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Strategies to develop cancer therapies using inhibitors that target matrix metalloproteinases (MMPs), particularly membrane type-1 MMP (MT1-MMP), have failed. This is predominantly attributed to the specificity of MMP inhibitors and numerous functions of MMPs; therefore, targeting substrates with such broad specificity can lead to off-target effects. Thus, new drug development for cancer therapeutics should focus on the ability of MT1-MMP to break down substrates, such as functional cell membrane proteins, to regulate the functions of these proteins that promote tumor malignancy. In this review, we discuss the mechanism by which proteolysis of cell surface proteins by MT1-MMP promotes progression of malignant tumor cells. In addition, we discuss the two protein fragments generated by limited cleavage of erythropoietin-producing hepatoma receptor tyrosine kinase A2 (EphA2-NF, -CF), which represent a promising basis for developing new cancer therapies and diagnostic techniques.

Discrimination among vegetation patches differing in quantity and quality is crucial to the foraging success of grazing animals living in grasslands. Animals are assumed to discriminate preferred patches from others first, before they visit patches to eat, and then when they are eating patches. We conducted six experiments to test the ability of cattle (Bos taurus) to discriminate among vegetation patches at these two stages during foraging. In each experiment, a group of Japanese Black cows was allowed to graze a tropical grass (Paspalum notatum) for 30 min in a 20 × 20 m area comprising 4, 6 or 9 types of patches. Animals almost always visited and grazed the patches selectively, with a longer residence (grazing) time per visit in more frequently visited patches. Allocation of grazing time was correlated more closely with allocation of visits than with residence time per visit. Faced with patchy vegetation, cattle can discriminate preferred patches from less-preferred and non-preferred patches at two stages during foraging. The first-stage discrimination (pre-visit-and-eating discrimination) is more important than the second (eating discrimination) as a determinant of grazing time allocation to patches.

Patients with recurrent hepatitis C after liver transplantation usually have a high viral load and are generally resistant to interferon (IFN)-alpha2b plus ribavirin (RBV) therapy. However, it remains unclear whether pretreatment viral titre determines the effectiveness of combination therapy, especially in patients with a high viral load. The aim of this study was to identify the viral factors associated with a sustained virological response (SVR) to antiviral therapy in patients with recurrent hepatitis C after living-donor liver transplantation. Twenty-three patients with recurrent hepatitis C received combination therapy of IFN-alpha2b plus RBV. SVR was achieved in 7 of the 23 patients (30.4%). Predictive factors for SVR included a 2 log10 decline in Hepatitis C virus (HCV) RNA at 2 weeks after the start of therapy and disappearance of HCV RNA at 4 or 24 weeks after the start of therapy. As the pretreatment high viral load showed no association with SVR, we asked whether other viral factor was associated with the response to the combination therapy in transplant recipients. We found the several novel defective HCV clones in 4 of 12 recipients' sera. All defective HCV clones had deletions in the envelope region. Interestingly, no patients with defective clones showed a prompt decrease in HCV RNA after the start of IFN-alpha2b plus RBV therapy. Thus, early decline in serum HCV RNA after treatment was closely associated with SVR. The circulating defective HCV clones are present and might be associated with the response to the combination therapy in patients with recurrent hepatitis after liver transplantation.