrophilum disease ecology and epidemiology.
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http://dx.doi.org/10.1111/jfd.13340DOI Listing
May 2021

Alterations in pregnancy-associated glycoprotein concentrations of pregnant sheep experimentally infected with bovine viral diarrhea virus.

Am J Vet Res 2021 Jan;82(1):63-70

Objective: To compare pregnancy-associated glycoprotein 1 (PAG1) concentrations in maternal (jugular vein) and fetal (uterine vein) circulations and amniotic fluid samples between pregnant ewes that were and were not experimentally infected with bovine viral diarrhea virus (BVDV).

Animals: 11 healthy pregnant yearling ewes.

Procedures: Before study initiation, all ewes were naïve to BVDV and confirmed pregnant by transabdominal ultrasonography at approximately 60 days of gestation. At 65 days of gestation, ewes were intranasally inoculated with a noncytopathic BVDV type 1b strain (concentration, 10 TCID/mL; 2 mL/nostril; n = 6) or an equal volume of BVDV-free viral culture medium (control; 5). A blood sample was collected for measurement of PAG1 concentration before inoculation. At 80 days of gestation, each ewe was anesthetized and underwent an ovariohysterectomy. While sheep were anesthetized, blood samples from the jugular and uterine veins and an amniotic fluid sample were collected for measurement of PAG1 concentration. Fetal tissues underwent real-time PCR analysis for BVDV RNA, and placental specimens underwent histologic evaluation and immunohistochemical staining for BVDV antigen.

Results: At 80 days of gestation, BVDV RNA in fetal tissues and mild placentitis were detected in 5 of 6 BVDV-inoculated ewes. Mean PAG1 concentrations in the maternal and fetal circulations of BVDV-inoculated ewes were significantly less than those in control ewes. Mean amniotic fluid PAG1 concentration did not differ significantly between the 2 groups.

Conclusions And Clinical Relevance: Concentration of PAG1 in the maternal circulation may be a useful biomarker for determining placental health in sheep after viral infection of the reproductive tract.
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http://dx.doi.org/10.2460/ajvr.82.1.63DOI Listing
January 2021

Inter-Institutional Partnerships to Develop Veterinarian-Investigators through the NIH Comparative Biomedical Scientist Training Program Benefit One Health Goals.

J Vet Med Educ 2020 Oct;47(5):619-631

Limitations in workforce size and access to resources remain perennial challenges to greater progress in academic veterinary medicine and engagement between human and veterinary medicine (One Health). Ongoing resource constraints occur in part due to limited public understanding of the role veterinarians play in improving human health. One Health interactions, particularly through interdisciplinary collaborations in biomedical research, present constructive opportunities to inform resource policies and advance health care. To this end, inter-institutional partnerships between individual veterinary medical education programs (VMEPs) and several National Institutes of Health (NIH) intramural research programs have created synergies beyond those provided by individual programs. In the NIH Comparative Biomedical Scientist Training Program (CBSTP), interdisciplinary cross-training of veterinarians consisting of specialty veterinary medicine coupled with training in human disease research leading to a PhD, occurs collaboratively on both VMEP and NIH campuses. Pre-doctoral veterinary student research opportunities have also been made available. Through the CBSTP, NIH investigators and national biomedical science policy makers gain access to veterinary perspective and expertise, while veterinarians obtain additional opportunities for NIH-funded research training. CBSTP Fellows serve as de facto ambassadors enhancing visibility for the profession while in residence at NIH, and subsequently through a variety of university, industry, and government research appointments, as graduates. Thus, the CBSTP represents an inter-institutional opportunity that not only addresses critical needs for veterinarian-scientists in the biomedical workforce, but also simultaneously exposes national policy makers to veterinarian-scientists' specialized training, leading to more effective realization of One Health goals to benefit human and animal health.
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http://dx.doi.org/10.3138/jvme.2019-0091DOI Listing
October 2020

Internal Tandem Duplication of Exon 8 of Is Associated With Longer Total Survival in Canine Cutaneous Mast Cell Tumors.

Vet Pathol 2021 Mar 24;58(2):315-324. Epub 2020 Nov 24.

116098Michigan State University Veterinary Diagnostic Laboratory, East Lansing, MI, USA.

