Highlights • Met amplification and protein hyperactivation is a resistance mechanism to both 1st and 3rd generation EGFR inhibitors • Met inhibition effectively overcomes the resistance to 3rd ...generation EGFR inhibitors both in vitro and in vivo, including enhancement of apoptosis or G1 cell cycle arrest. • Enhanced Bim stabilization is a critical mechanism that mediates augmented induction of apoptosis by combination of Met inhibition with a 3rd generation EGFR inhibitor.
The mammalian target of rapamycin (mTOR) critically regulates several essential biological functions, such as cell growth, metabolism, survival, and immune response by forming two important ...complexes, namely, mTOR complex 1 (mTORC1) and complex 2 (mTORC2). mTOR signaling is often dysregulated in cancers and has been considered an attractive cancer therapeutic target. Great efforts have been made to develop efficacious mTOR inhibitors, particularly mTOR kinase inhibitors, which suppress mTORC1 and mTORC2; however, major success has not been achieved. With the strong scientific rationale, the intriguing question is why cancers are insensitive or not responsive to mTOR-targeted cancer therapy in clinics. Beyond early findings on induced activation of PI3K/Akt, MEK/ERK, and Mnk/eIF4E survival signaling pathways that compromise the efficacy of rapalog-based cancer therapy, recent findings on the essential role of GSK3 in mediating cancer cell response to mTOR inhibitors and mTORC1 inhibition-induced upregulation of PD-L1 in cancer cells may provide some explanations. These new findings may also offer us the opportunity to rationally utilize mTOR inhibitors in cancer therapy. Further elucidation of the biology of complicated mTOR networks may bring us the hope to develop effective therapeutic strategies with mTOR inhibitors against cancer.
The mechanisms accounting for anticancer activity of AZD9291 (osimertinib or TAGRISSO), an approved third-generation EGFR inhibitor, in EGFR-mutant non-small cell lung cancer (NSCLC) cells and ...particularly for the subsequent development of acquired resistance are unclear and thus are the focus of this study.
AZD9219-resistant cell lines were established by exposing sensitive cell lines to AZD9291. Protein alterations were detected with Western blotting. Apoptosis was measured with annexin V/flow cytometry. Growth-inhibitory effects of tested drugs were evaluated
with cell number estimation and colony formation assay and
with mouse xenograft models. Protein degradation was determined by comparing protein half-lives and inhibiting proteasome. Gene knockdown were achieved with siRNA or shRNA.
AZD9291 potently induced apoptosis in EGFR-mutant NSCLC cell lines, in which ERK phosphorylation was suppressed accompanied with Bim elevation and Mcl-1 reduction likely due to enhanced Mcl-1 degradation and increased Bim stability. Blocking Bim elevation by gene knockdown or enforcing Mcl-1 expression attenuated or abolished AZD9291-induced apoptosis. Moreover, AZD9291 lost its ability to modulate Bim and Mcl-1 levels in AZD9291-resistant cell lines. The combination of a MEK inhibitor with AZD9291 restores the sensitivity of AZD9291-resistant cells including those with C797S mutation to undergo apoptosis and growth regression
and
Modulation of MEK/ERK-dependent Bim and Mcl-1 degradation critically mediates sensitivity and resistance of EGFR-mutant NSCLC cells to AZD9291 and hence is an effective strategy to overcome acquired resistance to AZD9291.
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Polydimethylsiloxanes (PDMS) foam as one of next‐generation polymer foam materials shows poor surface adhesion and limited functionality, which greatly restricts its potential applications. ...Fabrication of advanced PDMS foam materials with multiple functionalities remains a critical challenge. In this study, unprecedented self‐adhesive PDMS foam materials are reported with worm‐like rough structure and reactive groups for fabricating multifunctional PDMS foam nanocomposites decorated with MXene/cellulose nanofiber (MXene/CNF) interconnected network by a facile silicone foaming and dip‐coating strategy followed by silane surface modification. Interestingly, such self‐adhesive PDMS foam produces strong interfacial adhesion with the hybrid MXene/CNF nano‐coatings. Consequently, the optimized PDMS foam nanocomposites have excellent surface super‐hydrophobicity (water contact angle of ≈159o), tunable electrical conductivity (from 10−8 to 10 S m−1), stable compressive cyclic reliability in both wide‐temperature range (from −20 to 200 oC) and complex environments (acid, sodium, and alkali conditions), outstanding flame resistance (LOI value of >27% and low smoke production rate), good thermal insulating performance and reliable strain sensing in various stress modes and complex environmental conditions. It provides a new route for the rational design and development of advanced PDMS foam nanocomposites with versatile multifunctionalities for various promising applications such as intelligent healthcare monitoring and fire‐safe thermal insulation.
