Murine cancer models have been extremely useful for analyzing the biology of pathways involved in cancer initiation, promotion, and progression. Interestingly, several murine cancer models also exhibit heterogeneity, genomic instability and an intact immune system. However, they do not adequately represent several features that define cancer in humans, including long periods of latency, the complex biology of cancer recurrence and metastasis and outcomes to novel therapies. Therefore, additional models that better investigate the human disease are needed. In the pet population, with special references to the dog, cancer is a spontaneous disease and dogs naturally develop cancers that share many characteristics with human malignancies More than 40 years ago, optimization of bone marrow transplantation protocols was undertaken in dogs and recently novel targeted therapies such as liposomal muramyl tripeptide phosphatidylethanolamine and several tyrosine kinase inhibitors, namely masitinib (AB1010) and toceranib phosphate (SU11654), have been developed to treat dog tumors which have then been translated to human clinical trials. In this review article, we will analyze biological data from dog tumors and comparative features with human tumors, and new therapeutic approaches translated from dog to human cancer.

Cardiopulmonary infections by Angiostrongylus chabaudi affect domestic and wild felids but, due to limited information on the biology of this nematode, its pathogenicity remains unclear. This article describes the histopathological alterations associated with Angiostrongylus infection in a wildcat from Bulgaria, and reviews current literature on this feline angiostrongylid. Nematodes were isolated from lung lavage and faecal samples of a road killed wildcat in Southern Bulgaria. The morphological identification of parasite larvae as A. chabaudi was confirmed by molecular analysis of part of the 18S ribosomal RNA gene. Upon histopathological examination, severe granulomatous pneumonia, ranging from multifocal to coalescing, and pulmonary vascular lesions were observed. Extensive alveolar collapse, alveolar emphysematous changes, parenchymal haemorrhages and small artery wall hyperplasia were observed in the parenchyma adjacent to the granulomas. Histopathological examination revealed the presence of cross-sections of adult female parasites within the lumen of the pulmonary artery branches, the intima altered markedly by subendothelial proliferation and oedematous changes. This study compliments current knowledge of the pathogenesis of feline angiostrongylosis by A. chabaudi in wildcats, as well as of the distribution of this little-known parasite.

Comparative oncology has recently developed, in according to the quality of scientific research, as the result of reasonable opportunity to study neoplastic diseases in the pets "dogs and cats" that may provide new biological information and knowledge for the understanding and treatment of human cancers.Some spontaneous tumors of animals, such as mammary (breast),lymphohematopoietic, cutaneous (mastocytoma) and vescical, are considered models that share, with human cancers, biological aspects in terms of carcinogenesis and tumor progression and clinical aspects; thus, comes the need to preserve biological material in optimal condition and their associated data, in order to have a tissue heritage to be exploited over time to new insights and innovative laboratory techniques. The Faculty of Veterinary Medicine, University of Bari has signed an agreement with I.R.C.C.S Istituto Tumori "Giovanni Paolo II" di Bari to assist in the creation of an animal tissue-bank to collect samples of neoplastic organs. The collection, preservation and recording of biological sample are made according to a system of operating procedures (SOPs) and addressed to ensure common quality standards. The specimen is initially stored at the Faculty of Veterinary Medicine, then moved in accordance with procedures involving biological material transfer mode to I.R.C.C.S where a biobank institutional functioning. Is designing a computerized system for data management that meets the needs of the two structures. The samples data are currently recorded in the register "Comparative Biobank" and inserted into a database. For appropriate management the staff of both facilities has been instructed in order to have a unique mode of approach to research. The collaboration has developed national and international projects aimed at theme of the VEGF, Thymidine Phosphorylase, Ki-67 on different animal species tumors.

Canine cutaneous mast cell tumour (CMCT) is a c-Kit driven tumour sharing similar c-Kit aberrations found in human gastrointestinal stromal tumour. CMCT is classified into three forms: well-(G1), intermediately (G2) (more benign diseases), and poorly (G3) differentiated (malignant) forms. We assess a correlation between c-Kit status, grading, and angiogenesis in CMCTs to explore their potential significance in humans. C-Kit receptor (c-KitR) expression, microvascular density (MVD), and mast cell granulated and degranulated status density (MCGD and MCDD, resp.) were analyzed in 97 CMCTs, by means of histochemistry, immunohistochemistry double staining, and image analysis system. Data showed that predominantly diffuse cytoplasmic-and predominantly focal paranuclear-(Golgi-like) c-Kit protein (PDC-c-Kit and PFP-c-Kit, resp.) expression correlate with high MVD, G3 histopathological grade, and MCDD. Moreover, predominant cellmembrane-c-KitR (PCM-c-KitR) expression status correlates with low MVD, G1-G2 histopathological grade, and MCGD. These findings underline the key role of c-Kit in the biopathology of canine MCTs, indicating a link between aberrant c-Kit expression, increased angiogenesis, and higher histopathological grade. CMCT seems to be a model to study contributions of c-Kit activated MCs in tumour angiogenesis and to evaluate the inhibition of MCs activation by means of c-Kit tyrosine kinase inhibitors, currently translated in humans.

