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Scientific Reports May 2017Circulating microRNAs in the blood may provide diagnostic and prognostic information about canine neoplastic diseases, and their profiles may be conserved between human...
Circulating microRNAs in the blood may provide diagnostic and prognostic information about canine neoplastic diseases, and their profiles may be conserved between human and canine species. We performed RT-qPCR to obtain the profiles of circulating plasma microRNA-214 and -126 in total 181 cases of canine neoplastic diseases and healthy controls. MicroRNA-214 levels were high in 2 epithelial tumours (thyroid and mammary carcinomas) and 4 non-epithelial tumours (osteosarcoma, histiocytic sarcoma, chondrosarcoma, and hemangiosarcoma). In contrast, microRNA-126 levels were high in 6 epithelial tumours (mammary, hepatocellular, squamous cell, thyroid, transitional cell carcinomas, and adenocarcinoma) and 4 non-epithelial tumours (osteosarcoma, mast cell tumour, melanoma, and hemangiosarcoma). The diagnostic potential of microRNA-214 was relatively high in sarcomas, whereas that of microR-126 was high in most types of the tumours. MicroRNA-214 and -126 were prognostic predictors in 2 groups (adenocarcinoma and non-epithelial tumours except for osteosarcoma) and 3 groups (epithelial tumours, adenocarcinoma, and melanoma), respectively. Additionally, the microRNA levels did not show a strong correlation with the other clinical parameters. In conclusion, circulating microRNA-214 and -126 have the potential to be diagnostic and prognostic biomarkers for canine neoplastic diseases. Furthermore, their profiles may be key references as well for exploring novel biomarkers for human cancers.
Topics: Animals; Biomarkers, Tumor; Circulating MicroRNA; Dog Diseases; Dogs; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Kaplan-Meier Estimate; Neoplasms; Prognosis
PubMed: 28536479
DOI: 10.1038/s41598-017-02607-1 -
Journal of Dermatological Case Reports Dec 2016Multinucleated Cell Angiohistiocytoma (MCAH) is a rare disease, first described by Smith and Wilson Jones in 1985. Since then, less than 100 cases have been reported in...
BACKGROUND
Multinucleated Cell Angiohistiocytoma (MCAH) is a rare disease, first described by Smith and Wilson Jones in 1985. Since then, less than 100 cases have been reported in the literature. Clinically it is characterized by papules or plaques arising from a specific anatomical area such as lower extremities, dorsum of the hands and face. Some generalized cases have been reported.
MAIN OBSERVATIONS
We report a case of 77-year-old woman who presented with multiple itching. reddish to violaceous, flat to domed-shaped plaques on the lower legs with symmetrical and bilateral distribution along the saphena veins. On dermoscopy examination only a red-violaceous homogeneous area was visible. Histology showed remarkable proliferation of dilated small vessels in the upper and mid dermis and bizarre-shaped multinucleate giant cells with scalloped cytoplasm that were intermingled with numerous mononucleated spindle cells. Many mast cells containing the characteristic granules were also detected, often adjacent to the multinucleate cells. Based on the clinico-pathologic findings the diagnosis of MCAH was established.
CONCLUSIONS
To our knowledge, this is the first documented case of MCAH with a bilateral and linear pattern disposed on the lower limbs, following the saphena veins. In this patient chronic trauma induced by ambulation might have contributed to development of the lesions.
PubMed: 28435475
DOI: 10.3315/jdcr.2016.1237 -
Oncotarget Nov 2016Osteosarcoma (OS) is the most common bone sarcoma in adolescents, and has poor prognosis. A vicious cycle is established between OS cells and their microenvironment in...
