Search

Prolactin (PRL) is a key hormone involved in canine mammary development and tumorigenesis. In this study, the influence of a single nucleotide polymorphism (SNP) in the PRL gene (rs23932236) on the clinicopathological parameters and survival of dogs with canine mammary tumors (CMTs) was investigated. A total of 206 female dogs with spontaneous mammary tumors were enrolled in this study and circulating blood cells were genotyped. This specific SNP was associated with larger size (>3 cm diameter) for malignant tumors ( P = .036), tumors with infiltrative/invasive growth pattern ( P = .010), vascular invasion ( P = .006), and lymph node metastasis ( P = .004). Carriers of the variant allele had a shorter overall survival compared to the wild-type population with an overall survival of 18.7 months and 22.7 months, respectively ( P = .004). These findings suggest that SNP rs23932236 of canine PRL gene may be used as an indicator for the development of clinically aggressive forms of CMTs.

Reproducibility in animal research is crucial for its reliance and translational relevance. The 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced model of inflammatory bowel disease (IBD) is widely used but inconsistently and incompletely characterized throughout the literature. This hinders comparisons between studies and influences the low rate of translation of effective preclinical molecules. The purpose of this study was to categorize TNBS-induced colitis, based on macroscopic and microscopic scoring systems, and to identify basic routine parameters that could anticipate those categories. We retrospectively analysed male Wistar Rattus norvegicus (n=28 for the control group and n=87 for the TNBS group) and categorized TNBS-induced colitis in three phenotypes: Mild, Moderate and Severe colitis, as for human IBD. Also, we showed that the time course of food intake and fecal excretion (but not body weight, fluid intake or welfare scores) could foresee those categories. So, routine evaluation of food intake and fecal excretion may guide researchers in planning their experiments, selecting the animals with the severity of colitis that better matches their aims, or applying early humane endpoints to animals that will not be used in the experiments. In conclusion, categorizing TNBS-induced colitis enhances the reproducibility of data gathered with this experimental model and strengths its translational relevance.

This study aims to evaluate the efficacy and side effects of low dose cyclophosphamide chemotherapy plus meloxicam as an adjuvant treatment, compared with high dose doxorubicin or surgery alone in cats with mammary carcinoma. Medical records of 228 female cats treated for mammary carcinoma between 2008 and 2018, were reviewed in eight veterinary institutions. Only cats with complete tumour staging and radical mastectomy were included in the study. One hundred and thirty-seven cats were divided into three treatment groups: group 1 (n = 80) cats treated with surgery, group 2 (n = 34) cats that had surgery and adjuvant treatment with doxorubicin, and group 3 (n = 23) cats with surgery and adjuvant treatment with low dose metronomic cyclophosphamide and meloxicam. The study endpoints were disease free interval (DFI) and overall survival (OS). Toxicity was evaluated according to the VCOG-CTCAE criteria. The median DFI was 270, 226 and 372 days in groups 1, 2 and 3, respectively. The median OS was 338 (group 1), 421 (group 2) and 430 (group 3) days. The differences between groups were not significant (DFI P = .280 and OS P = .186). Toxicity was observed in 52.9% (n = 18) of cats in group 2 and 39.1% (n = 9) of cats in group 3, with mild to moderate intensity. Differences were not significant (P = .306). In conclusion, adjuvant chemotherapy treatment did not improve survival and the overall benefit remains unproven. Randomized prospective trials are necessary to clarify the effectiveness of adjuvant chemotherapy treatment for feline mammary carcinomas.

