Erratum to Simultaneous inhibition of PI3Kα and CDK4/6synergistically suppresses KRAS-mutated non-small cell lung cancer

In the published Figure 11,errors appeared in Figure 1B on page 69.In Figure 1B,bands for p-Akt S473,Akt,and Actin in H1355 cells were mistakenly placed.Here,we have updated Figure 1B to correct the mistake above.The errors do not impact the conclusions of this article.We apologize for the errors and for any confusion it may have caused.

Simultaneous inhibition of PI3Kα and CDK4/6 synergistically suppresses KRAS-mutated non-small cell lung cancer

Objective: Activating KRAS mutations are the most common drivers in the development of non-small cell lung cancer(NSCLC).However, unsuccess of treatment by direct inhibition of KRAS has been proven. Deregulation of PI3K signaling plays an important role in tumorigenesis and drug resistance in NSCLC. The activity of PI3Kα-selective inhibition against KRAS-mutated NSCLC remains largely unknown.Methods: Cell proliferation was detected by sulforhodamine B assay. Cell cycle distribution and apoptosis were measured by flow cytometry. Cell signaling was assessed by Western blot and immunohistochemistry. RNA interference was used to down-regulate the expression of cyclin D1. Human NSCLC xenografts were employed to detect therapeutic efficacy in vivo.Results: CYH33 possessed variable activity against a panel of KRAS-mutated NSCLC cell lines. Although CYH33 blocked AKT phosphorylation in all tested cells, Rb phosphorylation decreased in CYH33-sensitive, but not in CYH33-resistant cells, which was consistent with G1 phase arrest in sensitive cells. Combined treatment with the CDK4/6 inhibitor, PD0332991, and CYH33 displayed synergistic activity against the proliferation of both CYH33-sensitive and CYH33-resistant cells, which was accompanied by enhanced G1-phase arrest. Moreover, down-regulation of cyclin D1 sensitized NSCLC cells to CYH33. Reciprocally, CYH33 abrogated the PD0332991-induced up-regulation of cyclin D1 and phosphorylation of AKT in A549 cells. Co-treatment with these two drugs demonstrated synergistic activity against A549 and H23 xenografts, with enhanced inhibition of Rb phosphorylation.Conclusions: Simultaneous inhibition of PI3Kα and CDK4/6 displayed synergistic activity against KRAS-mutated NSCLC. These data provide a mechanistic rationale for the combination of a PI3Kα inhibitor and a CDK4/6 inhibitor for the treatment of KRASmutated NSCLC.

Optimal design of wavy microchannel heat sinks based on prediction and multi-objective optimization algorithm

In this paper,the multi-objective optimization of wavy microchannel heat sinks is performed by combining numerical calculation,prediction algorithm and genetic algorithm.In numerical calculation,the fluid-solid conjugate heat transfer of heat sinks with different parameters are simulated in Fluent.On this basis,the vari-able parameters and objective parameters are used to complete the training of neural network model,which aims to achieve accurate prediction of objective parameters.Finally,the multi-objective genetic algorithm is applied to find the Pareto front according to different requirements on the foundation of the prediction model.Results show that the coefficient of determination of the neural network models are all greater than 0.85,which proves that the prediction model has a high accuracy.The Pareto fronts are obtained by non-dominated sorting genetic algorithm(NSGA-II)with different objective parameters and they reveal that the channel with the optimal performance corresponds to a larger channel width or Reynolds number.In addition,it is also found the dimensionless temperature difference is correlated with Nusselt number.