Please help us test our new pre-print finding feature by giving the pre-print link a rating. A 5 star rating indicates the linked pre-print has the exact same content as the published article.
Authors:Adeyemi O. Adedeji, Tony Pourmohamad, Niraj Tripathi, Shelly Zhong, Kenna R. Degner, Fiona Zhong, Dewakar Sangaraju, Kevin Williams, Noel Dybdal Abstract: Toxicologic Pathology, Ahead of Print. 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. Citation: Toxicologic Pathology PubDate: 2023-09-13T09:18:17Z DOI: 10.1177/01926233231193395
Please help us test our new pre-print finding feature by giving the pre-print link a rating. A 5 star rating indicates the linked pre-print has the exact same content as the published article.
Authors:Alex A. Gutsol, Taben M. Hale, Jean-Francois Thibodeau, Chet E. Holterman, Rania Nasrallah, Jose W. N. Correa, Rhian M. Touyz, Chris R. J. Kennedy, Dylan Burger, Richard L. Hébert, Kevin D. Burns Abstract: Toxicologic Pathology, Ahead of Print. Assessment of hypertensive tubulopathy for more than fifty animal models of hypertension in experimental pathology employs criteria that do not correspond to lesional descriptors for tubular lesions in clinical pathology. We provide a critical appraisal of experimental hypertension with the same approach used to estimate hypertensive renal tubulopathy in humans. Four models with different pathogenesis of hypertension were analyzed—chronic angiotensin (Ang) II–infused and renin-overexpressing (TTRhRen) mice, spontaneously hypertensive (SHR), and Goldblatt two-kidney one-clip (2K1C) rats. Mouse models, SHR, and the nonclipped kidney in 2K1C rats had no regular signs of hypertensive tubulopathy. Histopathology in animals was mild and limited to variations in the volume density of tubular lumen and epithelium, interstitial space, and interstitial collagen. Affected kidneys in animals demonstrated lesion values that are significantly different compared with healthy controls but correspond to mild damage if compared with hypertensive humans. The most substantial human-like hypertensive tubulopathy was detected in the clipped kidney of 2K1C rats. For the first time, our study demonstrated the regular presence of chronic progressive nephropathy (CPN) in relatively young mice and rats with induced hypertension. Because CPN may confound the assessment of rodent models of hypertension, proliferative markers should be used to verify nonhypertensive tubulopathy. Citation: Toxicologic Pathology PubDate: 2023-08-26T11:22:12Z DOI: 10.1177/01926233231191128
Please help us test our new pre-print finding feature by giving the pre-print link a rating. A 5 star rating indicates the linked pre-print has the exact same content as the published article.
Authors:Brad Bolon Abstract: Toxicologic Pathology, Ahead of Print.
Please help us test our new pre-print finding feature by giving the pre-print link a rating. A 5 star rating indicates the linked pre-print has the exact same content as the published article.
Authors:Tracey L. Papenfuss, Lauren Himmel, C. Frieke Kuper, Sunish Mohanan, Johannes Harleman, Susan A. Elmore Abstract: Toxicologic Pathology, Ahead of Print. The evaluation of changes in the immune system serves to determine the efficacy and potential immunotoxicologic effects of new products under development. Toxicologic pathologists play critical roles in identifying immune system changes that drive the immunosafety determination. Standard pathology evaluations of therapies and chemicals remain similar; however, biopharmaceutical therapies have moved from simply affecting the immune system to being specifically developed to modify the immune system, which can impact interpretation. Recent explosive growth in immunomodulatory therapies presents a challenge to the toxicologic pathologist, toxicologist, and regulatory reviewer in terms of evaluating the clinical relevance and potential adversity of immune system changes. Beyond the recognition of such changes, there is an increasing expectation to evaluate, describe, and interpret how therapies affect complex immune system pathways for both immunomodulatory therapies and non-immunomodulatory drugs with off-target immunotoxic effects. In this opinion piece, considerations regarding immune system evaluation, the current landscape of immunomodulatory therapies, a brief description of immunotoxicologic (and immunopathologic) endpoints, the importance of integrating such immunosafety data, and relevance to adversity determination are discussed. Importantly, we describe how the current paradigm of determining adversity for immune system changes may be challenging or insufficient and propose a harmonized and flexible approach for assessing adversity. Citation: Toxicologic Pathology PubDate: 2023-08-14T12:02:28Z DOI: 10.1177/01926233231190382
Please help us test our new pre-print finding feature by giving the pre-print link a rating. A 5 star rating indicates the linked pre-print has the exact same content as the published article.
