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Toxicologic Pathology

Kathleen M Heinz-Taheny, Shannon M Harlan, Zhonghua Qi, Josef G Heuer
Diabetes mellitus (types 1 and 2) is the leading cause of glomerular disease and end-stage renal disease in most developed countries, with estimates that one-third of people living with diabetes will develop diabetic kidney disease (DKD). The current standard of care medications slow but do not arrest progression of kidney disease, and therefore, therapy for DKD is a highly unmet medical need for patients. To discover and test novel and durable new therapies, it is necessary to develop animal models of human DKD, which authentically recapitulate the human disease state and provide translatable efficacy to human patients...
September 13, 2018: Toxicologic Pathology
Erica E Carroll, Danielle L Ippolito, Matthew G Permenter, B Claire McDyre, Christine E Baer, David M Kumsher, Molly H Boyle, Valerie T DiVito, John A Lewis, Jason M Koontz
More than 80,000 chemicals are in commercial use worldwide. Hepatic metabolism to toxic intermediates is often a key mechanism leading to tissue damage and organ dysfunction. Effective treatment requires prompt detection of hepatotoxicity, ideally with rapid, minimally invasive diagnostic assays. In this study, archetypal histologic features of chemically induced hepatic injury were compared with clinical chemistries (including liver enzymes) and serum concentrations of microRNA-122 (miR-122, the processed form miR-122-5p), a biomarker of liver injury...
September 11, 2018: Toxicologic Pathology
Torrie A Crabbs
This article provides a brief overview of the second scientific session of the 37th Annual Symposium of the Society of Toxicologic Pathology in Indianapolis, Indiana, on June 18, 2018. The session was entitled "Acute Kidney Injury (AKI): The Toxicologic Pathologist's Constant Companion" and was co-chaired by Drs. Zaher Radi and Torrie Crabbs. The fundamentals of tubule and interstitial anatomy were covered by Dr. Kevin McDorman, followed by a review of International Harmonization of Nomenclature and Diagnostic Criteria, Standard for Exchange of Nonclinical Data, and Drug-Induced Kidney Injury terminology, which was presented by Dr...
September 6, 2018: Toxicologic Pathology
Torrie A Crabbs, Kevin S McDorman
This article provides a synopsis of the first two presentations from the second scientific session of the 37th Annual Symposium of the Society of Toxicologic Pathology in Indianapolis, Indiana, on June 18, 2018; the session focused on acute kidney injury. The first presentation, given by Dr. Kevin McDorman, focused on "Fundamentals of Renal Tubule and Interstitial Anatomy and Physiology." Several common background findings from toxicity studies were additionally discussed. Lastly, factors that impact the relevance and usefulness of historical control data, such as quality and consistency of histopathology, were discussed...
September 6, 2018: Toxicologic Pathology
Cierra N Sharp
Cisplatin causes nephrotoxicity that can lead to the development of acute kidney injury or chronic kidney disease. However, the current mouse model of cisplatin nephrotoxicity is neither physiologically nor clinically relevant. Our goal was to improve upon these deficits by developing a repeated, low-dose regimen of cisplatin and combining it with a transgenic mouse model of lung adenocarcinoma. This overview details how addressing these deficits have improved our understanding of cisplatin-induced kidney injury...
September 6, 2018: Toxicologic Pathology
Mary B Nabity, Joseph W Polli, Vishal Vaidya, Andrzej Krolewski, Warren E Glaab
A scientific session entitled "New Frontiers: Approaches to Understand the Mechanistic Basis of Renal Toxicity" focused on novel biomarkers to monitor kidney injury both preclinically and clinically, as well as providing mechanistic insight of the induced injury. Further, the role and impact of kidney membrane transporters in drug-induced kidney toxicity provided additional considerations when understanding kidney injury and the complex role of drug transporters in either sensitivity or resistance to drug-induced injury...
September 6, 2018: Toxicologic Pathology
Stefanie Lapp, Axel Bube, Florian A Colbatzky, Heinrich Ernst, Rupert Kellner, Thomas Nolte, Matthias Rinke
Microchip (passive radio-frequency identification device) implantation is a common and widely employed means of animal identification in laboratory animal facilities. However, these devices have been associated with tumors of the skin and subcutis in rodents. While microchip-associated tumors are rare, they pose a challenge for accurate diagnosis and documentation in preclinical toxicity studies. Documentation of these tumors should differentiate microchip-associated lesions with spontaneously occurring or test article-induced tumors...
