The dog as a naturally-occurring model for insulin-like growth factor type 1 receptor-overexpressing breast cancer: an observational cohort study.

BACKGROUND: Dogs spontaneously develop invasive mammary carcinoma with a high prevalence of the triple-negative (TN) subtype (lack of ER-Estrogen Receptor and PR-Progesterone Receptor expression, lack of HER2-Human Epidermal Growth Factor Receptor 2 overexpression), making this animal model relevant for investigating new therapeutic pathways. Insulin-like growth factor Type-1 receptor (IGF1R) is frequently overexpressed in primary human breast cancers, with a growing role in the TN phenotype. The purpose of this study was to investigate the Dog as a candidate model for IGF1R-overexpressing mammary carcinoma. METHODS: 150 bitches with canine mammary carcinoma (CMC) and a known 2-year follow-up were retrospectively included. IGF1R expression was assessed by immunohistochemistry (IHC) using a similar scoring system as for HER2 in breast cancer. The prognostic value of the IGF1R expression was assessed in terms of overall and specific survival as well as disease-free interval (DFI). RESULTS: 47 CMC (31 %) were classified as luminal and 103 (69 %) as triple-negative (TN-CMC). 41 % of CMC overexpressed IGF1R (IHC score 3+) of which 76 % were TN-CMC and 62 % grade III. IGF1R overexpression was associated with aggressive features including lymphovascular invasion, histological grade III, low ER expression and the TN phenotype. Univariate and multivariate analyses revealed that IGF1R overexpression was associated with shorter overall and specific survivals and shorter DFI in TN-CMC. CONCLUSIONS: IGF1R overexpression is common and related to a poor outcome in canine invasive mammary carcinoma, particularly in the triple negative subtype, as in human breast cancer. Preclinical studies using the Dog as a spontaneous animal model could be considered to investigate new therapies targeting IGF1R in triple-negative breast cancer.

Serum insulin-like growth factor type 1 concentrations in healthy dogs and dogs with spontaneous primary hypothyroidism.

Circulating insulin-like growth factor type 1 (IGF-1) concentrations in dogs have been correlated with standard breed bodyweight (SBBW or breed size). Thyroid and somatotropic functions, which have common effects and regulatory mechanisms, were investigated in hypothyroid dogs. IGF-1 was measured in 495 adult healthy dogs (N) and in 220 primary hypothyroid dogs (HOT) with clinical and biological signs of primary hypothyroidism. IGF-1 was determined as a function of SBBW (kg): ≤15 (group A); 1540 (group D). In HOT dogs, median fT4 and c-TSH values were 9pmol/L and 1.5ng/mL, respectively. A significant correlation between bodyweight (BW) and IGF-1 was observed in both HOT and N dogs. The median IGF-1 value (ng/mL) was significantly higher (P<0.01) in HOT dogs compared to N in groups B, C and D (230 vs. 182; 316 vs. 230; 606 vs. 306 respectively). In conclusion, IGF-1 concentration should be interpreted in the context of SBBW in dogs and increases in spontaneous primary hypothyroidism. However, it remains unclear if this association is directly due to hypothyroidism or is the result of the weight gain accompanying hypothyroidism.

Postprandial response of plasma insulin, amylin and acylated ghrelin to various test meals in lean and obese cats.

The propensity of diets of different composition to promote obesity is a current topic in feline medicine. The effects of three meals with different protein:fat ratios on hormones (insulin, acylated ghrelin and amylin) involved in the control of food intake and glucose metabolism were compared. Five lean (two females and three males, 28.6 (sd 3.4) % body fat mass (BFM), mean body weight (BW) 4590 g) and five obese (two females and three males, 37.1 (sd 4.1) % BFM, mean BW 4670 g) adult cats were studied. Only BFM differed significantly between obese and lean cats. The cats were fed a high-protein (HP), a high-fat and a high-carbohydrate diet in a randomised cross-over design. Food intake did not differ between cats fed on the different diets, but obese cats consumed significantly more energy, expressed as per kg fat-free mass, than lean cats. After a 6-week adaptation period, a test meal was given and blood samples were collected before and 0, 30, 60 and 100 min after the meal. Baseline concentrations of glucose, amylin and acylated ghrelin were higher in obese cats than in lean cats, and obese cats showed the highest postprandial responses of glucose and amylin. The HP diet led to higher postprandial amylin concentrations than the other diets, indicating a possible effect of amino acids on beta-cell secretion. Postprandial ghrelin concentrations were unaffected by diet composition. The relationship between insulin, amylin and ghrelin secretion and their relevant roles in food intake and glucose metabolism in cats require further study.

