journal
https://read.qxmd.com/read/36726336/cardiac-rhabdomyoma-in-four-g%C3%A3-ttingen-minipigs
#41
JOURNAL ARTICLE
Laine E Feller, Aaron Sargeant, E J Ehrhart, Bethany Balmer, Keith Nelson, Jennifer Lamoureux
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...
February 1, 2023: Toxicologic Pathology
https://read.qxmd.com/read/36695335/toxicologic-pathology-forum-opinion-on-approaches-for-reporting-toxic-and-adverse-dose-levels-in-nonclinical-toxicology-studies-supporting-the-development-of-anticancer-pharmaceuticals
#42
JOURNAL ARTICLE
Renee R Hukkanen, Tomoyuki Moriyama, Daniel J Patrick, Jonathan Werner
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...
January 25, 2023: Toxicologic Pathology
https://read.qxmd.com/read/36541591/pharmacobezoar-formation-from-hpmc-as-containing-spray-dried-formulations-in-nonclinical-safety-studies-in-rats
#43
JOURNAL ARTICLE
Hannes Gierke, Teresa Pfrommer, Kerstin Schäfer, Werner Weitschies, Thomas Nolte
Changing the physical state from crystalline to amorphous is an elegant method to increase the bioavailability of poorly soluble new chemical entity (NCE) drug candidates. Subsequently, we report findings from repeat-dose toxicity studies of an NCE formulated as a spray-dried amorphous solid dispersion (SD-ASD) based on hydroxypropyl methylcellulose acetate succinate (HPMC-AS) in rats. At necropsy, agglomerates of SD-ASD were found in the stomach and small intestine, which in reference to literature were termed pharmacobezoars...
December 2022: Toxicologic Pathology
https://read.qxmd.com/read/36377245/scientific-and-regulatory-policy-committee-best-practices-recommended-best-practices-for-informed-non-blinded-versus-masked-blinded-microscopic-evaluation-in-animal-toxicity-studies
#44
JOURNAL ARTICLE
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
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...
December 2022: Toxicologic Pathology
https://read.qxmd.com/read/36341579/toxicologic-pathology-forum-a-roadmap-for-building-state-of-the-art-digital-image-data-resources-for-toxicologic-pathology-in-the-pharmaceutical-industry
#45
JOURNAL ARTICLE
Xing-Yue Ge, Juergen Funk, Tom Albrecht, Merima Birkhimer, Moritz Gilsdorf, Matthew Hayes, Fangyao Hu, Pierre Maliver, Mark McCreary, Trung Nguyen, Fernando Romero-Palomo, Shanon Seger, Reina N Fuji, Vanessa Schumacher, Ruth Sullivan
Digitization of histologic slides brings with it the promise of enhanced toxicologic pathology practice through the increased application of computational methods. However, the development of these advanced methods requires access to substrate image data, that is, whole slide images (WSIs). Deep learning methods, in particular, rely on extensive training data to develop robust algorithms. As a result, pharmaceutical companies interested in leveraging computational methods in their digital pathology workflows must first invest in data infrastructure to enable data access for both data scientists and pathologists...
December 2022: Toxicologic Pathology
https://read.qxmd.com/read/36329562/neutropenia-in-cynomolgus-monkeys-with-anti-drug-antibodies-associated-with-administration-of-afucosylated-humanized-monoclonal-antibodies
#46
JOURNAL ARTICLE
Adeyemi O Adedeji, Fiona Zhong, Jennifer A Getz, Zoe Zhong, Wendy Halpern
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...
December 2022: Toxicologic Pathology
https://read.qxmd.com/read/36226581/toxicologic-pathology-forum-opinion-on-not-euthanizing-control-animals-in-the-recovery-phase-of-non-rodent-toxicology-studies
#47
JOURNAL ARTICLE
Kyathanahalli S Janardhan, Radhakrishna Sura, Smita Salian-Mehta, Thierry Flandre, Xavier Palazzi, Doris Zane, Bhanu Singh, Binod Jacob, Renee Rosemary Hukkanen, Muthafar Al-Haddawi, Bindu Bennet, Victoria Laast, Donna Lee, Richard Peterson, Annette Romeike, Frederic Schorsch, Magali Guffroy
Nonclinical toxicology studies that are required to support human clinical trials of new drug candidates are generally conducted in a rodent and a non-rodent species. These studies typically contain a vehicle control group and low, intermediate, and high dose test article groups. In addition, a dosing-free recovery phase is sometimes included to determine reversibility of potential toxicities observed during the dosing phase and may include additional animals in the vehicle control and one or more dose groups...
