Toxicologic Pathology最新文献

Trends and Challenges of the Modern Pathology Laboratory for Biopharmaceutical Research Excellence.

IF 1.4 4区医学

Toxicologic Pathology Pub Date : 2024-12-13 DOI: 10.1177/01926233241303898

Sílvia Sisó, Anoop Murthy Kavirayani, Suzana Couto, Birgit Stierstorfer, Sunish Mohanan, Caroline Morel, Mathiew Marella, Dinesh S Bangari, Elizabeth Clark, Annette Schwartz, Vinicius Carreira

{"title":"Trends and Challenges of the Modern Pathology Laboratory for Biopharmaceutical Research Excellence.","authors":"Sílvia Sisó, Anoop Murthy Kavirayani, Suzana Couto, Birgit Stierstorfer, Sunish Mohanan, Caroline Morel, Mathiew Marella, Dinesh S Bangari, Elizabeth Clark, Annette Schwartz, Vinicius Carreira","doi":"10.1177/01926233241303898","DOIUrl":"https://doi.org/10.1177/01926233241303898","url":null,"abstract":"Pathology, a fundamental discipline that bridges basic scientific discovery to the clinic, is integral to successful drug development. Intrinsically multimodal and multidimensional, anatomic pathology continues to be empowered by advancements in molecular and digital technologies enabling the spatial tissue detection of biomolecules such as genes, transcripts, and proteins. Over the past two decades, breakthroughs in spatial molecular biology technologies and advancements in automation and digitization of laboratory processes have enabled the implementation of higher throughput assays and the generation of extensive molecular data sets from tissue sections in biopharmaceutical research and development research units. It is our goal to provide readers with some rationale, advice, and ideas to help establish a modern molecular pathology laboratory to meet the emerging needs of biopharmaceutical research. This manuscript provides (1) a high-level overview of the current state and future vision for excellence in research pathology practice and (2) shared perspectives on how to optimally leverage the expertise of discovery, toxicologic, and translational pathologists to provide effective spatial, molecular, and digital pathology data to support modern drug discovery. It captures insights from the experiences, challenges, and solutions from pathology laboratories of various biopharmaceutical organizations, including their approaches to troubleshooting and adopting new technologies.","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":" ","pages":"1926233241303898"},"PeriodicalIF":1.4,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142824202","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Toxicologic Pathology Forum: Opinion on Digital Primary Read and Peer Review-Diving Head-First Into the Deep Digital Pool! 毒理病理学论坛：关于数字化初读和同行评审的意见--一头扎进数字化深潭！

IF 1.4 4区医学

Toxicologic Pathology Pub Date : 2024-12-12 DOI: 10.1177/01926233241303909

Krista M D La Perle

引用次数: 0

Neuropathological Findings in Nonclinical Species Following Administration of Adeno-Associated Virus (AAV)-Based Gene Therapy Vectors.

IF 1.4 4区医学

Toxicologic Pathology Pub Date : 2024-12-12 DOI: 10.1177/01926233241300314

Brad Bolon, Elizabeth Buza, Elizabeth Galbreath, Joan Wicks, Francesca Cargnin, Juliette Hordeaux

{"title":"Neuropathological Findings in Nonclinical Species Following Administration of Adeno-Associated Virus (AAV)-Based Gene Therapy Vectors.","authors":"Brad Bolon, Elizabeth Buza, Elizabeth Galbreath, Joan Wicks, Francesca Cargnin, Juliette Hordeaux","doi":"10.1177/01926233241300314","DOIUrl":"https://doi.org/10.1177/01926233241300314","url":null,"abstract":"Adeno-associated virus (AAV) gene therapy vectors are an accepted platform for treating severe neurological diseases. Test article (TA)-related and procedure-related neuropathological effects following administration of AAV-based vectors are observed in the central nervous system (CNS) and peripheral nervous system (PNS). Leukocyte accumulation (mononuclear cell infiltration > inflammation) may occur in brain, spinal cord, spinal nerve roots (SNRs), sensory and autonomic ganglia, and rarely nerves. Leukocyte accumulation may be associated with neuron necrosis (sensory ganglia > CNS) and/or glial changes (microgliosis and/or astrocytosis in the CNS, increased satellite glial cellularity in ganglia and/or Schwann cellularity in nerves). Axonal degeneration secondary to neuronal injury may occur in the SNR (dorsal > ventral), spinal cord (dorsal and occasionally lateral funiculi), and brainstem centrally and in nerves peripherally. Patterns of AAV-associated microscopic findings in the CNS and PNS differ for TAs administered into brain parenchyma (where tissue at the injection site is affected most) versus TAs delivered into cerebrospinal fluid (CSF) or systemically (which primarily impacts sensory ganglion neurons and their processes in SNR and spinal cord). Changes related to the TA and procedure may overlap. While often interpreted as adverse, AAV-associated neuronal necrosis and axonal degeneration of limited severity generally do not preclude clinical testing.","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":" ","pages":"1926233241300314"},"PeriodicalIF":1.4,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142819284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Mass Spectrometry Imaging Distinguishes Biliary Toxicants on the Basis of Cellular Distribution.

