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Toxicologic Pathology

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https://www.readbyqxmd.com/read/28641507/the-acvp-stp-coalition-for-veterinary-pathology-fellows-celebrates-32-new-training-positions
#1
Gary Cockerell, Cory Brayton, Anne Barger, Brad Bolon
Since its creation in 2004, the Coalition for Veterinary Pathology Fellows, a partnership between the American College of Veterinary Pathologists and the Society of Toxicologic Pathology, has established 32 new training positions backed by US$7.4 million in financial support from private sponsors.
June 2017: Toxicologic Pathology
https://www.readbyqxmd.com/read/28641506/regulatory-forum-opinion-piece-imaging-applications-in-toxicologic-pathology-recommendations-for-use-in-regulated-nonclinical-toxicity-studies
#2
Robert R Maronpot, Abraham Nyska, Sean P Troth, Kathleen Gabrielson, Polina Sysa-Shah, Vyacheslav Kalchenko, Yuri Kuznetsov, Alon Harmelin, Yael S Schiffenbauer, David Bonnel, Jonathan Stauber, Yuval Ramot
Available imaging systems for use in preclinical toxicology studies increasingly show utility as important tools in the toxicologic pathologist's armamentarium, permit longitudinal evaluation of functional and morphological changes in tissues, and provide important information such as organ and lesion volume not obtained by conventional toxicology study parameters. Representative examples of practical imaging applications in toxicology research and preclinical studies are presented for ultrasound, positron emission tomography/single-photon emission computed tomography, optical, magnetic resonance imaging, and matrix-assisted laser desorption ionization-imaging mass spectrometry imaging...
June 2017: Toxicologic Pathology
https://www.readbyqxmd.com/read/28641505/in-utero-exposure-to-di-n-butyl-phthalate-induces-morphological-and-biochemical-changes-in-rats-postpuberty
#3
Yuya Okayama, Shin Wakui, Michael F Wempe, Mitsuru Sugiyama, Masaya Motohashi, Tomoko Mutou, Hiroyuki Takahashi, Eisuke Kume, Hiroshi Ikegami
Pregnant Sprague-Dawley rats were orally administered di( n-butyl)phthalate (DBP; 100 mg/kg/day) on gestation days (GD) 12 to 21. We investigated the male offspring and probed morphological alterations in Sertoli cells at 7, 9, 14, and 17 weeks of age. Parameters assessed in this study included offspring number, sex ratios, body weights, testis weights, seminiferous tubule (ST) profile numbers and diameters, number of vimentin-labeled Sertoli cells, and both testosterone and follicle-stimulating hormone (FSH) levels...
June 2017: Toxicologic Pathology
https://www.readbyqxmd.com/read/28421969/dystrophic-mineralization-of-costal-cartilage-in-hartley-guinea-pigs
#4
Alexandria M Schauer, Adrienne Schucker, Cathy S Carlson
Hartley guinea pigs are widely used animal models of disease, particularly in studies of osteoarthritis. The purpose of this study was to investigate lesions in the costal cartilage from 16 male, 5- to 6-month-old Hartley guinea pigs. Routine histological sections from the costal cartilage and costochondral junction (longitudinal and cross sections) and sternum (for evaluation of bone marrow) were examined. All 16 (100%) animals had histological lesions involving the costal cartilage that included matrix degeneration and mineralization, reduced cellularity, and evidence of chondrocyte necrosis...
April 2017: Toxicologic Pathology
https://www.readbyqxmd.com/read/28421968/chronic-toxicology-studies-of-basal-insulin-peglispro-in-rats-and-dogs-a-novel-pegylated-insulin-lispro-analog-with-a-prolonged-duration-of-action
#5
Richard A Byrd, Jamie L Blackbourne, Mary Pat Knadler, Albert E Schultze, John L Vahle
Basal insulin peglispro (BIL) consists of insulin lispro with a 20-kDa polyethylene glycol (PEG) moiety covalently attached to lysine B28. Because chronic parenteral administration of PEGylated proteins to animals has sometimes resulted in PEG vacuolation of tissue macrophages, renal tubular cells, and choroid plexus ependymal cells, we investigated whether chronic subcutaneous (sc) injection of BIL in rats (52 weeks) and dogs (39 weeks) was associated with systemic toxicities or other changes, including vacuolation of tissue macrophages, renal tubular cells, and ependymal cells...
