IFIT1 and IFIT3 are abundant products of interferon-stimulating genes. While the importance of IFIT1 and IFIT3 in the prognosis of cancer has been reported, the molecular basis of IFIT1 and IFIT3 in ...cancer progression remains unexplored. In the present study, we investigated the modes of action and the clinical significance of IFIT1 and IFIT3 in oral squamous cell carcinoma (OSCC). Ectopic expression of IFIT1 or IFIT3 induced OSCC cell invasion by promoting the epithelial-mesenchymal transition, whereas IFIT1 or IFIT3 knockdown exhibited opposite effects. Overexpression of IFIT1 or IFIT3 promoted tumor growth, regional and distant metastasis in xenograft and orthotopic nude mice models. Most importantly, IFIT1 or IFIT3 overexpression increased the levels of p-EGFR
and p-AKT
in OSCC cells and also enhanced tumor inhibitory effect of gefitinib. By immunoprecipitation and LC-MS/MS analysis, we found that IFIT1 and IFIT3 interacted with ANXA2 that enhanced p-EGFR
endosomal recycling. Depletion of ANXA2 using siRNA therefore abolished p-EGFR
and p-AKT
expression in IFIT1- or IFIT3-overexpressed cells. Furthermore, a significant positive association of increased IFIT1 and IFIT3 expression with advanced T-stage, lymph node metastasis, perineural invasion, lymphovascular invasion, extranodal extension, and poor overall survival rate was confirmed in OSCC patients. We also found a statistically positive correlation of p-EGFR
expression with IFIT1 and IFIT3 in OSCC tumors and poor clinical outcome in patients. Collectively, we demonstrated a novel role of IFIT1 and IFIT3 in driving OSCC progression and metastasis by interacting with ANXA2 and hence enhancing p-EGFR recycling and its downstream signaling.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Here, an efficient intracellular delivery of molecules with high cell viability is reported using nanosecond-pulsed laser-activated plasmonic photoporation, mediated by high-aspect-ratio ...nano-corrugated mushroom-shaped gold-coated polystyrene nanoparticles (nm-AuPNPs) at near-infrared wavelength. Upon pulsed laser illumination, nm-AuPNPs exhibit greater plasmonic extinction than spherical AuPNPs, which increase their energy efficiency and reduce the necessary illumination of light, effectively controlling cell damage and improving the delivery efficiency. Nm-AuPNPs exhibit surface plasmon absorption at near infrared region with a peak at 945 nm. Pulsed laser illumination at this plasmon peak triggers explosive nanobubbles, which create transient membrane pores, allowing the delivery of dyes, quantum dots and plasmids into the different cell types. The results can be tuned by laser fluence, exposure time, molecular size and concentration of nm-AuPNPs. The best results are found for CL1-0 cells, which yielded a 94% intracellular PI dye uptake and ∼100% cell viability at 35 mJ cm
−2
laser fluence for 945 nm wavelength. Thus, the presented approach has proven to have an inevitable potential for biological cell research and therapeutic applications.
Here, an efficient intracellular delivery of molecules with high cell viability is reported using plasmonic photoporation mediated by nano-corrugated mushroom-shaped gold-coated polystyrene nanoparticles at near-infrared wavelength.
Personalized medical care focuses on prediction of disease risk and response to medications. To build the risk models, access to both large-scale genomic resources and human genetic studies is ...required. The Taiwan Biobank (TWB) has generated high-coverage, whole-genome sequencing data from 1492 individuals and genome-wide SNP data from 103,106 individuals of Han Chinese ancestry using custom SNP arrays. Principal components analysis of the genotyping data showed that the full range of Han Chinese genetic variation was found in the cohort. The arrays also include thousands of known functional variants, allowing for simultaneous ascertainment of Mendelian disease-causing mutations and variants that affect drug metabolism. We found that 21.2% of the population are mutation carriers of autosomal recessive diseases, 3.1% have mutations in cancer-predisposing genes, and 87.3% carry variants that affect drug response. We highlight how TWB data provide insight into both population history and disease burden, while showing how widespread genetic testing can be used to improve clinical care.
Cancer-initiating cells (CICs) are responsible for tumor initiation, progression, and therapeutic resistance; moreover, redox homeostasis is important in regulating cancer stemness. Previously, we ...have identified that cancer cells containing low intracellular reactive oxygen species levels (ROS
cells) display enhanced features of CICs. However, the specific metabolic signatures of CICs remain unclear and are required for further characterization by systemic screenings. Herein, we first showed CICs mainly relying on glycolysis that was important for the maintenance of stemness properties. Next, we revealed that NRF2, a master regulator of antioxidants, was able to maintain low intracellular ROS levels of CICs, even though in the absence of oxidative stress. We further characterized that NRF2 activation was required for the maintenance of CICs properties. Of ROS
cells, NRF2 activation not only directly activates the transcription of genes encoding glycolytic enzymes but also inhibited the conversion of pyruvate to acetyl-CoA by directly activating pyruvate dehydrogenase kinase 1 (PDK1) to lead to inhibition of tricarboxylic acid (TCA) cycle; therefore, to promote Warburg effect. A positive regulatory ROS-independent ER stress pathway (GRP78/p-PERK/NRF2 signaling) was identified to mediate the metabolic shift (Warburg effect) and stemness of CICs. Lastly, co-expression of p-PERK and p-NRF2 was significantly associated with the clinical outcome. Our data show that NRF2 acting as a central node in the maintenance of low ROS levels and stemness associated properties of the CICs, which is significantly associated with the clinical outcome, but independent from ROS stress. Future treatments by inhibiting NRF2 activation may exhibit great potential in targeting CICs.
