Comparison of Toxicities among Different Bumped Kinase Inhibitor Analogs for Treatment of Cryptosporidiosis.

Recent advances on the development of bumped kinase inhibitors for treatment of cryptosporidiosis have focused on the 5-aminopyrazole-4-carboxamide scaffold, due to analogs that have less hERG inhibition, superior efficacy, and strong safety profiles. Three compounds, BKI-1770, -1841, and -1708, showed strong efficacy in C. parvum infected mice.

Automated blood sampling in canine telemetry model: Enhanced assessment of immune liabilities.

Introduction: This manuscript presents a successful integration of multi-timepoint biomarker blood sampling (e.g., cytokines) in a conscious dog cardiovascular study using automated blood sampling via vascular access ports in telemetry instrumented dogs.

Bumped Kinase Inhibitors as therapy for apicomplexan parasitic diseases: lessons learned.

Bumped Kinase Inhibitors, targeting Calcium-dependent Protein Kinase 1 in apicomplexan parasites with a glycine gatekeeper, are promising new therapeutics for apicomplexan diseases. Here we will review advances, as well as challenges and lessons learned regarding efficacy, safety, and pharmacology that have shaped our selection of pre-clinical candidates.

Scientific and Regulatory Policy Committee Points to Consider*: Review of Scientific and Regulatory Policy Committee Points to Consider: Review of Current Practices for Ultrastructural Pathology Evaluations in Support of Nonclinical Toxicology Studies.

Anatomic pathology and clinical pathology end points are standard components of almost every nonclinical general toxicity study conducted during the risk assessment of novel pharmaceuticals and chemicals. On occasion, an ultrastructural pathology evaluation using transmission electron microscopy (TEM) may be included in nonclinical toxicity studies. Transmission electron microscopy is most commonly used when a light microscopic finding may require further characterization that could inform on the pathogenesis and/or mechanism of action.

Frontiers in preclinical safety biomarkers: microRNAs and messenger RNAs.

The measurement of plasma microRNAs (miRNAs) and messenger RNAs (mRNAs) is the most recent effort to identify novel biomarkers in preclinical safety. These genomic markers often display tissue-specific expression, may be released from the tissues into the plasma during toxic events, change early and with high magnitude in tissues and in the blood during specific organ toxicities, and can be measured using multiplex formats. Their validation as biomarkers has been challenged by the technical difficulties.

Computer-assisted imaging algorithms facilitate histomorphometric quantification of kidney damage in rodent renal failure models.

Introduction: Surgical 5/6 nephrectomy and adenine-induced kidney failure in rats are frequently used models of progressive renal failure. In both models, rats develop significant morphological changes in the kidneys and quantification of these changes can be used to measure the efficacy of prophylactic or therapeutic approaches. In this study, the Aperio Genie Pattern Recognition technology, along with the Positive Pixel Count, Nuclear and Rare Event algorithms were used to quantify histological changes in both rat renal failure models.

Ultrastructural analysis in preclinical safety evaluation.

The first electron microscopic images of biological specimens were made in the 1940s, and the next 30 years comprised an era of descriptive ultrastructure during which transmission electron microscopy (TEM) was integral to an explosion in cellular and molecular biology. However, when questions could no longer be answered by ultrastructural information alone, the use of TEM in biological research declined. Innovative molecular techniques and newer imaging technologies such as confocal fluorescence microscopy filled the gap, providing faster answers with less rigorous training as a prerequisite to data collection.

Squamous cell carcinoma.

Squamous cell carcinoma (SCC) is a relatively common, malignant neoplasm of dogs and cats that can arise in a variety of locations. The gross appearance of SCC can be variable and nonspecific, so definitive diagnosis requires microscopic examination of the tissue (cytology or histology). Several treatment modalities exist, but surgical excision, if possible, is regarded as the best treatment option.

Prostate cancer in dogs: comparative and clinical aspects.

The canine prostate gland shares many morphological and functional similarities with the human prostate and dogs are the only other large mammals that commonly develop spontaneous prostate cancer. However, the incidence of prostate cancer is much lower in dogs and the precise cell of origin is not known. Dogs with prostate cancer usually present with advanced disease that does not respond to androgen deprivation therapy.

Serum bile acids concentrations in healthy and clinically ill neonatal foals.

Background: Reference ranges for serum bile acids (SBA) concentration are well established in healthy adult horses. Increased values are indicative of hepatic disease.

Hypotheses: SBA concentrations are significantly greater in the neonatal period compared with mature horses, and illness in the neonatal period will further increase SBA.

A subcutaneous mass on the neck of a horse.