Canine cutaneous mast cell tumour (CMCT) seems to be a unique spontaneous model to study the role of mast cells in angiogenesis. Here we aim to evaluate the role of mast cell density (MCD), microvascular density (MVD), and endothelial area (EA) in CMCTs progression and to correlate they each othe

Embryonic stem cell-expressed Ras (ERas) encodes a constitutively active form of guanosine triphosphatase (GTPase) that binds to and activates phosphatidylinositol 3 kinase (PI3K), which in turn phosphorylates and activates downstream targets such as Akt. The current study evaluated ERas regulation and expression in papillomavirus-associated urothelial tumours in cattle grazing on lands rich in bracken fern. ERas was found upregulated and overexpressed by PCR, real time PCR and Western blot. Furthermore, protein overexpression was also confirmed by immunohistochemistry. ERas was found to interact physically and colocalise with the activated platelet derived growth factor β receptor (PDGFβR) by coimmunoprecipitation and laser scanning confocal investigations. Phosphorylation of Akt, a downstream effector both of ERas and PDGFβR, appeared to be increased in urothelial tumour cells. Altogether, these data indicate that ERas/PDGFβR complex could play a role in the pathogenesis of bovine papillomavirus-associated bladder neoplasia.

T cell receptors are heterodimers comprising alpha (TRA) and bet (TRB) or gamma (TRG) and delta (TRD) subunits, two combinations defining the two major lineages of T cells. alpha/beta T cells typically recognize peptide antigens presented on major histocompatibility complex (MHC) encoded molecules, while gamma/delta cells are either MHC restricted or resemble Ig in being able to bind free antigens. The bottlenosed dolphin is being sequenced by the Human Genome Sequencing Center (BCMHGSC) at the Baylor College of Medicine and the Broad Institute using a whole genome shotgun sequencing strategy (BioProject ID: 20367). We employed the NCBI draft genome assembly to identify the TRG and TRB loci of Tursiops truncatus. The dolphin gamma locus is the smallest and simplest of all the mammalian TRG loci as yet studied. It shows a gene cassette organization comprising two variable (V) genes, three joining (J) genes, and a single constant (C) gene. Expression analysis identified all the possible VJ rearrangements of the locus, although some transcripts are preferentially expressed. About half of the TRGV2 rearrangements originate transcripts unlikely to be functional due to stop codons in CDR3. Although a complete characterization was impossible because of gaps in the available assemblies, the dolphin beta locus is also very simple in comparison with human and ovine. We found that only four of the seven identified in the genome are TRBV expressed genes, with a significant bias toward expression of TRBV30, located immediately after the C gene in an inverted transcriptional orientation. However, there was no evidence of preferential rearrangement with regard to TRBD e TRBJ. Finally, multialignment analysis of TRGV and TRBV sequences confirmed, as expected, a close phylogenetic relationship between Tursiops truncatus and the Bovidae family of the Artiodactyla.

Masitinib mesylate (AB1010) is a novel potent and selective tyrosine kinase inhibitor, targeting mainly wild-type and mutated c-Kit receptor (c-KitR), Platelet Derived Growth Factor Receptor-alfa/beta (PDGFR alpha/beta), Lymphocyte-specific kinase (Lck), Lck/Yes-related protein (LYn), Fibroblast Growth Factor Receptor 3 (FGFR3) and Focal Adhesion Kinase (FAK). It is the first anticancer therapy approved in veterinary medicine for the treatment of unresectable canine mast cell tumors (CMCTs), harboring activating c-KitR mutations, at dose of 12.5 mg/kg once daily. Considering its anti-proliferative action, principally given by inhibiting the MCs c-KitR anti-angiogenic pathway that leads cancer progression, and its role as chemosensitizer, masitinib is under clinical investigation in several human malignancies (Gastro-Intestinal Stromal Tumors, acute myeloid leukemia, systemic mastocytosis, pancreatic cancer, multiple myeloma, non-small cell lung cancer, melanoma, ovarian and prostate cancer), which are characterized by similar canine c-JUT proto-oncogene mutations. Here, we analyze masitinib structure activity, its pharmacokinetics compared to imatinib, the c-KitR pathway referring to the most frequent c-KIT mutations sensitive or resistant to this novel drug compared to imatinib, and masitinib safety profile. We, also, explore preclinical and clinical (completed and ongoing) trials with the aim to emphasize as this recent anti-angiogenic therapy, at first approved in CMCTs and, currently in development for the treatment of several human neoplasms, could be represent a milestone in translational oncology, in which the murine experimental model of cancer research could be integrated by canine spontaneous tumor model.