Authors:Bindu M. Bennet, Ingrid D. Pardo, Basel T. Assaf, Elizabeth Buza, Sarah Cramer, LaTasha K. Crawford, Jeffery A. Engelhardt, Branka Grubor, James P. Morrison, Tanasa S. Osborne, Alok K. Sharma, Brad Bolon Abstract: Toxicologic Pathology, Ahead of Print. Certain biopharmaceutical products consistently affect dorsal root ganglia, trigeminal ganglia, and/or autonomic ganglia. Product classes targeting ganglia include antineoplastic chemotherapeutics, adeno-associated virus-based gene therapies, antisense oligonucleotides, and anti-nerve growth factor agents. This article outlines “points to consider” for sample collection, processing, evaluation, interpretation, and reporting of ganglion findings; these points are consistent with published best practices for peripheral nervous system evaluation in nonclinical toxicity studies. Ganglion findings often occur as a combination of neuronal injury (e.g., degeneration, necrosis, and/or loss) and/or glial effects (e.g., increased satellite glial cell cellularity) with leukocyte accumulation (e.g., mononuclear cell infiltration or inflammation). Nerve fiber degeneration and/or glial reactions may be seen in nerves, dorsal spinal nerve roots, spinal cord, and occasionally brainstem. Interpretation of test article (TA)-associated effects may be confounded by incidental background changes or experimental procedure-related changes and limited historical control data. Reports should describe findings at these sites, any TA relationship, and the criteria used for assigning severity grades. Contextualizing adversity of ganglia findings can require a weight-of-evidence approach because morphologic changes of variable severity occur in ganglia but often are not accompanied by observable overt in-life functional alterations detectable by conventional behavioral and neurological testing techniques. Citation: Toxicologic Pathology PubDate: 2023-07-25T09:07:00Z DOI: 10.1177/01926233231179707
Please help us test our new pre-print finding feature by giving the pre-print link a rating. A 5 star rating indicates the linked pre-print has the exact same content as the published article.
Authors:Josep M. Monné Rodríguez, Anna-Lena Frisk, Robert Kreutzer, Thomas Lemarchand, Stephane Lezmi, Chandrassegar Saravanan, Birgit Stierstorfer, Céline Thuilliez, Enrico Vezzali, Grazyna Wieczorek, Seong-Wook Yun, Dirk Schaudien Abstract: Toxicologic Pathology, Ahead of Print. In situ hybridization (ISH) is used for the localization of specific nucleic acid sequences in cells or tissues by complementary binding of a nucleotide probe to a specific target nucleic acid sequence. In the last years, the specificity and sensitivity of ISH assays were improved by innovative techniques like synthetic nucleic acids and tandem oligonucleotide probes combined with signal amplification methods like branched DNA, hybridization chain reaction and tyramide signal amplification. These improvements increased the application spectrum for ISH on formalin-fixed paraffin-embedded tissues. ISH is a powerful tool to investigate DNA, mRNA transcripts, regulatory noncoding RNA, and therapeutic oligonucleotides. ISH can be used to obtain spatial information of a cell type, subcellular localization, or expression levels of targets. Since immunohistochemistry and ISH share similar workflows, their combination can address simultaneous transcriptomics and proteomics questions. The goal of this review paper is to revisit the current state of the scientific approaches in ISH and its application in drug research and development. Citation: Toxicologic Pathology PubDate: 2023-07-14T09:22:38Z DOI: 10.1177/01926233231178282
Please help us test our new pre-print finding feature by giving the pre-print link a rating. A 5 star rating indicates the linked pre-print has the exact same content as the published article.
Authors:Diethilde Theil, Jens Kuhle, Dominique Brees, Elaine Tritto, François Pognan, Wilfried Frieauff, Kelley Penraat, Emily Meseck, Reginald Valdez, Andreas Hartmann Abstract: Toxicologic Pathology, Ahead of Print. Branaplam is a splicing modulator previously under development as a therapeutic agent for Spinal Muscular Atrophy Type 1 and Huntington’s disease. Branaplam increased the levels of survival motor neuron protein in preclinical studies and was well tolerated in early clinical studies; however, peripheral neurotoxicity was observed in a preclinical safety study in juvenile dogs. The aim of this study was to determine whether serum neurofilament light chain (NfL) concentrations in dogs could serve as a monitoring biomarker for branaplam-induced peripheral neurotoxicity. A 30-week time-course investigative study in dogs treated with vehicle control (negative control), neurotoxic pyridoxine (positive control), or branaplam was conducted to assess neuropathology, nerve morphometry, electrophysiological measurements, gene expression profiles, and correlation to NfL serum concentrations. In branaplam-treated animals, a mild to moderate nerve fiber degeneration was observed in peripheral nerves correlating with increased serum NfL concentrations, but there were no observed signs or changes in electrophysiological parameters. Dogs with pyridoxine-induced peripheral axonal degeneration displayed clinical signs and electrophysiological changes in addition to elevated serum NfL. This study suggests that NfL may be useful as an exploratory biomarker to assist in detecting and monitoring treatment-related peripheral nerve injury, with or without clinical signs, associated with administration of branaplam and other compounds bearing a neurotoxic risk. Citation: Toxicologic Pathology PubDate: 2023-07-13T06:07:27Z DOI: 10.1177/01926233231180179
Please help us test our new pre-print finding feature by giving the pre-print link a rating. A 5 star rating indicates the linked pre-print has the exact same content as the published article.
