Systems Pharmacology-Based Precision Therapy and Drug Combination Discovery for Breast Cancer.

Breast cancer (BC) is a common disease and one of the main causes of death in females worldwide. In the omics era, researchers have used various high-throughput sequencing technologies to accumulate massive amounts of biomedical data and reveal an increasing number of disease-related mutations/genes. It is a major challenge to use these data effectively to find drugs that may protect human health. In this study, we combined the GeneRank algorithm and gene dependency network to propose a precision drug discovery strategy that can recommend drugs for individuals and screen existing drugs that could be used to treat different BC subtypes. We used this strategy to screen four BC subtype-specific drug combinations and verified the potential activity of combining gefitinib and irinotecan in triple-negative breast cancer (TNBC) through in vivo and in vitro experiments. The results of cell and animal experiments demonstrated that the combination of gefitinib and irinotecan can significantly inhibit the growth of TNBC tumour cells. The results also demonstrated that this systems pharmacology-based precision drug discovery strategy effectively identified important disease-related genes in individuals and special groups, which supports its efficiency, high reliability, and practical application value in drug discovery.

[Effects of water and nitrogen coupling under drip irrigation on tree growth and soil nitrogen content of Populus ×euramericana cv. 'Guariento'.] / 滴灌水氮耦合对欧美108æ¨æž—æœ¨ç”Ÿé•¿å’ŒåœŸå£¤æ°®ç´ çš„å½±å“.

By using surface drip irrigation, a field experiment including nine drip irrigation and fertigation treatments was carried out, with non-irrigation and non-fertilization as control (CK), to evaluate the integrative effects of water and nitrogen management on the increment of diameter, tree height, and stem volume, and the total nitrogen content in the 0-60 cm soil layer in the poplar (Populus ×euramericana cv. 'Guariento') plantations. There were three irrigation levels (irrigation was initiated when soil water potentials at 20 cm soil depth reached -75, -50 and -25 kPa) and three levels of nitrogen addition (150, 300 and 450 g·tree-1·a-1). Surface drip irrigation and fertigation treatments were applied in the gro-wing seasons of 2012 and 2013. The results showed that the combined treatments of water and nitrogen addition significantly increased growth and stem volume of the poplar plantation. In the first year of the experiment, the annual increment of stem volume was 11.54 m3·hm-2·a-1 in high water and high fertilizer treatment (soil water potentials of -25 kPa + nitrogen addition of 450 g·tree-1·a-1), which was 44.1% higher than that in the CK (8.01 m3·hm-2·a-1). In the second year, the annual increment of stem volume was 27.85 m3·hm-2·a-1 in medium water and high fertilizer treatment (soil water potentials of -50 kPa + nitrogen addition of 450 g·tree-1·a-1), being 36.0% higher than that in CK (20.48 m3·hm-2·a-1). The successive combined treatments signi-ficantly increased the total N content in the 0-20 cm soil layer, with total N content of each soil layer in the first and second year of the experiment being 12.3%-59.4% and 71.1%-81.1% higher than CK, respectively. The increments of diameter and tree height were significantly positively correlated with soil total N content. Nitrogen addition and the interactive effects of water and nitrogen addition significantly affected the diameter and height of trees and soil N content, while irrigation showed no significant effect. In conclusion, the combined drip irrigation and fertigation significantly increased growth and stem volume of the poplar plantation by promoting the soil fertility especially nitrogen availability in the topsoil.

[Effects of fertilization method and nitrogen application rate on soil nitrogen vertical migration in a Populus xeuramericana cv. 'Guariento' plantation].

A field experiment was conducted to investigate the effects of fertilization methods, i.e., drip (DF) and furrow fertilization (GF), and nitrogen (N) application rates (25, 50, 75 g N · plant(-1) · time(-1)) on the dynamics of soil N vertical migration in a Populus x euramericana cv. 'Guariento' plantation. The results showed that soil NH4(+)-N and NO3(-)-N contents decreased with the increasing soil depth under different fertilization methods and N application rates. In the DF treatment, soil NH4(+)-N and NO3(-)-N were mainly concentrated in the 0-40 cm soil layer, and their contents ascended firstly and then descended, reaching their maximum values at the 5th day (211.1 mg · kg(-1)) and 10th day (128.8 mg · kg(-1)) after fertilization, respectively. In the GF treatment, soil NH4(+)-N and NO3(-)-N were mainly concentrated in the 0-20 cm layer, and the content of soil NO3(-)-N rose gradually and reached its maximum at the 20th day (175.7 mg · kg(-1)) after fertilization, while the NH4(+)-N content did not change significantly after fertilization. Overall, N fertilizer had an effect within 20 days in the DF treatment, and more than 20 days in the GF treatment. In the DF treatment, the content and migration depth of soil NH4(+)-N and NO3(-)-N increased with the N application rate. In the GF treatment, the NO3(-)-N content increased with the N application rate, but the NH4(+)-N content was not influenced. Under the DF treatment, the hydrolysis rate, nitrification rate and migration depth of urea were higher or larger than that under the GF treatment, and more N accumulated in deep soil as the N application rate increased. Considering the distribution characteristics of fine roots and soil N, DF would be a better fertilization method in P. xeuramericana cv. 'Guariento' plantation, since it could supply N to larger distribution area of fine roots. When the N application rate was 50 g · tree(-1) each time, nitrogen mainly distributed in the zone of fine roots and had no risk of deep leaching, consequently improving the fertilizer utilization efficiency.