Toxicologic Pathology最新文献

{"title":"Book Review: Toxicologic Pathology for Non-Pathologists","authors":"B. Bolon","doi":"10.1177/01926233231156614","DOIUrl":"https://doi.org/10.1177/01926233231156614","url":null,"abstract":"At first glance, publication of a book review on a tome dedicated to introducing major toxicologic pathology concepts to non-pathologists in a journal focused on the professional practice of toxicologic pathology would seem to be a pointless endeavor. Nothing could be further from the truth. This concise volume (892 pp [plus 27 pp for index] for the hardcover offering) offers a succinct introduction to many key topics in the field. While designed to edify toxicologists, regulatory reviewers, and basic investigators, Toxicologic Pathology for Non-Pathologists harbors much of value for toxicologic pathologists at all levels, from novice to expert. The text is framed in 20 chapters arranged to provide an orderly tutorial in the field. Each chapter has been written by one or more recognized subject matter experts for that topic, most of whom built their toxicologic pathology careers through long stints in contract research organizations, industry, research laboratories (academic or government), and/or consulting. Chapters possess a wealth of fundamental information, images, and tables as well as bibliographies designed to provide a relevant set of additional readings on that topic. The scope is broad, covering basic pathology practices (4 chapters), key organ systems (13 chapters), and several special problems (3 chapters). A thorough reading of this book will greatly speed the professional development of entry-level toxicologic pathologists while the numerous figures and tables will allow more experienced practitioners to better communicate with non-pathologist team members. The 4 chapters on basic pathology practices afford a masterful introduction to the field. Chapter 1 (“Introduction to Toxicologic Pathology”) paired with Chapter 3 (“Routine and Special Techniques in Toxicologic Pathology”) ably define expected qualifications of toxicologic pathologists, the tools they employ in tissue collection and analysis (focusing on structural [anatomic pathology] methods including in situ chemical and molecular procedures), and principal challenges in data generation (e.g., severity grading) and interpretation (e.g., adversity decisions). Chapter 17 (“Principles of Toxicologic Clinical Pathology”) covers similar considerations as they apply to analysis of cell and fluid samples, emphasizing the impact of such factors as animal species, husbandry, and study design parameters on the quality of the final data set. Chapter 2 (“The Pathology Report, Peer Review, and Pathology Working Group”) effectively addresses the elements that need to be included, or at least pondered, in preparing an accurate, brief, and clear pathology report. Such documents are the raison d'être for the toxicologic pathology role on a study team, and Chapter 2 readily outlines basic findings, their implications, and means of producing the best possible report. The 13 organ system chapters are abridged but nevertheless valuable synopses of major toxicologic pathology information for each","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":"75 1","pages":"87 - 88"},"PeriodicalIF":1.5,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74183820","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}

{"title":"Toxicologic Pathology Forum Opinion: Interpretation of Gliosis in the Brain and Spinal Cord Observed During Nonclinical Safety Studies.","authors":"Brad Bolon","doi":"10.1177/01926233231164557","DOIUrl":"10.1177/01926233231164557","url":null,"abstract":"<p><p>Gliosis, defined as a nonneoplastic reaction (hypertrophy and/or proliferation) of astrocytes and/or microglial cells, is a frequent finding in the central nervous system (CNS [brain and/or spinal cord]) in nonclinical safety studies. Gliosis in rodents and nonrodents occurs at low incidence as a spontaneous finding and is induced by various test articles (e.g., biomolecules, cell and gene therapies, small molecules) delivered centrally (i.e., by injection or infusion into cerebrospinal fluid or neural tissue) or systemically. Several CNS gliosis patterns occur in nonclinical species. First, gliosis may accompany degeneration and/or necrosis of cells (mainly neurons) or neural parenchyma (neuron processes and myelin). Second, gliosis often follows inflammation (i.e., leukocyte accumulation causing parenchymal damage) or neoplasm formation. Third, gliosis may appear as variably sized, randomly scattered foci of reactive glial cells in the absence of visible parenchymal damage or inflammation. In interpreting test article-related CNS gliosis, adversity is indicated by parenchymal injury (e.g., degeneration, necrosis, or inflammation) and not the mere existence of a glial reaction. In the absence of clear structural damage to the parenchyma, gliosis as a standalone CNS finding should be interpreted as a nonadverse reaction to regional alterations in microenvironmental conditions rather than as evidence of a glial reaction associated with neurotoxicity.</p>","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":"51 1-2","pages":"68-76"},"PeriodicalIF":1.5,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9647167","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}

