Publications by authors named "Amanda P Beck"

29 Publications

  • Page 1 of 1

Challenges and Opportunities for the Veterinary Pathologist in Biomedical Research.

Vet Pathol 2020 Dec 17:300985820974005. Epub 2020 Dec 17.

Albert Einstein College of Medicine, Bronx, NY, USA.

Animal models have critical roles in biomedical research in promoting understanding of human disease and facilitating development of new therapies and diagnostic techniques to improve human and animal health. In the study of myriad human conditions, each model requires in-depth characterization of its assets and limitations in order for it to be used to greatest advantage. Veterinary pathology expertise is critical in understanding the relevance and translational validity of animal models to conditions under study, assessing morbidity and mortality, and validating outcomes as relevant or not to the study interventions. Clear communication with investigators and education of research personnel on the use and interpretation of pathology endpoints in animal models are critical to the success of any research program. The veterinary pathologist is underutilized in biomedical research due to many factors including misconceptions about high fiscal costs, lack of perceived value, limited recognition of their expertise, and the generally low number of veterinary pathologists currently employed in biomedical research. As members of the multidisciplinary research team, veterinary pathologists have an important role to educate scientists, ensure accurate interpretation of pathology data, maximize rigor, and ensure reproducibility to provide the most reliable data for animal models in biomedical research.
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http://dx.doi.org/10.1177/0300985820974005DOI Listing
December 2020

Evolving challenges to model human diseases for translational research.

Cell Tissue Res 2020 May 4;380(2):305-311. Epub 2020 Mar 4.

Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA, USA.

Animal models are a significant component of biomedical research and play an important role in translational studies. Traditionally, rodent models have been the mainstay and principal choice of researchers but in recent years, there have been significant changes in the landscape of animal modeling. For example, newer techniques have greatly expanded the use and successful application of large animal models such as pigs for translational studies. The evolving types and species of animal models can influence the research landscape in terms of facilities, expertise, reproducibility and funding streams, which creates new challenges for research studies. It is also important that investigators are prepared to address the necessity of their animal model research and capable to educate the public regarding its value.
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http://dx.doi.org/10.1007/s00441-019-03134-3DOI Listing
May 2020

Histopathologic Evaluation and Scoring of Viral Lung Infection.

Methods Mol Biol 2020 ;2099:205-220

Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA.

Emergent coronaviruses such as MERS-CoV and SARS-CoV can cause significant morbidity and mortality in infected individuals. Lung infection is a common clinical feature and contributes to disease severity as well as viral transmission. Animal models are often required to study viral infections and therapies, especially during an initial outbreak. Histopathology studies allow for identification of lesions and affected cell types to better understand viral pathogenesis and clarify effective therapies. Use of immunostaining allows detection of presumed viral receptors and viral tropism for cells can be evaluated to correlate with lesions. In the lung, lesions and immunostaining can be qualitatively described to define the cell types, microanatomic location, and type of changes seen. These features are important and necessary, but this approach can have limitations when comparing treatment groups. Semiquantitative and quantitative tissue scores are more rigorous as these provide the ability to statistically compare groups and increase the reproducibility and rigor of the study. This review describes principles, approaches, and resources that can be useful to evaluate coronavirus lung infection, focusing on MER-CoV infection as the principal example.
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http://dx.doi.org/10.1007/978-1-0716-0211-9_16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7123785PMC
September 2020

Menagerie: A text-mining tool to support animal-human translation in neurodegeneration research.

PLoS One 2019 17;14(12):e0226176. Epub 2019 Dec 17.

Lister Hill National Center for Biomedical Communications, National Library of Medicine, Bethesda, Maryland, United States of America.

Discovery studies in animals constitute a cornerstone of biomedical research, but suffer from lack of generalizability to human populations. We propose that large-scale interrogation of these data could reveal patterns of animal use that could narrow the translational divide. We describe a text-mining approach that extracts translationally useful data from PubMed abstracts. These comprise six modules: species, model, genes, interventions/disease modifiers, overall outcome and functional outcome measures. Existing National Library of Medicine natural language processing tools (SemRep, GNormPlus and the Chemical annotator) underpin the program and are further augmented by various rules, term lists, and machine learning models. Evaluation of the program using a 98-abstract test set achieved F1 scores ranging from 0.75-0.95 across all modules, and exceeded F1 scores obtained from comparable baseline programs. Next, the program was applied to a larger 14,481 abstract data set (2008-2017). Expected and previously identified patterns of species and model use for the field were obtained. As previously noted, the majority of studies reported promising outcomes. Longitudinal patterns of intervention type or gene mentions were demonstrated, and patterns of animal model use characteristic of the Parkinson's disease field were confirmed. The primary function of the program is to overcome low external validity of animal model systems by aggregating evidence across a diversity of models that capture different aspects of a multifaceted cellular process. Some aspects of the tool are generalizable, whereas others are field-specific. In the initial version presented here, we demonstrate proof of concept within a single disease area, Parkinson's disease. However, the program can be expanded in modular fashion to support a wider range of neurodegenerative diseases.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0226176PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6917268PMC
March 2020

Aggregation properties of triamcinolone acetonide injection in human serum: considerations when performing epidural steroid injections.