Canine cutaneous mast cell tumors (ccMCTs) have a highly variable biological behavior and accurate prognostication is essential for therapeutic intervention. Internal tandem duplications (ITD) of exon 11 are the most commonly detected mutation in ccMCTs and are associated with poor prognosis and increased cellular proliferation. The prognostic value of detecting mutations in other exons of has not been systematically examined. In this study, we analyzed the prognostic value of ITD mutations of exon 8 in of ccMCTs in comparison to ccMCTs with ITD mutations of exon 11 and ccMCTs without mutations of exon 8 or 11. The mutational status, histological grade, KIT expression pattern, Ki67 index, AgNOR (argyrophilic nucleolar organizing region) score, and Ag67 score were determined in 221 ccMCTs, and outcome was available for 101 dogs. ITD mutations of exon 8 were found in 73/221 (33%), of exon 11 in 100/221 (45%), and none of these mutations in 50/221 (22%) of ccMCTs. None of the dogs with mutations of exon 8 died due to suspected ccMCT-related cause, but 23% dogs with ccMCTs with mutations of exon 11 died due to suspected ccMCT-related cause. Prognostic parameters in ccMCTs with exon 11 mutations were commonly associated with a high proliferative activity and poor prognosis, while prognostic markers in ccMCTs with mutations of exon 8 had lower values similar to those observed in ccMCTs without mutations in exons 8 or 11 of . This study indicates that screening for ITD mutations in exon 8 in ccMCTs may be helpful to identify less aggressive ccMCTs and may be recommended as a supplementary prognostic test.
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http://dx.doi.org/10.1177/0300985820973463DOI Listing
March 2021

Immunophenotypic Characterization of Canine Nodal T-Zone Lymphoma.

Vet Pathol 2021 Mar 19;58(2):288-292. Epub 2020 Nov 19.

3078Michigan State University Veterinary Diagnostic Laboratory, Lansing, MI, USA.

T-zone lymphoma (TZL) is an indolent nodal T-cell lymphoma most commonly observed in submandibular lymph nodes in dogs. The diagnosis is based on its distinct morphology and expression of CD3. TZL has been reported to have a low Ki67 index and to lack expression of CD45. The latter feature has been used to diagnose this type of lymphoma via fine needle aspirate and flow cytometry without confirmation of the characteristic tissue architecture. The goal of this study was to characterize the immunophenotype of canine nodal TZL in greater detail. Twenty-seven TZLs were selected based on their characteristic morphology. A tissue microarray was generated, and immunohistochemical expression of CD3, CD5, CD20, CD21, CD25, CD45, Bcl-6, and Ki67 was evaluated. Neoplastic T cells in all cases were positive for CD3, CD5, and CD25, and negative for CD20, CD21, and Bcl-6. Positive labelling for CD45 was detected in 2 of the 27 cases with the remaining 25 cases being negative. All cases had a low Ki67 index with an average index of 19.56%. For the CD45-positive TZLs, clonality of the T-cell antigen receptor gamma gene was confirmed in only one of these cases. The observed immunophenotype of canine TZL is similar to previous publications with the exception that 2 cases expressed CD45. Expression of CD45 in TZLs in this study emphasizes the importance of interpreting immunophenotypic findings in conjunction with histopathology to reach an accurate diagnosis and not to use lack of expression of a particular antigen as the sole diagnostic criterion.
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http://dx.doi.org/10.1177/0300985820974078DOI Listing
March 2021

Viral Load and Cell Tropism During Early Latent Equid Herpesvirus 1 Infection Differ Over Time in Lymphoid and Neural Tissue Samples From Experimentally Infected Horses.

Front Vet Sci 2020 4;7:621. Epub 2020 Sep 4.

Equine Hospital, Division of Medicine and Reproduction, Center for Clinical Veterinary Medicine, Ludwig-Maximilians University, Munich, Germany.

Upper respiratory tract infections with Equid Herpesvirus 1 (EHV-1) typically result in a peripheral blood mononuclear cell-associated viremia, which can lead to vasculopathy in the central nervous system. Primary EHV-1 infection also likely establishes latency in trigeminal ganglia (TG) via retrograde axonal transport and in respiratory tract-associated lymphatic tissue. However, latency establishment and reactivation are poorly understood. To characterize the pathogenesis of EHV-1 latency establishment and maintenance, two separate groups of yearling horses were experimentally infected intranasally with EHV-1, strain Ab4, and euthanized 30 days post infection (dpi), ( = 9) and 70 dpi ( = 6). During necropsy, TG, sympathetic trunk (ST), retropharyngeal and mesenteric lymph nodes (RLn, MesLn) and kidney samples were collected. Viral DNA was detected by quantitative PCR (qPCR) in TG, ST, RLn, and MesLn samples in horses 30 and 70 dpi. The number of positive TG, RLn and MesLn samples was reduced when comparing horses 30 and 70 dpi and the viral copy number in TG and RLn significantly declined from 30 to 70 dpi. EHV-1 late gene glycoprotein B reverse transcriptase PCR and IHC results for viral protein were consistently negative, thus lytic replication was excluded in the present study. Mild inflammation could be detected in all neural tissue samples and inflammatory infiltrates mainly consisted of CD3+ T-lymphocytes (T-cells), frequently localized in close proximity to neuronal cell bodies. To identify latently infected cell types, hybridization (ISH, RNAScope®) detecting viral DNA was used on selected qPCR- positive neural tissue sections. In ganglia 30 dpi, EHV-1 ISH signal was located in the neurons of TG and ST, but also in non-neuronal support or interstitial cells surrounding the neuron. In contrast, distinct EHV-1 signal could only be observed in neurons of TG 70 dpi. Overall, detection of latent EHV-1 in abdominal tissue samples and non-neuronal cell localization suggests, that EHV-1 uses T-cells during viremia as alternative route toward latency locations in addition to retrograde neuronal transport. We therefore hypothesize that EHV-1 follows the same latency pathways as its close relative human pathogen Varicella Zoster Virus.
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http://dx.doi.org/10.3389/fvets.2020.00621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499125PMC
September 2020

Hypomorphic mTOR Downregulates CDK6 and Delays Thymic Pre-T LBL Tumorigenesis.

