Leading the pack: Best practices in comparative canine cancer genomics to inform human oncology

Pet dogs develop spontaneous cancers at a rate estimated to be five times higher than that of humans, providing a unique opportunity to study disease biology and evaluate novel therapeutic strategies in a model system that possesses an intact immune system and mirrors key aspects of human cancer biology. Despite decades of interest, effective utilization of pet dog cancers has been hindered by a limited repertoire of necessary cellular and molecular reagents for both in vitro and in vivo studies, as well as a dearth of information regarding the genomic landscape of these cancers. Recently, many of these critical gaps have been addressed through the generation of a highly annotated canine reference genome, the creation of several tools necessary for multi-omic analysis of canine tumours, and the development of a centralized repository for key genomic and associated clinical information from canine cancer patients, the Integrated Canine Data Commons. Together, these advances have catalysed multidisciplinary efforts designed to integrate the study of pet dog cancers more effectively into the translational continuum, with the ultimate goal of improving human outcomes. The current review summarizes this recent progress and provides a guide to resources and tools available for comparative study of pet dog cancers.     

Descriptive epidemiology of joint injuries in Thoroughbred racehorses in training

Reasons for performing study: No large scale epidemiological studies have previously quantified the occurrence of carpal, metacarpo‐ and metatarsophalangeal (MCP/MTP) joint injuries in Thoroughbred racehorses. Objectives: To develop an objective classification system for carpal and MCP/MTP joint injuries and estimate the incidence of these injuries in young Thoroughbreds in flat race training. Methods: In a prospective cohort study, data on daily exercise and veterinary‐diagnosed carpal and MCP/MTP joint injuries were collected from Thoroughbreds monitored since starting training as yearlings, for up to 2 years. Cases were classified in one of 4 categories: 1) localised to a carpal or MCP/MTP joint based on clinical examination and/or diagnostic analgesia; no diagnostic imaging performed; 2) localised to a carpal or MCP/MTP joint based on clinical examination and/or diagnostic analgesia; radiographs taken but no abnormalities detected; 3) evidence of abnormality of subchondral bone and/or articular margin(s) on diagnostic imaging and 4) evidence of discontinuity of the articular surface on diagnostic imaging. Incidence rates and rate ratios were estimated using Poisson regression, adjusting for trainer‐level clustering. Results: A total of 647 horses from 13 trainers throughout England contributed 7785 months at risk of joint injury. One‐hundred‐and‐eighty‐four cases of carpal (n = 82) or MCP/MTP (n = 102) joint injury were reported in 165 horses and classified in Category 1 (n = 21), Category 2 (n = 21), Category 3 (n = 72) or Category 4 (n = 70). The overall joint injury rate was 1.8 per 100 horse months (95% CI = 1.2, 2.8); rates did not differ significantly between 2‐ and 3‐year‐olds but females sustained Category 1 injuries at triple the rate of males (P = 0.03). Joint injury rates differed significantly between trainers (P<0.001) and there was trainer variation in anatomical site and severity of injury. Conclusions and potential relevance: Carpal and MCP/MTP joint injuries are an important cause of morbidity in Thoroughbred racehorses. Identification of modifiable risk factors for these injuries may reduce their incidence.     

Understanding Change: Integrating Rancher Knowledge Into State-and-Transition Models

Arid and semiarid rangelands often behave unpredictably in response to management actions and environmental stressors, making it difficult for ranchers to manage for long-term sustainability. State-and-transition models (STMs) depict current understanding of vegetation responses to management and environmental change in box-and-arrow diagrams. They are based on existing knowledge of the system and can be improved with long-term ecological monitoring data, histories, and experimentation. Rancher knowledge has been integrated in STMs; however, there has been little systematic analysis of how ranchers describe vegetation change, how their knowledge informs model components, and what opportunities and challenges exist for integrating local knowledge into STMs. Semistructured and field interviews demonstrated that rancher knowledge is valuable for providing detailed management histories and identifying management-defined states for STMs. Interviews with ranchers also provided an assessment of how ranchers perceive vegetation change, information about the causes of transitions, and indicators of change. Interviews placed vegetation change within a broader context of social and economic history, including regional changes in land use and management. Despite its potential utility, rancher knowledge is often heterogeneous and partial and can be difficult to elicit. Ranchers’ feedback pointed to limitations in existing ecological site-based approaches to STM development, especially issues of spatial scale, resolution, and interactions among adjacent vegetation types. Incorporating local knowledge into STM development may also increase communication between researchers and ranchers, potentially yielding more management-relevant research and more structured ways to document and learn from the evolving experiential knowledge of ranchers.     

Knowledge in Practice: Documenting Rancher Local Knowledge in Northwest Colorado

For more than 150 years, ranchers in the West have gained insight about natural systems through daily interaction and management of landscapes, but this knowledge has never been systematically documented and analyzed. We interviewed 26 ranchers from a single watershed to understand how ranchers acquire their knowledge, document what they know about rangeland ecosystems, and explore how this knowledge varies within the ranching community. This exploratory study offers insight into the types of knowledge ranchers possess without attempting to survey all rancher knowledge or ascribe this set of knowledge to all ranchers. We identified three major knowledge categories in interviews: active knowledge applied to management decisions, embedded knowledge from living in place, and integrative knowledge that links ecological, economic, and social aspects of rangeland systems. We found rancher knowledge complemented scientific knowledge in its ability to provide site-specific information on management practices and ecological responses, and insight regarding potential indicators of rangeland health. Knowledge varies widely within the ranching community, and knowledgeable ranchers are readily identified through community referrals. Ranchers gained their knowledge primarily through experience and social interactions, and this knowledge is an untapped source of context-specific information. We did find that economic constraints, social norms, and proximity to the system might limit application of knowledge to practice. There is also a danger that this accumulated and dynamic knowledge base will be lost over the next generation, as many family ranches are sold to new ranchers or for nonranching uses. Based on our findings, we propose that more dialogue within ranching communities and between ranchers and scientists may lead to more sustainable land management practices and effective outreach efforts, and could expand and strengthen the informal social networks through which much rancher knowledge is shared and on which the social sustainability of ranching communities depends.     