J Pain Res 2019 20;12:1033-1039. Epub 2019 Mar 20.

Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA.

Background: Morbidity has been reported as a sequelae of crystalline steroid epidural steroid injections (ESIs), and particulate steroid size, aggregation, and embolization in brain and spinal cord may be the mechanism related to these neurologic effects.

Objective: The objective of the study was to examine the aggregation properties of triamcinolone acetonide in commonly used local anesthetics with and without human serum.

Setting: This study was conducted in an academic tertiary care center.

Hypothesis: Triamcinolone acetonide shows different aggregation characteristics in serum compared to a non-physiologic solution.

Design: Triamcinolone acetonide was mixed with lidocaine 1% (first group) and bupivacaine 0.5% (second group) in a 1:1 ratio and then mixed with either distilled water (control group) or serum ex vivo. A pathologist blinded to our hypothesis inspected all solutions under light microscopy with 100× and 400× magnifications. Total number of particulate steroid aggregates and the number of particles forming each aggregate (recorded as single,1 double,2 triple,3 quadruple,4 or large [>4} crystals) were counted. Particle size and aggregate size were measured (in μm). The ratios of quadruple to total aggregates, large to total, and quadruple with large to total aggregates were calculated. Steroid-serum solutions and steroid-sterile water were then compared.

Results: Triamcinolone aggregates showed an increased crystal and aggregate size when compared with other steroids. Within the triamcinolone subgroup, the mixture of lidocaine 1% and serum resulted in the largest crystal aggregates.

Limitations: Whole blood analysis may have provided a more physiologically accurate model but was not chosen due to poor microscopic analysis. Serum donor variability may also have affected particle characteristics.

Conclusion: Fewer large triamcinolone aggregates were noted in the presence of serum when compared to the non-serum control groups. However, when compared to previously studied particulate steroids, it had the largest aggregates when added to serum.
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http://dx.doi.org/10.2147/JPR.S181038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6430988PMC
March 2019

Fundamental Concepts for Semiquantitative Tissue Scoring in Translational Research.

ILAR J 2018 12;59(1):13-17

Department of Pathology, Albert Einstein College of Medicine, Bronx, New York.

Failure to reproduce results from some scientific studies has raised awareness of the critical need for reproducibility in translational studies. Macroscopic and microscopic examination is a common approach to determine changes in tissues, but text descriptions and visual images have limitations for group comparisons. Semiquantitative scoring is a way of transforming qualitative tissue data into numerical data that allow more robust group comparisons. Semiquantitative scoring has broad uses in preclinical and clinical studies for evaluation of tissue lesions. Reproducibility can be improved by constraining bias through appropriate experimental design, randomization of tissues, effective use of multidisciplinary collaborations, and valid masking procedures. Scoring can be applied to tissue lesions (eg, size, distribution, characteristics) and also to tissues through evaluation of staining distribution and intensity. Semiquantitative scores should be validated to demonstrate relevance to biological data and to demonstrate observer reproducibility. Statistical analysis should make use of appropriate tests to give robust confidence in the results and interpretations. Following key principles of semiquantitative scoring will not only enhance descriptive tissue evaluation but also improve quality, reproducibility, and rigor of tissue studies.
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http://dx.doi.org/10.1093/ilar/ily025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927897PMC
December 2018

Radiation-primed hepatocyte transplantation in murine monogeneic dyslipidemia normalizes cholesterol and prevents atherosclerosis.

J Hepatol 2019 06 14;70(6):1170-1179. Epub 2019 Jan 14.

Department of Pathology, Montefiore Medical Center and Albert Einstein College of Medicine, Bronx, NY, United States; Department of Surgery, Montefiore Medical Center and Albert Einstein College of Medicine, Bronx, NY, United States; Department of Radiation Oncology, Montefiore Medical Center and Albert Einstein College of Medicine, Bronx, NY, United States; Department of Medicine, Montefiore Medical Center and Albert Einstein College of Medicine, Bronx, NY, United States; The Marion Bessin Liver Research Center, Montefiore Medical Center and Albert Einstein College of Medicine, Bronx, NY, United States; Department of Urology, Montefiore Medical Center and Albert Einstein College of Medicine, Bronx, NY, United States. Electronic address:

Background & Aims: Inherited abnormalities in apolipoprotein E (ApoE) or low-density lipoprotein receptor (LDLR) function result in early onset cardiovascular disease and death. Currently, the only curative therapy available is liver transplantation. Hepatocyte transplantation is a potential alternative; however, physiological levels of hepatocyte engraftment and repopulation require transplanted cells to have a competitive proliferative advantage of over host hepatocytes. Herein, we aimed to test the efficacy and safety of a novel preparative regimen for hepatocyte transplantation.

Methods: Herein, we used an ApoE-deficient mouse model to test the efficacy of a new regimen for hepatocyte transplantation. We used image-guided external-beam hepatic irradiation targeting the median and right lobes of the liver to enhance cell transplant engraftment. This was combined with administration of the hepatic mitogen GC-1, a thyroid hormone receptor-β agonist mimetic, which was used to promote repopulation.