IF 1.4 4区医学

Toxicologic Pathology Pub Date : 2024-12-12 DOI: 10.1177/01926233241303890

Junhai Yang, Andrew P Bowman, Wayne R Buck, Rebecca Kohnken, Christopher J Good, David S Wagner

{"title":"Mass Spectrometry Imaging Distinguishes Biliary Toxicants on the Basis of Cellular Distribution.","authors":"Junhai Yang, Andrew P Bowman, Wayne R Buck, Rebecca Kohnken, Christopher J Good, David S Wagner","doi":"10.1177/01926233241303890","DOIUrl":"https://doi.org/10.1177/01926233241303890","url":null,"abstract":"Mass spectrometry imaging (MSI) was used to investigate and provide insights into observed biliary pathology found in dogs and rats after administration of two different compounds. Both compounds were associated with peribiliary inflammatory infiltrates and proliferation of the bile duct epithelium. However, MSI revealed very different spatial distribution profiles for the two compounds: Compound A showed significant accumulation within the bile duct epithelium with a much higher concentration than in the parenchymal hepatocytes, while Compound T exhibited only a slight increase in the bile duct epithelium compared to parenchymal hepatocytes. These findings implicate cholangiocyte uptake and accumulation as a key step in the mechanism of biliary toxicity. In both cases, compounds are shown at the site of toxicity in support of a direct mechanism of toxicity on the biliary epithelium. MSI is a powerful tool for localizing small molecules within tissue sections and improvements in sensitivity have enabled localization down to the cellular level in some cases. MSI was also able to identify biomarker candidates of toxicity by differential analysis of ion profiles comparing treated and control cholangiocytes from tissue sections.","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":" ","pages":"1926233241303890"},"PeriodicalIF":1.4,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142814228","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

IHI VICT3R: Developing and Implementing Virtual Control Groups to Reduce Animal Use in Toxicology Research.

IF 1.4 4区医学

Toxicologic Pathology Pub Date : 2024-12-12 DOI: 10.1177/01926233241303906

Thomas Steger-Hartmann, Ferran Sanz, Frank Bringezu, Inari Soininen

{"title":"IHI VICT3R: Developing and Implementing Virtual Control Groups to Reduce Animal Use in Toxicology Research.","authors":"Thomas Steger-Hartmann, Ferran Sanz, Frank Bringezu, Inari Soininen","doi":"10.1177/01926233241303906","DOIUrl":"https://doi.org/10.1177/01926233241303906","url":null,"abstract":"The virtual control group (VCG) concept was originally developed in the IMI2 project eTRANSAFE, using data of control animals which pharmaceutical companies have accrued over decades from animal toxicity studies. This control data could be repurposed to create virtual control animals to reduce or replace concurrent controls in animal studies. Initial work demonstrated the general feasibility of the VCG concept, but implementation requires significant further collaborative efforts. The new Innovative Health Initiative (IHI) project VICT3R aims to address these challenges and to obtain regulatory acceptance for the VCG concept. To achieve these goals, VICT3R will build a database comprising high-quality, standardized, and duly annotated control animal data from past and forthcoming toxicity studies. The VICT3R project will create workflows and computational tools to generate adequate VCGs based on statistical and artificial intelligence (AI) approaches. The validity, reproducibility, and robustness of the resulting VCGs will be assessed by comparing the performance of their use with that of real control groups.","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":" ","pages":"1926233241303906"},"PeriodicalIF":1.4,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142814225","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Session 5: Protein Degraders.

