Background
Osimertinib (AZD9291), a third‐generation, mutation‐selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (EGFR‐TKI), is an approved drug for patients who have ...non–small cell lung cancer (NSCLC) with activating EGFR mutations or those harboring a resistant T790M mutation. Unfortunately, all patients eventually relapse and develop resistance to osimertinib. The current study addressed whether ERK inhibition exerts effects similar to those produced by MEK inhibition in overcoming acquired resistance to osimertinib.
Methods
Drug effects on cell and tumor growth were assessed by measuring cell number alterations and colony formation in vitro and with xenografts in nude mice in vivo. Apoptosis was assessed with annexin V/flow cytometry and protein cleavage. Protein alterations in cells were detected with Western blot analysis. Gene overexpression and knockout were achieved with lentiviral infection and CRISPR/Cas9, respectively.
Results
The combination of osimertinib with an ERK inhibitor synergistically decreased the survival of osimertinib‐resistant cell lines with enhanced induction of apoptosis and effectively inhibited the growth of osimertinib‐resistant xenografts in nude mice. Moreover, the combination of an MEK or ERK inhibitor with a first‐generation (eg, erlotinib) or second‐generation (eg, afatinib) EGFR‐TKI also very effectively inhibited the growth of osimertinib‐resistant cells in vitro and of tumors in vivo, although these cell lines were cross‐resistant to first‐generation or second‐generation EGFR‐TKIs.
Conclusions
The current findings emphasize the importance of targeting MEK/ERK signaling in maintaining the long‐term benefit of osimertinib through overcoming acquired resistance to osimertinib, warranting further investigation of this therapeutic strategy to improve the therapeutic efficacy of osimertinib in the clinic.
Findings from this study emphasize the importance of targeting MEK/ERK signaling in maintaining the long‐term benefit of osimertinib through overcoming acquired resistance to osimertinib, warranting further investigation of this therapeutic strategy to improve the therapeutic efficacy of osimertinib in the clinic.
Virus-host interactions determine an infection outcome. The Asian lineage of Zika virus (ZIKV), responsible for the recent epidemics, has fixed a mutation in the NS1 gene after 2012 that enhances ...mosquito infection. Here we report that the same mutation confers NS1 to inhibit interferon-β induction. This mutation enables NS1 binding to TBK1 and reduces TBK1 phosphorylation. Engineering the mutation into a pre-epidemic ZIKV strain debilitates the virus for interferon-β induction; reversing the mutation in an epidemic ZIKV strain invigorates the virus for interferon-β induction; these mutational effects are lost in IRF3-knockout cells. Additionally, ZIKV NS2A, NS2B, NS4A, NS4B, and NS5 can also suppress interferon-β production through targeting distinct components of the RIG-I pathway; however, for these proteins, no antagonistic difference is observed among various ZIKV strains. Our results support the mechanism that ZIKV has accumulated mutation(s) that increases the ability to evade immune response and potentiates infection and epidemics.
The outbreak of Zika virus (ZIKV) and associated fetal microcephaly mandates efforts to understand the molecular processes of infection. Related flaviviruses produce noncoding subgenomic flaviviral ...RNAs (sfRNAs) that are linked to pathogenicity in fetal mice. These viruses make sfRNAs by co-opting a cellular exonudease via structured RNAs called xrRNAs. We found that ZIKV-infected monkey and human epithelial cells, mouse neurons, and mosquito cells produce sfRNAs. The RNA structure that is responsible for ZIKV sfRNA production forms a complex fold that is likely found in many pathogenic flaviviruses. Mutations that disrupt the structure affect exonudease resistance in vitro and sfRNA formation during infection. The complete ZIKV xrRNA structure clarifies the mechanism of exonudease resistance and identifies features that may modulate function in diverse flaviviruses.
Cancer is still one of the most serious threats to human worldwide. Aberrant patterns of glycosylation on the surface of cancer cells, which are correlated with various cancer development stages, can ...differentiate the abnormal tissues from the healthy ones. Therefore, tumor‐associated carbohydrate antigens (TACAs) represent the desired targets for cancer immunotherapy. However, these carbohydrate antigens may not able to evoke powerful immune response to combat with cancer for their poor immunogenicity and immunotolerance. Different approaches have been developed to address these problems. In this review, we want to summarize the latest advances in TACAs based anticancer vaccines.
In multiloci-based genetic association studies of complex diseases, a powerful and high efficient tool for analyses of linkage disequilibrium (LD) between markers, haplotype distributions and many ...chi-square/p values with a large number of samples has been sought for long. In order to achieve the goal of obtaining meaningful results directly from raw data, we developed a robust and user-friendly software platform with a series of tools for analysis in association study with high efficiency. The platform has been well evaluated by several sets of real data.
