Toxicologic Pathology最新文献_第10页

Scientific and Regulatory Policy Committee Best Practices: Recommended ("Best") Practices for Informed (Non-blinded) Versus Masked (Blinded) Microscopic Evaluation in Animal Toxicity Studies. 科学和监管政策委员会最佳实践:动物毒性研究中知情(非盲法)与蒙面(盲法)显微评估的推荐(“最佳”)实践。

IF 1.5 4区医学

Toxicologic Pathology Pub Date : 2022-12-01 DOI: 10.1177/01926233221135563

Brad Bolon, Sabine Francke, Jessica M Caverly Rae, Evelyne Polack, Karen S Regan, Elizabeth F McInnes, Jamie K Young, Kevin Keane, Rick Perry, Annette Romeike, Karyn Colman, Karl Jensen, Kyoko Nakano-Ito, Elizabeth J Galbreath

{"title":"Scientific and Regulatory Policy Committee Best Practices: Recommended (\"Best\") Practices for Informed (Non-blinded) Versus Masked (Blinded) Microscopic Evaluation in Animal Toxicity Studies.","authors":"Brad Bolon, Sabine Francke, Jessica M Caverly Rae, Evelyne Polack, Karen S Regan, Elizabeth F McInnes, Jamie K Young, Kevin Keane, Rick Perry, Annette Romeike, Karyn Colman, Karl Jensen, Kyoko Nakano-Ito, Elizabeth J Galbreath","doi":"10.1177/01926233221135563","DOIUrl":"https://doi.org/10.1177/01926233221135563","url":null,"abstract":"This article describes the Society of Toxicologic Pathology's (STP) five recommended (\"best\") practices for appropriate use of informed (non-blinded) versus masked (blinded) microscopic evaluation in animal toxicity studies intended for regulatory review. (1) Informed microscopic evaluation is the default approach for animal toxicity studies. (2) Masked microscopic evaluation has merit for confirming preliminary diagnoses for target organs and/or defining thresholds (\"no observed adverse effect level\" and similar values) identified during an initial informed evaluation, addressing focused hypotheses, or satisfying guidance or requests from regulatory agencies. (3) If used as the approach for an animal toxicity study to investigate a specific research question, masking of the initial microscopic evaluation should be limited to withholding only information about the group (control or test article-treated) and dose equivalents. (4) The decision regarding whether or not to perform a masked microscopic evaluation is best made by a toxicologic pathologist with relevant experience. (5) Pathology peer review, performed to verify the microscopic diagnoses and interpretations by the study pathologist, should use an informed evaluation approach. The STP maintains that implementing these five best practices has and will continue to consistently deliver robust microscopic data with high sensitivity for animal toxicity studies intended for regulatory review. Consequently, when conducting animal toxicity studies, the advantages of informed microscopic evaluation for maximizing sensitivity outweigh the perceived advantages of minimizing bias through masked microscopic examination.","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":"50 8","pages":"930-941"},"PeriodicalIF":1.5,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9452241","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: 4

Neutropenia in Cynomolgus Monkeys With Anti-Drug Antibodies Associated With Administration of Afucosylated Humanized Monoclonal Antibodies. 含抗药物抗体的食蟹猴中性粒细胞减少症与集中人源单克隆抗体有关。

IF 1.5 4区医学

Toxicologic Pathology Pub Date : 2022-12-01 DOI: 10.1177/01926233221131510

Adeyemi O Adedeji, Fiona Zhong, Jennifer A Getz, Zoe Zhong, Wendy Halpern

{"title":"Neutropenia in Cynomolgus Monkeys With Anti-Drug Antibodies Associated With Administration of Afucosylated Humanized Monoclonal Antibodies.","authors":"Adeyemi O Adedeji, Fiona Zhong, Jennifer A Getz, Zoe Zhong, Wendy Halpern","doi":"10.1177/01926233221131510","DOIUrl":"https://doi.org/10.1177/01926233221131510","url":null,"abstract":"Removal of the core fucose from the Fc region of humanized monoclonal antibodies (afucosylated antibodies) enhances their antibody-dependent cell cytotoxicity activities in killing cancer cells. Based on the authors’ experience and literature, administrations of afucosylated antibodies have been associated with neutropenia in cynomolgus monkeys. However, in a recent general toxicology study conducted with an afucosylated antibody in cynomolgus monkeys, transient neutropenia was observed and correlated with the emergence of anti-drug antibodies (ADAs) in the affected animals. To further explore the relationship between neutropenia, afucosylated antibodies, and ADAs in cynomolgus monkeys, we performed an investigational retrospective meta-analysis of data from general toxicology studies conducted with Genentech’s therapeutic antibodies administered to cynomolgus monkeys between 2005 and 2021. In this analysis, transient neutropenia strongly correlated with ADA-induced inflammation in cynomolgus monkeys administered afucosylated antibodies. This may reflect the simultaneous occurrence of two distinct processes of neutrophil elimination and utilization, thus overwhelming bone marrow reserve capacity leading to transient neutropenia. The integrated analysis of immunogenicity, and anatomic and clinical pathology results from these studies highlights the correlation of transient neutropenia in cynomolgus monkeys with ADA-related inflammation, potentially exacerbated by enhanced effector function of afucosylated antibodies.","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":"50 8","pages":"910-919"},"PeriodicalIF":1.5,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/4c/e5/10.1177_01926233221131510.PMC9806483.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10597173","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