The inflammatory cytokine interleukin-6 (IL-6) is critical for the expression of octamer-binding transcription factor 4 (OCT4), which is highly associated with early tumor recurrence and poor ...prognosis of hepatocellular carcinomas (HCC). DNA methyltransferase (DNMT) family is closely linked with OCT4 expression and drug resistance. However, the underlying mechanism regarding the interplay between DNMTs and IL-6-induced OCT4 expression and the sorafenib resistance of HCC remains largely unclear.
HCC tissue samples were used to examine the association between DNMTs/OCT4 expression levels and clinical prognosis. Serum levels of IL-6 were detected using ELISA assays (n = 144). Gain- and loss-of-function experiments were performed in cell lines and mouse xenograft models to determine the underlying mechanism in vitro and in vivo.
We demonstrate that levels of DNA methyltransferase 3 beta (DNMT3b) are significantly correlated with the OCT4 levels in HCC tissues (n = 144), and the OCT4 expression levels are positively associated with the serum IL-6 levels. Higher levels of IL-6, DNMT3b, or OCT4 predicted early HCC recurrence and poor prognosis. We show that IL-6/STAT3 activation increases DNMT3b/1 and OCT4 in HCC. Activated phospho-STAT3 (STAT-Y640F) significantly increased DNMT3b/OCT4, while dominant negative phospho-STAT3 (STAT-Y705F) was suppressive. Inhibiting DNMT3b with RNA interference or nanaomycin A (a selective DNMT3b inhibitor) effectively suppressed the IL-6 or STAT-Y640F-induced increase of DNMT3b-OCT4 and ALDH activity in vitro and in vivo. The fact that OCT4 regulates the DNMT1 expressions were further demonstrated either by OCT4 forced expression or DNMT1 silence. Additionally, the DNMT3b silencing reduced the OCT4 expression in sorafenib-resistant Hep3B cells with or without IL-6 treatment. Notably, targeting DNMT3b with nanaomycin A significantly increased the cell sensitivity to sorafenib, with a synergistic combination index (CI) in sorafenib-resistant Hep3B cells.
The DNMT3b plays a critical role in the IL-6-mediated OCT4 expression and the drug sensitivity of sorafenib-resistant HCC. The p-STAT3 activation increases the DNMT3b/OCT4 which confers the tumor early recurrence and poor prognosis of HCC patients. Findings from this study highlight the significance of IL-6-DNMT3b-mediated OCT4 expressions in future therapeutic target for patients expressing cancer stemness-related properties or sorafenib resistance in HCC.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
With the rapid development of technology, unmanned aerial vehicles (UAVs) have become more popular and are applied in many areas. However, there are some environments where the Global Positioning ...System (GPS) is unavailable or has the problem of GPS signal outages, such as indoor and bridge inspections. Visual inertial odometry (VIO) is a popular research solution for non-GPS navigation. However, VIO has problems of scale errors and long-term drift. This study proposes a method to correct the position errors of VIO without the help of GPS information for vertical takeoff and landing (VTOL) UAVs. In the initial process, artificial landmarks are utilized to improve the positioning results of VIO by the known landmark information. The position of the UAV is estimated by VIO. Then, the accurate position is estimated by the extended Kalman filter (EKF) with the known landmark, which is used to obtain the scale correction using the least squares method. The Inertial Measurement Unit (IMU) data are used for integration in the time-update process. The EKF can be updated with two measurements. One is the visual odometry (VO) estimated directly by a landmark. The other is the VIO with scale correction. When the landmark is detected during takeoff phase, or the UAV is returning to the takeoff location during landing phase, the trajectory estimated by the landmark is used to update the scale correction. At the beginning of the experiments, preliminary verification was conducted on the ground. A self-developed UAV equipped with a visual-inertial sensor to collect data and a high-precision real time kinematic (RTK) to verify trajectory are applied to flight tests. The experimental results show that the method proposed in this research effectively solves the problems of scale and the long-term drift of VIO.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Optomechanics of colloidal microparticles has wide applications in biological analysis and sensing. For colloidal microspheres or microdroplets, the optomechanical force can be magnified through the ...cavity enhancement effect. However, it is difficult to analyze the force since the colloidal microspheres are suspended in liquid, and addressing a movable microsphere at a specific position in three-dimensional space is also challenging. An on-chip integrated operating platform comprising waveguides and microelectromechanical systems is employed to study the cavity-enhanced optical gradient force on colloidal microspheres, owing to the ability to precisely control the distance between a suspended microsphere and a waveguide through dielectrophoretic force. We introduce two kinds of optomechanical coupling mechanisms at resonance, depending on the initial coupling gap without inclusion of the optical gradient force. One is self-adjusted coupling, where the coupling gap of a suspended microsphere continuously varies with the optical input power, and the other is bistable coupling, where the coupling gap hops from one state to the other as the input power exceeds over a threshold value, which is caused by the nature of nonlinear gap-dependent optical gradient force.
