Kinase inhibitors have limited success in cancer treatment because tumors circumvent their action. Using a quantitative proteomics approach, we assessed kinome activity in response to MEK inhibition in triple negative breast cancer (TNBC) cells and genetically engineered mice (GEMMs). MEK inhibition caused acute ERK activity loss, resulting in rapid c-Myc degradation that induced expression and activation of several receptor tyrosine kinases (RTKs). RNAi knockdown of ERK or c-Myc mimicked RTK induction by MEK inhibitors, whereas prevention of proteasomal c-Myc degradation blocked kinome reprogramming. MEK inhibitor-induced RTK stimulation overcame MEK2 but not MEK1 inhibition, reactivating ERK and producing drug resistance. The C3Tag GEMM for TNBC similarly induced RTKs in response to MEK inhibition. The inhibitor-induced RTK profile suggested a kinase inhibitor combination therapy that produced GEMM tumor apoptosis and regression where single agents were ineffective. This approach defines mechanisms of drug resistance, allowing rational design of combination therapies for cancer.
Chemical probes are powerful reagents with increasing impacts on biomedical research. However, probes of poor quality or that are used incorrectly generate misleading results. To help address these shortcomings, we will create a community-driven wiki resource to improve quality and convey current best practice.
A superhydrophobic-superoleophilic PVDF membrane is fabricated via an inert solvent-induced phase inversion for effective separation of both micrometer and nanometer-sized surfactant-free and surfactant-stabilized water-in-oil emulsions solely driven by gravity, with high separation efficiency (oil purity in filtrate after separation > 99.95 wt%) and high flux, which is several times higher than those of commercial filtration membranes and reported materials with similar permeation properties.
A novel all-inorganic Cu(OH)2 nanowire-haired membrane with superhydrophilicity and underwater ultralow adhesive superoleophobicity is fabricated by a facile surface oxidation of copper mesh that allows effective separation of both immiscible oil/water mixtures and oil-in-water emulsions solely driven by gravity, with extremely high separation efficiency. The all-inorganic membrane exhibits superior solvent and alkaline resistance and antifouling property compared to organic-based membranes.
Protein lysine methyltransferases G9a and GLP modulate the transcriptional repression of a variety of genes via dimethylation of Lys9 on histone H3 (H3K9me2) as well as dimethylation of non-histone targets. Here we report the discovery of UNC0638, an inhibitor of G9a and GLP with excellent potency and selectivity over a wide range of epigenetic and non-epigenetic targets. UNC0638 treatment of a variety of cell lines resulted in lower global H3K9me2 levels, equivalent to levels observed for small hairpin RNA knockdown of G9a and GLP with the functional potency of UNC0638 being well separated from its toxicity. UNC0638 markedly reduced the clonogenicity of MCF7 cells, reduced the abundance of H3K9me2 marks at promoters of known G9a-regulated endogenous genes and disproportionately affected several genomic loci encoding microRNAs. In mouse embryonic stem cells, UNC0638 reactivated G9a-silenced genes and a retroviral reporter gene in a concentration-dependent manner without promoting differentiation.
CdS/g-C3N4 core/shell nanowires with different g-C3N4 contents were fabricated by a combined solvothermal and chemisorption method and characterized by X-ray powder diffraction, scanning electronic microscopy, transmission electron microscopy, and UV-vis diffuse reflection spectroscopy. The photocatalytic hydrogen-production activities of these samples were evaluated using Na2S and Na2SO3 as sacrificial reagents in water under visible-light illumination (λ≥420 nm). The results show that after a spontaneous adsorption process g-C3N4 is successfully coated on CdS nanowires with intimate contact and can significantly improve the photocatalytic hydrogen-production rate of CdS nanowires, which reaches an optimal value of up to 4152 μmol h(-1) g(-1) at the g-C3N4 content of 2 wt %. More importantly, g-C3N4 coating can substantially reinforce the photostability of CdS nanowires even in a nonsacrificial system. The synergic effect between g-C3N4 and CdS, which can effectively accelerate the charge separation and transfer corrosive holes from CdS to robust C3N4, was proposed to be responsible for the enhancement of the photocatalytic activity and photostability. The possible conditions necessary for the synergic effect to work in a CdS/g-C3N4 core/shell configuration is also discussed.
As an alternative to polymer membranes, ultrathin free-standing single-walled carbon-nanotube network films are used to realize oil/water separation with ultrahigh flux. The films with tunable thickness of the tens of nanometer scale can effectively separate both micrometer and nanometer-sized surfactant-free and surfactant-stabilized water-in-oil emulsions with a flux 2-3 orders of magnitude higher than commercial filtration membranes with similar separation performance.
The separation of oily wastewater, especially emulsified oil/water mixtures, is a worldwide challenge because of the large amount of oily wastewater produced in many industrial processes and daily life. For the treatment of oily wastewater, membrane technology is considered the most efficient method because of its high separation efficiency and relatively simple operational process. In this short review, the recent development of advanced filtration membranes for emulsified oil/water mixture separation is presented. We provide an overview on both traditional filtration membranes, including polymer-dominated and ceramic-based filtration membranes, and recently developed nanomaterial-based functional filtration membranes, especially one-dimensional nanomaterials, for effectively treating emulsified oil/water mixtures. The liquid flux and antifouling property, which are the most important factors for membrane performance evaluation, are described for different types of membranes. Conclusions and perspectives concerning the future development of filtration membranes are also provided.
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