Results: The non-invasive preparative regimen of hepatic irradiation and GC-1 was well-tolerated in ApoE mice. This regimen led to robust liver repopulation by transplanted hepatocytes, which was associated with significant reductions in serum cholesterol levels after transplantation. Additionally, in mice receiving this regimen, ApoE was detected in the circulation 4 weeks after treatment and did not induce an immunological response. Importantly, the normalization of serum cholesterol prevented the formation of atherosclerotic plaques in this model.

Conclusions: Significant hepatic repopulation and the cure of dyslipidemia in this model, using a novel and well-tolerated preparative regimen, demonstrate the clinical potential of applying this method to the treatment of inherited metabolic diseases of the liver.

Lay Summary: Hepatocyte transplantation is a promising alternative to liver transplantation for the treatment of liver diseases. However, it is inefficient, as restricted growth of transplanted cells in the liver limits its therapeutic benefits. Preparative treatments improve the efficiency of this procedure, but no clinically-feasible options are currently available. In this study we develop a novel well-tolerated preparative treatment to improve growth of cells in the liver and then demonstrate that this treatment completely cures an inherited lipid disorder in a mouse model.
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http://dx.doi.org/10.1016/j.jhep.2019.01.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6986679PMC
June 2019

Glycogen depletion can increase the specificity of mucin detection in airway tissues.

BMC Res Notes 2018 Oct 25;11(1):763. Epub 2018 Oct 25.

Department of Veterinary Pathology, Iowa State University College of Veterinary Medicine, Ames, IA, USA.

Objective: Mucin is an important parameter for detection and assessment in studies of airway disease including asthma and cystic fibrosis. Histochemical techniques are often used to evaluate mucin in tissues sections. Periodic acid Schiff (PAS) is a common technique to detect neutral mucins in tissue, but this technique also detects other tissue components including cellular glycogen. We tested whether depletion of glycogen, a common cellular constituent, could impact the detection of mucin in the surface epithelium of the trachea.

Results: Normal tissues stained by PAS had significantly more staining than serial sections of glycogen-depleted tissue with PAS staining (i.e. dPAS technique) based on both quantitative analysis and semiquantitative scores. Most of the excess stain by the PAS technique was detected in ciliated cells adjacent to goblet cells. We also compared normal tissues using the Alcian blue technique, which does not have reported glycogen staining, with the dPAS technique. These groups had similar amounts of staining consistent with a high degree of mucin specificity. Our results suggest that when using PAS techniques to stain airways, the dPAS approach is preferred as it enhances the specificity for airway mucin.
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http://dx.doi.org/10.1186/s13104-018-3855-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6203197PMC
October 2018

Observational Study Design in Veterinary Pathology, Part 2: Methodology.

Vet Pathol 2018 11 18;55(6):774-785. Epub 2018 Sep 18.

20 Laboratory of Veterinary Pathology, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Izumisano City, Osaka, Japan.

Observational studies are a basis for much of our knowledge of veterinary pathology, yet considerations for conducting pathology-based observational studies are not readily available. In part 1 of this series, we offered advice on planning and carrying out an observational study. Part 2 of the series focuses on methodology. Our general recommendations are to consider using already-validated methods, published guidelines, data from primary sources, and quantitative analyses. We discuss 3 common methods in pathology research-histopathologic scoring, immunohistochemistry, and polymerase chain reaction-to illustrate principles of method validation. Some aspects of quality control include use of clear objective grading criteria, validation of key reagents, assessing sample quality, determining specificity and sensitivity, use of technical and biologic negative and positive controls, blinding of investigators, approaches to minimizing operator-dependent variation, measuring technical variation, and consistency in analysis of the different study groups. We close by discussing approaches to increasing the rigor of observational studies by corroborating results with complementary methods, using sufficiently large numbers of study subjects, consideration of the data in light of similar published studies, replicating the results in a second study population, and critical analysis of the study findings.
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http://dx.doi.org/10.1177/0300985818798121DOI Listing
November 2018

Common Pitfalls in Analysis of Tissue Scores.

Vet Pathol 2019 Jan 21;56(1):39-42. Epub 2018 Aug 21.

3 Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA.

Histopathology remains an important source of descriptive biological data in biomedical research. Recent petitions for enhanced reproducibility in scientific studies have elevated the role of tissue scoring (semiquantitative and quantitative) in research studies. Effective tissue scoring requires appropriate statistical analysis to help validate the group comparisons and give the pathologist confidence in interpreting the data. Each statistical test is typically founded on underlying assumptions regarding the data. If the underlying assumptions of a statistical test do not match the data, then these tests can lead to increased risk of erroneous interpretations of the data. The choice of appropriate statistical test is influenced by the study's experimental design and resultant data (eg, paired vs unpaired, normality, number of groups, etc). Here, we identify 3 common pitfalls in the analysis of tissue scores: shopping for significance, overuse of paired t-tests, and misguided analysis of multiple groups. Finally, we encourage pathologists to use the full breadth of resources available to them, such as using statistical software, reading key publications about statistical approaches, and identifying a statistician to serve as a collaborator on the multidisciplinary research team. These collective resources can be helpful in choosing the appropriate statistical test for tissue-scoring data to provide the most valid interpretation for the pathologist.
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http://dx.doi.org/10.1177/0300985818794250DOI Listing
January 2019

Observational Study Design in Veterinary Pathology, Part 1: Study Design.

