@article{beatty_tu_pesavento_cavasin_chen_lidbury_steiner_barrs_cullen_2024, title={Reply to Piewbang et al. Domestic Cat Hepadnavirus Antigens in Lymphoma Tissues. Comment on "Beatty et al. Domestic Cat Hepadnavirus and Lymphoma. <i>Viruses</i> 2023, <i>15</i>, 2294"}, volume={16}, ISSN={["1999-4915"]}, DOI={10.3390/v16010149}, abstractNote={We are grateful to the authors for providing additional data to demonstrate the presence of domestic cat hepadnavirus in lymphoma tissues [...].}, number={1}, journal={VIRUSES-BASEL}, author={Beatty, Julia A. and Tu, Thomas and Pesavento, Patricia A. and Cavasin, Joao P. and Chen, Min-Chun and Lidbury, Jonathan A. and Steiner, Joerg M. and Barrs, Vanessa R. and Cullen, John M.}, year={2024}, month={Jan} }
 @article{thompson_heintz_wolf_cheru_haws_cullen_2023, title={Assessment of Mouse Liver Histopathology Following Exposure to HFPO-DA With Emphasis on Understanding Mechanisms of Hepatocellular Death}, ISSN={["1533-1601"]}, DOI={10.1177/01926233231159078}, abstractNote={Ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate (HFPO-DA) is a short chain member of per- and polyfluoroalkyl substances (PFAS). To better understand the relevance of histopathological effects seen in livers of mice exposed to HFPO-DA for human health risk assessment, histopathological effects were summarized from hematoxylin and eosin (H&E)-stained sections in several repeat-dose toxicity studies in mice. Findings across studies revealed histopathological changes consistent with peroxisomal proliferation, whereas two reports of steatosis could not be confirmed in the published figures. In addition, mechanisms of hepatocellular death were assessed in H&E sections as well as with the apoptotic marker cleaved caspase-3 (CCasp3) in newly cut sections from archived liver blocks from select studies. A comparison of serially CCasp3 immunolabeled and H&E-stained sections revealed that mechanisms of hepatocellular death cannot be clearly discerned in H&E-stained liver sections alone as several examples of putatively necrotic cells were positive for CCasp3. Published whole genome transcriptomic data were also reevaluated for enrichment of various forms of hepatocellular death in response to HFPO-DA, which revealed enrichment of apoptosis and autophagy, but not ferroptosis, pyroptosis, or necroptosis. These morphological and molecular findings are consistent with transcriptomic evidence for peroxisome proliferator-activated receptor alpha (PPARα) signaling in HFPO-DA exposed mice.}, journal={TOXICOLOGIC PATHOLOGY}, author={Thompson, Chad M. and Heintz, Melissa M. and Wolf, Jeffrey C. and Cheru, Roza and Haws, Laurie C. and Cullen, John M.}, year={2023}, month={Mar} }
 @article{heintz_haws_klaunig_cullen_thompson_2023, title={Assessment of the mode of action underlying development of liver lesions in mice following oral exposure to HFPO-DA and relevance to humans}, ISSN={["1096-0929"]}, DOI={10.1093/toxsci/kfad004}, abstractNote={Abstract HFPO-DA (ammonium, 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)propanoate) is a short-chain polyfluorinated alkyl substance (PFAS) used in the manufacture of some types of fluorinated polymers. Like many PFAS, toxicity studies with HFPO-DA indicate the liver is the primary target of toxicity in rodents following oral exposure. Due to the structural diversity of PFAS, the mode of action (MOA) can differ between PFAS for the same target tissue. There is significant evidence for involvement of peroxisome proliferator-activated receptor alpha (PPARα) activation based on molecular and histopathological responses in the liver following HFPO-DA exposure, but other MOAs have also been hypothesized based on limited evidence. The MOA underlying the liver effects in mice exposed to HFPO-DA was assessed in the context of the Key Events (KEs) outlined in the MOA framework for PPARα activator-induced rodent hepatocarcinogenesis. The first 3 KEs (ie, PPARα activation, alteration of cell growth pathways, and perturbation of cell growth/survival) are supported by several lines of evidence from both in vitro and in vivo data available for HFPO-DA. In contrast, alternate MOAs, including cytotoxicity, PPARγ and mitochondrial dysfunction are generally not supported by the scientific literature. HFPO-DA-mediated liver effects in mice are not expected in humans as only KE 1, PPARα activation, is shared across species. PPARα-mediated gene expression in humans produces only a subset (ie, lipid modulating effects) of the responses observed in rodents. As such, the adverse effects observed in rodent livers should not be used as the basis of toxicity values for HFPO-DA for purposes of human health risk assessment.}, journal={TOXICOLOGICAL SCIENCES}, author={Heintz, Melissa M. and Haws, Laurie C. and Klaunig, James E. and Cullen, John M. and Thompson, Chad M.}, year={2023}, month={Jan} }
 @article{subramaniam_fares-gusmao_sato_cullen_takeda_farci_mcgivern_2023, title={Distinct disease features of acute and persistent genotype 3 hepatitis E virus infection in immunocompetent and immunosuppressed Mongolian gerbils}, volume={19}, ISSN={["1553-7374"]}, DOI={10.1371/journal.ppat.1011664}, abstractNote={Hepatitis E virus (HEV) causes self-limited acute hepatitis in immunocompetent individuals and can establish chronic infection in solid organ transplant recipients taking immunosuppressive drugs. A well characterized small animal model is needed to understand HEV pathogenesis. In this study, we established a robust model to study acute and persistent HEV infection using Mongolian gerbils (Meriones unguiculatus) with or without immunosuppression. Gerbils were implanted subcutaneously with continuous release tacrolimus pellet to induce immunosuppression. Gerbils with or without tacrolimus treatment were inoculated with HEV intraperitoneally. Viremia, fecal virus shedding, serum antibody and ALT levels, liver histopathological lesions, hepatocyte apoptosis, and liver macrophage distribution were assessed. Mild to moderate self-limited hepatitis and IgM and IgG antibody responses against HEV ORF2 were observed in immunocompetent gerbils. Levels of HEV-specific IgM responses were higher and lasted longer in immunocompetent gerbils with higher peak viremia. Persistent viremia and fecal virus shedding with either weak, or absent HEV antibody levels were seen in immunosuppressed gerbils. Following HEV infection, serum ALT levels were increased, with lower and delayed peaks observed in immunosuppressed compared to immunocompetent gerbils. In immunocompetent gerbils, foci of apoptotic hepatocytes were detected that were distributed with inflammatory infiltrates containing CD68+ macrophages. However, these foci were absent in immunosuppressed gerbils. The immunosuppressed gerbils showed no inflammation with no increase in CD68+ macrophages despite high virus replication in liver. Our findings suggest adaptive immune responses are necessary for inducing hepatocyte apoptosis, CD68+ macrophage recruitment, and inflammatory cell infiltration in response to HEV infection. Our studies show that Mongolian gerbils provide a promising model to study pathogenesis during acute and persistent HEV infection.}, number={9}, journal={PLOS PATHOGENS}, author={Subramaniam, Sakthivel and Fares-Gusmao, Rafaelle and Sato, Shinya and Cullen, John M. and Takeda, Kazuyo and Farci, Patrizia and Mcgivern, David R.}, year={2023}, month={Sep} }
 @article{beatty_tu_pesavento_cavasin_chen_lidbury_steiner_barrs_cullen_2023, title={Domestic Cat Hepadnavirus and Lymphoma}, volume={15}, ISSN={["1999-4915"]}, DOI={10.3390/v15122294}, abstractNote={We write to comment on Piewbang C et al [...].}, number={12}, journal={VIRUSES-BASEL}, author={Beatty, Julia A. and Tu, Thomas and Pesavento, Patricia A. and Cavasin, Joao P. and Chen, Min-Chun and Lidbury, Jonathan A. and Steiner, Joerg M. and Barrs, Vanessa R. and Cullen, John M.}, year={2023}, month={Dec} }
 @article{wheatley_shamoun_maggi_breitschwerdt_sommer_cullen_stowe_2023, title={Eosinophilic pericardial effusion and pericarditis in a cat}, volume={9}, ISSN={["2055-1169"]}, DOI={10.1177/20551169231213498}, abstractNote={Case summary A 10-year-old domestic shorthair cat presented for lethargy, anorexia and labored breathing. Significant pleural and pericardial effusions prompted thoracocentesis and pericardiocentesis. Cytologic evaluation of the pericardial effusion revealed a highly cellular hemorrhagic, eosinophilic (12%) effusion, with many markedly atypical suspected mesothelial cells, interpreted as concerning for neoplasia. Thoracoscopic subtotal pericardiectomy and histology of the pericardium revealed predominantly eosinophilic inflammation with multifocal mesothelial hypertrophy and ulceration. A peripheral eosinophilia was not present on serial complete blood counts. Initial infectious disease testing was mostly negative. Toxoplasma gondii titers were most consistent with prior exposure, although reactivation could not be excluded. The owner’s medical history included a prior diagnosis of bartonellosis. Owing to the challenges of definitive Bartonella species exclusion, the cat was treated empirically with pradofloxacin and doxycycline, and a subtotal pericardectomy. There was improvement at first but pleural effusion recurred approximately 3 months after discharge. The cat was euthanized and a necropsy was not performed. Subsequent pericardial effusion Piroplasma/Bartonella/Borrelia droplet digital PCR detected DNA of Bartonella vinsonii subspecies berkhoffii, and peripheral blood culture and sequencing revealed a rare apicomplexan organism (90% homology with Colpodella species) of unknown clinical significance. Testing for filamentous bacteria and fungal pathogens was not performed. Relevance and novel information This case offers several unique entities – eosinophilic pericardial effusion and eosinophilic pericarditis of unknown etiology – and illustrates the well-known marked atypia that may occur in reactive and hyperplastic mesothelial cells, particularly of infrequently sampled and cytologically described feline pericardial effusion, supporting a cautious interpretation of this cytology finding.}, number={2}, journal={JOURNAL OF FELINE MEDICINE AND SURGERY OPEN REPORTS}, author={Wheatley, Meagan Alisa and Shamoun, John and Maggi, Ricardo and Breitschwerdt, Edward B. and Sommer, Samantha L. and Cullen, John M. and Stowe, Devorah Marks}, year={2023}, month={Jul} }
 @article{gookin_hartley_aicher_mathews_cullen_cullen_callahan_stowe_seiler_jacob_et al._2023, title={Gallbladder microbiota in healthy dogs and dogs with mucocele formation}, volume={18}, ISSN={["1932-6203"]}, DOI={10.1371/journal.pone.0281432}, abstractNote={To date studies have not investigated the culture-independent microbiome of bile from dogs, a species where aseptic collection of bile under ultrasound guidance is somewhat routine. Despite frequent collection of bile for culture-based diagnosis of bacterial cholecystitis, it is unknown whether bile from healthy dogs harbors uncultivable bacteria or a core microbiota. The answer to this question is critical to understanding the pathogenesis of biliary infection and as a baseline to exploration of other biliary diseases in dogs where uncultivable bacteria could play a pathogenic role. A pressing example of such a disease would be gallbladder mucocele formation in dogs. This prevalent and deadly condition is characterized by excessive secretion of abnormal mucus by the gallbladder epithelium that can eventually lead to rupture of the gallbladder or obstruction of bile flow. The cause of mucocele formation is unknown as is whether uncultivable, and therefore unrecognized, bacteria play any systematic role in pathogenesis. In this study we applied next-generation 16S rRNA gene sequencing to identify the culture-negative bacterial community of gallbladder bile from healthy dogs and gallbladder mucus from dogs with mucocele formation. Integral to our study was the use of 2 separate DNA isolations on each sample using different extraction methods and sequencing of negative control samples enabling recognition and curation of contaminating sequences. Microbiota findings were validated by simultaneous culture-based identification, cytological examination of bile, and fluorescence in-situ hybridization (FISH) performed on gallbladder mucosa. Using culture-dependent, cytological, FISH, and 16S rRNA sequencing approaches, results of our study do not support existence of a core microbiome in the bile of healthy dogs or gallbladder mucus from dogs with mucocele formation. Our findings further document how contaminating sequences can significantly contribute to the results of sequencing analysis when performed on samples with low bacterial biomass.}, number={2}, journal={PLOS ONE}, author={Gookin, Jody L. and Hartley, Ashley N. and Aicher, Kathleen M. and Mathews, Kyle G. and Cullen, Rachel and Cullen, John M. and Callahan, Benjamin J. and Stowe, Devorah M. and Seiler, Gabriela S. and Jacob, Megan E. and et al.}, year={2023}, month={Feb} }
 @article{schreeg_cullen_robertson_gookin_2023, title={Histologic characterization of the major duodenal papilla and association with concurrent biliary, pancreatic, and intestinal pathology in cats}, volume={8}, ISSN={["1544-2217"]}, DOI={10.1177/03009858231189450}, abstractNote={Conjoining of the major pancreatic duct and common bile duct at the major duodenal papilla (MDP) is suspected to predispose cats to the clinical syndrome of "triaditis." However, microanatomy of the MDP or presence of lesions at the MDP has not been assessed in cats with or without triaditis. The aims of this study were to characterize feline MDP histomorphology and to identify associations between MDP anatomy/disease and the presence of biliary, pancreatic, or intestinal inflammation or neoplasia. Histologic assessment was prospectively performed on the MDP, duodenum, jejunum, ileum, liver, and pancreas from 124 client-owned cats undergoing postmortem examination. The majority of cats (104/124, 84%) had a complex ductular network at the MDP, with no distinction between pancreatic and common bile ducts. Lymphoid aggregates at the MDP were common (63/124, 51%). Inflammation of the MDP (MDPitis) was present in 35 of 124 cats (28%) and was often concurrent with cholangitis, pancreatitis, or enteritis (32/35, 91%), but was only associated with enteritis (19/35, 54%, P < .05). Triaditis was less common (19/124, 15%), but was associated with both conjoined MDP anatomy (19/19, 100%, P < .05) and MDPitis (12/19, 63%, P < .05). Neoplasia was present in 37 of 124 cats (29%), with lymphoma (28/37, 78%) predominating. Enteropathy-associated T-cell lymphoma type 2 (EATL2) was most common (n = 16/37, 43%) and was associated with triaditis and MDPitis (P < .05). These findings suggest that anatomy, immune activation, and/or inflammation of the MDP may play a role in the pathogenesis of triaditis. Further studies are needed to elucidate the relationships between triaditis, MDPitis, and EATL2.}, journal={VETERINARY PATHOLOGY}, author={Schreeg, Megan E. and Cullen, John M. and Robertson, James and Gookin, Jody L.}, year={2023}, month={Aug} }
 @article{hughes_radakovic_gorman_malinowska_cullen_2023, title={Immunohistochemical characterization of clear cell variant of hepatocellular carcinoma in a sheep}, volume={204}, ISSN={["1532-3129"]}, DOI={10.1016/j.jcpa.2023.06.002}, abstractNote={The cadaver and viscera of a mature female sheep (Ovis aries) underwent routine abattoir meat inspection. The liver was expanded by an infiltrative neoplastic mass comprising multifocal to coalescing, well-demarcated, pink to white–yellow nodules, up to 25 mm in diameter. An unencapsulated, moderately densely cellular, infiltrative neoplasm was present within the hepatic parenchyma. The neoplastic cells were arranged in solid sheets and acini supported by a moderately fine collagenous vascularized stroma. The neoplastic cells were moderately sized and polygonal, with clearly delineated cell borders and a moderate amount of cytoplasm that was clear or exhibited either globular eosinophilic deposits or fine fibrillar eosinophilic strands. The neoplastic cell nuclei were round and centrally located. The chromatin was lightly stippled and there was frequently a single, prominent, basophilic nucleolus. There were eight mitoses in 10 high-power fields (2.37 mm2). Most of the neoplastic cells had intense cytoplasmic immunolabelling for arginase 1, with frequent concurrent nuclear positivity, and mild to moderately intense punctate cytoplasmic labelling for hepatocyte specific antigen (Hep Par-1). The neoplastic cells did not label with anti-cytokeratin 19 antibody. Based on the histological appearance and the immunolabelling pattern, the neoplasm was diagnosed as the clear cell variant of a hepatocellular carcinoma.}, journal={JOURNAL OF COMPARATIVE PATHOLOGY}, author={Hughes, Katherine and Radakovic, Milorad and Gorman, Frank and Malinowska, Beata and Cullen, John M.}, year={2023}, month={Jul}, pages={47–50} }
 @article{wong_cullen_vila-gonzalez_pittaway_desmet_gillian_2023, title={Patent hepatic ciliated foregut remnant resulting in an umbilicobiliary sinus tract, with gallbladder agenesis, in an 8-wk-old male French Bulldog}, ISSN={["1943-4936"]}, DOI={10.1177/10406387221147317}, abstractNote={Hepatic ciliated foregut remnants or cysts are congenital abnormalities resulting from retention of embryonic ciliated foregut within the liver. These structures are rarely reported in the human medical literature and have not been reported in the veterinary literature previously, to our knowledge. We describe here a case of an 8-wk-old male French Bulldog with a congenital patent hepatic ciliated foregut remnant resulting in an umbilicobiliary sinus tract. The dog also had concurrent gallbladder agenesis. The patient had yellow fluid discharging from the umbilicus, mimicking a patent urachus. Surgical exploration, removal, and histology provided a conclusive diagnosis of a hepatic foregut remnant and therapeutic resolution of the clinical signs. The histologic appearance of a hepatic foregut remnant is classical, namely a duct composed of 4 layers: an inner ciliated epithelial lining, loose connective tissue, smooth muscle, and a fibrous capsule.}, journal={JOURNAL OF VETERINARY DIAGNOSTIC INVESTIGATION}, author={Wong, Hannah E. and Cullen, John M. and Vila-Gonzalez, Marta and Pittaway, Rachel and Desmet, Valeer J. and Gillian, Tammy D.}, year={2023}, month={Jan} }
 @article{dravid_murthy_attia_cassady_chandra_trivedi_vyas_gridly_holland_kumari_et al._2023, title={Phenotype and fate of liver-resident CD8 T cells during acute and chronic hepacivirus infection}, volume={19}, ISSN={["1553-7374"]}, DOI={10.1371/journal.ppat.1011697}, abstractNote={Immune correlates of hepatitis C virus (HCV) clearance and control remain poorly defined due to the lack of an informative animal model. We recently described acute and chronic rodent HCV-like virus (RHV) infections in lab mice. Here, we developed MHC class I and class II tetramers to characterize the serial changes in RHV-specific CD8 and CD4 T cells during acute and chronic infection in C57BL/6J mice. RHV infection induced rapid expansion of T cells targeting viral structural and nonstructural proteins. After virus clearance, the virus-specific T cells transitioned from effectors to long-lived liver-resident memory T cells (TRM). The effector and memory CD8 and CD4 T cells primarily produced Th1 cytokines, IFN-γ, TNF-α, and IL-2, upon ex vivo antigen stimulation, and their phenotype and transcriptome differed significantly between the liver and spleen. Rapid clearance of RHV reinfection coincided with the proliferation of virus-specific CD8 TRM cells in the liver. Chronic RHV infection was associated with the exhaustion of CD8 T cells (Tex) and the development of severe liver diseases. Interestingly, the virus-specific CD8 Tex cells continued proliferation in the liver despite the persistent high-titer viremia and retained partial antiviral functions, as evident from their ability to degranulate and produce IFN-γ upon ex vivo antigen stimulation. Thus, RHV infection in mice provides a unique model to study the function and fate of liver-resident T cells during acute and chronic hepatotropic infection.}, number={10}, journal={PLOS PATHOGENS}, author={Dravid, Piyush and Murthy, Satyapramod and Attia, Zayed and Cassady, Cole and Chandra, Rahul and Trivedi, Sheetal and Vyas, Ashish and Gridly, John and Holland, Brantley and Kumari, Anuradha and et al.}, year={2023}, month={Oct} }
 @article{kang_womble_cullen_harrison_premanandan_schreeg_2023, title={Severe bronchiectasis resulting from chronic bacterial bronchitis and bronchopneumonia in a jungle cat}, volume={11}, ISSN={["1943-4936"]}, DOI={10.1177/10406387231216181}, abstractNote={Bronchiectasis is irreversible bronchial dilation that can be congenital or acquired secondary to chronic airway obstruction. Feline bronchiectasis is rare and, to our knowledge, has not been reported previously in a non-domestic felid. An ~10-y-old female jungle cat (Felis chaus) was presented for evaluation of an abdominal mass and suspected pulmonary metastasis. The animal died during exploratory laparotomy and was submitted for postmortem examination. Gross examination revealed consolidation of the left caudal lung lobe and hila of the cranial lung lobes. Elsewhere in the lungs were several pale-yellow pleural foci of endogenous lipid pneumonia. On cut section, there was severe distension of bronchi with abundant white mucoid fluid. The remaining lung lobes were multifocally expanded by marginal emphysema. Histologically, ectatic bronchi, bronchioles, and fewer alveoli contained degenerate neutrophils, fibrin, and mucin (suppurative bronchopneumonia) with rare gram-negative bacteria. Aerobic culture yielded low growth of Proteus mirabilis and Escherichia coli. There was chronic bronchitis, marked by moderate bronchial gland hyperplasia, lymphoplasmacytic inflammation, and lymphoid hyperplasia. The palpated abdominal mass was a uterine endometrial polyp, which was considered an incidental, but novel, finding. Chronic bronchitis and bronchopneumonia should be considered as a cause of bronchiectasis and a differential diagnosis for respiratory disease in non-domestic felids.}, journal={JOURNAL OF VETERINARY DIAGNOSTIC INVESTIGATION}, author={Kang, Danyue and Womble, Mandy and Cullen, John M. and Harrison, Tara M. and Premanandan, Christopher and Schreeg, Megan E.}, year={2023}, month={Nov} }
