PI3K-Akt-mTOR and androgen receptor (AR) signaling are commonly aberrantly activated in metastatic castration-resistant prostate cancer (mCRPC), with PTEN loss associating with poor prognosis. We therefore conducted a phase Ib/II study of the combination of ipatasertib, an Akt inhibitor, with the CYP17 inhibitor abiraterone in patients with mCRPC. Patients were randomized 1:1:1 to ipatasertib 400 mg, ipatasertib 200 mg, or placebo, with abiraterone 1,000 mg orally. Coprimary efficacy endpoints were radiographic progression-free survival (rPFS) in the intent-to-treat population and in patients with PTEN-loss tumors. rPFS was prolonged in the ipatasertib cohort versus placebo, with similar trends in overall survival and time-to-PSA progression. A larger rPFS prolongation for the combination was demonstrated in PTEN-loss tumors versus those without. The combination was well tolerated, with no treatment-related deaths. In mCRPC, combined blockade with abiraterone and ipatasertib showed superior antitumor activity to abiraterone alone, especially in patients with PTEN-loss tumors.

In this paper, we report the formation of a series Zr-(Cu,Ag)-Al bulk metallic glasses (BMGs) with diameters at least 20 mm and demonstrate the formation of about 25 g amorphous metallic ingots in a wide Zr-(Cu,Ag)-Al composition range using a conventional arc-melting machine. The origin of high glass-forming ability (GFA) of the Zr-(Cu,Ag)-Al alloy system has been investigated from the structural, thermodynamic and kinetic points of view. The high GFA of the Zr-(Cu,Ag)-Al system is attributed to denser local atomic packing and the smaller difference in Gibbs free energy between amorphous and crystalline phases. The thermal, mechanical and corrosion properties, as well as elastic constants for the newly developed Zr-(Cu,Ag)-Al BMGs, are also presented. These newly developed Ni-free Zr-(Cu,Ag)-Al BMGs exhibit excellent combined properties: strong GFA, high strength, high compressive plasticity, cheap and non-toxic raw materials and biocompatible property, as compared with other BMGs, leading to their potential industrial applications.

Articles you may be interested inCalculation of driving force and local order to predict the favored and optimized compositions for Mg-Cu-Ni metallic glass formation Abnormal behavior of supercooled liquid region in bulk-forming metallic glassesWe have discovered low-cost bulk metallic glasses ͑BMGs͒ with diameters as large as 16 to 25 mm based on the ordinary engineering metal Mg. We also use this example to present a new strategy, to illustrate how to navigate in three-dimensional composition space for locating the best glass-forming compositions. The extraordinary glass-forming ability demonstrated by the inch-sized BMGs has implications for future development and applications of amorphous metals.

CHCl 3 solution; b) Calculated from the film UV-vis-NIR absorption onset; c) Measured from the CV; d) Calculated by the equation: E LUMO = E HOMO + E g .

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