Background The aetiology of pulmonary alveolar microlithiasis (PAM) in animals is still unknown. In humans, this pulmonary disorder is a rare autosomal recessive disorder triggered by a mutation in the gene SLC34A2, which causes deposition and aggregation of calcium and phosphate in the pulmonary parenchyma with formation of microliths. Although histopathological examination is required for a definite diagnosis, in humans, imaging modalities such as computed tomography can demonstrate typical patterns of the disease. This is the first description of the computed tomographic (CT) features of a histologically confirmed PAM in dogs. Case presentation The following report describes a case of a 7-year-old female Boxer dog evaluated for paroxysmal loss of muscle tone and consciousness with excitement. The main differential diagnoses considered were syncope, seizures, and narcolepsy-cataplexy. The results of the complete blood count, serum biochemistry panel, urinalysis, arterial blood pressure, echocardiography, abdominal ultrasound, Holter monitoring, and ECG were all within normal limits. Additional exams included thoracic radiographs, head and thorax CT, bronchoalveolar lavage (BAL), and CT-guided cytology. Thoracic radiographs revealed micronodular calcifications in the lungs, with sandstorm appearance. Computed tomography of the thorax showed the presence of numerous mineralized high-density agglomerates of multiple sizes throughout the pulmonary parenchyma, a reticular pattern with ground glass opacity and intense mineralized fibrosis of the pleural lining. Head CT was unremarkable. BAL and CT-guided cytology were inconclusive, but imaging features strongly suggest the diagnosis of PAM, which was histologically confirmed after necropsy. Conclusions This case report contributes to the clinicopathological and imaging characterization of pulmonary alveolar microlithiasis in dogs. In this species, the diagnosis of PAM should be considered when CT features evidence a reticular pattern with ground glass opacity and the presence of an elevated number and size of calcifications.

Angiotensin II (Ang II) regulates colon contraction, acting not only directly on smooth muscle but also indirectly, interfering with myenteric neuromodulation mediated by the activation of AT1 /AT2 receptors. In this article, we aimed to explore which mediators and cells were involved in Ang II-mediated colonic contraction in the TNBS-induced rat model of colitis. The contractile responses to Ang II were evaluated in distinct regions of the colon of control animals or animals with colitis in the absence and presence of different antagonists/inhibitors. Endogenous levels of Ang II in the colon were assessed by ELISA and the number of AT1/AT2 receptors by qPCR. Ang II caused AT1 receptor-mediated colonic contraction that was markedly decreased along the colons of TNBS-induced rats, consistent with reduced AT1 mRNA expression. However, the effect mediated by Ang II is much more intricate, involving (in addition to smooth muscle cells and nerve terminals) ICC and EGC, which communicate by releasing ACh and NO in a complex mechanism that changes colitis, unveiling new therapeutic targets.

Histopathology remains the cornerstone for diagnosing canine mammary tumors (CMTs). Recently, 2 classification systems (the World Health Organization [WHO] classification of 1999 and the proposal of 2011) and 2 grading methods based on the human Nottingham grade have been used by pathologists. Despite some evidence that the histological subtype and grade are prognostic factors, there is no comprehensive comparative study of these classification and grading systems in the same series of CMTs. In this study, the 2 classifications and the 2 grading methods were simultaneously applied to a cohort of 134 female dogs with CMTs. In 85 animals with malignant tumors, univariable and multivariable survival analyses were performed. Using the 2 systems, the proportion of benign (161/305, 53%) and malignant (144/305, 47%) tumors was similar and no significant differences existed in categorization of benign tumors. However, the 2011 classification subdivided malignant tumors in more categories—namely, those classified as complex, solid, and tubulopapillary carcinomas by the WHO system. Histological subtype according to both systems was significantly associated with survival. Carcinomas arising in benign tumors, complex carcinomas, and mixed carcinomas were associated with a better prognosis. In contrast, carcinosarcomas and comedocarcinomas had a high risk of tumor-related death. Slight differences existed between the 2 grading methods, and grade was related to survival only in univariable analysis. In this cohort, age, completeness of surgical margins, and 2 index formulas adapted from human breast cancer studies (including tumor size, grade, and vascular/lymph node invasion) were independent prognostic factors.

