Miika Vuorimaa, Ilona Kareinen, Petri Toivanen, Stefan Karlsson, Saku Ruohonen
As regulators of homeostasis, astrocytes undergo morphological changes after injury to limit the insult in central nervous system (CNS). Trimethyltin (TMT) is a known neurotoxicant that induces reactive astrogliosis in rat CNS. To evaluate the degree of reactive astrogliosis, the assessment relies on manual counting or semiquantitative scoring. We hypothesized that deep learning algorithm could be used to identify the grade of reactive astrogliosis in immunoperoxidase-stained sections in a quantitative manner...
September 20, 2022: Toxicologic Pathology
William J Reagan, Marjory B Brooks, Renata Grozovsky, Debra Pittman, Allison Vitsky, Karrie Brenneman
The session on the hemostatic system focused on new developments in coagulation and platelet biology as well as how therapeutic agents may affect hemostasis. The classic cascade model of coagulation was compared with the more recent models of cell-based and vascular-based coagulation, which may provide better insight on how the coagulation cascade works in vivo. A review of platelet biology highlighted that, as platelets age, desialylated platelets form and are recognized by Ashwell-Morell receptor (AMR), leading to hepatic uptake and subsequent increase in thrombopoietin (TPO) production...
September 17, 2022: Toxicologic Pathology
James J Vanhie, Michael De Lisio
Lifestyle factors are modifiable behavioral factors that have a significant impact on health and longevity. Diet-induced obesity and physical activity/exercise are two prevalent lifestyle factors that have strong relationships to overall health. The mechanisms linking obesity to negative health outcomes and the mechanisms linking increased participation in physical activity/exercise to positive health outcomes are beginning to be elucidated. Chronic inflammation, due in part to overproduction of myeloid cells from hematopoietic stem cells (HSCs) in the bone marrow, is an established mechanism responsible for the negative health effects of obesity...
September 16, 2022: Toxicologic Pathology
Kathryn E Gropp
During this presentation, a variety of class effects were reviewed by their differing effects on bone, including inhibition of endochondral ossification, inhibition of the growth hormone-insulin-like growth factor 1 axis, promotion of bone formation, inhibition of bone formation, abnormal bone formation, promotion of bone resorption, inhibition of bone resorption, and bone necrosis.
September 16, 2022: Toxicologic Pathology
A Eric Schultze, Lila Ramaiah
This session, held during the 41st Annual STP Symposium, focused on mechanisms of decreased erythropoiesis and erythroid cell injury. The speakers provided comprehensive overviews of physiologic and pathologic erythropoiesis, reviewed various mechanisms of erythroid cell injury, and shared innovative investigative research with the audience.
September 5, 2022: Toxicologic Pathology
Shima Mehrvar, Takahito Kambara
In nonclinical toxicity studies, stage-aware evaluation is often expected to assess drug-induced testicular toxicity. Although stage-aware evaluation does not require identification of specific stages, it is important to understand microscopic features of spermatogenic staging. Staging of the spermatogenic cycle in dogs is a challenging and time-consuming process. In this study, we first defined morphologic features for the eight spermatogenic stages in standard histology sections (H&E slides) of dog testes...
August 24, 2022: Toxicologic Pathology
Julie Boisclair, Bhupinder Bawa, Erio Barale-Thomas, Lise Bertrand, Jonathan Carter, Richard Crossland, Celine Dorn, Thomas Forest, Sabine Grote, Anja Gilis, Deon Hildebrand, Brian Knight, Sébastien Laurent, Heike Antje Marxfeld, Steen Jørgen Østergaard, Thibault Roguet, Thorsten Schlueter, Vanessa Schumacher, Richard Spehar, William Varady, Christian Zeugin
Digital toxicologic histopathology has been broadly adopted in preclinical compound development for informal consultation and peer review. There is now increased interest in implementing the technology for good laboratory practice-regulated study evaluations. However, the implementation is not straightforward because systems and work processes require qualification and validation, with consideration also given to security. As a result of the high-throughput, high-volume nature of safety evaluations, computer performance, ergonomics, efficiency, and integration with laboratory information management systems are further key considerations...
August 11, 2022: Toxicologic Pathology
William Siska, Albert Eric Schultze, Daniela Ennulat, Kathleen Biddle, Michael Logan, Adeyemi O Adedeji, Tara Arndt, Adam D Aulbach
Integrating clinical pathology data with anatomic pathology data is a common practice when reporting findings in the context of nonclinical toxicity studies and aids in understanding and communicating the nonclinical safety profile of test articles in development. Appropriate pathology data integration requires knowledge of analyte and tissue biology, species differences, methods of specimen acquisition and analysis, study procedures, and an understanding of the potential causes and effects of a variety of pathophysiologic processes...