Vet Pathol 2018 09 2;55(5):607-621. Epub 2018 Aug 2.

20 Laboratory of Veterinary Pathology, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Izumisano City, Osaka, Japan.

Observational studies are the basis for much of our knowledge of veterinary pathology and are highly relevant to the daily practice of pathology. However, recommendations for conducting pathology-based observational studies are not readily available. In part 1 of this series, we offer advice on planning and conducting an observational study with examples from the veterinary pathology literature. Investigators should recognize the importance of creativity, insight, and innovation in devising studies that solve problems and fill important gaps in knowledge. Studies should focus on specific and testable hypotheses, questions, or objectives. The methodology is developed to support these goals. We consider the merits and limitations of different types of analytic and descriptive studies, as well as of prospective vs retrospective enrollment. Investigators should define clear inclusion and exclusion criteria and select adequate numbers of study subjects, including careful selection of the most appropriate controls. Studies of causality must consider the temporal relationships between variables and the advantages of measuring incident cases rather than prevalent cases. Investigators must consider unique aspects of studies based on archived laboratory case material and take particular care to consider and mitigate the potential for selection bias and information bias. We close by discussing approaches to adding value and impact to observational studies. Part 2 of the series focuses on methodology and validation of methods.
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http://dx.doi.org/10.1177/0300985818785705DOI Listing
September 2018

Principles and approaches for reproducible scoring of tissue stains in research.

Lab Invest 2018 07 30;98(7):844-855. Epub 2018 May 30.

Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA.

Evaluation of tissues is a common and important aspect of translational research studies. Labeling techniques such as immunohistochemistry can stain cells/tissues to enhance identification of specific cell types, cellular activation states, and protein expression. While qualitative evaluation of labeled tissues has merit, use of semiquantitative and quantitative scoring approaches can greatly enhance the rigor of the tissue data. Adhering to key principles for reproducible scoring can enhance the quality and reproducibility of the tissue data so as to maximize its biological relevance and scientific impact.
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http://dx.doi.org/10.1038/s41374-018-0057-0DOI Listing
July 2018

The Xenobiotic Transporter Mdr1 Enforces T Cell Homeostasis in the Presence of Intestinal Bile Acids.

Immunity 2017 12;47(6):1182-1196.e10

Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL 33458, USA. Electronic address:

CD4 T cells are tightly regulated by microbiota in the intestine, but whether intestinal T cells interface with host-derived metabolites is less clear. Here, we show that CD4 T effector (Teff) cells upregulated the xenobiotic transporter, Mdr1, in the ileum to maintain homeostasis in the presence of bile acids. Whereas wild-type Teff cells upregulated Mdr1 in the ileum, those lacking Mdr1 displayed mucosal dysfunction and induced Crohn's disease-like ileitis following transfer into Rag1 hosts. Mdr1 mitigated oxidative stress and enforced homeostasis in Teff cells exposed to conjugated bile acids (CBAs), a class of liver-derived emulsifying agents that actively circulate through the ileal mucosa. Blocking ileal CBA reabsorption in transferred Rag1 mice restored Mdr1-deficient Teff cell homeostasis and attenuated ileitis. Further, a subset of ileal Crohn's disease patients displayed MDR1 loss of function. Together, these results suggest that coordinated interaction between mucosal Teff cells and CBAs in the ileum regulate intestinal immune homeostasis.
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http://dx.doi.org/10.1016/j.immuni.2017.11.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5741099PMC
December 2017

Metastatic Squamous Cell Carcinoma in a Northern Brown Bandicoot (Isoodon macrourus).

Vet Sci 2017 Feb 14;4(1). Epub 2017 Feb 14.

College of Public Health, Medical and Veterinary Sciences, James Cook University, Townsville 4811, Queensland, Australia.

Aside from a handful of notable exceptions, neoplasia is not reported as a major cause of mortality in wild animal populations and often goes undetected. For northern brown bandicoots specifically, there are few reported tumors in the literature and on file in the Australian Registry of Wildlife Health. This report describes a case of squamous cell carcinoma in a northern brown bandicoot (), with metastases to the draining lymph nodes and lung. This neoplasm consisted predominantly of well-differentiated squamous cells and multifocal keratin pearls, with areas possibly consistent with epithelial to mesenchymal transition, as identified by positive immunohistochemical staining by both pancytokeratin (AE1/AE3) and vimentin. Additional investigations were negative for bandicoot papillomatosis carcinomatosis viruses.
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http://dx.doi.org/10.3390/vetsci4010010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5606615PMC
February 2017

Approaches to Evaluate Lung Inflammation in Translational Research.

Vet Pathol 2018 01 16;55(1):42-52. Epub 2017 Aug 16.