Mol Cancer Ther 2020 10 3;19(10):2221-2232. Epub 2020 Aug 3.

Laboratory of Cancer Biology and Genetics, CCR, NCI, NIH, Bethesda, Maryland.

PI3K/AKT/mTOR pathway hyperactivation is frequent in T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL). To model inhibition of mTOR, pre-T-cell lymphoblastic leukemia/lymphoma (pre-T LBL) tumor development was monitored in mice with T lymphocyte-specific, constitutively active AKT (Lck-MyrAkt2) that were either crossed to mTOR knockdown (KD) mice or treated with the mTOR inhibitor everolimus. Lck-MyrAkt2;mTOR KD mice lived significantly longer than Lck-MyrAkt2;mTOR wild-type (WT) mice, although both groups ultimately developed thymic pre-T LBL. An increase in survival was also observed when Lck-MyrAkt2;mTOR WT mice were treated for 8 weeks with everolimus. The transcriptional profiles of WT and KD thymic lymphomas were compared, and Ingenuity Pathway Upstream Regulator Analysis of differentially expressed genes in tumors from mTOR WT versus KD mice identified let-7 and miR-21 as potential regulatory genes. mTOR KD mice had higher levels of let-7a and miR-21 than mTOR WT mice, and rapamycin induced their expression in mTOR WT cells. CDK6 was one of the most downregulated targets of both let-7 and miR21 in mTOR KD tumors. CDK6 overexpression and decreased expression of let-7 in mTOR KD cells rescued a G arrest phenotype. Combined mTOR (rapamycin) and CDK4/6 (palbociclib) inhibition decreased tumor size and proliferation in tumor flank transplants, increased survival in an intravenous transplant model of disseminated leukemia compared with single agent treatment, and cooperatively decreased cell viability in human T-ALL/LBL cell lines. Thus, mTOR KD mice provide a model to explore drug combinations synergizing with mTOR inhibitors and can be used to identify downstream targets of inhibition.
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http://dx.doi.org/10.1158/1535-7163.MCT-19-0671DOI Listing
October 2020

Disease Progression in Lake Trout () Experimentally Infected With Epizootic Epitheliotropic Disease Virus (Salmonid Herpesvirus-3).

Vet Pathol 2020 09 3;57(5):687-699. Epub 2020 Aug 3.

Department of Pathobiology and Diagnostic Investigation, College of Veterinary Medicine,3078Michigan State University, East Lansing, MI, USA.

Epizootic epitheliotropic disease virus (salmonid herpesvirus-3; EEDV) is responsible for the death of millions of hatchery-raised lake trout () in the Laurentian Great Lakes Basin. However, little is known about its biology, pathology, tropism, and host interactions. In this study, the presence and disease progression of EEDV were evaluated following exposure of naïve juvenile lake trout to EEDV via bath immersion under controlled laboratory conditions ( = 84 infected; = 44 control). Individual tissues ( = 10 per fish), collected over 6 weeks, were analyzed for viral load by quantitative polymerase chain reaction, gross and histopathologic changes, and virus cellular targets using in situ hybridization. Skin, fin, and ocular tissues were the earliest viral targets and yielded the highest viral loads throughout the course of infection. Early gross lesions included exophthalmia, ocular hemorrhage, fin congestion, and hyperemia of visceral blood vessels. Advanced disease was characterized by multifocal to coalescing erosions and ulcerations of the skin, and congestion of visceral organs. Microscopically, there was cellular degeneration and necrosis in the epidermis and spleen, and lymphohistiocytic perivasculitis of the dermis, omentum, and the epicardium. EEDV DNA was first detected by in situ hybridization in epithelial cells of the epidermis, with subsequent labeling in the epithelial lining of primary and secondary gill lamellae. During advanced disease, EEDV was detected in endothelial and dendritic cells as well as blood monocytes. This study characterized EEDV tissue tropism and associated pathologic features, to guide research aimed at understanding EEDV disease ecology and improving strategies for disease control.
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http://dx.doi.org/10.1177/0300985820941268DOI Listing
September 2020

Herpesvirus Encephalitis in a Little Blue Penguin ().

Vet Pathol 2020 07 21;57(4):582-585. Epub 2020 May 21.

Michigan State University, College of Veterinary Medicine, Veterinary Diagnostic Laboratory, East Lansing, MI, USA.