Angiogenesis is an important pathway of neoplastic growth and progression. Our several published studies suggest that angiogenesis represents an interspecies pathway of tumour growth due to its roles in several spontaneous canine tumour model. Stromal microenvironment, macrophages and mast cells play a main roles in tumour angiogenesis. Furthermore several recent studies strongly suggest that mast cells density and mast cell activation are correlated with microvascular density. In this context mast cells may stimulates angiogenesis by secretion of their angiogenetic factors such as Vascular Endothelial Growth Factor (VEGF), Tryptase and Chynase. VEGF represents the classical pro-angiogenic factor while Tryptase and Chynase are proteases identified as new pro-angiogenic factor.. Interstingly canine mast cell tumour model (CMCTM) represents a unique model to study the role of mast cells in angiogenetic pathway. CMCTM are classified in well, intermediate and poorly differenziated tumours with and different angiogenetic activity and metastatic capacity. We aim to study by mean of immunohistochemistry and ELISA methods primary mast cell tumour and mast cell tumour lines for the expression of angiogenic factors and mast cell activation. In this context will be possible to evaluate the inhibition of pro-angiogenic factors and mast cell degranulation as a new anti-angiogentic and anti tumour therapy.

Angiogenesis is an important pathway of neoplastic growth and progression. Our several published studies suggest that angiogenesis represents an interspecies pathway of tumour growth due to its roles in several spontaneous canine tumour model. Stromal microenvironment, macrophages and mast cells play a main roles in tumour angiogenesis. Furthermore several recent studies strongly suggest that mast cells density and mast cell activation are correlated with microvascular density. In this context mast cells may stimulates angiogenesis by secretion of their angiogenetic factors such as Vascular Endothelial Growth Factor (VEGF), Tryptase and Chynase. VEGF represents the classical pro-angiogenic factor while Tryptase and Chynase are proteases that presents new pro-angiogenic factor. We aim to study the role of mast cells in neoplastic growth and progression in canine mast cell tumour model. Canine mast cell tumour model represents a unique model with well, intermediate and poorly differenziated tumour and differently angiogenetic activity. We aim to study with immunohistochemistry and ELISA methods primary mast cell tumour and mast cell tumour lines for the expression of angiogenic factors and mast cell activation. In this context will be possible to hypothesize the inhibition of pro-angiogenic factors and mast cell degranulation as a new anti-angiogentic and anti tumour therapy.

Mast Cells (MCs) play a role in immune responses and more recently MCs have been involved in tumoral angiogenesis. In particular MCs can release tryptase, a potent in vivo and in vitro pro-angiogenic factor via proteinase-activated receptor-2 (PAR-2) activation and mitogen-activated protein kinase (MAPK) phosphorylation. MCs can release tryptase following c-Kit receptor activation. Nevertheless, no data are available concerning the relationship among MCs Density Positive to Tryptase (MCDPT) and Microvascular Density (MVD) in both primary gastric cancer tissue and loco-regional lymph node metastases. A series of 75 GC patients with stage T2-3N2-3M₀ (by AJCC for Gastric Cancer Seventh Edition) undergone to radical surgery were selected for the study. MCDPT and MVD were evaluated by immunohistochemistry and by image analysis system and results were correlated each to other in primary tumor tissue and in metastatic lymph nodes harvested. Furthermore, tissue parameters were correlated with important clinico-pathological features. A significant correlation between MCDPT and MVD was found in primary gastric cancer tissue and lymph node metastases. Pearson t-test analysis (r ranged from 0.74 to 0.79; p-value ranged from 0.001 to 0.003). These preliminary data suggest that MCDPT play a role in angiogenesis in both primary tumor and in lymph node metastases from GC. We suggest that MCs and tryptase could be further evaluated as novel targets for anti-angiogenic therapies.