 @article{sun_feng_misumi_shirasaki_hensley_gonzalez-lopez_shiota_chou_ting_cullen_et al._2023, title={Viral protease cleavage of MAVS in genetically modified mice with hepatitis A virus infection}, volume={78}, ISSN={["1600-0641"]}, DOI={10.1016/j.jhep.2022.09.013}, abstractNote={Consistent with its relatively narrow host species range, hepatitis A virus (HAV) cannot infect C57BL/6 mice. However, in Mavs-/- mice with genetic deficiency of the innate immune signaling adaptor MAVS, HAV replicates robustly in the absence of disease. The HAV 3ABC protease cleaves MAVS in human cells, thereby disrupting virus-induced IFN responses, but it cannot cleave murine MAVS (mMAVS) due to sequence differences at the site of scission. Here, we sought to elucidate the role of 3ABC MAVS cleavage in determining HAV pathogenesis and host species range.Using CRISPR/Cas9 gene editing, we established two independent lineages of C57BL/6 mice with knock-in mutations altering two amino acids in mMAVS ('mMAVS-VS'), rendering it susceptible to 3ABC cleavage without loss of signaling function. We challenged homozygous Mavsvs/vs mice with HAV, and compared infection outcomes with C57BL/6 and genetically deficient Mavs-/- mice.The humanized murine mMAVS-VS protein was cleaved as efficiently as human MAVS when co-expressed with 3ABC in Huh-7 cells. In embyronic fibroblasts from Mavsvs/vs mice, mMAVS-VS was cleaved by ectopically expressed 3ABC, significantly disrupting Sendai virus-induced IFN responses. However, in contrast to Mavs-/- mice with genetic MAVS deficiency, HAV failed to establish infection in Mavsvs/vs mice, even with additional genetic knockout of Trif or Irf1. Nonetheless, when crossed with permissive Ifnar1-/- mice lacking type I IFN receptors, Mavsvs/vsIfnar1-/- mice demonstrated enhanced viral replication coupled with significant reductions in serum alanine aminotransferase, hepatocellular apoptosis, and intrahepatic inflammatory cell infiltrates compared with Ifnar1-/- mice.MAVS cleavage by 3ABC boosts viral replication and disrupts disease pathogenesis, but it is not by itself sufficient to break the host-species barrier to HAV infection in mice.The limited host range of human hepatitis viruses could be explained by species-specific viral strategies that disrupt innate immune responses. Both hepatitis A virus (HAV) and hepatitis C virus express viral proteases that cleave the innate immune adaptor protein MAVS, in human but not mouse cells. However, the impact of this immune evasion strategy has never been assessed in vivo. Here we show that HAV 3ABC protease cleavage of MAVS enhances viral replication and lessens liver inflammation in mice lacking interferon receptors, but that it is insufficient by itself to overcome the cross-species barrier to infection in mice. These results enhance our understanding of how hepatitis viruses interact with the host and their impact on innate immune responses.}, number={2}, journal={JOURNAL OF HEPATOLOGY}, author={Sun, Lu and Feng, Hui and Misumi, Ichiro and Shirasaki, Takayoshi and Hensley, Lucinda and Gonzalez-Lopez, Olga and Shiota, Itoe and Chou, Wei-Chun and Ting, Jenny P. -Y. and Cullen, John M. and et al.}, year={2023}, month={Feb}, pages={271–280} }
 @article{robveille_cullen_2022, title={Hepatocellular carcinomas in captive prosimians}, ISSN={["1544-2217"]}, DOI={10.1177/03009858221114471}, abstractNote={We performed a retrospective examination of spontaneous hepatocellular carcinomas (HCCs) (primary and metastatic tumors) in 14 captive prosimians brought to the Veterinary Medical Diagnostic Laboratory in North Carolina State University over a period of 11 years (2003 to 2014) to characterize the tumors. These animals are endangered primates; a better understanding of the main fatal neoplasms is crucial. In addition to the histologic evaluation, an immunohistochemical study was also performed, using a hepatocyte marker (hepatocyte paraffin 1 [HepPar-1]) and 2 cholangiocyte markers (keratin 7 [K7] and keratin 19 [K19]), in an attempt to identify a specific profile for HCCs with metastatic behavior. Six of the 14 HCCs had pulmonary metastases. The most frequent histopathological findings were a trabecular pattern (14/14, 100%), presence of multinucleated cells (12/14, 85.7%), and foci of extramedullary hematopoiesis (9/14, 64.3%). The mitotic count was significantly higher in the metastatic HCCs (P < .05). HepPar-1 was detected in all primary and metastatic HCCs, with a strong intensity of staining. Labeling for K7 and K19 was positive in 12 HCCs (85.7%) and 1 HCC (7.1%), respectively. Contrary to the less aggressive HCCs, most of the metastatic HCCs (5/6) expressed K7 in more than 15% of cells. The percentage of K7-positive neoplastic hepatocytes was significantly higher in metastatic HCCs. This study suggests that K7 might be a prognostically relevant marker in HCCs of captive prosimians.}, journal={VETERINARY PATHOLOGY}, author={Robveille, Cynthia and Cullen, John M.}, year={2022}, month={Jul} }
 @article{li_misumi_shiota_sun_lenarcic_kim_shirasaki_hertel-wulff_tibbs_mitchell_et al._2022, title={The ZCCHC14/TENT4 complex is required for hepatitis A virus RNA synthesis}, volume={119}, ISSN={["1091-6490"]}, DOI={10.1073/pnas.2204511119}, abstractNote={Significance Despite excellent vaccines, unprecedented outbreaks of hepatitis A have resulted in more than 400 fatal infections in the United States since 2016. Many gaps exist in our current understanding of the responsible pathogen, hepatitis A virus (HAV), for which there are no available antiviral therapies. Here, we show how the RNA genome of this unique, hepatotropic picornavirus interacts with a host cell protein complex required for synthesis of the viral RNA. We demonstrate that targeting this complex with an orally delivered small-molecule therapeutic ablates viral replication and reverses liver inflammation in a mouse model of hepatitis A, providing proof-of-principle for antiviral therapy and showing the potential for chemoprevention of hepatitis A in outbreak settings.}, number={28}, journal={PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA}, author={Li, You and Misumi, Ichiro and Shiota, Tomoyuki and Sun, Lu and Lenarcic, Erik M. and Kim, Hyejeong and Shirasaki, Takayoshi and Hertel-Wulff, Adriana and Tibbs, Taylor and Mitchell, Joseph E. and et al.}, year={2022}, month={Jul} }
 @article{schreeg_miller_cullen_2021, title={Choledochal cyst with secondary cholangitis, choledochitis, duodenal papillitis, and pancreatitis in a young domestic shorthair cat}, ISSN={["1943-4936"]}, DOI={10.1177/10406387211017107}, abstractNote={Choledochal cysts, congenital segmental dilations of the common bile duct, have been reported in few cats, and histologic characterization is lacking. A 20-mo-old spayed female domestic shorthair cat was presented because of vomiting and weight loss. There was progressive elevation of liver enzyme activity (ALT > ALP, GGT) and hyperbilirubinemia. Diagnostic imaging identified focal cystic dilation of the common bile duct, dilation and tortuosity of adjacent hepatic ducts, and a prominent duodenal papilla. A choledochal cyst was suspected, and the animal was euthanized. On postmortem examination, there was a 2-cm, firm, thickened, cystic dilation of the common bile duct, patent with adjacent ducts. Histologically, the cyst wall was expanded by fibroblasts, collagen, and lymphoplasmacytic inflammation. Adjacent bile ducts were markedly dilated and tortuous, with lymphoplasmacytic inflammation and papillary mucosal hyperplasia that extended to the major duodenal papilla. There was chronic neutrophilic cholangitis, suggesting bacterial infection and/or disturbed bile drainage, extrahepatic obstruction, and lymphoplasmacytic pancreatitis with ductular metaplasia. Prominent lymphoid follicles within biliary ducts and duodenum suggested chronic antigenic stimulation. Choledochal cysts can be associated with chronic neutrophilic cholangitis, extrahepatic obstruction, choledochitis, duodenal papillitis, and pancreatitis, and should be a differential for increased hepatic enzymes and hyperbilirubinemia in young cats.}, journal={JOURNAL OF VETERINARY DIAGNOSTIC INVESTIGATION}, author={Schreeg, Megan E. and Miller, Sybille A. and Cullen, John M.}, year={2021}, month={May} }
 @article{patania_troan_cullen_2021, title={Ductal Plate Malformations in Captive Snakes}, ISSN={["1544-2217"]}, DOI={10.1177/03009858211011941}, abstractNote={Ductal plate malformations are abnormalities in the liver that arise from inappropriate or incomplete remodeling of the embryologic ductal plate. Various types of ductal plate malformations are reported in the human and veterinary literature, most commonly affecting domestic mammalian species but also fish. We investigated the occurrence and described the histopathologic features of ductal plate malformations in captive snakes. Malformations were identified in 18 snakes: 10 colubrids, 6 vipers, and 2 boids. There was no sex predilection, and the mean age was 17 years. The majority of lesions were incidental with most snakes having one or more comorbidities, most commonly neoplasia or systemic inflammation, that resulted in natural death or euthanasia. Ductal plate malformations in all livers were broadly characterized by a well-demarcated nodule of irregular bile ducts embedded within a varying amount of fibrous stroma. Malformations were further categorized based on the amount of fibrous stroma and dilation of the bile ducts as von Meyenburg complexes, cystic liver disease, and/or an intermediate hybrid subtype representative of cysts arising within von Meyenburg complexes. Histochemical and immunohistochemical staining, including Gomori’s trichome and pan-cytokeratin, respectively, were applied on select cases to confirm histologic features. Malignant transformation was not identified within this population.}, journal={VETERINARY PATHOLOGY}, author={Patania, Olivia M. and Troan, Brigid V. and Cullen, John M.}, year={2021}, month={May} }
 @article{sun_li_misumi_gonzalez-lopez_hensley_cullen_mcgivern_matsuda_suzuki_sen_et al._2021, title={IRF3-mediated pathogenicity in a murine model of human hepatitis A}, volume={17}, ISSN={["1553-7374"]}, DOI={10.1371/journal.ppat.1009960}, abstractNote={HAV-infected Ifnar1-/- mice recapitulate many of the cardinal features of hepatitis A in humans, including serum alanine aminotransferase (ALT) elevation, hepatocellular apoptosis, and liver inflammation. Previous studies implicate MAVS-IRF3 signaling in pathogenesis, but leave unresolved the role of IRF3-mediated transcription versus the non-transcriptional, pro-apoptotic activity of ubiquitylated IRF3. Here, we compare the intrahepatic transcriptomes of infected versus naïve Mavs-/- and Ifnar1-/- mice using high-throughput sequencing, and identify IRF3-mediated transcriptional responses associated with hepatocyte apoptosis and liver inflammation. Infection was transcriptionally silent in Mavs-/- mice, in which HAV replicates robustly within the liver without inducing inflammation or hepatocellular apoptosis. By contrast, infection resulted in the upregulation of hundreds of genes in Ifnar1-/- mice that develop acute hepatitis closely modeling human disease. Upregulated genes included pattern recognition receptors, interferons, chemokines, cytokines and other interferon-stimulated genes. Compared with Ifnar1-/- mice, HAV-induced inflammation was markedly attenuated and there were few apoptotic hepatocytes in livers of infected Irf3S1/S1Ifnar1-/- mice in which IRF3 is transcriptionally-inactive due to alanine substitutions at Ser-388 and Ser-390. Although transcriptome profiling revealed remarkably similar sets of genes induced in Irf3S1/S1Ifnar1-/- and Ifnar1-/- mice, a subset of genes was differentially expressed in relation to the severity of the liver injury. Prominent among these were both type 1 and type III interferons and interferon-responsive genes associated previously with apoptosis, including multiple members of the ISG12 and 2’-5’ oligoadenylate synthetase families. Ifnl3 and Ifnl2 transcript abundance correlated strongly with disease severity, but mice with dual type 1 and type III interferon receptor deficiency remained fully susceptible to liver injury. Collectively, our data show that IRF3-mediated transcription is required for HAV-induced liver injury in mice and identify key IRF3-responsive genes associated with pathogenicity, providing a clear distinction from the transcription-independent role of IRF3 in liver injury following binge exposure to alcohol.}, number={9}, journal={PLOS PATHOGENS}, author={Sun, Lu and Li, You and Misumi, Ichiro and Gonzalez-Lopez, Olga and Hensley, Lucinda and Cullen, John M. and McGivern, David R. and Matsuda, Mami and Suzuki, Ryosuke and Sen, Ganes C. and et al.}, year={2021}, month={Sep} }
 @article{misumi_li_sun_das_shiota_cullen_zhang_whitmire_lemon_2021, title={Iminosugar Glucosidase Inhibitors Reduce Hepatic Inflammation in Hepatitis A Virus-Infected Ifnar1(-/-) Mice}, volume={95}, ISSN={["1098-5514"]}, DOI={10.1128/JVI.00058-21.10}, number={11}, journal={JOURNAL OF VIROLOGY}, author={Misumi, Ichiro and Li, Zhucui and Sun, Lu and Das, Anshuman and Shiota, Tomoyuki and Cullen, John and Zhang, Qibin and Whitmire, Jason K. and Lemon, Stanley M.}, year={2021}, month={Jun} }
 @article{meuten_moore_donovan_bertram_klopfleisch_foster_smedley_dark_milovancev_stromberg_et al._2021, title={International Guidelines for Veterinary Tumor Pathology: A Call to Action}, ISSN={["1544-2217"]}, DOI={10.1177/03009858211013712}, abstractNote={Standardization of tumor assessment lays the foundation for validation of grading systems, permits reproducibility of oncologic studies among investigators, and increases confidence in the significance of study results. Currently, there is minimal methodological standardization for assessing tumors in veterinary medicine, with few attempts to validate published protocols and grading schemes. The current article attempts to address these shortcomings by providing standard guidelines for tumor assessment parameters and protocols for evaluating specific tumor types. More detailed information is available in the Supplemental Files, the intention of which is 2-fold: publication as part of this commentary, but more importantly, these will be available as “living documents” on a website (www.vetcancerprotocols.org), which will be updated as new information is presented in the peer-reviewed literature. Our hope is that veterinary pathologists will agree that this initiative is needed, and will contribute to and utilize this information for routine diagnostic work and oncologic studies. Journal editors and reviewers can utilize checklists to ensure publications include sufficient detail and standardized methods of tumor assessment. To maintain the relevance of the guidelines and protocols, it is critical that the information is periodically updated and revised as new studies are published and validated with the intent of providing a repository of this information. Our hope is that this initiative (a continuation of efforts published in this journal in 2011) will facilitate collaboration and reproducibility between pathologists and institutions, increase case numbers, and strengthen clinical research findings, thus ensuring continued progress in veterinary oncologic pathology and improving patient care.}, journal={VETERINARY PATHOLOGY}, author={Meuten, Donald J. and Moore, Frances M. and Donovan, Taryn A. and Bertram, Christof A. and Klopfleisch, Robert and Foster, Robert A. and Smedley, Rebecca C. and Dark, Michael J. and Milovancev, Milan and Stromberg, Paul and et al.}, year={2021}, month={Jul} }
 @misc{woicke_al-haddawi_bienvenu_caverly rae_chanut_colman_cullen_davis_fukuda_huisinga_et al._2021, title={International Harmonization of Nomenclature and Diagnostic Criteria (INHAND): Nonproliferative and Proliferative Lesions of the Dog}, volume={49}, ISSN={["1533-1601"]}, DOI={10.1177/0192623320968181}, abstractNote={The INHAND (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions) Project ( www.toxpath.org/inhand.asp ) is a joint initiative of the societies of toxicologic Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP), and North America (STP) to develop an internationally accepted nomenclature for proliferative and nonproliferative lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature for classifying lesions observed in most tissues and organs from the dog used in nonclinical safety studies. Some of the lesions are illustrated by color photomicrographs. The standardized nomenclature presented in this document is also available electronically on the internet ( http://www.goreni.org/ ). Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous lesions, lesions induced by exposure to test materials, and relevant infectious and parasitic lesions. A widely accepted and utilized international harmonization of nomenclature for lesions in laboratory animals will provide a common language among regulatory and scientific research organizations in different countries and increase and enrich international exchanges of information among toxicologists and pathologists.}, number={1}, journal={TOXICOLOGIC PATHOLOGY}, author={Woicke, Jochen and Al-Haddawi, Muthafar M. and Bienvenu, Jean-Guy and Caverly Rae, Jessica M. and Chanut, Franck J. and Colman, Karyn and Cullen, John M. and Davis, Wendell and Fukuda, Ryo and Huisinga, Maike and et al.}, year={2021}, month={Jan}, pages={5–109} }
 @article{misumi_mitchell_lund_cullen_lemon_whitmire_2021, title={T cells protect against hepatitis A virus infection and limit infection- induced liver injury}, volume={75}, ISSN={["1600-0641"]}, DOI={10.1016/j.jhep.2021.07.019}, abstractNote={Hepatitis A virus (HAV) is a common cause of enterically transmitted viral hepatitis. In non-immune individuals, infection results in typically transient but occasionally fulminant and fatal inflammatory liver injury. Virus-specific T cell frequencies peak when liver damage is at its zenith, leading to the prevalent notion that T cells exacerbate liver disease, as suspected for other hepatotropic virus infections. However, the overall contribution of T cells to the control of HAV and the pathogenesis of hepatitis A is unclear and has been impeded by a historic lack of small animal models.Ifnar1-/- mice are highly permissive for HAV and develop pathogenesis that recapitulates many features of hepatitis A. Using this model, we identified HAV-specific CD8+ and CD4+ T cells by epitope mapping, and then used tetramers and functional assays to quantify T cells in the liver at multiple times after infection. We assessed the relationships between HAV-specific T cell frequency, viral RNA amounts, and liver pathogenesis.A large population of virus-specific T cells accumulated within the livers of Ifnar1-/- mice during the first 1-2 weeks of infection and persisted over time. HAV replication was enhanced and liver disease exacerbated when mice were depleted of T cells. Conversely, immunization with a peptide vaccine increased virus-specific CD8+ T cell frequencies in the liver, reduced viral RNA abundance, and lessened liver injury.These data show that T cells protect against HAV-mediated liver injury and can be targeted to improve liver health.Hepatitis A virus is a leading cause of acute viral hepatitis worldwide. T cells were thought to contribute to liver injury during acute infection. We now show that virus-specific T cells protect against infection and limit liver injury.}, number={6}, journal={JOURNAL OF HEPATOLOGY}, author={Misumi, Ichiro and Mitchell, Joseph E. and Lund, Makayla M. and Cullen, John M. and Lemon, Stanley M. and Whitmire, Jason K.}, year={2021}, month={Dec}, pages={1323–1334} }
 @article{corder_gadi_vachieri_jayes_cullen_khan_taylor_2021, title={Using rheology to quantify the effects of localized collagenase treatments on uterine fibroid digestion}, volume={134}, ISSN={["1878-7568"]}, DOI={10.1016/j.actbio.2021.08.003}, abstractNote={Uterine fibroids are stiff, benign tumors containing excessive, disordered collagens that occur in 70-80% of women before age 50 and cause bleeding and pain. Collagenase Clostridium histolyticum (CCH) is a bacterial enzyme capable of digesting the collagens present in fibroids. By combining CCH with injectable drug delivery systems to enhance effectiveness, a new class of treatments could be developed to reduce the stiffness of fibroids, preventing the need for surgical removal and preserving fertility. In this work, we achieved localization of CCH via physical entrapment by co-injecting a thermoresponsive pNIPAM-based polymeric delivery system called LiquoGel (LQG), which undergoes a sol-gel transition upon heating. Toxicity study results for LQG injected subcutaneously into mice demonstrate that LQG does not induce lesions or other adverse effects. We then used rheology to quantify the effects of localized CCH injections on the modulus and viscoelasticity of uterine fibroids, which exhibit gel-like behavior, through ex vivo and in vivo digestion studies. Ex vivo CCH injections reduce the tissue modulus by over two orders of magnitude and co-injection of LQG enhances this effect. Rheological results from an in vivo digestion study in mice show a significant reduction in tissue modulus and increase in tissue viscoelasticity 7 days after a single injection of LQG+CCH. Parallel histological staining validates that the observed rheological changes correspond to an increase in collagen lysis after treatment by LQG+CCH. These results show promise for development of injectable and localized enzymatic therapies for uterine fibroids and other dense tumors. STATEMENT OF SIGNIFICANCE: Uterine fibroids are stiff, benign tumors containing high collagen levels that cause bleeding and pain in women. Fertility-preserving and minimally-invasive treatments to soften fibroids are needed as an alternative to surgical removal via hysterectomy. We demonstrate through ex vivo and in vivo studies that co-injecting a thermoresponsive polymer delivery system (LQG) alongside a bacterial collagenase (CCH) enzyme significantly increases treatment effectiveness at softening fibroids through CCH localization. We use rheology to measure the modulus and viscoelasticity of fibroids and histology to show that fibroid softening corresponds to a decrease in collagen after treatment with LQG+CCH. These results highlight the utility of rheology at quantifying tissue properties and present a promising injectable therapy for fibroids and other dense tumors.}, journal={ACTA BIOMATERIALIA}, author={Corder, Ria D. and Gadi, Sashi V and Vachieri, Robert B. and Jayes, Friederike L. and Cullen, John M. and Khan, Saad A. and Taylor, Darlene K.}, year={2021}, month={Oct}, pages={443–452} }
