The advance of the third­generation EGFR­TKI in the treatment of non­small cell lung cancer (Review).

Lung cancer is currently the second most common type of cancer with the second incidence rate and the first mortality rate worldwide. Non­small cell lung cancer (NSCLC) accounts for ~85% of the total number of cases of lung cancers. Concerning the treatment of NSCLC, targeted therapy has become a research hotspot in recent years because of its favorable efficacy, high selectivity and minimal adverse reactions. Among the drugs used in targeted therapy, the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the most common and are categorized into four generations. The use of first and second­generation drugs leads to drug resistance within 8­14 months. This resistance is primarily caused by the T790M mutation, which is the most observed mechanism. A third­generation drug has been developed to address this issue and a fourth­generation drug is expected to overcome multiple resistance mechanisms, including third­generation drug resistance. However, the fourth­generation drug has not been launched yet. At present, multiple third­generation targeted drugs have been launched globally, with three being launched in China and several being at research and clinical trial stages. The present article provides a review of the development process, mechanism of action and clinical trials of the third­generation EGFR­TKIs, aiming to provide some reference and suggestions for the clinical treatment of NSCLC and scientific research on third­generation targeted drugs.

An integrated distribution scheduling and route planning of food cold chain with demand surge.

With the rapid development of e-commerce, customers could order online to ensure timeliness. Therefore, e-commerce enterprises need to pick and distribute customers' orders. These two operations are interdependent. Order picking needs to consider the vehicle route planning. At the same time, the vehicle route planning is also based on the batching of orders. Considering the demand surge scenario of food cold chain, with the shortest time and lowest cost to complete all distribution tasks as the objective, this paper aims at the integrated optimization of distribution scheduling and route planning, and establishes a mixed integer programming mathematical model. Finally, we design a three-stage heuristic algorithm to solve this problem, and use the actual data to carry out numerical experiments to verify the reliability and effectiveness of the mathematical model and heuristic algorithm.

Plasma EGFR mutation abundance affects clinical response to first-line EGFR-TKIs in patients with advanced non-small cell lung cancer.

BACKGROUND: Activated epidermal growth factor receptor (EGFR) mutation is the main pathogenic cause of non-small cell lung cancer (NSCLC) in Asia. However, the impact of plasma EGFR mutation abundance, especially of the ultra-low abundance of EGFR mutation detected by highly sensitive techniques on clinical outcomes of first-line EGFR tyrosine kinase inhibitors (TKIs) for advanced NSCLC patients remains unclear. METHODS: We qualitatively detected baseline EGFR status of NSCLC tissues using amplification-refractory mutation system and quantified the plasma abundance of EGFR mutations through next-generation sequencing (NGS). Every 8-12 weeks, we performed dynamic detection of plasma mutation abundance and imaging evaluation. We analyzed the association between plasma abundance of EGFR sensitizing mutations, tumor size, tumor shrinkage percentage, concomitant TP53 mutations, and clinical response to TKIs. RESULTS: This prospective study enrolled 135 patients with advanced NSCLC. The objective response rate (ORR) and disease control rate (DCR) for EGFR mutation-positive patients were 50.0% and 87.0%, respectively. When the cutoff value of plasma EGFR mutation abundance was 0.1%, the ORRs of TKI-treated patients were significantly different (60.0% for the >0.1% group vs. 21.4% for the ≤0.1% group, P=0.028). Median progression-free survival (PFS) was significantly longer for participants with a mutation abundance above 0.1% compared to those with a 0.01-0.1% abundance (log rank, P=0.0115). There was no significant association between plasma abundance of EGFR sensitizing mutations and tumor size, tumor shrinkage percentage, or concomitant TP53 mutations. Cox multivariate analysis demonstrated that plasma mutation abundance was an independent predictive factor for PFS [hazard ratio (HR) 2.41, 95% confidence interval (CI): 1.12-5.20; P=0.025]. We identified 11 participants with the acquired T790M resistance mutation according to serial dynamic plasma samples. CONCLUSIONS: Liquid biopsy screening based on highly sensitive NGS is reliable for detecting drug resistance and actionable somatic mutations. The plasma abundance of the EGFR driver mutation affected clinical response to EGFR-TKIs in advanced NSCLC patients; prolongation of PFS was also observed in patients with an ultra-low abundance of EGFR sensitizing mutations.

Apatinib suppresses the Proliferation and Apoptosis of Gastric Cancer Cells via the PI3K/Akt Signaling Pathway.

PURPOSE: To observe the mechanism of the effects of Apatinib on the proliferation and apoptosis of human gastric cancer (HGC-27) cells via the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway through in vitro cytology experiments. METHODS: The human gastric cancer HGC-27 cell line was taken as the research object, and LY294002, an inhibitor of the PI3K/Akt signaling pathway, as the positive control. The experimental methods are as follows: (1) The proliferation of HGC-27 cells inhibited by Apatinib and LY294002 was observed by 3-(4,5)-dimethylthiahiazo-(z-y1)-3,5-diphenytetrazoli- umromide (MTT) assay; (2) flow cytometry was adopted to detect the apoptosis of cells after they were treated with drugs and the positive control; (3) different effects of varying concentrations of Apatinib on apoptosis-related genes and proteins, B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax) and cysteine-aspartic acid protease (Caspase) 9, were detected via fluorescence quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blotting (WB), and the effects of different concentrations of Apatinib on the protein expressions of PI3K, phosphorylated (p)-PI3K, Akt and p-Akt were detected by Western blotting. RESULTS: (1) MTT results showed that Apatinib could effectively inhibit the proliferation of HGC-27 cells in a dose-dependent manner. (2) Flow cytometry results manifested that Apatinib could induce the apoptosis of HGC-27 cells. (3) The results of qRT-PCR and Western blotting demonstrated that apatinib was capable of inducing the expression of the pro-apoptotic genes, Bax and Caspase 9, and inhibit the expression of the anti-apoptotic gene Bcl-2. The final results of Western blotting confirmed that Apatinib could decrease the protein expression levels of p-PI3K and p-Akt, thus inhibiting the phosphorylation of the PI3K/Akt pathway. CONCLUSIONS: The experiment proves that Apatinib can effectively suppress the proliferation and induce the apoptosis of human gastric cancer HGC-27 cells, the mechanism of which is related to the inhibition on phosphorylation of the PI3K/Akt signaling pathway.