April 2017: Toxicologic Pathology
https://www.readbyqxmd.com/read/28421967/lung-tumor-induction-by-26-week-dermal-application-of-1-2-dichloroethane-in-cb6f1-tg-rash2-mice
#6
Mayuko Suguro, Takamasa Numano, Mayumi Kawabe, Yuko Doi, Norio Imai, Yukinori Mera, Seiko Tamano
Short-term alternatives to traditional 2-year carcinogenic studies in rodents are being actively pursued. Recently, a 26-week short-term carcinogenicity study using CB6F1-Tg rasH2@Jcl (rasH2) mice has become a worldwide standard for the evaluation of chemical carcinogenesis. However, an acceptable short-term carcinogenic study model for dermally applied products is still lacking. To investigate the suitability of using the rasH2 mouse to test carcinogenic potential, 1,2-dichloroethane (1,2-DCE) was dermally applied to rasH2 mice: 1,2-DCE is a known carcinogen that causes lung bronchiolo-alveolar adenomas and adenocarcinomas when administered topically, orally, or by inhalation exposure; 1,2-DCE at a dose level of 126 mg/mouse in 200 μl acetone or acetone alone (vehicle control) was applied to the dorsal skin of 10 mice of each sex 3 times a week for 26 weeks...
April 2017: Toxicologic Pathology
https://www.readbyqxmd.com/read/28421966/regulatory-forum-review-utility-of-in-vitro-secondary-pharmacology-data-to-assess-risk-of-drug-induced-valvular-heart-disease-in-humans-regulatory-considerations
#7
Thomas Papoian, Gowraganahalli Jagadeesh, Muriel Saulnier, Natalie Simpson, Arippa Ravindran, Baichun Yang, Adebayo A Laniyonu, Imran Khan, Ana Szarfman
Drug-induced valvular heart disease (VHD) is a serious side effect linked to long-term treatment with 5-hydroxytryptamine (serotonin) receptor 2B (5-HT2B) agonists. Safety assessment for off-target pharmacodynamic activity is a common approach used to screen drugs for this undesired property. Such studies include in vitro assays to determine whether the drug is a 5-HT2B agonist, a necessary pharmacological property for development of VHD. Measures of in vitro binding affinity (IC50, Ki) or cellular functional activity (EC50) are often compared to maximum therapeutic free plasma drug levels ( fCmax) from which safety margins (SMs) can be derived...
April 2017: Toxicologic Pathology
https://www.readbyqxmd.com/read/28178900/influence-of-study-design-variables-on-clinical-pathology-data
#8
Adam Aulbach, Anne Provencher, Niraj Tripathi
A number of factors related to study design have the potential to impact clinical pathology test results during the conduct of nonclinical safety studies. A thorough understanding of these factors is paramount in drawing accurate conclusions from clinical pathology data generated during such studies, particularly when attempting to make the distinction between test article and nontest article-related effects. Study design and conduct variables with potential to impact clinical pathology data discussed in this overview include those related to species and test system, animal age, animal care and husbandry practices, fasting, acclimatization periods, effects of transportation and stressors, route of administration, effects of in-life and surgical procedures, influence of study length, timing of blood collections, impact of vehicle/formulation composition, and some general concepts related to drug class...
February 2017: Toxicologic Pathology
https://www.readbyqxmd.com/read/28178899/recognizing-and-reducing-analytical-errors-and-sources-of-variation-in-clinical-pathology-data-in-safety-assessment-studies
#9
A E Schultze, A R Irizarry
Veterinary clinical pathologists are well positioned via education and training to assist in investigations of unexpected results or increased variation in clinical pathology data. Errors in testing and unexpected variability in clinical pathology data are sometimes referred to as "laboratory errors." These alterations may occur in the preanalytical, analytical, or postanalytical phases of studies. Most of the errors or variability in clinical pathology data occur in the preanalytical or postanalytical phases...
February 2017: Toxicologic Pathology
https://www.readbyqxmd.com/read/28178898/deciphering-sources-of-variability-in-clinical-pathology-it-s-not-just-about-the-numbers
#10
Nancy E Everds
Preanalytical variables can have significant impacts on clinical pathology parameters evaluated during the conduct of a nonclinical safety or toxicity study. These preanalytical variables can be controlled by careful attention to factors such as animal dietary status (diet composition, fasted, and fed state), restraint and anesthesia, intercurrent procedures, timing of clinical pathology collections, and proficiency of animal technicians. The impact of preanalytical variables on test results can be significant enough to result in difficult interpretations and/or regulatory questions or can obfuscate the effects of a test article...