IF 1.4 4区医学

Toxicologic Pathology Pub Date : 2024-12-11 DOI: 10.1177/01926233241300452

Kiran Palyada, Renee Hukkanen, Stephanie Leuenroth-Quinn, Allison Vitsky, Richard Peterson, Katie Stamp, Clare Hoover, Laurie Volak

{"title":"Session 5: Protein Degraders.","authors":"Kiran Palyada, Renee Hukkanen, Stephanie Leuenroth-Quinn, Allison Vitsky, Richard Peterson, Katie Stamp, Clare Hoover, Laurie Volak","doi":"10.1177/01926233241300452","DOIUrl":"https://doi.org/10.1177/01926233241300452","url":null,"abstract":"The so-called undruggable space is an exciting area of potential growth for drug development. Undruggable proteins are defined as those unable to be targeted via conventional small molecule drugs. New modalities are being developed to potentially target these proteins. Targeted protein degradation (TPD) is one such new modality, which over the last two decades has moved from academia to industry. TPD makes use of the endogenous degradation machinery present in all cells, in which E3 ubiquitin ligases mark proteins for degradation via ubiquitin attachment. This session explored the challenges and perspectives of using protein degraders as novel therapeutic agents. The session began with a general introduction to the modality, followed by considerations in evaluating their on- and off-target toxicities including data from an IQ Consortium working group survey. Unique absorption, distribution, metabolism, and excretion (ADME) properties of degrader molecules were presented in relation to their effect on drug development and nonclinical safety assessment. The role of transgenic models in evaluating hemotoxicity associated with cereblon-based therapies was then discussed. A case study to derisk dose-limiting thrombocytopenia was also presented. Finally, a regulatory perspective on the challenges of having toxicity associated with protein degraders was presented.","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":" ","pages":"1926233241300452"},"PeriodicalIF":1.4,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142807216","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Proceedings of the 2024 Division of Translational Toxicology Satellite Symposium.

IF 1.4 4区医学

Toxicologic Pathology Pub Date : 2024-12-11 DOI: 10.1177/01926233241298895

Erin M Quist, Shambhunath Choudhary, Typhaine Lejeune, Emily Mackey, Priyanka Thakur, Kristen Hobbie, Amanda Duggan

引用次数: 0

A Pathologist's Guide to Non-clinical Safety Assessment of Adoptive Cell Therapy Products.

IF 1.4 4区医学

Toxicologic Pathology Pub Date : 2024-12-06 DOI: 10.1177/01926233241298570

Alessandra Piersigilli, Vinicius S Carreira, Frédéric Gervais, Keith Mansfield, Brian E McIntosh, Ingrid Cornax

{"title":"A Pathologist's Guide to Non-clinical Safety Assessment of Adoptive Cell Therapy Products.","authors":"Alessandra Piersigilli, Vinicius S Carreira, Frédéric Gervais, Keith Mansfield, Brian E McIntosh, Ingrid Cornax","doi":"10.1177/01926233241298570","DOIUrl":"https://doi.org/10.1177/01926233241298570","url":null,"abstract":"Through two decades of research and development, adoptive cell therapies (ACTs) have revolutionized treatment for hematologic malignancies. Many of the seven US Food and Drug Administration (FDA)-approved products are proven to be a curative last line of defense against said malignancies. The ACTs, known more commonly as chimeric antigen receptor (CAR) T-cells, utilize engineered lymphocytes to target and destroy cancer cells in a patient-specific, major histocompatibility complex (MHC)-independent manner, acting as \"living drugs\" that adapt to and surveil the body post-treatment. Despite their efficacy, CAR T-cell therapies present unique challenges in preclinical safety assessment. The safety and pharmacokinetics of CAR T-cells are influenced by numerous factors including donor and recipient characteristics, product design, and manufacturing processes that are not well-predicted by existing in vitro and in vivo preclinical safety models. The CAR therapy-mediated toxicities in clinical settings primarily arise from unintended targeting of non-tumor cells, potential tumorigenicity, and severe immune activation syndromes like cytokine release syndrome and immune effector cell-associated neurotoxicity. Addressing these issues necessitates a deep understanding of CAR target expression in normal tissues, inclusive of the spatial microanatomical distribution, off-target screening, and a deep understanding CAR cell manufacturing practices and immunopathology.","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":" ","pages":"1926233241298570"},"PeriodicalIF":1.4,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142792389","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The Role of Neuropathology Evaluation in the Nonclinical Assessment of Seizure Liability.

