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Article ; Online: Machine Learning and Veterinary Pathology: Be Not Afraid!

La Perle, Krista M D

2019 Volume 56, Issue 4, Page(s) 506–507

MeSH term(s)	Animals ; Humans ; Machine Learning ; Pathologists ; Pathology, Veterinary
Language	English
Publishing date	2019-06-12
Publishing country	United States
Document type	Editorial ; Introductory Journal Article
ZDB-ID	188012-3
ISSN	1544-2217 ; 0300-9858
ISSN (online)	1544-2217
ISSN	0300-9858
DOI	10.1177/0300985819848504
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Article ; Online: Comparative Pathologists: Ultimate Control Freaks Seeking Validation!

La Perle, Krista M D

Veterinary pathology

2018 Volume 56, Issue 1, Page(s) 19–23

Abstract: Definable, reproducible, and meaningful are elemental features of grading/scoring systems, while thoroughness, accuracy, and consistency are quality indicators of pathology reports. The expertise of pathologists is significantly underutilized when it is ... ...

Abstract	Definable, reproducible, and meaningful are elemental features of grading/scoring systems, while thoroughness, accuracy, and consistency are quality indicators of pathology reports. The expertise of pathologists is significantly underutilized when it is limited to rendering diagnoses. The opportunity to provide guidance on animal model development, experimental design, optimal sample collection, and data interpretation not only contributes to job satisfaction but also, more importantly, promotes validation of the pathology data. Keys to validation include standard operating procedures, experimental controls, and standardized nomenclature applied throughout the experimental design and execution, tissue sampling, and slide preparation, as well as the creation or adaptation and application of semiquantitative grading/scoring systems. Diagnostic drift, thresholds, mental noise, and various diurnal fluctuations strongly influence the repeatability of grading/scoring systems used by the same or different pathologists. Quantitative image analyses are not plagued by the visual and cognitive traps that affect manual semiquantitative grading schemes but may still be affected by technical variables associated with necropsy, tissue sampling, and slide preparation. The validity of a grading scheme is ultimately assessed by its repeatability and biologic relevance, so it is important to correlate scores with comprehensive pathobiology data such as results of antemortem imaging, clinical pathology data, body and organ weights, and histopathologic evaluation of full tissue sets.
MeSH term(s)	Animal Diseases/diagnosis ; Animal Diseases/pathology ; Animals ; Humans ; Image Interpretation, Computer-Assisted/standards ; Pathologists/standards ; Pathology, Clinical/standards ; Reproducibility of Results ; Research Design ; Validation Studies as Topic
Language	English
Publishing date	2018-10-28
Publishing country	United States
Document type	Journal Article
ZDB-ID	188012-3
ISSN	1544-2217 ; 0300-9858
ISSN (online)	1544-2217
ISSN	0300-9858
DOI	10.1177/0300985818806047
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Article ; Online: Comparative Pathologists: Ultimate Control Freaks Seeking Validation!

La Perle, Krista M. D.

Veterinary Pathology. 2019 Jan., v. 56, no. 1 p.19-23

2019

Abstract	Definable, reproducible, and meaningful are elemental features of grading/scoring systems, while thoroughness, accuracy, and consistency are quality indicators of pathology reports. The expertise of pathologists is significantly underutilized when it is limited to rendering diagnoses. The opportunity to provide guidance on animal model development, experimental design, optimal sample collection, and data interpretation not only contributes to job satisfaction but also, more importantly, promotes validation of the pathology data. Keys to validation include standard operating procedures, experimental controls, and standardized nomenclature applied throughout the experimental design and execution, tissue sampling, and slide preparation, as well as the creation or adaptation and application of semiquantitative grading/scoring systems. Diagnostic drift, thresholds, mental noise, and various diurnal fluctuations strongly influence the repeatability of grading/scoring systems used by the same or different pathologists. Quantitative image analyses are not plagued by the visual and cognitive traps that affect manual semiquantitative grading schemes but may still be affected by technical variables associated with necropsy, tissue sampling, and slide preparation. The validity of a grading scheme is ultimately assessed by its repeatability and biologic relevance, so it is important to correlate scores with comprehensive pathobiology data such as results of antemortem imaging, clinical pathology data, body and organ weights, and histopathologic evaluation of full tissue sets.
Keywords	animal models ; animal pathology ; cognition ; experimental design ; histopathology ; job satisfaction ; necropsy ; controls ; grading ; quantitative image analysis ; repeatability ; reproducibility ; scoring ; tissue trimming ; validation
Language	English
Dates of publication	2019-01
Size	p. 19-23.
Publishing place	SAGE Publications
Document type	Article ; Online
ZDB-ID	188012-3
ISSN	1544-2217 ; 0300-9858
ISSN (online)	1544-2217
ISSN	0300-9858
DOI	10.1177/0300985818806047
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Article: Cotton Rat Placenta Anatomy and Fc Receptor Expression and Their Roles in Maternal Antibody Transfer.

