Toxicologic Pathology最新文献

Session 4: mRNA and Self-Amplifying RNA (saRNA): Opportunities for Disease Prevention and Therapy. 会议 4：mRNA 和自扩增 RNA（saRNA）：疾病预防和治疗的机遇。

IF 1.4 4区医学

Toxicologic Pathology Pub Date : 2024-11-22 DOI: 10.1177/01926233241298572

Rani S Sellers, Lila Ramaiah, Sue-Jean Hong, Prashant Nambiar, Eric Jacquinet, Shan Naidu

{"title":"Session 4: mRNA and Self-Amplifying RNA (saRNA): Opportunities for Disease Prevention and Therapy.","authors":"Rani S Sellers, Lila Ramaiah, Sue-Jean Hong, Prashant Nambiar, Eric Jacquinet, Shan Naidu","doi":"10.1177/01926233241298572","DOIUrl":"https://doi.org/10.1177/01926233241298572","url":null,"abstract":"The unprecedented speed of developing vaccines against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for the COVID-19 pandemic, has propelled mRNA technologies into the public eye. The versatility of mRNA technology, often referred to as \"plug and play,\" offers immense promise for rapidly updating vaccines to address newer variants of respiratory diseases and combat emerging infectious diseases and lethal pathogens, such as the Ebolavirus. However, the potential applications of mRNA technology extend well beyond prophylactic vaccines. This session explored the two primary mRNA platforms: nonreplicating mRNA and self-amplifying mRNA (variably referred to as saRNA, samRNA, or SAM). Presentation topics were on current research efforts aimed at broadening the applications of mRNA modalities beyond vaccines. Topics included opportunities for delivering mRNA via intra-tumoral and inhalational routes, immunological and systemic inflammatory responses elicited by these modalities, and regulatory considerations involved in the development and licensing of these technologies.","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":" ","pages":"1926233241298572"},"PeriodicalIF":1.4,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142693617","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

Systemic Toxicity of Recombinant Adeno-Associated Virus Gene Therapy Vectors. 重组腺相关病毒基因疗法载体的全身毒性。

IF 1.4 4区医学

Toxicologic Pathology Pub Date : 2024-11-22 DOI: 10.1177/01926233241298892

Basel T Assaf

{"title":"Systemic Toxicity of Recombinant Adeno-Associated Virus Gene Therapy Vectors.","authors":"Basel T Assaf","doi":"10.1177/01926233241298892","DOIUrl":"https://doi.org/10.1177/01926233241298892","url":null,"abstract":"Recombinant adeno-associated virus (rAAV) vectors have emerged as a promising tool for gene therapy. However, the systemic administration of rAAV vectors is not without risks, particularly for dose levels >1 × 1014 viral genome per kilogram of body weight (vg/kg). rAAV-associated toxicities can variably manifest either acutely or in a delayed manner. Acute toxicities often present shortly after administration and can include severe immune responses, hepatotoxicity, and thrombotic microangiopathy (TMA). Delayed toxicities, on the other hand, may emerge weeks to months post-treatment, potentially involving chronic liver damage or prolonged immune activation. Thrombotic microangiopathy is often associated with complement activation and endothelial damage. The activation of the complement system can additionally trigger a cascade of inflammatory responses, exacerbating systemic toxicity. While many of these toxicities are reversible with appropriate medical intervention, there have been instances where the adverse effects were severe enough to lead to fatalities. Both human and animal studies have reported these adverse effects, highlighting the critical importance of thorough preclinical testing. However, a differential toxicity profile associated with systemic AAV administration exists between humans and nonhuman primates (NHPs), in which certain toxicities reported in humans are yet to be observed in NHPs, and vice versa. This review aims to explore the recent literature on systemic rAAV toxicities, focusing on dose levels, the role of the complement activation pathway, endothelial injury, TMA, hepatotoxicity, and the bidirectional translational safety profiles from both human and animal studies.","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":" ","pages":"1926233241298892"},"PeriodicalIF":1.4,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142688888","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

Opinion on the Importance of Sharing Toxicologic Pathology Data for Educational and/or Scientific Purposes. 关于为教育和/或科学目的共享毒理病理学数据的重要性的意见。

IF 1.4 4区医学

Toxicologic Pathology Pub Date : 2024-11-18 DOI: 10.1177/01926233241296122

Eveline de Rijk, Phaedra Cole, Anna-Lena Frisk, Frederic Gervais, Joost Lensen, Barbara Lenz, Lars Mecklenburg, Flavia Pasello Dos Santos, Annette Romeike, Catherine Ross