 @misc{bhat_cohen_gordon_wood_cullen_harris_proctor_thompson_2020, title={An adverse outcome pathway for small intestinal tumors in mice involving chronic cytotoxicity and regenerative hyperplasia: a case study with hexavalent chromium, captan, and folpet}, volume={50}, ISSN={["1547-6898"]}, DOI={10.1080/10408444.2020.1823934}, abstractNote={Abstract Small intestinal (SI) tumors are relatively uncommon outcomes in rodent cancer bioassays, and limited information regarding chemical-induced SI tumorigenesis has been reported in the published literature. Herein, we propose a cytotoxicity-mediated adverse outcome pathway (AOP) for SI tumors by leveraging extensive target species- and site-specific molecular, cellular, and histological mode of action (MOA) research for three reference chemicals, the fungicides captan and folpet and the transition metal hexavalent chromium (Cr(VI)). The gut barrier functions through highly efficient homeostatic regulation of SI epithelial cell sloughing, regenerative proliferation, and repair, which involves the replacement of up to 1011 cells per day. This dynamic turnover in the SI provides a unique local environment for a cytotoxicity mediated AOP/MOA. Upon entering the duodenum, cytotoxicity to the villous epithelium is the molecular initiating event, as indicated by crypt elongation, villous atrophy/blunting, and other morphologic changes. Over time, the regenerative capacity of the gut epithelium to compensate declines as epithelial loss accelerates, especially at higher exposures. The first key event (KE), sustained regenerative crypt proliferation/hyperplasia, requires sufficient durations, likely exceeding 6 or 12 months, due to extensive repair capacity, to create more opportunities for the second KE, spontaneous mutation/transformation, ultimately leading to proximal SI tumors. Per OECD guidance, biological plausibility, essentiality, and empirical support were assessed using modified Bradford Hill considerations. The weight-of-evidence also included a lack of induced mutations in the duodenum after up to 90 days of Cr(VI) or captan exposure. The extensive evidence for this AOP, along with the knowledge that human exposures are orders of magnitude below those associated with KEs in this AOP, supports its use for regulatory applications, including hazard identification and risk assessment.}, number={8}, journal={CRITICAL REVIEWS IN TOXICOLOGY}, author={Bhat, Virunya S. and Cohen, Samuel M. and Gordon, Elliot B. and Wood, Charles E. and Cullen, John M. and Harris, Mark A. and Proctor, Deborah M. and Thompson, Chad M.}, year={2020}, month={Sep}, pages={685–706} }
 @article{chappell_thompson_wolf_cullen_klaunig_haws_2020, title={Assessment of the Mode of Action Underlying the Effects of GenX in Mouse Liver and Implications for Assessing Human Health Risks}, volume={48}, ISSN={["1533-1601"]}, DOI={10.1177/0192623320905803}, abstractNote={ GenX is an alternative to environmentally persistent long-chain perfluoroalkyl and polyfluoroalkyl substances. Mice exposed to GenX exhibit liver hypertrophy, elevated peroxisomal enzyme activity, and other apical endpoints consistent with peroxisome proliferators. To investigate the potential role of peroxisome proliferator-activated receptor alpha (PPARα) activation in mice, and other molecular signals potentially related to observed liver changes, RNA sequencing was conducted on paraffin-embedded liver sections from a 90-day subchronic toxicity study of GenX conducted in mice. Differentially expressed genes were identified for each treatment group, and gene set enrichment analysis was conducted using gene sets that represent biological processes and known canonical pathways. Peroxisome signaling and fatty acid metabolism were among the most significantly enriched gene sets in both sexes at 0.5 and 5 mg/kg GenX; no pathways were enriched at 0.1 mg/kg. Gene sets specific to the PPARα subtype were significantly enriched. These findings were phenotypically anchored to histopathological changes in the same tissue blocks: hypertrophy, mitoses, and apoptosis. In vitro PPARα transactivation assays indicated that GenX activates mouse PPARα. These results indicate that the liver changes observed in GenX-treated mice occur via a mode of action (MOA) involving PPARα, an important finding for human health risk assessment as this MOA has limited relevance to humans. }, number={3}, journal={TOXICOLOGIC PATHOLOGY}, author={Chappell, Grace A. and Thompson, Chad M. and Wolf, Jeffrey C. and Cullen, John M. and Klaunig, James E. and Haws, Laurie C.}, year={2020}, month={Apr}, pages={494–508} }
 @article{simpson_hoover_davis_hickerson_miller_kiupel_cullen_dwyer_wei_rosol_et al._2020, title={Inter-Institutional Partnerships to Develop Veterinarian-Investigators through the NIH Comparative Biomedical Scientist Training Program Benefit One Health Goals}, volume={47}, ISSN={["1943-7218"]}, DOI={10.3138/jvme.2019-0091}, abstractNote={ 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. }, number={5}, journal={JOURNAL OF VETERINARY MEDICAL EDUCATION}, author={Simpson, R. Mark and Hoover, Shelley B. and Davis, Barbara J. and Hickerson, John and Miller, Margaret A. and Kiupel, Matti and Cullen, John M. and Dwyer, Jennifer E. and Wei, Bih-Rong and Rosol, Thomas J. and et al.}, year={2020}, month={Oct}, pages={619–631} }
 @article{cullen_lemon_2019, title={Comparative Pathology of Hepatitis A Virus and Hepatitis E Virus Infection}, volume={9}, ISSN={["2157-1422"]}, DOI={10.1101/cshperspect.a033456}, abstractNote={Hepatitis A virus (HAV) and hepatitis E virus (HEV) cause acute, self-limiting hepatic infections that are usually spread by the fecal-oral route in humans. Naturally occurring and experimental infections are possible in a variety of nonhuman primates and, in the case of HEV, a number of other species. Many advances in understanding the pathogenesis of these viruses have come from studies in experimental animals. In general, animals infected with these viruses recapitulate the histologic lesions seen in infected humans, but typically with less severe clinical and histopathological manifestations. This review describes the histopathologic changes associated with HAV and HEV infection in humans and experimental animals.}, number={4}, journal={COLD SPRING HARBOR PERSPECTIVES IN MEDICINE}, author={Cullen, John M. and Lemon, Stanley M.}, year={2019}, month={Apr} }
 @article{hostnik_parker_cullen_2019, title={Computed Tomography of Lobular Dissecting Hepatitis in a Young Golden Retriever}, volume={55}, ISSN={["1547-3317"]}, DOI={10.5326/JAAHA-MS-6867}, abstractNote={ABSTRACT}, number={2}, journal={JOURNAL OF THE AMERICAN ANIMAL HOSPITAL ASSOCIATION}, author={Hostnik, Eric T. and Parker, Valerie J. and Cullen, John M.}, year={2019} }
 @article{thompson_fitch_ring_rish_cullen_haws_2019, title={Development of an oral reference dose for the perfluorinated compound GenX}, volume={39}, ISSN={["1099-1263"]}, DOI={10.1002/jat.3812}, abstractNote={Abstract}, number={9}, journal={JOURNAL OF APPLIED TOXICOLOGY}, author={Thompson, Chad M. and Fitch, Seneca E. and Ring, Caroline and Rish, William and Cullen, John M. and Haws, Laurie C.}, year={2019}, month={Sep}, pages={1267–1282} }
 @article{quist_boorman_cullen_maronpot_remick_swenberg_freshwater_hardisty_2019, title={Reevaluation of Hepatocellular Neoplasms in CD-1 Mice from a 2-year Oral Carcinogenicity Study with Permethrin}, volume={47}, ISSN={["1533-1601"]}, DOI={10.1177/0192623318809304}, abstractNote={ A 24-month oral carcinogenicity study of permethrin was conducted by feeding male and female CD-1 mice diets containing concentrations of 0, 20, 500, and 2,000 ppm of permethrin (males) or 0, 20, 2,500, and 5,000 ppm of permethrin (females). After approximately two years on study, surviving mice were sacrificed for the evaluation of chronic toxicity and/or carcinogenicity. An expert panel of pathologists was convened as a Pathology Working Group (PWG) to review coded liver histology sections from male and female mice and to classify all liver neoplasms according to current nomenclature and diagnostic criteria guidelines. The PWG results indicate that permethrin induced a significant dose-dependent increase in the incidence of hepatocellular neoplasms in treated female mice ( p < .01) as well as a nonstatistically significant increase in the incidence of hepatocellular tumors in treated male mice. Given the continuum of the diagnoses of adenoma and carcinoma, and the difficulty in distinguishing some of the lesions, it is appropriate to consider only the combined incidences of hepatocellular tumors (adenoma and/or carcinoma) for biological significance and risk assessment. }, number={1}, journal={TOXICOLOGIC PATHOLOGY}, author={Quist, Erin M. and Boorman, Gary A. and Cullen, John M. and Maronpot, Robert R. and Remick, Amera K. and Swenberg, James A. and Freshwater, Les and Hardisty, Jerry F.}, year={2019}, month={Jan}, pages={11–17} }
 @article{canuti_williams_sagan_munnink_gadi_verhoeven_kellam_cotten_lang_junge_et al._2019, title={Virus discovery reveals frequent infection by diverse novel members of the Flaviviridae in wild lemurs}, volume={164}, ISSN={["1432-8798"]}, DOI={10.1007/s00705-018-4099-9}, abstractNote={Lemurs are highly endangered mammals inhabiting the forests of Madagascar. In this study, we performed virus discovery on serum samples collected from 84 wild lemurs and identified viral sequence fragments from 4 novel viruses within the family Flaviviridae, including members of the genera Hepacivirus and Pegivirus. The sifaka hepacivirus (SifHV, two genotypes) and pegivirus (SifPgV, two genotypes) were discovered in the diademed sifaka (Propithecus diadema), while other pegiviral fragments were detected in samples from the indri (Indri indri, IndPgV) and the weasel sportive lemur (Lepilemur mustelinus, LepPgV). Although data are preliminary, each viral species appeared host species-specific and frequent infection was detected (18 of 84 individuals were positive for at least one virus). The complete coding sequence and partial 5' and 3' untranslated regions (UTRs) were obtained for SifHV and its genomic organization was consistent with that of other hepaciviruses, with one unique polyprotein and highly structured UTRs. Phylogenetic analyses showed the SifHV belonged to a clade that includes several viral species identified in rodents from Asia and North America, while SifPgV and IndPgV were more closely related to pegiviral species A and C, that include viruses found in humans as well as New- and Old-World monkeys. Our results support the current proposed model of virus-host co-divergence with frequent occurrence of cross-species transmission for these genera and highlight how the discovery of more members of the Flaviviridae can help clarify the ecology and evolutionary history of these viruses. Furthermore, this knowledge is important for conservation and captive management of lemurs.}, number={2}, journal={ARCHIVES OF VIROLOGY}, author={Canuti, Marta and Williams, Cathy V. and Sagan, Selena M. and Munnink, Bas B. Oude and Gadi, Sashi and Verhoeven, Joost T. P. and Kellam, Paul and Cotten, Matthew and Lang, Andrew S. and Junge, Randall E. and et al.}, year={2019}, month={Feb}, pages={509–522} }
 @article{phillips_paez-rosas_flowers_cullen_law_colitz_deresienski_lohmann_lewbart_2018, title={EVALUATION OF THE OPHTHALMIC DISEASE AND HISTOPATHOLOGIC EFFECTS DUE TO THE OCULAR TREMATODE PHILOPHTHALMUS ZALOPHI ON JUVENILE GALAPAGOS SEA LIONS (ZALOPHUS WOLLEBAEKI)}, volume={49}, ISSN={["1937-2825"]}, DOI={10.1638/2017-0096.1}, abstractNote={Abstract The Galapagos sea lion (Zalophus wollebaeki) is an otariid species endemic to the Galapagos archipelago and is currently listed as endangered. The ocular trematode Philophthalmus zalophi was recently reported to affect the survival of juvenile Galapagos sea lions on Santa Cruz Island, resulting in marked ophthalmic changes. This study evaluated the ophthalmic disease and histopathologic effects of P. zalophi on juvenile Galapagos sea lions in the largest rookery located on San Cristóbal Island. Twenty juvenile Galapagos sea lions (10 male and 10 female) were evaluated among five sites in the rookery El Malecón. Ophthalmic examination, including fluorescein staining and evaluation of the adnexa, cornea, and sclera, were performed on each eye. The presence, number, and location of ocular parasites were determined, and parasites were collected for identification. Conjunctival biopsy was performed on 11 animals: 2 that lacked parasites and gross lesions and 9 with both parasites and gross lesions. All parasites collected were confirmed as P. zalophi and identified in 80% (16/20) of the study animals and 70% (28/40) of the examined eyes. Philophthalmus zalophi was most frequently found attached to the nictitating membrane but also located on the palpebral conjunctiva or cornea. The most common clinical signs were varying degrees of conjunctival hyperemia (28/40 eyes), most frequently of the nictitating membrane and mucoid ocular discharge (12/40 eyes). The number of parasites was significantly associated with the degree of conjunctival hyperemia (P < 0.001). Histopathology of conjunctival biopsies revealed organized lymphoid follicles and lymphoplasmacytic infiltrates. The histopathologic changes and gross lesions were likely due to the parasite's attachment to the conjunctiva. This study provides additional details of P. zalophi infection in juvenile Galapagos sea lions. Further research is warranted to detail the life cycle of this parasite, transmission to sea lions, and potential treatment protocols.}, number={3}, journal={JOURNAL OF ZOO AND WILDLIFE MEDICINE}, author={Phillips, Brianne E. and Paez-Rosas, Diego and Flowers, James R. and Cullen, John M. and Law, Jerry M. and Colitz, Carmen and Deresienski, Diane and Lohmann, Kenneth J. and Lewbart, Gregory A.}, year={2018}, month={Sep}, pages={581–590} }
 @article{raghu_ekena_cullen_webb_trepanier_2018, title={Evaluation of potential serum biomarkers of hepatic fibrosis and necroinflammatory activity in dogs with liver disease}, volume={32}, ISSN={["1939-1676"]}, DOI={10.1111/jvim.15064}, abstractNote={BackgroundSerum interleukin 6 (IL‐6), chemokine ligand 2 (CCL2), C‐reactive protein (CRP), and the ratio of aspartate transaminase to alanine transaminase (AST:ALT) have been correlated with fibrosis and necroinflammatory activity in humans with various hepatopathies.}, number={3}, journal={JOURNAL OF VETERINARY INTERNAL MEDICINE}, author={Raghu, Chantel and Ekena, Joanne and Cullen, John M. and Webb, Craig B. and Trepanier, Lauren A.}, year={2018}, pages={1009–1018} }
 @article{cassady_cullen_williams_2018, title={MORTALITY IN COQUEREL'S SIFAKAS (PROPITHECUS COQUERELI) UNDER HUMAN CARE: A RETROSPECTIVE SURVEY FROM THE DUKE LEMUR CENTER 1990-2015}, volume={49}, ISSN={["1937-2825"]}, DOI={10.1638/2017-0242.1}, abstractNote={Abstract:  Coquerel's sifakas (Propithecus coquereli) are diurnal, folivorous lemurs native to Madagascar and one of only two members of the genus Propithecus currently housed in human care settings outside of Madagascar. This species has a lifespan of approximately 30 yr but minimal information exists regarding morbidity and mortality in human care settings. In this retrospective study, medical records, postmortem exam, and autopsy reports from 56 animals housed at the Duke Lemur Center from 1990 to 2015 were evaluated. Mortality assessments included age, sex, time of year, histopathological findings, major organ system impacted, and etiological factors. Mortality was most prevalent among adults greater than 2 yr of age (42.9%) and neonates less than 7 days of age (30.4%). The top four morphological diagnoses accounted for 51.7% of all deaths and included stillbirths (19.6%), enteritis-colitis (12.5%), failure to thrive (10.7%), and systemic protozoal infections (8.9%). The two most commonly affected organ systems in animals over 7 days of age were multisystem disease (30.8%) and the gastrointestinal system (28.2%). Infections were the most common etiology with bacterial being the most prevalent followed by protozoal infections. The results provide insight into common causes of mortality of this species and can be used to guide management of this endangered primate and improve longevity in human care settings.}, number={2}, journal={JOURNAL OF ZOO AND WILDLIFE MEDICINE}, author={Cassady, Katherine and Cullen, John M. and Williams, Cathy V}, year={2018}, month={Jun}, pages={315–323} }
 @article{divers_tennant_kumar_mcdonough_cullen_bhuva_jain_chauhan_scheel_lipkin_et al._2018, title={New parvovirus associated with serum hepatitis in horses after inoculation of common biological product}, volume={24}, number={2}, journal={Emerging Infectious Diseases}, author={Divers, T. J. and Tennant, B. C. and Kumar, A. and McDonough, S. and Cullen, J. and Bhuva, N. and Jain, K. and Chauhan, L. S. and Scheel, T. K. H. and Lipkin, W. I. and et al.}, year={2018}, pages={303–310} }
 @article{gookin_mathews_cullen_seiler_2018, title={Qualitative metabolomics profiling of serum and bile from dogs with gallbladder mucocele formation}, volume={13}, ISSN={["1932-6203"]}, DOI={10.1371/journal.pone.0191076}, abstractNote={Mucocele formation is characterized by secretion of abnormally thick mucus by the gallbladder epithelium of dogs that may cause obstruction of the bile duct or rupture of the gallbladder. The disease is increasingly recognized and is associated with a high morbidity and mortality. The cause of gallbladder mucocele formation in dogs is unknown. There is a strong breed predisposition and affected dogs have a high incidence of concurrent endocrinopathy or hyperlipidemia. These observations suggest a significant influence of both genetic and metabolic factors on disease pathogenesis. In this study, we investigated a theory that mucocele formation is associated with a syndrome of metabolic disruption. We surmised that a global, untargeted metabolomics approach could provide unique insight into the systemic pathogenesis of gallbladder mucocele formation and identify specific compounds as candidate biomarkers or treatment targets. Moreover, concurrent examination of the serum and hepatic duct bile metabolome would enable the construction of mechanism-based theories or identification of specific compounds responsible for altered function of the gallbladder epithelium. Abnormalities observed in dogs with gallbladder mucocele formation, including a 33-fold decrease in serum adenosine 5’-monophosphate (AMP), lower quantities of precursors required for synthesis of energy transporting nucleotides, and increases in citric acid cycle intermediates, suggest excess metabolic energy and a carbon surplus. Altered quantities of compounds involved in protein translation and RNA turnover, together with accumulation of gamma-glutamylated and N-acetylated amino acids in serum suggest abnormal regulation of protein and amino acid metabolism. Increases in lathosterol and 7α-hydroxycholesterol suggest a primary increase in cholesterol synthesis and diversion to bile acid formation. A number of specific biomarker compounds were identified for their ability to distinguish between control dogs and those that formed a gallbladder mucocele. Particularly noteworthy was a significant decrease in quantity of biologically active compounds that stimulate biliary ductal fluid secretion including adenosine, cAMP, taurolithocholic acid, and taurocholic acid. These findings support the presence of significant metabolic disruption in dogs with mucocele formation. A targeted, quantitative analysis of the identified serum biomarkers is warranted to determine their utility for diagnosis of this disease. Finally, repletion of compounds whose biological activity normally promotes biliary ductal secretion should be examined for any therapeutic impact for resolution or prevention of mucocele formation.}, number={1}, journal={PLOS ONE}, author={Gookin, Jody L. and Mathews, Kyle G. and Cullen, John and Seiler, Gabriela}, year={2018}, month={Jan} }
 @article{trivedi_murthy_sharma_hartlage_kumar_gadi_simmonds_chauhan_scheel_billerbeck_et al._2018, title={Viral persistence, liver disease, and host response in a hepatitis C-like virus rat model}, volume={68}, ISSN={0270-9139}, url={http://dx.doi.org/10.1002/HEP.29494}, DOI={10.1002/HEP.29494}, abstractNote={The lack of a relevant, tractable, and immunocompetent animal model for hepatitis C virus (HCV) has severely impeded investigations of viral persistence, immunity, and pathogenesis. In the absence of immunocompetent models with robust HCV infection, homolog hepaciviruses in their natural host could potentially provide useful surrogate models. We isolated a rodent hepacivirus from wild rats (Rattus norvegicus), RHV‐rn1; acquired the complete viral genome sequence; and developed an infectious reverse genetics system. RHV‐rn1 resembles HCV in genomic features including the pattern of polyprotein cleavage sites and secondary structures in the viral 5′ and 3′ untranslated regions. We used site‐directed and random mutagenesis to determine that only the first of the two microRNA‐122 seed sites in the viral 5′ untranslated region is required for viral replication and persistence in rats. Next, we used the clone‐derived virus progeny to infect several inbred and outbred rat strains. Our results determined that RHV‐rn1 possesses several HCV‐defining hallmarks: hepatotropism, propensity to persist, and the ability to induce gradual liver damage. Histological examination of liver samples revealed the presence of lymphoid aggregates, parenchymal inflammation, and macrovesicular and microvesicular steatosis in chronically infected rats. Gene expression analysis demonstrated that the intrahepatic response during RHV‐rn1 infection in rats mirrors that of HCV infection, including persistent activation of interferon signaling pathways. Finally, we determined that the backbone drug of HCV direct‐acting antiviral therapy, sofosbuvir, effectively suppresses chronic RHV‐rn1 infection in rats. Conclusion: We developed RHV‐rn1‐infected rats as a fully immunocompetent and informative surrogate model to delineate the mechanisms of HCV‐related viral persistence, immunity, and pathogenesis. (Hepatology 2018).}, number={2}, journal={Hepatology}, publisher={Wiley}, author={Trivedi, Sheetal and Murthy, Satyapramod and Sharma, Himanshu and Hartlage, Alex S. and Kumar, Arvind and Gadi, Sashi V. and Simmonds, Peter and Chauhan, Lokendra V. and Scheel, Troels K.H. and Billerbeck, Eva and et al.}, year={2018}, month={May}, pages={435–448} }