Polydimethylsiloxanes (PDMS) foam usually exhibits poor surface adhesion and limited functionality, restricting the potential applications. Here, self‐adhesive PDMS foams with worm‐like rough structure and reactive groups are fabricated by a facile silicone foaming approach. Decorating with MXene/cellulose nanofiber interconnected network and using silane modification, exceptional multifunctionalities PDMS nanocomposites are prepared, showing versatile applications in thermal insulating and smart sensing fields.
Citric acid is consumed in the largest tonnage among organic acids; it is also the second largest fermentation product after ethanol. Citric acid has high economic value due to its numerous ...applications. The production of citric acid is increasing steadily, along with improved yield efficiency and more advanced technologies. The focus of this review is the two categories of processes producing citric acid using Aspergillus niger, the first starting with whole maize flour and the second starting from maize starch. Alternate substrates and recent methods to improve citric acid fermentation are discussed. The latest patents on production of citric acid are listed and summarized.
This review compares the two categories of processes producing citric acid using Aspergillus niger, the first starting with maize flour and the second starting from maize starch. Alternate substrates and recent methods to improve citric acid fermentation are discussed. The latest patents on production of citric acid are listed and summarized.
•Eleven indicators are designed to evaluate public blockchains.•The weights of technology, recognition and activity are 16.80%, 59.00% and 24.20%.•Bitcoin, Ethereum and EOS are ranked in the top ...three public blockchains.•Most of public blockchains lack popularity.
Blockchains have attracted worldwide attention in recent years. With the increasing number of public blockchains, the evaluation of public blockchains becomes meaningful. This paper aims to make a comprehensive evaluation of public blockchains from multiple dimensions. Three first-level indicators and eleven second-level indicators are designed to evaluate the public blockchains. The technique for order preferences by similarity to an ideal solution (TOPSIS) method is used to rank public blockchains. The entropy method is used to calculate the weights of different indicators objectively. Since Bitcoin has an absolute advantage, a let-the-first-out (LFO) strategy is proposed to reduce the criteria of the positive ideal solution and make a more reasonable evaluation. The evaluation indicators and the ranking results of public blockchains can provide related researchers and managers with references and support their decisions. The three first-level indicators are technology, recognition, and activity. Their weights are 16.80%, 59.00%, and 24.20% respectively. The evaluation result shows that Bitcoin, Ethereum, and EOS are ranked in the top three public blockchains.
Despite limited genomic diversity, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has shown a wide range of clinical manifestations in different patient populations. The mechanisms ...behind these host differences are still unclear. Here, we examined host response gene expression across infection status, viral load, age, and sex among shotgun RNA sequencing profiles of nasopharyngeal (NP) swabs from 430 individuals with PCR-confirmed SARS-CoV-2 and 54 negative controls. SARS-CoV-2 induced a strong antiviral response with up-regulation of antiviral factors such as OAS1-3 and IFIT1-3 and T helper type 1 (Th1) chemokines CXCL9/10/11, as well as a reduction in transcription of ribosomal proteins. SARS-CoV-2 culture in human airway epithelial (HAE) cultures replicated the in vivo antiviral host response 7 days post infection, with no induction of interferon-stimulated genes after 3 days. Patient-matched longitudinal specimens (mean elapsed time = 6.3 days) demonstrated reduction in interferon-induced transcription, recovery of transcription of ribosomal proteins, and initiation of wound healing and humoral immune responses. Expression of interferon-responsive genes, including ACE2, increased as a function of viral load, while transcripts for B cell-specific proteins and neutrophil chemokines were elevated in patients with lower viral load. Older individuals had reduced expression of the Th1 chemokines CXCL9/10/11 and their cognate receptor CXCR3, as well as CD8A and granzyme B, suggesting deficiencies in trafficking and/or function of cytotoxic T cells and natural killer (NK) cells. Relative to females, males had reduced B cell-specific and NK cell-specific transcripts and an increase in inhibitors of nuclear factor kappa-B (NF-κB) signaling, possibly inappropriately throttling antiviral responses. Collectively, our data demonstrate that host responses to SARS-CoV-2 are dependent on viral load and infection time course, with observed differences due to age and sex that may contribute to disease severity.