Martinez, Margaret E / Niewiesk, Stefan / La Perle, Krista M D

Comparative medicine

2020 Volume 70, Issue 6, Page(s) 510–519

Abstract: Respiratory syncytial virus (RSV) is the leading cause of bronchiolitis and viral pneumonia in infants and young children worldwide. Currently no vaccine is available to prevent RSV infection, but virus-neutralizing monoclonal antibodies can be given ... ...

Abstract	Respiratory syncytial virus (RSV) is the leading cause of bronchiolitis and viral pneumonia in infants and young children worldwide. Currently no vaccine is available to prevent RSV infection, but virus-neutralizing monoclonal antibodies can be given prophylactically, emphasizing the protective potential of antibodies. One concept of RSV vaccinology is mothers' immunization to induce high antibody titers, leading to passive transfer of high levels of maternal antibody to the fetus through the placenta and to the neonate through colostrum. Cotton rats are an excellent small animal model for RSV infection and have been used to test maternal immunization. To mechanistically understand antibody transfer in the cotton rat model, we characterized the cotton rat placenta and Fc receptor localization. Placentas from cotton rats at midgestation (approximately day 14) and at late gestation (approximately day 25) and neonatal (younger than 1 wk) gastrointestinal tracts were collected for light microscopy, immunohistochemistry, and transmission electron microscopy. The cotton rat placenta is hemotrichorial and has 5 distinct layers: decidua, junctional zone, labyrinth, chorionic plate, and yolk sac. Consistent with the transfer of maternal antibodies, the majority of the Fc receptors are present in the yolk sac endoderm and fetal capillary endothelium of the chorionic plate, involving 10% of the cells within the labyrinth. In addition, Fc receptors are present on duodenal and jejunal enterocytes in cotton rats, similar to humans, mice, and rats. These findings provide the structural basis for the pre- and postnatal transfer of maternal antibodies described in cotton rats.
MeSH term(s)	Animals ; Antibodies, Neutralizing ; Antibodies, Viral ; Female ; Mice ; Placenta ; Pregnancy ; Receptors, Fc ; Respiratory Syncytial Virus Infections ; Sigmodontinae ; Viral Fusion Proteins
Chemical Substances	Antibodies, Neutralizing ; Antibodies, Viral ; Receptors, Fc ; Viral Fusion Proteins
Language	English
Publishing date	2020-10-29
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2006425-1
ISSN	1532-0820 ; 0023-6764
ISSN	1532-0820 ; 0023-6764
DOI	10.30802/AALAS-CM-20-000040
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Article ; Online: Pathology Principles and Practices for Analysis of Animal Models.

Knoblaugh, Sue E / Hohl, Tobias M / La Perle, Krista M D

ILAR journal

2019 Volume 59, Issue 1, Page(s) 40–50

Abstract: Over 60% of NIH extramural funding involves animal models, and approximately 80% to 90% of these are mouse models of human disease. It is critical to translational research that animal models are accurately characterized and validated as models of human ... ...