An 11-day-old little blue penguin () died unexpectedly. Prior to hatching, the egg experienced trauma and resultant defects were repaired. The chick hatched without complication and was clinically normal prior to death. Necropsy revealed congested lungs. Histologic examination showed moderate nonsuppurative encephalitis with focally extensive neuronal necrosis and intranuclear inclusions in neurons within necrotic foci. Herpesvirus DNA was detected in brain tissue with a generic herpesvirus polymerase chain reaction. Sanger sequencing demonstrated 100% and 98% sequence homology to sphenicid alphaherpesvirus 1 and penguin herpesvirus 2, respectively. In situ hybridization demonstrated large amounts of herpesvirus nucleic acid in intranuclear inclusions and neuronal nuclei. Combined histology, polymerase chain reaction, Sanger sequencing, and in situ hybridization results were most consistent with herpesviral encephalitis, most likely caused by sphenicid alphaherpesvirus 1. To our knowledge, this is the first report of a herpesvirus infection causing encephalitis in a penguin and the first report of herpesvirus in this species.
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http://dx.doi.org/10.1177/0300985820926678DOI Listing
July 2020

Automated Five-Color Multiplex Co-detection of MicroRNA and Protein Expression in Fixed Tissue Specimens.

Methods Mol Biol 2020 ;2148:257-276

Precision Health Program, Michigan State University, East Lansing, MI, USA.

microRNAs are an important class of noncoding regulatory RNAs with functional roles in development, physiology, and disease. Visualization of microRNA expression at a single-cell level has contributed to a better understanding of their biological function in animal models and their etiological contribution to human diseases. In addition, several microRNAs have been highlighted as potential biomarkers carrying diagnostic and prognostic information. Co-detection of microRNA expression with that of cell-type-specific proteins can enhance the interpretative power of expression changes during development or altered expression in pathological conditions. Here, we describe an automated fluorescence-based five-color multiplex assay for co-detection of microRNA (e.g., miR-10b, miR-21, miR-205), noncoding RNA (e.g., snRNA U6, 18S rRNA), and protein expression (e.g., cytokeratin 19, vimentin, collagen I) in paraffin-embedded formalin-fixed tissue slides on a Leica Bond Rx staining station. While this protocol uses mainly mouse tissues to demonstrate multiplex detection, it can be generally applied to single-cell expression analysis of other animal models and clinical specimens.
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http://dx.doi.org/10.1007/978-1-0716-0623-0_17DOI Listing
March 2021

Loss of microRNA-21 leads to profound stromal remodeling and short survival in K-Ras-driven mouse models of pancreatic cancer.

Int J Cancer 2020 10 26;147(8):2265-2278. Epub 2020 May 26.

Precision Health Program, Michigan State University, East Lansing, Michigan, USA.

The microenvironment of pancreatic cancer adenocarcinoma (PDAC) is highly desmoplastic with distinct tumor-restraining and tumor-promoting fibroblast subpopulations. Re-education rather than indiscriminate elimination of these fibroblasts has emerged as a new strategy for combination therapy. Here, we studied the effects of global loss of profibrotic noncoding regulatory microRNA-21 (miR-21) in K-Ras-driven p53-deleted genetically engineered mouse models of PDAC. Strikingly, loss of miR-21 accelerated tumor initiation via mucinous cystic neoplastic lesions and progression to locally advanced invasive carcinoma from which animals precipitously succumbed at an early age. The absence of tumor-restraining myofibroblasts and a massive infiltrate of immune cells were salient phenotypic features of global miR-21 loss. Stromal miR-21 activity was required for induction of tumor-restraining myofibroblasts in in vivo isograft transplantation experiments. Low miR-21 expression negatively correlated with a fibroblast gene expression signature and positively with an immune cell gene expression signature in The Cancer Genome Atlas PDAC data set (n = 156) mirroring findings in the mouse models. Our results exposed an overall tumor-suppressive function of miR-21 in in vivo PDAC models. These results have important clinical implications for anti-miR-21-based inhibitory therapeutic approaches under consideration for PDAC and other cancer types. Mechanistic dissection of the cell-intrinsic role of miR-21 in cancer-associated fibroblasts and other cell types will be needed to inform best strategies for pharmacological modulation of miR-21 activity to remodel the tumor microenvironment and enhance treatment response in PDAC.
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http://dx.doi.org/10.1002/ijc.33041DOI Listing
October 2020

Giant Cell Sarcomas in Domestic Rabbits ().

Vet Pathol 2020 07 29;57(4):490-496. Epub 2020 Apr 29.

Michigan State University, Lansing, MI, USA.