Substrate-induced volatile organic compound emissions from compost-amended soils

The agronomic effects of composts, mineral fertiliser and combinations thereof on chemical, biological and physiological soil properties have been studied in an 18-year field experiment. The present study aimed at tracing treatment effects by evaluating the volatile organic compound (VOC) emission of the differently treated soils: non-amended control, nitrogen fertilisation and composts (produced from organic waste and sewage sludge, respectively) in combination with nitrogen fertiliser. Microbial community structure was determined by denaturing gradient gel electrophoresis (DGGE). Aerobic and anaerobic soil VOC emission was determined after glucose amendment using proton transfer reaction–mass spectrometry (PTR-MS). After inducing VOC production by substrate (glucose) addition and at the same time reducing oxygen availability to impair degradation of the produced VOCs, we were able to differentiate among the treatments. Organic waste compost did not alter the VOC emissions compared to the untreated control, whilst sewage sludge composts and mineral fertilisation showed distinct effects. This differentiation was supported by DGGE analysis of fungal 18S rDNA fragments and confirms earlier findings on bacterial communities. Three major conclusions can be drawn: (1) VOC patterns are able to discriminate among soil treatments. (2) Sewage sludge compost and mineral fertilisation have not only the strongest impact on microbial community composition but also on VOC emission patterns, but specific tracer VOCs could not be identified. (3) Future efforts should aim at a PTR-MS-linked identification of the detected masses.     

Influence of asparaginase on a combination chemotherapy protocol for canine multicentric lymphoma

Combination chemotherapy is superior to single-agent chemotherapy for treating canine lymphoma, but the effect of each drug on efficacy remains unknown. By comparing 34 dogs treated with a modified cyclophosphamide, vincristine, prednisone (COP) chemotherapy protocol and 42 dogs given asparaginase in the induction phase of the same protocol, the effect of asparaginase on the chemotherapeutic protocol was determined. Both groups were compared based on clinical response at 2 weeks and 6 weeks, and on the progression-free interval. Asparaginase did not significantly increase the likelihood of a clinical remission or prolong the initial progression-free interval in the dogs studied.     

Evaluation of cisplatin combined with piroxicam for the treatment of oral malignant melanoma and oral squamous cell carcinoma in dogs

OBJECTIVE: To determine the maximum tolerated dose (MTD) of cisplatin administered with piroxicam, the antitumor activity and toxicity of cisplatin combined with piroxicam in dogs with oral malignant melanoma (OMM) and oral squamous cell carcinoma (SCC), and the effects of piroxicam on the pharmacokinetics of cisplatin in dogs with tumors. DESIGN: Prospective nonrandomized clinical trial. ANIMALS: 25 dogs. PROCEDURE: Dogs were treated with a combination of cisplatin (escalating dose with 6 hours of diuresis with saline [0.9% NaCI] solution) and piroxicam (0.3 mg/kg 10.14 mg/lb], PO, q 24 h).The initial cisplatin dose (50 mg/m2) was increased by 5 mg/m2 until the MTD was reached. Tumor stage and size were determined at 6-week intervals during treatment. The pharmacokinetics of cisplatin were determined in dogs receiving a combination of cisplatin and piroxicam during the clinical trial and dogs that were treated with cisplatin alone. RESULTS: 11 dogs with OMM and 9 dogs with SCC were included in the clinical trial. The MTD of cisplatin when administered in combination with piroxicam was 50 mg/m2. Tumor remission occurred in 5 of 9 dogs with SCC and 2 of 11 dogs with OMM. The most common abnormality observed was renal toxicosis. Clearance of cisplatin in dogs that were treated with cisplatin alone was not significantly different from that in dogs treated with a combination of cisplatin and piroxicam. CONCLUSIONS AND CLINICAL RELEVANCE: Cisplatin administered in combination with piroxicam had antitumor activity against OMM and SCC. The level of toxicity was acceptable, although renal function must be monitored carefully.     

Carboplatin and piroxicam therapy in 31 dogs with transitional cell carcinoma of the urinary bladder

Invasive transitional cell carcinoma (TCC) of the urinary bladder responds poorly to medical therapy. Combining platinum chemotherapy with a cyclooxygenase (cox) inhibitor has shown promise against canine TCC, where the disease closely mimics the human condition. A phase II clinical trial of carboplatin combined with the cox inhibitor, piroxicam, was performed in 31 dogs with naturally occurring, histopathologically confirmed, measurable TCC. Complete tumour staging was performed before and at 6‐week intervals during therapy. Tumour responses in 29 dogs included 11 partial remissions, 13 stable disease and five progressive disease. Two of the 31 dogs were withdrawn prior to the re‐staging of the tumour. Gastrointestinal toxicity was observed in 23 dogs. Hematologic toxicity was noted in 11 dogs. The median survival was 161 days from first carboplatin treatment to death. In conclusion, carboplatin/piroxicam induced remission in 40% of dogs providing evidence that a cox inhibitor enhances the antitumour activity of carboplatin. The frequent toxicity and limited survival, however, do not support the use of this specific protocol against TCC.