RESUMEN
A novel nano-scale manipulator capable of handling low-dimensional materials with three-dimensional linear motion, gripping action, and push-pull action of the gripper was developed for an in situ experiment in transmission electron microscopy. X-Y-Z positioning and push-pull action were accomplished by a piezotubing system, combined with a specially designed assembly stage that consisted of a lever-action gripping tip backed by a push-pull piezostack. The gripper tip consisted of tungsten wire fabricated by electrochemical etching followed by a focused ion beam process. Performance of the nano-scale manipulator was demonstrated in a grab-and-pick test of a single silver nanowire and in an in situ tensile test of a pearlitic steel sample with a specific orientation.
RESUMEN
Loss of function mutations in Kelch-like ECH Associated Protein 1 (KEAP1), or gain-of-function mutations in nuclear factor erythroid 2-related factor 2 (NRF2), are common in non-small cell lung cancer (NSCLC) and associated with therapeutic resistance. To discover novel NRF2 inhibitors for targeted therapy, we conducted a quantitative high-throughput screen using a diverse set of â¼400â¯000 small molecules (Molecular Libraries Small Molecule Repository Library, MLSMR) at the National Center for Advancing Translational Sciences. We identified ML385 as a probe molecule that binds to NRF2 and inhibits its downstream target gene expression. Specifically, ML385 binds to Neh1, the Cap 'N' Collar Basic Leucine Zipper (CNC-bZIP) domain of NRF2, and interferes with the binding of the V-Maf Avian Musculoaponeurotic Fibrosarcoma Oncogene Homologue G (MAFG)-NRF2 protein complex to regulatory DNA binding sequences. In clonogenic assays, when used in combination with platinum-based drugs, doxorubicin or taxol, ML385 substantially enhances cytotoxicity in NSCLC cells, as compared to single agents. ML385 shows specificity and selectivity for NSCLC cells with KEAP1 mutation, leading to gain of NRF2 function. In preclinical models of NSCLC with gain of NRF2 function, ML385 in combination with carboplatin showed significant antitumor activity. We demonstrate the discovery and validation of ML385 as a novel and specific NRF2 inhibitor and conclude that targeting NRF2 may represent a promising strategy for the treatment of advanced NSCLC.