Most cases of hepatocellular carcinoma (HCC) arise with the fibrotic microenvironment where hepatic stellate cells (HSCs) and carcinoma-associated fibroblasts (CAFs) are critical components in HCC ...progression. Therefore, CAF normalization could be a feasible therapy for HCC. Galectin-1 (Gal-1), a β-galactoside-binding lectin, is critical for HSC activation and liver fibrosis. However, few studies has evaluated the pathological role of Gal-1 in HCC stroma and its role in hepatic CAF is unclear. Here we showed that Gal-1 mainly expressed in HCC stroma, but not cancer cells. High expression of Gal-1 is correlated with CAF markers and poor prognoses of HCC patients. In co-culture systems, targeting Gal-1 in CAFs or HSCs, using small hairpin (sh)RNAs or an therapeutic inhibitor (LLS30), downregulated plasminogen activator inhibitor-2 (PAI-2) production which suppressed cancer stem-like cell properties and invasion ability of HCC in a paracrine manner. The Gal-1-targeting effect was mediated by increased a disintegrin and metalloprotease 17 (ADAM17)-dependent TNF-receptor 1 (TNFR1) shedding/cleavage which inhibited the TNF-α → JNK → c-Jun/ATF2 signaling axis of pro-inflammatory gene transcription. Silencing Gal-1 in CAFs inhibited CAF-augmented HCC progression and reprogrammed the CAF-mediated inflammatory responses in a co-injection xenograft model. Taken together, the findings uncover a crucial role of Gal-1 in CAFs that orchestrates an inflammatory CSC niche supporting HCC progression and demonstrate that targeting Gal-1 could be a potential therapy for fibrosis-related HCC.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
CBLC (CBL proto-oncogene c) belongs to the CBL protein family, which has E3 ubiquitin ligase activity toward activated receptor tyrosine kinases. CBLC is frequently upregulated in non-small cell lung ...cancer (NSCLC), yet very little is known about the functions of CBLC in tumorigenesis. Here we show that
is an epigenetically demethylated target and its expression can be upregulated in NSCLC after treatment with the DNA methylation inhibitor 5'-azacytidine. Depletion of CBLC significantly inhibited cell viability and clonogenicity
and reduced tumor growth in a xenograft model. CBLC silencing further sensitized EGFR-mutated NSCLC cells to treatment with tyrosine kinase inhibitors. Conversely, ectopic expression of CBLC enhanced the activation of EGFR and downstream ERK1/2 signaling after ligand stimulation by competing with CBL for EGFR binding. Analysis of ubiquitin linkages on activated EGFR (aEGFR) revealed that CBLC ubiquitinated and positively regulated aEGFR stability through the conjugation of polyubiquitin by K6 and K11 linkages. This CBLC-mediated polyubiquitination promoted either preferential recycling of aEGFR back to the plasma membrane or trafficking to the cell nucleus. IHC analyses revealed a positive correlation between phospho-EGFR and CBLC in lung adenocarcinoma. In summary, we demonstrate a novel mechanism by which aEGFR escapes lysosomal degradation in a CBLC/ubiquitin-dependent manner to sustain its activation. Our work identifies CBLC as a potential diagnostic biomarker and also points to its utilization as a novel therapeutic target for NSCLC therapy.
This work demonstrates the role of CBLC expression as a diagnostic biomarker and potential therapeutic target in lung adenocarcinoma.
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This study investigated the relationship among tourists’ perceived sustainability, aesthetic experience, and behavioral intention toward reused heritage buildings by employing ...stimulus–organism–response theory. There were 354 valid questionnaires collected from the Sputnik Lab in Tainan, Taiwan. A positive correlation was found between tourists’ perception of sustainability and aesthetic experience. When tourists perceived higher aesthetic experience, they also had stronger behavioral intention. Structural equation modeling analysis verified that the aesthetic experience of tourists had mediating effects between perceived sustainability and behavioral intention in the reused heritage space. The reuse of space should be attached significantly to the aesthetic display of space and service so as to promote such scenic spots and increase tourists’ intention to revisit through word of mouth.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
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