Abstract	Over 60% of NIH extramural funding involves animal models, and approximately 80% to 90% of these are mouse models of human disease. It is critical to translational research that animal models are accurately characterized and validated as models of human disease. Pathology analysis, including histopathology, is essential to animal model studies by providing morphologic context to in vivo, molecular, and biochemical data; however, there are many considerations when incorporating pathology endpoints into an animal study. Mice, and in particular genetically modified models, present unique considerations because these modifications are affected by background strain genetics, husbandry, and experimental conditions. Comparative pathologists recognize normal pathobiology and unique phenotypes that animals, including genetically modified models, may present. Beyond pathology, comparative pathologists with research experience offer expertise in animal model development, experimental design, optimal specimen collection and handling, data interpretation, and reporting. Critical pathology considerations in the design and use of translational studies involving animals are discussed, with an emphasis on mouse models.
MeSH term(s)	Animals ; Disease Models, Animal ; Pathology/methods ; Research Design ; Translational Medical Research/methods
Language	English
Publishing date	2019-04-29
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2192062-X
ISSN	1930-6180 ; 1084-2020
ISSN (online)	1930-6180
ISSN	1084-2020
DOI	10.1093/ilar/ilz001
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Article: Characterization of Cotton Rat (

Green, M Gia / Petroff, Natasha / La Perle, Krista M D / Niewiesk, Stefan

Comparative medicine

2018 Volume 68, Issue 1, Page(s) 31–40

Abstract: Eosinophils have been postulated to play a protective role against infection with respiratory syncytial virus (RSV), increase the severity of allergic asthma during respiratory viral infection, and drive vaccine-enhanced disease. To address these ... ...

Abstract	Eosinophils have been postulated to play a protective role against infection with respiratory syncytial virus (RSV), increase the severity of allergic asthma during respiratory viral infection, and drive vaccine-enhanced disease. To address these questions in the cotton rat model of RSV infection, we characterized cotton rat eosinophils by electron microscopy as well as by bronchoalveolar lavage and histology of lung sections. Using these methods, we demonstrated that eosinophils comprise approximately half of all cells in the bronchoalveolar lavage fluids from cotton rats. The function of these cells was comparable to that of eosinophils of other species. Ex vivo, eosinophils stimulated with calcium ionophores secreted eosinophil peroxidase. In vivo, treatment with house dust mite antigen increased eosinophil numbers in lung. Infection with Staphylococcus aureus lead to a marked increase in neutrophils without an increase in eosinophils, and eosinophil numbers were not influenced by infection with influenza virus or measles virus. Similarly, infection with RSV did not result in an increase in eosinophils. Lastly, RSV infection did not increase eosinophil recruitment into the lung after challenge with house dust mite antigen, but it did increase eosinophil recruitment into the lungs of cotton rats previously immunized with formalin-inactivated RSV vaccine, thus contributing to vaccine-enhanced disease.
MeSH term(s)	Animals ; Calcium Ionophores/pharmacology ; Eosinophil Peroxidase/metabolism ; Eosinophils/immunology ; Eosinophils/physiology ; Eosinophils/ultrastructure ; Neutrophils/immunology ; Pyroglyphidae/immunology ; Respiratory Syncytial Virus Infections/immunology ; Respiratory Syncytial Virus Infections/pathology ; Respiratory Syncytial Virus Vaccines/immunology ; Sigmodontinae/immunology ; Staphylococcal Infections/immunology
Chemical Substances	Calcium Ionophores ; Respiratory Syncytial Virus Vaccines ; Eosinophil Peroxidase (EC 1.11.1.-)
Language	English
Publishing date	2018-02-26
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2006425-1
ISSN	1532-0820 ; 0023-6764
ISSN	1532-0820 ; 0023-6764
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Article ; Online: Spontaneous reproductive pathology in female guinea pigs.

Veiga-Parga, Tamara / La Perle, Krista M D / Newman, Shelley J

Journal of veterinary diagnostic investigation : official publication of the American Association of Veterinary Laboratory Diagnosticians, Inc

2016 Volume 28, Issue 6, Page(s) 656–661

Abstract: Reproductive pathology of domestic guinea pigs is underreported to date. To provide a comprehensive review of uterine disease in guinea pigs, we performed a retrospective study of the pathology archives of the University of Tennessee, College of ... ...