Multinucleated giant cells (MGCs) are a prominent histological feature of various mesenchymal neoplasms and are often considered a criterion of malignancy. Mesenchymal neoplasms with MGCs for which the cell lineage is unclear generally are referred to as giant cell sarcomas. Here we characterize the gross, histologic, and immunohistochemical features of 90 giant cell sarcomas in domestic pet rabbits. Based on the anatomic location and histologic and immunohistochemical findings, 18 cases were classified as histiocytic sarcomas (HS) and 72 cases as anaplastic sarcomas (AS). At postmortem examination, HS was either localized HS ( = 7) always affecting the lungs, or disseminated HS ( = 10) that affected the lungs ( = 10), liver ( = 6), kidneys ( = 4), pleura ( = 2), mediastinum ( = 2), heart ( = 4), skeletal muscle ( = 1), adipose tissue ( = 1), and lymph node ( = 1). Additionally, one cecal biopsy was consistent with HS. Microscopically, HS were characterized by sheets of neoplastic polygonal to round cells that contained single to several, often greatly enlarged nuclei as well as abundant cytoplasm. HS were always positive for CD204 and always negative for SMA and desmin. In contrast, AS arose most commonly from the skin or subcutis ( = 62) and rarely the skeletal muscle ( = 8) or abdominal organs ( = 2). In 29% of extra-abdominal AS, the tumor deeply invaded into surrounding connective tissue, skeletal muscle, tendons, and bone causing pathological fractures. Five of 9 postmortem cases metastasized to various organs often including the lungs. Microscopically, AS were characterized by sheets of spindle or pleomorphic cells admixed with variable numbers of MGCs. Immunohistochemically, AS were always negative for CD204 and often (71%) positive for SMA and/or desmin.
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http://dx.doi.org/10.1177/0300985820921814DOI Listing
July 2020

Characterization of feline herpesvirus-1 deletion mutants in tissue explant cultures.

Virus Res 2020 07 19;284:197981. Epub 2020 Apr 19.

Department of Pathobiology and Diagnostic Investigation, College of Veterinary Medicine, Michigan State University, 784 Wilson Road, East Lansing, MI 48824, USA. Electronic address:

Feline herpesvirus-1 (FHV-1) is the primary cause of viral respiratory and ocular disease in cats. While commercial vaccines can provide clinical protection, they do not protect from infection or prevent latency. Moreover, they are not safe for intranasal administration. Our overall objective is to develop a new mucosal vaccine against FHV-1 disease to address these shortcomings. Feline herpesvirus-1 deletion mutants of glycoprotein C (gC-), gE (gE-), US3-encoded serine/threonine protein kinase (PK-), and both gE and thymidine kinase (gE-TK-) were generated by bacterial artificial chromosome (BAC) mutagenesis. Tracheal tissue explants from eight cats were used to compare the pattern of viral infection and associated tissue damage, as well as virus spread through the basement membrane following inoculation with wild-type virus (WT), and gE-, gE-TK-, PK-, and gC- mutants. Tissues were collected at 24, 48, or 72  hours post-inoculation (hpi) followed by immunohistochemistry (IHC) for FHV-1. Histological changes were graded based on the distribution of virus infected cells and the severity of tissue damage. Inoculations with the WT virus resulted in maximal scores at 72 hpi both at a multiplicity of infection (MOI) of 1 and 0.1. Inoculation with the gE- mutant produced scores similar to scores of explants inoculated with the WT virus at 24 and 48 hpi, but scores were significantly decreased at 72 hpi. Explants inoculated with the gE-TK- mutant showed significantly decreased scores at all time points. Further, the majority of explants inoculated with the PK- mutant resulted in scores of zero at all time points, regardless of MOI. Finally, inoculation with WT resulted in significant stromal invasion below the infected epithelium, while stromal invasion was observed in less than 50 % of the samples following inoculation with gE-, gE-TK-, PK-, or gC- mutants and confined closely to the area surrounding the infected epithelium. In conclusion, the gE-TK- and PK- mutants exhibited significantly reduced virulence, tissue damage and spread to the underlying stroma, suggesting that they may be good vaccine candidates for in vivo testing.
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http://dx.doi.org/10.1016/j.virusres.2020.197981DOI Listing
July 2020

Tantalum oxide nanoparticles as versatile contrast agents for X-ray computed tomography.

Nanoscale 2020 Apr 25;12(14):7720-7734. Epub 2020 Mar 25.

Department of Radiology, Michigan State University, East Lansing, MI 48823, USA.

Here, we describe the synthesis, characterization and in vitro and in vivo performance of a series of tantalum oxide (TaO) based nanoparticles (NPs) for computed tomography (CT). Five distinct versions of 9-12 nm diameter silane coated TaO nanocrystals (NCs) were fabricated by a sol-gel method with varying degrees of hydrophilicity and with or without fluorescence, with the highest reported Ta content to date (78%). Highly hydrophilic NCs were left bare and were evaluated in vivo in mice for micro-CT of full body vasculature, where following intravenous injection, TaO NCs demonstrate high vascular CT contrast, circulation in blood for ∼3 h, and eventual accumulation in RES organs; and following injection locally in the mammary gland, where the full ductal tree structure can be clearly delineated. Partially hydrophilic NCs were encapsulated within mesoporous silica nanoparticles (MSNPs; TaO@MSNPs) and hydrophobic NCs were encapsulated within poly(lactic-co-glycolic acid) (PLGA; TaO@PLGA) NPs, serving as potential CT-imagable drug delivery vehicles. Bolus intramuscular injections of TaO@PLGA NPs and TaO@MSNPs to mimic the accumulation of NPs at a tumor site produce high signal enhancement in mice. In vitro studies on bare NCs and formulated NPs demonstrate high cytocompatibility and low dissolution of TaO. This work solidifies that TaO-based NPs are versatile contrast agents for CT.
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http://dx.doi.org/10.1039/d0nr01234cDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7185737PMC
April 2020

NCOA5 deficiency promotes a unique liver protumorigenic microenvironment through p21 overexpression, which is reversed by metformin.

