Toxicologic Pathology最新文献_第5页

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":null,"pages":null},"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

Assessment of Color Reproducibility and Mitigation of Color Variation in Whole Slide Image Scanners for Toxicologic Pathology. 评估用于毒理病理学的整张切片图像扫描仪的色彩再现性和色彩变异缓解情况。

IF 1.5 4区医学

Toxicologic Pathology Pub Date : 2023-08-01 Epub Date: 2024-01-30 DOI: 10.1177/01926233231224468

Mei-Lan Chu, Xing-Yue M Ge, Jeffrey Eastham, Trung Nguyen, Reina N Fuji, Ruth Sullivan, Daniel Ruderman

{"title":"Assessment of Color Reproducibility and Mitigation of Color Variation in Whole Slide Image Scanners for Toxicologic Pathology.","authors":"Mei-Lan Chu, Xing-Yue M Ge, Jeffrey Eastham, Trung Nguyen, Reina N Fuji, Ruth Sullivan, Daniel Ruderman","doi":"10.1177/01926233231224468","DOIUrl":"10.1177/01926233231224468","url":null,"abstract":"Digital pathology workflows in toxicologic pathology rely on whole slide images (WSIs) from histopathology slides. Inconsistent color reproduction by WSI scanners of different models and from different manufacturers can result in different color representations and inter-scanner color variation in the WSIs. Although pathologists can accommodate a range of color variation during their evaluation of WSIs, color variability can degrade the performance of computational applications in digital pathology. In particular, color variability can compromise the generalization of artificial intelligence applications to large volumes of data from diverse sources. To address these challenges, we developed a process that includes two modules: (1) assessing the color reproducibility of our scanners and the color variation among them and (2) applying color correction to WSIs to minimize the color deviation and variation. Our process ensures consistent color reproduction across WSI scanners and enhances color homogeneity in WSIs, and its flexibility enables easy integration as a post-processing step following scanning by WSI scanners of different models and from different manufacturers.","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":null,"pages":null},"PeriodicalIF":1.5,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139576460","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 Interpretive Challenges for Procedure-Related Effects Associated With Direct Central Nervous System Delivery of Oligonucleotides to Rodents, Dogs, and Nonhuman Primates. 毒理病理学论坛：关于啮齿动物、狗和非人灵长类动物中枢神经系统直接给药寡核苷酸的程序相关效应的解释性挑战的意见。

IF 1.5 4区医学

Toxicologic Pathology Pub Date : 2023-08-01 Epub Date: 2024-01-05 DOI: 10.1177/01926233231218953

Lisa D Berman-Booty, Stephanie K Klein, Curt Mazur, Joseph Schroeder, Sven Korte, Florian T Ludwig, Annette Romeike, Brad Bolon, Jessica L Grieves

{"title":"Toxicologic Pathology Forum: Opinion on Interpretive Challenges for Procedure-Related Effects Associated With Direct Central Nervous System Delivery of Oligonucleotides to Rodents, Dogs, and Nonhuman Primates.","authors":"Lisa D Berman-Booty, Stephanie K Klein, Curt Mazur, Joseph Schroeder, Sven Korte, Florian T Ludwig, Annette Romeike, Brad Bolon, Jessica L Grieves","doi":"10.1177/01926233231218953","DOIUrl":"10.1177/01926233231218953","url":null,"abstract":"Direct delivery of therapeutics to the central nervous system (CNS) greatly expands opportunities to treat neurological diseases but is technically challenging. This opinion outlines principal technical aspects of direct CNS delivery via intracerebroventricular (ICV) or intrathecal (IT) injection to common nonclinical test species (rodents, dogs, and nonhuman primates) and describes procedure-related clinical and histopathological effects that confound interpretation of test article-related effects. Direct dosing is by ICV injection in mice due to their small body size, while other species are dosed IT in the lumbar cistern. The most frequent procedure-related functional effects are transient absence of lower spinal reflexes after IT injection or death soon after ICV dosing. Common procedure-related microscopic findings in all species include leukocyte infiltrates in CNS meninges or perivascular (Virchow-Robin) spaces; nerve fiber degeneration in the spinal cord white matter (especially dorsal and lateral tracts compressed by dosing needles or indwelling catheters), spinal nerve roots, and sciatic nerve; meningeal fibrosis at or near IT injection sites; hemorrhage; and gliosis. Findings typically are minimal to occasionally mild. Findings tend to be more severe and/or have a higher incidence in the spinal cord segments and spinal nerve roots at or close to the site of administration.","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":null,"pages":null},"PeriodicalIF":1.5,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139098676","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

