Identification by whole genome sequencing of genes associated with delayed postoperative hemorrhage in Scottish deerhounds.

Background: Delayed postoperative hemorrhage (DEPOH) is an important health concern for Scottish deerhounds.

Hypothesis/objectives: Identify genes associated with DEPOH in Scottish deerhounds.

Animals: Two hundred sixty-nine privately owned Scottish deerhounds.

Toxicity and toxicokinetic assessment of an anti-tubercular drug pretomanid in cynomolgus monkeys.

Pretomanid is a nitroimidazooxazine antimycobacterial drug that was approved in more than 10 countries as part of a three-drug, all oral regimen, consisting of bedaquiline, pretomanid, and linezolid (BPaL) for 6-months treatment of adults with pulmonary extensively drug-resistant tuberculosis (XDR-TB) or with complicated forms of multidrug-resistant tuberculosis (MDR-TB). The toxicological profile of pretomanid was thoroughly evaluated in repeat-dose oral toxicity studies up to 39 weeks long in cynomolgus monkeys. Exposures up to 10-fold higher than in humans at the approved pretomanid dose (200 mg) were achieved in acute studies allowing for characterization of dose-limiting toxicity.

Assessment of the Carcinogenic Potential of Pretomanid in Transgenic Tg.rasH2 Mice.

Pretomanid is a nitroimidazooxazine antimycobacterial drug that was approved as part of a three-drug oral regimen, consisting of bedaquiline, pretomanid, and linezolid, for 6-months treatment of adults with pulmonary extensively drug-resistant tuberculosis or with complicated forms of multidrug-resistant tuberculosis by the food and drug administration in the United States and regulatory bodies in over 10 other countries. Nitroaromatic compounds as a class carry a risk of genotoxicity and potential carcinogenicity based on reactive metabolite formation. A battery of good laboratory practice genotoxicity studies on pretomanid indicated that the compound was not genotoxic, however its hydroxy imidazole metabolite (M50) was genotoxic in the Ames assay.

Identification of 2,2-Dimethylbutanoic Acid (HST5040), a Clinical Development Candidate for the Treatment of Propionic Acidemia and Methylmalonic Acidemia.

Propionic acidemia (PA) and methylmalonic acidemia (MMA) are rare autosomal recessive disorders of propionyl-CoA (P-CoA) catabolism, caused by a deficiency in the enzymes P-CoA carboxylase and methylmalonyl-CoA (M-CoA) mutase, respectively. PA and MMA are classified as intoxication-type inborn errors of metabolism because the intramitochondrial accumulation of P-CoA, M-CoA, and other metabolites results in secondary inhibition of multiple pathways of intermediary metabolism, leading to organ dysfunction and failure. Herein, we describe the structure-activity relationships of a series of short-chain carboxylic acids which reduce disease-related metabolites in PA and MMA primary hepatocyte disease models.

Acute Histopathologic Findings Related to Needle Puncture Trauma during Subcutaneous Injection in the Sprague-Dawley Rat Model.

It is important to detect injection site reactions during the nonclinical phases of drug development. However, differentiating between normal changes following needle trauma and changes due to the toxicity of injected drugs can be challenging. Therefore, we used the Sprague-Dawley rat model to evaluate the pathological findings expected following a single subcutaneous injection of normal saline.

Career Transition Points in Toxicologic Pathology: Management and Consulting.

In the constantly evolving field of toxicologic pathology, a pathologist's career is often characterized by multiple career transitions. However, these transitions can be challenging and/or overwhelming and may require a shift in focus, strategic approach, and acquisition of new skills and expertise. In order to provide a forum to discuss challenges associated with career transitions and skill set/competencies required to navigate career changes effectively and successfully, the Career Development and Outreach Committee of the Society of Toxicologic Pathology (STP) sponsored a career development workshop entitled "Transitions in a Pathologist's Career" in conjunction with the STP 36th annual symposium.

Osteosarcoma inheritance in two families of Scottish deerhounds.

Background: Osteosarcoma is the most common neoplastic disease in Scottish Deerhounds. For Deerhounds, a 2007 population-based study concluded that a single dominant genetic factor largely governed disease risk. For Greyhounds, Rottweilers, and Irish Wolfhounds, a 2013 genome-wide association study found multiple genetic markers in each breed, with each marker only weakly associated with the disease.

A lifetime cancer bioassay of quinacrine administered into the uterine horns of female rats.

This study investigated if quinacrine can induce a tumorigenic response in rats when administered in a manner similar to the intended human use for female non-surgical sterilization. Young sexually mature female rats received two doses of quinacrine (or 1% methylcellulose control) into each uterine horn approximately 21 days apart, and were observed for 23 months after the second dose administration. Dose levels were 0/0, 0/0, 10/10, 70/70, and 70/250-350 mg/kg (first dose/second dose), which represent local doses in the uterus at approximate multiples of 1x, 8x and 40x the human dose (mg quinacrine/g uterine weight) used for female non-surgical sterilization.

Heritability and segregation analysis of osteosarcoma in the Scottish deerhound.

Osteosarcoma is the most common malignant bone tumor in dogs and, like its human orthologue, is characterized by aggressive local behavior and high metastatic rates. The Scottish deerhound is a breed of dog with a >15% incidence of osteosarcoma and represents an excellent spontaneously occurring large-animal model of the human disease. We modeled the transmission of the osteosarcoma phenotype in a population of over 1000 related deerhounds ascertained as part of a prospective health study.

A one-year neonatal mouse carcinogenesis study of quinacrine dihydrochloride.

Quinacrine is an acridine derivative under investigation for its use in nonsurgical female sterilization. Safety issues regarding the carcinogenic potential of quinacrine have been raised because it is mutagenic and clastogenic in vitro. The objective of the study was to evaluate the carcinogenic potential of quinacrine dihydrochloride (quinacrine) in neonatal mice treated with single intraperitoneal doses on postpartum days 8 and 15 and observed for 52 weeks.