1. Cell cycle-dependent activity of the novel dual PI3K-MTORC1/2 inhibitor NVP-BGT226 in acute leukemia
Marcus Matthias Schittenhelm, Kerstin Maria Kampa-Schittenhelm, Michael Charles Heinrich, Figen Akmut, Barbara Illing, Katharina Henriette Rasp, Konstanze Döhner, Hartmut Döhner Mol Cancer . 2013 May 24;12:46. doi: 10.1186/1476-4598-12-46.
Background:Dysregulation of the PI3Kinase/AKT pathway is involved in the pathogenesis of many human malignancies. In acute leukemia, the AKT pathway is frequently activated, however mutations in the PI3K/AKT pathway are uncommon. In some cases, constitutive AKT activation can be linked to gain-of-function tyrosine kinase (TK) mutations upstream of the PI3K/AKT pathway. Inhibitors of the PI3K/AKT pathway are attractive candidates for cancer drug development, but so far clinical efficacy of PI3K inhibitors against various neoplasms has been moderate. Furthermore, specific MTORC1 inhibitors, acting downstream of AKT, have the disadvantage of activating AKT via feed-back mechanisms. We now evaluated the antitumor efficacy of NVP-BGT226, a novel dual pan-PI3K and MTORC1/2 inhibitor, in acute leukemia.Methods:Native leukemia blasts were stained to analyze for AKT phosphorylation levels on a flow cytometer. Efficacy of NVP-BGT226 in comparison to a second dual inhibitor, NVP-BEZ235, was determined with regard to cellular proliferation, autophagy, cell cycle regulation and induction of apoptosis in in vitro and ex vivo cellular assays as well as on the protein level. An isogenic AKT-autoactivated Ba/F3 model, different human leukemia cell lines as well as native leukemia patient blasts were studied. Isobologram analyses were set up to calculate for (super) additive or antagonistic effects of two agents.Results:We show, that phosphorylation of AKT is frequently augmented in acute leukemia. NVP-BGT226 as well as NVP-BEZ235 profoundly and globally suppress AKT signaling pathways, which translates into potent antiproliferative effects. Furthermore, NVP-BGT226 has potent proapoptotic effects in vitro as well as in ex vivo native blasts. Surprisingly and in contrast, NVP-BEZ235 leads to a profound G1/G0 arrest preventing significant induction of apoptosis. Combination with TK inhibitors, which are currently been tested in the treatment of acute leukemia subtypes, overcomes cell cycle arrest and results in (super)additive proapoptotic effects for NVP-BGT226--but also for NVP-BEZ235. Importantly, mononuclear donor cells show lower phospho-AKT expression levels and consequently, relative insensitivity towards dual PI3K-MTORC1/2 inhibition.Conclusions:Our data suggest a favorable antileukemic profile for NVP-BGT226 compared to NVP-BEZ235--which provides a strong rationale for clinical evaluation of the dual PI3K-MTORC1/2 inhibitor NVP-BGT226 in acute leukemia.
2. Na3V2(PO4)3: an advanced cathode for sodium-ion batteries
Dan Yang, Xianhong Rui, Dong Chen, Shaoming Huang, Xianghua Zhang, Yan Yu, Huiteng Tan Nanoscale . 2019 Feb 7;11(6):2556-2576. doi: 10.1039/c8nr09391a.
Sodium-ion batteries (SIBs) are considered to be the most promising electrochemical energy storage devices for large-scale grid and electric vehicle applications due to the advantages of resource abundance and cost-effectiveness. The electrochemical performance of SIBs largely relies on the intrinsic chemical properties of the cathodic materials. Among the various cathodes, rhombohedral Na3V2(PO4)3 (NVP), a typical sodium super ionic conductor (NASICON) compound, is very popular owing to its high Na+ mobility and firm structural stability. However, the relatively low electronic conductivity makes the theoretical capacity of NVP cathodes unviable even at low rates, not to mention the high rate of charging/discharging. This is a major drawback of NVPs, limiting their future large-scale applications. Herein, a comprehensive review of the recent progresses made in NVP fabrication has been presented, mainly including the strategies of developing NVP/carbon hybrid materials and elemental doping to improve the electronic conductivity of NVP cathodes and designing 3D porous architectures to enhance Na-ion transportation. Moreover, the application of NVP cathodic materials in Na-ion full batteries is summarized, too. Finally, some remarks are made on the challenges and perspectives for the future development of NVP cathodes.
3. Sonidegib
No information is available on the clinical use of sonidegib during breastfeeding. Because sonidegib is 97% bound to plasma proteins, the amount in milk is likely to be low. However, its half-life is about 28 days and it might accumulate in the infant. The manufacturer recommends that breastfeeding be discontinued during sonidegib therapy.