Osteosarcoma (OS) is the most common bone sarcoma in adolescents, and has poor prognosis. A vicious cycle is established between OS cells and their microenvironment in order to facilitate the tumor growth and cell spreading. The present work aims to better characterize the tumor microenvironment in OS in order to identify new therapeutic targets relating to metastatic process. Tissue microarrays of pre-chemotherapy OS biopsies were used for characterizing the tumor niche by immunohistochemistry. Parameters studies included: immune cells (M1, M2-subtypes of tumor-associated macrophages (TAM); T, B lymphocytes; mast cells), vascularization (endothelial, perivascular cells), OPG, RANKL, and mitotic index. Two groups of patients were defined, 22 localized OS (OS Meta-) and 28 metastatic OS (OS Meta+). The OS Meta- group was characterized by a higher infiltration of INOS+ M1-polarizedmacrophages and upregulated OPG immunostaining. OS Meta+ tumors showed a significant increase in CD146+ cells. INOS+ M1-macrophages were correlated with OPG staining, and negatively with the presence of metastases. CD163+ M2-macrophages were positively correlated with CD146+ cells. In multivariate analysis, INOS and OPG were predictive factors for metastasis. An older age, non-metastatic tumor, good response to chemotherapy, and higher macrophage infiltration were significantly associated with better overall survival. TAMs are associated with better overall survival and a dysregulation of M1/M2 polarized-macrophages in favor of M1 subtype was observed in non-metastatic OS.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Biomarkers, Tumor; Bone Neoplasms; CD146 Antigen; Cell Plasticity; Child; Humans; Immunohistochemistry; Logistic Models; Macrophages; Middle Aged; Multivariate Analysis; Nitric Oxide Synthase Type II; Odds Ratio; Osteopontin; Osteosarcoma; Phenotype; Proportional Hazards Models; RANK Ligand; Receptors, Cell Surface; Risk Factors; Tissue Array Analysis; Treatment Outcome; Tumor Microenvironment; Young Adult
PubMed: 27823976
DOI: 10.18632/oncotarget.13055 -
Oncotarget Oct 2016Mast cell sarcoma (MCS) is a rare form of mastocytosis characterized by the presence of solid tumor(s) comprising malignant mast cells that harbor destructive... (Review)
Review
Mast cell sarcoma (MCS) is a rare form of mastocytosis characterized by the presence of solid tumor(s) comprising malignant mast cells that harbor destructive infiltration capability and metastatic potential. Here, we present an extensive literature review and report on 23 cases of MCS, including 3 new cases from the French National Reference Center for Mastocytosis. From our analysis, it appears that MCS can occur at any age. It can manifest de novo or, to a lesser extent, may evolve from a previously established mastocytosis. Bone tumor is a frequent manifestation, and symptoms of mast cell activation are rare. Histological diagnosis can be difficult because MCS is frequently composed of highly atypical neoplastic mast cells and can thus mimic other tumors. Unexpectedly, the canonical KIT D816V mutation is found in only 21% of MCS; therefore, complete KIT gene sequencing is required. The prognosis of patients with MCS is poor, with a median survival time of less than 18 months, and progression to mast cell leukemia is not unusual. Because conventional chemotherapies usually fail, the role of targeted therapies and bone marrow transplantation warrants further investigation in such aggressive neoplasms.
Topics: Disease Progression; Humans; Mast-Cell Sarcoma; Prognosis
PubMed: 27602777
DOI: 10.18632/oncotarget.11812 -
Clinical Sarcoma Research 2016A chronic inflammatory cell infiltrate is commonly seen in response to primary malignant tumours of bone. This is known to contain tumour-associated macrophages (TAMs)...
BACKGROUND
A chronic inflammatory cell infiltrate is commonly seen in response to primary malignant tumours of bone. This is known to contain tumour-associated macrophages (TAMs) and lymphocytes; dendritic cells (DCs) and mast cells (MCs) have also been identified but whether these and other inflammatory cells are seen commonly in specific types of bone sarcoma is uncertain.
METHODS
In this study we determined the nature of the inflammatory cell infiltrate in 56 primary bone sarcomas. Immunohistochemistry using monoclonal antibodies was employed to assess semiquantitatively CD45+ leukocyte infiltration and the extent of the DC, MC, TAM and T and B lymphocyte infiltrate.