Literature data suggest that cells such asmast cells (MCs), are involved in angiogenesis.MCs can stimulate angiogenesis by releasing of several proangiogenic cytokines stored in their cytoplasm. In particular MCs can release tryptase, a potent in vivo and in vitro proangiogenic factor. Nevertheless few data are available concerning the role of MCs positive to tryptase in primary pancreatic cancer angiogenesis. This study analyzed MCs and angiogenesis in primary tumour tissue from patients affected by pancreatic ductal adenocarcinoma (PDAC). Method. A series of 31 PDAC patients with stage T2-3N0-1M0 (by AJCC for Pancreas Cancer Staging 7th Edition) was selected and then underwent surgery. Tumour tissue samples were evaluated bymeans of immunohistochemistry and image analysis methods in terms of number of MCs positive to tryptase (MCDPT), area occupied by MCs positive to tryptase (MCAPT), microvascular density (MVD), and endothelial area (EA). The above parameters were related to each other and to the main clinicopathological features. Results. A significant correlation betweenMCDPT,MCAPT,MVD, and EAgroupwas foundby Pearson’s -test analysis ( ranged from0.69 to 0.81; value ranged from0.001 to 0.003).No other significant correlation was found. Conclusion. Our pilot data suggest that MCs positive to tryptase may play a role in PDAC angiogenesis and they could be further evaluated as a novel tumour biomarker and as a target of antiangiogenic therapy.

Livers of 12 loggerhead sea turtles, Caretta caretta from the Eastern Mediterranean Sea (Adriatic Sea) were analyzed for the presence of polychlorinated biphenyls (PCBs), polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs). Pathological and microbiological studies were also carried out in order to provide a contribution to the knowledge of causes of Mediterranean turtle death. Boat-strike injuries, entanglement in derelict fishing nets and ingestion of hooks and monofilament lines are the causes of death most frequently observed. PCBs (average: 1399ngg-1 fat basis) were the dominant chemicals, followed by PCDFs (average: 61pgg-1 fat basic) and PCDDs (average: 16pgg-1 fat basis). Hexachlorobiphenyl 153 accounted for the greatest proportion of the total PCBs, followed in order by PCB 138 and PCB 180 (14.1%). Mid-chlorinated, penta-through hepta-PCBs were among the top contributors to the sum of total PCBs, while the homolog pattern of PCCD/Fs was dominated by the tetra- to hexa-substituted congeners. In general the contamination level observed here was comparable with that reported in literature for specimens from different marine areas. Average TEQPCDD/Fs+Dl-PCBs concentration was 27.02pgg-1 wet weight (305.1pgg-1 lipid weight), with dioxin like-PCBs (93.4%) contributing much more to the total than PCDFs (3.9%) and PCDDs (2.7%). The appreciable concentration of TEQ would at first suggest that there are signs of potential threats to the health of these marine reptiles. Apart from PCBs, this is the first study documenting concentrations of PCDD/Fs in marine turtles from the Mediterranean Sea. Further investigations are urgently needed to characterize their contamination level for a better future protection and conservation of this endangered animal.

Mast cells (MCs), located ubiquitously near blood vessels, are descended from CD34(+) hematopoietic stem cells. Initially, although their role has been well defined in hypersensitivity reactions, the discovery of their sharing in both innate and adaptive immunity has allowed to redefine their crucial interplay on the regulatory function between inflammatory and tumor cells through the release of mediators granule-associated (mainly tryptase and vascular endothelial growth factor). In particular, in several animal and human malignancies it has been well demonstrated that activated c-Kit receptor (c-KitR) and tryptase (an agonist of the proteinase-activated receptor-2) take pivotal part in tumor angiogenesis after the MCs activation, contributing to tumor cells invasion and metastasis. In this review, we focused on crucial MCs density (MCD) role in colorectal cancer (CRC) development and progression angiogenesis-mediated; then, we will analyze the principal studies that have focused on MCD as possible prognostic factor. Finally, we will consider a possible role of MCD as novel therapeutic target mainly by c-KitR tyrosine kinase inhibitors (imatinib, masitinib) and tryptase inhibitors (gabexate and nafamostat mesylate) with the aim to prevent CRC progression.

The expression of sigma-2 receptor (S2R) was assayed in blood and bladder samples from healthy cattle and in blood and bladder of cattle with deltapapillomavirus-associated urothelial tumors. Samples of bladder from cattle with neoplasia had significantly higher S2R than samples of bladder from healthy cattle (95% CI 0.31-0.82, P < 0.05). In addition, significantly higher S2R was detected in the blood of cattle with bladder cancer than blood from healthy cattle (95% CI 0.22-0.41, P < 0.05). The results provide evidence that increased expression of SR2 in blood could be useful as circulating biomarker for bladder cancer in cattle. PGRMC1 protein levels were also found to be increased in blood and bladder from cattle with cancer and increased expression of PGRMC1 transcripts was detected by quantitative real time PCR in samples from cattle neoplasia. Furthermore, electron microscopy revealed phagophores and numerous autophagosomes, ultrastructural hallmark of autophagy.