 @article{lidbury_hoffmann_ivanek_cullen_porter_oliveira_van winkle_grinwis_sucholdolski_steiner_2017, title={Interobserver Agreement Using Histological Scoring of the Canine}, volume={31}, ISSN={["1939-1676"]}, DOI={10.1111/jvim.14684}, abstractNote={BackgroundGrading schemes for the assessment of hepatic fibrosis and necroinflammatory activity in humans previously have been applied to dogs with chronic hepatitis. Interobserver agreement is a desirable characteristic for any histological scoring scheme.}, number={3}, journal={JOURNAL OF VETERINARY INTERNAL MEDICINE}, author={Lidbury, J. A. and Hoffmann, A. Rodrigues and Ivanek, R. and Cullen, J. M. and Porter, B. F. and Oliveira, F. and Van Winkle, T. J. and Grinwis, G. C. and Sucholdolski, J. S. and Steiner, J. M.}, year={2017}, pages={778–783} }
 @article{adamovicz_kennedy-stoskopf_talley_cullen_cohen_bizikova_grunkemeyer_2017, title={MYCOBACTERIUM INTRACELLULARE INFECTION CAUSING A RETROPERITONEAL MASS IN A BINTURONG (ARCTICTIS BINTURONG)}, volume={48}, ISSN={["1937-2825"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85026496685&partnerID=MN8TOARS}, DOI={10.1638/2016-0117r.1}, abstractNote={Abstract A 19-yr-old castrated male binturong (Arctictis binturong) with a history of recurrent pyogranulomatous panniculitis, lymphangitis, and dermatitis was presented for evaluation of hyporexia and tenesmus. A large caudal abdominal mass was palpated on physical examination. On ultrasound, the mass encircled and obstructed the left ureter, resulting in hydroureter and hydronephrosis. The animal was euthanized, and necropsy revealed a large retroperitoneal pyogranuloma with acid-fast organisms identified in both the mass and the perineal skin. The acid-fast organisms within the retroperitoneal mass were identified as Mycobacterium intracellulare by PCR. This case represents an unusual presentation of M. intracellulare in a novel species.}, number={2}, journal={JOURNAL OF ZOO AND WILDLIFE MEDICINE}, author={Adamovicz, Laura and Kennedy-Stoskopf, Suzanne and Talley, Ashley and Cullen, John M. and Cohen, Eli B. and Bizikova, Petra and Grunkemeyer, Vanessa}, year={2017}, month={Jun}, pages={544–548} }
 @article{billerbeck_wolfisberg_fahnoe_xiao_quirk_luna_cullen_hartlage_chiriboga_ghoshal_et al._2017, title={Mouse models of acute and chronic hepacivirus infection}, volume={357}, ISSN={["1095-9203"]}, DOI={10.1126/science.aal1962}, abstractNote={New York City rats provide a gift to virologists}, number={6347}, journal={SCIENCE}, author={Billerbeck, Eva and Wolfisberg, Raphael and Fahnoe, Ulrik and Xiao, Jing W. and Quirk, Corrine and Luna, Joseph M. and Cullen, John M. and Hartlage, Alex S. and Chiriboga, Luis and Ghoshal, Kalpana and et al.}, year={2017}, month={Jul}, pages={204-+} }
 @article{cullen_meng_2017, title={Other viruses: Hepeviridae, hepadnaviridae, deltaviruses, nodaviridae, and unclassified viruses}, journal={Fenner's Veterinary Virology, 5th Edition}, author={Cullen, J. M. and Meng, X. J.}, year={2017}, pages={547–555} }
 @article{das_hirai-yuki_gonzalez-lopez_rhein_moller-tank_brouillette_hensley_misumi_lovell_cullen_et al._2017, title={TIM1 (HAVCR1) Is Not Essential for Cellular Entry of Either Quasi-enveloped or Naked Hepatitis A Virions}, volume={8}, ISSN={["2150-7511"]}, DOI={10.1128/mbio.00969-17}, abstractNote={ABSTRACT}, number={5}, journal={MBIO}, author={Das, Anshuman and Hirai-Yuki, Asuka and Gonzalez-Lopez, Olga and Rhein, Bethany and Moller-Tank, Sven and Brouillette, Rachel and Hensley, Lucinda and Misumi, Ichiro and Lovell, William and Cullen, John M. and et al.}, year={2017} }
 @article{cullen_faiola_melich_peterson_jordan_kimbrough_miller_2016, title={Acute Alpha-Naphthylisothiocyanate-induced Liver Toxicity in Germfree and Conventional Male Rats}, volume={44}, ISSN={["1533-1601"]}, DOI={10.1177/0192623316662360}, abstractNote={ Differences in the responses of conventional and germfree male Sprague-Dawley rats to acute injury induced by alpha-naphthylisothiocyanate (ANIT), a well-characterized biliary epithelial toxicant, were evaluated. Conventional and germfree rats were dosed once orally with 50 mg/kg of ANIT or corn oil alone and serially sacrificed daily for the next 3 days. Germfree rats treated with ANIT tended to have greater increases in virtually all liver and biliary-related analytes compared with conventional rats treated with ANIT; however, significant differences were found only in a few of these analytes including increased bile acids on day 3, total bilirubin on day 4, glutamate dehydrogenase (GLDH) on day 3, and reduced paraoxonase 1 (PON1) on days 2 and 3. Histologic differences between the conventional and germfree rats were modest, but most pronounced on day 2 (24-hr post dosing). Based on subjective scoring, biliary necrosis, neutrophilic cholangitis, and portal tract edema were more severe in germfree rats at 24 hr post dosing compared with conventional rats. Biliary epithelial replication did not differ between treated groups, however. Overall, germfree rats had a modestly greater level of biliary tract injury based on subjective histologic scoring and clinical chemistry measurements following an acute exposure to the well-characterized biliary toxin, ANIT; however, the difference between the ANIT-treated germfree and conventional groups was modest and most evident only within the first day following exposure. These findings suggest that the microbiome did not significantly affect ANIT-induced acute biliary tract injury in the conditions of this study. }, number={7}, journal={TOXICOLOGIC PATHOLOGY}, author={Cullen, John M. and Faiola, Brenda and Melich, David H. and Peterson, Richard A. and Jordan, Holly L. and Kimbrough, Carie L. and Miller, Richard T.}, year={2016}, month={Oct}, pages={987–997} }
 @article{swisher_phillips_tobias_cullen_gieger_grunkemeyer_2016, title={External beam radiation therapy of squamous cell carcinoma in the beak of an African grey parrot (Psittacus timneh)}, volume={30}, DOI={10.1647/2015-106}, abstractNote={Abstract Squamous cell carcinoma has been reported in a variety of bird species, most commonly psittacine and gallinaceous birds. The long-term prognosis in nongallinaceous birds is generally poor if complete surgical excision is not possible. Squamous cell carcinoma of the rhinotheca was diagnosed in a 34-year-old timneh African grey parrot (Psittacus timneh) with a 2-year history of beak abnormalities. No evidence of metastasis or local invasion were found on results of radiographs or computed tomography scan. The bird was treated with surgical debulking and palliative megavoltage radiation therapy. After 4 radiation treatments, the affected tissue was necrotic and was debrided to reveal healthy granulation tissue. The bird died approximately 7 months after diagnosis and 4 months after cessation of radiation treatment. At the time of death, a small scab lesion remained at the left oral commissure, but no visible tumor regrowth was evident. A postmortem examination was not performed, however, and tumor recurrence could not be ruled out in this bird.}, number={3}, journal={Journal of Avian Medicine and Surgery}, author={Swisher, S. D. and Phillips, K. L. and Tobias, J. R. and Cullen, J. M. and Gieger, Tracy and Grunkemeyer, V. L.}, year={2016}, pages={250–256} }
 @article{sherman_cullen_westermeyer_grindem_gilger_2016, title={Histiocytic chorioretinitis in a dog}, volume={21}, ISSN={1463-5216}, url={http://dx.doi.org/10.1111/vop.12421}, DOI={10.1111/vop.12421}, abstractNote={Abstract}, number={1}, journal={Veterinary Ophthalmology}, publisher={Wiley}, author={Sherman, Amanda B. and Cullen, John M. and Westermeyer, Hans D. and Grindem, Carol and Gilger, Brian C.}, year={2016}, month={Aug}, pages={88–95} }
 @article{swartley_foley_livingston_cullen_elmore_2016, title={Histology Atlas of the Developing Mouse Hepatobiliary Hemolymphatic Vascular System with Emphasis on Embryonic Days 11.5-18.5 and Early Postnatal Development}, volume={44}, ISSN={["1533-1601"]}, DOI={10.1177/0192623316630836}, abstractNote={ A critical event in embryo development is the proper formation of the vascular system, of which the hepatobiliary system plays a pivotal role. This has led researchers to use transgenic mice to identify the critical steps involved in developmental disorders associated with the hepatobiliary vascular system. Vascular development is dependent upon normal vasculogenesis, angiogenesis, and the transformation of vessels into their adult counterparts. Any alteration in vascular development has the potential to cause deformities or embryonic death. Numerous publications describe specific stages of vascular development relating to various organs, but a single resource detailing the stage-by-stage development of the vasculature pertaining to the hepatobiliary system has not been available. This comprehensive histology atlas provides hematoxylin & eosin and immunohistochemical-stained sections of the developing mouse blood and lymphatic vasculature with emphasis on the hepatobiliary system between embryonic days (E) 11.5–18.5 and the early postnatal period. Additionally, this atlas includes a 3-dimensional video representation of the E18.5 mouse venous vasculature. One of the most noteworthy findings of this atlas is the identification of the portal sinus within the mouse, which has been erroneously misinterpreted as the ductus venosus in previous publications. Although the primary purpose of this atlas is to identify normal hepatobiliary vascular development, potential embryonic abnormalities are also described. }, number={5}, journal={TOXICOLOGIC PATHOLOGY}, author={Swartley, Olivia M. and Foley, Julie F. and Livingston, David P., III and Cullen, John M. and Elmore, Susan A.}, year={2016}, month={Jul}, pages={705–725} }
 @article{hirai-yuki_hensley_mcgivern_gonzalez-lopez_das_feng_sun_wilson_hu_feng_et al._2016, title={MAVS-dependent host species range and pathogenicity of human hepatitis A virus}, volume={353}, ISSN={["1095-9203"]}, DOI={10.1126/science.aaf8325}, abstractNote={Hepatotropic viruses are important causes of human disease, but the intrahepatic immune response to hepatitis viruses is poorly understood because of a lack of tractable small- animal models. We describe a murine model of hepatitis A virus (HAV) infection that recapitulates critical features of type A hepatitis in humans. We demonstrate that the capacity of HAV to evade MAVS-mediated type I interferon responses defines its host species range. HAV-induced liver injury was associated with interferon-independent intrinsic hepatocellular apoptosis and hepatic inflammation that unexpectedly resulted from MAVS and IRF3/7 signaling. This murine model thus reveals a previously undefined link between innate immune responses to virus infection and acute liver injury, providing a new paradigm for viral pathogenesis in the liver.}, number={6307}, journal={SCIENCE}, author={Hirai-Yuki, Asuka and Hensley, Lucinda and McGivern, David R. and Gonzalez-Lopez, Olga and Das, Anshuman and Feng, Hui and Sun, Lu and Wilson, Justin E. and Hu, Fengyu and Feng, Zongdi and et al.}, year={2016}, month={Sep}, pages={1541–1545} }
 @article{cullen_ward_thompson_2016, title={Reevaluation and Classification of Duodenal Lesions in B6C3F1 Mice and F344 Rats from 4 Studies of Hexavalent Chromium in Drinking Water}, volume={44}, ISSN={["1533-1601"]}, DOI={10.1177/0192623315611501}, abstractNote={ Thirteen-week and 2-year drinking water studies conducted by the National Toxicology Program (NTP) reported that hexavalent chromium (Cr(VI)) induced diffuse epithelial hyperplasia in the duodenum of B6C3F1 mice but not F344 rats. In the 2-year study, Cr(VI) exposure was additionally associated with duodenal adenomas and carcinomas in mice only. Subsequent 13-week Cr(VI) studies conducted by another group demonstrated non-neoplastic duodenal lesions in B6C3F1 mice similar to those of the NTP study as well as mild duodenal hyperplasia in F344 rats. Because intestinal lesions in mice are the basis for proposed safety standards for Cr(VI), and the histopathology data are relevant to the mode of action, consistency (an important Hill criterion for causality) was assessed across the aforementioned studies. Two veterinary pathologists applied uniform diagnostic criteria to the duodenal lesions in rats and mice from the 4 repeated-dose studies. Comparable non-neoplastic intestinal lesions were evident in mice and rats from all 4 studies; however, the incidence and severity of intestinal lesions were greater in mice than rats. These findings demonstrate consistency across studies and species and highlight the importance of standardized nomenclature for intestinal pathology. The differences in the severity of non-neoplastic lesions also likely contribute to the differential tumor response. }, number={2}, journal={TOXICOLOGIC PATHOLOGY}, author={Cullen, John M. and Ward, Jerrold M. and Thompson, Chad M.}, year={2016}, month={Feb}, pages={279–289} }
 @article{hartlage_cullen_kapoor_2016, title={The Strange, Expanding World of Animal Hepaciviruses}, volume={3}, ISSN={["2327-0578"]}, DOI={10.1146/annurev-virology-100114-055104}, abstractNote={ Hepaciviruses and pegiviruses constitute two closely related sister genera of the family Flaviviridae. In the past five years, the known phylogenetic diversity of the hepacivirus genera has absolutely exploded. What was once an isolated infection in humans (and possibly other primates) has now expanded to include horses, rodents, bats, colobus monkeys, cows, and, most recently, catsharks, shedding new light on the genetic diversity and host range of hepaciviruses. Interestingly, despite the identification of these many animal and primate hepaciviruses, the equine hepaciviruses remain the closest genetic relatives of the human hepaciviruses, providing an intriguing clue to the zoonotic source of hepatitis C virus. This review summarizes the significance of these studies and discusses current thinking about the origin and evolution of the animal hepaciviruses as well as their potential usage as surrogate models for the study of hepatitis C virus. }, journal={ANNUAL REVIEW OF VIROLOGY, VOL 3}, author={Hartlage, Alex S. and Cullen, John M. and Kapoor, Amit}, year={2016}, pages={53–75} }
 @article{gookin_correa_peters_malueg_mathews_cullen_seiler_2015, title={Association of Gallbladder Mucocele Histologic Diagnosis with Selected Drug Use in Dogs: A Matched Case-Control Study}, volume={29}, ISSN={["1939-1676"]}, DOI={10.1111/jvim.13649}, abstractNote={BackgroundThe cause of gallbladder mucocele (GBM) formation in dogs currently is unknown. Many available drugs represent a newer generation of xenobiotics that may predispose dogs to GBM formation.}, number={6}, journal={JOURNAL OF VETERINARY INTERNAL MEDICINE}, author={Gookin, J. L. and Correa, M. T. and Peters, A. and Malueg, A. and Mathews, K. G. and Cullen, J. and Seiler, G.}, year={2015}, pages={1464–1472} }
 @article{shapiro_raghunath_williams_motsinger-reif_cullen_liu_albertson_ruvolo_bergstrom lucas_jin_et al._2015, title={Canine urothelial carcinoma: genomically aberrant and comparatively relevant}, volume={23}, ISSN={0967-3849 1573-6849}, url={http://dx.doi.org/10.1007/S10577-015-9471-Y}, DOI={10.1007/S10577-015-9471-Y}, abstractNote={Urothelial carcinoma (UC), also referred to as transitional cell carcinoma (TCC), is the most common bladder malignancy in both human and canine populations. In human UC, numerous studies have demonstrated the prevalence of chromosomal imbalances. Although the histopathology of the disease is similar in both species, studies evaluating the genomic profile of canine UC are lacking, limiting the discovery of key comparative molecular markers associated with driving UC pathogenesis. In the present study, we evaluated 31 primary canine UC biopsies by oligonucleotide array comparative genomic hybridization (oaCGH). Results highlighted the presence of three highly recurrent numerical aberrations: gain of dog chromosome (CFA) 13 and 36 and loss of CFA 19. Regional gains of CFA 13 and 36 were present in 97 % and 84 % of cases, respectively, and losses on CFA 19 were present in 77 % of cases. Fluorescence in situ hybridization (FISH), using targeted bacterial artificial chromosome (BAC) clones and custom Agilent SureFISH probes, was performed to detect and quantify these regions in paraffin-embedded biopsy sections and urine-derived urothelial cells. The data indicate that these three aberrations are potentially diagnostic of UC. Comparison of our canine oaCGH data with that of 285 human cases identified a series of shared copy number aberrations. Using an informatics approach to interrogate the frequency of copy number aberrations across both species, we identified those that had the highest joint probability of association with UC. The most significant joint region contained the gene PABPC1, which should be considered further for its role in UC progression. In addition, cross-species filtering of genome-wide copy number data highlighted several genes as high-profile candidates for further analysis, including CDKN2A, S100A8/9, and LRP1B. We propose that these common aberrations are indicative of an evolutionarily conserved mechanism of pathogenesis and harbor genes key to urothelial neoplasia, warranting investigation for diagnostic, prognostic, and therapeutic applications.}, number={2}, journal={Chromosome Research}, publisher={Springer Science and Business Media LLC}, author={Shapiro, S. G. and Raghunath, S. and Williams, C. and Motsinger-Reif, A. A. and Cullen, J. M. and Liu, T. and Albertson, D. and Ruvolo, M. and Bergstrom Lucas, A. and Jin, J. and et al.}, year={2015}, month={Mar}, pages={311–331} }
 @article{pinto_mcmullen_linder_cullen_gilger_2015, title={Clinical, histopathological and immunohistochemical characterization of a novel equine ocular disorder: heterochromic iridocyclitis with secondary keratitis in adult horses}, volume={18}, ISSN={["1463-5224"]}, DOI={10.1111/vop.12234}, abstractNote={Abstract}, number={6}, journal={VETERINARY OPHTHALMOLOGY}, author={Pinto, Nelson I. and McMullen, Richard J., Jr. and Linder, Keith E. and Cullen, John M. and Gilger, Brian C.}, year={2015}, month={Nov}, pages={443–456} }
 @article{laduke_ehling_cullen_baeumer_2015, title={Effects of azathioprine, 6-mercaptopurine, and 6-thioguanine on canine primary hepatocytes}, volume={76}, ISSN={["1943-5681"]}, DOI={10.2460/ajvr.76.7.649}, abstractNote={Abstract}, number={7}, journal={AMERICAN JOURNAL OF VETERINARY RESEARCH}, author={LaDuke, Kathleen E. and Ehling, Sarah and Cullen, John M. and Baeumer, Wolfgang}, year={2015}, month={Jul}, pages={649–655} }
 @article{kesimer_cullen_cao_radicioni_mathews_seiler_gookin_2015, title={Excess Secretion of Gel-Forming Mucins and Associated Innate Defense Proteins with Defective Mucin Un-Packaging Underpin Gallbladder Mucocele Formation in Dogs}, volume={10}, ISSN={["1932-6203"]}, DOI={10.1371/journal.pone.0138988}, abstractNote={Mucosal protection of the gallbladder is vital yet we know very little about the mechanisms involved. In domestic dogs, an emergent syndrome referred to as gallbladder mucocele formation is characterized by excessive secretion of abnormal mucus that results in obstruction and rupture of the gallbladder. The cause of gallbladder mucocele formation is unknown. In these first mechanistic studies of this disease, we investigated normal and mucocele-forming dog gallbladders to determine the source, identity, biophysical properties, and protein associates of the culprit mucins with aim to identify causes for abnormal mucus behavior. We established that mucocele formation involves an adoptive excess secretion of gel forming mucins with abnormal properties by the gallbladder epithelium. The mucus is characterized by a disproportionally significant increase in Muc5ac relative to Muc5b, defective mucin un-packaging, and mucin-interacting innate defense proteins that are capable of dramatically altering the physical and functional properties of mucus. These findings provide an explanation for abnormal mucus behavior and based on similarity to mucus observed in the airways of people with cystic fibrosis, suggest that abnormal mechanisms for maintenance of gallbladder epithelial hydration may be an instigating factor for mucocele formation in dogs.}, number={9}, journal={PLOS ONE}, author={Kesimer, Mehmet and Cullen, John and Cao, Rui and Radicioni, Giorgia and Mathews, Kyle G. and Seiler, Gabriela and Gookin, Jody L.}, year={2015}, month={Sep} }
 @article{hailey_nold_brown_cullen_holder_jordan_ennulat_miller_2014, title={Biliary Proliferative Lesions in the Sprague-Dawley Rat: Adverse/Non-adverse}, volume={42}, ISSN={["1533-1601"]}, DOI={10.1177/0192623313499976}, abstractNote={ Whether biliary proliferative lesions in nonclinical species are predictive of potential hepatotoxicity in humans depends, at least in part, on the nature and severity of such changes in the nonclinical species. We reviewed published literature (clinical and nonclinical) and experimental data from rat toxicology studies conducted by GlaxoSmithKline and the National Institute of Environmental Health Sciences’ National Toxicology Program in an effort to better characterize the relative risk of hepatobiliary effects in humans. Available evidence supports the interpretation that minimal “typical” appearing bile duct hyperplasia limited to the portal triads may be considered non-adverse in the rat and is of little to no concern to humans. The toxicological relevance of mild to moderate “typical” hyperplasia is less certain, and may be considered adverse in the rat and potentially pose a risk for humans, particularly if accompanied by evidence of hepatobiliary injury or functional compromise. In addition, any proliferative lesion that includes atypical or dysplastic epithelial changes, oval cell proliferation, and/or significant extension beyond the portal tracts is considered more ominous and may be considered adverse in the rat. }, number={5}, journal={TOXICOLOGIC PATHOLOGY}, author={Hailey, James R. and Nold, James B. and Brown, Roger H. and Cullen, John M. and Holder, Julie C. and Jordan, Holly L. and Ennulat, Daniela and Miller, Richard T.}, year={2014}, month={Jul}, pages={844–854} }
