Inhibition of AKT with the Orally Active Allosteric AKT Inhibitor, MK-2206, Sensitizes Endometrial Cancer Cells to Progestin

Progestin resistance is a major obstacle to treating early stage, well-differentiated endometrial cancer as well as recurrent endometrial cancer. The mechanism behind the suboptimal response to progestin is not well understood. The PTEN tumor suppressor gene is frequently mutated in type I endometrial cancers and this mutation results in hyperactivation of the PI3K/AKT pathway. We hypothesized that increased activation of AKT promotes an inadequate response to progestins in endometrial cancer cells. Ishikawa cells stably transfected with progesterone receptor B (PRB23 cells) were treated with the AKT inhibitor, MK-2206, which effectively decreased levels of p(Ser473)-AKT in a dose-dependent (10 nM to 1 uM) and time-dependent manner (0.5 h to 24 h). MK-2206 inhibited levels of p(Thr308)-AKT and a downstream target, p(Thr246)-PRAS40, but did not change levels of p(Thr202/Tyr204)ERK or p(Thr13/Tyr185)SAPK/JNK, demonstrating specificity of MK-2206 for AKT. Additionally, MK-2206 treatment of PRB23 cells resulted in a significant increase in levels of progesterone receptor B (PRB) protein. Microarray analysis of PRB23 cells identified PDK4 as the most highly upregulated gene among 70 upregulated genes in response to R5020. Inhibition of AKT further upregulated progestin-mediated expression of PDK4 but did not affect another progestin-responsive gene, SGK1. Treatment of PRB23 cells with R5020 and MK-2206 independently decreased viability of cells while the combination of R5020 and MK-2206 caused the greatest decrease in cell viability. Furthermore, mice with xenografted tumors treated with MK-2206 alone or with progesterone alone exhibited modest reductions in their tumor volume. The largest decrease in tumor size was observed in the mice treated with both MK-2206 and progesterone; these tumors exhibited the least proliferation (Ki67) and the most apoptosis (cleaved caspase-3) of all the treatment groups. In summary, inhibition of AKT stabilizes the Progesterone Receptor B and augments progesterone response in endometrial cancer cells that have hyperactivated AKT

Trans-Regime Structural Transition of (In3+ + Nb5+) Co-Doped Anatase TiO2 Nanocrystals under High Pressure

Chemical co-doping and high pressure reactions have been broadly used to synthesize novel materials or to tune the physicochemical properties of traditional materials. Here, we take In3+ and Nb5+ ions co-doped anatase TiO2 nanocrystals as an example and report that a combination of both a chemical and a high pressure reaction route is more powerful for the preparation of metastable polymorphs. It is experimentally demonstrated that In3+ and Nb5+ co-doping significantly changes the high-pressure reaction behaviors of anatase TiO2 nanocrystals (<10 nm) and leads to their trans-regime structural transition in terms of in situ Raman analysis, from an anatase to a baddeleyite-like phase under compressive pressures and then to an α-PbO2-like structure under decompressive pressures. This abnormal phase transition is attributed to a defect-induced heterogeneous nucleation mechanism. Furthermore, the stiffness of co-doped TiO2 nanocrystals is significantly enhanced due to the synergistic effects of co-dopants. This research not only proposes a potentially effective strategy to synthesize co-doped metastable polymorphic phases but also suggests one feasible method to improve the mechanical properties of anatase TiO2 nanocrystals

CCTs as new biomarkers for the prognosis of head and neck squamous cancer

The chaperonin-containing T-complex protein 1 (CCT) subunits participate in diverse diseases. However, little is known about their expression and prognostic values in human head and neck squamous cancer (HNSC). This article aims to evaluate the effects of CCT subunits regarding their prognostic values for HNSC. We mined the transcriptional and survival data of CCTs in HNSC patients from online databases. A protein–protein interaction network was constructed and a functional enrichment analysis of target genes was performed. We observed that the mRNA expression levels of CCT1/2/3/4/5/6/7/8 were higher in HNSC tissues than in normal tissues. Survival analysis revealed that the high mRNA transcriptional levels of CCT3/4/5/6/7/8 were associated with a low overall survival. The expression levels of CCT4/7 were correlated with advanced tumor stage. And the overexpression of CCT4 was associated with higher N stage of patients. Validation of CCTs’ differential expression and prognostic values was achieved by the Human Protein Atlas and GEO datasets. Mechanistic exploration of CCT subunits by the functional enrichment analysis suggests that these genes may influence the HNSC prognosis by regulating PI3K-Akt and other pathways. This study implies that CCT3/4/6/7/8 are promising biomarkers for the prognosis of HNSC

Metal-Organic Framework-Derived Sea-Cucumber-like FeS2@C Nanorods with Outstanding Pseudocapacitive Na-Ion Storage Properties

Sodium-ion batteries (SIBs) are supposed to be attractive energy strorage and supply devices due to the abundant reserves of sodium. Their limited specific capacity and rate capacity, however, are standing in the way of the extensive application of SIBs. It is reported herein that porous sea-cucumber-like FeS2@C nanorods can act as efficient cathode materials to satisfy the rigorous requirements of the proposed applications. The fabrication of the sea-cucumber-like FeS2@C nanorods involves the hydrothermal growth of F-MIL (where F = Fe, MIL = materials from the Lavoisier Institute) nanorods, and subsequent sulfidation. The electrochemical results demonstrate that the FeS2@C nanorods are an outstanding cathode material for SIBs with high specific capacity (385 mAh/g), ultralong lifetime (160 mAh/g after 10 000 cycles at 20 A/g), and exceptional rate capability. The metal−organic framework (MOF) template method provides a useful route toward the development of high-performance electrode materials with robust power and cyclability

3D spongy CoS2nanoparticles/carbon composite as high-performance anode material for lithium/sodium ion batteries

A spongy CoS 2 /carbon composite assembled from CoS 2 nanoparticles (∼20 nm) homogeneously anchored on a spongy carbon matrix was synthesized through a facile freeze-drying method and a hydrothermal process. As anode material for lithium/sodium ion batteries (LIBs/SIBs), this composite shows significantly enhanced lithium/sodium storage performance with the synergetic effects due to the electrical conductivity of the carbon matrix and the porous structure, which provide buffer spaces for volume expansion during charge/discharge processes and feasible transfer pathways for electrons/ions. The electrochemical results demonstrate that the spongy CoS 2 /carbon composite is an outstanding anode material for LIBs and SIBs. It delivers a high specific capacity of 610 mAh g −1 at 500 mA g −1 after 120 cycles in LIBs and 330 mAh g −1 at 500 mA g −1 after 60 cycles in SIBs, respectively. Moreover, the freeze-drying/hydrothermal process developed in this work could be useful for the construction of many other high-capacity metal sulfide composites as electrode materials for sodium ion batteries

Pyrite FeS2@C nanorods as smart cathode for sodium ion battery with ultra-long lifespan and notable rate performance from tunable pseudocapacitance

Sodium ion batteries (SIBs) are a promising replacement for the widely prevalent Li-ion batteries (LIBs) as an efficient energy storage technology. Development of electrode materials with high energy density and high power density is the key to achieving high performance SIBs. Here, we demonstrate a high-capacity and high-rate SIB cathode which is made of one-dimensional FeS 2 nanorods, where an extrinsic pseudocapacitance contribution is found and verified by cyclic voltammetry. The carbon coated FeS 2 nanorods exhibit ultra-long lifespan (9000 cycles), high reversible capacity (506.9 mAh g -1 at 500 mA g -1 ), and outsta nding rate capability (140 mAh g -1 at 20 A g -1 )