September 3, 2018: Toxicologic Pathology
John L Vahle
This article summarizes a continuing education presentation on immunogenicity that was part of a continuing education course entitled, "Clinical Pathology of Biotherapeutics." Immunogenicity of a biotherapeutic can have diverse impacts including altered systemic exposure and pharmacologic responses and, in a fraction of the cases, safety concerns including cross-reactive neutralization of endogenous proteins or sequela related to immune complex disease (ICD). In most cases, immune complexes are readily cleared from circulation; however, based on physiochemical properties, insoluble complexes form, activate complement, and deposit in tissues...
August 29, 2018: Toxicologic Pathology
Jiayi Wang, Jianyong Zhong, Hai-Chun Yang, Agnes B Fogo
Tubular injury sensitizes glomeruli to injury. We review potential mechanisms of this tubuloglomerular cross talk. In the same nephron, tubular injury can cause stenosis of the glomerulotubular junction and finally result in atubular glomeruli. Tubular injury also affects glomerular filtration function through tubuloglomerular feedback. Progenitor cells, that is, parietal epithelial cells and renin positive cells, can be involved in repair of injured glomeruli and also may be modulated by tubular injury. Loss of nephrons induces additional workload and stress on remaining nephrons...
August 29, 2018: Toxicologic Pathology
Maja M Janas, Carole E Harbison, Victoria K Perry, Brenda Carito, Jessica E Sutherland, Akshay K Vaishnaw, Natalie D Keirstead, Garvin Warner
Short interfering RNAs (siRNAs) and antisense oligonucleotides (ASOs) are the most clinically advanced oligonucleotide-based platforms. A number of N-acetylgalactosamine (GalNAc)-conjugated siRNAs (GalNAc-siRNAs), also referred to as RNA interference (RNAi) therapeutics, are currently in various stages of development, though none is yet approved. While the safety of ASOs has been the subject of extensive review, the nonclinical safety profiles of GalNAc-siRNAs have not been reported. With the exception of sequence differences that confer target RNA specificity, GalNAc-siRNAs are largely chemically uniform, containing limited number of phosphorothioate linkages, and 2'-O-methyl and 2'-deoxy-2'-fluoro ribose modifications...
August 23, 2018: Toxicologic Pathology
Kendall S Frazier, Leslie A Obert
Prevalence of immune-mediated glomerulonephritis has increased in preclinical toxicity studies, with more frequent use of biotherapeutic agents (especially antigenic humanized molecules) and antisense oligonucleotide (ASO) therapies. Immune complex disease affects a small number of study monkeys, often correlates with antidrug antibody (ADA) titers, and occurs at a dose that favors immune complex formation or impedes clearance. While preclinical glomerulonephritis often fails to correlate with evidence of glomerular or vascular injury in human clinical trials and is not considered predictive, additional animal investigative immunohistochemical work may be performed to substantiate evidence for immune complex pathogenesis...
August 8, 2018: Toxicologic Pathology
(no author information available yet)
Kozlowski, C., Brumm, J., and Cain, G. (2018). An Automated Image Analysis Method to Quantify Veterinary Bone Marrow Cellularity on H&E Sections. Tox Path46, 324-335. (Original DOI: 10.1177/0192623318766457). Kozlowski, C., Fullerton, A., Cain, G., Katavolos, P., Bravo, J., and Tarrant, J. M. (2018). Proof of Concept for an Automated Image Analysis Method to Quantify Rat Bone Marrow Hematopoietic Lineages on H&E Sections. Tox Path46, 336-347. (Oringinal DOI: 10.1177/0192623318766458). In the print issue and initial version of the online issue, the figures for Kozlowski, Brumm, and Cain were mistakenly placed into Kozlowski, Fullerton, et al...
August 2, 2018: Toxicologic Pathology
Jochen Woicke, Solomon Haile, Jagannatha Mysore, Michael Peden, Typhaine Lejeune, Thomas P Sanderson, Thomas Brodie
No abstract text is available yet for this article.