Comparison of prednisolone and dexamethasone effects in the presence of environmental control in heaves-affected horses.

This study was designed to compare the efficacy of oral prednisolone and intramuscular (IM) dexamethasone in heaves-affected horses with environmental control. A total of 16 horses, aged 8-20years, with heaves were included in the study. Complete examinations were performed on Day 0 (before treatment), Day 13 (after treatment) and Day 30. Clinical variables, arterial blood gases, mucus scoring and carina evaluation (during endoscopy), and bronchoalveolar lavage (BAL) cytological analysis were all assessed. The horses were randomly assigned to receive either oral prednisolone (1mg/kg) or IM dexamethasone (0.1mg/kg). The animals were clinically scored and mucus accumulation evaluated. Results were analysed by repeated measures ANOVA with time (days of treatment) and treatment as the main effects. When combined with environmental control, prednisolone and dexamethasone treatments had similar effects on heaves score, blood gases and endoscopic scores. However, dexamethasone had a more beneficial effect on BAL cytology.

The effects of obesity-associated insulin resistance on mRNA expression of peroxisome proliferator-activated receptor-gamma target genes, in dogs.

Visceral adipose tissue and skeletal muscle have central roles in determining whole-body insulin sensitivity. The peroxisome proliferator-activated receptor-gamma (PPARgamma) is a potential mediator of insulin sensitivity. It can directly modulate the expression of genes that are involved in glucose and lipid metabolism, including GLUT4, lipoprotein lipase (LPL) and adipocytokines (leptin and adiponectin). In this study, we aimed to determine the effects of obesity-associated insulin resistance on mRNA expression of PPARgamma and its target genes. Dogs were studied when they were lean and at the end of an overfeeding period when they had reached a steady obese state. The use of a sensitive, real-time PCR assay allowed a relative quantification of mRNA expression for PPARgamma, LPL, GLUT4, leptin and adiponectin, in adipose tissue and skeletal muscle. In visceral adipose tissue and/or skeletal muscle, mRNA expression of PPARgamma, LPL and GLUT4 were at least 2-fold less in obese and insulin-resistant dogs compared with the same animals when they were lean and insulin-sensitive. The mRNA expression and plasma concentration of leptin was increased, whereas the plasma level and mRNA expression of adiponectin was decreased, by obesity. In adipose tissue, PPARgamma expression was correlated with leptin and adiponectin. These findings, in an original model of obesity induced by a prolonged period of overfeeding, showed that insulin resistance is associated with a decrease in PPARgamma mRNA expression that could dysregulate expression of several genes involved in glucose and lipid metabolism.

Spontaneous hormonal variations in male cats following gonadectomy.

The increased prevalence of obesity after neutering in cats is problematic in veterinary practice. Although many factors seem to be involved, the role of prolactin (PRL) and insulin-like growth factor-I (IGF-I), both implicated in adipose tissue development and glucose intolerance, should be considered. Seven male cats were castrated when 11 months old. Body weight was then recorded for 56 weeks and PRL, IGF-I and leptin assayed for 44 weeks. Body weight increased steadily but only significantly after 36 weeks. It stabilised after 44 weeks, and the cats then gained about 20% of their initial body weight. IGF-I increased rapidly and was significantly higher by week 3. PRL and leptin increased with initial peaks during the eighth and eleventh weeks, respectively. This study confirms that castration rapidly modifies the hormonal balance, partly explaining the body weight increase, and that hormonal changes precede this body weight increase. Hyperleptinaemia is apparently a consequence of excess weight.