Background: Mass strandings of sperm whales (Physeter macrocephalus) remain peculiar and rather unexplained events, which rarely occur in the Mediterranean Sea. Solar cycles and related changes in the geomagnetic field, variations in water temperature and weather conditions, coast geographical features and human activities have been proposed as possible causes. In December 2009, a pod of seven male sperm whales stranded along the Adriatic coast of Southern Italy. This is the sixth instance from 1555 in this basin. Methodology/Principal Findings: Complete necropsies were performed on three whales whose bodies were in good condition, carrying out on sampled tissues histopathology, virology, bacteriology, parasitology, and screening of veins looking for gas emboli. Furthermore, samples for age determination, genetic studies, gastric content evaluation, stable isotopes and toxicology were taken from all the seven specimens. The animals were part of the same group and determined by genetic and photo-identification to be part of the Mediterranean population. Causes of death did not include biological agents, or the "gas and fat embolic syndrome", associated with direct sonar exposure. Environmental pollutant tissue concentrations were relatively high, in particular organochlorinated xenobiotics. Gastric content and morphologic tissue examinations showed a prolonged starvation, which likely caused, at its turn, the mobilization of lipophilic contaminants from the adipose tissue. Chemical compounds subsequently entered the blood circulation and may have impaired immune and nervous functions. Conclusions/Significance: A multi-factorial cause underlying this sperm whales' mass stranding is proposed herein based upon the results of postmortem investigations as well as of the detailed analyses of the geographical and historical background. The seven sperm whales took the same "wrong way" into the Adriatic Sea, a potentially dangerous trap for Mediterranean sperm whales. Seismic surveys should be also regarded as potential co-factors, even if no evidence of direct impact has been detected.

Staphylococcus aureus and Methicillin-resistant Staphylococcus aureus (MRSA), are traditionally human pathogens capable of causing foodborne intoxications and several type of infections. s. aureus could enter the pork production chain during the slaughter process. The aims of this study were to determine the prevalence and the enterotoxigenic characteristics of S. aureus and MRSA isolated from pigs at slaughterhouses. Overall, 60 (63.8%) of the 94 superficial swabs analyzed, resulted positive. From these 13 strains of S. aureus were isolated, of which 7 (53.8) resulted enterotoxigenic, and 47 strains of MRSA. The authors emphasize the need to raise the standards of the hygiene process in order to reduce the foodborne risk linked to the consumption of pork contaminated with the investigated microorganisms.

Tryptase, a serine protease stored and released from mast cells (MCs) granules has been identified as a new non-classical angiogenetic factor and it is an agonist of the proteinase-activated receptor-2 (PAR-2).Published in vitro data suggest that tryptase may increase capillary growth and endothelial cell proliferation by activation of PAR-2. According to these data we shown that MCDPT, PAR-2 and MVD paralleled to each other suggesting a role in in vivo breast cancer angiogenesis. In this context several tryptase inhibitors such as gabexate mesilate and nafamostat mesilate might be evaluated in clinical trials as a new antiangiogenetic drugs.

Published data strongly suggest that tumor progression and malignancy are associated with increased angiogenesis. However, no data have been published concerning the relationship between microvascular density (MVD), tumor cytosol, and blood vascular endothelial growth factor (VEGF) concentrations in canine non-Hodgkin lymphoma (C-NHL), a neoplasm that shares biological and clinical characteristics with human NHL. We have evaluated MVD and tumor cytosol, serum (S), platelet-poor plasma (P-PP), plasma-activated platelet rich (P-APR) VEGF concentration in a series of 63 B-cells C-NHL by means of immunohistochemistry and enzyme-linked immuno-sorbent assay (ELISA) detection of VEGF. We found that MVD, VEGF from cytosol, and VEGF from P-APR are significantly correlated (p ranging from 0.001 to 0.003) and that these parameters paralleled with the malignancy degree of NHL. Accordingly, spontaneous C-NHL seems to be an interesting model to study the role of angiogenesis as interspecies pathway of tumor malignancy and we suggest that VEGF from P-APR might be a novel useful circulating bio-marker of tumor angiogenesis.