{"title":"Opinion on the Importance of Sharing Toxicologic Pathology Data for Educational and/or Scientific Purposes.","authors":"Eveline de Rijk, Phaedra Cole, Anna-Lena Frisk, Frederic Gervais, Joost Lensen, Barbara Lenz, Lars Mecklenburg, Flavia Pasello Dos Santos, Annette Romeike, Catherine Ross","doi":"10.1177/01926233241296122","DOIUrl":"10.1177/01926233241296122","url":null,"abstract":"Sharing pathology data is critical for educational and scientific purposes. Since most pharmaceutical or (agro)chemical companies outsource nonclinical safety assessment studies to contract research organizations (CROs), the pathology data of those studies are not owned by the investigator but is the legal property of the respective company sponsoring the work. Although some companies have installed policies that govern sharing of pathology data, many companies generally do not allow the external use of data by either the CRO-based study pathologist or the sponsor pathologist. Policies for governing the external use of data vary significantly. In this article, we present an overview of the different approaches taken across different companies (CROs, pharmaceutical/chemical companies, or other institutes) for sharing pathology material for educational and/or scientific purposes. The results of a survey and interviews with legal departments of different companies will be presented (anonymously) and discussed. In addition, the importance of sharing pathology data is addressed, as well as the challenges and opportunities this presents. Suggestions will be provided regarding what material should be made available and what will be needed to achieve agreement for this to happen.","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":" ","pages":"1926233241296122"},"PeriodicalIF":1.4,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142669315","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 Nonneoplastic Lesions of Sprague Dawley Rats in 104-Week Carcinogenicity Studies. 在为期 104 周的致癌性研究中，Sprague Dawley 大鼠自发性非肿瘤性病变的历史控制背景发生率。

IF 1.4 4区医学

Toxicologic Pathology Pub Date : 2024-10-29 DOI: 10.1177/01926233241289116

Marie Bockenstedt, Amit Kumar, Victoria Laast, Alok Sharma

{"title":"Historical Control Background Incidence of Spontaneous Nonneoplastic Lesions of Sprague Dawley Rats in 104-Week Carcinogenicity Studies.","authors":"Marie Bockenstedt, Amit Kumar, Victoria Laast, Alok Sharma","doi":"10.1177/01926233241289116","DOIUrl":"https://doi.org/10.1177/01926233241289116","url":null,"abstract":"Microscopic observation data collected from approximately 1800 male and female Sprague Dawley (SD) control rats used on 104-week carcinogenicity studies performed at North American Labcorp Early Development, Inc, Madison, WI, were retrospectively evaluated for spontaneous nonneoplastic findings. This study provides incidence of the most common spontaneous nonneoplastic microscopic findings in each organ system of SD rats encountered during 104-week carcinogenicity studies. Some of the most common spontaneous background findings were cardiomyopathy; chronic progressive nephropathy; uterine cystic endometrial hyperplasia; prostate inflammation; pulmonary alveolar macrophage infiltrates; hepatocyte vacuolation, bile duct hyperplasia, and basophilic foci in the liver; pancreatic fibrosis; splenic extramedullary hematopoiesis and pigment; decreased lymphocytes and epithelial hyperplasia in the thymus; ventral brain compression; cystic degeneration and hyperplasia of the adrenal cortex; and mammary gland hyperplasia. The most common nonneoplastic findings in male SD rats were chronic progressive nephropathy (80.9%) and rodent progressive cardiomyopathy (73.2%). The most common nonnenoplastic findings in female SD rats were cystic degeneration of the adrenal cortex (64.7%) and ventral compression of the brain due to pituitary neoplasms (62.7%).","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":" ","pages":"1926233241289116"},"PeriodicalIF":1.4,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142523192","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

Exogenous Growth Hormone Exacerbates Post-Irradiation Atherosclerosis in Susceptible Epicardial Coronary Arteries 外源性生长激素加剧易受辐射影响的心外膜冠状动脉辐射后动脉粥样硬化

IF 1.5 4区医学

Toxicologic Pathology Pub Date : 2024-09-10 DOI: 10.1177/01926233241277454

Krystal J. Vail, J. Daniel Bourland, Gregory O. Dugan, Benny J. Chen, Thomas B. Clarkson, J. Mark Cline, Giselle C. Meléndez