Clinical, biological and hormonal study of mid-pregnancy termination in cats with aglepristone.

In order to evaluate the efficacy, the safety and the variation in plasma concentrations of estrogens, progesterone, PGFM, oxytocin, cortisol and prolactin after mid-pregnancy termination induced by aglepristone, 61 pregnant queens (33.3 + 4.2 days), were injected subcutaneously with 15 [corrected] mg/kg aglepristone, (Alizine) [corrected] repeated once 24 h later. Five queens served as control and received a placebo. The efficacy of aglepristone was 88.5% and termination of pregnancy was achieved in 50% of the queens within 3 days. Brief periods of depression and anorexia were noted in 9.3% of the queens before fetal expulsion (these symptoms were attributed to the phenomenon of fetal expulsions). Not one of the queens that aborted developed uterine disease. There were no changes in plasma concentrations of estrogen, prostaglandin, prolactin or oxytocin following aglepristone administration. However, there were significant increases in plasma concentrations of progesterone and cortisol 60 and 30 h, respectively, after aglepristone administration. Termination of pregnancy occurred with high plasma progesterone concentrations. Fetal expulsion was characterised by an increase in estrogen, PGFM and oxytocin concentrations, whereas prolactin and cortisol levels remained at a basal level.

Effects of dietary fat and energy on body weight and composition after gonadectomy in cats.

OBJECTIVE: To evaluate the effect of dietary fat and energy density on body weight gain, body composition, and total energy expenditure (TEE) in neutered and sexually intact cats. ANIMALS: 12 male and 12 female cats PROCEDURE: Male cats were castrated (castrated male [CM]) or underwent no surgical procedure (sexually intact male [IM]). Female cats underwent ovariectomy (spayed female [SF]) or laparotomy and ligation of both uterine tubes without ovary removal (sexually intact female [IF]). Cats were fed either the low-fat (LF) or high-fat (HF) diet for 26 weeks, with the final allocation consisting of 8 groups: IF-LF IF-HE SF-LF, SF-HF IM-LF, IM-HF, CM-LF, and CM-HF. Mean food intake for each group was recorded daily, and body weight was monitored weekly throughout the study. Body composition and TEE were measured before surgery in week 0 and at the end of the study (week 26) by isotope dilution (double-labelled water). RESULTS: N eutered cats gained significantly more body fat and body weight (53.80+/-5.79%) than sexually intact cats (27.11+/-5.79%) during the study. Body weight gain of neutered cats fed the HF diet was greater than those fed the LF diet. Following correction for body composition, TEE was similar in all groups and no pattern towards increased food intake was evident. CONCLUSIONS AND CLINICAL RELEVANCE: Weight gain in neutered cats was decreased by feeding an LF, low energy-dense diet. To prevent weight gain in cats after neutering, a suitable LF diet should be fed in carefully controlled meals rather than ad libitum.

Restoration of the integrity of rat caeco-colonic mucosa by resistant starch, but not by fructo-oligosaccharides, in dextran sulfate sodium-induced experimental colitis.

Butyrate is recognised as efficient in healing colonic inflammation, but cannot be used as a long-term treatment. Dietary fibre that produces a high-butyrate level when fermented represents a promising alternative. We hypothesised that different types of dietary fibre do not have the same efficiency of healing and that this could be correlated to their fermentation characteristics. We compared short-chain fructo-oligosaccharides (FOS) and type 3 resistant starch (RS) in a previously described dextran sulfate sodium (DSS)-induced colitis model. Seventy-two Sprague-Dawley rats received water (control rats) or DSS (50 g DSS/l for 7 d then 30 g DSS/l for 7 (day 7) or 14 (day 14) d). The rats were fed a basal diet (BD), or a FOS or RS diet creating six groups: BD-control, BD-DSS, FOS-control, FOS-DSS, RS-control and RS-DSS. Caeco-colonic inflammatory injuries were assessed macroscopically and histologically. Short-chain fatty acids (SCFA) were quantified in caeco-colon, portal vein and abdominal aorta. At days 7 and 14, caecal and distal macroscopic and histological observations were improved in RS-DSS compared with BD-DSS and also with FOS-DSS rats. Caeco-colonic SCFA were reduced in FOS-DSS and RS-DSS groups compared with healthy controls. The amount of butyrate was higher in the caecum of the RS-DSS rats than in the BD-DSS and FOS-DSS rats, whereas distal butyrate was higher in FOS-DSS rats. Partially explained by higher luminal levels of SCFA, especially butyrate, the healing effect of RS confirms the involvement of some types of dietary fibre in inflammatory bowel disease. Moreover, the ineffectiveness of FOS underlines the importance of the type of dietary substrate.