Citric acid is the world's largest consumed organic acid and is widely used in beverage, food and pharmaceutical industries. Aspergillus niger is the main industrial workhorse for citric acid ...production. Since the release of the genome sequence, extensive multi-omic data are being rapidly obtained, which greatly boost our understanding of the citric acid accumulation mechanism in A. niger to a molecular and system level. Most recently, the rapid development of CRISPR/Cas9 system facilitates highly efficient genome-scale genetic perturbation in A. niger. In this review, we summarize the impact of systems biology on the citric acid molecular regulatory mechanisms, the advances in metabolic engineering strategies for enhancing citric acid production and discuss the development and application of CRISPR/Cas9 systems for genome editing in A. niger. We believe that future systems metabolic engineering efforts will redesign and engineer A. niger as a highly optimized cell factory for industrial citric acid production.
Background
The major clinical obstacle that limits the long‐term benefits of treatment with osimertinib (AZD9291) in patients with epidermal growth factor receptor‐mutant non–small cell lung cancer ...is the development of acquired resistance. Therefore, effective strategies that can overcome acquired resistance to osimertinib are urgently needed. The authors' current efforts in this direction have identified LBH589 (panobinostat), a clinically used histone deacetylase inhibitor, as a potential agent in overcoming osimertinib resistance.
Methods
Cell growth and apoptosis in vitro were evaluated by measuring cell numbers and colony formation and by detecting annexin V‐positive cells and protein cleavage, respectively. Drug effects on tumor growth in vivo were assessed with xenografts in nude mice. Alterations of tested proteins in cells were monitored with Western blot analysis. Gene knockout was achieved using the CRISPR/Cas9 technique.
Results
The combination of LBH589 and osimertinib synergistically decreased the survival of different osimertinib‐resistant cell lines, including those harboring C797S mutations, with greater inhibition of cell colony formation and growth. The combination enhanced the induction of apoptosis in osimertinib‐resistant cells. Importantly, the combination effectively inhibited the growth of osimertinib‐resistant xenograft tumors in nude mice. Mechanistically, the combination of LBH589 and osimertinib enhanced the elevation of Bim in osimertinib‐resistant cells. Knockout of Bim in osimertinib‐resistant cells substantially attenuated or abolished apoptosis enhanced by the LBH589 and osimertinib combination. These results collectively support a critical role of Bim elevation in the induction of apoptosis of osimertinib‐resistant cells for this combination.
Conclusions
The current findings provide strong preclinical evidence in support of the potential for LBH589 to overcome osimertinib resistance in the clinic.
The major clinical obstacle that limits the long‐term benefits of treatment with osimertinib in patients with epidermal growth factor receptor–mutant non–small cell lung cancer is the development of acquired resistance. This study provides strong preclinical evidence in support of the potential for histone deacetylase inhibition to overcome osimertinib resistance in the clinic.
Supramolecular polymers are constructed based on the novel bisalkynylplatinum(II) terpyridine molecular tweezer/pyrene recognition motif. Successive addition of anthracene as the diene and ...cyano‐functionalized dienophile triggers the reversible supramolecular polymerization process, thus advancing the concept of utilizing Diels–Alder chemistry to access stimuli‐responsive materials in compartmentalized systems.
Trigger happy: Supramolecular polymers are constructed based on the novel bisalkynylplatinum(II) terpyridine molecular tweezer/pyrene recognition motif. Successive addition of anthracene as the diene and a cyano‐functionalized dienophile triggers the reversible supramolecular polymerization process, thus advancing the concept of utilizing Diels–Alder chemistry to access stimuli‐responsive materials in compartmentalized systems.
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