{"title":"Exogenous Growth Hormone Exacerbates Post-Irradiation Atherosclerosis in Susceptible Epicardial Coronary Arteries","authors":"Krystal J. Vail, J. Daniel Bourland, Gregory O. Dugan, Benny J. Chen, Thomas B. Clarkson, J. Mark Cline, Giselle C. Meléndez","doi":"10.1177/01926233241277454","DOIUrl":"https://doi.org/10.1177/01926233241277454","url":null,"abstract":"Cardiac exposure to ionizing radiation can damage both the microvasculature and coronary arteries, as well as increase the long-term risk of heart disease, myocardial fibrosis, and conduction abnormalities. Therapeutic agents capable of promoting recovery from radiation injury to the heart are limited. Growth hormone is linked to improved cardiac function following injury. Here, we leveraged a cynomolgus macaque model to determine the long-term outcomes of recombinant human growth hormone (rhGH) therapy on the heart following low-dose ionizing radiation. Macaques were exposed to 2 Gy radiation, treated with rhGH for one month, and assessed after 2 years. Overall, plasma lipid profile, cardiac function, and coronary artery disease were similar between rhGH and placebo treated animals. However, a subgroup of rhGH-treated animals exhibited more extensive atherosclerotic plaques in the coronary arteries. Together, these findings indicate that transient human growth hormone therapy subsequent to a single low dose of ionizing radiation involving the heart does not result in long-term changes to plasma cholesterol but may promote exacerbated coronary artery disease in a subset of individuals.","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":"64 1","pages":"1926233241277454"},"PeriodicalIF":1.5,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142177883","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*: mRNA Vaccine Safety–Separating Fact From Fiction 毒理病理学论坛*：mRNA 疫苗安全性--分清事实与虚构

IF 1.5 4区医学

Toxicologic Pathology Pub Date : 2024-09-10 DOI: 10.1177/01926233241278298

Rani S. Sellers, Philip R. Dormitzer

{"title":"Toxicologic Pathology Forum*: mRNA Vaccine Safety–Separating Fact From Fiction","authors":"Rani S. Sellers, Philip R. Dormitzer","doi":"10.1177/01926233241278298","DOIUrl":"https://doi.org/10.1177/01926233241278298","url":null,"abstract":"SARS-CoV-2 spread rapidly across the globe, contributing to the death of millions of individuals from 2019 to 2023, and has continued to be a major cause of morbidity and mortality after the pandemic. At the start of the pandemic, no vaccines or anti-viral treatments were available to reduce the burden of disease associated with this virus, as it was a novel SARS coronavirus. Because of the tremendous need, the development of vaccines to protect against COVID-19 was critically important. The flexibility and ease of manufacture of nucleic acid–based vaccines, specifically mRNA-based products, allowed the accelerated development of COVID-19 vaccines. Although mRNA-based vaccines and therapeutics had been in clinical trials for over a decade, there were no licensed mRNA vaccines on the market at the start of the pandemic. The rapid development of mRNA-based COVID-19 vaccines reduced serious complications and death from the virus but also engendered significant public concerns, which continue now, years after emergency-use authorization and subsequent licensure of these vaccines. This article summarizes and addresses some of the safety concerns that continue to be expressed about these vaccines and their underlying technology.","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":"4 1","pages":"1926233241278298"},"PeriodicalIF":1.5,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142177884","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

Intra-abdominal Abscesses in Two Göttingen Minipigs. 两只哥廷根小型猪的腹内脓肿

IF 1.4 4区医学

Toxicologic Pathology Pub Date : 2024-08-01 Epub Date: 2024-10-17 DOI: 10.1177/01926233241289112

Nanna Grand, Gitte Jeppesen, Abraham Nyska

引用次数: 0

Classic Lesions of the Biliary Tree. 胆管的典型病变

IF 1.4 4区医学

Toxicologic Pathology Pub Date : 2024-08-01 Epub Date: 2024-08-27 DOI: 10.1177/01926233241257912

John M Cullen, David Malarkey, John R Foster

引用次数: 0

A Minimal Approach to Demonstrate Concordance of Digital and Conventional Microscopy in Toxicologic Pathology. 在毒理病理学中展示数字显微镜和传统显微镜一致性的最低限度方法。