Oncogene 2020 05 20;39(19):3821-3836. Epub 2020 Mar 20.

Department of Physiology, Michigan State University, East Lansing, Michigan, 48824, USA.

Prevention and treatment options for hepatocellular carcinoma (HCC) are presently limited, underscoring the necessity for further elucidating molecular mechanisms underlying HCC development and identifying new prevention and therapeutic targets. Here, we demonstrate a unique protumorigenic niche in the livers of Ncoa5 mouse model of HCC, which is characterized by altered expression of a subset of genes including p21 and proinflammatory cytokine genes, increased putative hepatic progenitors, and expansions of activated and tissue-resident memory (TRM) CD8+ T lymphocytes, myeloid-derived suppressor cells (MDSCs), and alternatively activated M2 macrophages. Importantly, prophylactic metformin treatment reversed these characteristics including aberrant p21 expression and subsequently reduced HCC incidence in Ncoa5 male mice. Heterozygous deletion of the p21 gene alleviated the key features associated with the protumorigenic niche in the livers of Ncoa5 male mice. Moreover, transcriptomic analysis reveals that preneoplastic livers of Ncoa5 mice are similar to the livers of nonalcoholic steatohepatitis patients as well as the adjacent noncancerous liver tissues of a subset of HCC patients with a relatively poor prognosis. Together, our results suggest that p21 overexpression is essential in the development of protumorigenic microenvironment induced by NCOA5 deficiency and metformin prevents HCC development via alleviating p21 overexpression and protumorigenic microenvironment.
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http://dx.doi.org/10.1038/s41388-020-1256-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7210077PMC
May 2020

Acute human orthopneumovirus infection in a captive white-handed gibbon.

J Vet Diagn Invest 2020 May 13;32(3):450-453. Epub 2020 Mar 13.

Iowa State University, Ames, IA (Sojka).

We report herein a fatal case of acute human orthopneumovirus (formerly respiratory syncytial virus) infection in a captive white-handed gibbon (). Other members of the housing group had mild respiratory signs. Gross examination revealed bilateral pulmonary congestion and froth in the bronchi. Microscopically, the lungs had lymphocytic, neutrophilic infiltration of the interstitium and alveolar walls. There was necrosis of terminal bronchiolar epithelium and terminal bronchioles, and surrounding alveoli contained necrotic and exfoliated epithelial cells admixed with histiocytes and syncytial cells. Additional lesions included nonsuppurative meningoencephalitis, and epidermal hyperkeratosis and hyperplasia with syncytial cell formation. PCR screening for 12 human respiratory viruses was positive for orthopneumovirus in multiple tissues, including lung, and immunohistochemical staining for human orthopneumovirus detected viral antigen within bronchial epithelial cells. IHC and PCR for measles virus on preserved sections were negative. White-handed gibbons have not been previously reported as hosts for human orthopneumovirus, an important respiratory pathogen of both primates and humans.
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http://dx.doi.org/10.1177/1040638720910521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7377618PMC
May 2020

Novel Engraftment and T Cell Differentiation of Human Hematopoietic Cells in SCID Pigs.

Front Immunol 2020 6;11:100. Epub 2020 Feb 6.

Department of Animal Science, Iowa State University, Ames, IA, United States.

Pigs with severe combined immunodeficiency (SCID) are an emerging biomedical animal model. Swine are anatomically and physiologically more similar to humans than mice, making them an invaluable tool for preclinical regenerative medicine and cancer research. One essential step in further developing this model is the immunological humanization of SCID pigs. In this work we have generated T B NK SCID pigs through site directed CRISPR/Cas9 mutagenesis of within a naturally occurring genetic background. We confirmed pigs lacked T, B, and NK cells in both peripheral blood and lymphoid tissues. Additionally, we successfully performed a bone marrow transplant on one male SCID pig with bone marrow from a complete swine leukocyte antigen (SLA) matched donor without conditioning to reconstitute porcine T and NK cells. Next, we performed injections of cultured human CD34 selected cord blood cells into the fetal SCID pigs. At birth, human CD45 CD3ε cells were detected in cord and peripheral blood of injected SCID piglets. Human leukocytes were also detected within the bone marrow, spleen, liver, thymus, and mesenteric lymph nodes of these animals. Taken together, we describe critical steps forwards the development of an immunologically humanized SCID pig model.
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http://dx.doi.org/10.3389/fimmu.2020.00100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017803PMC
March 2021

Adjuvant medical therapy provides no therapeutic benefit in the treatment of dogs with low-grade mast cell tumours and early nodal metastasis undergoing surgery.