 @misc{kavanagh_wylie_tucker_hamp_gharaibeh_fodor_cullen_2014, title={Effects of excess dietary fructose on liver pathology study have significant methodologic limitations: Reply}, volume={99}, number={1}, journal={American Journal of Clinical Nutrition}, author={Kavanagh, K. and Wylie, A. T. and Tucker, K. L. and Hamp, T. J. and Gharaibeh, R. Z. and Fodor, A. A. and Cullen, J. M.}, year={2014}, pages={210–210} }
 @article{twedt_cullen_mccord_janeczko_dudak_simpson_2014, title={Evaluation of fluorescence in situ hybridization for the detection of bacteria in feline inflammatory liver disease}, volume={16}, ISSN={["1532-2750"]}, DOI={10.1177/1098612x13498249}, abstractNote={ The etiopathogenesis of feline inflammatory liver disease (ILD) is unclear. Therefore, we sought to determine the presence and distribution of bacteria within the livers of cats with ILD using eubacterial fluorescence in situ hybridization (FISH). Histopathology from 39 cats with ILD and 19 with histologically normal livers (C) were classified using World Small Animal Veterinary Association guidelines. Hepatic sections were examined by 16 and 23S ribosomal RNA FISH. Antibodies against cytokeratins and factor VIIIa were used to distinguish bile ducts and vascular structures. Histopathologic findings included non-specific reactive hepatitis (12), neutrophilic cholangitis (NC; 12), lymphocytic cholangitis (seven), cholestasis/obstruction (three), probable lymphoma (three) and acute hepatitis (two). Bacteria were observed in 21/39 ILD and 3/19 C ( P = 0.0054). In 8/39 ILD and 2/19 C bacteria were restricted to the outer liver capsule ( P = 0.29) and may represent contaminants. The prevalence of intrahepatic bacteria was higher ( P = 0.008) in ILD (13/31) than C (1/17). Bacteria in ILD were more frequently ( P <0.0001) localized to portal vessels, venous sinusoids and parenchyma (12/13) than bile duct (1/13). Bacterial colonization was highest in Escherichia coli-positive NC cats. Concurrent non-hepatic disease, predominantly pancreatic and intestinal (8/10 cats biopsied), was present in all 13 cats with intrahepatic bacteria. Bacterial culture was positive (predominantly E coli and Enterococcus species) in 11/23 (48%) samples, and concurred with FISH in 15/23 cases. The presence of intrahepatic bacteria in 13/31 (41%) cats with ILD suggests a role in etiopathogenesis. The distribution of bacteria within the liver supports the possibility of colonization via either enteric translocation or hematogenous seeding. }, number={2}, journal={JOURNAL OF FELINE MEDICINE AND SURGERY}, author={Twedt, David C. and Cullen, John and McCord, Kelly and Janeczko, Stephanie and Dudak, Julie and Simpson, Kenny}, year={2014}, month={Feb}, pages={109–117} }
 @article{breitschwerdt_goldkamp_castleman_cullen_mascarelli_thalhem_schaer_2014, title={Hyperinsulinemic Hypoglycemia Syndrome in 2 Dogs with Bartonellosis}, volume={28}, ISSN={0891-6640}, url={http://dx.doi.org/10.1111/jvim.12381}, DOI={10.1111/jvim.12381}, abstractNote={A 6-month-old male castrated, 21-kg Weimaraner developed seizures after surgical castration and umbilical hernia repair. Two weeks earlier, presurgical laboratory abnormalities included lymphocytosis (7,800/lL), eosinophilia (1,700/lL), monocytosis (1,200/lL), basophilia (170/lL), thrombocytosis (459,000/lL), and an elevated ALP activity (135 IU/ L). Blood glucose was 111 mg/dL. Surgery and recovery were uncomplicated, until 2 hours postoperatively when generalized tonic clonic seizures developed. Seizures continued despite 2 doses of diazepam (1.5 mL IV), so propofol (10 mg) was administered IV. Hypoglycemia was not suspected and blood glucose was not measured. The dog was transported to an emergency clinic, where laboratory abnormalities included neutrophilia (16,210/lL) and hyperphosphatemia (7.7 mg/ dL), with a normal blood glucose concentration (106 mg/dL). When transferred to a specialty hospital the following morning, the dog was dysphoric, nonambulatory, and had absent menace reflexes bilaterally. No other cranial nerve deficits or anisocoria were noted. Serum chemistry and bile acid values before (1.3 lmol/L) and after feeding (1.8 lmol/L) were within reference intervals. After intravenous administration of mannitol and phenobarbital, no additional seizures were observed, but the dog remained stuporous, with absent menace reflexes until discharged 2 days later. Phenobarbital was continued (2 mg/kg PO q12). The following morning, the dog was found salivating, minimally responsive, and recumbent. Laboratory abnormalities included hypoglycemia (glucose 25 mg/ dL), neutrophilia (12,030/lL), and monocytosis (3,290/ lL). A blood ammonia concentration (30 lmol/L) was within reference intervals. Enrofloxacin (5 mg/kg IV) and a 5% dextrose infusion were administered. The dog was fed every 2 hours and periodically determined glucose values ranged from 40 to 75 mg/dL. After transfer to a specialty hospital, hypoglycemia (59, 48, 22, 41, 23, and 40 mg/dL at 10:00 PM, 1:00, 3:00, 4:00, 5:00, and 6:00 AM, respectively) persisted, despite frequent small feedings and continuous administration of 10% dextrose solution with periodic boluses. Dexamethasone sodium phosphate (0.15 mg/kg IV) was administered, after which the dog was referred to NCSU-CVM-VTH for further evaluation. Historically purchased from a breeder in Virginia, the dog had been healthy before surgery 6 days earlier. Littermates were reportedly healthy, vaccinations current, heartworm, flea, and tick preventive medications were used routinely. The owner denied exposure of the dog to toxins such as xylitol or oral hypoglycemic drugs. At NCSU-CVM-VTH, the dog was laterally recumbent, pupils fixed, menace reflexes absent bilaterally, and blood glucose was 20 mg/dL. Hematologic abnormalities included mild microcytic, normochromic, nonregenerative anemia (PCV 32%, reticulocytes 0.44%), and monocytosis (2,129/lL). Normoglycemia (129 mg/dL) was documented after an intravenous bolus of dextrose. Serum biochemical abnormalities included hypoalbuminemia (2.4 g/dL), low SUN (4 mg/dL) and creatinine (0.3 mg/dL), hypomagnesemia (1.7 mg/dL) and hypokalemia (3.7 mmol/L), all potentially related to fluid administration, and hemodilution. Blood ammonia (11 lmol/L) and coagulation measurements were normal, except for a mildly From the Intracellular Pathogens Research Laboratory, Center for Comparative Medicine and Translational Research, College of Veterinary Medicine, North Carolina State University, Raleigh, NC (Breitschwerdt, Mascarelli); the University of Florida College of Veterinary Medicine, Gainesville, FL (Goldkamp, Castleman, Schaer); and the Veterinary Health Complex, College of Veterinary Medicine, North Carolina State University, Raleigh, NC (Cullen, Thalhem). Corresponding author: Dr E.B. Breitschwerdt, College of Veterinary Medicine, North Carolina State University, 1060 William Moore Drive, Raleigh, NC 27607; e-mail: ed_breitschwerdt@ncsu. edu. Submitted September 9, 2013; Revised January 23, 2014; Accepted April 22, 2014. Copyright © 2014 by the American College of Veterinary Internal Medicine DOI: 10.1111/jvim.12381 Abbreviations:}, number={4}, journal={Journal of Veterinary Internal Medicine}, publisher={Wiley}, author={Breitschwerdt, E.B. and Goldkamp, C. and Castleman, W.L. and Cullen, J.M. and Mascarelli, P.E. and Thalhem, L. and Schaer, M.}, year={2014}, month={Jun}, pages={1331–1335} }
 @article{cullen_willson_minch_kimbrough_mealey_2014, title={Lack of association of ABCB4 insertion mutation with gallbladder mucoceles in dogs}, volume={26}, ISSN={["1943-4936"]}, DOI={10.1177/1040638714532099}, abstractNote={ The etiology of canine gallbladder mucocele (GBM) has not yet been identified. However, several studies have linked GBM in dogs to particular breeds (Shetland Sheepdogs are commonly implicated), concurrent endocrine disease (hyperadrenocorticism and/or hypothyroidism), and a mutation in the canine ABCB4 gene ( ABCB4 1583_1584G), particularly in Shetland Sheepdogs. The current study assessed ABCB4 1583_1584G, in a wider sample of dogs with GBM compared with age and breed-matched controls. ABCB4 1583_1584G was identified in 4 of 8 Shetland Sheepdogs and 13 of 28 other breeds with GBM. ABCB4 1583_1584G was also detected in 9 of 12 Shetland Sheepdogs and 23 of 37 other breeds that did not have GBM. No statistically significant association existed between ABCB4 1583_1584G and the presence of GBM for all dogs combined or for Shetland Sheepdogs alone. In contrast to previously reported findings, the current study did not identify a strong association between ABCB4 1583_1584G and GBM in Shetland Sheepdogs or other breeds. }, number={3}, journal={JOURNAL OF VETERINARY DIAGNOSTIC INVESTIGATION}, author={Cullen, John M. and Willson, Cynthia J. and Minch, Jonathan D. and Kimbrough, Carie L. and Mealey, Katrina L.}, year={2014}, month={May}, pages={434–436} }
 @article{harrill_eaddy_rose_cullen_ramanathan_wanaski_collins_ho_watkins_lecluyse_2014, title={Liver biomarker and in vitro assessment confirm the hepatic origin of aminotransferase elevations lacking histopathological correlate in beagle dogs treated with GABA(A) receptor antagonist NP260}, volume={277}, ISSN={["1096-0333"]}, DOI={10.1016/j.taap.2014.03.015}, abstractNote={NP260 was designed as a first-in-class selective antagonist of α4-subtype GABAA receptors that had promising efficacy in animal models of pain, epilepsy, psychosis, and anxiety. However, development of NP260 was complicated following a 28-day safety study in dogs in which pronounced elevations of serum aminotransferase levels were observed, although there was no accompanying histopathological indication of hepatocellular injury. To further investigate the liver effects of NP260, we assayed stored serum samples from the 28-day dog study for liver specific miRNA (miR-122) as well as enzymatic biomarkers glutamate dehydrogenase and sorbitol dehydrogenase, which indicate liver necrosis. Cytotoxicity assessments were conducted in hepatocytes derived from dog, rat, and human liver samples to address the species specificity of the liver response to NP260. All biomarkers, except ALT, returned toward baseline by Day 29 despite continued drug treatment, suggesting adaptation to the initial injury. In vitro analysis of the toxicity potential of NP260 to primary hepatocytes indicated a relative sensitivity of dog > human > rat, which may explain, in part, why the liver effects were not evident in the rodent safety studies. Taken together, the data indicate that a diagnostic biomarker approach, coupled with sensitive in vitro screening strategies, may facilitate interpretation of toxicity potential when an adaptive event masks the underlying toxicity.}, number={2}, journal={TOXICOLOGY AND APPLIED PHARMACOLOGY}, author={Harrill, Alison H. and Eaddy, John S. and Rose, Kelly and Cullen, John M. and Ramanathan, Lakshmi and Wanaski, Stephen and Collins, Stephen and Ho, Yu and Watkins, Paul B. and LeCluyse, Edward L.}, year={2014}, month={Jun}, pages={131–137} }
 @article{spruiell_richardson_cullen_awumey_gonzalez_gyamfi_2014, title={Role of Pregnane X Receptor in Obesity and Glucose Homeostasis in Male Mice}, volume={289}, ISSN={["1083-351X"]}, DOI={10.1074/jbc.m113.494575}, abstractNote={Background: PXR is a xenobiotic nuclear receptor that defends against toxic agents. Results: In male mice fed a HFD, the mouse PXR gene promoted obesity, whereas mice lacking the PXR or possessing the human transgene were hyperglycemic. Conclusion: The impact of PXR on HFD-induced obesity and hyperglycemia is species-dependent. Significance: The current data provide in vivo significance of PXR in metabolic syndrome. Clinical obesity is a complex metabolic disorder affecting one in three adults. Recent reports suggest that pregnane X receptor (PXR), a xenobiotic nuclear receptor important for defense against toxic agents and for eliminating drugs and other xenobiotics, may be involved in obesity. Noting differences in ligand specificities between human and mouse PXRs, the role of PXR in high fat diet (HFD)-induced obesity was examined using male PXR-humanized (hPXR) transgenic and PXR-knock-out (PXR-KO) mice in comparison to wild-type (WT) mice. After 16 weeks on either a control diet or HFD, WT mice showed greater weight gain, whereas PXR-KO mice gained less weight due to their resistance to HFD-induced decreases in adipose tissue peroxisome proliferator-activated receptor α and induction of hepatic carnitine palmitoyltransferase 1, suggesting increased energy metabolism. Interestingly, control-fed PXR-KO mice exhibited hepatomegaly, hyperinsulinemia, and hyperleptinemia but hypoadiponectinemia and lower adiponectin receptor R2 mRNA levels relative to WT mice. Evaluation of these biologic indicators in hPXR mice fed a control diet or HFD revealed further differences between the mouse and human receptors. Importantly, although HFD-fed hPXR mice were resistant to HFD-induced obesity, both PXR-KO and hPXR mice exhibited impaired induction of glucokinase involved in glucose utilization and displayed elevated fasting glucose levels and severely impaired glucose tolerance. Moreover, the basal hepatic levels of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase 1 were increased in hPXR mice compared with WT mice. Altogether, although the mouse PXR promotes HFD-induced obesity, the hPXR mouse carries a genetic predisposition for type 2 diabetes and thus provides a model for exploring the role of human PXR in the metabolic syndrome.}, number={6}, journal={JOURNAL OF BIOLOGICAL CHEMISTRY}, author={Spruiell, Krisstonia and Richardson, Ricardo M. and Cullen, John M. and Awumey, Emmanuel M. and Gonzalez, Frank J. and Gyamfi, Maxwell A.}, year={2014}, month={Feb}, pages={3244–3261} }
 @article{spruiell_jones_cullen_awumey_gonzalez_gyamfi_2014, title={Role of human pregnane X receptor in high fat diet-induced obesity in pre-menopausal female mice}, volume={89}, ISSN={["1873-2968"]}, DOI={10.1016/j.bcp.2014.03.019}, abstractNote={Obesity is a complex metabolic disorder that is more prevalent among women. Until now, the only relevant rodent models of diet-induced obesity were via the use of ovariectomized ("postmenopausal") females. However, recent reports suggest that the xenobiotic nuclear receptor pregnane X receptor (PXR) may contribute to obesity. Therefore, we compared the roles of mouse and human PXRs in diet-induced obesity between wild type (WT) and PXR-humanized (hPXR) transgenic female mice fed either control or high-fat diets (HFD) for 16 weeks. HFD-fed hPXR mice gained weight more rapidly than controls, exhibited hyperinsulinemia, and impaired glucose tolerance. Fundamental differences were observed between control-fed hPXR and WT females: hPXR mice possessed reduced estrogen receptor α (ERα) but enhanced uncoupling protein 1 (UCP1) protein expression in white adipose tissue (WAT); increased protein expression of the hepatic cytochrome P450 3A11 (CYP3A11) and key gluconeogenic enzymes phosphoenolpyruvate carboxykinase and glucose 6-phosphatase, and increased total cholesterol. Interestingly, HFD ingestion induced both UCP1 and glucokinase protein expression in WT mice, but inhibited these enzymes in hPXR females. Unlike WT mice, CYP3A11 protein, serum 17β-estradiol levels, and WAT ERα expression were unaffected by HFD in hPXR females. Together, these studies indicate that the hPXR gene promotes obesity and metabolic syndrome by dysregulating lipid and glucose homeostasis while inhibiting UCP1 expression. Furthermore, our studies indicate that the human PXR suppresses the protective role of estrogen in metabolic disorders. Finally, these data identify PXR-humanized mice as a promising in vivo research model for studying obesity and diabetes in women.}, number={3}, journal={BIOCHEMICAL PHARMACOLOGY}, author={Spruiell, Krisstonia and Jones, Dominique Z. and Cullen, John M. and Awumey, Emmanuel M. and Gonzalez, Frank J. and Gyamfi, Maxwell A.}, year={2014}, month={Jun}, pages={399–412} }
 @article{tobias_cullen_2014, title={Thymofibrolipoma in a Labrador Retriever}, volume={51}, ISSN={["1544-2217"]}, DOI={10.1177/0300985813502816}, abstractNote={ While thymomas are uncommon but well-known mediastinal masses, collagen-rich variants are exceedingly rare. Thymofibrolipoma and sclerosing thymoma tumor variants have been recently recognized in medical pathology, and thymofibrolipoma has been only rarely reported in dogs. A cranial thoracic mass was identified in a 6-year-old Labrador Retriever that was characterized by robust collagenous stroma dissected by thin cords of cytokeratin-positive neoplastic epithelial cells and bordered by mildly pleomorphic epithelial cells with occasional lymphocytic aggregates and rare Hassall corpuscles. To the authors’ knowledge, this is only the second report of thymofibrolipoma in veterinary medicine and the first to describe a variant with a mitotically active and relatively pleomorphic, adjacent thymic epithelial population. }, number={4}, journal={VETERINARY PATHOLOGY}, author={Tobias, J. R. and Cullen, J. M.}, year={2014}, month={Jul}, pages={816–819} }
 @article{livingston_tuong_kissling_cullen_2014, title={Visualizing surface area and volume of lumens in three dimensions using images from histological sections}, volume={256}, ISSN={["1365-2818"]}, DOI={10.1111/jmi.12171}, abstractNote={Summary}, number={3}, journal={JOURNAL OF MICROSCOPY}, author={Livingston, David P., III and Tuong, Tan D. and Kissling, Grace E. and Cullen, John M.}, year={2014}, month={Dec}, pages={190–196} }
 @article{kane_defrancesco_boyle_malarkey_ritchey_atkins_cullen_kornegay_keene_2013, title={Cardiac structure and function in female carrier's of a canine model of Duchenne muscular dystrophy}, volume={94}, ISSN={["1532-2661"]}, DOI={10.1016/j.rvsc.2012.09.027}, abstractNote={This investigation tested the hypothesis that carriers of golden retriever muscular dystrophy (GRMD), a genetically homologous condition of Duchenne muscular dystrophy (DMD), have quantifiable abnormalities in myocardial function, structure, or cardiac rhythm. Eleven GRMD carriers and four matched controls had cardiac evaluations and postmortem examinations. 24-h ECG Holter monitoring disclosed ventricular ectopy in 10 of 11 carriers and 2 of 4 controls. Conventional echocardiography failed to demonstrate significant differences between carriers and controls in systolic function. All carriers had multifocal, minimal to marked myofiber necrosis, fibrosis, mineralization, inflammation, and/or fatty change in their hearts. Immunohistochemistry revealed a mosaic dystrophin deficiency in scattered cardiac myofibers in all carriers. No controls had cardiac histologic lesions; all had uniform dystrophin staining. Despite cardiac mosaic dystrophin expression and degenerative cardiac lesions, GRMD carriers at up to 3 years of age could not be distinguished statistically from normal controls by echocardiography or 24-h Holter monitoring.}, number={3}, journal={RESEARCH IN VETERINARY SCIENCE}, author={Kane, A. M. and DeFrancesco, T. C. and Boyle, M. C. and Malarkey, D. E. and Ritchey, J. W. and Atkins, C. E. and Cullen, J. M. and Kornegay, J. N. and Keene, B. W.}, year={2013}, month={Jun}, pages={610–617} }
 @article{piper_ribeiro_smith_briggs_huitt_nanda_spears_quiles_cullen_thomas_et al._2013, title={Chikungunya Virus Host Range E2 Transmembrane Deletion Mutants Induce Protective Immunity against Challenge in C57BL/6J Mice}, volume={87}, ISSN={["1098-5514"]}, DOI={10.1128/jvi.03357-12}, abstractNote={ABSTRACT}, number={12}, journal={JOURNAL OF VIROLOGY}, author={Piper, Amanda and Ribeiro, Mariana and Smith, Katherine M. and Briggs, Caitlin M. and Huitt, Emerson and Nanda, Kavita and Spears, Carla J. and Quiles, Michelle and Cullen, John and Thomas, Malcolm E. and et al.}, year={2013}, month={Jun}, pages={6748–6757} }
 @article{kavanagh_wylie_tucker_hamp_gharaibeh_fodor_cullen_2013, title={Dietary fructose induces endotoxemia and hepatic injury in calorically controlled primates}, volume={98}, ISSN={["1938-3207"]}, DOI={10.3945/ajcn.112.057331}, abstractNote={BACKGROUND
Controversy exists regarding the causative role of dietary fructose in obesity and fatty liver diseases. Clinical trials have indicated that negative health consequences may occur only when fructose is consumed within excess calories. Animal studies have suggested that fructose impairs intestinal integrity and leads to hepatic steatosis (HS).


OBJECTIVES
We assessed nonhuman primates after chronic ad libitum and short-term calorically controlled consumption of a high-fructose (HFr), low-fat diet (24% of calories). Microbial translocation (MT), microbiome, and metabolic health indexes were evaluated.


DESIGN
Seventeen monkeys fed 0.3–7 y of an HFr ad libitum diet were compared with 10 monkeys fed a low-fructose, low-fat diet (control). Ten middle-aged, weight-stable, fructose-naive monkeys were stratified into HFr and control groups fed for 6 wk at caloric amounts required to maintain weight stability. Metabolic endpoints, feces, liver, small and large intestinal biopsies, and portal blood samples were collected.


RESULTS
Monkeys allowed ad libitum HFr developed HS in contrast to the control diet, and the extent of ectopic fat was related to the duration of feeding. Diabetes incidence also increased. Monkeys that consumed calorically controlled HFr showed significant increases in biomarkers of liver damage, endotoxemia, and MT indexes and a trend for greater hepatitis that was related to MT; however, HS did not develop.