{"title":"Post-Pandemic Pathology Practice.","authors":"Kenneth A Schafer","doi":"10.1177/01926233231160518","DOIUrl":"10.1177/01926233231160518","url":null,"abstract":"","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":"51 1-2","pages":"67"},"PeriodicalIF":1.5,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10064181/pdf/10.1177_01926233231160518.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9675691","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}

{"title":"Cardiac Rhabdomyoma in Four Göttingen Minipigs.","authors":"Laine E Feller, Aaron Sargeant, E J Ehrhart, Bethany Balmer, Keith Nelson, Jennifer Lamoureux","doi":"10.1177/01926233221148393","DOIUrl":"10.1177/01926233221148393","url":null,"abstract":"<p><p>Göttingen minipigs are increasingly used as an alternative large animal model in nonclinical toxicology studies, and proliferative lesions in this species are rare. Here, we report four cases of cardiac rhabdomyoma in Göttingen minipigs, an incidental and benign mass in the heart. Three cases lacked gross observations and had a microscopic nodule in either the left ventricle or interventricular septum. The last case had a large, firm, raised nodule on a left ventricular papillary muscle noted at necropsy, with additional microscopic intramural masses in the left ventricular wall. In all cases, microscopic evaluation revealed well-circumscribed, expansile nodules composed of bundles of large, highly vacuolated, ovoid to polygonal cells with variable cytoplasmic processes radiating from a centrally located nucleus. Cells displayed patchy accumulation of intracytoplasmic, PAS-positive material and haphazardly arranged cytoplasmic cross-striations. There was no evidence of cardiac insufficiency or other data to suggest the masses were clinically meaningful. Cardiac rhabdomyomas have been reported in meat-hybrid swine, with a breed predisposition in red wattle. This lesion is well established in guinea pigs, but documentation in other laboratory species used in toxicologic studies is limited to two beagle dogs. To our knowledge, this is the first report of spontaneous cardiac rhabdomyoma in Göttingen minipigs.</p>","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":"51 1-2","pages":"61-66"},"PeriodicalIF":1.4,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9645411","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}

{"title":"Investigation of the Proliferative Potential of FGF21 or FGF19 in Liver-Specific FGFR4-Deficient Mice.","authors":"Kerstin Wäse, Thomas Bartels, Uwe Schwahn, Mostafa Kabiri","doi":"10.1177/01926233231164097","DOIUrl":"10.1177/01926233231164097","url":null,"abstract":"<p><p>Fibroblast growth factor 21 (FGF21) and FGF15/FGF19 belong to the same subgroup of FGFs and are believed to have therapeutic potential in the treatment of type 2 diabetes and associated metabolic dysfunctionalities and pathological conditions. FGF19 has been proposed to induce hyperplasia and liver tumors in FVB mice (named after its susceptibility to Friend leukemia virus B), mediated by the FGF receptor 4 (FGFR4). The goal of this work was to investigate whether FGF21 might also have a potential proliferative effect mediated via FGFR4 using liver-specific <i>Fgfr4</i> knockout (KO) mice. We conducted a mechanistic 7-day study involving female <i>Fgfr4</i> fl/fl and <i>Fgfr4</i> KO mice with a treatment regimen of twice daily or daily subcutaneous injections of FGF21 or FGF19 (positive control), respectively. The Ki-67 liver labeling index (LI) was evaluated by a semi-automated bioimaging analysis. The results showed a statistically significant increase in FGF21- and FGF19-treated <i>Fgfr4</i> fl/fl mice. Interestingly, in <i>Fgfr4</i> KO mice, this effect was absent following both treatments of FGF19 and FGF21, indicating that not only the FGFR4 receptor is pivotal for the mediation of hepatocellular proliferation by FGF19 leading finally to liver tumors but it seems also that FGFR4/FGF21 signaling has an impact on the hepatocellular proliferative activity, which does not promote the formation of hepatocellular liver tumors based on the current knowledge.</p>","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":"51 1-2","pages":"27-38"},"PeriodicalIF":1.5,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9650358","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}