Abstract	Reproductive pathology of domestic guinea pigs is underreported to date. To provide a comprehensive review of uterine disease in guinea pigs, we performed a retrospective study of the pathology archives of the University of Tennessee, College of Veterinary Medicine. By histology, 13 of 37 uterine lesions in 23 animals were neoplastic; the other 24 nonneoplastic lesions included cystic endometrial hyperplasia (16 of 24), endometrial hemorrhage (3 of 24), pyometra (2 of 24), polyp (2 of 24), and mucometra (1 of 24). The most common guinea pig uterine neoplasms were uterine leiomyomas (6 of 13), followed by adenomas (3 of 13) and leiomyosarcomas (1 of 13). Other neoplasms included anaplastic tumors of unknown origin (2 of 13) and choriocarcinoma (1 of 13). Both anaplastic tumors and the choriocarcinoma were positive for vimentin. The choriocarcinoma was positive for HSD83B1, indicating a trophoblastic origin and its final diagnosis. All were negative for cytokeratin and smooth muscle. In multiple animals, more than 1 tumor or lesion was reported. Estrogen receptor and progesterone receptor expression was nearly 100% in uterine neoplasms. Nearly all animals for which data were available had cystic rete ovarii (18 of 19); the animal with no cystic rete ovarii had paraovarian cysts. In our study, female pet guinea pigs had a tendency to develop cystic endometrial hyperplasia and uterine neoplasia. Factors for the development of these lesions could be cystic rete ovarii, hormone dysregulation, and/or age. Other factors could contribute to the development of uterine lesions. As in other species, early ovariohysterectomy could decrease the prevalence of uterine lesions.
MeSH term(s)	Animals ; Female ; Guinea Pigs ; Retrospective Studies ; Rodent Diseases/epidemiology ; Rodent Diseases/pathology ; Tennessee/epidemiology ; Uterine Diseases/epidemiology ; Uterine Diseases/pathology ; Uterine Diseases/veterinary ; Uterine Neoplasms/epidemiology ; Uterine Neoplasms/pathology ; Uterine Neoplasms/virology
Language	English
Publishing date	2016-10-03
Publishing country	United States
Document type	Journal Article
ZDB-ID	287603-6
ISSN	1943-4936 ; 1040-6387
ISSN (online)	1943-4936
ISSN	1040-6387
DOI	10.1177/1040638716665429
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Article ; Online: Scientific and Regulatory Policy Committee Points to Consider: Biological Sample Retention From Nonclinical Toxicity Studies.

Harbison, Carole E / Aulbach, Adam D / Bennet, Bindu M / Boyle, Molly H / Carsillo, Mary E / Crabbs, Torrie A / Keirstead, Natalie D / La Perle, Krista M D / Pandiri, Arun R / Shoieb, Ahmed M / Siska, William D

Toxicologic pathology

2021 Volume 50, Issue 2, Page(s) 252–265

Abstract: Samples of biologic specimens and their derivatives (eg, wet tissues, paraffin-embedded tissue blocks, histology slides, frozen tissues, whole blood, serum/plasma, and urine) are routinely collected during the course of nonclinical toxicity studies. Good ...