The enzyme catechol-o-methyltransferase (COMT) is responsible for inactivation of catechol estrogens, which are well-recognized carcinogenic metabolites. Two single-nucleotide polymorphisms (SNPs) in canine COMT gene were previously associated with the age of onset of mammary tumours and with the clinical progression of the disease. However, no information is available regarding the impact of other known SNPs in COMT gene in canine mammary tumours. The aim of the present study is to evaluate the influence of COMT SNP in clinicopathological features and outcome of canine mammary tumours. A case series study was conducted involving 155 non-neutered bitches with mammary tumours submitted to follow-up for 24 months after surgery. Three genotypes were considered: Genotype 1 (rs853046495); Genotype 2 (rs23350589, rs23322686, rs23336579, and rs852564758); Genotype 3 (rs851328636 and rs853133060). Genotype 1 was associated to low degree of tubular differentiation. Genotype 2 was related to the development of intermediate/high-histological-grade carcinomas and to vascular invasion. Genotype 3 was associated to reduced nuclear pleomorphism and well-differentiated carcinomas. Data from the present investigation allowed the identification of COMT genetic profiles associated with pathological features of mammary tumours that constitute relevant prognostic factors. The assessment of the COMT genotypes may represent a helpful tool in the clinical management of canine mammary tumours, assisting in the selection of individualized preventive and therapeutic strategies, according to the animals' genetic profile.

Grading of canine mammary carcinomas (CMC) is associated to subjective assessments made by the pathologists. Due to its unbiased nature, stereology can be used to objectively quantify morphological parameters associated with grading and malignancy. However, the use of stereology in CMC has not been fully disclosed. The nuclear numerical density [NV (nuclei, tumor)] is a cellularity-associated parameter that can be estimated by the optical disector. Herein, it was estimated in 44 CMC and its association with clinicopathologic factors - such as tumor size, histological subtype and grade, vascular/lymph node invasion, nuclear pleomorphism, and survival - was evaluated. Considering all the cases, the mean NV (nuclei, tumor) was 1.6 × 106 ± 0.5 × 106 nuclei/mm3 . Lower values were attained in complex carcinomas, comparing to simple carcinomas, in tumors smaller than 5 cm, with low mitotic activity and in those with high nuclear pleomorphism. No statistically significant association with grade or vascular/lymph node invasion was observed, but tumors with disease progression had lower nuclear densities. The NV (nuclei, tumor) and the correlated parameters mirror to some extension those in human breast cancer, suggesting an interesting interspecies agreement. This first estimation of the nuclear numerical density in CMC highlights the feasibility of the optical disector and their utility for objective morphological assessments in CMC. The association between nuclear numerical density and disease progression warrants future studies.

Background Estrogens are essential for the development and proper function of several hormone-dependent organs. There are, however, several lines of evidence associating estrogens with mammary carcinogenesis. A marked individual genetic variability concerning estrogens biosynthesis, metabolism and mechanism of action was recognized and associated with human breast cancer susceptibility, clinical features and progression. Although some genetic variations in canine ESR1 gene were reported, their influence in clinicopathological features and progression of canine mammary tumors has not been fully evaluated. This study aims to assess the influence of SNPs in ESR1 gene (rs397512133, rs397510462, rs851327560, rs397510612, rs852887655, rs852684753 and rs852398698) in canine mammary tumors characteristics and progression. A group of 155 non-neutered bitches with mammary tumors was included in the study. Follow-up information was assessed 24 months after surgery. Results Genetic profiles associated with a later onset of mammary tumors and less aggressive clinicopathological features, namely smaller tumor size (≤ 3 cm) with extensive tubular differentiation and low canine-adapted prognostic index (vet-NPI), were identified in this study. Conclusions Our data suggest that the ESR1 genetic profile may help on the decision regarding the selection of individual tailored preventive measures against canine mammary tumors development, such as early neutering.

Summary Histological examination of canine mammary tumours is mandatory for determining the histological type and grade of the lesions, features that provide relevant information regarding the biological behaviour of the disease. Different histological classification systems and grading methods have been used to characterize canine mammary tumours. In this study, the relationship between the genetic profile of 87 female dogs (i.e. single nucleotide polymorphisms [SNPs] in genes known to be involved in mammary carcinogenesis) and the histological type and grade of malignant mammary tumours was assessed. The results demonstrated a significant relationship between genetic variation in genes RAD51, BRCA2, CHEK2, HER2, CDH1, COMT and PGR and these morphological features of the mammary lesions. Specifically, SNPs in RAD51 (rs23623251 and rs23642734), CHEK2 (rs397511718), HER2 (rs24537329) and PGR (rs8875007) were related to aggressive histotypes, with moderate to high histological grade. In contrast, SNPs in BRCA2 (rs23255542), HER2 (rs24537331), CDH1 (rs852280880 and rs850805755) and COMT (rs851328636, rs853133060 and rs85346495) were associated with tumour histotypes of good prognosis and of low histological grade. These data provide preliminary evidence for a genotypic–phenotypic correlation in canine mammary tumours, highlighting the mechanisms of their genesis, development and progression.