Pathological Characterization of Spontaneous AA Amyloidosis in Microminipigs. 微型猪自发性AA淀粉样变性的病理学特征。

IF 1.5 4区医学

Toxicologic Pathology Pub Date : 2023-07-01 Epub Date: 2023-10-24 DOI: 10.1177/01926233231204019

Misaki Inoue, Shinya Miyazaki, Natsumi Kobayashi, Akihisa Kangawa, Tomoaki Murakami

{"title":"Pathological Characterization of Spontaneous AA Amyloidosis in Microminipigs.","authors":"Misaki Inoue, Shinya Miyazaki, Natsumi Kobayashi, Akihisa Kangawa, Tomoaki Murakami","doi":"10.1177/01926233231204019","DOIUrl":"10.1177/01926233231204019","url":null,"abstract":"The minipig has been used as a non-rodent species in nonclinical toxicology studies, but little is known about amyloid A (AA) amyloidosis in this species. Among domestic pigs, reports of AA amyloidosis have been limited to animals with mutations in the N-terminal residue of serum AA (SAA), which is thought to be a primary etiological factor. In this study, we histologically examined 26 microminipigs aged 0.6 to 10 years and observed amyloid deposition in one 0.6-year-old and six 5-year-old or older microminipigs. The amyloid deposits were identified as AA based on mass spectrometry (MS) and immunohistochemistry (IHC). The 0.6-year-old microminipig showed severe deposition in the renal cortex and spleen, whereas 5-year-old or older animals had severe deposition in the renal medulla. MS and IHC detected serum amyloid P-component (SAP) in amyloid deposits in older animals but not in a 0.6-year-old animals. Based on the proteomic analysis and gene sequencing, amino acid mutations of SAA, previously found in domestic pigs, were not involved in the pathogenesis of AA amyloidosis in microminipigs. This study demonstrates that microminipigs with wild-type SAA develop AA amyloidosis and presents the possibility that differences in the environment surrounding amyloid, such as SAP, may influence differences in the pathological phenotype.","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":null,"pages":null},"PeriodicalIF":1.5,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49692445","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

Safety Findings of Dosing Gene Therapy Vectors in NHP With Pre-existing or Treatment-Emergent Anti-capsid Antibodies. 在NHP中用预先存在的或治疗出现的抗衣壳抗体给药基因治疗载体的安全性发现。

IF 1.5 4区医学

Toxicologic Pathology Pub Date : 2023-07-01 Epub Date: 2023-11-03 DOI: 10.1177/01926233231202995

Sundeep Chandra, Brian R Long, Carlos Fonck, Andrew C Melton, Jeremy Arens, Jill Woloszynek, Charles A O'Neill

{"title":"Safety Findings of Dosing Gene Therapy Vectors in NHP With Pre-existing or Treatment-Emergent Anti-capsid Antibodies.","authors":"Sundeep Chandra, Brian R Long, Carlos Fonck, Andrew C Melton, Jeremy Arens, Jill Woloszynek, Charles A O'Neill","doi":"10.1177/01926233231202995","DOIUrl":"10.1177/01926233231202995","url":null,"abstract":"Replication-incompetent adeno-associated virus (AAV)-based vectors are nonpathogenic viral particles used to deliver therapeutic genes to treat multiple monogenic disorders. AAVs can elicit immune responses; thus, one challenge in AAV-based gene therapy is the presence of neutralizing antibodies against vector capsids that may prevent transduction of target cells or elicit adverse findings. We present safety findings from two 12-week studies in nonhuman primates (NHPs) with pre-existing or treatment-emergent antibodies. In the first study, NHPs with varying levels of naturally acquired anti-AAV5 antibodies were dosed with an AAV5-based vector encoding human factor VIII (hFVIII). In the second study, NHPs with no pre-existing anti-AAV antibodies were dosed with an AAV5-based vector carrying the beta subunit of choriogonadotropic hormone (bCG); this led to the induction of high-titer antibodies against the AAV5 capsid. Four weeks later, the same NHPs received an equivalent dose of an AAV5-based vector carrying human factor IX (hFIX). In both of these studies, the administration of vectors carrying hFVIII, bCG, and hFIX was well-tolerated in NHPs with no adverse clinical pathology or microscopic findings. These two studies demonstrate the safety of AAV-based vector administration in NHPs with either low-titer pre-existing anti-AAV5 antibodies or re-administration, even in the presence of high-titer antibodies.","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":null,"pages":null},"PeriodicalIF":1.5,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71427091","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

