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Toxicologic Pathology

Cleopatra Kozlowski, Aaron Fullerton, Gary Cain, Paula Katavolos, Joseph Bravo, Jacqueline M Tarrant
The bone marrow is an important site for assessment of the hematopoietic toxicity of new drug candidates. Here, we extended our previous work, where we developed a computer algorithm to automatically quantitate overall bone marrow cell density by analyzing digitized images of standard hematoxylin and eosin (H&E) slides of rat bone marrow and further evaluated the capability to quantify myeloid: erythroid + lymphoid (M:EL) ratio and megakaryocyte cell density. We tested the algorithm in a toxicity study, where rats were dosed with two molecules known to affect bone marrow composition, monomethyl auristatin E, and a Bcl-xL inhibitor...
April 2018: Toxicologic Pathology
Cleopatra Kozlowski, Jochen Brumm, Gary Cain
Bone marrow toxicity is a common finding when assessing safety of drug candidate molecules. Standard hematoxylin and eosin (H&E) marrow tissue sections are typically manually evaluated to provide a semiquantitative assessment of overall cellularity. Here, we developed an automated image analysis method that allows quantitative assessment of changes in bone marrow cell population in sternal bone. In order to test whether the method was repeatable and sensitive, we compared the automated method with manual subjective histopathology scoring of total cellularity in rat sternal bone marrow samples across 17 independently run studies...
April 2018: Toxicologic Pathology
Rodrigo Portes Ureshino, Angelica Jardim Costa, Adolfo Garcia Erustes, Gustavo José da Silva Pereira, Rita Sinigaglia-Coimbra, Soraya Soubhi Smaili
Aging is a multifactorial process associated with functional deficits, and the brain is more prone to developing chronic degenerative diseases such as Parkinson's disease. Several groups have tried to correlate the age-related ultrastructural alterations to the neurodegeneration process using in vivo pharmacological models, but due to the limitations of the animal models, particularly in aged animals, the results are difficult to interpret. In this work, we investigated neurodegeneration induced by rotenone, as a pharmacological model of Parkinson's disease, in both young and aged Wistar rats...
April 2018: Toxicologic Pathology
Michael Creane, Mary McElroy, Aoife Duffy, Chaansha Shaik Dawood, Timothy O'Brien
Critical limb ischemia (CLI) represents the severest manifestation of peripheral arterial disease and is a major unmet medical need. This disease occurs when the arterial blood supply within the limb fails to meet the metabolic demands of the resting muscle or tissue, resulting in chronic ischemic rest pain and/or tissue necrosis. Human mesenchymal stromal cells, termed hMSCs, represent an exciting therapeutic modality for the treatment of this disease due to their immunomodulatory and tissue reparative functions...
April 2018: Toxicologic Pathology
Nathália P Souza, Gordon C Hard, Lora L Arnold, Kirk W Foster, Karen L Pennington, Samuel M Cohen
Chronic progressive nephropathy (CPN) occurs commonly in rats, more frequently and severely in males than females. High-grade CPN is characterized by increased layers of the renal papilla lining, designated as urothelial hyperplasia in the International Harmonization of Nomenclature and Diagnostic Criteria classification. However, urothelium lining the pelvis is not equivalent to the epithelium lining the papilla. To evaluate whether the epithelium lining the renal papilla is actually urothelial in nature and whether CPN-associated multicellularity represents proliferation, kidney tissues from aged rats with CPN, from rats with multicellularity of the renal papilla epithelium of either low-grade or marked severity, and from young rats with normal kidneys were analyzed and compared...
April 2018: Toxicologic Pathology
Jochen Woicke, Solomon Haile, Jagannatha Mysore, W Michael Peden, Typhaine Lejeune, Thomas Sanderson, Thomas Brodie
Spontaneous findings noted in the eyes of Mauritian cynomolgus monkeys are described and descriptions are supplemented with illustrations. Findings observed after extensive histopathologic examinations (20 to 44 sections per eye) from 20 control, 17 treatment-naive stock monkeys, and 2 findings noted in drug-treated monkeys that were considered to be spontaneous are included. Also included are findings from 361 control monkeys of routine toxicity studies performed at our laboratories, for most of which a standard histopathological examination of 1 section per eye was conducted...
April 2018: Toxicologic Pathology
Susan A Elmore
No abstract text is available yet for this article.