E-cadherin is a cell adhesion molecule that participates in several cellular processes that guarantee the maintenance of structural and functional integrity of epithelial tissues. E-cadherin plays an important role in mammary carcinogenesis, and various studies have demonstrated the effect of CDH1 genetic variation in risk, progression and biological behaviour of human breast cancer. Although there are some recognized genetic variations in canine CDH1 gene, their influence in canine mammary tumour development and progression has not been previously evaluated. In this study, we aim to assess the influence of CDH1 SNPs rs850805755, rs852280880 and rs852639930 in the risk, clinicopathological features and clinical outcome of canine mammary tumours. A case-control study was conducted involving 206 bitches with mammary tumours and 161 bitches free of mammary neoplasia. CDH1 SNPs rs850805755 and rs852280880 were associated with a decreased risk and a later onset of mammary tumour development. Furthermore, these SNPs were related to the development of small size carcinomas, of low histological grade and low nuclear pleomorphism. SNP rs852639930 was associated with the development of small size tumours with a non-infiltrative, non-invasive growth pattern. Data from the present investigation demonstrate that these CDH1 genetic variants could have a protective role in canine mammary tumours, by being associated with low risk of tumour development, delayed onset of the disease and less aggressive clinicopathological features.

Cancer is a complex disease involving genetic and phenotypic changes. Several single nucleotide polymorphisms (SNPs) have been associated with the risk of breast cancer development in women; however, little is known regarding their influence on canine mammary tumor risk. We assessed the influence of SNPs in genes related to human breast cancer susceptibility, with respect to the risk of development of mammary tumors in dogs. Sixty-seven canine SNPs in proto-oncogenes, tumor suppressor genes, genes involved in DNA repair, and in hormonal metabolism were evaluated in 212 bitches with mammary tumors and in 161 bitches free of mammary neoplasia. A significant association with mammary neoplasia risk was identified for 2 SNPs in RAD51 ( rs23623251 and rs23642734) and one SNP in the STK11 gene ( rs22928814). None of the other SNPs were related to the risk of mammary tumor development. The identification of genetic profiles associated with risk of mammary neoplasia is of great importance, supporting the implementation of specific clinical management strategies in high-risk animals.

Neoplastic mammary disease in female dogs represents a major health concern for dog owners and veterinarians, but the genomic basis of the disease is poorly understood. In this study, we performed high resolution oligonucleotide array comparative genomic hybridisation (oaCGH) to assess genome wide DNA copy number changes in 10 malignant canine mammary tumours from seven female dogs, including multiple tumours collected at one time from each of three female dogs. In all but two tumours, genomic imbalances were detected, with losses being more common than gains. Canine chromosomes 9, 22, 26, 27, 34 and X were most frequently affected. Dissimilar oaCGH ratio profiles were observed in multiple tumours from the same dogs, providing preliminary evidence for probable independent pathogenesis. Analysis of adjacent samples of one tumour revealed regional differences in the number of genomic imbalances, suggesting heterogeneity within tumours.

Background Cadherins are calcium-dependent cell-to-cell adhesion glycoproteins playing a critical role in the formation and maintenance of normal tissue architecture. In normal mammary gland, E-cadherin is expressed by luminal epithelial cells, while P-cadherin is restricted to myoepithelial cells. Changes in the expression of classical E- and P-cadherins have been observed in mammary lesions and related to mammary carcinogenesis. P-cadherin and E-cadherin expressions were studied in a series of feline normal mammary glands, hyperplastic/dysplastic lesions, benign and malignant tumours by immunohistochemistry and double-label immunofluorescence. Results In normal tissue and in the majority of hyperplastic/dysplastic lesions and benign tumours, P-cadherin was restricted to myoepithelial cells, while 80% of the malignant tumours expressed P-cadherin in luminal epithelial cells. P-cadherin expression was significantly related to high histological grade of carcinomas (p