Now showing 1 - 4 of 4
  • Publication
    Cleavage of the extracellular domain of junctional adhesion molecule-A is associated with resistance to anti-HER2 therapies in breast cancer settings
    BACKGROUND: Junctional adhesion molecule-A (JAM-A) is an adhesion molecule whose overexpression on breast tumor tissue has been associated with aggressive cancer phenotypes, including human epidermal growth factor receptor-2 (HER2)-positive disease. Since JAM-A has been described to regulate HER2 expression in breast cancer cells, we hypothesized that JAM-dependent stabilization of HER2 could participate in resistance to HER2-targeted therapies. METHODS: Using breast cancer cell line models resistant to anti-HER2 drugs, we investigated JAM-A expression and the effect of JAM-A silencing on biochemical/functional parameters. We also tested whether altered JAM-A expression/processing underpinned differences between drug-sensitive and -resistant cells and acted as a biomarker of patients who developed resistance to HER2-targeted therapies. RESULTS: Silencing JAM-A enhanced the anti-proliferative effects of anti-HER2 treatments in trastuzumab- and lapatinib-resistant breast cancer cells and further reduced HER2 protein expression and Akt phosphorylation in drug-treated cells. Increased epidermal growth factor receptor expression observed in drug-resistant models was normalized upon JAM-A silencing. JAM-A was highly expressed in all of a small cohort of HER2-positive patients whose disease recurred following anti-HER2 therapy. High JAM-A expression also correlated with metastatic disease at the time of diagnosis in another patient cohort resistant to trastuzumab therapy. Importantly, cleavage of JAM-A was increased in drug-resistant cell lines in conjunction with increased expression of ADAM-10 and -17 metalloproteases. Pharmacological inhibition or genetic silencing studies suggested a particular role for ADAM-10 in reducing JAM-A cleavage and partially re-sensitizing drug-resistant cells to the anti-proliferative effects of HER2-targeted drugs. Functionally, recombinant cleaved JAM-A enhanced breast cancer cell invasion in vitro and both invasion and proliferation in a semi-in vivo model. Finally, cleaved JAM-A was detectable in the serum of a small cohort of HER2-positive patients and correlated significantly with resistance to HER2-targeted therapy. CONCLUSIONS: Collectively, our data suggest a novel model whereby increased expression and cleavage of JAM-A drive tumorigenic behavior and act as a biomarker and potential therapeutic target for resistance to HER2-targeted therapies.
      179Scopus© Citations 23
  • Publication
    Non-functional thyroid cystadenoma in three boxer dogs
    Background: Thyroid neoplasia is a common endocrine neoplasm in dogs. The boxer is one of the reported breeds predisposed to malignant thyroid neoplasia. However, the association between thyroid neoplasia, malignancy and breed should be considered with caution. Cases presentation: This article describes the presentation, clinical pathological findings, computed tomographic (CT) imaging findings and histopathological features of benign cystic thyroid tumour (cystadenoma) diagnosed in three boxers. These three dogs were presented for investigation of unilateral (n = 2) or bilateral (n = 1) cervical masses with no associated clinical signs of thyroid dysfunction. In each case, post-contrast CT scan identified a large, lateralised, non-invasive, well-defined homogeneous cystic structure with a hyperattenuating contrast-enhancing capsule of suspected thyroid origin displacing the surrounding cervical tissues. Ultrasound-guided fine needle aspiration of the cysts yielded fluid with a high thyroxine concentration in each case. Histopathology was consistent with thyroid cystadenoma in all cases. One dog was concurrently diagnosed with oral melanoma and euthanased. Two dogs underwent surgical excision with one lost to follow-up after 36 months and the other euthanased after 16 months following diagnosis of mast cell tumour. Conclusions: To the authors' knowledge, this is the first detailed report of non-functional benign thyroid cystadenoma in dogs and provides relevant information about case management for this type of tumour. The presence of a large cystic structure associated with benign non-functional thyroid neoplasia may be a condition to which boxer dogs are predisposed.
      232Scopus© Citations 1
  • Publication
    Occipital condylar dysplasia in a jacob lamb (Ovis aries)
    (Faculty of Veterinary Medicine, University of Tripoli, 2017-05-06) ; ; ;
    Jacob sheep (Ovis aries) are a pedigree breed known for their “polycerate” (multihorned) phenotype. We describe a four-horned Jacob lamb that exhibited progressive congenital hindlimb ataxia and paresis, and was euthanased four weeks post-partum. Necropsy and CT-scan revealed deformity and asymmetry of the occipital condyles, causing narrowing of the foramen magnum and spinal cord compression. Histopathology demonstrated Wallerian degeneration of the cervical spinal cord at the level of the foramen magnum. These findings are consistent with occipital condylar dysplasia. This condition has been infrequently reported in the literature as a suspected heritable disease of polycerate Jacob sheep in the USA, and is assumed to arise during selection for the polycerate trait. This is the first reported case in European-bred Jacob sheep. Occipital condylar dysplasia should be considered as a differential diagnosis in polycerate Jacob lambs showing ataxia. It is important to raise awareness of this disease due to its suspected heritability and link to the popular polycerate trait.
      147Scopus© Citations 3
  • Publication
    Multiple myeloma in an Amur tiger (Panthera tigris altaica)
    (Faculty of Veterinary Medicine, University of Tripoli, 2017-11-08) ; ; ;
    The Amur tiger (Panthera tigris altaica) is an endangered tiger subspecies. An adult zoo-bred female was found collapsed, and died despite supportive treatment. Hematology and biochemistry showed pancytopenia and hyperglobulinemia, and serum protein electrophoresis revealed a monoclonal band in the β-globulin region. Necropsy demonstrated hemoabdomen, multifocal lytic bone marrow lesions, splenomegaly, and hemorrhagic hepatic nodules, with left medial lobe rupture. There were mutifocal hemorrhages in the subcutis, lung, epicardium, and intestinal mucosa. Histopathology demonstrated plasmacytoid cells infiltrating the bone marrow, liver and spleen, and circulating within blood vessels. On immunohistochemistry, cell infiltrates of the three tissues were positive for λ light chains, bone marrow infiltrates were positive for MUM-1 and bone marrow and spleen infiltrates were positive for CD20. These findings indicate that this animal died of hemoabdomen subsequent to multiple myeloma. This is the first time this disease has been reported in a tiger.
      137Scopus© Citations 3