Toxicologic Pathology最新文献_第10页

Translational Relevance of Rodent Models to Predict Human Liver Disease. 预测人类肝病的啮齿动物模型的转化意义

IF 1.5 4区医学

Toxicologic Pathology Pub Date : 2023-10-01 Epub Date: 2024-03-18 DOI: 10.1177/01926233241230543

Debabrata Mahapatra, Robert Maronpot

{"title":"Translational Relevance of Rodent Models to Predict Human Liver Disease.","authors":"Debabrata Mahapatra, Robert Maronpot","doi":"10.1177/01926233241230543","DOIUrl":"10.1177/01926233241230543","url":null,"abstract":"Animals models are essential to understand the complex pathobiology of human diseases. George Box's aphorism based on statistics \"All models are wrong, but some are useful\" certainly applies to animal models of disease. In this session, the translational relevance of various animal models applicable to human liver disease was explored starting with a historic overview of the rodent cancer bioassay with emphasis on hepatocarcinogenesis from early work at the National Cancer Institute, refinement by the National Toxicology Program and contemporary efforts to identify potential mechanisms and their relevance to human cancer risk. Subsequently, recently elucidated understanding of the molecular drivers and signaling mechanisms of liver pathophysiology and liver cancer, including factors associated with liver regeneration, metabolic hepatocellular zonation, and the role of macrophages and their crosstalk with stellate cells in understanding human liver disease was discussed. Next, our contemporary understanding of the role of nuclear receptors in hepatic homeostasis and drug response highlighting nuclear receptor activation and crosstalk in modulating biological responses associated with liver damage and neoplastic response were discussed. Finally, an overview and translational relevance of different drug-induced liver injury (DILI) rodent model systems focused on pathology and mechanisms with commentary on current relevant Food and Drug Administration (FDA) perspective were summarized with closing remarks.","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":" ","pages":"482-486"},"PeriodicalIF":1.5,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140144117","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

Hepatic Bile Acid Transporters and Drug-induced Hepatotoxicity. 肝胆汁酸转运体与药物性肝毒性。

IF 1.5 4区医学

Toxicologic Pathology Pub Date : 2023-10-01 Epub Date: 2023-11-20 DOI: 10.1177/01926233231212255

Chitra Saran, Kim L R Brouwer

{"title":"Hepatic Bile Acid Transporters and Drug-induced Hepatotoxicity.","authors":"Chitra Saran, Kim L R Brouwer","doi":"10.1177/01926233231212255","DOIUrl":"10.1177/01926233231212255","url":null,"abstract":"Drug-induced liver injury (DILI) remains a major concern in drug development from a patient safety perspective because it is the leading cause of acute liver failure. One mechanism of DILI is altered bile acid homeostasis and involves several hepatic bile acid transporters. Functional impairment of some hepatic bile acid transporters by drugs, disease, or genetic mutations may lead to toxic accumulation of bile acids within hepatocytes and increase DILI susceptibility. This review focuses on the role of hepatic bile acid transporters in DILI. Model systems, primarily in vitro and modeling tools, such as DILIsym, used in assessing transporter-mediated DILI are discussed. Due to species differences in bile acid homeostasis and drug-transporter interactions, key aspects and challenges associated with the use of preclinical animal models for DILI assessment are emphasized. Learnings are highlighted from three case studies of hepatotoxic drugs: troglitazone, tolvaptan, and tyrosine kinase inhibitors (dasatinib, pazopanib, and sorafenib). The development of advanced in vitro models and novel biomarkers that can reliably predict DILI is critical and remains an important focus of ongoing investigations to minimize patient risk for liver-related adverse reactions associated with medication use.","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":" ","pages":"405-413"},"PeriodicalIF":1.5,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11014762/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138047997","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Risk Assessment for Hepatobiliary Toxicity Liabilities in Drug Development. 药物开发中的肝胆毒性责任风险评估。