Abstract	Samples of biologic specimens and their derivatives (eg, wet tissues, paraffin-embedded tissue blocks, histology slides, frozen tissues, whole blood, serum/plasma, and urine) are routinely collected during the course of nonclinical toxicity studies. Good Laboratory Practice regulations and/or guidance specify minimum requirements for specimen retention duration, with the caveat that retention of biologic specimens need not extend beyond the duration of sample stability. However, limited availability of published data regarding stability for various purposes following storage of each specimen type has resulted in confusion, uncertainty, and inconsistency as to the appropriate duration for storage of these specimens. To address these issues, a working group of the Society of Toxicologic Pathology Scientific and Regulatory Policy Committee was formed to review published information, regulations, and guidance pertinent to this topic and to summarize the current practices and rationales for retention duration through a survey-based approach. Information regarding experiences reaccessing biologic specimens and performing sample stability investigations was also collected. Based on this combined information, the working group developed several points to consider that may be referenced when developing or revising sample retention practices. [Box: see text].
MeSH term(s)	Policy ; Research Design
Language	English
Publishing date	2021-10-26
Publishing country	United States
Document type	Journal Article
ZDB-ID	841009-4
ISSN	1533-1601 ; 0192-6233
ISSN (online)	1533-1601
ISSN	0192-6233
DOI	10.1177/01926233211049156
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Article ; Online: MAPK- and AKT-activated thyroid cancers are sensitive to group I PAK inhibition.

Knippler, Christina M / Saji, Motoyasu / Rajan, Neel / Porter, Kyle / La Perle, Krista M D / Ringel, Matthew D

Endocrine-related cancer

2019 Volume 26, Issue 8, Page(s) 699–712

Abstract: The number of individuals who succumb to thyroid cancer has been increasing and those who are refractory to standard care have limited therapeutic options, highlighting the importance of developing new treatments for patients with aggressive forms of the ...

Abstract	The number of individuals who succumb to thyroid cancer has been increasing and those who are refractory to standard care have limited therapeutic options, highlighting the importance of developing new treatments for patients with aggressive forms of the disease. Mutational activation of MAPK signaling, through BRAF and RAS mutations and/or gene rearrangements, and activation of PI3K signaling, through mutational activation of PIK3CA or loss of PTEN, are well described in aggressive thyroid cancer. We previously reported overactivation and overexpression of p21-activated kinases (PAKs) in aggressive human thyroid cancer invasive fronts and determined that PAK1 functionally regulated thyroid cancer cell migration. We reported mechanistic crosstalk between the MAPK and PAK pathways that are BRAF-dependent but MEK independent, suggesting that PAK and MEK inhibition might be synergistic. In the present study, we tested this hypothesis. Pharmacologic inhibition of group I PAKs using two PAK kinase inhibitors, G-5555 or FRAX1036, reduced thyroid cancer cell viability, cell cycle progression and migration and invasion, with greater potency for G-5555. Combination of G-5555 with vemurafenib was synergistic in BRAFV600E-mutated thyroid cancer cell lines. Finally, G-5555 restrained thyroid size of BRAFV600E-driven murine papillary thyroid cancer by >50% (P < 0.0001) and reduced carcinoma formation (P = 0.0167), despite maintenance of MAPK activity. Taken together, these findings suggest both that group I PAKs may be a new therapeutic target for thyroid cancer and that PAK activation is functionally important for BRAFV600E-mediated thyroid cancer development.
MeSH term(s)	Animals ; Cell Cycle/drug effects ; Cell Line, Tumor ; Cell Movement/drug effects ; Cell Survival/drug effects ; Drug Resistance, Neoplasm ; Drug Synergism ; Female ; Humans ; MAP Kinase Signaling System/drug effects ; Male ; Mice ; Mice, Transgenic ; Mitogen-Activated Protein Kinases/metabolism ; Mutation ; Protein Kinase Inhibitors/pharmacology ; Proto-Oncogene Proteins B-raf/genetics ; Proto-Oncogene Proteins B-raf/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Pyridines/pharmacology ; Pyrimidines/pharmacology ; Thyroid Neoplasms/drug therapy ; Thyroid Neoplasms/genetics ; Thyroid Neoplasms/metabolism ; Thyroid Neoplasms/pathology ; Vemurafenib/pharmacology ; p21-Activated Kinases/antagonists & inhibitors ; p21-Activated Kinases/metabolism
Chemical Substances	G-5555 compound ; Protein Kinase Inhibitors ; Pyridines ; Pyrimidines ; Vemurafenib (207SMY3FQT) ; AKT1 protein, human (EC 2.7.11.1) ; BRAF protein, human (EC 2.7.11.1) ; PAK1 protein, human (EC 2.7.11.1) ; Proto-Oncogene Proteins B-raf (EC 2.7.11.1) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; p21-Activated Kinases (EC 2.7.11.1) ; Mitogen-Activated Protein Kinases (EC 2.7.11.24)
Language	English
Publishing date	2019-05-30
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1218450-0
ISSN	1479-6821 ; 1351-0088
ISSN (online)	1479-6821
ISSN	1351-0088
DOI	10.1530/ERC-19-0188
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Article ; Online: Pathology of wild Norway rats in Vancouver, Canada.