CONCLUSIONS
Even in the absence of weight gain, fructose rapidly causes liver damage that we suggest is secondary to endotoxemia and MT. HS relates to the duration of fructose consumption and total calories consumed. These data support fructose inducing both MT and ectopic fat deposition in primates.}, number={2}, journal={AMERICAN JOURNAL OF CLINICAL NUTRITION}, author={Kavanagh, Kylie and Wylie, Ashley T. and Tucker, Kelly L. and Hamp, Timothy J. and Gharaibeh, Raad Z. and Fodor, Anthony A. and Cullen, John M.}, year={2013}, month={Aug}, pages={349–357} }
 @misc{meuten_law_stromberg_cullen_2013, title={From Bipeds to an Honorary Member of the American College of Veterinary Pathologists}, volume={50}, ISSN={["1544-2217"]}, DOI={10.1177/0300985813480219}, abstractNote={For a moment, we thought Dr de Lahunta would remain complimentary of our article that questioned the use of the words autopsy vs necropsy. His point is well made—if we are going to suggest nomenclature preferences, we should be accurate with our use of nomenclature. The crus or leg is, as he states, there are no 4-legged animals. We hope we have it correct this time. It has been 42 years since Dr ‘‘d’’ said to one of us (D.J.M.) in a barn at Cornell, ‘‘Hello, my name is Sandy de Lahunta; come look at this goat and let’s see if we can figure out where his neurologic deficit is.’’ Don had no idea he was about to be grilled by a legend, and the legend is still grilling. Dr Russ Cattley also reminded us of an important reference: Autopsy of the Horse, by James Rooney. Russ is absolutely correct we should have cited this excellent book and/or just followed Dr Rooney’s lead from 40 years ago. Fortunately, Dr Rooney agreed with the preference of the word autopsy and apparently felt the distinction from necropsy quite pedantic. We are enjoying the exchanges we have stimulated, and if we are correct and using the term autopsy results in more animals being autopsied, then can we support the recommendation? The autopsy remains the quality control standard for human and veterinary hospitals, yet the percentage of cases being submitted for an autopsy appears to be on the decline. Medicine, pathology, and all our specialties are dependent on follow-up data to assess diseases, diagnoses, and treatments, medical and surgical. For oncology, there is no more certain way to assess disease-free intervals, recurrence, and metastases than an autopsy. Extracting data from clinical assessment, palpation of excision lines, palpation of regional lymph nodes, and imaging body cavities are good, but they are not as definitive as the results of an autopsy. However, the number of studies that use an autopsy and histopathology to report accurate clinical outcome data is minuscule. It is essential to conclude these expensive and lengthy studies with an autopsy and histopathology. If the word autopsy is more acceptable to pet owners than necropsy, then we hope all clinicians will use this term, written and verbally, as they explain how further examination of their pet is essential to help other pets and researchers. No one better knows the value of correlating clinical signs with postmortem lesions than Dr de Lahunta. He made a distinguished career and raised neuropathology to new standards by integrating neurology and pathology (via autopsies). Thank you.}, number={3}, journal={VETERINARY PATHOLOGY}, author={Meuten, D. J. and Law, J. M. and Stromberg, P. C. and Cullen, J. M.}, year={2013}, month={May}, pages={365–365} }
 @article{park_kim_lee_lee_kwak_hong_cullen_jeong_2013, title={Granulomatous metritis caused by suspected Dirofilaria immitis in a dog: a case report}, volume={58}, ISSN={["1805-9392"]}, DOI={10.17221/6984-vetmed}, abstractNote={Here we describe a unique uterine mass in a dog with granulomatous lesions caused by filarial larvae from the family Onchocercidae. An 8-year-old female Maltese was presented to a local animal hospital with anorexia, depression, and vaginal discharge. A markedly distended uterus was observed on lateral abdominal radiographs, leading to a clinical diagnosis of pyometra or uterine mass of an unknown origin. During surgery, the left uterine horn contained a 5 cm diameter mass adhered to adjacent soft tissue. On gross inspection, the mass contained numerous white nematodes. Microscopically, this mass was characterised by a granulomatous inflammation of the myometrium and endometrium. Because all of the nematodes were dead, definitive species identification was not possible. However, based on the histologic appearance, these nematodes were tentatively identified as Dirofilaria immitis larvae.}, number={8}, journal={VETERINARNI MEDICINA}, author={Park, J. K. and Kim, A. Y. and Lee, E. M. and Lee, E. J. and Kwak, D. M. and Hong, I. H. and Cullen, J. M. and Jeong, K. S.}, year={2013}, month={Aug}, pages={437–441} }
 @article{asakawa_cullen_linder_2013, title={Necrolytic migratory erythema associated with a glucagon-producing primary hepatic neuroendocrine carcinoma in a cat}, volume={24}, ISSN={["0959-4493"]}, DOI={10.1111/vde.12041}, abstractNote={BackgroundIn humans, necrolytic migratory erythema (NME) is a syndrome with a characteristic skin rash that is associated most often with a pancreatic glucagonoma and is recognized as part of the glucagonoma syndrome. In veterinary medicine, NME (also called as superficial necrolytic dermatitis, hepatocutaneous syndrome or metabolic epidermal necrosis) has been described in dogs in association with chronic liver diseases or, less frequently, glucagonoma, but NME associated with glucagonoma has not previously been reported in cats.}, number={4}, journal={VETERINARY DERMATOLOGY}, author={Asakawa, Midori G. and Cullen, John M. and Linder, Keith E.}, year={2013}, month={Aug}, pages={466–E110} }
 @misc{kavanagh_wylie_tucker_hamp_gharaibeh_fodor_cullen_2013, title={Primate fructose study misses mark due to preventable design flaws Reply}, volume={98}, number={5}, journal={American Journal of Clinical Nutrition}, author={Kavanagh, K. and Wylie, A. T. and Tucker, K. L. and Hamp, T. J. and Gharaibeh, R. Z. and Fodor, A. A. and Cullen, J. M.}, year={2013}, pages={1370–1370} }
 @article{cullen_2012, title={Cutting Through to the Truth: Laser Capture Microscopy and Acute Toxic Biliary Injury}, volume={146}, ISSN={0021-9975}, url={http://dx.doi.org/10.1016/j.jcpa.2011.11.002}, DOI={10.1016/j.jcpa.2011.11.002}, number={1}, journal={Journal of Comparative Pathology}, publisher={Elsevier BV}, author={Cullen, J.M.}, year={2012}, month={Jan}, pages={45} }
 @article{harrington_mcmullen_cullen_gilger_2012, title={Evaluation of diode endoscopic cyclophotocoagulation in bovine cadaver eyes}, volume={73}, ISSN={["0002-9645"]}, DOI={10.2460/ajvr.73.9.1445}, abstractNote={Abstract}, number={9}, journal={AMERICAN JOURNAL OF VETERINARY RESEARCH}, author={Harrington, Jay T. and McMullen, Richard J., Jr. and Cullen, John M. and Gilger, Brian C.}, year={2012}, month={Sep}, pages={1445–1452} }
 @article{hutchins_breitschwerdt_cullen_bissett_gookin_2012, title={Limited yield of diagnoses of intrahepatic infectious causes of canine granulomatous hepatitis from archival liver tissue}, volume={24}, ISSN={1040-6387 1943-4936}, url={http://dx.doi.org/10.1177/1040638712453583}, DOI={10.1177/1040638712453583}, abstractNote={ Canine granulomatous hepatitis is an uncommon morphologic diagnosis that has been associated with a variety of diseases, including a number of systemic infectious etiologies. Formalin-fixed, paraffin-embedded (FFPE) tissues are typically the only source of liver tissue remaining for additional testing for the presence of infectious disease within granulomas. It is unclear if the more common infectious culprits of granulomatous hepatitis can be identified from such specimens. The aim of the current study was to retrospectively investigate archival FFPE liver tissue from dogs with granulomatous hepatitis for the presence of infectious agents. Semiquantitative analysis of copper accumulation in liver specimens was also performed. Medical records were examined for recorded evidence of systemic infectious disease diagnosis. Formalin-fixed, paraffin-embedded liver was prospectively evaluated for infectious agents via differential staining techniques ( n = 13), eubacterial fluorescent in situ hybridization ( n = 11), and Bartonella polymerase chain reaction assays ( n = 15). An infectious cause of granulomatous hepatitis was not identified within liver tissue from any dog using these diagnostic methodologies. Six out of 25 (24%) dogs were diagnosed with concurrent systemic or localized bacterial infections at the time of presentation. Nine out of 17 (53%) dogs had excessive hepatic copper accumulation when evaluated by a semiquantitative histologic grading scheme or quantitative copper analysis. As definitive infectious causes of granulomatous hepatitis were not identified within archival liver biopsy samples, it was concluded that investigation of infectious etiologies within FFPE liver specimens using these diagnostic approaches may be of low yield. }, number={5}, journal={Journal of Veterinary Diagnostic Investigation}, publisher={SAGE Publications}, author={Hutchins, Rae G. and Breitschwerdt, Edward B. and Cullen, John M. and Bissett, Sally A. and Gookin, Jody L.}, year={2012}, month={Aug}, pages={888–894} }
 @article{minter_cullen_loomis_2012, title={Reye's or Reye's-like syndrome in western lowland gorilla (Gorilla gorilla gorilla)}, volume={41}, ISSN={["0047-2565"]}, DOI={10.1111/j.1600-0684.2012.00554.x}, abstractNote={Abstract}, number={5}, journal={JOURNAL OF MEDICAL PRIMATOLOGY}, author={Minter, Larry J. and Cullen, John M. and Loomis, Michael R.}, year={2012}, month={Oct}, pages={329–331} }
 @article{burbelo_dubovi_simmonds_medina_henriquez_mishra_wagner_tokarz_cullen_ladarola_et al._2012, title={Serology-Enabled Discovery of Genetically Diverse Hepaciviruses in a New Host}, volume={86}, ISSN={["1098-5514"]}, DOI={10.1128/jvi.00250-12}, abstractNote={ABSTRACT}, number={11}, journal={JOURNAL OF VIROLOGY}, author={Burbelo, Peter D. and Dubovi, Edward J. and Simmonds, Peter and Medina, Jan L. and Henriquez, Jose A. and Mishra, Nischay and Wagner, Jason and Tokarz, Rafal and Cullen, John M. and Ladarola, Michael J. and et al.}, year={2012}, month={Jun}, pages={6171–6178} }
 @article{burke_cullen_state_gadi_wilber_rosenthal_bulysheva_pease_mauro_fuchs_2011, title={Development of an Animal Model for Radiofrequency Ablation of Primary, Virally Induced Hepatocellular Carcinoma in the Woodchuck}, volume={22}, ISSN={["1051-0443"]}, DOI={10.1016/j.jvir.2011.08.020}, abstractNote={To develop a consistent and reproducible method in an animal model for studies of radiofrequency (RF) ablation of primary hepatocellular carcinoma (HCC).Fifteen woodchucks were inoculated with woodchuck hepatitis virus (WHV) to establish chronic infections. When serum γ-glutamyl transpeptidase levels became elevated, the animals were evaluated with ultrasound, and, in most cases, preoperative magnetic resonance (MR) imaging to confirm tumor development. Ultimately, RF ablation of tumors was performed by using a 1-cm probe with the animal submerged in a water bath for grounding. Ablation effectiveness was evaluated with contrast-enhanced MR imaging and gross and histopathologic analysis.RF ablation was performed in 15 woodchucks. Modifications were made to the initial study design to adapt methodology for the woodchuck. The last 10 of these animals were treated with a standardized protocol using a 1-cm probe that produced a consistent area of tumor necrosis (mean size of ablation, 10.2 mm × 13.1 mm) and led to no complications.A safe, reliable and consistent method was developed to study RF ablation of spontaneous primary HCC using chronically WHV-infected woodchucks, an animal model of hepatitis B virus-induced HCC.}, number={11}, journal={JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY}, author={Burke, Charles T. and Cullen, John M. and State, Andrei and Gadi, Sashi and Wilber, Kathy and Rosenthal, Michael and Bulysheva, Anna and Pease, Anthony and Mauro, Mathew A. and Fuchs, Henry}, year={2011}, month={Nov}, pages={1613–1618} }
 @article{cullen_williams_zadrozny_otstot_solomon_sills_hong_2011, title={H-ras Consensus Sequence and Mutations in Primary Hepatocellular Carcinomas of Lemurs and Lorises}, volume={48}, ISSN={["0300-9858"]}, DOI={10.1177/0300985810388526}, abstractNote={ The authors have determined a consensus sequence for exons 1 and 2 of H -ras from captive lemurs and lorises and evaluated samples of nonneoplastic liver and hepatocellular carcinomas (HCC) from affected animals for mutations in these exons. Frozen liver samples were collected from 20 animals representing 9 different species with a sex distribution of 10 males and 10 females. A total of 26 liver samples, including 11 normal livers, 9 HCC, and 6 samples from nonneoplastic regions of liver from animals with HCC, were evaluated. This is the first report of the consensus sequence for exons 1 and 2 of H- ras in prosimians, and the authors have determined that it is identical to that of human H- ras and differs only slightly from the chimpanzee sequence. Point mutations were identified in 6 of the 9 HCC samples examined with codons 7, 22, 32, 56, 61, 84, and 96 affected. Two carcinomas had double mutations, and one tumor had triple mutations. One HCC had a mutation in codon 61, which is identical to a recognized affected codon for an H- ras “hot spot” in rodent neoplasia that has also been reported in human tumors. Although not statistically different, metastasis occurred in 5 of 6 HCC with H- ras mutation and only 1 of 3 HCC without mutations. There were 4 silent mutations that did not contain changes in the encoded amino acids, 2 of which were found in nonneoplastic regions of tumor-bearing liver. }, number={4}, journal={VETERINARY PATHOLOGY}, author={Cullen, J. M. and Williams, C. and Zadrozny, L. and Otstot, J. T. and Solomon, G. G. and Sills, R. C. and Hong, H-H. L.}, year={2011}, month={Jul}, pages={868–874} }
 @article{hedan_thomas_motsinger-reif_abadie_andre_cullen_breen_2011, title={Molecular cytogenetic characterization of canine histiocytic sarcoma: A spontaneous model for human histiocytic cancer identifies deletion of tumor suppressor genes and highlights influence of genetic background on tumor behavior}, volume={11}, journal={BMC Cancer}, author={Hedan, B. and Thomas, R. and Motsinger-Reif, A. and Abadie, J. and Andre, C. and Cullen, J. and Breen, M.}, year={2011} }
 @article{law_stromberg_meuten_cullen_2011, title={Necropsy or Autopsy? It’s All About Communication!}, volume={49}, ISSN={0300-9858 1544-2217}, url={http://dx.doi.org/10.1177/0300985811410722}, DOI={10.1177/0300985811410722}, abstractNote={Several of us have decided that communication is more important than tradition. Yes, Virginia, we were all drilled in the discipline of veterinary pathology by traditionalists. We’re stubborn individualists, aren’t we? Greats like John King have necropsied thousands of animals, and we want our procedure to be distinguished from the ‘‘other’’ side—the RDs (well okay, the MDs). The short answer is that ‘‘necropsy’’ literally means ‘‘death examination’’ or examination of death and finds its application in the study of bodies following death. The term is general without reference to species. ‘‘Autopsy’’ literally means ‘‘self-examination,’’ and some of us were taught that the frame of reference for ‘‘self’’ referred to the postmortem examination of ‘‘ourselves’’ or our own species, humans. As such, postmortem examination of nonhumans was proscribed from using the term and was designated ‘‘necropsy.’’ But hold on there a minute, let’s see what Webster has to say. Or as Don Meuten likes to say, ‘‘Show me the reference!’’}, number={2}, journal={Veterinary Pathology}, publisher={SAGE Publications}, author={Law, M. and Stromberg, P. and Meuten, D. and Cullen, J.}, year={2011}, month={Jun}, pages={271–272} }
 @article{kamstock_ehrhart_getzy_bacon_rassnick_moroff_liu_straw_mcknight_amorim_et al._2011, title={Recommended guidelines for submission, trimming, margin evaluation, and reporting of tumor biopsy specimens in veterinary surgical pathology}, volume={48}, number={1}, journal={Veterinary Pathology}, author={Kamstock, D. A. and Ehrhart, E. J. and Getzy, D. M. and Bacon, N. J. and Rassnick, K. M. and Moroff, S. D. and Liu, S. M. and Straw, R. C. and McKnight, C. A. and Amorim, R. L. and et al.}, year={2011}, pages={19–31} }
 @article{webster_dennis_dervisis_heller_bacon_bergman_bienzle_cassali_castagnaro_cullen_et al._2011, title={Recommended guidelines for the conduct and evaluation of prognostic studies in veterinary oncology}, volume={48}, number={1}, journal={Veterinary Pathology}, author={Webster, J. D. and Dennis, M. M. and Dervisis, N. and Heller, J. and Bacon, N. J. and Bergman, P. J. and Bienzle, D. and Cassali, G. and Castagnaro, M. and Cullen, J. and et al.}, year={2011}, pages={7–18} }
 @article{faiola_peterson_kimbrough_jordan_cullen_2010, title={Acute ANIT Toxicity in Male IL-10 Knockout and Wild-type Mice}, volume={38}, ISSN={["1533-1601"]}, DOI={10.1177/0192623310374970}, abstractNote={ The innate immune response is known to modify hepatocellular injury induced by toxicants. To assess the role of IL-10, a component of the innate immune response, in toxicant-induced injury of biliary epithelium, wild-type (WT) and IL-10 knockout mice (KO) were given a single toxic dose (50 mg/kg) of α-napthylisothiocyanate (ANIT) and assessed at twenty-four–hour intervals for four days following treatment. Clinical signs of toxicity were greater in WT mice. Unexpectedly, over the course of the study, there was a consistent tendency for ANIT-treated IL-10 KO mice to have less hepatocellular injury than WT mice. However, changes in the biliary epithelium differed in that there was more histologic evidence of inflammation and necrosis on days 2 and 3, respectively, in ANIT-treated IL-10 KO mice compared with WT mice. Proliferation of biliary epithelium and hepatocytes was greater and/or occurred earlier in the ANIT-treated IL-10 KO mice compared with the ANIT-treated WT mice, suggesting a greater reparative response was needed for recovery after toxicant injury in the IL-10 KO mice. Overall, our data suggest that IL-10 KO mice have less hepatocellular injury than WT mice following a toxic dose of ANIT and that biliary epithelial injury is accentuated in the KO mice. }, number={5}, journal={TOXICOLOGIC PATHOLOGY}, author={Faiola, Brenda and Peterson, Richard A. and Kimbrough, Carrie L. and Jordan, Holly L. and Cullen, John M.}, year={2010}, month={Aug}, pages={745–755} }
 @article{brown_van winkle_cecere_rushton_brachelente_cullen_2010, title={Congenital Hepatic Fibrosis in 5 Dogs}, volume={47}, ISSN={["0300-9858"]}, DOI={10.1177/0300985809353313}, abstractNote={ Congenital hepatic fibrosis is a disorder of biliary system development histologically characterized by diffuse periportal to bridging fibrosis with numerous small often-irregular bile ducts and reduction in the number of portal vein branches. The condition results from abnormal development of the ductal plate, the embryonic precursor to the interlobular bile ducts. It has rarely been reported in veterinary species, and it has never been reported in dogs. This article describes 5 cases of a ductal plate malformation in dogs consistent with congenital hepatic fibrosis. On light microscopy, all 5 livers had severe bridging fibrosis with a marked increase in the number of small bile ducts, which often had irregular, dilated profiles reminiscent of the developing ductal plate. In addition, 80% (4 of 5) of cases lacked typical portal vein profiles. Cytokeratin 7 and proliferating cell nuclear antigen immunohistochemistry was performed on the 3 cases for which paraffin-embedded tissue was available. The bile duct profiles were strongly positive for cytokeratin 7 in all 3 cases, and they were negative for proliferating cell nuclear antigen or only had rare positive cells. All 5 dogs presented with clinical signs of portal hypertension. Congenital hepatic fibrosis should be considered in the differential diagnosis in young dogs that present with portal hypertension and lesions that may have been interpreted as bridging biliary hyperplasia or extrahepatic biliary obstruction. }, number={1}, journal={VETERINARY PATHOLOGY}, author={Brown, D. L. and Van Winkle, T. and Cecere, T. and Rushton, S. and Brachelente, C. and Cullen, J. M.}, year={2010}, month={Jan}, pages={102–107} }
 @article{asakawa_mackillop_olby_robertson_cullen_2010, title={Imaging diagnosis-neuronal ceroid lipofuscinosis with a chronic subdural hematoma}, volume={51}, number={2}, journal={Veterinary Radiology & Ultrasound}, author={Asakawa, M. G. and Mackillop, E. and Olby, N. J. and Robertson, I. D. and Cullen, J. M.}, year={2010}, pages={155–158} }
 @article{zadrozny_williams_remick_cullen_2010, title={Spontaneous Hepatocellular Carcinoma in Captive Prosimians}, volume={47}, ISSN={["1544-2217"]}, DOI={10.1177/0300985809359380}, abstractNote={Spontaneous hepatocellular carcinoma has been reported as a relatively common neoplasm in prosimians; however, the cause is unknown. To investigate possible pathogenic mechanisms, the authors performed a review of all adult animals from a captive prosimian population that had postmortem examinations over the past 10 years. They performed a detailed histologic evaluation of all suspected proliferative liver lesions and diagnosed hepatocellular carcinoma in 14 of 145 lemurs (9.7%). Affected animals ranged between the ages of 6 and 40 years old. The tumors had an unusually aggressive growth pattern for animal species; metastasis to the lungs or mediastinum was evident in 7 of 14 animals. Thirty-one animals—9 with hepatocellular carcinomas and 22 age-matched controls without hepatic neoplasia—were tested to evaluate the relationship between hepatic iron stores (as well as other trace metals) and the presence of hepatocellular carcinoma. There was no difference between the hepatic iron, copper, or molybdenum in lemurs with hepatocellular carcinoma and those without, suggesting that iron is not a key element in the pathogenesis of liver tumor formation. Analysis of 22 serum samples from animals with and without liver tumors indicated no evidence of active infection with a hepadnavirus, the virus family that includes hepatitis B virus. Hepatitis C virus and aflatoxin B1 were considered as potential causes and ruled out owing to lack of associated histopathologic lesions. In conclusion, hepatocellular neoplasia is relatively common in captive prosimians, although previously suspected etiologies seem unlikely.}, number={2}, journal={VETERINARY PATHOLOGY}, author={Zadrozny, L. M. and Williams, C. V. and Remick, A. K. and Cullen, J. M.}, year={2010}, month={Mar}, pages={306–311} }