February 2017: Toxicologic Pathology
https://www.readbyqxmd.com/read/28178897/contemporary-and-emerging-applications-in-clinical-pathology
#11
Adam D Aulbach, Holly Jordan, Jacqueline Tarrant
No abstract text is available yet for this article.
February 2017: Toxicologic Pathology
https://www.readbyqxmd.com/read/28056663/principles-for-assessing-adversity-in-toxicologic-clinical-pathology
#12
Lila Ramaiah, Lindsay Tomlinson, Niraj K Tripathi, Laura C Cregar, Allison Vitsky, Barbara von Beust, Valerie G Barlow, William J Reagan, Daniela Ennulat
There is limited direction in the literature or regulatory guidance on determination of adversity for clinical pathology (CP) biomarkers in preclinical safety studies. Toxicologic clinical pathologists representing the American Society for Veterinary Clinical Pathology-Regulatory Affairs Committee and Society of Toxicologic Pathology-Clinical Pathology Interest Group identified principles, overall approach, and unique considerations for assessing adversity in CP data interpretation to provide a consensus opinion...
February 2017: Toxicologic Pathology
https://www.readbyqxmd.com/read/28013573/evaluation-of-mir-216a-and-mir-217-as-potential-biomarkers-of-acute-exocrine-pancreatic-toxicity-in-rats
#13
Jianying Wang, Wenhu Huang, Stephane Thibault, Thomas P Brown, Walter Bobrowski, Hovhannes J Gukasyan, Winston Evering, Wenyue Hu, Annette John-Baptiste, Allison Vitsky
Detecting and monitoring exocrine pancreatic damage during nonclinical and clinical testing is challenging because classical biomarkers amylase and lipase have limited sensitivity and specificity. Novel biomarkers for drug-induced pancreatic injury are needed to improve safety assessment and reduce late-stage attrition rates. In a series of studies, miR-216a and miR-217 were evaluated as potential biomarkers of acute exocrine pancreatic toxicity in rats. Our results revealed that miR-216a and miR-217 were almost exclusively expressed in rat pancreas and that circulating miR-216a and miR-217 were significantly increased in rats following administration of established exocrine pancreatic toxicants caerulein (CL) and 1-cyano-2-hydroxy-3-butene (CHB) as well as in rats administered a proprietary molecule known to primarily affect the exocrine pancreas...
February 2017: Toxicologic Pathology
https://www.readbyqxmd.com/read/28007014/evaluation-of-pepsinogen-i-as-a-biomarker-of-drug-induced-gastric-mucosal-injury-in-cynomolgus-monkeys
#14
Daniela Ennulat, Karen M Lynch, Carie L Kimbrough, Rosanna C Mirabile, Sabine Rehm
Gastric mucosal injury is frequently observed in nonclinical studies of nonhuman primates. Because microscopic evaluation of stomach is generally a terminal procedure, our objective was to determine whether serum pepsinogen I (PG I) could serve as a noninvasive biomarker for detection of gastric mucosal injury in monkey. Serum PG I was measured using a commercial human immunoassay in cynomolgus monkeys ( n = 166) prior to dosing and/or terminally in 11 studies of up to 1 month duration. Mean ( SD) PG I values (ug/L) for monkeys with ( n = 59) and without ( n = 100) gastric mucosal degeneration were 101 (215) and 28 (12...
February 2017: Toxicologic Pathology
https://www.readbyqxmd.com/read/27879436/cytological-bone-marrow-cell-differential-counts-and-morphologic-findings-in-healthy-cynomolgus-monkeys-macaca-fascicularis-from-nonclinical-toxicology-studies
#15
Caitlyn M Carter, Laura C Cregar, Adam D Aulbach
Cytological bone marrow evaluation is utilized in nonclinical toxicology studies to characterize hematopoietic effects when the combined interpretation of histologic and complete blood count data does not yield sufficient information. Results from cytological bone marrow examination should be interpreted in the context of variability observed in concurrent control animals with consideration of cytologist experience and historical/published data. Cytological bone marrow differential counts and cellular morphologic findings from 130 (66 male, 64 female) healthy control cynomolgus monkeys from nonclinical toxicology studies were retrospectively analyzed...