Identifying Erythrocyte Injury in Toxicology Studies. 在毒理学研究中识别红细胞损伤。

IF 1.5 4区医学

Toxicologic Pathology Pub Date : 2022-10-01 DOI: 10.1177/01926233221127942

Erica Behling-Kelly

引用次数: 2

To Clot or Not to Clot: Deepening Our Understanding of Alterations in the Hemostatic System. 凝血还是不凝血:加深我们对止血系统改变的认识。

IF 1.5 4区医学

Toxicologic Pathology Pub Date : 2022-10-01 DOI: 10.1177/01926233221125172

William J Reagan, Marjory B Brooks, Renata Grozovsky, Debra Pittman, Allison Vitsky, Karrie Brenneman

{"title":"To Clot or Not to Clot: Deepening Our Understanding of Alterations in the Hemostatic System.","authors":"William J Reagan, Marjory B Brooks, Renata Grozovsky, Debra Pittman, Allison Vitsky, Karrie Brenneman","doi":"10.1177/01926233221125172","DOIUrl":"https://doi.org/10.1177/01926233221125172","url":null,"abstract":"The session on the hemostatic system focused on new developments in coagulation and platelet biology as well as how therapeutic agents may affect hemostasis. The classic cascade model of coagulation was compared with the more recent models of cell-based and vascular-based coagulation, which may provide better insight on how the coagulation cascade works in vivo. A review of platelet biology highlighted that, as platelets age, desialylated platelets form and are recognized by Ashwell-Morell receptor (AMR), leading to hepatic uptake and subsequent increase in thrombopoietin (TPO) production. Administration of therapeutics that induce thrombocytopenia was also discussed, including Mylotarg, which is an antibody-drug conjugate that was shown to decrease human megakaryocyte development but had no effect on platelet aggregation. An acetyl co-A carboxylase inhibitor was shown to cause thrombocytopenia by inhibiting de novo lipogenesis, which is critical for the formation of the megakaryocyte demarcation membrane system responsible for platelet production. It was also illustrated how preclinical translation models have been very helpful in the development of adeno-associated virus (AAV) hemophilia B gene therapy and what old and new preclinical tools we have that can predict the risk of a prothrombotic state in people.","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":"50 7","pages":"890-894"},"PeriodicalIF":1.5,"publicationDate":"2022-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10456523","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: 1

How Does Lifestyle Affect Hematopoiesis and the Bone Marrow Microenvironment? 生活方式如何影响造血和骨髓微环境？

IF 1.4 4区医学

Toxicologic Pathology Pub Date : 2022-10-01 Epub Date: 2022-09-16 DOI: 10.1177/01926233221123523

James J Vanhie, Michael De Lisio

{"title":"How Does Lifestyle Affect Hematopoiesis and the Bone Marrow Microenvironment?","authors":"James J Vanhie, Michael De Lisio","doi":"10.1177/01926233221123523","DOIUrl":"10.1177/01926233221123523","url":null,"abstract":"Lifestyle factors are modifiable behavioral factors that have a significant impact on health and longevity. Diet-induced obesity and physical activity/exercise are two prevalent lifestyle factors that have strong relationships to overall health. The mechanisms linking obesity to negative health outcomes and the mechanisms linking increased participation in physical activity/exercise to positive health outcomes are beginning to be elucidated. Chronic inflammation, due in part to overproduction of myeloid cells from hematopoietic stem cells (HSCs) in the bone marrow, is an established mechanism responsible for the negative health effects of obesity. Recent work has shown that exercise training can reverse the aberrant myelopoiesis present in obesity in part by restoring the bone marrow microenvironment. Specifically, exercise training reduces marrow adipose tissue, increases HSC retention factor expression, and reduces pro-inflammatory cytokine levels in the bone marrow. Other, novel mechanistic factors responsible for these exercise-induced effects, including intercellular communication using extracellular vesicles (EVs), is beginning to be explored. This review will summarize the recent literature describing the effects of exercise on hematopoiesis in individuals with obesity and introduce the potential contribution of EVs to this process.","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":"50 7","pages":"858-866"},"PeriodicalIF":1.4,"publicationDate":"2022-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/92/75/10.1177_01926233221123523.PMC9669729.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10394778","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

Black Cohosh Herbal Extract and Hematologic Alterations in B6C3F1/N Mice. 黑升麻草药提取物对B6C3F1/N小鼠血液学的影响。