Reduced Fasting Duration in Cynomolgus Monkeys Enhances Animal Welfare During Toxicology Studies. 在毒理学研究中，食蟹猴禁食时间的缩短提高了动物的福利。

IF 1.5 4区医学

Toxicologic Pathology Pub Date : 2023-07-01 Epub Date: 2023-09-13 DOI: 10.1177/01926233231193395

Adeyemi O Adedeji, Tony Pourmohamad, Niraj Tripathi, Shelly Zhong, Kenna R Degner, Fiona Zhong, Dewakar Sangaraju, Kevin Williams, Noel Dybdal

{"title":"Reduced Fasting Duration in Cynomolgus Monkeys Enhances Animal Welfare During Toxicology Studies.","authors":"Adeyemi O Adedeji, Tony Pourmohamad, Niraj Tripathi, Shelly Zhong, Kenna R Degner, Fiona Zhong, Dewakar Sangaraju, Kevin Williams, Noel Dybdal","doi":"10.1177/01926233231193395","DOIUrl":"10.1177/01926233231193395","url":null,"abstract":"During toxicology studies, fasting animals prior to clinical pathology blood collection is believed to reduce variability in some clinical chemistry analytes. However, fasting adds stress to animals that are already stressed from the administration of potentially toxic doses of the test article. The purpose of this study was to assess the impacts of different fasting durations on cynomolgus monkeys' welfare during toxicology studies. To this end, we assessed the cynomolgus monkeys traditional and ancillary clinical pathology endpoints at different fasting times. We showed that most clinical pathology endpoints were largely comparable between different fasting times suggesting that cynomolgus monkeys could be fasted for as little as 4 hours for toxicology studies, as longer fasting times (up to 20 hours) resulted in stress, dehydration, and significant decreases in blood glucose- changes that impacts animal welfare. Shorter fasting times were associated with higher triglycerides variability among individual animals. Therefore, we propose that shorter fasting time (i.e., 4 hours) should be adequate for most toxicology studies except when: (1) parameters that could be affected by non-fasting conditions are important for safety and pharmacodynamic assessments (i.e., glucose and lipids) and (2) fasting would be needed for the bioavailability of an orally administered test article.","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":null,"pages":null},"PeriodicalIF":1.5,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10696910/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10225238","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

Effects of LRRK2 Inhibitors in Nonhuman Primates. LRRK2抑制剂在非人类灵长类动物中的作用。

IF 1.5 4区医学

Toxicologic Pathology Pub Date : 2023-07-01 Epub Date: 2023-11-02 DOI: 10.1177/01926233231205895

Glen K Miller, Sabu Kuruvilla, Binod Jacob, Lisa LaFranco-Scheuch, Vasudevan Bakthavatchalu, Jason Flor, Kristin Flor, Julie Ziegler, Christine Reichard, Phil Manfre, Suzanne Firner, Tara McNutt, Diane Quay, Sairam Bellum, Greg Doto, Paul J Ciaccio, Kara Pearson, Jack Valentine, Pete Fuller, Matt Fell, Takayuki Tsuchiya, Toni Williamson, Gordon Wollenberg

