Different expression patterns of p63 and p73 in Felis catus papillomavirus type 2-associated feline Merkel cell carcinomas and other epidermal carcinomas.

Merkel cell carcinoma (MCC) is a cutaneous neuroendocrine tumor, and more than 90% of feline MCC cases test positive for Felis catus papillomavirus type 2 (FcaPV2). In the present study, basal cell markers p40, p63, and p73 and the stem cell marker SOX2 and cytokeratin 14 (CK14) were immunohistochemically examined in normal fetal, infant, and adult feline skin tissues. The expression of these proteins was examined in tumors positive for FcaPV2, including MCC, basal cell carcinoma (BCC), Bowenoid in situ carcinoma (BISC), and squamous cell carcinoma (SCC). Infant and adult feline skin tissues had mature Merkel cells, which were CK14-, CK18+, CK20+, SOX2+, synaptophysin+ and CD56+, while fetal skin tissue had no mature Merkel cells. MCC was immunopositive for p73, CK18, and SOX2 in 32/32 cases, and immunonegative for CK14 in 31/32 cases and for p40 and p63 in 32/32 cases. These results indicate that MCC exhibits different immunophenotypes from Merkel cells (p73-) and basal cells (p40+, p63+, and SOX2-). In contrast, all 3 BCCs, 1 BISC, and 2 SCCs were immunopositive for the basal cell markers p40, p63, and p73. The life cycle of papillomavirus is closely associated with the differentiation of infected basal cells, which requires the transcription factor p63. Changes in p63 expression in FcaPV2-positive MCC may be associated with unique cytokeratin expression patterns (CK14-, CK18+, and CK20+). Furthermore, SOX2 appears to be involved in Merkel cell differentiation in cats, similar to humans and mice.

Safety of the novel protease-activated receptor-1 antagonist vorapaxar in Japanese patients with a history of ischemic stroke.

BACKGROUND: Vorapaxar, formerly SCH 530348, is a novel, orally active, potent thrombin receptor inhibitor selective for the protease-activated receptor-1 (PAR-1). Previous phase II studies of patients undergoing urgent or scheduled percutaneous coronary intervention treated with vorapaxar plus aspirin and clopidogrel or ticlopidine showed a trend toward reducing major adverse cardiac events, particularly myocardial infarction, without increasing bleeding risk. The present study evaluated the safety of vorapaxar in Japanese patients with a history of ischemic stroke receiving aspirin. METHODS: Ninety patients with previous ischemic stroke (≥14 days to <1 year before randomization) were randomized to receive vorapaxar (1 or 2.5 mg) or placebo once daily for 60 days. All patients received aspirin (75-150 mg/day). The primary endpoint was overall incidence of adverse events during the protocol-defined treatment phase (60 days). RESULTS: Addition of vorapaxar to aspirin did not significantly increase the overall incidence of adverse events, including serious adverse events. None of the patients treated with vorapaxar plus aspirin experienced thrombolysis in myocardial infarction major or minor bleeding versus 1 patient treated with placebo. Nonfatal stroke occurred in 1 patient allocated to placebo and 1 patient allocated to vorapaxar. CONCLUSIONS: Vorapaxar used in combination with standard doses of aspirin was safe and well tolerated in Japanese subjects with a history of ischemic stroke.

Malignant Leydig cell tumor in dogs: two cases and a review of the literature.

Malignant Leydig cell tumor (MLCT) is a rare testicular tumor in dogs. We report herein 2 dogs with MLCT and cutaneous metastasis. Grossly, marked enlargement and distortion of the involved testes were noted; on cut surface, the parenchyma was completely replaced by neoplastic tissue. In addition, these tumors had extensive necrosis and hemorrhage. Case 1 had a rapidly growing cutaneous mass in the left angle of the mouth; the lesion was well-circumscribed and had an indistinct lobular pattern. Case 2 had multiple cutaneous masses in the dorsal neck region, the thoracic back region, and the right hindlimb. Microscopically, the tumor lobules were composed of oval-to-polyhedral cells with eosinophilic cytoplasm and resembled testicular tumors. By immunohistochemistry, the neoplastic cells in both the testicular and cutaneous tumors were positive for inhibin-alpha and melan A. The mitotic counts of the primary tumors from cases 1 and 2 were 21 and 11 per 10 high-power fields, respectively. Based on these findings, the cases were diagnosed as MLCT with cutaneous metastasis. Ki-67 expression in the neoplastic cells of the 2 cases was higher than in benign Leydig cell tumors. Our findings may be helpful for the diagnosis of canine MLCT.

Basic and translational research on proteinase-activated receptors: antagonism of the proteinase-activated receptor 1 for thrombin, a novel approach to antiplatelet therapy for atherothrombotic disease.

Atherothrombotic disease is a leading public health problem. Although current antiplatelet agents, such as aspirin and adenosine diphosphate (ADP)-receptor antagonists, reduce the morbidity and mortality associated with atherothrombotic disease, the residual risk for ischemic events remains substantial. The high residual risk despite dual antiplatelet therapy can be attributed to the fact that platelets possess multiple pathways of activation that are not all inhibited by aspirin and ADP-receptor antagonists. Among these, binding of thrombin to the proteinase-activated receptor 1 (PAR(1)) is the most potent platelet activation pathway. In addition, the PAR(1) pathway does not appear to be essential for initiating hemostasis. Inhibition of the PAR(1) receptor thus offers a possible new therapeutic approach with a potentially improved benefit-to-risk profile for treatment of patients with atherothrombotic disease. Preclinical and clinical studies have confirmed that SCH 530348, a potent, orally active thrombin-receptor antagonist selective for PAR(1), does not increase bleeding liability when added to dual antiplatelet therapy. Currently, two large ongoing phase 3 clinical trials are evaluating the efficacy and safety of SCH 530348 in combination with the standard of care in patients with acute coronary syndromes as well as for secondary prevention in patients with previous history of atherothrombotic disease.