December 2022: Toxicologic Pathology
https://read.qxmd.com/read/36200583/extraintestinal-pathogenic-escherichia-coli-causes-necrohemorrhagic-pneumonia-in-multiple-research-dogs
#48
JOURNAL ARTICLE
Sarah E Coe, Michelle A Magagna, Annie Zimmerman, April George, Caitlyn Carter, Charissa Dean, Keith Nelson
Extraintestinal pathogenic Escherichia coli expressing cytotoxic necrotizing factor (CNF) 1 and 2 virulence factors is a rarely reported cause of acute, fatal necrohemorrhagic pneumonia in canines. A review of cases of necrohemorrhagic pneumonia in beagles at our facility between 2013 and 2021 revealed 21 dogs that died or were euthanized after acute onset lethargy, dyspnea, and hemorrhage. Some affected animals had recently been transported to the facility. In all dogs, lung lobes were discolored dark red and consolidated...
October 6, 2022: Toxicologic Pathology
https://read.qxmd.com/read/36200575/gemtuzumab-ozogamicin-treatment-results-in-decreased-proliferation-and-differentiation-of-human-megakaryocytes-but-does-not-inhibit-mature-platelet-function
#49
JOURNAL ARTICLE
Allison Vitsky, Aida Sacaan, Wenyue Hu, Martin Finkelstein, William Reagan
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...
October 6, 2022: Toxicologic Pathology
https://read.qxmd.com/read/36373576/black-cohosh-herbal-extract-and-hematologic-alterations-in-b6c3f1-n-mice
#50
REVIEW
Michelle Cora
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)...
October 2022: Toxicologic Pathology
https://read.qxmd.com/read/36305575/methodologies-and-emerging-technologies-for-the-evaluation-of-the-hematopoietic-system
#51
REVIEW
Florence Poitout-Belissent, Allison Vitsky, Mark A Smith, Madhu P Sirivelu
Hematology and bone marrow analysis is central to our understanding of the hematopoietic system and how it responds to insults, and this session presented during the 2022 STP symposium provided a review of current and novel approaches for the evaluation of the hematopoietic system in the context of nonclinical investigations. This publication summarizes the information presented on novel approaches for evaluation of the hematopoietic system using automated hematology analyzers, including details around the quantitative assessment of bone marrow cell suspensions as well as introducing several newly available hematology parameters...
October 2022: Toxicologic Pathology
https://read.qxmd.com/read/36200573/identifying-erythrocyte-injury-in-toxicology-studies
#52
JOURNAL ARTICLE
Erica Behling-Kelly
The hematological impacts of a drug can affect erythropoiesis at the level of the bone marrow, or decrease the life span of the RBC (red blood cell). The most common and recognizable clinical manifestation of either type of drug-induced erythropoietic injury is a decrease in RBC mass, or what is clinically referred to as an anemia. A decrease in RBC production can generally be separated from increased destruction (hemolysis) by evaluation of the hemogram for evidence of regeneration. In most healthy mammalian species, hemolysis will result in a regenerative response characterized by an increase in circulating reticulocytes...
October 2022: Toxicologic Pathology
https://read.qxmd.com/read/36165586/proceedings-of-the-2022-national-toxicology-program-satellite-symposium
#53
JOURNAL ARTICLE
Erin M Quist, Shambhunath Choudhary, Richard Lang, Debra A Tokarz, Mark Hoenerhoff, Jonathan Nagel, Jeffrey I Everitt
The 2022 annual National Toxicology Program Satellite Symposium, entitled "Pathology Potpourri," was held in Austin, Texas at the Society of Toxicologic Pathology's 40th annual meeting during a half-day session on Sunday, June 19. The goal of this symposium was to present and discuss challenging diagnostic pathology and/or nomenclature issues. This article presents summaries of the speakers' talks along with select images that were used by the audience for voting and discussion. Various lesions and topics covered during the symposium included induced and spontaneous neoplastic and nonneoplastic lesions in the mouse lung, spontaneous lesions in the reproductive tract of a female cynomolgus macaque, induced vascular lesions in a mouse asthma model and interesting case studies in a rhesus macaque, dog and genetically engineered mouse model...
