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Abstract Background Spontaneous tumors in dog have been demonstrated to share many features with their human counterparts, including relevant molecular targets, histological appearance, genetics, biological behavior and response to conventional treatments. Mammary tumors in dog therefore provide an attractive alternative to more classical mouse models, such as transgenics or xenografts, where the tumour is artificially induced. To assess the extent to which dog tumors represent clinically significant human phenotypes, we performed the first genome-wide comparative analysis of transcriptional changes occurring in mammary tumors of the two species, with particular focus on the molecular pathways involved. Results We analyzed human and dog gene expression data derived from both tumor and normal mammary samples. By analyzing the expression levels of about ten thousand dog/human orthologous genes we observed a significant overlap of genes deregulated in the mammary tumor samples, as compared to their normal counterparts. Pathway analysis of gene expression data revealed a great degree of similarity in the perturbation of many cancer-related pathways, including the 'PI3K/AKT', 'KRAS', 'PTEN', 'WNT-beta catenin' and 'MAPK cascade'. Moreover, we show that the transcriptional relationships between different gene signatures observed in human breast cancer are largely maintained in the canine model, suggesting a close interspecies similarity in the network of cancer signalling circuitries. Conclusion Our data confirm and further strengthen the value of the canine mammary cancer model and open up new perspectives for the evaluation of novel cancer therapeutics and the development of prognostic and diagnostic biomarkers to be used in clinical studies.

Abstract Background - Rabbits provide an excellent model for many animal and human diseases, such as cardiovascular diseases, for the development of new vaccines in wound healing management and in the field of tissue engineering of tendon, cartilage, bone and skin. The study presented herein aims to investigate the biological properties of bone marrow rabbit MSCs cultured in different conditions, in order to provide a basis for their clinical applications in veterinary medicine. Findings - MSCs were isolated from 5 New Zealand rabbits. Fold increase, CFU number, doubling time, differentiation ability and immunophenotype were analyzed. With the plating density of 10 cells/cm2 the fold increase was significantly lower with DMEM-20%FCS and MSCs growth was significantly higher with αMEM-hEGF. The highest clonogenic ability was found at 100 cell/cm2 with MSCBM and at 10 cell/cm2 with M199. Both at 10 and 100 cells/cm2, in αMEM medium, the highest CFU increase was obtained by adding bFGF. Supplementing culture media with 10%FCS-10%HS determined a significant increase of CFU. Conclusion - Our data suggest that different progenitor cells with differential sensitivity to media, sera and growth factors exist and the choice of culture conditions has to be carefully considered for MSC management.

A captive-kept adult male tiger presented with a large cutaneous and subcutaneous mass on the thigh with a fistula. During sedation, multiple nodules were detected and samples for a histopathological exam were collected. Histologically, granulomatous panniculitis and dermatitis were seen around dense aggregates of pigmented fungal hyphae, and a diagnosis of phaeohyphomycosis was made; considering the clinical features, it was classified as a eumycotic mycetoma. This is a rarely reported subcutaneous fungal infection in humans and animals, caused by dematiaceous fungi. Clinically, it is characterized by tumefaction, fistulous sinus tracts, and the formation of macroscopically visible grains. In the literature, only a few infections in wild felids have been reported. In this case, Fontana-Masson staining better showed pigmentation and panfungal PCR and sequencing identified Madurella pseudomyectomatis (OP623507) as the causative agent. Systemic therapy with oral administration of itraconazole was planned, but the patient died during the first period of treatment. The animal was not submitted for post-mortem examination. Visceral dissemination of the agent cannot be excluded. To the authors' knowledge, this is the first report of eumycotic mycetoma by Madurella pseudomycetomatis in a captive tiger.

In humans, chronic liver disease may cause alterations in amino acids (AAs) metabolism, with serum branched-chain AAs (BCAAs) decreasing and aromatic AAs (AAAs) increasing. A reduced Fischer ratio (BCAAs/AAAs) has been found to be associated with hepatic fibrosis and is useful for assessing prognosis in human patients. In veterinary medicine, few studies have been performed, and in contrast to human patients, dogs with different kinds of hepatopathy tend to show both increased AAAs and BCAAs. In dogs, the association between histological scores and serum AAs has not been previously investigated. The aim of this study was to evaluate serum AAs in dogs with chronic hepatitis (CH) compared with a healthy control group (C) and, among CH dogs, in relation to their histological fibrosis and necroinflammatory activity scores. Leftover serum samples of 16 dogs with histological CH and 25 healthy dogs were employed. Serum AAs were measured by high performance liquid chromatography. Proline and the AAAs phenylalaine and tyrosine progressively increased with the histological severity. In contrast, cysteine, tryptophan and BCAA isoleucine progressively reduced. Lysine and the BCAAs leucine and valine showed a non-linear trend with the histological findings. The BCAAs/AAAs ratio was significatively reduced if higher grades of liver fibrosis were present.

