Targeting RAF dimers in RAS mutant tumors:From biology to clinic

RAS mutations occur in approximately 30%of tumors worldwide and have a poor prognosis due to limited therapies.Covalent targeting of KRAS G12C has achieved significant success in recent years,but there is still a lack of efficient therapeutic approaches for tumors with non-G12C KRAS mutations.A highly promising approach is to target the MAPK pathway downstream of RAS,with a particular focus on RAF kinases.First-generation RAF inhibitors have been authorized to treat BRAF mutant tumors for over a decade.However,their use in RAS-mutated tumors is not recommended due to the paradoxical ERK activation mainly caused by RAF dimerization.To address the issue of RAF dimerization,type II RAF inhibitors have emerged as leading candidates.Recent clinical studies have shown the initial effectiveness of these agents against RAS mutant tumors.Promisingly,type II RAF inhibitors in combination with MEK or ERK inhibitors have demonstrated impressive efficacy in RAS mutant tumors.This review aims to clarify the importance of RAF dimerization in cellular signaling and resistance to treatment in tumors with RAS mutations,as well as recent progress in therapeutic approaches to address the problem of RAF dimerization in RAS mutant tumors.

谁会成为在线学习的赢家——K12学生在线自我调节学习能力及其影响

自我调节学习作为一种重要的学习策略对在线学习至关重要,学生能否在在线学习环境中取得成功在很大程度上取决于其在线自我调节学习能力,因此对K12学生在线自我调节学习开展研究对于促进基础教育领域在线教育实践发展具有重要指导意义。本研究以新冠肺炎疫情期间参与在线学习的981名中学生为研究对象收集数据,探究我国K12学生在线自我调节学习能力水平、差异及其对学生学习成果的影响。研究发现:(1)绝大多数学生的在线自我调节学习能力处于中等水平,高水平者较少。(2)学生在线自我调节学习能力在性别上不存在显著差异,但在年级和区域上存在显著差异,不同学段学生在线自我调节学习能力呈现出"两端低中间高"特征;不同地区学生在目标设置、环境建构、任务策略、时间管理、寻求帮助和努力调节六方面均存在显著差异,事后多重比较分析显示省会城市和地级市学生显著高于县城和农村地区学生。(3)多元回归分析发现学生在线自我调节学习能力对学习满意度和感知学习均有显著影响。基于以上研究发现,研究就如何促进学生在线自我调节学习能力发展提出了针对性建议。