75,020 research outputs found
Silencing AREG Enhances Sensitivity to Irradiation by Suppressing the PI3K/AKT Signaling Pathway in Colorectal Cancer Cells
No full textWenbing Zhang,1,* Wenjuan Zhang,2,* Chenling Tang,3,4,* Yan Hu,5 Ke Yi,5 Xiaohui Xu,3– 5 Zhihua Chen3,4 1Department of Gastrointestinal Surgery, Anqing First People’s Hospital Affiliated to Anhui Medical University, Anqing, Anhui, 246000, People’s Republic of China; 2Department of Anesthesiology, QingPu Branch of Zhongshan Hospital Affiliated to Fudan University, Shanghai, People’s Republic of China; 3The First People’s Hospital of Taicang City, Taicang Affiliated Hospital of Soochow University, Suzhou, Jiangsu, People’s Republic of China; 4Suzhou Medical College of Soochow University, Suzhou, Jiangsu, People’s Republic of China; 5Central Laboratory, The First People’s Hospital of Taicang, Taicang Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215400, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhihua Chen; Xiaohui Xu, The First People’s Hospital of Taicang, Taicang Affiliated Hospital of Soochow University, No. 58 Changsheng South Road, Taicang, 215400, Jiangsu, People’s Republic of China, Email [email protected]; [email protected]: It has been established that Spalt-Like Transcription Factor 4 (SALL4) promotes Colorectal Cancer (CRC) cell proliferation. Furthermore, Amphiregulin (AREG) is crucially involved in cancer cell proliferation and therapeutic resistance regulation. In this regard, this study aimed to establish whether SALL4 affects the radiosensitization of CRC cells via AREG expression regulation.Methods: Transcriptome sequencing and the Human Transcription Factor Database (HumanTFDB) were used to identify the potential SALL4 targets. The dual-luciferase reporter analysis was used to confirm the SALL4-induced AREG activation. Western Blot (WB) and Reverse Transcription quantitative Polymerase Chain Reaction (RT-qPCR) assays were used to examine the effect of X-ray irradiation on SALL4 and AREG expression. The AREG-KD (Knockdown) stable cell lines were created through lentiviral infection. Cell proliferation was tracked using Cell Counting Kit 8 (CCK-8) and 5-Ethynyl-2′-deoxyuridine (EdU)-incorporation assays. Cell cycle and apoptosis were examined through flow cytometry. The cells were exposed to a controlled X-ray radiation dose (6 Gy) for imaging purposes.Results: SALL4 could bound to the AREG promoter, enhancing AREG expression. Furthermore, irradiation upregulated SALL4 and AREG in CRC cells. Additionally, AREG knockdown in CRC cells led to reduced DNA replication efficiency, suppressed cell proliferation, increased DNA damage, and enhanced G1 phase arrest and apoptosis following irradiation. On the other hand, AREG overexpression reversed the inhibitory effects of SALL4 downregulation on AREG expression.Conclusion: In CRC cells, SALL4 downregulation suppressed AREG expression, regulating CRC cell radiosensitivity via the PI3K-AKT pathway, thus presenting a potential therapeutic pathway for CRC treatment using Radiotherapy (RT).Keywords: colorectal cancer, SALL4, AREG, PI3K-AKT, radiosensitivit
miRNA-34c-5p inhibits amphiregulin-induced ovarian cancer stemness and drug resistance via downregulation of the AREG-EGFR-ERK pathway
No full textAbstractEpithelial ovarian cancer is the most lethal gynecological cancer mainly due to late diagnosis, easy spreading and rapid development of chemoresistance. Cancer stem cells are considered to be one of the main mechanisms for chemoresistance, as well as metastasis and recurrent disease. To explore the stemness characteristics of ovarian cancer stem cells, we successfully enriched ovarian cancer stem-like cells from an established ovarian cancer cell line (SKOV-I6) and a fresh ovarian tumor-derived cell line (OVS1). These ovarian cancer stem-like cells possess important cancer stemness characteristics including sphere-forming and self-renewing abilities, expressing important ovarian cancer stem cell and epithelial–mesenchymal transition markers, as well as increased drug resistance and potent tumorigenicity. Microarray analysis of OVS1-derived sphere cells revealed increased expression of amphiregulin (AREG) and decreased expression of its conserved regulatory microRNA, miR-34c-5p, when compared with the OVS1 parental cells. Overexpression of AREG and decreased miR-34c-5p expression in SKOV-I6 and OVS1 sphere cells were confirmed by quantitative real-time PCR analysis. Luciferase reporter assay and mutant analysis confirmed that AREG is a direct target of miR-34c-5p. Furthermore, AREG-mediated increase of sphere formation, drug resistance toward docetaxel and carboplatin, as well as tumorigenicity of SKOV-I6 and OVS1 cells could be abrogated by miR-34c-5p. We further demonstrated that miR-34c-5p inhibited ovarian cancer stemness through downregulation of the AREG-EGFR-ERK pathway. Overexpression of AREG was found to be correlated with advanced ovarian cancer stages and poor prognosis. Taken together, our data suggest that AREG promotes ovarian cancer stemness and drug resistance via the AREG-EGFR-ERK pathway and this is inhibited by miR-34c-5p. Targeting AREG, miR-34c-5p could be a potential strategy for anti-cancer-stem cell therapy in ovarian cancer.</jats:p
