Small structural changes of the imidazopyridine diacylglycerol acyltransferase 2 (DGAT2) inhibitors produce an improved safety profile.

Small molecule DGAT2 inhibitors have shown promise for the treatment of metabolic diseases in preclinical models. Herein, we report the first toxicological evaluation of imidazopyridine-based DGAT2 inhibitors and show that the arteriopathy associated with imidazopyridine 1 can be mitigated with small structural modifications, and is thus not mechanism related.

Recommended guidelines for submission, trimming, margin evaluation, and reporting of tumor biopsy specimens in veterinary surgical pathology.

Neoplastic diseases are typically diagnosed by biopsy and histopathological evaluation. The pathology report is key in determining prognosis, therapeutic decisions, and overall case management and therefore requires diagnostic accuracy, completeness, and clarity. Successful management relies on collaboration between clinical veterinarians, oncologists, and pathologists. To date there has been no standardized approach or guideline for the submission, trimming, margin evaluation, or reporting of neoplastic biopsy specimens in veterinary medicine. To address this issue, a committee consisting of veterinary pathologists and oncologists was established under the auspices of the American College of Veterinary Pathologists Oncology Committee. These consensus guidelines were subsequently reviewed and endorsed by a large international group of veterinary pathologists. These recommended guidelines are not mandated but rather exist to help clinicians and veterinary pathologists optimally handle neoplastic biopsy samples. Many of these guidelines represent the collective experience of the committee members and consensus group when assessing neoplastic lesions from veterinary patients but have not met the rigors of definitive scientific study and investigation. These questions of technique, analysis, and evaluation should be put through formal scrutiny in rigorous clinical studies in the near future so that more definitive guidelines can be derived.

Recommended guidelines for the conduct and evaluation of prognostic studies in veterinary oncology.

There is an increasing need for more accurate prognostic and predictive markers in veterinary oncology because of an increasing number of treatment options, the increased financial costs associated with treatment, and the emotional stress experienced by owners in association with the disease and its treatment. Numerous studies have evaluated potential prognostic and predictive markers for veterinary neoplastic diseases, but there are no established guidelines or standards for the conduct and reporting of prognostic studies in veterinary medicine. This lack of standardization has made the evaluation and comparison of studies difficult. Most important, translating these results to clinical applications is problematic. To address this issue, the American College of Veterinary Pathologists' Oncology Committee organized an initiative to establish guidelines for the conduct and reporting of prognostic studies in veterinary oncology. The goal of this initiative is to increase the quality and standardization of veterinary prognostic studies to facilitate independent evaluation, validation, comparison, and implementation of study results. This article represents a consensus statement on the conduct and reporting of prognostic studies in veterinary oncology from veterinary pathologists and oncologists from around the world. These guidelines should be considered a recommendation based on the current state of knowledge in the field, and they will need to be continually reevaluated and revised as the field of veterinary oncology continues to progress. As mentioned, these guidelines were developed through an initiative of the American College of Veterinary Pathologists' Oncology Committee, and they have been reviewed and endorsed by the World Small Animal Veterinary Association.

Anal sac gland carcinoma in 64 cats in the United kingdom (1995-2007).

A retrospective study was performed to characterize 64 cases of anal sac gland carcinoma (ASGC) in cats. All ASGCs diagnosed between 1995 and 2007 at a private diagnostic laboratory in the UK were reviewed. Apocrine gland origin was confirmed in a subset of these tumors by immunohistochemistry and the use of the glandular cytokeratin antibody (CAM 5.2). Associated clinical, gross, and histologic features were compared with those of canine ASGC. Anal sac gland carcinoma accounted for 0.5% of all feline skin neoplasms. Thirty-nine of the cats with ASGC were female, with a female male ratio of 1.56. Fifty-two (81.1%) of the 64 tumors were in Domestic Shorthair cats, 5 (7.8%) in Siamese, 3 (4.8%) in Domestic Longhair, 2 (3.1%) in Burmese, and 1 (1.6%) each in a Birman and a Persian cat. Significant differences in prevalence of ASGC among breeds were not detected. Cats ranged in age from 6 to 17 years (median and mean age, 12 years). More than three quarters of the affected cats for which postsurgical outcome was known were euthanatized or died as a direct consequence of the neoplasm, with a median survival of 3 months. Survival rates at 1 and 2 years were 19 and 0%, respectively.

