Dielectric Properties and Switching Processes of Barium Titanate⁻Barium Zirconate Ferroelectric Superlattices.

This article is devoted to the investigation of the dielectric and repolarization properties of barium zirconate and barium titanate BaZrO3/BaTiO3 superlattices with a period of 13.322 nm on a monocrystal magnesium oxide (MgO) substrate. Synthesized superlattices demonstrated a ferroelectric phase transition at a temperature of approximately 393 °C, which is far higher than the Curie temperature of BaTiO3 thin films and bulk samples. The dielectric permittivity of the superlattice reached more than 104 at maximum. As the electric field frequency increased, the dielectric constant of the studied superlattice decreased over the entire study temperature range, but position of the maximum dielectric constant remained the same with changing frequency. The temperature dependence of the inverse dielectric permittivity 1/ε(T) for the studied samples shows that, in the investigated superlattice, both Curie⁻Weiss law and the law of "two" were followed. Additionally, the ε(T) dependences showed practically no temperature hysteresis with heating and cooling. Samples of synthesized superlattices had a relatively small internal bias field, which was directed from the superlattice towards the substrate.

Prognostic Value of Oxygen Kinetics During Recovery From Cardiopulmonary Exercise Testing in Patients With Chronic Heart Failure.

BACKGROUND: Peak oxygen uptake (V˙O2peak) is a well-established prognostic marker in chronic heart failure (CHF). Cardiopulmonary exercise testing (CPET) provides physiological parameters other than V˙O2peak that might have prognostic value. We aimed at determining whether exercise recovery data kinetics have prognostic implications over V˙O2peak and Heart Failure Survival Score. METHODS: Exercise data from 200 consecutive CHF patients evaluated for possible heart transplantation and received CPET at our institution between 2004 and 2011 were analyzed. The rate of recovery of oxygen uptake (V˙O2) at 2 minutes after exercise (V˙O2-REC2) was calculated using the difference between V˙O2peak and V˙O2 at minute 2 of recovery and expressed as a percentage of V˙O2peak. The composite primary end point was the time from CPET to the first event including death, heart transplant, or mechanical heart implantation. RESULTS: Mean follow-up period was 1271 ± 61 days during which there were 108 first events including 35 deaths, 66 heart transplants, and 7 mechanical heart implantations. The strongest prognostic factors in the univariate analysis were V˙O2-REC2, V˙O2peak, V˙O2 efficiency slope, and ventilation to carbon dioxide excretion ratio slope (all P < 0.0001). Multivariate analysis showed that V˙O2-REC2 (P < 0.0001), ventilation to carbon dioxide excretion ratio slope (P = 0.0022), use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (P = 0.0042), presence of a defibrillator (P = 0.0127), and mean arterial pressure (P = 0.0151) were independent predictors of event-free survival time. CONCLUSIONS: V˙O2-REC2 was the strongest prognostic marker of death, heart transplantation, and mechanical heart implantation in severe CHF. This finding should be confirmed prospectively.

3D imaging of the response to CDC25 inhibition in multicellular spheroids.

Multicellular tumor spheroids closely mimic the 3D organization of avascular microregions within tumors and thereby represent a valuable model for the evaluation of anticancer drugs. In this study, we performed a 3D analysis of the response to the CDC25 phosphatase inhibitor IRC-083864 in HCT116 spheroids. Continuous exposure to IRC-083864 strongly inhibits the growth of spheroids and is shown to correlate with a decrease in Ki-67 positive cells. The cytotoxicity induced by IRC-083864 was examined by two-photon laser microscopy imaging and 3D reconstruction. Visualization in 3D allowed us to demonstrate that IRC-083864 treatment results in the inhibition of mitosis and induces cell death specifically localized in the outer proliferative cell layers of the spheroid structure. These results emphasize the importance of 3D models and of in toto analysis for the evaluation of anticancer drugs cytotoxicity.

Inhibition of heterotrimeric G protein signaling by a small molecule acting on Galpha subunit.

The simultaneous activation of many distinct G protein-coupled receptors (GPCRs) and heterotrimeric G proteins play a major role in various pathological conditions. Pan-inhibition of GPCR signaling by small molecules thus represents a novel strategy to treat various diseases. To better understand such therapeutic approach, we have characterized the biomolecular target of BIM-46187, a small molecule pan-inhibitor of GPCR signaling. Combining bioluminescence and fluorescence resonance energy transfer techniques in living cells as well as in reconstituted receptor-G protein complexes, we observed that, by direct binding to the Galpha subunit, BIM-46187 prevents the conformational changes of the receptor-G protein complex associated with GPCR activation. Such a binding prevents the proper interaction of receptors with the G protein heterotrimer and inhibits the agonist-promoted GDP/GTP exchange. These observations bring further evidence that inhibiting G protein activation through direct binding to the Galpha subunit is feasible and should constitute a new strategy for therapeutic intervention.

IRC-083864, a novel bis quinone inhibitor of CDC25 phosphatases active against human cancer cells.

CDC25 phosphatases are key actors in cyclin-dependent kinases activation whose role is essential at various stages of the cell cycle. CDC25 expression is upregulated in a number of human cancers. CDC25 phosphatases are therefore thought to represent promising novel targets in cancer therapy. Here, we report the identification and the characterization of IRC-083864, an original bis-quinone moiety that is a potent and selective inhibitor of CDC25 phosphatases in the low nanomolar range. IRC-083864 inhibits cell proliferation of a number of cell lines, regardless of their resistance to other drugs. It irreversibly inhibits cell proliferation and cell cycle progression and prevents entry into mitosis. In addition, it inhibits the growth of HCT-116 tumor spheroids with induction of p21 and apoptosis. Finally, IRC-083864 reduced tumor growth in mice with established human prostatic and pancreatic tumor xenografts. This study describes a novel compound, which merits further study as a potential anticancer agent.

Inhibitors of the CDC25 phosphatases.

As essential cell cycle regulators, the CDC25 phosphatases are currently considered as potential targets for the development of novel therapeutic approaches. Here, we review the function and regulation of CDC25 phosphatases, their involvement in cancer and Alzheimer's disease, and the properties of several recently identified inhibitors.

Glucocorticoids and hippocampal atrophy after heart transplantation.

The glucocorticoid cascade hypothesis proposes that hippocampal atrophy may result from excessive steroid exposure. Although demonstrated in animal models and some human hypercortisolemic states, hippocampal damage as a possible consequence of posttransplant steroid immunosuppression has not been investigated in human heart transplant recipients. We report a case of a 37-year-old female heart transplant recipient who had the clinical, neuropsychiatric, and neuroimaging findings consistent with hippocampal atrophy after 5 years of steroid exposure.