The focal nature of atherosclerotic lesions suggests an important role of local hemodynamic environment. Recent studies have demonstrated significant roles of Yes-associated protein (YAP) and ...transcriptional coactivator with PDZ-binding motif (TAZ) in mediating mechanotransduction and vascular homeostasis. The objective of this study is to investigate the functional role of YAP/TAZ in the flow regulation of atheroprone endothelial phenotypes and the consequential development of atherosclerotic lesions. We found that exposure of cultured endothelial cells (ECs) to the atheroprone disturbed flow resulted in YAP/TAZ activation and translocation into EC nucleus to up-regulate the target genes, including cysteine-rich angiogenic inducer 61 (CYR61), connective tissue growth factor (CTGF), and ankyrin repeat domain 1 (ANKRD1). In contrast, the athero-protective laminar flow suppressed YAP/TAZ activities. En face analysis of mouse arteries demonstrated an increased nuclear localization of YAP/TAZ and elevated levels of the target genes in the endothelium in atheroprone areas compared with athero-protective areas. YAP/TAZ knockdown significantly attenuated the disturbed flow induction of EC proliferative and proinflammatory phenotypes, whereas overexpression of constitutively active YAP was sufficient to promote EC proliferation and inflammation. In addition, treatment with statin, an antiatherosclerotic drug, inhibited YAP/TAZ activities to diminish the disturbed flow-induced proliferation and inflammation. In vivo blockade of YAP/TAZ translation by morpholino oligos significantly reduced endothelial inflammation and the size of atherosclerotic lesions. Our results demonstrate a critical role of the activation of YAP/TAZ by disturbed flow in promoting atheroprone phenotypes and atherosclerotic lesion development. Therefore, inhibition of YAP/TAZ activation is a promising athero-protective therapeutic strategy.
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) is a major advance in treating NSCLC with EGFR-activating mutations. However, acquired resistance, due partially to secondary ...mutations limits their use. Here we report that NSCLC cells with acquired resistance to gefitinib or osimertinib (AZD9291) exhibit EMT features, with a decrease in E-cadherin, and increases in vimentin and stemness, without possessing any EGFR secondary mutations. Knockdown of E-cadherin in parental cells increased gefitinib resistance and stemness, while knockdown of vimentin in resistant cells resulted in opposite effects. Src activation and Hakai upregulation were found in gefitinib-resistant cells. Knockdown of Hakai elevated E-cadherin expression, attenuated stemness, and resensitized the cells to gefitinib. Clinical cancer specimens with acquired gefitinib resistance also showed a decrease in E-cadherin and an increase in Hakai expression. The dual HDAC and HMGR inhibitor JMF3086 inhibited the Src/Hakai and Hakai/E-cadherin interaction to reverse E-cadherin expression, and attenuated vimentin and stemness to restore gefitinib sensitivity. The EMT features of AZD9291-resistant H1975 cells were related to the upregulation of Zeb1. Both gefitinib and AZD9291 sensitivity was restored by JMF3086 through reversing EMT. Our study not only revealed a common mechanism of EMT in both gefitinib and AZD9291 resistance beyond EGFR mutations per se, but also provides a new strategy to overcome it.
Macrophages form a major cell population in the tumor microenvironment. They can be activated and polarized into tumor-associated macrophages (TAM) by the tumor-derived soluble molecules to promote ...tumor progression and metastasis. Here, we used comparative metabolomics coupled with biochemical and animal studies to show that cancer cells release succinate into their microenvironment and activate succinate receptor (SUCNR1) signaling to polarize macrophages into TAM. Furthermore, the results from in vitro and in vivo studies revealed that succinate promotes not only cancer cell migration and invasion but also cancer metastasis. These effects are mediated by SUCNR1-triggered PI3K-hypoxia-inducible factor 1α (HIF-1α) axis. Compared with healthy subjects and tumor-free lung tissues, serum succinate levels and lung cancer SUCNR1 expression were elevated in lung cancer patients, suggesting an important clinical relevance. Collectively, our findings indicate that the secreted tumor-derived succinate belongs to a novel class of cancer progression factors, controlling TAM polarization and promoting tumorigenic signaling.
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•Cancer cells secrete succinate to promote TAM polarization and cancer metastasis•Cancer-cell-derived secreted succinate is related to reduction of SDH activity•SUCNR1-triggered PI3K-HIF-1α axis mediates TAM polarization and cancer metastasis•Serum succinate is elevated in patients with lung cancer and serves as a biomarker
We have shown that cancer cells secrete succinate into extracellular milieu, which mediates TAM polarization and promotes cancer metastasis. Succinate exerts its effects on TAM polarization and cancer metastasis via a specific membrane receptor, SUCNR1, which transmits signaling through the PI3K/HIF-1α pathway.
The best of three worlds: Gold nanorods coated with poly(styrene‐alt‐maleic acid) (see picture; pink), the photosensitizer indocyanine green (black), and antibodies (green “Y”) serve not only as ...photodynamic therapy and hyperthermia agents to destroy malignant cells, but they also act as optical contrast agents to simultaneously to monitor cells by imaging in the near‐IR region.
•A series of single-phase duodenary high-entropy oxides are synthesized.•An order-disorder transition occurs with changing composition.•Increased modulus-to-thermal conductivity ratios from the rule ...of mixture.•Unexpected increases in Young's modulus at low doping levels.•Temperature-dependence reveals ultralow glass-like thermal conductivity.