5 Department of Veterinary Pathology, Iowa State University, Ames, IA, USA.

Inflammation is a common feature in several types of lung disease and is a frequent end point to validate lung disease models, evaluate genetic or environmental impact on disease severity, or test the efficacy of new therapies. Questions relevant to a study should be defined during experimental design and techniques selected to specifically address these scientific queries. In this review, the authors focus primarily on the breadth of techniques to evaluate lung inflammation that have both clinical and preclinical applications. Stratification of approaches to assess lung inflammation can diminish weaknesses inherent to each technique, provide data validation, and increase the reproducibility of a study. Specialized techniques (eg, imaging, pathology) often require experienced personnel to collect, evaluate, and interpret the data; these experts should be active contributors to the research team through reporting of the data. Scoring of tissue lesions is a useful method to transform observational pathologic data into semiquantitative or quantitative data for statistical analysis and enhanced rigor. Each technique to evaluate lung inflammation has advantages and limitations; understanding these parameters can help identify approaches that best complement one another to increase the rigor and translational significance of data.
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http://dx.doi.org/10.1177/0300985817726117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5600706PMC
January 2018

5α-reductase 1 mRNA levels are positively correlated with TRAMP mouse prostate most severe lesion scores.

PLoS One 2017 11;12(5):e0175874. Epub 2017 May 11.

Department of Food, Nutrition, Dietetics and Health, Kansas State University, Manhattan, KS, United States of America.

Background: The contribution of 5α-reductase 1 and 5α-reductase 2 to prostate cancer development and progression is not clearly understood. TRAMP mice are a common prostate cancer model, in which 5α-reductase 1 and 5α-reductase 2 expression levels, along with prostate lesions scores, have not been investigated at different time points to further understand prostate carcinogenesis.

Method/principal Findings: To this end, 8-, 12-, 16-, and 20-week-old male C57BL/6TRAMP x FVB mice prostate most severe and most common lesion scores, 5α-reductase 1 and 5α-reductase 2 in situ hybridization expression, and Ki-67, androgen receptor, and apoptosis immunohistochemistry levels were measured. Levels of these markers were quantified in prostate epithelium, hyperplasia, and tumors sections. Mice developed low- to high-grade prostatic intraepithelial neoplasia at 8 weeks as the most severe and most common lesions, and moderate- and high-grade prostatic intraepithelial neoplasia at 12 and 16 weeks as the most severe lesion in all lobes. Moderately differentiated adenocarcinoma was observed at 20 weeks in all lobes. Poorly differentiated carcinoma was not observed in any lobe until 12-weeks-old. 5α-reductase 1 and 5α-reductase 2 were not significantly decreased in tumors compared to prostate epithelium and hyperplasia in all groups, while proliferation, apoptosis, and androgen receptor were either notably or significantly decreased in tumors compared with prostate epithelium and hyperplasia in most or all groups. Prostate 5αR1 levels were positively correlated with adjusted prostate most severe lesion scores.

Conclusion: Downregulation of androgen receptor and 5α-reductase 2, along with upregulation of 5α-reductase 1 in tumors may promote prostatic intraepithelial neoplasia and prostate cancer development in TRAMP mice.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0175874PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5426600PMC
September 2017

inactivation, but not obesity, synergizes with deficiency to drive intestinal stem cell-derived tumorigenesis.

Endocr Relat Cancer 2017 06 28;24(6):253-265. Epub 2017 Mar 28.

Department of Molecular PharmacologyAlbert Einstein College of Medicine, Bronx, New York, USA

Obesity is a major risk factor for colorectal cancer and can accelerate Lgr5+ intestinal stem cell (ISC)-derived tumorigenesis after the inactivation of However, whether non-canonical pathways involving PI3K-Akt signaling in ISCs can lead to tumor formation, and if this can be further exacerbated by obesity is unknown. Despite the synergy between and inactivation in epithelial cells on intestinal tumor formation, their combined role in Lgr5+-ISCs, which are the most rapidly dividing ISC population in the intestine, is unknown. Lgr5+-GFP mice were provided low-fat diet (LFD) or high-fat diet (HFD) for 8 months, and the transcriptome was evaluated in Lgr5+-ISCs. For tumor studies, Lgr5+-GFP and Lgr5+-GFP- mice were tamoxifen treated to inactivate in ISCs and provided LFD or HFD until 14-15 months of age. Finally, various combinations of Lgr5+-ISC-specific, and -deleted mice were generated and evaluated for histopathology and survival. HFD did not overtly alter Akt signaling in ISCs, but did increase other metabolic pathways. deficiency, but not HFD, increased BrdU-positive cells in the small intestine ( < 0.05). However, combining and deficiency synergistically increased proliferative markers, tumor pathology and mortality, in a dose-dependent fashion ( < 0.05). In summary, we show that HFD alone fails to drive Akt signaling in ISCs and that deficiency is dispensable as a tumor suppressor in Lgr5+-ISCs. However, combining and deficiency in ISCs synergistically increases proliferation, tumor formation and mortality. Thus, aberrant Wnt/β-catenin, rather than PI3K-Akt signaling, is requisite for obesity to drive Lgr5+ ISC-derived tumorigenesis.
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http://dx.doi.org/10.1530/ERC-16-0536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5505256PMC
June 2017

Established patterns of animal study design undermine translation of disease-modifying therapies for Parkinson's disease.