 @article{cullen_falls_brown_yoon_cariello_faiola_kimbrough_jordan_miller_2010, title={Time Course Gene Expression Using Laser Capture Microscopy-Extracted Bile Ducts, but Not Hepatic Parenchyma, Reveals Acute Alpha-Naphthylisothiocyanate Toxicity}, volume={38}, ISSN={["0192-6233"]}, DOI={10.1177/0192623310373774}, abstractNote={ Acute toxic responses to a 50-mg/kg oral dose of 1-naphthylisothiocyanate (ANIT) were evaluated by microarray analysis of laser capture–microdissected rat biliary epithelium or hepatic parenchyma obtained 2 and 6 hours postdose. Distinct differences in gene expression patterns between biliary epithelium and hepatic parenchyma were noted at the 2-hour postdose time point, where 375 genes were altered in biliary epithelium but only 38 genes were altered in hepatic parenchyma. Endoplasmic reticulum stress genes were uniquely expressed in biliary epithelial cells at 2 hours postdose. By 6 hours postdose, 620 genes were altered in biliary epithelium, but only 32 genes were altered in hepatic parenchyma. In biliary epithelium, expression of genes involved in the unfolded protein response had decreased compared with the 2-hour time point, while expression of genes involved in protein degradation such as proteasome-ubquination pathways and cell death pathways had increased. At this same time, hepatic parenchymal gene expression changed little. Within 6 hours following oral exposure to ANIT, prior to morphologic changes, specific biliary epithelial gene expression changes, indicative of a vigorous unfolded protein response with protein destruction and cell death pathway activation were noted, in contrast to minor changes in the hepatic parenchyma. }, number={5}, journal={TOXICOLOGIC PATHOLOGY}, author={Cullen, John Michael and Falls, James Greg and Brown, Harlan Roger and Yoon, Lawrence Wonsik and Cariello, Neal Foster and Faiola, Brenda and Kimbrough, Carie Lynette and Jordan, Holly Lynn and Miller, Richard Thomas}, year={2010}, month={Aug}, pages={715–729} }
 @article{tuttle_maclean_linder_cullen_wolfe_loomis_2009, title={ACQUIRED ARTERIOVENOUS FISTULA IN A GRIZZLY BEAR (URSUS ARCTOS HORRIBILIS)}, volume={40}, ISSN={["1042-7260"]}, DOI={10.1638/2007-0030.1}, abstractNote={Abstract A captive adult male grizzly bear (Ursus arctos horribilis) was evaluated due to multifocal wounds of the skin and subcutaneous tissues sustained as a result of trauma from another grizzly bear. On presentation, one lesion that was located in the perineal region seemed to be a deep puncture with purple tissue protruding from it. This perineal wound did not heal in the same manner or rate as did the other wounds. Twenty-five days after initial detection, substantial active hemorrhage from the lesion occurred and necessitated anesthesia for examination of the bear. The entire lesion was surgically excised, which later proved curative. An acquired arteriovenous fistula was diagnosed via histopathology. Arteriovenous fistulas can develop after traumatic injury and should be considered as a potential complication in bears with nonhealing wounds.}, number={1}, journal={JOURNAL OF ZOO AND WILDLIFE MEDICINE}, author={Tuttle, Allison D. and MacLean, Robert A. and Linder, Keith and Cullen, John M. and Wolfe, Barbara A. and Loomis, Michael}, year={2009}, month={Mar}, pages={193–195} }
 @article{cullen_brown_kissling_foley_rizzo_marion_parron_french_2009, title={Aflatoxin B1 and/or Hepatitis B Virus Induced Tumor Spectrum in a Genetically Engineered Hepatitis B Virus Expression and Trp53 Haploinsufficient Mouse Model System for Hepatocarcinogenesis}, volume={37}, ISSN={["1533-1601"]}, DOI={10.1177/0192623309333137}, abstractNote={ The authors investigated the spectrum of tumors and Trp53 mutations in genetically engineered models using the FVB/N mouse that expressed the hepatitis B virus genome and/or carried a Trp53 null and wildtype allele and/or were exposed to aflatoxin B1. Liver tumor incidence was increased when all three risk factors were present. Without aflatoxin B1 exposure, neither Trp53 haploinsufficiency nor HBV expression affected liver tumor development. Liver tumor prevalence increased with aflatoxin B1 exposure ( p < .001), as thirteen of fourteen mice with liver tumors were initiated with aflatoxin B1. Liver tumors were more frequent in males (12/190) than females (2/170). Seventy-three mice developed sarcomas. Trp53 haploinsufficiency was associated with increased sarcoma incidence in males and females ( p < .001). In Trp53 haploinsufficient mice, the HBV transgene increased the risk of sarcoma in males and females ( p < .001). Lymphoma was significantly increased in Trp53 haploinsufficient FVB/N mice. There was no loss of heterozygosity at the wildtype Trp53 locus in twenty-five sarcomas or four hepatocellular tumors examined. No mutations were identified in the mRNA (exons 2–11) of Trp53 in six liver neoplasms or twenty-four sarcomas. In this model system, HBV expression affected only hepatocellular neoplasia in association with both aflatoxin B1 initiation and p53 haploinsufficiency. }, number={3}, journal={TOXICOLOGIC PATHOLOGY}, author={Cullen, John M. and Brown, Danielle L. and Kissling, Grace E. and Foley, Julie F. and Rizzo, Jennifer and Marion, Patricia L. and Parron, Vandy I. and French, John E.}, year={2009}, month={Apr}, pages={333–342} }
 @article{thomas_valli_ellis_bell_karlsson_cullen_lindblad-toh_langford_breen_2009, title={Microarray-based cytogenetic profiling reveals recurrent and subtype-associated genomic copy number aberrations in feline sarcomas}, volume={17}, ISSN={["1573-6849"]}, DOI={10.1007/s10577-009-9096-0}, abstractNote={Injection-site-associated sarcomas (ISAS), commonly arising at the site of routine vaccine administration, afflict as many as 22,000 domestic cats annually in the USA. These tumors are typically more aggressive and prone to recurrence than spontaneous sarcomas (non-ISAS), generally receiving a poorer long-term prognosis and warranting a more aggressive therapeutic approach. Although certain clinical and histological factors are highly suggestive of ISAS, timely diagnosis and optimal clinical management may be hindered by the absence of definitive markers that can distinguish between tumors with underlying injection-related etiology and their spontaneous counterpart. Specific nonrandom chromosome copy number aberrations (CNAs) have been associated with the clinical behavior of a vast spectrum of human tumors, providing an extensive resource of potential diagnostic and prognostic biomarkers. Although similar principles are now being applied with great success in other species, their relevance to feline molecular oncology has not yet been investigated in any detail. We report the construction of a genomic microarray platform for detection of recurrent CNAs in feline tumors through cytogenetic assignment of 210 large-insert DNA clones selected at intervals of approximately 15 Mb from the feline genome sequence assembly. Microarray-based profiling of 19 ISAS and 27 non-ISAS cases identified an extensive range of genomic imbalances that were highly recurrent throughout the combined panel of 46 sarcomas. Deletions of two specific regions were significantly associated with the non-ISAS phenotype. Further characterization of these regions may ultimately permit molecular distinction between ISAS and non-ISAS, as a tool for predicting tumor behavior and prognosis, as well as refining means for therapeutic intervention.}, number={8}, journal={CHROMOSOME RESEARCH}, author={Thomas, Rachael and Valli, Victor E. and Ellis, Peter and Bell, Jerold and Karlsson, Elinor K. and Cullen, John and Lindblad-Toh, Kerstin and Langford, Cordelia F. and Breen, Matthew}, year={2009}, month={Dec}, pages={987–1000} }
 @article{cullen_2009, title={Summary of the World Small Animal Veterinary Association Standardization Committee Guide to Classification of Liver Disease in Dogs and Cats}, volume={39}, ISSN={["1878-1306"]}, DOI={10.1016/j.cvsm.2009.02.003}, abstractNote={Liver disease is a frequently encountered problem in small animal practice. The World Small Animal Veterinary Association has formed a group of experienced clinicians and pathologists to develop a standardized format for diagnostic terminology. This is hoped to lead to greater uniformity in diagnoses and better communication between clinicians and pathologists alike. The aim is to find a sound scientific basis of diagnostic and treatment protocols for hepatobiliary diseases. This article provides an overview of that monograph.}, number={3}, journal={VETERINARY CLINICS OF NORTH AMERICA-SMALL ANIMAL PRACTICE}, author={Cullen, John M.}, year={2009}, month={May}, pages={395-+} }
 @article{macias_marva_senderowicz_cullen_rodriguez-puebla_2008, title={Expression of CDK4 or CDK2 in mouse oral cavity is retained in adult pituitary with distinct effects on tumorigenesis}, volume={68}, ISSN={["0008-5472"]}, DOI={10.1158/0008-5472.CAN-07-2461}, abstractNote={Abstract}, number={1}, journal={CANCER RESEARCH}, author={Macias, Everardo and Marva, Paula L. Miliani and Senderowicz, Adrian and Cullen, John and Rodriguez-Puebla, Marcelo L.}, year={2008}, month={Jan}, pages={162–171} }
 @article{ranck_cullen_waggie_marion_2008, title={Harderian gland neoplasms in captive, wild-caught Beechey ground squirrels (Spermophilus beecheyi)}, volume={45}, ISSN={["0300-9858"]}, DOI={10.1354/vp.45-3-388}, abstractNote={ Harderian gland neoplasms were identified in 18 aged, adult Beechey ground squirrels ( Spermophilus beecheyi) from the records of 167 wild-caught captive animals that were necropsied. All but one animal had tumors that were classified as carcinomas, with infiltrative growth and frequent metastases. This is the first detailed report of Harderian gland neoplasia in wild Sciuridae, although this neoplasm has been described in other rodent species. Clinically, affected ground squirrels typically were inappetent and presented with weight loss and exophthalmos. The biologic behavior of Harderian gland neoplasia is variable among rodent species; in Beechey ground squirrels there was a high incidence of malignant behavior. Eleven of 17 tumor-bearing animals for which the gender was known were male, and 6 were female. Nine of 16 for which data were available were uninfected, and 7 had evidence of current or prior infection with ground squirrel hepatitis virus. Tumor development occurred in older animals; all but 2 were 5.5 years of age or older. The presence of metastasis was not related to gender or chronic ground squirrel hepatitis virus infection. }, number={3}, journal={VETERINARY PATHOLOGY}, author={Ranck, R. S. and Cullen, J. M. and Waggie, K. S. and Marion, P. L.}, year={2008}, month={May}, pages={388–392} }
 @article{cullen_lindsey-pegram_cote_2008, title={Serologic survey of woodchuck hepatitis virus in North Carolina woodchucks (Marmota monax)}, volume={39}, ISSN={["1937-2825"]}, DOI={10.1638/2007-0119R.1}, abstractNote={Abstract The prevalence of woodchuck hepatitis virus (WHV) in wild populations of woodchucks is understudied and therefore unclear. Although infection is common in the southeastern region of Pennsylvania and surrounding states, it is virtually absent in New York and New England. Sera were collected from wild woodchucks from Orange County, North Carolina and tested for the presence of markers of current or previous infection with WHV. Of the 24 woodchucks tested, there were three animals (12.5%) with WHV surface antigen as well as antibodies to woodchuck hepatitis core antigen in their serum, indicative of active infection. There were four (17%) animals with antibodies to WHV core antigen but no woodchuck hepatitis surface antigen, indicative of prior infections. The remaining 17 animals had no detectable markers of WHV infection. These data indicate that WHV is present in central North Carolina at rates approaching those seen in endemic areas, such as the mid-Atlantic region of the United States.}, number={2}, journal={JOURNAL OF ZOO AND WILDLIFE MEDICINE}, author={Cullen, J. M. and Lindsey-Pegram, D. and Cote, P. J.}, year={2008}, month={Jun}, pages={263–265} }
 @article{hess_barnes_woolard_johnson_cullen_collins_frelinger_2007, title={Selective deletion of antigen-specific CD8(+) T cells by MHC class I tetramers, coupled to the type I ribosome-inactivating protein saporin}, volume={109}, ISSN={["0006-4971"]}, DOI={10.1182/blood-2006-06-028001}, abstractNote={Abstract}, number={8}, journal={BLOOD}, author={Hess, Paul R. and Barnes, Carie and Woolard, Matthew D. and Johnson, Michael D. L. and Cullen, John M. and Collins, Edward J. and Frelinger, Jeffrey A.}, year={2007}, month={Apr}, pages={3300–3307} }
 @article{xu_yamamoto_zhou_aldrich_frank_cullen_jilbert_mason_2007, title={The liver of woodchucks chronically infected with the woodchuck hepatitis virus contains foci of virus core antigen-negative hepatocytes with both altered and normal morphology}, volume={359}, ISSN={["0042-6822"]}, DOI={10.1016/j.virol.2006.09.034}, abstractNote={The livers of woodchucks chronically infected with woodchuck hepatitis virus (WHV) contain foci of morphologically altered hepatocytes (FAH) with "basophilic", "amphophilic" and "clear cell" phenotypes, which are possibly pre-neoplastic in nature. Interestingly, most fail to express detectable levels of WHV proteins and nucleic acids. We studied sections of WHV-infected liver tissue to determine if all foci of hepatocytes that failed to express detectable levels of WHV, as assessed by immunoperoxidase staining for WHV core antigen, could be classified morphologically as FAH. We found that at least half of the foci of WHV core antigen-negative hepatocytes did not show clear morphological differences in either H&E or PAS (periodic acid Schiff) stained sections from surrounding hepatocytes, and were therefore not designated as FAH. In the second approach, we assayed core antigen-negative foci for the presence of fetuin B, a serum protein produced by normal hepatocytes, but not by neoplastic hepatocytes in hepatocellular carcinomas. Basophilic and amphophilic FAH had reduced levels of fetuin B compared to hepatocytes present in the surrounding liver; fetuin B staining was detected in clear cell FAH but the level could not be accurately assessed because of the displacement of fetuin B to the cell periphery by accumulated glycogen. The foci of morphologically normal WHV core antigen-negative hepatocytes had similar levels of fetuin B to that of the surrounding hepatocytes. The co-existence of at least four types of WHV core antigen-negative foci, including those with no obvious morphologic changes, raises the possibility that the different foci arise from distinct primary events. We hypothesize that a common event is loss of the ability to express WHV, allowing these hepatocytes to escape immune mediated cell death and to undergo clonal expansion to form distinct foci.}, number={2}, journal={VIROLOGY}, author={Xu, Chunxiao and Yamamoto, Toshiki and Zhou, Tianlun and Aldrich, Carol E. and Frank, Katy and Cullen, John M. and Jilbert, Allison R. and Mason, William S.}, year={2007}, month={Mar}, pages={283–294} }
 @article{johnson_divers_freckleton_mckenzie_mitchell_cullen_mcdonough_2006, title={Fall panicum (Panicum dichotomiflorum) hepatotoxicosis in horses and sheep}, volume={20}, ISSN={["1939-1676"]}, DOI={10.1892/0891-6640(2006)20[1414:FPPDHI]2.0.CO;2}, number={6}, journal={JOURNAL OF VETERINARY INTERNAL MEDICINE}, author={Johnson, A. L. and Divers, T. J. and Freckleton, M. L. and McKenzie, H. C. and Mitchell, E. and Cullen, J. M. and McDonough, S. P.}, year={2006}, pages={1414–1421} }
 @article{xu_yamamoto_zhou_aldrich_cullen_jilbert_mason_2006, title={P.050 Appearance of core antigen negative hepatocytes in woodchucks chronically infected with woodchuck hepatitis virus}, volume={36}, ISSN={1386-6532}, url={http://dx.doi.org/10.1016/S1386-6532(06)80233-7}, DOI={10.1016/S1386-6532(06)80233-7}, abstractNote={Interleukin 10 (IL-10) is a pleiotropic cytokine acting on a variety of immune cells through the cell surface receptor (IL-10R). It has been suggested to resuscitate antiviral immunity by interfering with IL-10/IL-10R pathway. The woodchuck model infected by woodchuck hepatitis virus (WHV) represents an informative animal model to study hepatitis B virus (HBV) infection. In this study, the woodchuck IL-10R (wIL-10R) was molecularly cloned and characterized, showing high similarity of its nucleotide and amino acid sequences to that of other mammalian species. The expression level of wIL-10R mRNA in woodchuck peripheral blood mononuclear cells was significantly increased in acute WHV infection but down-regulated during chronic WHV infection. Specific rabbit antibodies against wIL-10R were prepared and showed the ability to enhance the proliferation and degranulation of specific T-cells from chronically WHV-infected woodchucks in vitro. The present work on wIL-10R provided a good basis for future preclinical studies on therapeutic approaches for chronic HBV infection.}, journal={Journal of Clinical Virology}, publisher={Elsevier BV}, author={Xu, C. and Yamamoto, T. and Zhou, T. and Aldrich, C. and Cullen, J.M. and Jilbert, A.R. and Mason, W.S.}, year={2006}, month={Jan}, pages={S76} }
 @misc{cullen_miller_2006, title={The role of pathology in the identification of drug-induced hepatic toxicity}, volume={2}, ISSN={["1744-7607"]}, DOI={10.1517/17425255.2.2.241}, abstractNote={Pathologists play a central role in the recognition and prevention of drug-induced toxicity. Pathologists engaged in clinical practice must identify a pattern of histological lesions that are interpreted in concert with a variety of clinical data to determine the probability of drug-induced toxicity versus background disease processes and the most likely drug, often of many, to have caused the specific injury. Toxicological pathologists, working in concert with other scientists, have the responsibility of preventing drug-induced toxicity in humans by identifying potentially toxic drugs and keeping them from the marketplace. In this process of drug development, a broad array of invivo testing using a number of animal species and invitro assays are used. Technological advances require pathologists to integrate molecular-based mechanistic data effectively with traditional morphological evaluation to develop a more detailed grasp of the pathogenesis of drug-induced injury. All pathologists have the responsibility to effectively and accurately communicate their findings and interpretations to the appropriate audiences.}, number={2}, journal={EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY}, author={Cullen, John M. and Miller, Richard T.}, year={2006}, month={Apr}, pages={241–247} }
 @article{hajjou_norel_carver_marion_cullen_rogler_rogler_2005, title={CDNA microarray analysis of HBV transgenic mouse liver identifies genes in lipid biosynthetic and growth control pathways affected by HBV}, volume={77}, ISSN={["1096-9071"]}, DOI={10.1002/jmv.20427}, abstractNote={Abstract}, number={1}, journal={JOURNAL OF MEDICAL VIROLOGY}, author={Hajjou, M and Norel, R and Carver, R and Marion, P and Cullen, J and Rogler, LE and Rogler, CE}, year={2005}, month={Sep}, pages={57–65} }
 @article{cullen_2005, title={Mechanistic Classification of Liver Injury}, volume={33}, ISSN={0192-6233 1533-1601}, url={http://dx.doi.org/10.1080/01926230590522428}, DOI={10.1080/01926230590522428}, abstractNote={ Toxic injury occurs in the liver more often than any other organ. This can be attributed to the fact that virtually all ingested substances that are absorbed are first presented to the liver and that the liver is responsible for the metabolism and elimination of many substances. Drug-induced liver injury has become a serious health problem in contemporary society. Moreover, liver toxicity is a significant impediment to development of new pharmaceuticals. A classification of liver injury is presented as a means to better understand the spectrum of known mechanisms of liver injury and to assist in discovering novel pathways of toxic liver injury. }, number={1}, journal={Toxicologic Pathology}, publisher={SAGE Publications}, author={Cullen, John M.}, year={2005}, month={Jan}, pages={6–8} }
 @article{elmore_basseches_anhalt_cullen_olivry_2005, title={Paraneoplastic pemphigus in a dog with splenic sarcoma}, volume={42}, ISSN={["1544-2217"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-13244258427&partnerID=MN8TOARS}, DOI={10.1354/vp.42-1-88}, abstractNote={ Paraneoplastic pemphigus (PNP) is an autoimmune blistering skin disease of humans that consists of characteristic skin lesions associated with concurrent neoplasia. in this study we provide histologic and serologic evidence to support a diagnosis of PNP in a dog with splenic sarcoma. Skin lesions consisted of widespread erosions involving haired skin, mucocutaneous junctions, and oral mucosa. Microscopic examination of skin and mucosae revealed lesions consistent with both pemphigus vulgaris and erythema multiforme. Immunoprecipitation confirmed that circulating IgG autoantibodies from this patient recognized five distinct antigens, presumed to represent epidermal plakins. Clinical, histopathologic, and immunologic findings in this patient were similar to those observed in human patients with PNP. The splenic neoplasia in this dog was diagnosed as a phenotypically variable spindle cell sarcoma. To date, only one other dog has been reported with PNP. This is the second reported case of canine PNP and the first patient in whom skin lesions were identified in association with splenic neoplasia. }, number={1}, journal={VETERINARY PATHOLOGY}, author={Elmore, SA and Basseches, J and Anhalt, GJ and Cullen, JM and Olivry, T}, year={2005}, month={Jan}, pages={88–91} }
 @article{zhu_cullen_aldrich_saputelli_miller_seeger_mason_jilbert_2004, title={Adenovirus-based gene therapy during clevudine treatment of woodchucks chronically infected with woodchuck hepatitis virus}, volume={327}, ISSN={["0042-6822"]}, DOI={10.1016/j.virol.2004.06.017}, abstractNote={Interferon-alpha (IFN-α) is a potent suppressor of hepatitis B virus (HBV) replication in the HBV-transgenic mouse, depleting virus replication intermediates from infected hepatocytes via pathways mediated by interferon-gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α). It has also been hypothesized that cytokines induce curing of infected hepatocytes via non-cytolytic pathways during resolution of transient hepadnavirus infections. We have therefore evaluated therapy of chronic woodchuck hepatitis virus (WHV) infections using treatment with the nucleoside analog clevudine [L-FMAU; 1-(2-fluoro-5-methyl-b-l-arabinofuranosyl) uracil] and therapy with adenovirus vectors expressing INF-γ, TNF-α, and beta-galactosidase. Before their use in vivo, expression of IFN-γ and TNF-α from the adenovirus vectors was evaluated in vitro. Conditioned media from adenovirus-infected WC-3 cells was shown to inhibit WHV replication in baculovirus-transduced cells. Adenovirus super-infection of the liver in woodchucks led to declines in the percentage of hepatocytes with detectable core antigen and nucleic acids, and in levels of covalently closed circular DNA (cccDNA) and total WHV DNA, but a major long-term benefit of adenovirus super-infection during clevudine treatment was not demonstrated. Moreover, the effect took at least 2 weeks to develop suggesting that the declines in the percentage of WHV-infected cells, ccc, and total WHV DNA resulted from induction of the adaptive immune response by the adenovirus super-infection, and only indirectly from the expression of cytokines by the vectors.}, number={1}, journal={VIROLOGY}, author={Zhu, Y and Cullen, JM and Aldrich, CE and Saputelli, J and Miller, D and Seeger, C and Mason, WS and Jilbert, AR}, year={2004}, month={Sep}, pages={26–40} }