{"title":"Effects of LRRK2 Inhibitors in Nonhuman Primates.","authors":"Glen K Miller, Sabu Kuruvilla, Binod Jacob, Lisa LaFranco-Scheuch, Vasudevan Bakthavatchalu, Jason Flor, Kristin Flor, Julie Ziegler, Christine Reichard, Phil Manfre, Suzanne Firner, Tara McNutt, Diane Quay, Sairam Bellum, Greg Doto, Paul J Ciaccio, Kara Pearson, Jack Valentine, Pete Fuller, Matt Fell, Takayuki Tsuchiya, Toni Williamson, Gordon Wollenberg","doi":"10.1177/01926233231205895","DOIUrl":"10.1177/01926233231205895","url":null,"abstract":"Toxicology studies in nonhuman primates were conducted to evaluate selective, brain penetrant inhibitors of LRRK2. GNE 7915 was limited to 7-day administration in cynomolgus monkeys at 65 mg/kg/day or limited to 14 days in rhesus at 22.5 mg/kg b.i.d. due to physical signs. Compound 25 demonstrated acceptable tolerability at 50 and 225 mg/kg b.i.d. for 7 days in rhesus monkeys. MK-1468 was tolerated during 7-day administration at 100, 200 or 800 mg/kg/day or for 30-day administration at 30, 100, or 500 mg/kg b.i.d. in rhesus monkeys. The lungs revealed hypertrophy of type 2 pneumocytes, with accumulation of intra-alveolar macrophages. Transmission electron microscopy confirmed increased lamellar structures within hypertrophic type 2 pneumocytes. Hypertrophy and hyperplasia of type 2 pneumocytes with accumulation of intra-alveolar macrophages admixed with neutrophils were prominent at peripheral lungs of animals receiving compound 25 or MK-1468. Affected type 2 pneumocytes were immuno-positive for pro-surfactant C, but negative for CD11c, a marker for intra-alveolar macrophages. Accumulation of collagen within alveolar walls, confirmed by histochemical trichrome stain, accompanied changes described for compound 25 and MK-1468. Following a 12-week treatment-free interval, animals previously receiving MK-1468 for 30 days exhibited remodeling of alveolar structure and interstitial components that did not demonstrate reversibility.","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":null,"pages":null},"PeriodicalIF":1.5,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71427090","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

Scientific and Regulatory Policy Committee Technical Review: Biology and Pathology of Ganglia in Animal Species Used for Nonclinical Safety Testing. 科学和法规政策委员会技术评论:用于非临床安全性测试的动物物种神经节的生物学和病理学。

IF 1.5 4区医学

Toxicologic Pathology Pub Date : 2023-07-01 DOI: 10.1177/01926233231213851

Bindu M Bennet, Ingrid D Pardo, Basel T Assaf, Elizabeth Buza, Sarah D Cramer, LaTasha K Crawford, Jeffery A Engelhardt, Elizabeth J Galbreath, Branka Grubor, James P Morrison, Tanasa S Osborne, Alok K Sharma, Brad Bolon

{"title":"Scientific and Regulatory Policy Committee Technical Review: Biology and Pathology of Ganglia in Animal Species Used for Nonclinical Safety Testing.","authors":"Bindu M Bennet, Ingrid D Pardo, Basel T Assaf, Elizabeth Buza, Sarah D Cramer, LaTasha K Crawford, Jeffery A Engelhardt, Elizabeth J Galbreath, Branka Grubor, James P Morrison, Tanasa S Osborne, Alok K Sharma, Brad Bolon","doi":"10.1177/01926233231213851","DOIUrl":"10.1177/01926233231213851","url":null,"abstract":"Dorsal root ganglia (DRG), trigeminal ganglia (TG), other sensory ganglia, and autonomic ganglia may be injured by some test article classes, including anti-neoplastic chemotherapeutics, adeno-associated virus-based gene therapies, antisense oligonucleotides, nerve growth factor inhibitors, and aminoglycoside antibiotics. This article reviews ganglion anatomy, cytology, and pathology (emphasizing sensory ganglia) among common nonclinical species used in assessing product safety for such test articles (TAs). Principal histopathologic findings associated with sensory ganglion injury include neuron degeneration, necrosis, and/or loss; increased satellite glial cell and/or Schwann cell numbers; and leukocyte infiltration and/or inflammation. Secondary nerve fiber degeneration and/or glial reactions may occur in nerves, dorsal spinal nerve roots, spinal cord (dorsal and occasionally lateral funiculi), and sometimes the brainstem. Ganglion findings related to TA administration may result from TA exposure and/or trauma related to direct TA delivery into the central nervous system or ganglia. In some cases, TA-related effects may need to be differentiated from a spectrum of artifactual and/or spontaneous background changes.","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":null,"pages":null},"PeriodicalIF":1.5,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138478623","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

Musings on Education for Toxicologic Pathology Proficiency in a Post-pandemic, Remotely Working World. 流行病后远程工作世界毒理学病理学能力教育集锦。

IF 1.5 4区医学

Toxicologic Pathology Pub Date : 2023-06-01 Epub Date: 2023-08-14 DOI: 10.1177/01926233231190403

Brad Bolon

引用次数: 0