Authors:Allan D. Rasmussen, Nathalie Truchot, Agnete Dyssegaard, Pierluigi Fant Abstract: Toxicologic Pathology, Ahead of Print. In this study, we assessed the toxicity and toxicokinetics of racemic vigabatrin and its S- and R-enantiomers (vigabatrin consists of 50:50% of the two enantiomers) by administering doses of the three test articles to male Long Evans rats via oral gavage. The animals were housed under high-intensity light conditions and the study consisted of an escalating dose phase and a 21-day fixed-dose phase. Systemic toxicity of vigabatrin appears to be due to the Vig-S-enantiomer only, as increasing doses of Vig-S or Vig-RS caused body weight loss, decreased food consumption, and affected activity. Administration of the Vig-R-enantiomer did not cause any such effects. Systemic exposure to R- and S-enantiomers was approximately linear with dose. Compared to administration of the racemate, there appeared to be a tendency for animals to take up higher amounts of Vig-R and lower amounts of Vig-S when administered as enantiomer. Bilateral retinal atrophy was observed in the fixed-dose phase in rats receiving Vig-S (either alone or as part of Vig-RS) and was characterized by irregular thinning and disorganization of the outer nuclear layer and thinning of the photoreceptor layer. The administration of the R-enantiomer alone did not cause any microscopic retinal change. Citation: Toxicologic Pathology PubDate: 2023-07-04T09:20:28Z DOI: 10.1177/01926233231179147
Please help us test our new pre-print finding feature by giving the pre-print link a rating. A 5 star rating indicates the linked pre-print has the exact same content as the published article.
Please help us test our new pre-print finding feature by giving the pre-print link a rating. A 5 star rating indicates the linked pre-print has the exact same content as the published article.
Authors:Takeshi Izawa, Gregory S. Travlos, Ricardo A. Cortes, Natasha P. Clayton, Robert C. Sills, Arun R. Pandiri Abstract: Toxicologic Pathology, Ahead of Print. Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease and its influence on drug-induced liver injury (DILI) is not fully understood. We investigated whether NAFLD can influence acetaminophen (APAP [N-acetyl-p-aminophenol])-induced hepatotoxicity in a diet-induced obese (DIO) mouse model of NAFLD. The male C57BL/6NTac DIO mice, fed a high-fat diet for more than 12 weeks, developed obesity, hyperinsulinemia, impaired glucose tolerance, and hepatomegaly with hepatic steatosis, similar to human NAFLD. In the acute toxicity study after a single dose of APAP (150 mg/kg), compared with control lean mice, the DIO mice had decreased serum transaminase levels and less severe hepatocellular injury. The DIO mice also had altered expression of genes related to APAP metabolism. Chronic APAP exposure for 26 weeks did not predispose the DIO mice with NAFLD to more severe hepatotoxicity compared with the lean mice. These results suggested that the C57BL/6NTac DIO mouse model appears to be more tolerant to APAP-induced hepatotoxicity than lean mice, potentially related to altered xenobiotic metabolizing capacity in the fatty liver. Further mechanistic studies with APAP and other drugs in NAFLD animal models are necessary to investigate the mechanism of altered susceptibility to intrinsic DILI in some human NAFLD patients. Citation: Toxicologic Pathology PubDate: 2023-05-09T12:11:45Z DOI: 10.1177/01926233231171101
Please help us test our new pre-print finding feature by giving the pre-print link a rating. A 5 star rating indicates the linked pre-print has the exact same content as the published article.
Authors:Renee R. Hukkanen, Michelle Trapani, Tana Derringer, Victoria Laast, Zbigniew W. Wojcinski, Rosa Anna Manno, Matthias Rinke, Eric van Esch, Alys E. Bradley, Patrizia Cristofori, Roger Alison, Barb Munch Abstract: Toxicologic Pathology, Ahead of Print. Toxicologic/veterinary pathologists are working remotely from Good Laboratory Practice (GLP) test facilities (TFs) in increasing numbers, most commonly in home-office settings. A study pathologist (SP) generating data on GLP-compliant nonclinical studies must be keenly aware of applicable national GLP regulations and comply with TF and protocol requirements. This Toxicological Pathology Forum Opinion Piece will summarize primary areas of emphasis for the SP generating GLP data using glass slides. Peer review and digital review of whole slide images are out of scope for this opinion piece. Key GLP considerations for primary pathology on glass slides are discussed with respect to SP location and employment status, including pathologist qualifications, specimen management, facilities, equipment, archive, and quality assurance. Notable differences between national GLP regulations of the United States, the United Kingdom, Germany, the Netherlands, France, Ireland, Switzerland, Italy, and Israel are presented. With the understanding that each combination of location and employment is unique, the authors provide a general overview of considerations for successful remote GLP work. Citation: Toxicologic Pathology PubDate: 2023-04-26T12:04:05Z DOI: 10.1177/01926233231168133
Hybrid journal (It can contain Open Access articles)
[1176 journals]
