•Comparative oncology is poised to have an impact on animals and human beings with cancer.•It leverages the unique advantages of large animal models of human cancer sharing our environment.•Key ...advances already have been made in cancer genetics, pathogenesis, diagnosis and therapy using a comparative approach.•Ethical considerations and standardization of studies are important caveats to the use of companion animal models.•At least as important as the benefit to human patients is the parallel advance in veterinary cancer care.
Comparative oncology is poised to have a far-reaching impact on both animals and human beings with cancer. The field is gaining momentum and has repeatedly proven its utility in various aspects of oncology, including study of the genetics, development, progression, immunology and therapy of cancer. Companion animals provide many advantages over both traditional rodent models and human beings for studying cancer biology and accelerating the development of novel anti-cancer therapies. In this review, several examples of the ability of companion animals with spontaneous cancers to fill a unique niche in the field of oncology are discussed. In addition, potential caveats of the use of companion animals in research are reviewed, as well as ethical considerations and efforts to standardize veterinary clinical trials.
BACKGROUND: Cholecystocentesis can be part of the diagnostic workup of hepatobiliary disease in small animals, but literature on cytological evaluation of bile is scant. OBJECTIVES: To determine the ...diagnostic utility of cytological assessment of bile aspirates. ANIMALS: Fifty‐six and 78 client‐owned dogs and cats, respectively, with bile collected by cholecystocentesis and submitted to our diagnostic laboratory between 1999 and 2014. METHODS: Retrospective study describing cytological findings of bile, concurrent bacterial culture results, hematological and serum biochemical data, gallbladder biopsy results, as well as final diagnosis and complications after cholecystocentesis. RESULTS: Infectious agents were found in 30% of canine and 22% of feline bile aspirates, and inflammation in 5% and 19% respectively. Presence of microorganisms was more often detected on cytological examination (24%) than by culture (21%). The most common bacterial isolates were Escherichia coli and Enterococcus spp., isolated from 14.8% and 6.7% of cultured samples respectively. Only increased canine pancreatic lipase immunoreactivity concentration (cPLI) was significantly associated with the presence of microorganisms, inflammatory cells, or both in bile. Clinically relevant complications of cholecystocentesis occurred in 2 dogs. The majority of the animals undergoing cholecystocentesis suffered from hepatic, pancreatic, gastrointestinal disease, or a combination thereof. CONCLUSIONS AND CLINICAL IMPORTANCE: Cytological examination of bile is inexpensive and straightforward, and yields diagnostically relevant information that precedes and complements bacterial culture.
CD4+CD25+ regulatory T cells (Tregs) have far-reaching immunotherapeutic applications, the realization of which will require a greater understanding of the factors influencing their function and ...phenotype during ex vivo manipulation. In murine models, IL-2 plays an important role in both the maintenance of a functional Treg population in vivo and the activation of suppression in vitro. We have found that IL-2 maintains optimal function of human CD4+CD25+ Tregs in vitro and increases expression of both forkhead box protein 3, human nomenclature (FOXP3) and the distinctive markers CD25, cytotoxic T lymphocyte antigen-4 (CTLA-4) and glucocorticoid-induced tumor necrosis factor receptor superfamily member number 18 (GITR). Although IL-2 reduced spontaneous apoptosis of Tregs, this property alone could not account for the optimal maintenance of the regulatory phenotype. The inhibition of phosphatidylinositol 3-kinase (PI3K) signaling by LY294002, a chemical inhibitor of PI3K, abolished the maintenance of maximal suppressive potency by IL-2, yet had no effect on the up-regulation of FOXP3, CD25, CTLA-4 and GITR. Other common gamma chain (γc) cytokines—IL-4, IL-7 and IL-15—had similar properties, although IL-4 showed a unique lack of effect on the expression of FOXP3 or Treg markers despite maintaining maximal regulatory function. Taken together, our data suggest a model in which the γc cytokines IL-2, IL-4, IL-7 and IL-15 maintain the optimal regulatory function of human CD4+CD25+ T cells in a PI3K-dependent manner, offering new insight into the effective manipulation of Tregs ex vivo.