Improved thermomechanical properties have been reported for various high-entropy oxides containing typically five metal cations. This study further investigates a series of duodenary (11 metals + oxygen) high-entropy oxides by mixing different fractions of a five-cation fluorite-structured niobate and a seven-cation pyrochlore (both containing Yb) with matching lattice constants. Nine compositions of duodenary high-entropy oxides have been examined. All of them exhibit single high-entropy phases of either disordered fluorite or ordered pyrochlore structure. An order-disorder transition (ODT) is evident with changing composition, accompanied by a reduction in thermal conductivity (k). In comparison with the ODT criteria developed from ternary oxides, these duodenary oxides are more prone to disorder, but the ODT is still controlled by similar factors (but at different thresholds). Interestingly, there are abrupt increases in Young's modulus (E) at low mixing concentrations near both endmembers. The E/k ratios are increased, in comparison with both endmembers. This study suggests a new route to tailor high-entropy ceramics via controlling cation ordering vs. disordering.
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Endothelial cells respond to changes in subendothelial stiffness by altering their migration and mechanics, but whether those responses are due to transcriptional reprogramming remains largely ...unknown. We measured traction force generation and also performed gene expression profiling for two endothelial cell types grown in monolayers on soft or stiff matrices: primary human umbilical vein endothelial cells (HUVEC) and immortalized human microvascular endothelial cells (HMEC-1). Both cell types respond to changes in subendothelial stiffness by increasing the traction stresses they exert on stiffer as compared to softer matrices, and exhibit a range of altered protein phosphorylation or protein conformational changes previously implicated in mechanotransduction. However, the transcriptome has only a minimal role in this conserved biomechanical response. Only few genes were differentially expressed in each cell type in a stiffness-dependent manner, and none were shared between them. In contrast, thousands of genes were differentially regulated in HUVEC as compared to HMEC-1. HUVEC (but not HMEC-1) upregulate expression of TGF-β2 on stiffer matrices, and also respond to application of exogenous TGF-β2 by enhancing their endogenous TGF-β2 expression and their cell-matrix traction stresses. Altogether, these findings provide insights into the relationship between subendothelial stiffness, endothelial mechanics and variation of the endothelial cell transcriptome, and reveal that subendothelial stiffness, while critically altering endothelial cells' mechanical behavior, minimally affects their transcriptome.
Increasing evidence shows that hepatocellular carcinoma (HCC) is a principal cause of cancer-related mortality globally, especially among Asian and African populations. Collagen type I α1 (COL1A1) is ...the major component of type I collagen. While aberrant expression of COL1A1 and COL1A2 is implicated in numerous cancers, the differential role of COL1A1 in malignant, premalignant and normal tissues remains unclear, and its clinical significance in HCC has not been elucidated. In this study, using bioinformatics analysis of publicly-available HCC microarray data from Gene Expression Omnibus (GEO) and RNAseq data from The Cancer Genome Atlas (TCGA) database, we determined that COL1A1 is significantly upregulated in HCC tumor tissues in comparison to normal tissues. Our analysis also revealed that COL1A1 confers survival advantage and enhanced oncogenicity on HCC cells. Interestingly, the siRNA-mediated silencing of COL1A1 expression (siCOLIA1) suppressed HCC cells clonogenicity, motility, invasiveness and tumorsphere formation. Concomitantly, siCOL1A1 abrogated Slug-dependent epithelial-to-mesenchymal transition (EMT) and HCC stemness gene-signature, by attenuating expression of stemness markers SOX2, OCT4 and CD133. The present study provides some mechanistic insight into COL1A1 activity in HCC and highlights its putative role as an important diagnostic biomarker and potential therapeutic target in early development and metastasis of HCC.
The Forming phenomenon is observed via in situ transmission electron microscopy in the Ag/Ta2O5/Pt system. The device is switched to a low‐resistance state as the dual filament is connected to the ...electrodes. The results of energy dispersive spectrometer and electron energy loss spectroscopy analyses demonstrate that the filament is composed by a stack of oxygen vacancies and Ag metal.
Taking advantage of the character of Au nanorods (NRs) to absorb NIR light, a NIR‐responsive oligonucleotide‐gated ensemble is developed to perform intracellular drug delivery. Using an ...oligonucleotide bio‐gate enables siRNA release into cells for translational regulation as well as cytotoxicity in anti‐cancer drug delivery.
This study analyze the morphological characteristics of branching vascular networks (BVN) in polypoidal choroidal vasculopathy (PCV) using optical coherence tomography angiography (OCTA), and ...correlate imaging characteristics with clinical presentations. We presented a retrospective observational case series for fifty cases of PCV confirmed by indocyanine green angiography. Macular OCTA were done by the AngioVue. The PCV cases were classified by distinct morphologic patterns of BVN by two retina specialists and clinical features were analyzed. The sensitivity of polyp detection by OCTA was 86% after manual segmentation and that of BVN was 90%. Three distinct morphologic patterns of BVN were identified. (1) The "Trunk" pattern (47%) exhibited major vessel trunk with features including presence of drusens, thin choroid, and larger BVN area. (2) The "Glomeruli" pattern (33%) showed anastomotic vascular network without major trunk. (3) The "Stick" pattern (20%) had localized BVN and the thickest choroid. Subtypes 2 and 3 held higher recurrence rate. In conclusions, the precise visualization of BVN on OCTA supported that OCTA might be a noninvasive tool to study the morphology of BVN in PCV, which exhibits three different morphological types. Identifying the morphology of BVN has the potential to prognosticate outcomes in PCV patients.