新自由主义背景下美国高校终身制教师学术身份的冲突与适应—John S.Levin教授专访

新自由主义不仅影响了不同类型高等教育机构的组织和实践,也挑战了传统的教师学术身份。在此背景下,美国高校中的终身制教师通过不同方式寻求其学术职业身份的合理化:他们选择在各种规范中适应、顺从、怀旧或\"类似怀旧\"、伪装、牺牲,或抵制。借此,终身制教师通过优先考虑学术逻辑、削弱新自由主义力量的方式来维持着自身的学术身份。国家留学基金(留基发[2017]3109号)资

Histone deacetylase 6 inhibition exploits selective metabolic vulnerabilities in LKB1 mutant, KRAS driven non-small cell lung cancer

IntroductionIn KRAS-mutant NSCLC, co-occurring alterations in LKB1 confer a negative prognosis compared with other mutations such as TP53. LKB1 is a tumor suppressor that coordinates several signaling pathways in response to energetic stress. Our recent work on pharmacologic and genetic inhibition of histone deacetylase 6 (HDAC6) revealed the impaired activity of numerous enzymes involved in glycolysis. On the basis of these previous findings, we explored the therapeutic window for HDAC6 inhibition in metabolically-active KRAS-mutant lung tumors.MethodsUsing cell lines derived from mouse autochthonous tumors bearing the KRAS/LKB1 (KL) and KRAS/TP53 mutant genotypes to control for confounding germline and somatic mutations in human models, we characterize the metabolic phenotypes at baseline and in response to HDAC6 inhibition. The impact of HDAC6 inhibition was measured on cancer cell growth in vitro and on tumor growth in vivo.ResultsSurprisingly, KL-mutant cells revealed reduced levels of redox-sensitive cofactors at baseline. This is associated with increased sensitivity to pharmacologic HDAC6 inhibition with ACY-1215 and blunted ability to increase compensatory metabolism and buffer oxidative stress. Seeking synergistic metabolic combination treatments, we found enhanced cell killing and antitumor efficacy with glutaminase inhibition in KL lung cancer models in vitro and in vivo.ConclusionsExploring the differential metabolism of KL and KRAS/TP53-mutant NSCLC, we identified decreased metabolic reserve in KL-mutant tumors. HDAC6 inhibition exploited a therapeutic window in KL NSCLC on the basis of a diminished ability to compensate for impaired glycolysis, nominating a novel strategy for the treatment of KRAS-mutant NSCLC with co-occurring LKB1 mutations.</p