Rothenburger, Jamie L / Himsworth, Chelsea G / La Perle, Krista M D / Leighton, Frederick A / Nemeth, Nicole M / Treuting, Piper M / Jardine, Claire M

Journal of veterinary diagnostic investigation : official publication of the American Association of Veterinary Laboratory Diagnosticians, Inc

2019 Volume 31, Issue 2, Page(s) 184–199

Abstract: To achieve a contemporary understanding of the common and rare lesions that affect wild, urban Norway rats ( Rattus norvegicus), we conducted a detailed pathology analysis of 672 rats from Vancouver, British Columbia, Canada. Grossly evident lesions, ... ...

Abstract	To achieve a contemporary understanding of the common and rare lesions that affect wild, urban Norway rats ( Rattus norvegicus), we conducted a detailed pathology analysis of 672 rats from Vancouver, British Columbia, Canada. Grossly evident lesions, such as wounds, abscesses, and neoplasms, were present in 71 of 672 rats (11%) and tended to be severe. The most common and significant lesions were infectious and inflammatory, most often affecting the respiratory tract and associated with bite wounds. We assessed a subset of rats (up to n = 406 per tissue) for the presence of microscopic lesions in a variety of organ systems. The most frequent lesions that could impact individual rat health included cardiomyopathy (128 of 406; 32%), chronic respiratory tract infections as indicated by pulmonary inducible bronchus-associated lymphoid tissue (270 of 403; 67%), tracheitis (192 of 372; 52%), and thyroid follicular hyperplasia (142 of 279; 51%). We isolated 21 bacterial species from purulent lesions in rats with bacterial infections, the most frequent of which were Escherichia coli, Enterococcus sp., and Staphylococcus aureus. Parasitic diseases in rats resulted from infection with several invasive nematodes: Capillaria hepatica in the liver (242 of 672; 36%), Eucoleus sp. in the upper gastrointestinal tract (164 of 399; 41%), and Trichosomoides crassicauda in the urinary bladder (59 of 194; 30%). Neoplastic, congenital, and degenerative lesions were rare, which likely reflects their adverse effect on survival in the urban environment. Our results establish a baseline of expected lesions in wild urban rats, which may have implications for urban rat and zoonotic pathogen ecology, as well as rat control in cities worldwide.
MeSH term(s)	Animals ; Bacterial Infections/epidemiology ; Bacterial Infections/pathology ; Bacterial Infections/veterinary ; British Columbia/epidemiology ; Cities ; Congenital Abnormalities/epidemiology ; Congenital Abnormalities/pathology ; Congenital Abnormalities/veterinary ; Heart Diseases/epidemiology ; Heart Diseases/pathology ; Heart Diseases/veterinary ; Neoplasms/epidemiology ; Neoplasms/pathology ; Neoplasms/veterinary ; Parasitic Diseases, Animal/epidemiology ; Parasitic Diseases, Animal/pathology ; Rats ; Respiratory Tract Diseases/epidemiology ; Respiratory Tract Diseases/pathology ; Respiratory Tract Diseases/veterinary ; Rodent Diseases/epidemiology ; Rodent Diseases/pathology
Language	English
Publishing date	2019-01-26
Publishing country	United States
Document type	Journal Article
ZDB-ID	287603-6
ISSN	1943-4936 ; 1040-6387
ISSN (online)	1943-4936
ISSN	1040-6387
DOI	10.1177/1040638719833436
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