RESULTS
The extent of the inflammatory infiltrate in individual sarcomas was very variable. A moderate or heavy leukocyte infiltrate was more commonly seen in conventional high-grade osteosarcoma, undifferentiated pleomorphic sarcoma and giant cell tumour of bone (GCTB) than in Ewing sarcoma, chordoma and chondrosarcoma. CD14+/CD68+ TAMs and CD3+ T lymphocytes were the major components of the inflammatory cell response but (DC-SIGN/CD11c+) DCs were also commonly noted when there was a significant TAM and T lymphocyte infiltrate. MCs were identified mainly at the periphery of sarcomas, including the osteolytic tumour-bone interface.
DISCUSSION
Our findings indicate that, although variable, some malignant bone tumours (e.g. osteosarcoma, GCTB) are more commonly associated with a pronounced inflammatory cell infiltrate than others (e.g. chondrosarcoma. Ewing sarcoma); the infiltrate is composed mainly of TAMs but includes a significant DC, T lymphocyte and MC infiltrate.
CONCLUSION
Tumours that contain a heavy inflammatory cell response, which includes DCs, TAMs and T lymphocytes, may be more amenable to immunomodulatory therapy. MCs are present mainly at the tumour edge and are likely to contribute to osteolysis and tumour invasion.
PubMed: 27482375
DOI: 10.1186/s13569-016-0053-3 -
Veterinary Surgery : VS Aug 2016To assess the ability of a novel imaging system designed for intraoperative detection of residual cancer in tumor beds to distinguish neoplastic from normal tissue in...
OBJECTIVE
To assess the ability of a novel imaging system designed for intraoperative detection of residual cancer in tumor beds to distinguish neoplastic from normal tissue in dogs undergoing resection of soft tissue sarcoma (STS) and mast cell tumor (MCT).
STUDY DESIGN
Non-randomized prospective clinical trial.
ANIMALS
12 dogs with STS and 7 dogs with MCT.
METHODS
A fluorescent imaging agent that is activated by proteases in vivo was administered to the dogs 4-6 or 24-26 hours before tumor resection. During surgery, a handheld imaging device was used to measure fluorescence intensity within the cancerous portion of the resected specimen and determine an intensity threshold for subsequent identification of cancer. Selected areas within the resected specimen and tumor bed were then imaged, and biopsies (n=101) were obtained from areas that did or did not have a fluorescence intensity exceeding the threshold. Results of intraoperative fluorescence and histology were compared.
RESULTS
The imaging system correctly distinguished cancer from normal tissue in 93/101 biopsies (92%). Using histology as the reference, the sensitivity and specificity of the imaging system for identification of cancer in biopsies were 92% and 92%, respectively. There were 10/19 (53%) dogs which exhibited transient facial erythema soon after injection of the imaging agent which responded to but was not consistently prevented by intravenous diphenhydramine.
CONCLUSION
A fluorescence-based imaging system designed for intraoperative use can distinguish canine soft tissue sarcoma (STS) and mast cell tumor (MCT) tissue from normal tissue with a high degree of accuracy. The system has potential to assist surgeons in assessing the adequacy of tumor resections during surgery, potentially reducing the risk of local tumor recurrence. Although responsive to antihistamines, the risk of hypersensitivity needs to be considered in light of the potential benefits of this imaging system in dogs.
Topics: Animals; Biopsy; Dog Diseases; Dogs; Female; Mastocytoma; Neoplasm Recurrence, Local; Neoplasm, Residual; Prospective Studies; Sarcoma
PubMed: 27281113
DOI: 10.1111/vsu.12487 -
International Journal of... Dec 2016Mast cells are vital mediators of drug allergy and, therefore, studying the relationship between drug allergy and mast cells is essential. Sinomenine is the principal...