PLoS One 2017 9;12(2):e0171790. Epub 2017 Feb 9.

Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, United States of America.

Translation of disease-modifying therapies in neurodegenerative disease has been disappointing. Parkinson's disease (PD) was used to compare patterns of preclinical study design for symptomatic and potentially disease-modifying interventions. We examined the relationship of model, intervention type and timing, outcomes and outcome measures in 543 animal and human studies (1973-2015) across a contemporary cohort of animal and human interventional studies (n = 445), animal studies for approved interventions (n = 28), animal and human studies for those that failed to translate (n = 70). Detailed study design data were collected for 216 studies in non-human primate (NHP) and rodent toxin-induced models. Species-specific patterns of study design prevailed regardless of whether interventions were symptomatic or potentially disease-modifying. In humans and NHPs, interventions were typically given to both sexes well after the PD phenotype was established, and clinical outcome measures were collected at single (symptomatic) or multiple (disease-modifying) time-points. In rodents, interventions often preceded induction of the model, acute toxic protocols were common, usually given to young males, clinical outcome measures were used less commonly, and outcomes were less commonly assessed at multiple time points. These patterns were more prevalent in mice than rats. In contrast, study design factors such as randomization and blinding did not differ appreciably across symptomatic and disease-modifying intervention categories. The translational gap for potentially disease-modifying interventions in PD in part results from study designs, particularly in mice, that fail to model the progressive nature and relatively late intervention characteristic of PD, or that anchor mechanistic and neuropathologic data to longitudinal clinical outcomes. Even if measures to improve reproducibility are broadly adopted, perpetuation of these norms will continue to impede effective translation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0171790PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5300282PMC
September 2017

Demodex musculi Infestation in Genetically Immunomodulated Mice.

Comp Med 2016 ;66(4):278-85

Department of Comparative Medicine, Mayo Clinic, Rochester, Minnesota, USA.

Demodex musculi, a prostigmatid mite that has been reported infrequently in laboratory mice, has been identified with increasing frequency in contemporary colonies of immunodeficient mice. Here we describe 2 episodes of D. musculi infestation with associated clinical signs in various genetically engineered mouse strains, as well as treatment strategies and an investigation into transmissibility and host susceptibility. The first case involved D. musculi associated with clinical signs and pathologic lesions in BALB/c-Tg(DO11.10)Il13(tm) mice, which have a defect in type 2 helper T cell (Th2) immunity. Subsequent investigation revealed mite transmission to both parental strains (BALB/c-Tg[DO11.10] and BALB/c-Il13(tm)), BALB/c-Il13/Il4(tm), and wild-type BALB/c. All Tg(DO11.10)Il13(tm) mice remained infested throughout the investigation, and D. musculi were recovered from all strains when they were cohoused with BALB/c-Tg(DO11.10)Il13(tm) index mice. However, only Il13(tm) and Il13/Il4(tm) mice demonstrated persistent infestation after index mice were removed. Only BALB/c-Tg(DO11.10)Il13(tm) showed clinical signs, suggesting that the phenotypic dysfunction of Th2 immunity is sufficient for persistent infestation, whereas clinical disease associated with D. musculi appears to be genotype-specific. This pattern was further exemplified in the second case, which involved NOD.Cg-Prkdc(scid)Il2r(tm1Wjl)/SzJ (NSG) and C;129S4 Rag2(tm1.1Flv) Il2rg(tm1.1Flv)/J mice with varying degrees of blepharitis, conjunctivitis, and facial pruritis. Topical amitraz decreased mite burden but did not eliminate infestation or markedly ameliorate clinical signs. Furthermore, mite burden began to increase by 1 mo posttreatment, suggesting that topical amitraz is an ineffective treatment for D. musculi. These experiences illustrate the need for vigilance regarding opportunistic and uncommon pathogens in rodent colonies, especially among mice with immunologic deficits.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4983169PMC
October 2017

Disseminated Hemangiosarcoma in a Juvenile Rhesus Macaque (Macaca mulatta).

Comp Med 2016 ;66(3):246-53

Michale E. Keeling Center for Comparative Medicine and Research Department of Veterinary Sciences, The University of Texas MD Anderson Cancer Center, Bastrop, Texas, USA.

Hemangiosarcoma is a malignant tumor of vascular endothelial origin that is sporadically reported in rhesus macaques. This report describes the clinicopathologic features of a 1-y-old rhesus macaque with spontaneous disseminated hemangiosarcoma that originally presented as a focal cutaneous mass. Histopathologic examination of multiple tumor foci revealed regions in which the neoplastic cells formed diffuse sheets, as well as the well-defined vascular channels typically associated with hemangiosarcoma. Multiple endothelial cell immunomarkers were used to confirm the diagnosis in this rhesus macaque. The tumor exhibited staining properties consistent with those seen in domestic animals and humans. In addition, to our knowledge, this animal represents the youngest case of any form of spontaneous hemangiosarcoma reported in the rhesus macaque to date.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4907535PMC
November 2017

Malignant Neoplasia of the Sex Skin in 2 Chimpanzees (Pan troglodytes).