A high-throughput platform would greatly facilitate coronavirus disease 2019 (COVID-19) serological testing and antiviral screening. Here we present a high-throughput nanoluciferase severe ...respiratory syndrome coronavirus 2 (SARS-CoV-2-Nluc) that is genetically stable and replicates similarly to the wild-type virus in cell culture. SARS-CoV-2-Nluc can be used to measure neutralizing antibody activity in patient sera within 5 hours, and it produces results in concordance with a plaque reduction neutralization test (PRNT). Additionally, using SARS-CoV-2-Nluc infection of A549 cells expressing human ACE2 receptor (A549-hACE2), we show that the assay can be used for antiviral screening. Using the optimized SARS-CoV-2-Nluc assay, we evaluate a panel of antivirals and other anti-infective drugs, and we identify nelfinavir, rupintrivir, and cobicistat as the most selective inhibitors of SARS-CoV-2-Nluc (EC
0.77 to 2.74 µM). In contrast, most of the clinically approved antivirals, including tenofovir alafenamide, emtricitabine, sofosbuvir, ledipasvir, and velpatasvir were inactive at concentrations up to 10 µM. Collectively, this high-throughput platform represents a reliable tool for rapid neutralization testing and antiviral screening for SARS-CoV-2.
Metal–organic framework is a kind of novel electrode materials for lithium ion batteries. Here, a 3D metal–organic framework Co2(OH)2BDC (BDC=1,4-benzenedicarboxylate) was synthesized for the first ...time by the reaction of Co2+ with a bio-inspired renewable organic ligand 1,4-benzenedicarboxylic acid through a solvothermal method. As an anode material for lithium ion batteries, this material exhibited an excellent cyclic stability as well as a large reversible capacity of ca. 650mAhg−1 at a current density of 50mAg−1 after 100 cycles within the voltage range of 0.02–3.0V, higher than that of other BDC based anode.
The PXRD pattern and the cycleability curves (inset) of Co2(OH)2BDC. Display omitted
•Co2(OH)2BDC was synthesized through a one pot solvothermal process.•The solvent had a great effect on the purity of this material.•This material was used as anode material for lithium ion batteries for the first time.•Co2(OH)2BDC showed improved capacity and cycling stability.
The mammalian target of rapamycin (mTOR), via forming two important complexes: mTOR complex 1 (mTORC1) and complex 2 (mTORC2), plays an important role in the regulation of immunity in addition to ...exerting many other biological funcions. Beyond its regulatory effects on immune cells, the mTOR axis also regulates the expression of programmed death-ligand 1 (PD-L1) in cancer cells; accordingly, inhibition of mTOR alters PD-L1 levels in different cancer cell types. However, the currently published studies on mTOR inhibition-induced PD-L1 alteration have generated conflicting results. This review will focus on summarizing current findings in this regard and discussing possible reasons for the discrepancies and their potential implications for PD-L1 modulation in cancer therapy.
Terrestrial ecosystem productivity (TEP) is an important component of ecological services. The variability of the TEP is driven by multiple factors, both natural and anthropogenic. However, little is ...known about the dominant factor driving the TEP change at the pixel level, which may hinder ecosystem management particularly in face of global climate changes. In this study, a 22‐year‐long dataset including climate, net primary production (NPP), and human activity was obtained to identify, at a pixel level, the dominant factors of NPP variation in China from 1992 to 2013. The results showed that: (a) the total NPP of China varied from 3.37 to 4.55 PgC/yr and continued to increase with a larger proportion being contributed from eastern China, (b) radiation is the greatest contributor to the NPP variation in China, followed by temperature and precipitation, (c) human activity‐driven pixels are relatively dispersed, and are mainly located in the rural–urban fringe zones, and (d) a total of five subregions are identified, of which Regions I and II require more attention with regard to future NPP evolution. The results of this study are important at the policy level for future management of China's ecosystems.
Cracks are a growing threat to road conditions and have drawn much attention to the construction of intelligent transportation systems. However, as the key part of an intelligent transportation ...system, automatic road crack detection has been challenged because of the intense inhomogeneity along the cracks, the topology complexity of cracks, the inference of noises with similar texture to the cracks, and so on. In this paper, we propose CrackForest, a novel road crack detection framework based on random structured forests, to address these issues. Our contributions are shown as follows: 1) apply the integral channel features to redefine the tokens that constitute a crack and get better representation of the cracks with intensity inhomogeneity; 2) introduce random structured forests to generate a high-performance crack detector, which can identify arbitrarily complex cracks; and 3) propose a new crack descriptor to characterize cracks and discern them from noises effectively. In addition, our method is faster and easier to parallel. Experimental results prove the state-of-the-art detection precision of CrackForest compared with competing methods.
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