April 2018: Toxicologic Pathology
B Lenz, A Braendli-Baiocco, J Engelhardt, P Fant, H Fischer, S Francke, R Fukuda, S Gröters, T Harada, H Harleman, W Kaufmann, S Kustermann, T Nolte, X Palazzi, G Pohlmeyer-Esch, A Popp, A Romeike, A Schulte, B Silva Lima, L Tomlinson, J Willard, C E Wood, M Yoshida
Lysosomes have a central role in cellular catabolism, trafficking, and processing of foreign particles. Accumulation of endogenous and exogenous materials in lysosomes represents a common finding in nonclinical toxicity studies. Histologically, these accumulations often lack distinctive features indicative of lysosomal or cellular dysfunction, making it difficult to consistently interpret and assign adverse dose levels. To help address this issue, the European Society of Toxicologic Pathology organized a workshop where representative types of lysosomal accumulation induced by pharmaceuticals and environmental chemicals were presented and discussed...
February 2018: Toxicologic Pathology
Mark Tirmenstein, Evan Janovitz, Thomas Dorr, Yunling Song, Shen-Jue Chen, Karen Granaldi, Kristina D Chadwick, Raja Mangipudy, Michael Graziano, Bassem Attalla, Solomon Haile, Melissa Czajkowski, John R Foster, Ann-Marie Bergholm, Martin Billger, Magnus Söderberg
The purpose of this study was to establish a 2-stage model of urinary bladder carcinogenesis in male Sprague-Dawley rats to identify tumor promoters. In phase 1 of the study, rats ( n = 170) were administered 100 mg/kg of the tumor initiator, N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN), twice weekly by oral gavage (po) for a period of 6 weeks. Phase 2 consisted of dividing rats into 4 groups ( n = 40 per group) and administering one of the following for 26 weeks to identify putative tumor promoters: (1) vehicle po, (2) 25 mg/kg/day rosiglitazone po, (3) 5% dietary sodium l-ascorbate, and (4) 3% dietary uracil...
February 2018: Toxicologic Pathology
Zuhal Dincer, Virginie Piccicuto, Ursula Junker Walker, Andreas Mahl, Sean McKeag
Arteritis/polyarteritis occurs spontaneously in many species used in preclinical toxicology studies. In Göttingen minipigs, arteritis/polyarteritis is an occasionally observed background change. In the minipig, this finding differs in frequency and nature from age-related polyarteritis nodosa in rats or monkeys, and Beagle pain syndrome in dogs. In minipigs, it can be present in a single small- or medium-sized artery of an organ or a few organs and is most commonly recorded in the cardiac and extracardiac blood vessels, vagina, oviduct, rectum, epididymis, spinal cord, pancreas, urinary bladder, kidneys, and stomach...
February 2018: Toxicologic Pathology
Michaela E Sharpe
Gene-engineered T-cell therapies have the potential to revolutionize the treatment of cancer. These therapies have shown exceptional clinical efficacy specifically in the field of B-cell malignancies and the first products (Kymriah™ and Yescarta™) have recently been approved in the United States for specific indications. The power of these treatments is also linked with a distinct set of toxicities both predicted and unpredicted, including off-tumor activity, cytokine release syndromes, and neurotoxicity, occasionally with fatal consequences...
February 2018: Toxicologic Pathology
Phanie L Charest, Vanessa Vrolyk, Pauline Herst, Maryse Lessard, Deborah M Sloboda, Mathieu Dalvai, Julius Haruna, Janice L Bailey, Marie-Odile Benoit-Biancamano
Histological examination of the rat placenta and fetus is uncommon. Toxicological studies mainly rely on gross examination of the fetus and on fetal and placental weights. These are often insufficient to assess the fetal and placental toxicity of xenobiotics. The small size of the fetus makes its dissection labor-intensive. Thus, our objective was to develop a simple and accurate technique to evaluate the rat fetus and placenta. Sprague-Dawley rat fetuses at gestational day 19.5 ( n = 18) and their placentas ( n = 32) were fixed in formalin...
February 2018: Toxicologic Pathology
Ramesh C Kovi, Charles S Johnson, Silvia Balbo, Stephen S Hecht, M Gerard O'Sullivan
Lung cancer is the most common cause of cancer-related deaths in humans worldwide. There is strong evidence that the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and its metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) play an important role in carcinogenesis caused by tobacco products. NNK and racemic NNAL are reported to induce lung and pancreatic tumors in rats. The carcinogenicity in Fischer 344 rats of NNK, NNAL, and its enantiomers ( R)-NNAL and ( S)-NNAL has been studied recently, and all test compounds induced significant numbers of lung tumors...
February 2018: Toxicologic Pathology
David B Resnik, Susan A Elmore
No abstract text is available yet for this article.