Comp Med 2016 Apr;66(2):154-61

Michaele E. Keeling Center for Comparative Medicine and Research, Department of Veterinary Sciences, The University of Texas MD Anderson Cancer Center, Bastrop, Texas, USA.

This report describes 2 cases of spontaneous malignant neoplasia within the sex skin of aged female chimpanzees. In both cases, the initial presentation resembled nonhealing traumatic wounds to the sex skin, with different degrees of infection, ulceration, and tissue necrosis. Histopathology of the lesions confirmed the diagnosis of squamous cell carcinoma in one case and of adenocarcinoma with metastasis in the other. Advanced age and previous trauma likely contributed to the development of the neoplasias in both cases; long-term sun exposure may also have contributed to the development of the squamous cell carcinoma. To our knowledge, these 2 cases represent the first reports of sex skin neoplasia in chimpanzees.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4825966PMC
April 2016

Invasive ductular carcinoma in 2 rhesus macaques (Macaca mulatta).

Comp Med 2014 Aug;64(4):314-22

Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.

In the United States, breast cancer is the most common malignancy among women, with an estimated lifetime incidence of approximately 12% in American women. Invasive ductal carcinoma is the most common form of breast cancer in women, accounting for approximately 60% of all breast carcinomas. Prognostic markers are used to assess aggressiveness, invasiveness, and extent of spread of a neoplasm and thus may be correlated with patient survival. Immunohistochemistry is currently widely used for this purpose, with a variety of prognostication markers available. Classic markers for breast cancer in women include estrogen and progesterone receptor steroid hormone proteins and human epidermal growth factor receptor 2. Many additional markers have been used in diagnosis and prognostication, including p53, p63, and E-cadherin and cell proliferation markers such as Ki67. Despite an estimated lifetime incidence of approximately 6.1%, naturally occurring mammary neoplasms in nonhuman primates are uncommonly reported, with only sporadic references over the past 75 y. The majority of reported tumors occur in rhesus macaques, although this prevalence has been suggested to be a consequence of their high frequency of usage in biomedical research. Here we present 2 cases of mammary carcinoma in adult female intact rhesus macaques, with cytology, histopathology, and extensive immunohistochemical analysis. According to current classifications for human breast tumors, both tumors were classified as invasive ductal carcinoma. The prognostic value of immunohistochemical markers in human breast cancer and in reported cases in nonhuman primates is discussed.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4170097PMC
August 2014

Use of (18)F-fluorodeoxyglucose positron emission tomography-computed tomography to aid in diagnosing intestinal adenocarcinoma in 2 rhesus macaques (Macaca mulatta).

Comp Med 2014 Jun;64(3):211-20

Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.

Two aged female rhesus macaques (Macaca mulatta) presented with weight loss and intermittent inappetence. The signalment and constellation of clinical signs led clinicians to suspect the presence of intestinal adenocarcinoma. Because of each animal's advanced age and inconclusive radiographic findings, a noninvasive diagnostic tool was preferred over exploratory laparotomy to assist in determining a diagnosis. Consequently, 2-[(18)F]fluoro-2-deoxy-d-glucose (FDG) positron emission tomography-CT (FDG-PET-CT) was chosen to aid in confirming a suspicion of gastrointestinal adenocarcinoma in both animals. FDG is a glucose analogue labeled with fluorine-18 and is taken up by highly metabolically active cells, as observed in many cancers. Tomography revealed an annular constriction of the small intestine with focal FDG uptake in one animal, and an FDG avid transmural mass in the ascending colon of the second animal. Necropsy later confirmed both sites to be adenocarcinomas. This report supports the use of FDG-PET-CT as an adjunct to conventional radiography in the diagnosis of intestinal adenocarcinoma in nonhuman primates.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4067585PMC
June 2014

Pathology in practice. HaPyV infection in a pet Syrian hamster.

J Am Vet Med Assoc 2014 May;244(9):1037-9

Section of Comparative Medicine, School of Medicine, Yale University, New Haven, CT 06520.

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http://dx.doi.org/10.2460/javma.244.9.1037DOI Listing
May 2014

Endometrial decidualization and deciduosis in aged rhesus macaques (Macaca mulatta).

Comp Med 2014 Apr;64(2):148-56

Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.