The term angiomatosis is used to denote a group of well-known to poorly characterized proliferative vascular entities. In animals, cutaneous progressive angiomatosis (CPA) is a disorder with variable prognosis related to the extension and depth of infiltration of the surrounding tissues by vessels. CPA may share some microscopical features with other vascular proliferations such as low-grade well-differentiated capillaritic hemangiosarcoma (HS), making the diagnosis not always straightforward, especially in small biopsies. The aim of this study is to retrospectively assess the most common diagnostic microscopical features of CPA in dogs. In this work, 11 histopathological criteria were analyzed on 31 CPA and 11 primary cutaneous HS in dogs. Features significantly associated with CPA included: lobular growth, interposition of connective tissue and adnexa between the vascular proliferation, presence of nerve fibers, and a mixed vascular proliferative component. Absence of plump/prominent endothelial cells, lack of atypia, and lack of mitoses were also significant factors differentiating CPA from HS. Additional distinctive findings in CPA, although with no statistical association to CPA diagnosis, were vascular shunting, absence of necrosis, and endothelial cell piling up. In conclusion, the combined use of different microscopical clues allowed for the distinction of CPA from HS and was considered useful for the diagnosis of CPA.

Serum protein electrophoresis (SPE) shows the distribution of protein fractions, helping clinicians to characterize some pathologic processes. Information is lacking in the literature about SPE alterations in dogs with chronic hepatitis (CH). Our aim was to describe SPE alterations in canine CH, to compare SPE results to histologic scores, and to study SPE trends during follow-up. We reviewed retrospectively case data from dogs with a histologic diagnosis of CH. Only cases with SPE, CBC, and serum chemistry results available were included. Dogs were divided into subgroups based on histologic necroinflammatory activity (A) and fibrosis (F) scores (groups A0-1 and A>1; groups F<2 and F≥2). We included 26 dogs; 15 had follow-up SPE. The most common SPE alterations at admission were hypoalbuminemia ( n  = 16), increases in α1-globulins ( n  = 11), γ-globulins ( n  = 11), α2-globulins ( n  = 8), β2-globulins ( n  = 7), and β1-globulins ( n  = 6), and decreased albumin:globulin (A:G) ratios ( n  = 20). Four of 11 dogs had β-γ bridging. Groups with higher A and F scores had higher β2-globulins. Eleven of 15 dogs with a post-treatment SPE had a decrease in γ-globulins and increase in A:G ratio compared to their T0, although there was no statistically significant difference. Although further studies are warranted, SPE may be useful for monitoring canine CH.

Mutations in the EPM2A gene encoding laforin cause Lafora disease (LD), a progressive myoclonic epilepsy characterized by drug-resistant seizures and progressive neurological impairment. To date, rodents are the only available models for studying LD; however, their use for drug screening is limited by regulatory restrictions and high breeding costs. To investigate the role of laforin loss of function in early neurodevelopment, and to screen for possible new compounds for treating the disorder, we developed a zebrafish model of LD. Our results showed the epm2a -/- zebrafish to be a faithful model of LD, exhibiting the main disease features, namely motor impairment and neuronal hyperexcitability with spontaneous seizures. The model also showed increased inflammatory response and apoptotic death, as well as an altered autophagy pathway that occurs early in development and likely contributes to the disease progression. Early administration of trehalose was found to be effective for rescuing motor impairment and neuronal hyperexcitability associated with seizures. Our study adds a new tool for investigating LD and might help to identify new treatment opportunities.

What happens to patients with cancer engaged in biomedical research when intellectual property regimes and ethical regimes intersect? This qualitative historical study addresses this question by situating the experiences, hopes, and reasons of patients to enter clinical trials within the historical trajectory of informed consent and monoclonal antibodies, the biotechnology underpinning many targeted drugs used in oncological clinical trials and biobank research. Based on fieldwork we undertook in a German university hospital where we interviewed patients and the medical personnel, a historical review, and an ethical analysis we inquire into the effects that financial, legal, and technological changes connected to the relevant pharmaceutical research and commerce have on cancer patients engaged in clinical trials and biobank research. We find that the controversial aspects of monoclonal antibodies, especially those related to the commercial interests at stake, enter the informed consent process mainly in the form of informative gaps. We highlight how a qualitative analysis of the clinic, especially when it is situated against the backdrop of the history of related technological advancements and patent regime, it can serve the purpose of giving voice to subjects who are silenced by regimes of an ethical, epistemic, and commercial kind while pointing to informed consent as an unhelpful device for addressing risks arising from the commercial purposes of biomedical products and infrastructure., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 D’Abramo, Bont and Nüßlein.)