IF 1.5 4区医学

Toxicologic Pathology Pub Date : 2022-10-01 DOI: 10.1177/01926233221133549

Michelle Cora

{"title":"Black Cohosh Herbal Extract and Hematologic Alterations in B6C3F1/N Mice.","authors":"Michelle Cora","doi":"10.1177/01926233221133549","DOIUrl":"https://doi.org/10.1177/01926233221133549","url":null,"abstract":"Black cohosh is a readily available dietary supplement currently marketed as a remedy for dysmenorrhea and menopausal symptoms and is one of the top-selling herbal supplements in the United States. Black cohosh extract (BCE) was nominated to the National Toxicology Program (NTP) by the National Cancer Institute and the National Institute of Environmental Health Sciences due to its widespread use and lack of animal toxicity studies. Results of the NTP BCE subchronic mouse toxicity study revealed a dose-dependent, non-regenerative decrease in the erythron with an increase in the mean corpuscular volume (macrocytosis). Howell-Jolly bodies, or micronuclei, were significantly increased. These particular changes indicated an ineffective erythropoiesis consistent with a condition known as megaloblastic anemia. Megaloblastic anemia is due to disruptions in DNA synthesis during hematopoiesis and can be a result of an inherited or drug-induced disorder or a consequence of folate or cobalamin deficiency. Subsequent mouse studies revealed hematological and biochemical changes that were consistent with a functional cobalamin deficiency. This article will review basic mechanisms and laboratory features of megaloblastic anemia. The results of our studies including morphological abnormalities of the erythron and biomarkers of folate and cobalamin deficiencies, as well as hepatic microarray gene changes, are also discussed.","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":"50 7","pages":"886-889"},"PeriodicalIF":1.5,"publicationDate":"2022-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10396382","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

Pathology of Bone: Changes Associated With Different Classes of Compounds. 骨病理:与不同种类化合物相关的变化。

IF 1.5 4区医学

Toxicologic Pathology Pub Date : 2022-10-01 DOI: 10.1177/01926233221123778

Kathryn E Gropp

引用次数: 0

Overview of Session 3 Mechanisms of Decreased Erythropoiesis and Erythroid Cell Injury. 第三部分:红细胞生成减少和红细胞损伤的机制综述。

IF 1.5 4区医学

Toxicologic Pathology Pub Date : 2022-10-01 DOI: 10.1177/01926233221120550

A Eric Schultze, Lila Ramaiah

引用次数: 0

Methodologies and Emerging Technologies for the Evaluation of the Hematopoietic System. 评估造血系统的方法和新兴技术。

IF 1.5 4区医学

Toxicologic Pathology Pub Date : 2022-10-01 DOI: 10.1177/01926233221128755

Florence Poitout-Belissent, Allison Vitsky, Mark A Smith, Madhu P Sirivelu

引用次数: 0

Gemtuzumab Ozogamicin Treatment Results in Decreased Proliferation and Differentiation of Human Megakaryocytes but Does Not Inhibit Mature Platelet Function. 吉妥珠单抗Ozogamicin治疗导致人巨核细胞增殖和分化减少，但不抑制成熟血小板功能。

IF 1.5 4区医学

Toxicologic Pathology Pub Date : 2022-10-01 DOI: 10.1177/01926233221129202

Allison Vitsky, Aida Sacaan, Wenyue Hu, Martin Finkelstein, William Reagan

{"title":"Gemtuzumab Ozogamicin Treatment Results in Decreased Proliferation and Differentiation of Human Megakaryocytes but Does Not Inhibit Mature Platelet Function.","authors":"Allison Vitsky, Aida Sacaan, Wenyue Hu, Martin Finkelstein, William Reagan","doi":"10.1177/01926233221129202","DOIUrl":"https://doi.org/10.1177/01926233221129202","url":null,"abstract":"Mylotarg (Gemtuzumab ozogamicin [GO]), an antibody drug conjugate comprising a CD33-directed antibody linked to calicheamicin, is approved for use in certain acute myeloid leukemia patients. Following reports of prolonged thrombocytopenia and hemorrhagic events in a subset of patients, a detailed series of in vitro and ex vivo studies was performed at the request of regulators, both to look at the effects of GO on platelet production and to determine whether treatment with GO was likely to affect platelet aggregation under a variety of conditions. Treatment with GO resulted in cellular cytotoxicity and/or decreased differentiation during human megakaryocyte development. However, GO did not impair platelet aggregation under the experimental conditions evaluated. Ultimately, the effect of GO on megakaryocyte development observed in our studies was determined to have no impact on the risk-benefit assessment in the intended patient population, as thrombocytopenia is a known side effect of GO, and monitoring of platelet counts in patients is already strongly recommended.","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":"50 7","pages":"871-880"},"PeriodicalIF":1.5,"publicationDate":"2022-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10762701","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