Anti-myeloma Activity by Thiazolidine-2,4-dione compounds

Proviral Integrations of Moloney virus 2 (PIM2) kinase is overexpressed in multiple myeloma (MM) cells, and regarded as an important therapeutic target. Here, we aimed to validate the therapeutic efficacy of different types of PIM inhibitors against MM cells for their possible clinical application. Intriguingly, the thiazolidine 2,4 dione family compounds SMI 16a and SMI 4a reduced PIM2 protein levels and impaired MM cell survival preferentially in acidic conditions, in contrast to other types of PIM inhibitors, including AZD1208, CX 6258 and PIM447. SMI 16a also suppressed the drug efflux function of breast cancer resistance protein, minimized the sizes of side populations, and reduced in vitro colony forming capacity and in vivo tumorigenic activity in MM cells, suggesting impairment of their clonogenic capacity. PIM2 is known to be subject to ubiquitination-independent proteasomal degradation. Consistently, the proteasome inhibitors bortezomib and carfilzomib increased PIM2 protein levels in MM cells without affecting its mRNA levels. However, SMI 16a mitigated the PIM2 protein increase and cooperatively enhanced anti MM effects in combination with carfilzomib. Collectively, the thiazolidine 2,4 dione family compounds SMI 16a and SMI 4a uniquely reduce PIM2 protein in MM cells, which may contribute to their profound efficacy in addition to their immediate kinase inhibition. Their combination with proteasome inhibitors is envisioned

Shaking table tests on spherical sliding bearings taking eccentricity and uplift into account

Although rubber bearings are popular in Japan as seismic isolation bearings, spherical sliding bearings (SSBs) or friction pendulum bearings are widely used in many countries, including the U.S. In this study, shake table tests on a braced frame supported by SSBs are carried out, and their dependence on pressure and velocity is investigated. Tests under eccentric dead loads and uplift conditions are also conducted to capture their performance. Analytical models that consider pressure and velocity dependence are proposed, and their validity against the experimental results is discussed