The photoinduced etiopathology of actinic keratosis and squamous cell carcinoma in feline species is well known. This etiology has also been reported for non-epithelial cutaneous tumors in other species. To date, no cases of auricular non-epithelial cutaneous neoplasms erased in a contest of actinic keratosis in cats have been reported. The aim of this study was to describe feline auricular non-epithelial cutaneous neoplasms associated with typical UV-induced cutaneous lesions and solar elastosis. The study was conducted on five feline cases diagnosed with auricular non-epithelial cutaneous tumors (two fibrosarcomas, one mixosarcoma, one epithelioid melanoma and one hemangiosarcoma), selected from the Tumor Registry of the Department of Veterinary Sciences of the University of Pisa (1998-2018). Ten and six feline auricular biopsies of normal skin and skin with actinic keratosis, respectively, were used as controls. Orcein stain was used to investigate solar elastosis. Histological changes related to chronic solar irradiation were documented in the skin adjacent to the neoplastic lesions in the five cats. Considering the anatomical localization and the results of histopathology, this study suggests that non-epithelial cutaneous neoplasms may have a UV-induced etiopathogenesis in the feline species.

Cutaneous lymphocytosis (CL) is an uncommon and controversial lymphoproliferative disorder described in dogs and cats. CL is generally characterized by a heterogeneous clinical presentation and histological features that may overlap with epitheliotropic lymphoma. Therefore, its neoplastic or reactive nature is still debated. Here, we describe clinicopathological, immunohistochemical, and clonality features of a retrospective case series of 19 cats and 10 dogs with lesions histologically compatible with CL. In both species, alopecia, erythema, and scales were the most frequent clinical signs. Histologically, a dermal infiltrate of small to medium-sized lymphocytes, occasionally extending to the subcutis, was always identified. Conversely, when present, epitheliotropism was generally mild. In cats, the infiltrate was consistently CD3+; in dogs, a mixture of CD3+ and CD20+ lymphocytes was observed only in 4 cases. The infiltrate was polyclonal in all cats, while BCR and TCR clonal rearrangements were identified in dogs. Overall, cats had a long-term survival (median overall survival = 1080 days) regardless of the treatment received, while dogs showed a shorter and variable clinical course, with no evident associations with clinicopathological features. In conclusion, our results support a reactive nature of the disease in cats, associated with prolonged survival; despite a similar histological picture, canine CL is associated with a more heterogeneous lymphocytic infiltrate, clonality results, and response to treatment, implying a more challenging discrimination between CL and CEL in this species. A complete diagnostic workup and detailed follow-up information on a higher number of cases is warrant for dogs.

Numerous canine papillomaviruses (CPVs) have been identified (CPV1-23). CPV1, 2, and 6 have been associated with inverted papillomas (IPs). We retrieved 19 IPs from 3 histopathology archives, and evaluated and scored koilocytes, inclusion bodies, giant keratohyalin granules, cytoplasmic pallor, ballooning degeneration, and parakeratosis. IHC targeting major capsid proteins of PV was performed, and CPV genotyping was achieved by PCR testing. Tissue localization of CPV DNA and RNA was studied by chromogenic and RNAscope in situ hybridization (DNA-CISH, RNA-ISH, respectively). IPs were localized to the limbs (50%), trunk (30%), and head (20%), mainly as single nodules (16 of 19). In 15 of 19 cases, immunopositivity was detected within the nuclei in corneal and subcorneal epidermal layers. PCR revealed CPV1 in 11 IPs and CPV2 DNA in 3 IPs. Overall, 14 of 17 cases were positive by both DNA-CISH and RNA-ISH, in accord with PCR results. A histologic score >5 was always obtained in cases in which the viral etiology was demonstrated by IHC, DNA-CISH, and RNA-ISH. IHC and molecular approaches were useful to ascertain the viral etiology of IPs. Although IHC is the first choice for diagnostic purposes, ISH testing allows identification of PV type and the infection phase. RNA-ISH seems a promising tool to deepen our understanding of the pathogenesis of different PV types in animal species.

