Toxicologic Pathology最新文献

The high metabolic demand and complex blood supply of the central nervous system (CNS) render it susceptible to both global and focal ischemic insults, which represent a leading cause of morbidity and mortality in humans. The effects of ischemia in the CNS are determined by duration, severity, and neuroanatomical location of the insult. The pathophysiology of ischemic cell death represents a dynamic process in which necrosis, apoptosis, and other forms of regulated cell death (i.e., necroptosis, pyroptosis, ferroptosis, and autophagic cell death) can be involved. Multiple molecular signaling pathways are implicated in ischemic cell death associated with ATP depletion, excitotoxicity, calcium overload, oxidative stress, mitochondrial dysfunction, and rough endoplasmic reticulum dysfunction. Multiple animal models have been developed to advance knowledge in the field, though translational gaps remain. Therapeutic approaches focus on timely reperfusion and emerging cytoprotective strategies. Toxicologic pathologists play a pivotal role in expanding translational research and supporting the development of emerging therapies.

A 28-year-old, female Rhesus macaque (Macaca mulatta) was lethargic and inappetent despite supportive treatment. Euthanasia was elected. Necropsy revealed numerous nodules in the liver and lung. Microscopically, the liver and lung were multifocally effaced by a poorly demarcated proliferation of neoplastic epithelial cells arranged in irregular and tortuous tubules and nests. Neoplastic cells showed positive immunolabeling for CK7 and negative immunolabeling for Hep-Par1. Findings in the liver and lung were consistent with cholangiocarcinoma, which is a rare neoplasm in non-human primates and has not been previously reported as a spontaneous finding in laboratory-kept Rhesus macaques. Rhesus macaques exhibit increased tumor incidence with age similar to humans, emphasizing the need for a comprehensive understanding of spontaneous neoplasia in this species.

Thrombotic complications including myocardial infarction, stroke, venous thrombosis and pulmonary thromboembolism are common causes of drug attrition often discovered at late stages of drug development. Current nonclinical safety assessments include screening tests that detect hemorrhagic complications but do not identify conditions signaling a risk of thrombosis. Our study aimed to identify sensitive tests for detecting prothrombotic imbalance, without overt thrombosis, for use in early nonclinical drug safety assessments in rodents. Sprague Dawley rats were administered different doses of thromboplastin or tranexamic acid to induce variable intensity hypercoagulable or hypofibrinolytic states, respectively. A panel of functional and quantitative assays measuring hemostatic proteins and pathways were evaluated, in concert with traditional coagulation screening tests and blood cell counts. Profound changes were observed with different patterns of test abnormalities for the different stimuli. Measurements of D-dimer and thrombin antithrombin complex concentrations, plasminogen activator inhibitor-1 and Factor VIIa activity were among the most sensitive tests of hypercoagulability. In contrast, hypofibrinolysis was best characterized in a kinetic, turbidimetric assay. Traditional coagulation screening tests were relatively insensitive, and no single test defined the cause of prothrombotic imbalance. Our results demonstrate that customized biomarker panels can detect early drug-induced prothrombotic states in rats arising from distinct mechanisms.

Conscious telemetry-instrumented dogs are used during cardiovascular safety assessment in early drug development for the collection of cardiovascular function parameters such as electrocardiography (ECG), heart rate, mean arterial pressure, and cardiac contractility. To refine the use of animals for exploratory toxicology studies, these dogs may be repurposed into these studies following failure of their implanted device. Telemetry instrumentation involves surgical placement of a pressure catheter through the left ventricular apex of the heart. Slight variations in placement and extension of the catheter tip into the ventricular chamber lead to variability in cardiac pathology associated with the instrumentation. Reuse of these animals in toxicologic assessments therefore requires the pathologist to be aware of the spectrum of histologic changes that may occur because of telemetry instrumentation. This report describes cardiac findings in 12 telemetry-instrumented male dogs with implant duration ranging from 7 to 37 months and discusses considerations and recommendations for use of these animals.

Digital pathology (DP) for the purpose of primary reads has emerged as a transformative tool in the practice of histopathology and has already proved to be suitable, bringing numerous advantages over traditional light microscopy (LM). This position paper promotes the adoption of DP, particularly whole slide imaging (WSI), within toxicologic pathology, emphasizing its applicability in Good Laboratory Practice (GLP)-compliant nonclinical safety assessments. With established benefits such as efficiency, remote collaboration, data security, and compatibility with artificial intelligence AI-based tools, DP represents a reliable and advanced alternative. This paper offers a counterpoint to recent skepticism expressed in the literature on the readiness of DP including discussion of implementation strategies, technical requirements, and the growing body of validation evidence supporting DP's utility in toxicologic pathology.