Vet Comp Oncol 2020 Sep 17;18(3):409-415. Epub 2020 Jan 17.

Department of Veterinary Medical Sciences, University of Bologna, Bologna, Italy.

Lymph node (LN) metastasis is a negative prognostic factor in dogs with cutaneous mast cell tumours (cMCTs). While elective lymphadenectomy of metastatic LNs improves outcome, the benefit of adjuvant medical therapy in dogs with early metastatic (HN2) LNs is debated. The aim of this retrospective multicentre study was to evaluate the therapeutic benefit of adjuvant medical therapy following surgical removal of the primary low-grade cMCT (Patnaik grade 1-2 and Kiupel low-grade) and lymphadenectomy of HN2 LNs by analysing survival rates and patterns of recurrence. Seventy-three dogs were included: 42 received adjuvant medical treatment (chemotherapy and/or kinase inhibitors), and 31 did not. The median follow-up time for medically treated dogs was 619 days: two experienced local recurrence, three nodal relapse and four distant relapse. For dogs undergoing surgery only, the median follow-up time was 545 days. None of them experienced local recurrence, nodal, or distant relapse. Time to progression was significantly shorter in dogs receiving adjuvant medical treatment (P = .021). A similar tendency was observed for overall survival (P = .056). The current study shows that dogs with low-grade cMCTs, that undergo surgical excision of the primary tumour and elective lymphadenectomy of the HN2 regional LN harbour a good prognosis. The use of adjuvant medical treatment in these dogs does not seem to provide any benefit in terms of progression and survival.
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http://dx.doi.org/10.1111/vco.12566DOI Listing
September 2020

Computerized Calculation of Mitotic Count Distribution in Canine Cutaneous Mast Cell Tumor Sections: Mitotic Count Is Area Dependent.

Vet Pathol 2020 03 6;57(2):214-226. Epub 2019 Dec 6.

Institute of Veterinary Pathology, Freie Universität Berlin, Berlin, Germany.

Mitotic count (MC) is an important element for grading canine cutaneous mast cell tumors (ccMCTs) and is determined in 10 consecutive high-power fields with the highest mitotic activity. However, there is variability in area selection between pathologists. In this study, the MC distribution and the effect of area selection on the MC were analyzed in ccMCTs. Two pathologists independently annotated all mitotic figures in whole-slide images of 28 ccMCTs (ground truth). Automated image analysis was used to examine the ground truth distribution of the MC throughout the tumor section area, which was compared with the manual MCs of 11 pathologists. Computerized analysis demonstrated high variability of the MC within different tumor areas. There were 6 MCTs with consistently low MCs (MC<7 in all tumor areas), 13 cases with mostly high MCs (MC ≥7 in ≥75% of 10 high-power field areas), and 9 borderline cases with variable MCs around 7, which is a cutoff value for ccMCT grading. There was inconsistency among pathologists in identifying the areas with the highest density of mitotic figures throughout the 3 ccMCT groups; only 51.9% of the counts were consistent with the highest 25% of the ground truth MC distribution. Regardless, there was substantial agreement between pathologists in detecting tumors with MC ≥7. Falsely low MCs below 7 mainly occurred in 4 of 9 borderline cases that had very few ground truth areas with MC ≥7. The findings of this study highlight the need to further standardize how to select the region of the tumor in which to determine the MC.
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http://dx.doi.org/10.1177/0300985819890686DOI Listing
March 2020

Effect of mouse strain and diet on feasibility of MRI-based cell tracking in the liver.

Magn Reson Med 2020 06 25;83(6):2276-2283. Epub 2019 Nov 25.

Department of Radiology and Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, Michigan.

Purpose: MRI-based cell tracking identifies the location of magnetically labeled cells with hypointense voxels. Here we demonstrate a strain-dependent effect of liver MRI background on the feasibility of MRI-based cell tracking of transplanted cells in the mouse liver.

Methods: FVB mice (GFP-LUC and NOG) and C57BL/6 mice (GFP+ and wild-type) were fed 3 different diets with varying iron content. In vivo -weighted images and maps of the liver were acquired at different ages. Magnetically labeled cancer cells were injected intrasplenically for hepatic migration; then, mice were imaged by in vivo MRI and bioluminescence imaging. Livers were also imaged ex vivo by magnetic particle imaging.

Results: increased with age in FVB and FVB mice that were fed diets sufficient in iron. FVB mice developed a mottled appearance in their livers with age that did not occur in FVB mice. was unchanging with age in C57BL/6 mice, and the liver remained bright and homogenous. Labeled cells were not detectable by MRI in some livers despite successful engraftment as shown by bioluminescence imaging and magnetic particle imaging.