IF 1.4 4区医学

Toxicologic Pathology Pub Date : 2024-12-05 DOI: 10.1177/01926233241300065

Katie Sokolowski, Judy Liu, Marcus S Delatte, Simon Authier, Owen McMaster, Brad Bolon

{"title":"The Role of Neuropathology Evaluation in the Nonclinical Assessment of Seizure Liability.","authors":"Katie Sokolowski, Judy Liu, Marcus S Delatte, Simon Authier, Owen McMaster, Brad Bolon","doi":"10.1177/01926233241300065","DOIUrl":"https://doi.org/10.1177/01926233241300065","url":null,"abstract":"Test article (TA)-induced seizures represent a major safety concern in drug development. Seizures (altered brain wave [electrophysiological] patterns) present clinically as abnormal consciousness with or without tonic/clonic convulsions (where \"tonic\" = stiffening and \"clonic\" = involuntary rhythmical movements). Neuropathological findings following seizures may be detected using many methods. Neuro-imaging may show a structural abnormality underlying seizures, such as focal cortical dysplasia or hippocampal sclerosis in patients with chronic epilepsy. Neural cell type-specific biomarkers in blood or cerebrospinal fluid may highlight neuronal damage and/or glial reactions but are not specific indicators of seizures while serum electrolyte and glucose imbalances may induce seizures. Gross observations and brain weights generally are unaffected by TAs with seizurogenic potential, but microscopic evaluation may reveal seizure-related neuron death in some brain regions (especially neocortex, hippocampus, and/or cerebellum). Current globally accepted best practices for neural sampling in nonclinical general toxicity studies provide a suitable screen for brain regions that are known sites of electrical disruption and/or display seizure-induced neural damage. Conventional nonclinical studies can afford an indication that a TA has a potential seizure liability (via in-life signs and/or microscopic evidence of neuron necrosis), but confirmation requires measuring brain electrical (electroencephalographic) activity in a nonclinical study.","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":" ","pages":"1926233241300065"},"PeriodicalIF":1.4,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142781006","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Characterization of Pulmonary Pathology in the Golden Syrian Hamster Model of COVID-19 Using Micro-Computed Tomography.

IF 1.4 4区医学

Toxicologic Pathology Pub Date : 2024-12-05 DOI: 10.1177/01926233241300451

Julita A Ramirez, Micah D Dunlap, Reyna Prosnitz, Anderson Watson, Mary K Montgomery, Matthew Gutman, Timothy M Coskran, Samantha L Levinson, Katharine Yang, Isis Kanevsky, Shambhunath Choudhary

{"title":"Characterization of Pulmonary Pathology in the Golden Syrian Hamster Model of COVID-19 Using Micro-Computed Tomography.","authors":"Julita A Ramirez, Micah D Dunlap, Reyna Prosnitz, Anderson Watson, Mary K Montgomery, Matthew Gutman, Timothy M Coskran, Samantha L Levinson, Katharine Yang, Isis Kanevsky, Shambhunath Choudhary","doi":"10.1177/01926233241300451","DOIUrl":"https://doi.org/10.1177/01926233241300451","url":null,"abstract":"The Golden Syrian hamster is a well-characterized rodent model for severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2)-associated pneumonia. We sought to characterize the pulmonary disease course during SARS-CoV-2 infection (strain USA-WA1/2020) in the hamster model using micro-computed tomography (micro-CT) and compare radiologic observations with histopathologic findings. We observed a range of radiologic abnormalities, including ground glass opacities (GGOs), consolidations, air bronchograms, and pneumomediastinum. The appearance, distribution, and progression of these abnormalities in hamsters were similar to those observed in the lungs of coronavirus disease 2019 (COVID-19) patients by clinical CT and chest X-rays, and correlated with clinical signs and weight loss during the course of disease. Histopathological analysis of infected hamsters revealed lung pathology characteristic of COVID-19 pneumonia, and we observed a strong association between CT and histopathologic scorings. We also analyzed accumulation of air in the thoracic cavity by both manual and automated threshold-based segmentation and found that automated analysis significantly decreases the time needed for data analysis. Data presented here demonstrate that micro-CT imaging can be a major tool in preclinical investigative studies using animal models by providing early and detailed assessment of disease severity and outcomes.","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":" ","pages":"1926233241300451"},"PeriodicalIF":1.4,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142781005","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0