Lipoproteins abnormalities in obese insulin-resistant dogs.

Many studies have shown that obesity and low insulin sensitivity are associated with lipoprotein abnormalities, which are risk factors for coronary heart disease. The effects of insulin resistance on lipoprotein metabolism were investigated in hyperenergetic-fed beagle dogs, a new model of insulin resistance. Insulin resistance was assessed by the 3-hour euglycemic-hyperinsulinemic glucose clamp technique. Lipoproteins were separated by fast-protein liquid chromatography (FPLC) and lipid composition of the different lipoproteins was determined by enzymatic methods. Hyperenergetic diet was associated with a 43% +/- 5% increase in dog body weight and a reduction in insulin-mediated glucose uptake (28 +/- 3 to 16 +/- 1 mg. kg(-1). min(-1), P <.05). Low insulin sensitivity associated with obesity was related to an increase in plasma triglyceride (TG) through an increase in very-low-density lipoprotein (VLDL)-TG (0.071 +/- 0.020 v 0.382 +/- 0.242 mmol/L, P <.05) and high-density lipoprotein (HDL)-TG (0.025 +/- 0.012 v 0.242 +/- 0.143 mmol/L, P <.05). Other lipid abnormalities common in insulin resistant humans were also found: lower plasma HDL-cholesterol (4.690 +/- 0.151 v 3.937 +/- 0.141 mmol/L, P <.05) and higher plasma nonesterified fatty acids (NEFA) (0.974 +/- 0.094 v 1.590 +/- 0.127 mmol/L, P <.05) levels. These data show that this model of the insulin-resistant obese dog could be useful in studying insulin resistance-associated dyslipidemia.

Predominance of caecal injury in a new dextran sulphate sodium treatment in rats: histopathological and fermentative characteristics.

OBJECTIVES: Cyclic administrations of dextran sulphate sodium (DSS) alternating with distilled water usually induce chronic colitis after a few weeks. In order to obtain stable chronic colitis (without recovery or relapse) in a few days, a new continuous DSS treatment was tested and characterized. Short-chain fatty acids (SCFAs), which remain poorly documented in experimental colitis, were also investigated. METHODS: Thirty-six Sprague-Dawley rats were treated with 5% DSS for 7 days (DI) followed by 3% DSS for 7 days (DM) or 14 days (DF). Control rats received only water. Inflammatory injuries in the caecum and the colon were assessed by macroscopic (colon length, caecum weight, damages score) and histological parameters. SCFAs (acetate, propionate, butyrate) were quantified individually in caecal, proximal and distal contents. RESULTS: Macroscopic and histological observations revealed that this continuous DSS treatment induced acute inflammation (DI) followed rapidly by chronic active colitis. The latter was uncommonly predominant in the caecum and the distal colon, and was also associated with some fermentative disturbances. Caecal SCFA concentrations decreased with DSS at DI and DM. The molar ratio of caecal butyrate increased with DSS. Acetate decreased in the colon while propionate increased. CONCLUSION: This new DSS treatment is able to induce in a few days stable chronic inflammation with caecal and distal predominant injuries, and mild fermentative caeco-colonic alterations. This model could contribute to the study of potential anti-inflammatory effects of prebiotics.