February 2018: Toxicologic Pathology
B Claire McDyre, Mohamed Diwan M AbdulHameed, Matthew G Permenter, William E Dennis, Christine E Baer, Jason M Koontz, Molly H Boyle, Anders Wallqvist, John A Lewis, Danielle L Ippolito
The past decade has seen an increase in the development and clinical use of biomarkers associated with histological features of liver disease. Here, we conduct a comparative histological and global proteomics analysis to identify coregulated modules of proteins in the progression of hepatic steatosis or fibrosis. We orally administered the reference chemicals bromobenzene (BB) or 4,4'-methylenedianiline (4,4'-MDA) to male Sprague-Dawley rats for either 1 single administration or 5 consecutive daily doses. Livers were preserved for histopathology and global proteomics assessment...
February 2018: Toxicologic Pathology
Dhanush Krishna Balakrishnan-Nair, Narayanan Divakaran Nair, Syam Kunnekkattu Venugopal, Vijayan Narayana Das, Sisilamma George, Mammen John Abraham, Saji Eassow, Malcolm Ronald Alison, Anoop Sainulabdeen, Thapasimuthu Vijayamma Anilkumar
With the increasing use of animal-based biomaterials for regenerative medical applications, the need for their safety assessment is paramount. A porcine cholecyst-derived scaffold (CDS), intended as a muscle repair graft, prepared by a nondetergent/enzymatic method was engrafted in a rat abdominal wall defect model. Host tissue-scaffold interface samples were collected 2, 8, and 16 weeks postimplantation and evaluated by histopathology, immunohistochemistry, and electron microscopy. The nature of the tissue reaction was compared with those induced by a jejunum-derived scaffold (JDS) prepared by the same method and a commercial-grade small intestinal submucosa (CSIS) scaffold...
February 2018: Toxicologic Pathology
Ayako Sayama, Keiko Okado, Koichi Nakamura, Tatsuya Kawaguchi, Takuma Iguchi, Toshihiko Makino, Koichi Yabe, Kiyonori Kai, Kazuhiko Mori
Mer proto-oncogene tyrosine kinase (MerTK), which is expressed in the retinal pigment epithelium (RPE), regulates phagocytosis of shed photoreceptor outer segments (POS). To investigate the effects of drug-induced MerTK inhibition on the retina, UNC569, a specific MerTK inhibitor, was orally administered to male mice at a concentration of 60, 100, or 150 mg/kg for up to 14 days. Furthermore, MerTK inhibition in the retinal tissue sample was examined using a phosphorylation assay following a single dose of UNC569 at 100 mg/kg...
February 2018: Toxicologic Pathology
Brad Bolon
Regulatory guidances for nonclinical toxicity testing require brain evaluation but do not require a specific analytical strategy. The Society of Toxicologic Pathology (STP) has produced "best practice" recommendations for brain sampling and processing in general toxicity (GT) studies in adult rodents and nonrodents as well as developmental neurotoxicity (DNT) studies in rodents. This article explains acceptable brain trimming strategies as described in these 2 STP documents. Figures in the DNT and GT "best practices" illustrate coronal brain trimming at specific levels as defined by discrete external and internal anatomic landmarks...
February 2018: Toxicologic Pathology
Kathryn E Gropp, Cathy S Carlson, Mark G Evans, Cedo M Bagi, William J Reagan, Susan I Hurst, David L Shelton, Mark A Zorbas
Tanezumab, an anti-nerve growth factor (NGF) antibody, is in development for management of chronic pain. During clinical trials of anti-NGF antibodies, some patients reported unexpected adverse events requiring total joint replacements, resulting in a partial clinical hold on all NGF inhibitors. Three nonclinical toxicology studies were conducted to evaluate the effects of tanezumab or the murine precursor muMab911 on selected bone and joint endpoints and biomarkers in cynomolgus monkeys, Sprague-Dawley rats, and C57BL/6 mice...
January 1, 2018: Toxicologic Pathology
Javiera Bahamonde, Bonnie Brenseke, Matthew Y Chan, Ronald D Kent, Peter J Vikesland, M Renee Prater
Nanotoxicity studies are greatly needed to advance nanomedical technologies into clinical practice. We assessed the toxic effects of a single intravenous exposure to commercially available gold nanoparticles (GNPs) in mice and rats. Fifteen-nm GNPs were purchased and independently characterized. Animals were exposed to either 1,000 mg GNPs/kg body weight (GNP group) or phosphate-buffered saline. Subsets of animals were euthanized and samples collected at 1, 7, 14, 21, and 28 days postexposure. Independent characterization demonstrated that the physicochemical properties of the purchased GNPs were in good agreement with the information provided by the supplier...
January 1, 2018: Toxicologic Pathology
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