August 2022: Toxicologic Pathology
Ancuta Apreutese, Michela Levi, Ian Taylor, Radu Apreutese, Sydney Mukaratirwa, Vasanthi Mowat
A retrospective study was performed to establish the causes of mortality and incidence patterns of tumors in young (<50 weeks) control CD-1® mice from Charles River Laboratories. Tumor incidences (fatal and nonfatal) and nonneoplastic causes of death observed during the first 50 weeks of the study were collected from 48 thirteen-week toxicity studies conducted between 2009 and 2018 and from 43 carcinogenicity studies conducted between 2005 and 2018. Thirteen-week studies had a mortality rate of 8/620 (1...
August 2022: Toxicologic Pathology
Huong Huynh, Priya Upadhyay, Cora H Lopez, Malia K Miyashiro, Laura S Van Winkle, Sara M Thomasy, Kent E Pinkerton
Engineered silver nanoparticles (AgNPs), including silver silicate nanoparticles (Ag-SiO2 NPs), are used in a wide variety of medical and consumer applications. Inhaled AgNPs have been found to translocate to the olfactory bulb (OB) after inhalation and intranasal instillation. However, the biological effects of Ag-SiO2 NPs and their potential nose-to-brain transport have not been evaluated. The present study assessed whether inhaled Ag-SiO2 NPs can elicit microglial activation in the OB. Adult Sprague-Dawley rats inhaled aerosolized Ag-SiO2 NPs at a concentration of 1 mg/ml for 6 hours...
August 2022: Toxicologic Pathology
Ronnie Chamanza, Chidozie J Amuzie, Jennifer Chilton, Jeffery A Engelhardt
Nonhuman primates (NHPs) are utilized in nonclinical safety testing due to their phylogenetic proximity to humans and similarity in physiology and anatomy. However, ethical considerations and the increased demand for NHPs, coupled with the current shortage in their supply, have increased the calls to minimize their use. In addition, the increased demand and supply shortage of NHPs have increased the use of animals sourced from different geographical origins, and animals of different ages, which can complicate the interpretation of study results...
July 2022: Toxicologic Pathology
Thierry D Flandre, Keith G Mansfield, Pascal J Espié, Tina Rubic-Schneider, Peter Ulrich
CFZ533 (iscalimab) is a nondepleting anti-CD40 antibody intended for inhibition of transplant organ rejection and treatment of autoimmune diseases. In a safety assessment in rhesus monkeys, CFZ533 was administered for 13 weeks up to 150 mg/kg/week subcutaneously. CFZ533 was shown previously to completely inhibit primary and secondary T-cell-dependent antibody responses. CD40 is expressed on B cells, antigen-presenting cells, and endothelial and epithelial cells, but is not expressed on T cells. Here, we demonstrate the complete suppression of germinal center formation in lymphoid organs...
July 2022: Toxicologic Pathology
Molly Liepnieks, Caitlyn Carter, Michael J Caruso, Zac Lloyd, Michael Muzyka, Daniel Patrick
Cynomolgus macaques, the most commonly utilized nonhuman primate in nonclinical toxicology studies, are acquired from purpose-bred colonies across various geographic locations, including China, Cambodia, and Vietnam. Importation challenges and limited availability have restricted animals suitable for inclusion in nonclinical studies. The coronavirus disease 2019 (COVID-19) outbreak further stressed supply chains, reducing the ability to source animals from a singular location to complete a drug development program...
July 2022: Toxicologic Pathology
Ronnie Chamanza, Stuart W Naylor, Michela Gregori, Molly Boyle, Marcia E Pereira Bacares, Elodie Drevon-Gaillot, Annette Romeike, Cynthia Courtney, Kelsey Johnson, Julie Turner, Nadine Swierzawski, Alok K Sharma
To investigate the influence of geographical origin, age, and sex on toxicologically relevant spontaneous histopathology findings in cynomolgus macaques ( Macaca fascicularis ), we performed a comparative analysis of historical control data (HCD) from 13 test sites that included 3351 animals (1645 females and 1706 males) sourced from Mauritius, China, Vietnam, and Cambodia, aged from 2 to 9.5 years, and from 446 toxicology studies evaluated between 2016 and 2021. The most common findings were mononuclear infiltrates in the kidney, liver, brain, and lung, which showed highest incidences in Mauritian macaques, and heart, salivary glands, and gastrointestinal tract (GIT), which showed highest incidences of mononuclear infiltrates in mainland Asian macaques...