February 2017: Toxicologic Pathology
https://www.readbyqxmd.com/read/27729587/practical-considerations-in-clinical-pathology-data-interpretation-and-description
#16
Robert L Hall
Although interpretation and description of clinical pathology test results for any preclinical safety assessment study should employ a consistent standard approach, companies differ regarding that approach and the appearance of the end product. Some rely heavily on statistical analysis, others do not. Some believe reference intervals are important, most do not. Some prefer severity of effects be described by percentage differences from, or multiples of, baseline or control, others prefer only word modifiers...
February 2017: Toxicologic Pathology
https://www.readbyqxmd.com/read/27565173/mek-and-erk-kinase-inhibitors-increase-circulating-ceruloplasmin-and-cause-green-serum-in-rats
#17
Dolores Diaz, Rama Pai, Gary Cain, Nghi La, Donna Dambach, Jacob Schwartz, Jacqueline M Tarrant
Inhibition of the mitogen-activated protein kinase/extracellular signal-regulated (MAPK/ERK) pathway is an attractive therapeutic approach for human cancer therapy. In the course of evaluating structurally distinct small molecule inhibitors that target mitogen-activated protein kinase kinase (MEK) and ERK kinases in this pathway, we observed an unusual, dose-related increase in the incidence of green serum in preclinical safety studies in rats. Having ruled out changes in bilirubin metabolism, we demonstrated a 2- to 3-fold increase in serum ceruloplasmin levels, likely accounting for the observed green color...
February 2017: Toxicologic Pathology
https://www.readbyqxmd.com/read/27543323/assessment-of-cardiac-troponin-i-responses-in-nonhuman-primates-during-restraint-blood-collection-and-dosing-in-preclinical-safety-studies
#18
William J Reagan, Robert Barnes, Peter Harris, Sandy Summers, Sarah Lopes, Makeida Stubbs, David Blackwell, Jill Steidl-Nichols
Limited information has been published on the use of cardiac troponin I (cTnI) as a biomarker of cardiac injury in monkeys. The purpose of these studies was to characterize the cTnI response seen in cynomolgus macaques during routine dosing and blood collection procedures typically used in preclinical safety studies and to better understand the pathogenesis of this response. We measured cTnI using two different methods, the Siemens Immulite cTnI assay and the more sensitive Siemens Troponin I-Ultra assay. We were able to demonstrate that after oral, subcutaneous, or intravenous dosing of common vehicles, as well as serial chair restraint for venipuncture blood collection, that minimal to mild transient increases in cTnI could be detected in monkeys with both assays...
February 2017: Toxicologic Pathology
https://www.readbyqxmd.com/read/27189632/identification-and-evaluation-of-novel-microrna-biomarkers-in-plasma-and-feces-associated-with-drug-induced-intestinal-toxicity
#19
Dalia Y Kalabat, Allison Vitsky, Wesley Scott, Erick Kindt, Kyle Hayes, Annette John-Baptiste, Wenhu Huang, Amy H Yang
Gastrointestinal toxicity is dose limiting with many therapeutic and anticancer agents. Real-time, noninvasive detection of markers of toxicity in biofluids is advantageous. Ongoing research has revealed microRNAs as potential diagnostic and predictive biomarkers for the detection of select organ toxicities. To study the potential utility of microRNA biomarkers of intestinal injury in a preclinical toxicology species, we evaluated 3 rodent models of drug-induced intestinal toxicity, each with a distinct mechanism of toxicity...
February 2017: Toxicologic Pathology
https://www.readbyqxmd.com/read/27102652/serum-natriuretic-peptides-as-differential-biomarkers-allowing-for-the-distinction-between-physiologic-and-pathologic-left-ventricular-hypertrophy
#20
Michael E Dunn, Thomas G Manfredi, Kevin Agostinucci, Steven K Engle, Josh Powe, Nicholas M P King, Luis A Rodriguez, Kathryn E Gropp, Matthew Gallacher, Frederick J Vetter, Vijay More, Prajakta Shimpi, David Serra, Heidi M Colton
Given the proven utility of natriuretic peptides as serum biomarkers of cardiovascular maladaptation and dysfunction in humans and the high cross-species sequence conservation of atrial natriuretic peptides, natriuretic peptides have the potential to serve as translational biomarkers for the identification of cardiotoxic compounds during multiple phases of drug development. This work evaluated and compared the response of N-terminal proatrial natriuretic peptide (NT-proANP) and N-terminal probrain natriuretic peptide (NT-proBNP) in rats during exercise-induced and drug-induced increases in cardiac mass after chronic swimming or daily oral dosing with a peroxisome proliferator-activated receptor γ agonist...
February 2017: Toxicologic Pathology
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