Rational Design and Real Time, In-Cell Detection of the Proapoptotic Activity of a Novel Compound Targeting Bcl-XL

AbstractAntiapoptotic Bcl-2-family proteins Bcl-2 and Bcl-XL have been recently validated as drug discovery targets for cancer. Here, by using a combination of molecular modeling, NMR-based structural analysis, fluorescence polarization assays, and cell-based assays, we have designed and characterized a novel proapoptotic compound targeting these proteins. Our compound, Apogossypol, is capable of binding and inhibiting Bcl-2 and Bcl-XL with high affinity and induces apoptosis of tumor cell lines. Mechanistic studies on the action of our compound were also performed via confocal microscopy that provided real-time detection of the interaction with Bcl-XL in intact cells. Finally, preliminary data on cells freshly isolated from patients affected by chronic lymphocytic leukemia strongly suggest potential applications of Bcl-2 antagonists as chemosensitizers in cancer therapy

Pharmacist-physician collaborative care for outpatients with left ventricular assist devices using a cloud-based home medical management information-sharing system: a case report

[Background] The standard anticoagulation therapy for patients implanted with left ventricular assist devices (LVADs) includes warfarin therapy. We developed a cloud-based home medical management information-sharing system named as LVAD@home. The LVAD@home system is an application designed to be used on iPad tablet computers. This system enables the sharing of daily information between a patient and care providers in real time. In this study, we reported cases of outpatients with LVADs using this system to manage anticoagulation therapy. [Case presentation] The patient, a man in his 40s with end-stage heart failure owing to non-ischemic dilated cardiomyopathy, underwent LVAD implantation and warfarin was started on postoperative day 1. He started to use LVAD@home to manage warfarin therapy after discharge (postoperative day 47). He sent his data to care providers daily. By using this system, the pharmacist observed his signs of reduced dietary intake 179 days after discharge, and after consulting the physician, told the patient to change the timing of the next measurement earlier than usual. On the next day, the prothrombin time-international normalized ratio increased from 2.0 to 3.0, and thus the dose was decreased by 0.5 mg. Four patients used this system to monitor warfarin therapy from October 2015 to March 2018. In these patients, the time in therapeutic range was 90.1 ± 1.3, which was higher than that observed in previous studies. Additionally, there were no thromboembolic events or bleeding events. [Conclusions] The cloud-based home management system can be applied to share real-time patient information of factors, including dietary intake that interact with warfarin. It can help to improve long-term anticoagulation outcomes in patients implanted with LVAD

Right ventricular enlargement predicts responsiveness to tolvaptan in congestive heart failure patients with reduced ejection fraction

Background: Tolvaptan is a vasopressin type 2 receptor antagonist used in heart failure (HF) with refractory diuretic resistance. However, since tolvaptan is also ineffective in some HF patients with reduced ejection fraction (HFrEF), the identification of responders is important. Methods: The study population consisted of 51 HFrEF patients who were administered tolvaptan (EF, 28 ± 7%). We defined responders as patients with a ≥50% increase in urine volume during the 24-hours after administration of tolvaptan. All patients underwent comprehensive transthoracic echocardiography before administration of tolvaptan. Patients were followed for 120 days to ascertain secondary events (cardiac death and rehospitalization for HF). Results: Multiple regression analysis indicated that right ventricular (RV) enlargement (defined as basal RV diameter > 41 mm and midlevel RV diameter > 35 mm, according to guidelines) remained a predictor of response after adjustment for age, sex, starting dosage of tolvaptan, and estimated glomerular filtration rate (odds ratio, 4.88; 95%-confidence interval, 1.26–18.9; P < 0.05), whereas left ventricular parameters and RV dysfunction were not. Kaplan-Meier curves indicated responsiveness to tolvaptan was associated with better prognosis among the overall population (P < 0.05); similar trends were observed among patients with RV dilatation (P = 0.056). Conclusions: These findings suggest that RV enlargement, which represents right-sided volume overload, elevated filling pressure, and diastolic dysfunction similar to that seen in constrictive pericarditis, predicts responsiveness to tolvaptan in patients with HFrEF. Moreover, administration of tolvaptan may have the potential to improve the reportedly poor prognosis for HFrEF patients with RV dilatation. Keywords: Heart failure, Echocardiography, Tolvaptan, Right ventricle, Drug responde

Microtubule-Targeting Drugs Induce Bcl-2 Phosphorylation and Association with Pin1

Ghana, New road construction, 130ColorVolume 83, Page 1

Synthesis and Electrochemical Properties of Li₄MoO₅–NiO Binary System as Positive Electrode Materials for Rechargeable Lithium Batteries

Synthesis and Electrochemical Properties of Li₄MoO₅–NiO Binary System as Positive Electrode Materials for Rechargeable Lithium Batterie