IF 1.5 4区医学

Toxicologic Pathology Pub Date : 2023-10-01 Epub Date: 2024-01-20 DOI: 10.1177/01926233231223751

Richard T Miller

{"title":"Risk Assessment for Hepatobiliary Toxicity Liabilities in Drug Development.","authors":"Richard T Miller","doi":"10.1177/01926233231223751","DOIUrl":"10.1177/01926233231223751","url":null,"abstract":"Risk assessment of hepatobiliary toxicities represents one of the greatest challenges and, more often than not, one of the most rewarding activities in which toxicologic pathologists can partake, and often times lead. This is in part because each liver toxicity picture is a bit different, informed by a broad range and diversity of relevant data, and also in part because the heavily relied upon animal models are imperfect regarding predictivity of hepatic effects in humans. Following identification and characterization of a hepatotoxicity hazard, typically in nonclinical toxicology studies, a holistic and integrated assessment of liver-relevant endpoints is conducted that typically incorporates ADME (absorption, distribution, metabolism, and excretion) information (ideally, including extensive transporter data, exposure margins, and possibly concentration of parent/metabolite at region of injury), target expression/function, in silico prediction data, in vitro hepatocyte data, liver/circulating biomarkers, and importantly, species specificity of any of these data. Of course, a thorough understanding, developed in close partnership with clinical colleagues, of the anticipated liver disease status of intended patient populations is paramount to hepatic risk assessment. This is particularly important since the likelihood of translatable determinant hepatic events observed in nonclinical models to occur in humans has been reasonably well established.","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":" ","pages":"432-436"},"PeriodicalIF":1.5,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139502685","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 2023 Division of Translational Toxicology Satellite Symposium. 2023 年转化毒理学分部卫星研讨会论文集》。

IF 1.4 4区医学

Toxicologic Pathology Pub Date : 2023-10-01 Epub Date: 2024-03-06 DOI: 10.1177/01926233241231287

Erin M Quist, Ronnie Chamanza, Amanda J Martinot, Allison Boone, Gregory A Krane, Martha E Hensel, Shawn V Lennix

引用次数: 0

Toxicologic Neuropathology of Novel Biotherapeutics. 新型生物治疗药物的毒理神经病理学。

IF 1.5 4区医学

Toxicologic Pathology Pub Date : 2023-10-01 Epub Date: 2024-02-21 DOI: 10.1177/01926233241230542

Dinesh S Bangari, Lisa G Lanigan, Sarah D Cramer, Jessica L Grieves, René Meisner, Arlin B Rogers, Elizabeth J Galbreath, Brad Bolon

{"title":"Toxicologic Neuropathology of Novel Biotherapeutics.","authors":"Dinesh S Bangari, Lisa G Lanigan, Sarah D Cramer, Jessica L Grieves, René Meisner, Arlin B Rogers, Elizabeth J Galbreath, Brad Bolon","doi":"10.1177/01926233241230542","DOIUrl":"10.1177/01926233241230542","url":null,"abstract":"Biotherapeutic modalities such as cell therapies, gene therapies, nucleic acids, and proteins are increasingly investigated as disease-modifying treatments for severe and life-threatening neurodegenerative disorders. Such diverse bio-derived test articles are fraught with unique and often unpredictable biological consequences, while guidance regarding nonclinical experimental design, neuropathology evaluation, and interpretation is often limited. This paper summarizes key messages offered during a half-day continuing education course on toxicologic neuropathology of neuro-targeted biotherapeutics. Topics included fundamental neurobiology concepts, pharmacology, frequent toxicological findings, and their interpretation including adversity decisions. Covered biotherapeutic classes included cell therapies, gene editing and gene therapy vectors, nucleic acids, and proteins. If agents are administered directly into the central nervous system, initial screening using hematoxylin and eosin (H&E)-stained sections of currently recommended neural organs (brain [7 levels], spinal cord [3 levels], and sciatic nerve) may need to expand to include other components (e.g., more brain levels, ganglia, and/or additional nerves) and/or special neurohistological procedures to characterize possible neural effects (e.g., cell type-specific markers for reactive glial cells). Scientists who evaluate the safety of novel biologics will find this paper to be a practical reference for preclinical safety testing and risk assessment.","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":" ","pages":"414-431"},"PeriodicalIF":1.5,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139913491","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: Rational Approaches to Expanded Neurohistopathology Evaluation for Nonclinical General Toxicity Studies and Juvenile Animal Studies. 毒理病理学论坛意见：非临床一般毒性研究和幼年动物研究中扩大神经组织病理学评估的合理方法。