A 25-year-old Arabian gelding was presented for investigation of a subcutaneous neck mass. Fine-needle aspirates and impression smears revealed mast cells with widely varying degrees of cytoplasmic granulation and scattered eosinophils. Histopathology revealed a poorly circumscribed mass composed of sheets and bundles of mast cells with a large population of eosinophils.

New bone formation and osteolysis by a metastatic, highly invasive canine prostate carcinoma xenograft.

Background: Osteoblastic metastases are commonly induced by prostate cancer. A canine prostate carcinoma xenograft (Ace-1) was developed and used to evaluate neoplastic prostate cell growth, metastasis, and effects on bone formation in nude mice.

Methods: Characteristics of the Ace-1 cells were evaluated with histopathology, radiography, and bioluminescent imaging (BLI).

Risk factors associated with renal insufficiency in horses with primary gastrointestinal disease: 26 cases (2000-2003).

Objective: To identify factors associated with renal insufficiency in colic- or colitis-affected horses with high serum creatinine (SCr) concentrations evaluated at a referral hospital.

Design: Retrospective case series.

Animals: 167 colic- or colitis-affected horses (88 represented a random sample [hospital population], and 79 had high SCr concentration at initial evaluation [study population]).

Tail-base mass from a "horse of a different color".

A 14-year-old bay Thoroughbred gelding was presented for evaluation of a mass at the base of the tail. The mass had been present for 1 year, and recently had begun to increase in size. Additional masses were found around the eye and shoulder.

Prostatic carcinoma causing urethral obstruction and obstipation in a cat.

A 9-year-old intact male cat was presented for vomiting and straining to defecate. A large abdominal mass was palpated. The urinary bladder was full and non-expressible.

Hypercalcemia and high serum parathyroid hormone-related protein concentration in a horse with multiple myeloma.

A 13-year-old gelding was examined because of weight loss, hyperglobulinemia, and hypercalcemia. Possible causes of hypercalcemia that were considered included renal failure, primary hyperparathyroidism, vitamin D toxicosis, and malignancy. There was no history of vitamin D ingestion, and serum creatinine and parathyroid hormone concentrations were normal, making renal failure and primary hyperparathyroidism unlikely.

Canine prostate stimulates osteoblast function using the endothelin receptors.

Background: Bone metastases are common in humans and dogs with late-stage prostate cancer. A unique feature of prostate cancer metastases is new bone formation at metastatic sites ("osteoblastic metastases"). Many carcinomas that metastasize to bone cause bone destruction, not new bone formation.

Effects of transforming growth factor-beta1 on parathyroid hormone-related protein mRNA expression and protein secretion in canine prostate epithelial, stromal, and carcinoma cells.

Background: Bone metastases of prostate carcinoma are associated with osteoblastic metastases. Tumor-derived factors, such as parathyroid hormone-related protein (PTHrP), may promote the development of osteoblastic metastases. We examined the effect of transforming growth factor-beta1 (TGF beta 1) on PTHrP mRNA expression and PTHrP secretion in normal canine prostate epithelial cells (PEC) and stromal cells (PSC), and in canine prostate carcinoma cells (PCC).

Animal models of bone metastasis.

Background: Animal models are important tools to investigate the pathogenesis and develop treatment strategies for bone metastases in humans. However, there are few spontaneous models of bone metastasis despite the fact that rodents (rats and mice) and other animals (dogs and cats) often spontaneously develop cancer. Therefore, most experimental models of bone metastasis in rodents require injection or implantation of neoplastic cells into orthotopic locations, bones, or the left ventricle of the heart.

New bone formation in nude mouse calvaria induced by canine prostate tissue.

Osteoblastic metastases are common in patients with advanced prostate cancer. The pathophysiology of the new bone formation at metastatic sites is not currently known, but it is hypothesized that growth factors secreted by the prostate may be involved. Unfortunately, most rodent models of prostate cancer with metastasis to bone are osteolytic and not osteoblastic.

Artifactually increased serum bicarbonate values in two horses and a calf with severe rhabdomyolysis.

Extremely high bicarbonate (HCO3-) and anion gap values were measured in two horses and a calf using the Hitachi 911 automated serum biochemistry analyzer. All three animals had severe muscle disease as evidenced by markedly increased aspartate aminotransferase and creatine kinase activities. Laboratory error was suspected as the source of the increased HCO3- because values calculated from blood gas analysis were normal.

Canine prostate induces new bone formation in mouse calvaria: A model of osteoinduction by prostate tissue.

Background: Osteoblastic metastases are common in patients with advanced prostate cancer. The pathophysiology of the new bone formation at metastatic sites is not currently known, but it is hypothesized that growth factors secreted by the prostate may be involved. Unfortunately, most rodent models of prostate cancer with metastasis to bone are osteolytic and not osteoblastic.