 @article{li_kumanogoh_cao_parnes_cullen_2004, title={Woodchuck interleukin-6 gene: structure,characterization, and biologic activity}, volume={342}, ISSN={["1879-0038"]}, DOI={10.1016/j.gene.2004.07.034}, abstractNote={Woodchuck is an important animal model for studying human hepatitis B virus (HBV) infection. Within the cytokine network, interleukin-6 (IL-6) plays an important role in immune responses that may lead to viral clearance. To further understand woodchuck IL-6 biology, we cloned and characterized the IL-6 gene from white blood cells. The complete woodchuck IL-6 gene is about 7 kb and consists of five exons and four introns. The IL-6 gene organization of the woodchuck is similar to those of the human, rat, and mouse. Also several elements are highly conserved in the 300 bp promoter region of the IL-6 gene, including a nuclear factor kappa B (NF-kappaB) binding site. The woodchuck IL-6 gene encodes a polypeptide of 207 amino acids in a precursor form and 189 amino acids in the mature form. The expressed protein was 23 kDa according to SDS-PAGE. To demonstrate biologic activity, we expressed woodchuck IL-6 and showed that the purified recombinant protein induced terminal differentiation, as reflected by upregulation of Fcgamma receptor expression, and substantially inhibited proliferation of M1 cells, a murine myeloid leukemia cell line. The inhibitory effect of woodchuck IL-6 on M1 cells was blocked by an anti-gp130 monoclonal antibody, suggesting that woodchuck IL-6 activity is specifically mediated by signaling through the IL-6 receptor complex. Cloning of the woodchuck IL-6 gene and demonstrating biologic activity of the gene product will facilitate studies of human hepatitis B virus using the woodchuck model.}, number={1}, journal={GENE}, author={Li, DH and Kumanogoh, A and Cao, TM and Parnes, JR and Cullen, JM}, year={2004}, month={Nov}, pages={157–164} }
 @article{gillespie_washabau_goldschmidt_cullen_rogala_breitschwerdt_2003, title={Detection of Bartonella henselae and Bartonella clarridgeiae DNA in hepatic specimens from two dogs with hepatic disease}, volume={222}, ISSN={0003-1488}, url={http://dx.doi.org/10.2460/javma.2003.222.47}, DOI={10.2460/javma.2003.222.47}, abstractNote={A 4-year-old Basset Hound and a 6-year-old Doberman Pinscher were referred for diagnostic evaluation following documentation of persistently increased hepatic enzyme activities and hepatic dysfunction. Histologic evaluation of hepatic biopsy specimens from the 2 dogs revealed granulomatous hepatitis in the Basset Hound and lymphocytic hepatitis with fibrosis and copper accumulation in the Doberman Pinscher. No etiologic agents were identified histologically. Bartonella henselae DNA was subsequently amplified from hepatic tissue from the Basset Hound and Bartonella clarridgeiae was amplified from hepatic tissue from the Doberman Pinscher. Amplification was performed with a polymerase chain reaction assay incorporating primers that target a portion of the 16S-23S rRNA intergenic spacer region. Both dogs were treated with azithromycin, in combination with a variety of other medications and herbal treatments, and improved clinically. Identification of Bartonella DNA in these dogs indicates the need for future prospective studies to determine the clinical relevance of Bartonella spp infection in dogs with hepatic disease.}, number={1}, journal={Journal of the American Veterinary Medical Association}, publisher={American Veterinary Medical Association (AVMA)}, author={Gillespie, Tracey N. and Washabau, Robert J. and Goldschmidt, Michael H. and Cullen, John M. and Rogala, Allison R. and Breitschwerdt, Edward B.}, year={2003}, month={Jan}, pages={47–51} }
 @article{fox_shen_xu_feng_dangler_dewhirst_paster_cullen_2002, title={Helicobacter marmotae sp nov isolated from livers of woodchucks and intestines of cats}, volume={40}, ISSN={["0095-1137"]}, DOI={10.1128/JCM.40.7.2513-2519.2002}, abstractNote={ABSTRACT}, number={7}, journal={JOURNAL OF CLINICAL MICROBIOLOGY}, author={Fox, JG and Shen, ZL and Xu, SL and Feng, Y and Dangler, CA and Dewhirst, FE and Paster, BJ and Cullen, JM}, year={2002}, month={Jul}, pages={2513–2519} }
 @article{cullen_ll_brown_eisenberg_cundy_wolfe_toole_gibbs_2001, title={Antiviral efficacy and pharmacokinetics of oral adefovir dipivoxil in chronically woodchuck hepatitis virus-infected woodchucks}, volume={45}, ISSN={["1098-6596"]}, DOI={10.1128/AAC.45.10.2740-2745.2001}, abstractNote={ABSTRACT}, number={10}, journal={ANTIMICROBIAL AGENTS AND CHEMOTHERAPY}, author={Cullen, JM and Ll, DH and Brown, C and Eisenberg, EJ and Cundy, KC and Wolfe, J and Toole, J and Gibbs, C}, year={2001}, month={Oct}, pages={2740–2745} }
 @article{bunch_johnson_cullen_2001, title={Idiopathic noncirrhotic portal hypertension in dogs: 33 cases (1982-1998)}, volume={218}, ISSN={["0003-1488"]}, DOI={10.2460/javma.2001.218.392}, abstractNote={Abstract}, number={3}, journal={JOURNAL OF THE AMERICAN VETERINARY MEDICAL ASSOCIATION}, author={Bunch, SE and Johnson, SE and Cullen, JM}, year={2001}, month={Feb}, pages={392–399} }
 @article{zhu_yamamoto_cullen_saputelli_aldrich_miller_litwin_furman_jilbert_mason_2001, title={Kinetics of hepadnavirus loss from the liver during inhibition of viral DNA synthesis}, volume={75}, ISSN={["0022-538X"]}, DOI={10.1128/JVI.75.1.311-322.2001}, abstractNote={ABSTRACT}, number={1}, journal={JOURNAL OF VIROLOGY}, author={Zhu, Y and Yamamoto, T and Cullen, J and Saputelli, J and Aldrich, CE and Miller, DS and Litwin, S and Furman, PA and Jilbert, AR and Mason, WS}, year={2001}, month={Jan}, pages={311–322} }
 @article{hervas-stubbs_lasarte_sarobe_vivas_condreay_cullen_prieto_borras-cuesta_2001, title={T-helper cell response to woodchuck hepatitis virus antigens after therapeutic vaccination of chronically-infected animals treated with lamivudine}, volume={35}, ISSN={["0168-8278"]}, DOI={10.1016/S0168-8278(01)00063-0}, abstractNote={Immunotherapy of patients chronically-infected with hepatitis B virus (HBV) may have the risk of fulminant hepatitis. This risk might be diminished if immunotherapy was carried out under conditions of low viremia.Five woodchucks chronically-infected with woodchuck hepatitis virus (WHV), a virus closely related to HBV, were treated with lamivudine for 23 weeks. At week 10, when viremia had decreased by 3-5 logs, three woodchucks were vaccinated with woodchuck hepatitis virus surface antigen (WHsAg) plus the T-helper determinant FISEAIIHVLHSR.It was found that the administration of lamivudine only, had no effect on the T-helper response against WHV antigens. By contrast, vaccination induced T-helper responses against WHV antigens, shifting the cytokine profile from Th2 to Th0/Th1, but was without effect on viremia, WHsAg levels, or anti-WHs antibodies. Analysis of liver biopsies showed that lamivudine administration may have reduced hepatic inflammation. By contrast, vaccination clearly enhanced hepatic inflammation. After lamivudine withdrawal, viremia returned to high levels.These results suggest that therapeutic vaccination of chronically-infected woodchucks under conditions of low viremia shifts the cytokine profile against viral antigens towards Th0/Th1. This shift may prevent the efficient induction of anti-WHs antibodies.}, number={1}, journal={JOURNAL OF HEPATOLOGY}, author={Hervas-Stubbs, S and Lasarte, JJ and Sarobe, P and Vivas, I and Condreay, L and Cullen, JM and Prieto, J and Borras-Cuesta, F}, year={2001}, month={Jul}, pages={105–111} }
 @article{ohashi_marion_nakai_meuse_cullen_bordier_schwall_greenberg_glenn_kay_2000, title={Sustained survival of human hepatocytes in mice: A model for in vivo infection with human hepatitis B and hepatitis delta viruses}, volume={6}, DOI={10.1038/73187}, abstractNote={Persistence of hepatocytes transplanted into the same or related species has been established. The long-term engraftment of human hepatocytes into rodents would be useful for the study of human viral hepatitis, where it might allow the species, technical and size limitations of the current animal models to be overcome. Although transgenic mice expressing the hepatitis B virus (HBV) genome produce infectious virus in their serum, the viral life cycle is not complete, in that the early stages of viral binding and entry into hepatocytes and production of an episomal transcriptional DNA template do not occur. As for hepatitis delta virus (HDV), another cause of liver disease, no effective therapy exists to eradicate infection, and it remains resistant even to recent regimens that have considerably changed the treatment of HBV (ref. 13). Here, we demonstrate long-term engraftment of primary human hepatocytes transplanted in a matrix under the kidney capsule of mice with administration of an agonistic antibody against c-Met. These mice were susceptible to HBV infection and completion of the viral life cycle. In addition, we demonstrate super-infection of the HBV-infected mice with HDV. Our results describe a new xenotransplant model that allows study of multiple aspects of human hepatitis viral infections, and may enhance studies of human liver diseases.}, number={3}, journal={Nature Medicine}, author={Ohashi, K. and Marion, P. L. and Nakai, H. and Meuse, L. and Cullen, J. M. and Bordier, B. B. and Schwall, R. and Greenberg, H. B. and Glenn, J. S. and Kay, M. A.}, year={2000}, pages={327–331} }
 @article{li_havell_brown_cullen_2000, title={Woodchuck lymphotoxin-alpha, -beta and tumor necrosis factor genes: structure, characterization and biological activity}, volume={242}, ISSN={["0378-1119"]}, DOI={10.1016/S0378-1119(99)00494-1}, abstractNote={We cloned and characterized the woodchuck tumor necrosis factor (TNF) and lymphotoxin-alpha, -beta (LT-alpha, -beta) cDNAs, genes and proteins to facilitate study of the functions of these cytokines during the course of woodchuck hepatitis virus (WHV) infection. Woodchuck cDNA and genomic DNA libraries were screened with woodchuck-specific DNA probes to isolate the cDNA and gene clones for TNF, LT-alpha and LT-beta. The cDNAs for woodchuck TNF, LT-alpha and LT-beta code for proteins of 233, 205 and 310 amino acids respectively. The polypeptide encoded by each gene among woodchucks, humans and mice can differ: the human TNF, LT-alpha and LT-beta genes encode polypeptides of 233, 205 and 244 amino acids respectively, whereas the mouse TNF, LT-alpha and LT-beta genes encode polypeptides of 235, 202 and 306 amino acids respectively. In the woodchuck, there are four exons for TNF, four exons for LT-alpha and three exons for LT-beta. The RNA splicing patterns for TNF, LT-alpha and LT-beta genes are identical among woodchucks, humans and mice, except that the human LT-beta gene contains four exons. The woodchuck TNF gene promoter contains consensus sequences for binding of AP-1, AP-2, C/EBPbeta, CRE, Egr-1, Ets, NF-AT, NF-kappaB and SP-1 transcription factors. LT-alpha has AP-2, Ets, NF-kappaB, SP-1 and STAT binding sites, and LT-beta has Egr-1/SP-1, Ets and NF-kappaB binding sites. The bacterially expressed woodchuck TNF and LT-alpha proteins exhibited cytotoxic activities on both mouse L929B and woodchuck A2 cells in the presence of actinomycin D. The specific activities of TNF and LT-alpha were 2.62x10(8) units/mg and 2.22x10(3) units/mg respectively for L929B cells, and 1.05x10(9) units/mg and 3.56x10(4) units/mg respectively for A2 cells. However, only woodchuck TNF showed cytotoxic activity on human HepG2 cells, with a specific activity of 6.55x10(7) units/mg in the presence of actinomycin D. The data obtained from this study will be useful to future investigations of the TNF and LT antitumor and anti-viral activities, and their therapeutic potential in the woodchuck model for human hepatitis B virus (HBV).}, number={1-2}, journal={GENE}, author={Li, DH and Havell, EA and Brown, CL and Cullen, JM}, year={2000}, month={Jan}, pages={295–305} }
 @article{sharp_davis_guy_cullen_steingold_kornegay_1999, title={Hydranencephaly and cerebellar hypoplasia in two kittens attributed to intrauterine parvovirus infection}, volume={121}, ISSN={["0021-9975"]}, DOI={10.1053/jcpa.1998.0298}, abstractNote={Six weeks after vaccination with modified live feline parvovirus vaccine, a cat gave birth to five kittens, three of which died soon afterwards. The remaining two kittens (A and B) survived, but at 8 weeks of age were unable to walk and showed abnormal behaviour, with lack of menace and oculovestibular responses, and severe dysmetria. These signs suggested multifocal disease associated with the cerebrum and cerebellum. Magnetic resonance imaging demonstrated severe bilateral (kitten A) or unilateral (kitten B) hydrocephalus or hydranencephaly, combined with cerebellar agenesis (kitten A) or severe hypoplasia (kitten B). Hydranencephaly was confirmed histopathologically in both kittens. Parvovirus was isolated from the kidney of one kitten. Parvoviral DNA was amplified by the polymerase chain reaction (PCR) from paraffin wax-embedded brain of both kittens. The severe malformations observed in these kittens presumably resulted from an in-utero parvovirus infection, possibly due to vaccination, that occurred late in the first, or early in the second, trimester of pregnancy.}, number={1}, journal={JOURNAL OF COMPARATIVE PATHOLOGY}, author={Sharp, NJH and Davis, BJ and Guy, JS and Cullen, JM and Steingold, SF and Kornegay, JN}, year={1999}, month={Jul}, pages={39–53} }
 @article{mason_cullen_moraleda_saputelli_aldrich_miller_tennant_frick_averett_condreay_et al._1998, title={Lamivudine therapy of WHV-infected woodchucks}, volume={245}, ISSN={["0042-6822"]}, DOI={10.1006/viro.1998.9150}, abstractNote={Hepatitis B viruses establish a chronic, productive, and noncytopathic infection of hepatocytes. Viral products are produced by transcription from multiple copies (5-50) of covalently closed circular (ccc) viral DNA. This cccDNA does not replicate, but can be replaced by DNA precursors that are synthesized in the cytoplasm. The present study was carried out to determine if long-term treatment with an inhibitor of viral DNA synthesis would lead to loss of virus products, including cccDNA, from the liver of woodchucks chronically infected with woodchuck hepatitis virus. Viral DNA synthesis was inhibited with the nucleoside analog, lamivudine (2'-deoxy-3'-thiacytidine). Lamivudine treatment produced a slow but progressive decline in viral titers in serum, to about 0.3% or less of the initial level. However, even after maintenance of drug therapy for 3-12 months, > 95% of the hepatocytes in most animals were still infected. Significant declines in the percentage of infected hepatocytes and of intrahepatic cccDNA levels were observed in only three woodchucks, two in the group receiving lamivudine and one in the placebo control group. Moreover, virus titers eventually rose in woodchucks receiving lamivudine, suggesting that drug-resistant viruses began to spread through the liver starting at least as early as 9-12 months of treatment. Three types of mutation that may be associated with drug resistance were found at this time, in a region upstream of the YMDD motif in the active site of the viral reverse transcriptase. The YMDD motif itself remained unchanged. Not unexpectedly, the lamivudine therapy did not have a impact on development of liver cancer.}, number={1}, journal={VIROLOGY}, author={Mason, WS and Cullen, J and Moraleda, G and Saputelli, J and Aldrich, CE and Miller, DS and Tennant, B and Frick, L and Averett, D and Condreay, LD and et al.}, year={1998}, month={May}, pages={18–32} }
 @article{cullen_smith_davis_dunn_botteron_cecchi_linsey_linzey_frick_paff_et al._1997, title={In vivo antiviral activity and pharmacokinetics of (-)-cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine in woodchuck hepatitis virus-infected woodchucks}, volume={41}, ISSN={["0066-4804"]}, DOI={10.1128/aac.41.10.2076}, abstractNote={The (-) enantiomer of cis-5-fluoro-1l-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine [(-)-FTC)], a substituted oxathiolane compound with anti-hepatitis B virus activity in vitro, was assessed for its efficacy in woodchucks with naturally acquired woodchuck hepatitis virus (WHV) infection. Pharmacokinetics and in vitro anabolism were also determined. (-)-FTC was anabolized to the 5'-triphosphate in a dose-related fashion, reaching a maximum concentration at about 24 h in cultured woodchuck hepatocytes. Following administration of a dose of 10 mg/kg of body weight intraperitoneally (i.p.), the clearance of (-)-FTC from plasma was monoexponential, the terminal half-life was 3.76 +/- 1.4 h, and the systemic clearance was 0.12 +/- 0.06 liters/h/kg. The antiviral efficacy of (-)-FTC in the woodchuck model was assessed by quantitation of serum WHV DNA levels and by WHV particle-associated DNA polymerase activity at two dosages, 30 and 20 mg/kg given i.p. twice daily (b.i.d.), respectively. The level of WHV DNA in serum was reduced 20- to 150-fold (average, 56-fold) in the 30-mg/kg-b.i.d. treatment group and 6- to 49-fold (average, 27-fold) in the 20-mg/kg-b.i.d. treatment group. Viral DNA polymerase levels diminished accordingly. One week after treatment was discontinued, WHV levels returned to pretreatment levels in both studies. These animals were biopsied before and following treatment with 30 mg of (-)-FTC per kg. Their livers were characterized by a mild increase in cytoplasmic lipid levels, but this change was not associated with altered liver enzyme levels. Serum chemistry and hematology results were within the normal ranges for all treated animals. We conclude that (-)-FTC is a potent antihepadnaviral agent and that it has no detectable toxic effects in woodchucks when given for up to 25 days. Further development of (-)-FTC as an anti-hepatitis B virus therapy for patients is warranted.}, number={10}, journal={ANTIMICROBIAL AGENTS AND CHEMOTHERAPY}, author={Cullen, JM and Smith, SL and Davis, MG and Dunn, SE and Botteron, C and Cecchi, A and Linsey, D and Linzey, D and Frick, L and Paff, MT and et al.}, year={1997}, month={Oct}, pages={2076–2082} }
 @article{hervasstubbs_lasarte_sarobe_prieto_cullen_roggendorf_borrascuesta_1997, title={Therapeutic vaccination of woodchucks against chronic woodchuck hepatitis virus infection}, volume={27}, ISSN={["0168-8278"]}, DOI={10.1016/S0168-8278(97)80090-6}, abstractNote={Therapeutic vaccination is a new approach to treat patients with chronic hepatitis B virus infection. We have used the woodchuck model to examine the efficacy and safety of this approach.Seven woodchucks chronically infected with woodchuck hepatitis virus were immunized with surface antigen from this virus, purified from plasma, in conjunction with a peptide named FIS (encompassing amino acids 106-118: FISEAIIHVLHSR from sperm whale myoglobin), which is recognized by T helper lymphocytes. As controls, two woodchucks chronically infected with woodchuck hepatitis virus were immunized: one with FIS only and the other with surface antigen only.Co-immunization with surface antigen and FIS, but not with FIS or surface antigen alone, induced anti-surface antibodies in 7/7 immunized woodchucks. In the two woodchucks in which the highest titer of anti-surface antibody was elicited, severe liver damage was observed: one died of fulminant hepatitis and the other became seriously ill with hepatic injury and had to be sacrificed.Co-immunization of chronically infected woodchucks with surface antigen and a peptide recognized by T helper cells produces a good anti-surface antibody response. However, this strategy needs to be optimized before its implementation in humans. Although our experiments are not strictly comparable to vaccination of chronically hepatitis B virus-infected patients with recombinant or plasma-derived vaccines, we believe that precautions should be taken to avoid the risk of severe liver injury when immunizing hepatitis B virus carriers.}, number={4}, journal={JOURNAL OF HEPATOLOGY}, author={HervasStubbs, S and Lasarte, JJ and Sarobe, P and Prieto, J and Cullen, J and Roggendorf, M and BorrasCuesta, F}, year={1997}, month={Oct}, pages={726–737} }
 @article{cullen_sandgren_brinster_maronpot_1993, title={HISTOLOGIC CHARACTERIZATION OF HEPATIC CARCINOGENESIS IN TRANSGENIC MICE EXPRESSING SV40 T-ANTIGENS}, volume={30}, ISSN={["1544-2217"]}, DOI={10.1177/030098589303000203}, abstractNote={ The development of hepatic neoplasms was histologically characterized in transgenic mice that expressed an albumin enhancer-promotor/SV40 T-antigen fusion gene. At least five transgenic and three control mice were examined at monthly intervals over a 3-month period. At 1 month of age, five transgenic mice (two male, three female) and three controls (one male, two female) were examined. Five transgenic mice (two male, three female) and three controls (one male, two female) were examined at 2 months of age. Fourteen transgenic mice (12 male, two female) and three controls (two male, one female) were examined at 3 months of age. At 1 month of age, liver-to-body weight ratios of transgenic mice were increased nearly twofold as compared with controls. Histologically, livers from transgenic mice were characterized by dysplastic hepatocytes with marked variation in nucleus and cell size. At 2 months of age, livers from transgenic mice were 2.5 times larger than control livers and contained numerous 1–5-mm cystic spaces. Transgenic livers also contained multiple eosinophilic, basophilic, and clear foci, as well as cystic, hyperplastic bile ducts and biliary adenomas. At 3 months of age, transgenic livers were enlarged over eightfold as compared with controls and contained numerous cysts and solid masses up to 2 cm in diameter. Trabecular, glandular, and anaplastic hepatocellular carcinomas, as well as benign and malignant biliary neoplasms, were diagnosed. No metastasis was observed. Subcutaneous trabecular hepatocellular carcinomas developed in two of three syngeneic mice that had received transplants of a solid hepatic neoplasm, confirming the neoplastic behavior of these tumors. These experiments, in which viral oncogene expression is targeted to all hepatocytes, support the multistage hypothesis of tumor development and illustrate the similarities in morphologic response of liver to a variety of carcinogenic insults. }, number={2}, journal={VETERINARY PATHOLOGY}, author={CULLEN, JM and SANDGREN, EP and BRINSTER, RL and MARONPOT, RR}, year={1993}, month={Mar}, pages={111–118} }
 @article{cullen_marion_sherman_hong_newbold_1990, title={Hepatic neoplasms in aflatoxin B1-treated, congenital duck hepatitis B virus-infected, and virus-free Pekin ducks}, volume={50}, number={13}, journal={Cancer Research}, author={Cullen, J. M. and Marion, P. L. and Sherman, G. J. and Hong, X. and Newbold, J. E.}, year={1990}, pages={4072} }
 @article{cullen_levine_1987, title={Pathologic manifestations of experimental Babesia microti infection in hamsters}, volume={37}, journal={Laboratory Animal Science}, author={Cullen, J. and Levine, J. F.}, year={1987}, pages={640–643} }
 @article{shearin_hedan_cadieu_erich_schmidt_faden_cullen_abadie_kwon_grone_et al., title={The MTAP-CDKN2A locus confers susceptibility to a naturally occurring canine cancer}, volume={21}, number={7}, journal={Cancer Epidemiology Biomarkers}, author={Shearin, A. L. and Hedan, B. and Cadieu, E. and Erich, S. A. and Schmidt, E. V. and Faden, D. L. and Cullen, J. and Abadie, J. and Kwon, E. M. and Grone, A. and et al.}, pages={1019–1027} }