The Benefits of Being Economics Professor A (and not Z)
No full textAlphabetic name ordering on multi-authored academic papers, which is the convention in the economics discipline and various other disciplines, is to the advantage of people whose last name initials are placed early in the alphabet. As it turns out, Professor A, who has been a first author more often than Professor Z, will have published more articles and experienced afaster growth rate over the course of her career as a result of reputation and visibility. Moreover, authors know that name ordering matters and indeed take ordering seriously: Several characteristics of an author group composition determine the decision to deviate from the default alphabetic name order to a significant extent.performance measurement, incentives, economists, name ordering
Final word on Jersey Dutch
No full textIn this article, William Z. Shetter compares and contrasts the dialects that developed between different Dutch colonies in the New World. He explores in-depth the nuances of Jersey Dutch, and provides theories to explain how Dutch and colonial languages blended. The article is reprinted from American Speech, December 1958, Volum XXXIII, No. 4
Coastal sea responses to atmospheric forcings at two different resolutions
No full textWe investigated coastal sea responses to three, multi-day strong wind episodes that occurred in the middle Adriatic during the Target Operational Period (TOP) of the European COastal sea OPerational observing and forecasting system (ECOOP) project. A high-resolution oceanographic model (1 km horizontal, 16 σ vertical layers) based on the modified Princeton Ocean Model (POM) was applied to a highly complex domain located in the coastal area of the eastern Adriatic Sea. The oceanographic model was nested into the Adriatic REGional model (AREG-2) covering the entire Adriatic Sea. Meteorological forcing was prepared by two atmospheric models. The coarser model was the European Centre for Medium-range Weather Forecast model (ECMWF, with horizontal and temporal resolutions of 0.25° and 6 h, respectively), and the finer one was the Aire Limitée Adaptation dynamique Développement InterNational model (ALADIN, with horizontal and temporal resolutions of 8 km and 3 h, respectively, and winds dynamically adapted to a horizontal resolution of 2 km). The results show that small-scale atmospheric features, which arise due to the orographically complex mainland and the number of islands and were not reproduced by the coarser atmospheric model, substantially affected surface currents, mass transports, sea surface temperature (SST) and surface salinity in the coastal area during strong Bora. For strong Sirocco, the atmospheric model's resolution was important for currents on the lee sides of islands. © Author(s) 2011
Heparan sulfate regulates amphiregulin programming of tissue reparative lung mesenchymal cells during influenza A virus infection in mice
No full textAbstract Amphiregulin (Areg), a growth factor produced by regulatory T (Treg) cells to facilitate tissue repair, contains a heparan sulfate (HS) binding domain. How HS, a highly sulfated glycan subtype that alters growth factor signaling, influences Areg repair functions is unclear. Here we report that inhibition of HS in various cell lines and primary lung mesenchymal cells (LMC) qualitatively alters Areg downstream signaling. Utilization of a panel of cell lines with targeted deletions in HS synthesis–related genes identifies the glypican family of HS proteoglycans as critical for Areg signaling. In the context of influenza A virus (IAV) infection in vivo, an Areg-responsive subset of reparative LMC upregulate glypican-4 and HS; conditional deletion of HS primarily within this LMC subset results in reduced repair characteristics following IAV infection. This study demonstrates that HS on a specific lung mesenchymal population is a mediator of Treg cell–derived Areg reparative signaling
Epidermal growth factor (EGF) receptor-ligand based molecular staging predicts prognosis in head and neck squamous cell carcinoma partly due to deregulated EGF- induced amphiregulin expression
No full textBackground
Increased expression of epidermal growth factor receptor (EGFR) and its ligands is associated with poor prognosis and chemoresistance in many carcinoma types, but its role in head and neck squamous cell carcinoma (HNSCC) is unclear. Our aim was to clarify whether mRNA expression of EGFR-ligands was linked to prognosis and cisplatin resistance, and if so, which ligand was most important and how was the expression regulated.
Methods
To examine the prognostic effect of EGFR-ligand expression, we analyzed tumorous mRNA expression in 399 HNSCC patients. The intracellular signaling pathways controlling epidermal growth factor (EGF)-induced amphiregulin (AREG) expression were examined in three oral squamous cell carcinoma (OSCC) cell lines. Effect of AREG on cisplatin resistance was examined by viability assays in four-, and by association in 11 OSCC cell lines.
