Background: Detection of free light chains (fLC) in animals relies on protein electrophoresis or the Bence-Jones protein test on urine. Objective: To describe the detection of both serum fLC (sfLC) and urine fLC (ufLC) in 8 dogs and 2 cats using a commercially available human immunofixation (IF) kit.
The MEK inhibitors cobimetinib and trametinib are used in combination with BRAF inhibitors to treat metastatic melanoma but increase rates of hemorrhage relative to BRAF inhibitors alone. Platelets express several members of the MAPK signalling cascade including MEK1 and MEK2 and ERK1 and ERK2 but their role in platelet function and haemostasis is ambiguous as previous reports have been contradictory. It is therefore unclear if MEK inhibitors might be causing platelet dysfunction and contributing to increased hemorrhage. In the present study we performed pharmacological characterisation of cobimetinib and trametinib in vitro to investigate potential for MEK inhibitors to cause platelet dysfunction. We report that whilst both cobimetinib and trametinib are potent inhibitors of platelet MEK activity, treatment with trametinib did not alter platelet function. Treatment with cobimetinib results in inhibition of platelet aggregation, integrin activation, alpha-granule secretion and adhesion but only at suprapharmacological concentrations. We identified that the inhibitory effects of high concentrations of cobimetinib are associated with off-target inhibition on Akt and PKC. Neither inhibitor caused any alteration in thrombus formation on collagen under flow conditions in vitro. Our findings demonstrate that platelets are able to function normally when MEK activity is fully inhibited, indicating MEK activity is dispensable for normal platelet function. We conclude that the MEK inhibitors cobimetinib and trametinib do not induce platelet dysfunction and are therefore unlikely to contribute to increased incidence of bleeding reported during MEK inhibitor therapy.
The dog is an important companion animal and also purpose-bred for research studies. Coagulopathies in dogs are common, although the availability of blood products for therapy is inconsistent throughout the profession. A pro-coagulant therapeutic that is readily available and easily stored would be useful for the treatment of coagulopathies. Tricarbonyldichlororuthenium (II) dimer [Carbon monoxide-releasing molecule-2 (CORM-2)] acts as a prothrombotic agent in plasma by increasing the velocity of clot formation and clot strength, and by decreasing the clot's vulnerability to fibrinolysis. We sought to test CORM-2's effect on coagulation and fibrinolysis in vitro in canine plasma using thromboelastography. Measures of the rate of clot formation and clot strength in plasma without CORM-2 were highly correlated with fibrinogen concentration. We found that CORM-2 significantly enhanced the rate of clot formation and clot strength and significantly reduced the rate of fibrinolysis and the clot lysis time. The per cent change in rate of clot formation and clot strength was not significantly correlated with fibrinogen concentration, indicating that CORM-2's pro-coagulant effect is not dependent on fibrinogen concentration. This study corroborates studies in other species that show that CORM-2 is pro-coagulant in plasma, and lays the groundwork for developing CORM-2 as a therapeutic agent for canine coagulopathies. Future studies will evaluate the effect of CORM-2 on whole blood both in vitro and in vivo.
Background: Erythrocyte microcytosis in some dogs with hepatocellular carcinoma (HCC) suggests a derangement in systemic iron. Hepcidin, the master regulator of iron, is secreted by the liver in response to interleukin 6 (IL-6) and/or bone morphogenetic protein 6 (BMP6) and can cause microcytosis.Objectives: Pilot study to compare the quantities of hepcidin, IL-6, and BMP6 RNA molecules in archival tumoral (HCC) and adjacent peritumoral (non-HCC) hepatic tissue to determine if they are different between tissue types or associated with microcytosis.Methods: RNA was isolated from formalin-fixed, paraffin-embedded HCC and non-HCC tissue from seven microcytic dogs and four normocytic dogs. Digital RNA counts of hepcidin, IL-6, or BMP6, and six other iron-regulatory genes were determined using the Nanostring nCounter system. The area of blue on each section was digitally evaluated to measure the extent of Prussian blue staining objectively. Parameters were compared between HCC and non-HCC tissue and between microcytic and normocytic groups.Results: Hepcidin was decreased, and transferrin receptor 1 (TfR1) was increased in HCC tissue compared with non-HCC tissue. Non-HCC hepcidin RNA counts correlated negatively with MCV and positively with the extent of iron staining. Hepcidin expression was higher in non-HCC tissue of microcytic cases than in normocytic cases.Conclusions: Canine HCC cases showed relatively increased iron staining in non-HCC tissue and decreased hepcidin RNA in HCC tissue. Microcytic cases had higher hepcidin RNA in non-HCC tissue than normocytic cases. Future studies may extend these findings to protein quantification, cellular localization of RNA changes, and determining if iron loading in canine liver is a predisposing factor for HCC.
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