{"title":"Assessing the Carcinogenicity of Vadadustat, an Oral Hypoxia-Inducible Factor Prolyl-4-Hydroxylase Inhibitor, in Rodents.","authors":"Heather Kowalski, Debie Hoivik, Michael Rabinowitz","doi":"10.1177/01926233231168836","DOIUrl":"10.1177/01926233231168836","url":null,"abstract":"<p><p>Vadadustat is an investigational oral hypoxia-inducible factor (HIF) prolyl-4-hydroxylase inhibitor to treat anemia due to chronic kidney disease (CKD). Some studies suggest that HIF activation promotes tumorigenesis by activating angiogenesis downstream of vascular endothelial growth factor, while other studies suggest that elevated HIF activity may produce an antitumor phenotype. To evaluate the potential carcinogenicity of vadadustat in mice and rats, we dosed CByB6F1/Tg.rasH2 hemizygous (transgenic) mice orally by gavage with 5 to 50 mg/kg/d of vadadustat for 6 months and dosed Sprague-Dawley rats orally by gavage with 2 to 20 mg/kg/d for approximately 85 weeks. Doses were selected based on the maximally tolerated dose established for each species in previous studies. The tumors that were identified in the studies were not considered to be treatment-related for statistical reasons or within the historical control range. There was no carcinogenic effect attributed to vadadustat in mice or rats.</p>","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":"51 1-2","pages":"56-60"},"PeriodicalIF":1.5,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/28/16/10.1177_01926233231168836.PMC10278385.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9720991","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}

{"title":"Chronic Inhalation Exposure to Antimony Trioxide Exacerbates the MAPK Signaling in Alveolar Bronchiolar Carcinomas in B6C3F1/N Mice.","authors":"Thai-Vu T Ton, Hue-Hua L Hong, Ramesh C Kovi, Keith R Shockley, Shyamal D Peddada, Kevin E Gerrish, Kyathanahalli S Janardhan, Gordon Flake, Mathew D Stout, Robert C Sills, Arun R Pandiri","doi":"10.1177/01926233231157322","DOIUrl":"10.1177/01926233231157322","url":null,"abstract":"<p><p>Antimony trioxide (AT) is used as a flame retardant in fabrics and plastics. Occupational exposure in miners and smelters is mainly through inhalation and dermal contact. Chronic inhalation exposure to AT particulates in B6C3F1/N mice and Wistar Han rats resulted in increased incidences and tumor multiplicities of alveolar/bronchiolar carcinomas (ABCs). In this study, we demonstrated <i>Kras</i> (43%) and <i>Egfr</i> (46%) hotspot mutations in mouse lung tumors (n = 80) and only <i>Egfr</i> (50%) mutations in rat lung tumors (n = 26). Interestingly, there were no differences in the incidences of these mutations in ABCs from rats and mice at exposure concentrations that did and did not exceed the pulmonary overload threshold. There was increased expression of p44/42 mitogen-activated protein kinase (MAPK) (Erk1/2) protein in ABCs harboring mutations in <i>Kras</i> and/or <i>Egfr</i>, confirming the activation of MAPK signaling. Transcriptomic analysis indicated significant alterations in MAPK signaling such as ephrin receptor signaling and signaling by Rho-family GTPases in AT-exposed ABCs. In addition, there was significant overlap between transcriptomic data from mouse ABCs due to AT exposure and human pulmonary adenocarcinoma data. Collectively, these data suggest chronic AT exposure exacerbates MAPK signaling in ABCs and, thus, may be translationally relevant to human lung cancers.</p>","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":"51 1-2","pages":"39-55"},"PeriodicalIF":1.4,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11368139/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9640244","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}

{"title":"Early-Onset albuminuria and Associated Renal Pathology in Leucine-Rich Repeat Kinase 2 Knockout Rats.","authors":"Yi-Zhong Gu, Katerina Vlasakova, Glen Miller, Nicholas T Gatto, Paul J Ciaccio, Sabu Kuruvilla, Elizabeth G Besteman, Roger Smith, Spencer J Reynolds, Rupesh P Amin, Warren E Glaab, Gordon Wollenberg, Jose Lebron, Frank D Sistare","doi":"10.1177/01926233231162809","DOIUrl":"10.1177/01926233231162809","url":null,"abstract":"<p><p>Activating mutations of the leucine-rich repeat kinase 2 (<i>LRRK2</i>) gene are associated with Parkinson disease (PD), prompting development of LRRK2 inhibitors as potential treatment for PD. However, kidney safety concerns have surfaced from LRRK2 knockout (KO) mice and rats and from repeat-dose studies in rodents administered LRRK2 inhibitors. To support drug development of this therapeutic target, we conducted a study of 26 weeks' duration in 2-month-old wild-type and LRRK2 KO Long-Evans Hooded rats to systematically examine the performance of urinary safety biomarkers and to characterize the nature of the morphological changes in the kidneys by light microscopy and by ultrastructural evaluation. Our data reveal the time course of early-onset albuminuria at 3 and 4 months in LRRK2 KO female and male rats, respectively. The increases in urine albumin were not accompanied by concurrent increases in serum creatinine, blood urea nitrogen, or renal safety biomarkers such as kidney injury molecule 1 or clusterin, although morphological alterations in both glomerular and tubular structure were identified by light and transmission electron microscopy at 8 months of age. Diet optimization with controlled food intake attenuated the progression of albuminuria and associated renal changes.</p>","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":"51 1-2","pages":"15-26"},"PeriodicalIF":1.5,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9678375","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}