Superficial decidualization of the endometrial stroma is an essential feature of the implantation stage of pregnancy in rhesus macaques and other primates. Decidualization involves proliferation of the endometrial stromal cells, with differentiation into morphologically distinct decidual cells. Previous reports involving nonpregnant rhesus monkeys have described local- ized and widespread endometrial decidualization in response to administration of progesterone and synthetic progestogens. Ectopic decidua or 'deciduosis' describes the condition in which groups of decidual cells are located outside of the endometrium, most often in the ovaries, uterus and cervix but also in various other organs. In humans, most cases of deciduosis are associated with normal pregnancy, and ectopic decidua can be found in the ovary in nearly all term pregnancies. Here we describe pronounced endometrial decidualization in 2 rhesus macaques. Both macaques had been treated long-term with medroxyprogesterone acetate for presumed endometriosis, which was confirmed in one of the macaques at postmortem examination. In one animal, florid extrauterine and peritoneal serosal decidualization was admixed multifocally with carcinomatosis from a primary colonic adenocarcinoma. Cells constituting endometrial and serosal decidualization reactions were immunopositive for the stromal markers CD10, collagen IV, smooth muscle actin, and vimentin and immunonegative for cytokeratin. In contrast, carcinomatous foci were cytokeratin-positive. To our knowledge, this report describes the first cases of serosal peritoneal decidualization in rhesus macaques. The concurrent presentation of serosal peritoneal decidualization with carcinomatosis is unique.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3997294PMC
April 2014

Preventive and therapeutic efficacy of finasteride and dutasteride in TRAMP mice.

PLoS One 2013 18;8(10):e77738. Epub 2013 Oct 18.

Department of Human Nutrition, Kansas State University, Manhattan, Kansas, United States of America.

Background: The prostate cancer prevention trial (PCPT) and Reduction by dutasteride of Prostate Cancer Events (REDUCE) trial found that 5α-reductase (5αR) inhibitors finasteride and dutasteride respectively, decreased prostate cancer prevalence but also increased the incidence of high-grade tumors. 5αR2 is the main isoenzyme in normal prostate tissue; however, most prostate tumors have high 5αR1 and low 5αR2 expression. Because finasteride inhibits only 5αR2, we hypothesized that it would not be as efficacious in preventing prostate cancer development and/or progression in C57BL/6 TRAMP x FVB mice as dutasteride, which inhibits both 5αR1 and 5αR2.

Method/principal Findings: Six-week-old C57BL/6 TRAMP x FVB male mice were randomized to AIN93G control or pre- and post- finasteride and dutasteride diet (83.3 mg drug/kg diet) groups (n =30-33) that began at 6 and 12 weeks of age, respectively, and were terminated at 20 weeks of age. The pre- and post- finasteride and dutasteride groups were designed to test the preventive and therapeutic efficacy of the drugs, respectively. Final body weights, genitourinary tract weights, and genitourinary tract weights as percentage of body weights were significantly decreased in the Pre- and Post-dutasteride groups compared with the control. The Post-dutasteride group showed the greatest inhibition of prostatic intraepithelial neoplasia progression and prostate cancer development. Surprisingly, the Post-dutasteride group showed improved outcomes compared with the Pre-dutasteride group, which had increased incidence of high-grade carcinoma as the most common and most severe lesions in a majority of prostate lobes. Consistent with our hypothesis, we found little benefit from the finasteride diets, and they increased the incidence of high-grade carcinoma.

Conclusion: Our findings have commonalities with previously reported PCPT, REDUCE, and the Reduction by dutasteride of Clinical Progression Events in Expectant Management (REDEEM) trial results. Our results may support the therapeutic use of dutasteride, but not finasteride, for therapeutic or preventive use.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0077738PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3799703PMC
August 2014

Human xenografts are not rejected in a naturally occurring immunodeficient porcine line: a human tumor model in pigs.

Biores Open Access 2012 Apr;1(2):63-8

Department of Anatomy and Physiology, Kansas State University , Manhattan, Kansas.

Animal models for cancer therapy are invaluable for preclinical testing of potential cancer treatments; however, therapies tested in such models often fail to translate into clinical settings. Therefore, a better preclinical model for cancer treatment testing is needed. Here we demonstrate that an immunodeficient line of pigs can host and support the growth of xenografted human tumors and has the potential to be an effective animal model for cancer therapy. Wild-type and immunodeficient pigs were injected subcutaneously in the left ear with human melanoma cells (A375SM cells) and in the right ear with human pancreatic carcinoma cells (PANC-1). All immunodeficient pigs developed tumors that were verified by histology and immunohistochemistry. Nonaffected littermates did not develop tumors. Immunodeficient pigs, which do not reject xenografted human tumors, have the potential to become an extremely useful animal model for cancer therapy because of their similarity in size, anatomy, and physiology to humans.
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http://dx.doi.org/10.1089/biores.2012.9902DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3559234PMC
April 2012

Chondrosarcoma of the scapula of an 8-month-old Holstein steer.

J Vet Diagn Invest 2012 Jul 17;24(4):791-3. Epub 2012 May 17.

Department of Diagnostic Medicine and Pathobiology, Kansas State University, College of Veterinary Medicine, 1800 Denison Avenue, Manhattan, KS 66506, USA.

Malignant neoplasms occur commonly in cattle, with lymphosarcoma being the most common. Chondrosarcoma rarely has been described and only in mature cattle. The present report describes a chondrosarcoma of the left scapula of an 8-month-old Holstein steer. Histologic examination of the mass revealed an unencapsulated, multilobular neoplasm composed of neoplastic spindle cells embedded in irregular islands of chondroid matrix, consistent with a diagnosis of chondrosarcoma.
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http://dx.doi.org/10.1177/1040638712445774DOI Listing
July 2012