IF 1.5 4区医学

Toxicologic Pathology Pub Date : 2023-08-01 Epub Date: 2024-01-30 DOI: 10.1177/01926233231225239

Brad Bolon

{"title":"Toxicologic Pathology Forum Opinion: Rational Approaches to Expanded Neurohistopathology Evaluation for Nonclinical General Toxicity Studies and Juvenile Animal Studies.","authors":"Brad Bolon","doi":"10.1177/01926233231225239","DOIUrl":"10.1177/01926233231225239","url":null,"abstract":"Existing nervous system sampling and processing \"best practices\" for nonclinical general toxicity studies (GTS) were designed to assess test articles with unknown, no known, or well-known neurotoxic potential. Similar practices are applicable to juvenile animal studies (JAS). In GTS and JAS, the recommended baseline sampling for all species includes brain (7 sections), spinal cord (cervical and lumbar divisions [cross and longitudinal sections for each]), and 1 nerve (sciatic or tibial [cross and longitudinal sections]) in hematoxylin and eosin-stained sections. Extra sampling and processing (ie, an \"expanded neurohistopathology evaluation\" [ENHP]) are used for agents with anticipated neuroactivity (toxic ± therapeutic) of incompletely characterized location and degree. Expanded sampling incorporates additional brain (usually 8-15 sections total), spinal cord (thoracic ± sacral divisions), ganglia (somatic ± autonomic, often 2-8 total), and/or nerves (2-6 total) depending on the species and study objectives. Expanded processing typically adds special neurohistological procedures (usually 1-4 for selected samples) to characterize glial reactions, myelin integrity, and/or neuroaxonal damage. In my view, GTS and JAS designs should sample neural tissues at necropsy as if ENHP will be needed eventually, and when warranted ENHP may incorporate expanded sampling and/or expanded processing depending on the study objective(s).","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":" ","pages":"363-374"},"PeriodicalIF":1.5,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139576489","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

Historical Control Background Incidence of Spontaneous Neoplastic Lesions of Sprague-Dawley Rats in 104-Week Toxicity Studies. 在为期 104 周的毒性研究中，Sprague-Dawley 大鼠自发性肿瘤病变的历史对照背景发生率。

IF 1.5 4区医学

Toxicologic Pathology Pub Date : 2023-08-01 Epub Date: 2024-01-28 DOI: 10.1177/01926233231224466

Amit Kumar, Marie Bockenstedt, Victoria Laast, Alok Sharma

{"title":"Historical Control Background Incidence of Spontaneous Neoplastic Lesions of Sprague-Dawley Rats in 104-Week Toxicity Studies.","authors":"Amit Kumar, Marie Bockenstedt, Victoria Laast, Alok Sharma","doi":"10.1177/01926233231224466","DOIUrl":"10.1177/01926233231224466","url":null,"abstract":"Data collected from approximately 1800 male and 1800 female Sprague-Dawley (SD) rats used in 104-week carcinogenicity studies were archived in a historical control database at Labcorp Early Development, Inc, and the neoplastic microscopic observation data from these rats were retrospectively evaluated. Historical control data can provide useful information on the range and incidence of spontaneously occurring background neoplasms in the species and strain of the test animal used in different types of toxicity studies, including studies of differing lengths, delivery of test article, and test animal. Some of the most common malignant findings noted included fibrosarcoma of skin/subcutis and thyroid C-cell carcinoma in males (2.1% each) while mammary gland carcinoma and pituitary carcinoma (25% and 2.6%) were most common in females. Pituitary adenoma of pars distalis was found to be the most prevalent benign neoplasm in both males and females (56.4% and 77.1%). Fibroadenoma of mammary gland (35.6%) and thyroid C-cell adenoma (8.5%) were the second and third most common benign tumors in female SD rats. In males, the thyroid C-cell adenoma (10.9%) and benign pheochromocytoma (8.9%) were the second and third most common tumors.","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":" ","pages":"329-356"},"PeriodicalIF":1.5,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139571509","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

