Toxicologic Pathology最新文献

In 2016, the publication of the Society of Toxicologic Pathology's (STP) "best practice" recommendations on determining and communicating adversity and the European Society of Toxicologic Pathology's (ESTP) expert working group report on adversity were key milestones in addressing adversity determinations for nonclinical studies as translational tools for assessing human risk. Since then, many publications attest to the ongoing difficulty in adversity decision-making posed by unique context-specific challenges. The STP gathered input on current adversity practices from Society members via an open discussion at the 2024 STP Town Hall session (held at the STP 43rd Annual Symposium) and by a subsequent online survey. Most STP pathologists make adversity determinations by applying the STP and/or ESTP recommendations at their discretion. Adversity decisions are generally made for pivotal toxicity studies but occasionally may be assigned for other study types. Adversity determinations are difficult for certain organ systems (immune, reproductive, and endocrine) and product classes (eg, cell and gene therapies, proteins, and small molecules). Most pathologists assign adversity based on direct effects of the test article, but other factors (eg, secondary pharmacology, species relevance, adaptive responses) are also considered. Procedural adversity (eg, effects of administration/implantation) is a key factor in some circumstances.

The basis for current and future neurologic disease research and therapeutic discovery and development is rooted in the understanding of genetic, transcriptional, and molecular expression profiles of cells and their spatial interplays in anatomical context. Neuro omics aim to analyze all possible molecular and morphological types within the nervous system using specific methods such as genomics, transcriptomics, proteomics, metabolomics, and pathomics (ie, radiology and histology). In this scientific session of the Society of Toxicologic Pathology's 44th Annual Symposium, speakers with diverse experience in drug discovery and nonclinical development presented scientific principles and practical applications of some of the emerging omics technologies as applied to the pursuit of target discovery, preclinical safety, and mechanistic investigations of novel human therapeutics. Spanning both human biology, such as Alzheimer disease, and nonclinical models, session speakers also shared their insights on the promise as well as pitfalls of the omics workflow in nonclinical drug development laboratories.

The 2025 Town Hall meeting of the Society of Toxicologic Pathology (STP) discussed virtual control groups (VCG) in nonclinical toxicity testing, which are being pursued by multiple organizations to reduce animal use in product development. The current VCG literature infrequently reflects the toxicologic pathology perspective. Audience members noted that concurrent control groups (CCG) are the gold standard for toxicity studies, essential for replenishing the historical control data (HCD) from which VCG are generated. The utility of VCG is context-dependent: acceptable when test article (TA)-related effects are easily separated from background findings but likely unsuitable where subtle findings must be distinguished. Global regulatory acceptance is of paramount concern in trying to shift from CCG to partly or wholly relying on VCG. Alternative approaches to reduce animal use include eliminating studies that are a common regulatory expectation but lack scientific justification, obtaining early regulatory agreement that single-species testing is sufficient, and altering study designs to reduce group numbers, sharing CCG, or blending CCG and VCG. The most effective way for toxicologic pathologists to influence this debate is to dispassionately consider opportunities and challenges of VCG related to pathology diagnoses and interpretations and communicate this perspective clearly to the broader (non-pathologist) scientific community.

Risdiplam is the only approved small molecule mRNA splice modifier to date. Over more than five years since its first approval, thousands of patients with spinal muscular atrophy have benefited from risdiplam therapy. Yet, the nonclinical development of risdiplam was marked by toxicological challenges requiring new strategies and approaches, which ultimately translated into clinical success. This minireview covers key aspects of the nonclinical development of risdiplam, particularly focusing on its toxicological characterization and histopathological features in animal studies.