Abnormalities of peripheral tolerance are thought to contribute to the pathogenesis of a number of inflammatory, autoimmune and neoplastic diseases of both humans and animals. Furthermore, the ...induction of allograft tolerance is the ‘holy grail’ of clinical transplantation. Of the various mechanisms underlying peripheral tolerance, regulatory T cells (Tregs) have risen to particular prominence. Various Treg subsets have been characterised, including naturally occurring cells that develop along a regulatory lineage in the thymus and induced cells that arise in the periphery from conventional T cell precursors. The transcription factor Forkhead box (Foxp3) serves a crucial role in stabilising the Treg transcriptome and is a faithful marker of peripheral Tregs in the mouse, though its expression is somewhat more promiscuous in man. Regulatory T cells display a wide spectrum of suppressive and cytotoxic mechanisms and may convert to specific T helper cell subsets in response to appropriate inflammatory cues. Although knowledge of Tregs in domestic animal species is still in its infancy, a growing body of literature is accumulating in the dog, cat, pig, cow, sheep and horse. We highlight our own and other studies of Tregs in the dog, an important veterinary species and a model for a number of human diseases. The ethos of ‘One Health, One Medicine’ is anticipated to accelerate efforts to close the knowledge gap between domestic animal and mainstream species in this field. We predict that the prodigious pace of research into Tregs will continue unabated for years to come, fuelled by the exciting therapeutic potential of these cells.
Biginelli reactions have been monitored by direct infusion electrospray ionization mass spectrometry (ESI‐MS) and key cationic intermediates involved in this three‐component reaction have been ...intercepted and further characterized by tandem MS experiments (ESI‐MS/MS). Density functional theory calculations were also used to investigate the feasibility of the major competing mechanisms proposed for the Biginelli reaction. The experimental and theoretical results were found to corroborate the iminium mechanism proposed by Folkers and Johnson, whereas no intermediates directly associated with either the more energy demanding Knoevenagel or enamine mechanisms could be intercepted.
Key cationic intermediates involved in the three‐component Biginelli reaction (see scheme) have been intercepted and further characterized by tandem MS experiments (ESI‐MS/MS). The experimental and theoretical results were found to corroborate the iminium mechanism proposed by Folkers and Johnson, whereas no intermediates directly associated with either the more energy demanding Knoevenagel or enamine mechanisms could be intercepted.
The pathogenesis of chronic enteropathies in dogs likely involves an interaction between the intestinal immune system and luminal intestinal bacteria. German shepherd dogs (GSD) are particularly ...predisposed to chronic enteropathies. The present study sought to evaluate expression patterns of certain pattern recognition receptors of the innate immunity (Toll-like receptors, TLR), clinical disease activity and histopathological severity in GSD with chronic enteropathies.
Mucosal biopsies were collected from the duodenum, colon and ileum of 13 affected GSD and 10 healthy greyhounds as controls. Dogs were objectively assessed using published scoring systems for clinical and histological severity of disease. Diversity of the duodenal microbiota was assessed by construction of 16S rRNA gene libraries. Expression of TLR2, TLR4, TLR5 and TLR9 in biopsies of the duodenum, ileum and colon was assessed by quantitative real-time PCR.
TLR4 expression was increased in all intestinal segments in GSD, however, TLR5 expression was very low compared to the healthy dogs. The microbiota in the duodenum of GSDs was significantly different to that of the greyhounds, with an over-representation of 16S rRNA gene sequences belonging to the classes of
Bacilli, and
Erysipelotrichi, and to the orders of
Lactobacillales,
Actinomycetales and
Erysipelotrichales.
These findings could point to a distinct pathogenesis of chronic enteropathies in GSD, with differentially high and low expression of TLR4 and TLR5, respectively, and increased proportions of specific members of the
Lactobacillales potentially playing a role.
Background
Paroxysmal gluten‐sensitive dyskinesia (PGSD) in border terriers (BTs) results from an immunologic response directed against transglutaminase (TG)2 and gliadin. Recent evidence suggests ...that PGSD is only one aspect of a range of possible manifestations of gluten sensitivity in the breed.
Hypothesis/Objectives
Gluten sensitivity in BTs is a heterogeneous disease process with a diverse clinical spectrum; to characterize the phenotype of PGSD using TG2 and gliadin autoantibodies as diagnostic markers.
Animals
One hundred twenty‐eight client‐owned BTs with various disorders.
Methods
Prospective study. BTs with paroxysmal episodes and a normal interictal examination were phenotyped using footage of a representative episode and assigned to 3 groups: idiopathic epilepsy (IE), paroxysmal dyskinesia (PD), or other. Owners of each dog completed a questionnaire to obtain information regarding clinical signs. Healthy BTs formed a control group. Serum antibodies against TG2 and AGA were measured in all dogs.