Conclusion: Strain, diet, and age are important considerations for MRI-based cell tracking in the liver. If a model with excessive liver iron must be used, alternative imaging methods such as magnetic particle imaging can be considered.
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http://dx.doi.org/10.1002/mrm.28081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7047545PMC
June 2020

Immunohistochemical Features of Epithelial-Mesenchymal Transition in Feline Oral Squamous Cell Carcinoma.

Vet Pathol 2019 11 22;56(6):826-839. Epub 2019 Jul 22.

College of Veterinary Medicine, Oregon State University, Corvallis, OR, USA.

Feline oral squamous cell carcinoma (FOSCC) is an aggressive malignancy with invasive and metastatic behavior. It is poorly responsive to chemotherapy and radiation. Neoplastic epithelial-mesenchymal transition (EMT) portends highly malignant behavior and enhances resistance to therapy. In transitioning to a more malignant phenotype, carcinoma stem cells undergo transformation mediated by expression of proteins, endowing them with mesenchymal properties advantageous to cell survival. The goal of the current study was to identify proteins associated with EMT in FOSCC. This study documents protein expression patterns in 10 FOSCC biopsies and 3 FOSCC cell lines (SCCF1, SCCF2, SCCF3), compatible with an EMT phenotype. As markers of EMT, P-cadherin, N-cadherin, vimentin, nuclear transcription factors Twist and Snail, hypoxia inducible factor 1α (HIF-1α), programmed death ligand 1, and vascular endothelial growth factor D, as well as E-cadherin, were examined using immunohistochemistry, Western blot, and enzyme-linked immunosorbent assay. P-cadherin, Twist, HIF-1α, and programmed death ligand 1 were commonly expressed in biopsies and cell lines. N-cadherin, classically associated with EMT, was not highly expressed, and E-cadherin was coexpressed along with proteins characteristic of EMT in all specimens. Production of vascular endothelial growth factor A by cell lines, a process regulated by HIF-1α expression, was suppressed by the small-molecule inhibitor dasatinib. These data are consistent with EMT in FOSCC and shed light on cellular changes that could contribute to the aggressive behavior of FOSCC.
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http://dx.doi.org/10.1177/0300985819859873DOI Listing
November 2019

Activating Mutations in and in Canine Histiocytic Sarcomas.

Genes (Basel) 2019 07 4;10(7). Epub 2019 Jul 4.

Comparative Medicine and Integrative Biology Program, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824, USA.

While the genetic contributions to the predisposition of Bernese mountain dogs (BMDs) to histiocytic sarcoma (HS) remains unclear, some insights into key genetic drivers have been gained. Our group recently reported a mutation in the gene (E76K). We have now identified a second missense mutation in PTPN11 (G503V), and a mutation in KRAS (Q61H) present in HS cell lines. These mutations are associated with malignancies in humans, and known to be gain-of-function mutations that result in activation of the mitogen-activated protein kinase (MAPK) pathway. The goal of the present study was to evaluate the prevalence of these mutations in a large sample of HS cases from BMDs and golden retrievers, and in lymphoma cases, from a cohort of BMDs. Mutations in were present in HS in 41/96 (43%) BMDs, and in 3/13 (23%) golden retrievers. PTPN11 mutations E76K and G503V did not coexist in the same neoplasm. The mutation was much less frequent, with a prevalence of 3.1% (3/96). We did not identify either nor mutations in any of the lymphoma samples. These results point out the potential relevance of and mutations as activators of the oncogenic MAPK pathway for canine HS, particularly in BMDs.
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http://dx.doi.org/10.3390/genes10070505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678586PMC
July 2019

DIFFERENTIATING ENTEROPATHY-ASSOCIATED T-CELL LYMPHOMA TYPE 2 FROM INFLAMMATORY BOWEL DISEASE IN A SNOW LEOPARD ().

J Zoo Wildl Med 2019 Jun 13;50(2):474-477. Epub 2019 Jun 13.

Diagnostic Center for Population and Animal Health, Lansing, MI 48910, USA,

After a history of intermittent vomiting, endoscopic biopsies of stomach and duodenum were collected from a 13-yr-old male snow leopard (). On microscopic examination, monomorphic small lymphocytes expanded the duodenal mucosa and occasionally formed intraepithelial nests. Immunohistochemistry of the infiltrating small lymphocytes in the mucosa and within the epithelium had strong, perimembranous labeling for CD3e, with few CD79a-positive lymphocytes located at the base of the villi. Polymerase chain reaction (PCR) for antigen receptor rearrangements (PARR) of feline T-cell receptor gamma (TCRG) detected a monoclonal cell population. The sequence of the PCR product was 100% homologous with the feline TCRG gene. By histology, immunophenotyping, and PARR testing, a final diagnosis of enteropathy-associated T-cell lymphoma, small cell type, was made. Homology in the nucleotide sequence between and the domestic cat () indicates that feline PARR testing for TCRG may be diagnostic in snow leopards.
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http://dx.doi.org/10.1638/2017-0202DOI Listing
June 2019