The cerebellum has intricate connections either directly or indirectly with most levels of the brain. While many of these are functionally relevant, prominent neuropathologic changes that reflect the underlying anatomy arise from injury to a few major pathways. Identifying these pathologic sequelae can help to identify the cells involved in the underlying disease. The cerebellum has two distinct components: the aesthetically pleasing cortical dendritic folia and the deep nuclei. The uniform and monotonous cerebellar cortex contains molecular, Purkinje, and granular layers. Several deep nuclei are the main efferent projections from the cerebellum. Key neuron types relevant to cerebellar pathology include the cortical excitatory granular input and inhibitory Purkinje output neurons, the deep nuclear excitatory projection neurons, as well as key afferent nuclei (eg, inferior olivary, pontine, and sensory neurons) and efferent targets (eg, red nucleus, thalamus). Pathologic processes that affect one or more of these neuron groups lead to stereotypic anatomical changes, which in turn signal the existence of those processes. This article first reviews key aspects of human cerebellar anatomy and histology, then discusses some key connections, and finally presents a selection of cases from humans that illustrate these interconnections.

Non-invasive predictive biomarkers for preclinical Alzheimer's disease (AD) may inform future dementia risk and support early intervention for AD. In this review, we describe clinical, biomarker and neuropathologic characteristics in spontaneously aged Old World monkeys (OWMs) in the context of preclinical AD. Reliable age-related amyloid-β (Aβ) plaque deposition occurs in OWMs. Plaque composition is complex, signifying significant disruption of synaptic connectivity. Pretangle pTau pathology in brainstem nuclei and limbic system prevails, consistent with Braak Stage 1b in macaques. Soluble pTau distribution approximates Braak Stage III-IV stage in perfused frozen macaque tissue, and colocalizes with Aβ and acetylcholinesterase labeling in AD-vulnerable circuits. Tau and Aβ pathology in OWMs is accompanied by fluid biomarker changes consistent with Core 1 AD diagnosis in humans but cannot be visualized using amyloid or tau tracers. Despite age-related cognitive decline, aging OWMs do not experience significant hippocampal atrophy or neuropathologic co-morbidities. Minimal expression of senescence markers implicates differences in rates of biological brain aging between OWMs and humans. OWMs support mechanistic studies and biomarker discovery in the areas of Aβ plaque and pTau evolution and resolution following anti-amyloid or Tau-directed therapeutics, as well as effects of senotherapeutics, lifestyle intervention or co-morbidities on biological brain aging.

In this half-day session of the Society of Toxicologic Pathology Annual meeting, we focused on hot topics, future directions, and challenges faced in toxicologic neuropathology. The panel of speakers addressed issues with direct delivery of agents to the brain, the dilemma of cervical dorsal root ganglia collection, and new approaches using digital pathology techniques for assessment of the nervous system.

Neuronal cell death is an irreversible, end-stage cellular response. Programmed cell death of neurons is integral to nervous system development. However, terminally differentiated neurons represent an essentially non-regenerative cell population; therefore, toxicant-induced neuronal death has significant implications for safety assessment, and histologic examination is a critical endpoint for detection of this signal. The most recognized appearance of neuronal necrosis is a shrunken hypereosinophilic cell body, or "red dead" neuron, but other histomorphologies of neuronal cell death occur. Artifactual "dark" neurons must be distinguished from true neuron necrosis. Fluorescence microscopy and special histochemical stains can aid detection of dying neurons. Remnants of dead neurons are removed by glial cells, after which neuron death may be indicated only by secondary glial foci or neuronal loss. The transient window of neuronal necrosis and removal is an important consideration in designing timepoints and selecting ancillary diagnostics for neurotoxicity studies.

Contemporary pathology is increasingly multimodal and requires the application and integration of newer molecular methods to complement classical morphologic evaluation. In diagnostic medical pathology, especially cancer pathology, integrative diagnoses combining morphology, immunohistochemistry, and molecular data including methylation profiling and clinical sequencing are often routine. Such integrative approaches have refined classifications of diseases and enhanced therapeutic decision making. However, in toxicologic pathology, the integration of multiple modalities is relatively nascent. Many pathologists do not have direct and cost-effective access to the information and expertise needed to leverage the availability of advanced molecular modalities. This half-day continuing education course sought to familiarize participants with the evolution of pathology from its early days to state-of-the art applications of molecular, spatial, and computational pathology. The course also aimed to encourage them to implement advanced molecular modalities in their workflows for enhanced understanding of mechanisms of disease and toxicologic processes. This would hopefully facilitate more precise human-relevant translation of preclinical animal model data.