Results
One hundred twenty‐eight BTs were enrolled; 45 with PD, 28 with IE, 35 with other conditions, and 20 controls. Three overlapping phenotypes were identified; PD, signs suggestive of gastrointestinal disease, and dermatopathy. AGA‐IgG concentrations were increased in PD, compared with IE (P = 0.012), controls (P < 0.0001) and other (P = 0.018) conditions. Anti‐canine TG2‐IgA concentrations were increased in PD, compared with IE (P < 0.0001), controls (P < 0.0001) and other (P = 0.012) conditions. Serological markers are highly specific for PGSD but lack sensitivity.
Conclusions
PGSD appears part of a syndrome of gluten intolerance consisting of episodes of transient dyskinesia, signs suggestive of gastrointestinal disease, and dermatological hypersensitivity.
Sepsis, the systemic inflammatory response to infection, represents the major cause of death in critically ill veterinary patients. Whereas important advances in our understanding of the ...pathophysiology of this syndrome have been made, much remains to be elucidated. There is general agreement on the key interaction between pathogen‐associated molecular patterns and cells of the innate immune system, and the amplification of the host response generated by pro‐inflammatory cytokines. More recently, the concept of immunoparalysis in sepsis has also been advanced, together with an increasing recognition of the interplay between regulatory T cells and the innate immune response. However, the heterogeneous nature of this syndrome and the difficulty of modeling it in vitro or in vivo has both frustrated the advancement of new therapies and emphasized the continuing importance of patient‐based clinical research in this area of human and veterinary medicine.
BACKGROUND: Canine epileptoid cramping syndrome (CECS) is a paroxysmal movement disorder of Border Terriers (BTs). These dogs might respond to a gluten‐free diet. OBJECTIVES: The objective of this ...study was to examine the clinical and serological effect of a gluten‐free diet in BTs with CECS. ANIMALS: Six client‐owned BTs with clinically confirmed CECS. METHODS: Dogs were prospectively recruited that had at least a 6‐month history of CECS based on the observed phenomenology (using video) and had exhibited at least 2 separate episodes on different days. Dogs were tested for anti‐transglutaminase 2 (TG2 IgA) and anti‐gliadin (AGA IgG) antibodies in the serum at presentation, and 3, 6, and 9 months after the introduction of a gluten‐free diet. Duodenal biopsies were performed in 1 dog. RESULTS: Serum TG2 IgA titers were increased in 6/6 BTs (P = .006) and AGA IgG titers were increased in 5/6 BTs at presentation compared to those of controls (P = .018). After 9 months, there was clinical and serological improvement in all BTs with CECS strictly adhering to a gluten‐free diet (5/5). One dog had persistently increased antibody titers. This dog scavenged horse manure. On the strict introduction of a gluten‐free diet this dog also had an improved clinical and serological response. The diet‐associated improvement was reversible in 2 dogs on completion of the study, both of which suffered a relapse of CECS on the re‐introduction of gluten. CONCLUSIONS: Canine epileptoid cramping syndrome in BTs is a gluten‐sensitive movement disorder triggered and perpetuated by gluten and thus responsive to a gluten‐free diet.
Background
Canine chronic enteropathies (CE) are believed to be caused by an aberrant immune response towards the intestinal microbiome. Administration of probiotics can alleviate colitis in people. ...In vitro effects of the probiotic Enterococcus faecium NCIMB 10415 E1707 (EF) previously have been evaluated using canine cells (e.g., whole blood, intestinal biopsies), but data on in vivo efficacy are lacking.
Hypothesis/Objectives
Administration of EF to dogs with food‐responsive CE will improve clinical outcome and decrease the intestinal inflammatory profile.
Animals
Dogs diagnosed with CE were prospectively recruited to receive a hydrolyzed elimination diet plus either a synbiotic product containing EF or placebo for 6 weeks. Both veterinary staff and owners were blinded to the treatment.
Methods
Clinical severity index (CCECAI), clinicopathological data and gene expression using intestinal biopsies (TLR2/4/5/9, IL‐17A, IL‐22, IL‐23p19, RORC, IL‐2, IL‐12p35, TNFα, IL‐4, IFNy, IL‐10, TGFβ, IL‐1β, IL‐18, NLRP3, casp‐1, TFF1, TFF3 and PPARy) before and after 6 weeks of treatment were analyzed using linear mixed modeling.
Results
Of the 45 cases recruited, 12 finished the clinical trial. Seven received the synbiotic and 5 the placebo product. There was no difference between groups or treatments regarding clinical efficacy, histology scores or expression of any of the investigated genes.
Conclusions and clinical importance
Standard dietary treatment induced rapid clinical response in all cases. Because the study was underpowered, it was not possible to determine whether or not EF had an additional effect within the time period of 6 weeks.
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