Mast cells are vital mediators of drug allergy and, therefore, studying the relationship between drug allergy and mast cells is essential. Sinomenine is the principal active component of Sinomenium acutum, which has anti-inflammatory and anti-immune effects, and is used to treat various rheumatoid diseases. However, allergic responses to sinomenine are frequently reported. Therefore, this study assessed the effects of sinomenine on mast cell activation to characterize its allergic effects and the underlying mechanisms. Enzyme-linked immunosorbent assay (ELISA), western blot analyses, and degranulation assays were performed to measure pro-inflammatory and allergic mediators in P815 cells. The allergenic effects of sinomenine were also determined in mice by using active general anaphylaxis (ASA). The results indicated that sinomenine induced inositol-1,4,5-trisphosphate (IP) production and the release of histamine, interleukin (IL)-6, and endoplasmic reticulum Ca in P815 cells. Furthermore, sinomenine upregulated the phosphorylation of sarcoma (Src), phospholipase C (PLC)-γ1, and IP receptor (R). Therefore, sinomenine induced concentration-dependent mast cell activation directly in vitro Furthermore, our in vivo data identified an appropriate intravenous dose that did not induce these allergic effects, thereby providing information for the potential safe clinical use of sinomenine.
Topics: Anaphylaxis; Animals; Anti-Allergic Agents; Anti-Inflammatory Agents; Calcium; Cell Degranulation; Cell Line, Tumor; Drug Hypersensitivity; Inflammation; Inositol 1,4,5-Trisphosphate Receptors; Interleukin-6; Male; Mast Cells; Mice; Mice, Inbred BALB C; Morphinans; Phospholipase C gamma; Phosphorylation; Signal Transduction; Up-Regulation; src-Family Kinases
PubMed: 26714520
DOI: 10.1177/0394632015621768 -
Journal of the American Veterinary... Jan 2016To evaluate the clinical response, adverse effects, and outcomes associated with palliative radiation therapy (PRT) in dogs with various solid tumor types at various...
OBJECTIVE
To evaluate the clinical response, adverse effects, and outcomes associated with palliative radiation therapy (PRT) in dogs with various solid tumor types at various body locations.
DESIGN
Retrospective case series.
ANIMALS
103 dogs with solid tumors.
PROCEDURES
Medical records for dogs with solid tumors treated with PRT between July 2007 and January 2011 at a veterinary teaching hospital were reviewed. Data collected included signalment, tumor type and location, initial staging results, PRT protocol, other tumor-specific treatments, patient and tumor response, outcome, and acute and chronic adverse effects. Median progression-free survival time, median survival time (MST), and other descriptive statistics were calculated.
RESULTS
Types of tumors treated included carcinoma, sarcoma, melanoma, primary bone tumor, mast cell tumor, and ameloblastoma. For all dogs, the overall tumor and clinical response rates to PRT were 75% and 77%, respectively, and the MST was 134 days, but those responses varied substantially among tumor types. Dogs that developed a positive clinical response or maintained stable disease after PRT had a significantly longer MST than did dogs with progressive disease. Tumor location was not significantly associated with median progression-free survival time or MST. Most dogs tolerated the PRT well. Acute and chronic adverse effects were observed in 57 and 8 dogs, respectively, but were generally self-limiting.
CONCLUSIONS AND CLINICAL RELEVANCE
Results indicated that dogs with various types of solid tumors that received PRT had objective beneficial responses and an improvement in quality of life that was positively associated with survival time.
Topics: Animals; Antineoplastic Agents; Dog Diseases; Dogs; Female; Male; Neoplasms; Palliative Care; Radiotherapy; Retrospective Studies; Treatment Outcome
PubMed: 26684094
DOI: 10.2460/javma.248.1.72 -
Journal of Virology Dec 2015Gammaherpesviruses are important human and animal pathogens. Despite the fact that they display the classical architecture of herpesviruses, the function of most of...
UNLABELLED
Gammaherpesviruses are important human and animal pathogens. Despite the fact that they display the classical architecture of herpesviruses, the function of most of their structural proteins is still poorly defined. This is especially true for tegument proteins. Interestingly, a potential role in immune evasion has recently been proposed for the tegument protein encoded by Kaposi's sarcoma-associated herpesvirus open reading frame 63 (ORF63). To gain insight about the roles of ORF63 in the life cycle of a gammaherpesvirus, we generated null mutations in the ORF63 gene of murid herpesvirus 4 (MuHV-4). We showed that disruption of ORF63 was associated with a severe MuHV-4 growth deficit both in vitro and in vivo. The latter deficit was mainly associated with a defect of replication in the lung but did not affect the establishment of latency in the spleen. From a functional point of view, inhibition of caspase-1 or the inflammasome did not restore the growth of the ORF63-deficient mutant, suggesting that the observed deficit was not associated with the immune evasion mechanism identified previously. Moreover, this growth deficit was also not associated with a defect in virion egress from the infected cells. In contrast, it appeared that MuHV-4 ORF63-deficient mutants failed to address most of their capsids to the nucleus during entry into the host cell, suggesting that ORF63 plays a role in capsid movement. In the future, ORF63 could therefore be considered a target to block gammaherpesvirus infection at a very early stage of the infection.