September 27, 2022: Toxicologic Pathology
https://read.qxmd.com/read/36125102/deep-learning-based-segmentation-of-morphologically-distinct-rat-hippocampal-reactive-astrocytes-after-trimethyltin-exposure
#54
JOURNAL ARTICLE
Miika Vuorimaa, Ilona Kareinen, Petri Toivanen, Stefan Karlsson, Saku Ruohonen
As regulators of homeostasis, astrocytes undergo morphological changes after injury to limit the insult in central nervous system (CNS). Trimethyltin (TMT) is a known neurotoxicant that induces reactive astrogliosis in rat CNS. To evaluate the degree of reactive astrogliosis, the assessment relies on manual counting or semiquantitative scoring. We hypothesized that deep learning algorithm could be used to identify the grade of reactive astrogliosis in immunoperoxidase-stained sections in a quantitative manner...
September 20, 2022: Toxicologic Pathology
https://read.qxmd.com/read/36117463/to-clot-or-not-to-clot-deepening-our-understanding-of-alterations-in-the-hemostatic-system
#55
JOURNAL ARTICLE
William J Reagan, Marjory B Brooks, Renata Grozovsky, Debra Pittman, Allison Vitsky, Karrie Brenneman
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...
September 17, 2022: Toxicologic Pathology
https://read.qxmd.com/read/36114677/how-does-lifestyle-affect-hematopoiesis-and-the-bone-marrow-microenvironment
#56
JOURNAL ARTICLE
James J Vanhie, Michael De Lisio
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...
September 16, 2022: Toxicologic Pathology
https://read.qxmd.com/read/36114676/pathology-of-bone-changes-associated-with-different-classes-of-compounds
#57
JOURNAL ARTICLE
Kathryn E Gropp
During this presentation, a variety of class effects were reviewed by their differing effects on bone, including inhibition of endochondral ossification, inhibition of the growth hormone-insulin-like growth factor 1 axis, promotion of bone formation, inhibition of bone formation, abnormal bone formation, promotion of bone resorption, inhibition of bone resorption, and bone necrosis.
September 16, 2022: Toxicologic Pathology
https://read.qxmd.com/read/36062427/overview-of-session-3-mechanisms-of-decreased-erythropoiesis-and-erythroid-cell-injury
#58
JOURNAL ARTICLE
A Eric Schultze, Lila Ramaiah
This session, held during the 41st Annual STP Symposium, focused on mechanisms of decreased erythropoiesis and erythroid cell injury. The speakers provided comprehensive overviews of physiologic and pathologic erythropoiesis, reviewed various mechanisms of erythroid cell injury, and shared innovative investigative research with the audience.
September 5, 2022: Toxicologic Pathology
https://read.qxmd.com/read/36000561/morphologic-features-and-deep-learning-based-analysis-of-canine-spermatogenic-stages
#59
JOURNAL ARTICLE
Shima Mehrvar, Takahito Kambara
In nonclinical toxicity studies, stage-aware evaluation is often expected to assess drug-induced testicular toxicity. Although stage-aware evaluation does not require identification of specific stages, it is important to understand microscopic features of spermatogenic staging. Staging of the spermatogenic cycle in dogs is a challenging and time-consuming process. In this study, we first defined morphologic features for the eight spermatogenic stages in standard histology sections (H&E slides) of dog testes...
August 24, 2022: Toxicologic Pathology
https://read.qxmd.com/read/35950710/it-qa-and-regulatory-aspects-of-digital-pathology-results-of-the-8th-estp-international-workshop
#60
JOURNAL ARTICLE
Julie Boisclair, Bhupinder Bawa, Erio Barale-Thomas, Lise Bertrand, Jonathan Carter, Richard Crossland, Celine Dorn, Thomas Forest, Sabine Grote, Anja Gilis, Deon Hildebrand, Brian Knight, Sébastien Laurent, Heike Antje Marxfeld, Steen Jørgen Østergaard, Thibault Roguet, Thorsten Schlueter, Vanessa Schumacher, Richard Spehar, William Varady, Christian Zeugin
Digital toxicologic histopathology has been broadly adopted in preclinical compound development for informal consultation and peer review. There is now increased interest in implementing the technology for good laboratory practice-regulated study evaluations. However, the implementation is not straightforward because systems and work processes require qualification and validation, with consideration also given to security. As a result of the high-throughput, high-volume nature of safety evaluations, computer performance, ergonomics, efficiency, and integration with laboratory information management systems are further key considerations...
August 11, 2022: Toxicologic Pathology
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