Kerstin Wäse, Thomas Bartels, Uwe Schwahn, Mostafa Kabiri
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 Fgfr4 knockout (KO) mice...
April 26, 2023: Toxicologic Pathology
Rani S Sellers
Nonclinical toxicity testing (GLP) of prophylactic vaccines to support human clinical trials is outlined in the World Health Organization nonclinical vaccine-development guidelines, which are followed by most regulatory agencies globally. Vaccine GLP toxicity studies include at least two groups: a buffer control (often phosphate-buffered saline) group and a highest anticipated clinical dose formulation group. However, studies may include additional groups, including lower-dose formulation groups and adjuvant-containing formulation control groups...
April 21, 2023: Toxicologic Pathology
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
Activating mutations of the leucine-rich repeat kinase 2 ( LRRK2 ) 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...
April 20, 2023: Toxicologic Pathology
Brad Bolon
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...
April 14, 2023: Toxicologic Pathology
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
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 Kras (43%) and Egfr (46%) hotspot mutations in mouse lung tumors (n = 80) and only Egfr (50%) mutations in rat lung tumors (n = 26)...
April 3, 2023: Toxicologic Pathology
Kenneth A Schafer
No abstract text is available yet for this article.
March 29, 2023: Toxicologic Pathology
Chad M Thompson, Melissa M Heintz, Jeffrey C Wolf, Roza Cheru, Laurie C Haws, John M Cullen
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...
March 29, 2023: Toxicologic Pathology
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
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
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
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
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
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
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
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
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
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
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
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
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
Fetch more papers »
Fetching more papers... Fetching...
Remove bar
Read by QxMD icon Read

Save your favorite articles in one place with a free QxMD account.


Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"

We want to hear from doctors like you!

Take a second to answer a survey question.