IMPORTANCE
The important diseases caused by gammaherpesviruses in human and animal populations justify a better understanding of their life cycle. In particular, the role of most of their tegument proteins is still largely unknown. In this study, we used murid herpesvirus 4, a gammaherpesvirus infecting mice, to decipher the role of the protein encoded by the viral ORF63 gene. We showed that the absence of this protein is associated with a severe growth deficit both in vitro and in vivo that was mainly due to impaired migration of viral capsids toward the nucleus during entry. Together, our results provide new insights about the life cycle of gammaherpesviruses and could allow the development of new antiviral strategies aimed at blocking gammaherpesvirus infection at the very early stages.
Topics: Animals; Biological Transport; Capsid; Cell Line; Cricetinae; Female; Gene Deletion; Herpesviridae Infections; Histocytochemistry; Lung; Mice, Inbred BALB C; Rhadinovirus; Viral Proteins; Virus Internalization
PubMed: 26676769
DOI: 10.1128/JVI.02942-15 -
PloS One 2015Both canine cutaneous mast cell tumor (MCT) and human systemic mastocytosis (SM) are characterized by abnormal proliferation and accumulation of mast cells in tissues...
INTRODUCTION
Both canine cutaneous mast cell tumor (MCT) and human systemic mastocytosis (SM) are characterized by abnormal proliferation and accumulation of mast cells in tissues and, frequently, by the presence of activating mutations in the receptor tyrosine kinase V-Kit Hardy-Zuckerman 4 Feline Sarcoma Viral Oncogene Homolog (c-KIT), albeit at different incidence (>80% in SM and 10-30% in MCT). In the last few years, it has been discovered that additional mutations in other genes belonging to the methylation system, the splicing machinery and cell signaling, contribute, with c-KIT, to SM pathogenesis and/or phenotype. In the present study, the mutational profile of the Tet methylcytosine dioxygenase 2 (TET2), the isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2), the serine/arginine-rich splicing factor 2 (SRSF2), the splicing factor 3b subunit 1 (SF3B1), the Kirsten rat sarcoma viral oncogene homolog (KRAS) and the neuroblastoma RAS viral oncogene homolog (NRAS), commonly mutated in human myeloid malignancies and mastocytosis, was investigated in canine MCTs.
METHODS
Using the Sanger sequencing method, a cohort of 75 DNA samples extracted from MCT biopsies already investigated for c-KIT mutations were screened for the "human-like" hot spot mutations of listed genes.
RESULTS
No mutations were ever identified except for TET2 even if with low frequency (2.7%). In contrast to what is observed in human TET2 no frame-shift mutations were found in MCT samples.
CONCLUSION
Results obtained in this preliminary study are suggestive of a substantial difference between human SM and canine MCT if we consider some target genes known to be involved in the pathogenesis of human SM.
Topics: Amino Acid Sequence; Animals; DNA-Binding Proteins; Dioxygenases; Dog Diseases; Dogs; GTP Phosphohydrolases; Gene Frequency; Genetic Predisposition to Disease; Humans; Isocitrate Dehydrogenase; Mast Cells; Mastocytosis, Systemic; Membrane Proteins; Molecular Sequence Data; Mutation; Nuclear Proteins; Phosphoproteins; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); RNA Splicing Factors; Ribonucleoprotein, U2 Small Nuclear; Ribonucleoproteins; Sequence Analysis, DNA; Sequence Homology, Amino Acid; Serine-Arginine Splicing Factors
PubMed: 26562302
DOI: 10.1371/journal.pone.0142450