This report presents the findings of a spontaneous case of acute myeloid leukemia (AML) in a 6-year-old male cynomolgus macaque enrolled in a 9-month repeat dose-toxicity and toxicokinetic study. Abnormal hematology findings occurred approximately 6 months into daily oral dosing that included markedly decreased red blood cell mass and reticulocyte count, moderately decreased platelet counts, and the identification of abnormal cells in blood that were interpreted as neoplastic. Cytologic characteristics of the neoplastic cells included a moderate to high nucleus to cytoplasm ratio, medium to deep blue cytoplasm, and a round to oval nucleus with fine chromatin, often with multiple, irregularly shaped nucleoli. Following humane euthanasia, evaluation of bone marrow smears and formalin fixed paraffin embedded tissues revealed neoplastic cells of similar morphology. A panel of immunohistochemistry and cytochemical stains demonstrated expression of CD68 and myeloperoxidase, with weaker and less consistent expression of CD11c and CD45. No staining was detected for CD34, CD14, and T (CD3) and B (CD20) lymphoid markers. The neoplastic cells did not stain for any of the cytochemical stains applied (Periodic Acid Schiff, α-naphthyl acetate esterase, Sudan Black B, α-naphthyl butyrate esterase, and chloroacetate esterase). An interpretation of AML was made suggestive of a myelomonocytic lineage.

The molecular identification of alpha2 urinary protein in male rat kidneys is crucial in distinguishing human relevant from rat-specific cases of nephropathy caused by protein accumulation. As protein accumulation in the kidney presents uniformly as hyaline eosinophilic droplets, the identification of the causative protein can be very difficult, especially if suitable antibodies are lacking. We describe the successful identification of two morphologically similar protein accumulations (alpha2u protein and lysozyme) in rat kidneys by the matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI MSI). The potential benefits of MSI may extend to other areas of toxicologic pathology, including instances where the protein accumulation must be characterized and the initial steps are unclear or the composition is unknown.

The veterinary research community requires statistically robust reference intervals in which to contextualize the results of laboratory tests obtained in research studies. While published reference intervals are available for veterinary clinical practice, they typically do not account for differences in animal husbandry, variations in analytical equipment, and the diverse range of species encountered in a research setting. In addition, existing guidelines for statistical calculation of reference intervals do not address commonly encountered issues with data quality, sample size, research-induced population biases, and other impediments. In this manuscript, we document our pipeline to extract, partition, analyze, and statistically summarize in-house clinical pathology data for developing useful reference intervals to support research at the Integrated Research Facility at Fort Detrick (National Institute of Allergy and Infectious Diseases) and showcase a practical application of statistical methodology that can guide other facilities in their own determination of clinical pathology reference intervals.

Clinical pathology endpoints are routinely assessed in nonclinical toxicity studies and the magnitude of test article-related changes is frequently expressed using quantitative and/or qualitative severity descriptors. Quantitative descriptors (ie, percent or fold change) are easily calculated to express numerical magnitude of a change but may not adequately convey biological relevance. A specific quantitative magnitude may be associated with vastly different levels of pathophysiologic relevance depending on several factors, including the nature of the endpoint, the animal species/strain, and the magnitude and direction of change. Qualitative descriptors (eg, minimal and mild) offer a succinct way to provide additional context to the pathophysiologic relevance but are more challenging to ascribe to a change. The assignment of qualitative descriptors often requires a subjective, comprehensive, and multifaceted approach using various factors in addition to numerical calculation. Because of the subjectivity involved, the qualitative severity descriptor assigned to a specific change may differ among clinical pathology endpoints, species/strain, contributing scientists, and studies/programs. Quantitative and qualitative severity descriptors may provide complementary information and may be used individually or in combination. This opinion piece primarily explains the process and discusses caveats and various factors taken into consideration by clinical pathologists while ascribing qualitative severity descriptors.

This brief communication details the clinical, macroscopic, histological, and immunohistochemical features of a spontaneous case of uveodermatologic syndrome (UDS) in a laboratory beagle dog. A bilateral and symmetrical panuveitis, rich in macrophages and T lymphocytes, with distinctive extracellular clumped or phagocytised melanin pigment granules, and Dalen-Fuchs nodules was diagnosed following occurrence of ocular symptoms and subsequent blindness in a female peripubertal 9.5-month-old beagle dog. Although no macroscopic lesions were visible in the skin, microscopic examination revealed a histiocytic and lymphocytic lichenoid dermatitis with pigmentary incontinence. UDS has not been described as a background finding in laboratory beagle dogs before, although it is a well-known immune-mediated disease in certain canine breeds. Knowledge that UDS can occur in laboratory beagle dogs involved in preclinical studies, especially ocular studies, is essential for toxicologic pathologists.