July 2022: Toxicologic Pathology
Tara Arndt, Mandy Meindel, Joseph Clarke, Amanda Shaw, Michela Gregori
Cynomolgus macaques ( Macaca fascicularis ) are commonly used in safety assessment and as translational models for drug development. Recent supply chain pressures, exportation bans, and increased demand for drug safety assessment studies exacerbated by the COVID-19 pandemic have prompted the investigation of utilizing macaques of different geographic origin in preclinical toxicity studies. This study compares routine hematology, coagulation, and clinical chemistry endpoints of 3 distinct subpopulations of mainland Asia origin (Cambodia, China, and Vietnam) with Mauritius origin macaques compiling results of 3,225 animals from 123 regulatory toxicology studies conducted at North American and European Union contract research organization facilities between 2016 and 2019...
July 2022: Toxicologic Pathology
Rachel Amato, Jean F Gardin, Janet A Tooze, J Mark Cline
Laboratory animal research is an important contributor to both human and animal medicine. Currently, there is extensive use of cynomolgus monkeys ( Macaca fascicularis ) in pathology and toxicology research. The purpose of this study was to define reference values for absolute and percentage organ weights in M fascicularis of different ages and sex. Organ weights were obtained from necropsies of 1022 cynomolgus monkeys at the Wake Forest School of Medicine from 1997 to 2018. Distributions of absolute and percentage weights for each organ were described; sex and age groups were compared using analysis of variance...
July 2022: Toxicologic Pathology
Diya Sharma, Heather Priest, Angela Wilcox
Important hematologic changes can be observed in nonhuman primates with malaria, including inaccurate reticulocyte counts by the ADVIA 2120 hematology analyzer. A 5-year-old male purpose-bred cynomolgus macaque ( Macaca fascicularis ) imported from a commercial source in Cambodia was enrolled in a nonclinical toxicity study investigating the effects of an immunomodulatory pharmaceutical agent. On study day 22, an increase in large unstained cells (LUCs), due to increased monocytes (2.20 × 103 /µl, reference interval: 0...
July 2022: Toxicologic Pathology
Maureen T O'Brien, JoAnn C L Schuh, Lyn M Wancket, Sarah D Cramer, Kathleen A Funk, Nicolette D Jackson, Kamala Kannan, Kevin Keane, Abraham Nyska, Serge D Rousselle, Adrienne Schucker, Valerie S Thomas, Stefan Tunev
Nonclinical implantation studies are a common and often critical step for medical device safety assessment in the bench-to-market pathway. Nonclinical implanted medical devices or drug-device combination products require complex macroscopic and microscopic pathology evaluations due to the physical presence of the device itself and unique tissue responses to device materials. The Medical Device Implant Site Evaluation working group of the Society of Toxicologic Pathology's (STP) Scientific and Regulatory Policy Committee (SRPC) was tasked with reviewing scientific, technical, and regulatory considerations for these studies...
June 28, 2022: Toxicologic Pathology
Xavier Palazzi, Ingrid D Pardo, Hayley Ritenour, Deepa B Rao, Brad Bolon, Robert H Garman
Beagle dogs are a key nonrodent species in nonclinical safety evaluation of new biomedical products. The Society of Toxicologic Pathology (STP) has published "best practices" recommendations for nervous system sampling in nonrodents during general toxicity studies ( Toxicol Pathol 41[7]: 1028-1048, 2013), but their adaptation to the Beagle dog has not been defined specifically. Here we provide 2 trimming schemes suitable for evaluating the unique neuroanatomic features of the dog brain in nonclinical toxicity studies...
June 22, 2022: Toxicologic Pathology
Yuval Ramot, Oleg Dolkart, Michal Steiner, Sabrina Jahn, Ronit Goldberg, Orna Cacical, Yossi Lavie, Nati Ezov, Gabi Agar, Abraham Nyska
Osteoarthritis (OA) can lead to a significant functional disability. Poly[2-(methacryloyloxy)ethyl phosphorylcholine] (pMPC) liposomes are a novel treatment modality for OA, intended to restore the natural lubrication properties of articular cartilage. Here, we report on two studies aimed to assess the local and systemic safety and toxicity of pMPCylated liposomes in comparison with physiological saline, in Sprague-Dawley (SD) rats and in sheep after a single intra-articular (IA) injection. The animals were sacrificed after 1 and 6 weeks (rats) and 3 and 6 weeks (sheep)...
June 21, 2022: Toxicologic Pathology
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