August 2018: Toxicologic Pathology
Armando R Irizarry Rovira, Bindu M Bennet, Brad Bolon, Annamaria Braendli-Baiocco, Sundeep Chandra, Renaud Fleurance, Robert Garman, David Hutto, Joan Lane, Annette Romeike, Aaron Sargeant, Bevin Zimmerman
Colorless, intracytoplasmic vacuoles occur in multiple tissues in animals following repeated administration of polyethylene glycol (PEG)-conjugated molecules. The extent of vacuolation depends on physical characteristics and molecular backbone of the PEG and the dose, product, drug target/pharmacology, and duration of exposure. The collective experience gathered from multiple nonclinical toxicology studies of PEGylated biopharmaceuticals indicates that in general, PEG-related vacuolation is not associated with demonstrable cell and tissue damage or dysfunction and is reversible with sufficient duration of drug-free periods...
August 2018: Toxicologic Pathology
Natasha P Clayton, Alanna Burwell, Heather Jensen, Barbara F Williams, Quashana D Brown, Pamela Ovwigho, Sreenivasa Ramaiahgari, Tonia Hermon, Darlene Dixon
The use of three-dimensional (3-D) in vitro culture systems (spheroids, organoids) in biomolecular and drug discovery research has become increasingly popular. The popularity is due, in part, to a diminished reliance on animal bioassays and a desire to develop physiologically relevant cell culture systems that simulate the in vivo tissue microenvironment. Most evaluations of 3-D cultures are by confocal microscopy and high-content imaging; however, these technologies do not allow for detailed cellular morphologic assessments or permit basic hematoxylin and eosin histologic evaluations...
August 2018: Toxicologic Pathology
Daniela Ennulat, Michael Ringenberg, Kendall S Frazier
Nephrotoxicity is one of the more common causes of attrition in nonclinical drug development. Like most tissues, the kidney has a limited number of ways of responding to toxicological insults from diverse mechanistic pathways, which can limit the ability to determine mechanisms of renal injury using the assays routinely performed in preclinical toxicologic studies. In situations where the renal injury is unusual in morphology or if a therapeutic margin is low, additional investigative techniques may be needed to identify a potential mechanism of toxicity in order to inform clinical risk assessment or establish human relevance and translatability of the toxicity...
August 2018: Toxicologic Pathology
Scott S Auerbach, Miaofei Xu, B Alex Merrick, Mark J Hoenerhoff, Dhiral Phadke, Debra J Taxman, Ruchir Shah, Hue-Hua L Hong, Thai-Vu Ton, Ramesh C Kovi, Robert C Sills, Arun R Pandiri
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide; however, the mutational properties of HCC-associated carcinogens remain largely uncharacterized. We hypothesized that mechanisms underlying chemical-induced HCC can be characterized by evaluating the mutational spectra of these tumors. To test this hypothesis, we performed exome sequencing of B6C3F1/N HCCs that arose either spontaneously in vehicle controls ( n = 3) or due to chronic exposure to gingko biloba extract (GBE; n = 4) or methyleugenol (MEG; n = 3)...
August 2018: Toxicologic Pathology
Steve Teo, Madhav Paranjpe, Marie Mckeon, Peter Mann, Sophie Lee, Richard LaRock, Tom Brown
Benzonatate is a peripheral oral antitussive that dampens the activity of cough stretch receptors. Rodent carcinogenicity studies were performed in Tg.rasH2 mice and Wistar Han rats. Mice were orally gavaged benzonatate at 10, 30, 75, and 100 mg/kg/day for males and 5, 15, and 50 mg/kg/day for females. Rats were gavaged at 10, 30, and 90 mg/kg/day for males and 5, 15, and 50 mg/kg/day for females. Higher doses in males were due to differences in maximum tolerated doses in dose-ranging studies. In both species, benzonatate was not detected in plasma because of rapid ester hydrolysis producing 4-(butylamino) benzoic acid (BBA) and methylated polyethylene glycol polymer...
August 2018: Toxicologic Pathology
Yuval Ramot, Zadik Hazan, Andre Lucassen, Konstantin Adamsky, Vanessa Ross, Nigel Young, Matt Saunders, Helmut Ehall, Abraham Nyska
Mastic gum extracts are widely used as herbal remedies and are being tested for several clinical indications. Nevertheless, information on their safety is limited. RPh201 is an extract of the mastic gum, formulated and stabilized in a proprietary method, which is being developed as a novel drug candidate for neurological indications. The aim of this study was to assess the systemic toxic potential of RPh201, administered twice weekly by subcutaneous injections to minipigs, after 39 weeks of administration followed by a recovery period of 6 weeks...
August 2018: Toxicologic Pathology
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