Background: Although the influence of copper ([Cu]) on chronic hepatitis (CH) has been widely studied in dogs, little information is available about the accumulation of other metals., Hypothesis/objectives: We assessed the concentration of lead ([Pb]) in the livers of dogs with CH with or without abnormal hepatic [Cu] to establish if any association existed between [Pb] and either hematologic or biochemical variables, fibrosis, necrosis and inflammation of the liver on histology., Animals: Thirty-four dogs with CH that had hepatic [Cu] and [Pb] determined., Methods: Retrospective review of medical records of dogs with CH and hepatic [Cu] and [Pb]. Chronic hepatitis was defined using current American College of Veterinary Internal Medicine consensus statement guidelines. Hepatic [Cu] and [Pb] were determined using square wave anodic stripping voltammetry. Dogs were divided into 2 groups based on [Cu]: <400 ppm (LoCu) and ≥400 ppm (HiCu)., Results: The median [Cu] and [Pb] were 357 ppm (range, 100-7743 ppm) and 58.7 (range, 6.89-224.4 ppm), respectively. Nineteen dogs had LoCu and 15 dogs had HiCu. Median [Pb] was significantly higher in HiCu compared to LoCu dogs (P < .001). Hepatic [Pb] and [Cu] were significantly correlated (rho = 0.7; P < .001). Dogs with microcytosis had higher [Pb] than did dogs with normal red cell volume (P = .02). Hepatic [Pb] was not correlated with either necroinflammatory or fibrosis scores., Conclusions and Clinical Importance: Although additional studies are needed to better understand the clinical role of hepatic [Pb], dogs with abnormal hepatic [Cu] may also have higher hepatic [Pb]. In addition, in dogs with high hepatic [Pb], microcytosis may be present., (© 2021 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.)

Feline leishmaniosis (FeL) is increasingly reported throughout the world and skin lesions predominate in the clinical picture. There are, however, few evidence-based data on cutaneous feline leishmaniosis and directions are strongly needed for a better management of the disease. In this study, we systematically reviewed what is currently known about the clinical dermatological presentation of FeL through analysis of the literature and, further, by adding unpublished cases managed by Italian veterinary dermatologists. Sixty-six feline cases of cutaneous leishmaniosis published in 33 articles between 1990 and 2020 met the inclusion criteria and were analyzed. Six unpublished cases of cutaneous FeL managed by Italian dermatologists were also reviewed. The majority of cases were reported from South America, followed by Europe and North America. Nodules were the most frequently reported clinical signs and the presence of Leishmania in lesioned skin was assessed mainly by cytology. A total of six Leishmania species have been identified as being responsible for skin lesions. Coinfections by FIV or FeLV were reported in 12.1% and 9.1% of the cases, respectively. Clinical data including treatment have been analyzed and discussed to provide directives for proper management of the disease for which cats may also serve as domestic reservoirs for human infections.

Objectives: The objective of this study was to assess the efficacy of a single intramuscular administration of gonadorelin to induce ovulation in queens in oestrus., Methods: Twenty-seven queens presented in oestrus for elective ovariectomy were divided into a treatment (n = 19) and a placebo (n = 8) group. Treated queens received a 50 µg dose of gonadorelin, while placebo-treated queens were injected intramuscularly (IM) with an equal amount of saline solution. All treatments were performed between the second and fourth days of heat., Results: Two days later, signs of behavioural heat had disappeared in all gonadorelin-treated queens, while 5/8 placebo-treated queens were still in heat. Following ovariectomy, performed 4 days after drug administration, the ovaries of each queen were evaluated histologically and the number of corpora lutea were counted. Sixteen of 19 (84%) gonadorelin-treated queens had ovulated and developed five (range 2-9) corpora lutea, while 3/8 (37%) placebo-treated queens had ovulated and developed five (range 3-6) corpora lutea., Conclusions and Relevance: This is the first study to document the efficacy of a 50 µg/cat gonadorelin dose to induce ovulation in oestrous queens when administered IM on days 2-4 following the onset of oestrus.

Canine cutaneous round cell tumors (RCT) represent one of the routine diagnostic challenges for veterinary pathologists. Computer-aided approaches are developed to overcome these restrictions and to increase accuracy and consistency of diagnosis. These systems are also of high benefit reducing errors when a large number of cases are screened daily. In this study we describe ARCTA (Automated Round Cell Tumors Assessment), a fully automated algorithm for cutaneous RCT classification and mast cell tumors grading in canine histopathological images. ARCTA employs a deep learning strategy and was developed on 416 RCT images and 213 mast cell tumors images. In the test set, our algorithm exhibited an excellent classification performance in both RCT classification (accuracy: 91.66%) and mast cell tumors grading (accuracy: 100%). Misdiagnoses were encountered for histiocytomas in the train set and for melanomas in the test set. For mast cell tumors the reduction of a grade was observed in the train set, but not in the test set. To the best of our knowledge, the proposed model is the first fully automated algorithm in histological images specifically developed for veterinary medicine. Being very fast (average computational time 2.63 s), this algorithm paves the way for an automated and effective evaluation of canine tumors., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Salvi, Molinari, Iussich, Muscatello, Pazzini, Benali, Banco, Abramo, De Maria and Aresu.)