Results
The patients were divided into five groups according to the median mRNA expression levels of four EGFR ligands, i.e. AREG, EGF, heparin-binding EGF-like growth factor (HBEGF) and beta-cellulin (BTC). The number of increased-expressed EGFR-ligands were progressively correlated to five-year survival, even in advanced TNM-stage IV patients, where five-year mortality increased from 26 % if tumor expressed none to one EGFR-ligand, to 45 % in three to four ligand expressing tumors. Thus, staging the tumor according to these EGFR-ligand mRNA expression pattern completely out performed TNM staging in predicting prognosis. Multivariate analysis identified AREG as the dominating predictor, and AREG was overexpressed in OSCC compared to tumors from other sites. Both EGF and HBEGF stimulation induced strong AREG increase in OSCC cell lines, which was partially mediated by the extracellular signal-regulated kinase 1/2 pathway, and negatively regulated by p38, c-Jun N-terminal kinase, and phosphoinositide-3 kinase. Although increased AREG mRNA expression predicted unfavorable prognosis in platinum treated HNSCC patients, AREG did not mediate cisplatin resistance in the OSCC cell lines.
Conclusions
Increased tumorous mRNA expression of four EGFR ligands was progressively associated with poor prognosis in HNSCC. Thus, EGFR-ligands mRNA expression pattern may be a new prognostic biomarker. The tightly regulated EGF-induced AREG mRNA expression was partly lost in the OSCC cell lines and restoring its regulation may be a new target in cancer treatment.
Trial registration
Not applicable as the clinical data of the 498 HNSCC patients and their mRNA expression profiles were collected from the open TCGA database:
http://cancergenome.nih.gov/cancersselected/headandneck
Logarithmic variance profiles and the corresponding f-1 spectra of temperature fluctuations in turbulent Rayleigh-Bénard convection
No full textWe report experimental results for the temperature variance 2(z) and the corresponding frequency spectra P(f) in turbulent Rayleigh-Bénard convection (RBC) in a cylindrical sample of aspect ratioT= D/L = 1:00 (D = 1:12 m is the diameter and L = 1:12 m the height). The measurements were conducted in the Rayleigh-number range 1011 < Ra < 1:35 1014 and Pr ' 0:8. For Ra = 1:35x1014, 2(z) could be described well by a logarithmic dependence on the vertical position z in a range of z 1 < z < z 2 with z 1 ' 70 and z 2 = 0:1L. Here L=(2Nu) is the thickness of a thin thermal sublayer adjacent to the horizontal plate where the heat flux (denoted by the Nusselt number Nu) is carried mostly by thermal diffusion. In the log layer, we found that the temperature spectra had a significant frequency range over which P(f) f with close to 1. As Ra decreased, increased so that the log layer became thinner. At Ra = 2:05 1011, z 2 < z 1 and therefore there was no range for a log layer. Correspondingly, the temperature spectrum near the horizontal plate did not have the f1 scaling form either
Statistics of the subgrid scales after the shock-turbulence interaction
No full textThe interaction of a normal shock with isotropic turbulence (IT) represents a basic problem for studying some of the phenomena associated with high speed flows, such as hypersonic flight, supersonic combustion and Inertial Confinement Fusion (ICF). In general, in practical applications, the shock width is much smaller than the turbulence scales and the upstream turbulent Mach number is modest. In this case, recent high resolution shock-resolved Direct Numerical Simulations (DNS) (Ryu and Livescu, J. Fluid Mech., 756, R1, 2014) show that the interaction can be described by the Linear Interaction Approximation (LIA). By using LIA to alleviate the need to solve the shock, DNS post-shock data can be generated at much higher Reynolds numbers than previously possible. Here, such results with Taylor Reynolds number around are used to investigate the properties of the subgrid scales (SGS). In particular, it is shown that the shock interaction decreases the asymmetry of the SGS dissipation PDF as the shock Mach number increases, with a significant enhancement in size of the regions and magnitude of backscatter
Transition to turbulence in a qblique shock-wave/boundary-layer interaction at M=15
No full textDirect numerical simulations are carried out for different forcing techniques to trigger transition during the interaction between an oblique shock-wave and a laminar boundary-layer at M = 1.5. Three forcing methods are used: a) forcing of oblique unstable modes, whose shape and behaviour are determined by the local linear stability theory, b) broadband free-stream acoustic disturbances, and c) a cold plasma flow control device. While the oblique-mode breakdown is dominant for low-amplitude forcing, long streaky structures drive the transition process in a high-amplitude disturbance environment. LES are also performed on the experimental setup by the Institute of Theoretical and Applied Mechanics (ITAM) from Novosibirsk State University with cold plasma actuation. As well as the disturbance type, the effect of Reynolds number and forcing amplitude will be investigated
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