Detection and clinical significance of plasma glutathione-S-transferases in dogs with lymphoma.

BACKGROUND: The objective of this study was to determine if glutathione-S-transferases were detectable in the plasma of dogs and to determine if concentrations of the a- and pi-subtypes were related with tumor response to single agent anthracycline (e.g., doxorubicin) chemotherapy in dogs with lymphoma. MATERIALS AND METHODS: Plasma was obtained from 10 healthy, normal dogs and from 11 dogs with lymphoma before treatment, 3 weeks after 1 dose of doxorubicin and every 3 weeks thereafter until relapse (the physical detection of recurrent and enlarged peripheral lymph nodes). Plasma concentration of alpha and pi-GST was determined by use of an ELISA technique with well plates pre-coated with IgG[anti-Canine alpha-GST or anti-Human pi-GST]. RESULTS: Mean plasma alpha-GST concentrations did not significantly decline after 1 dose of doxorubicin chemotherapy; however, mean plasma alpha-GST concentrations were markedly increased (p < 0.05) at the time of relapse (the physical detection of recurrent and enlarged peripheral lymph nodes). CONCLUSIONS: In this study we show that a relationship exists between the plasma alpha-GST concentration and the clinical response of dogs with lymphoma to doxorubicin chemotherapy.

An in vivo/in vitro experimental model system for the study of human osteosarcoma: canine osteosarcoma cells (COS31) which retain osteoblastic and metastatic properties in nude mice.

BACKGROUND: In this report we describe the establishment, characterization, and research utility of a cell line derived from a dog having a spontaneously occurring osteosarcoma. MATERIALS AND METHODS: Tumor samples were collected from a dog with a naturally occurring osteosarcoma and processed for light microscopy, electron microscopy, immunocytochemistry, immunohistochemistry, karyology, and cell culture. Established cells from passage 31 (COS31; canine Qsteosarcoma cells from passage 31) were inoculated subcutaneously between the scapula and in the right abdominal side of athymic nude mice and evaluated similarly. RESULTS: COS31 cells derived in cell culture and in nude mice had morphological and biochemical properties comparable in all respects to the original canine tumor specimen. CONCLUSIONS: The ability of COS31 cells to produce tumors in nude mice (i.e. a small animal model) typical of canine osteosarcoma (i.e. a large animal model) with a similar pathological and biological behavior (e.g. alkaline phosphatase and osteocalcin positive immunostaining, osteoid production, rapid growth, and wide spread metastases) demonstrates the potential utility of COS31 cells as a in vitro and in vivo model system in the development of new strategies in the treatment of human osteosarcoma.

In vitro reversal of glutathione-S-transferase-mediated resistance in canine osteosarcoma (COS31) cells.

BACKGROUND: In this report we describe the establishment, characterization, and research utility of a cell line derived from a dog having a spontaneously occurring osteosarcoma (COS) made resistant to the cytotoxic effects of cisplatin chemotherapy. MATERIALS AND METHODS: Established cells from passage 31 (COS31) were exposed to increasing sublethal concentrations of cisplatin in vitro. RESULTS: A 2.2-fold increase in glutathione-S-transferase (GST) activity was found to be induced in this cell line (COS31/rCDDP) compared to parent cells. Furthermore, these cells were 7.8-fold more resistant to the cytotoxic effects of higher concentrations of cisplatin compared to parent cells. Ethacrynic acid was found to inhibit GST enzymatic activity and increase cisplatin cytotoxicity in resistant COS31 (COS31/rCDDP) cells. CONCLUSIONS: Inhibiting the function of GST with ethacrynic acid pretreatment in humans and dogs with osteosarcoma may result in more tumor cells than normal cells killed in vivo by cisplatin, thus significantly prolonging lifespan without increasing host toxicity.