{"title":"Assessment of Mouse Liver Histopathology Following Exposure to HFPO-DA With Emphasis on Understanding Mechanisms of Hepatocellular Death.","authors":"Chad M Thompson, Melissa M Heintz, Jeffrey C Wolf, Roza Cheru, Laurie C Haws, John M Cullen","doi":"10.1177/01926233231159078","DOIUrl":"10.1177/01926233231159078","url":null,"abstract":"<p><p>Ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate (HFPO-DA) is a short chain member of per- and polyfluoroalkyl substances (PFAS). To better understand the relevance of histopathological effects seen in livers of mice exposed to HFPO-DA for human health risk assessment, histopathological effects were summarized from hematoxylin and eosin (H&E)-stained sections in several repeat-dose toxicity studies in mice. Findings across studies revealed histopathological changes consistent with peroxisomal proliferation, whereas two reports of steatosis could not be confirmed in the published figures. In addition, mechanisms of hepatocellular death were assessed in H&E sections as well as with the apoptotic marker cleaved caspase-3 (CCasp3) in newly cut sections from archived liver blocks from select studies. A comparison of serially CCasp3 immunolabeled and H&E-stained sections revealed that mechanisms of hepatocellular death cannot be clearly discerned in H&E-stained liver sections alone as several examples of putatively necrotic cells were positive for CCasp3. Published whole genome transcriptomic data were also reevaluated for enrichment of various forms of hepatocellular death in response to HFPO-DA, which revealed enrichment of apoptosis and autophagy, but not ferroptosis, pyroptosis, or necroptosis. These morphological and molecular findings are consistent with transcriptomic evidence for peroxisome proliferator-activated receptor alpha (PPARα) signaling in HFPO-DA exposed mice.</p>","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":"51 1-2","pages":"4-14"},"PeriodicalIF":1.5,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/5f/85/10.1177_01926233231159078.PMC10278389.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9657655","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}

{"title":"Toxicologic Pathology Forum: Opinion on Approaches for Reporting Toxic and Adverse Dose Levels in Nonclinical Toxicology Studies Supporting the Development of Anticancer Pharmaceuticals.","authors":"Renee R Hukkanen, Tomoyuki Moriyama, Daniel J Patrick, Jonathan Werner","doi":"10.1177/01926233221146937","DOIUrl":"10.1177/01926233221146937","url":null,"abstract":"<p><p>The advancement of an investigational new drug in humans is a significant developmental milestone. In first-in-human (FIH)-enabling toxicology studies, the highest dose without a test article-related adverse effect (no-observed-adverse-effect-level [NOAEL]) serves as the basis for deriving a safe FIH starting dose. For anticancer pharmaceuticals, the FIH dose may be calculated using the highest non-severely toxic dose (HNSTD) in nonrodent models or the dose severely toxic to 10% (STD₁₀) in rodents. Given the practice of reporting the NOAEL, but the lack of regulatory requirements to do so for anticancer pharmaceuticals, we conducted an informal survey of 20 companies to answer the question \"How is our industry reporting toxic/adverse dose levels in FIH-enabling toxicology studies for anticancer indications?\" The data indicated 4 reporting approaches, each providing a path to regulatory acceptance. Within the integrated toxicology study report, 45% of respondents report the HNSTD/STD₁₀, 25% report the NOAEL, 20% report both the HNSTD/STD₁₀ and NOAEL, and 10% do not define either, reserving definitions for regulatory submissions. One reporting approach may be preferred over another for reasons including consistency across indications, repurposing pharmaceuticals, regulatory feedback, or simplicity. The reporting approach should be defined in advance of study initiation, and the pathologist should provide context to support the chosen approach.</p>","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":"51 1-2","pages":"81-86"},"PeriodicalIF":1.5,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9647526","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}