Analyses of compounds in clinical development have shown that ligand efficient-molecules with privileged physical properties and low dose are less likely to fail in the various stages of clinical testing, have fewer postapproval withdrawals, and are less likely to receive black box safety warnings. However, detailed side-by-side examination of molecular interactions and properties within single drug classes are lacking. As a class, VEGF receptor tyrosine kinase inhibitors (VEGFR TKIs) have changed the landscape of how cancer is treated, particularly in clear cell renal cell carcinoma, which is molecularly linked to the VEGF signaling axis. Despite the clear role of the molecular target, member molecules of this validated drug class exhibit distinct clinical efficacy and safety profiles in comparable renal cell carcinoma clinical studies. The first head-to-head randomized phase III comparative study between active VEGFR TKIs has confirmed significant differences in clinical performance [Rini BI, et al. (2011) Lancet 378:193–1939]. To elucidate how fundamental drug potency–efficiency is achieved and impacts differentiation within the VEGFR TKI class, we determined potencies, time dependence, selectivities, and X-ray structures of the drug–kinase complexes using a VEGFR2 TK construct inclusive of the important juxtamembrane domain. Collectively, the studies elucidate unique drug–kinase interactions that are dependent on distinct juxtamembrane domain conformations, resulting in significant potency and ligand efficiency differences. The identified structural trends are consistent with in vitro measurements, which translate well to clinical performance, underscoring a principle that may be broadly applicable to prospective drug design for optimal in vivo performance.
The return of migrant workers is an important trend in labor mobility in China. The location of the return determines the direction of the flow and affects the choice of settlement. Based on first-hand data from a field survey, statistical analysis and binary logistic analysis methods are used to analyze the location characteristics and influencing factors of the return flow. The study found that (1) returning to the county is the basic spatial feature of the return of migrant workers. Most workers return to villages and counties outside the township. Before returning, most worked in other cities and counties. Counties and small towns near the village have become the main sites for migrant workers’ return to employment. Although the general trend of rural-urban migration has not changed, the intensity has declined to a certain extent. (2) The main reason for return is to take care of the family, followed by old age, difficulty finding a job, low wages and high costs, poor health, etc. In addition, hometown employment conditions have an impact. The push from other places and the local pull work together on migrant workers, eventually producing a return pattern. (3) Most return flow has occurred in the last 5 years, and it has been intensifying. Return flow and outflow are the two basic forms of labor mobility. Under normal circumstances, migrant workers choose to return when they cannot obtain a higher income or cannot find a job. It is foreseeable that as the county-level economy continues to develop, the trend of return will continue to strengthen. (4) Factors such as years of education, skills, working years, number of work sites, family generation, distance from the city, and relative position in the village reached significance in the regression model for the choice to return to the county. Only the family generation coefficient was negative, and the other coefficients were positive. Employment and income and taking care of the family are the main mechanisms influencing migrant workers' return location selection.
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