IF 1.4 4区医学

Toxicologic Pathology Pub Date : 2024-07-01 Epub Date: 2024-06-03 DOI: 10.1177/01926233241255125

Charlotte Lempp, Stefanie Arms, Christof Albert Bertram, Robert Klopfleisch, Bernd-Wolfgang Igl, Leonie Hezler, Thomas Nolte, Gabriele Pohlmeyer-Esch

{"title":"A Minimal Approach to Demonstrate Concordance of Digital and Conventional Microscopy in Toxicologic Pathology.","authors":"Charlotte Lempp, Stefanie Arms, Christof Albert Bertram, Robert Klopfleisch, Bernd-Wolfgang Igl, Leonie Hezler, Thomas Nolte, Gabriele Pohlmeyer-Esch","doi":"10.1177/01926233241255125","DOIUrl":"10.1177/01926233241255125","url":null,"abstract":"Digitalization of pathology workflows has undergone a rapid evolution and has been widely established in the diagnostic field but remains a challenge in the nonclinical safety context due to lack of regulatory guidance and validation experience for good laboratory practice (GLP) use. One means to demonstrate that digital slides are fit for purpose, that is, provide sufficient quality for pathologists to reach a diagnosis, is conduction of comparison studies, which have been published both, for veterinary and human diagnostic pathology, but not for toxicologic pathology. Here, we present an approach that uses study material from nonclinical safety studies and that allows for the statistical comparison of concordance rates for glass and digital slide evaluation while minimizing time and effort for the involved personnel. Using a benchmark study design, we demonstrate that evaluation of digital slides fits the purpose of nonclinical safety evaluation. These results add to reports of successful workflow validations and support the full adaptation of digital pathology in the regulatory field.","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":" ","pages":"251-257"},"PeriodicalIF":1.4,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141200582","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

Ginsenoside Rh2 Regulates the Calcium/ROS/CK1α/MLKL Pathway to Promote Premature Eryptosis and Hemolysis in Red Blood Cells. 人参皂苷 Rh2 调节钙/ROS/CK1α/MLKL 通路，促进红细胞过早嗜酸化和溶血

IF 1.4 4区医学

Toxicologic Pathology Pub Date : 2024-07-01 Epub Date: 2024-08-16 DOI: 10.1177/01926233241268846

Sumiah A Alghareeb, Jawaher Alsughayyir, Mohammad A Alfhili

{"title":"Ginsenoside Rh2 Regulates the Calcium/ROS/CK1α/MLKL Pathway to Promote Premature Eryptosis and Hemolysis in Red Blood Cells.","authors":"Sumiah A Alghareeb, Jawaher Alsughayyir, Mohammad A Alfhili","doi":"10.1177/01926233241268846","DOIUrl":"10.1177/01926233241268846","url":null,"abstract":"Ginsenoside Rh2 (GRh2) exhibits significant potential as an anticancer agent; however, progress in developing chemotherapeutic drugs is impeded by their toxicity toward off-target tissues. Specifically, anemia caused by chemotherapy is a debilitating side effect and can be caused by red blood cell (RBC) hemolysis and eryptosis. Cells were exposed to GRh2 in the antitumor range and hemolytic and eryptotic markers were examined under different experimental conditions using photometric and cytofluorimetric methods. GRh2 caused Ca2+-independent, concentration-responsive hemolysis in addition to disrupted ion trafficking with K+ and Cl- leakage. Significant increases in cells positive for annexin-V-fluorescein isothiocyanate, Fluo4, and 2,7-dichlorofluorescein were noted upon GRh2 treatment coupled with a decrease in forward scatter and acetylcholinesterase activity. Importantly, the cytotoxic effects of GRh2 were mitigated by ascorbic acid and by blocking casein kinase 1α (CK1α) and mixed lineage kinase domain-like (MLKL) signaling. In contrast, Ca2+ omission, inhibition of KCl efflux, and isosmotic sucrose aggravated GRh2-induced RBC death. In whole blood, GRh2 selectively targeted reticulocytes and lymphocytes. Altogether, this study identified novel mechanisms underlying GRh2-induced RBC death involving Ca2+ buildup, loss of membrane phospholipid asymmetry and cellular volume, anticholinesterase activity, and oxidative stress. These findings shed light on the hematologic toxicity of GRh2 which is crucial for optimizing its utilization in cancer treatment.","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":" ","pages":"284-294"},"PeriodicalIF":1.4,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141988978","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