Early-Onset Asymptomatic Polypoid Cystitis in Two Adolescent Male Beagle Dogs. 两只青春期雄性比格犬早期出现的无症状多发性膀胱炎

IF 1.5 4区医学

Toxicologic Pathology Pub Date : 2023-08-01 Epub Date: 2024-01-09 DOI: 10.1177/01926233231224462

Giulia Tosi, Jennifer Rachael Barnes

引用次数: 0

Toxicologic Pathology Forum Opinion Piece: Use of Virtual Control Groups in Nonclinical Toxicity Studies: The Anatomic Pathology Perspective. 毒理病理学论坛观点文章：在非临床毒性研究中使用虚拟对照组：解剖病理学的视角。

IF 1.5 4区医学

Toxicologic Pathology Pub Date : 2023-08-01 Epub Date: 2024-01-31 DOI: 10.1177/01926233231224805

Armelle Grevot, Julie Boisclair, Magali Guffroy, Peter Hall, Gabriele Pohlmeyer-Esch, Matt Jacobsen, Ute Bach, Anna Lena Frisk, Noel Dybdal, Xavier Palazzi

{"title":"Toxicologic Pathology Forum Opinion Piece: Use of Virtual Control Groups in Nonclinical Toxicity Studies: The Anatomic Pathology Perspective.","authors":"Armelle Grevot, Julie Boisclair, Magali Guffroy, Peter Hall, Gabriele Pohlmeyer-Esch, Matt Jacobsen, Ute Bach, Anna Lena Frisk, Noel Dybdal, Xavier Palazzi","doi":"10.1177/01926233231224805","DOIUrl":"10.1177/01926233231224805","url":null,"abstract":"In the last decade, numerous initiatives have emerged worldwide to reduce the use of animals in drug development, including more recently the introduction of Virtual Control Groups (VCGs) concept for nonclinical toxicity studies. Although replacement of concurrent controls (CCs) by virtual controls (VCs) represents an exciting opportunity, there are associated challenges that will be discussed in this paper with a more specific focus on anatomic pathology. Coordinated efforts will be needed from toxicologists, clinical and anatomic pathologists, and regulators to support approaches that will facilitate a staggered implementation of VCGs in nonclinical toxicity studies. Notably, the authors believe that a validated database for VC animals will need to include histopathology (digital) slides for microscopic assessment. Ultimately, the most important step lies in the validation of the concept by performing VCG and the full control group in parallel for studies of varying duration over a reasonable timespan to confirm there are no differences in outcomes (dual study design). The authors also discuss a hybrid approach, whereby control groups comprised both concurrent and VCs to demonstrate proof-of-concept. Once confidence is established by sponsors and regulators, VCs have the potential to replace some or all CC animals.","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":" ","pages":"390-396"},"PeriodicalIF":1.5,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139642955","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

Can Historical Control Group Data Be Used to Replace Concurrent Controls in Animal Studies? 在动物研究中，历史对照组数据可以用来代替同期对照吗？

IF 1.5 4区医学

Toxicologic Pathology Pub Date : 2023-08-01 Epub Date: 2023-10-31 DOI: 10.1177/01926233231208987

Thomas Steger-Hartmann, Matthew Clark

引用次数: 0