ARPC2 is a subunit of the Arp2/3 complex, which is essential for lamellipodia, invadopodia and filopodia, and ARPC2 has been identified as a migrastatic target molecule. To identify ARPC2 inhibitors, ...we generated an ARPC2 knockout DLD‐1 human colon cancer cell line using the clustered regularly interspaced short palindromic repeats/CRISPR‐associated protein 9 (CRISPR/Cas9) system and explored gene signature‐based strategies, such as a connectivity map (CMap) using the gene expression profiling data of ARPC2 knockout and knockdown cells. From the CMap‐based drug discovery strategy, we identified pimozide (a clinically used antipsychotic drug) as a migrastatic drug and ARPC2 inhibitor. Pimozide inhibited the migration and invasion of various cancer cells. Through drug affinity responsive target stability (DARTS) analysis and cellular thermal shift assay (CETSA), it was confirmed that pimozide directly binds to ARPC2. Pimozide increased the lag phase of Arp2/3 complex‐dependent actin polymerization and inhibited the vinculin‐mediated recruitment of ARPC2 to focal adhesions in cancer cells. To validate the likely binding of pimozide to ARPC2, mutant cells, including ARPC2F225A, ARPC2F247A and ARPC2Y250F cells, were prepared using ARPC2 knockout cells prepared by gene‐editing technology. Pimozide strongly inhibited the migration of mutant cells because the mutated ARPC2 likely has a larger binding pocket than the wild‐type ARPC2. Therefore, pimozide is a potential ARPC2 inhibitor, and ARPC2 is a new molecular target. Taken together, the results of the present study provide new insights into the molecular mechanism and target that are responsible for the antitumor and antimetastatic activity of pimozide.
Pimozide is identified as a migrastatic drug and ARPC2 inhibitor from connectivity map‐based drug discovery strategy. Pimozide inhibits migration and invasion in various cancer cell lines, and suppresses metastasis in an in vivo antimetastatic assay. Through drug affinity responsive target stability (DARTS) analysis and cellular thermal shift assay (CETSA), it was confirmed that pimozide directly binds to ARPC2.
Thin-film transistor (TFT)-driven full-color organic light-emitting diodes (OLEDs) with vertically stacked structures are developed herein using photolithography processes, which allow for ...high-resolution displays of over 2,000 pixels per inch. Vertical stacking of OLEDs by the photolithography process is technically challenging, as OLEDs are vulnerable to moisture, oxygen, solutions for photolithography processes, and temperatures over 100 °C. In this study, we develop a low-temperature processed Al
O
/SiN
bilayered protection layer, which stably protects the OLEDs from photolithography process solutions, as well as from moisture and oxygen. As a result, transparent intermediate electrodes are patterned on top of the OLED elements without degrading the OLED, thereby enabling to fabricate the vertically stacked OLED. The aperture ratio of the full-color-driven OLED pixel is approximately twice as large as conventional sub-pixel structures, due to geometric advantage, despite the TFT integration. To the best of our knowledge, we first demonstrate the TFT-driven vertically stacked full-color OLED.
To investigate the triglyceride-glucose (TyG) index association with coronary artery calcification (CAC) progression in adult Koreans.
Various cardiovascular risk factors and anthropometric profiles ...were assessed in 1,175 subjects who previously had a CAC evaluation at least twice by multidetector computed tomography in a health care center. The TyG index was determined using ln(fasting triglycerides mg/dL × fasting glucose mg/dL/2). The CAC progression was defined as either incident CAC in a CAC-free population at baseline or an increase of ≥2.5 units between the square roots of the baseline and follow-up coronary artery calcium scores (CACSs) of subjects with detectable CAC at baseline.
CAC progression was seen in 312 subjects (27%) during 4.2 years follow-up. On the basis of the TyG index, subjects were stratified into three groups. Follow-up CACS and incidence of CAC progression were markedly elevated with rising TyG index tertile. Logistic regression analysis adjusted for various risk factors revealed an odds ratio for CAC progression of 1.82 (95% CI 1.20-2.77;
≤ 0.01) when the highest and lowest TyG index tertiles were compared.
The TyG index is an independent predictor of CAC progression.
Cancer cells, compared to normal cells, are under oxidative stress associated with an elevated level of reactive oxygen species (ROS) and are more vulnerable to oxidative stress induced by ROS ...generating agents. Thus, manipulation of the ROS level provides a logical approach to kill cancer cells preferentially, without significant toxicity to normal cells, and great efforts have been dedicated to the development of strategies to induce cytotoxic oxidative stress for cancer treatment. Fenton reaction is an important biological reaction in which irons convert hydrogen peroxide (H2O2) to highly toxic hydroxyl radicals that escalate ROS stress. Here, we report Fenton reaction-performing polymer (PolyCAFe) micelles as a new class of ROS-manipulating anticancer therapeutic agents. Amphiphilic PolyCAFe incorporates H2O2-generating benzoyloxycinnamaldehyde and iron-containing compounds in its backbone and self-assembles to form micelles that serve as Nano-Fenton reactors to generate cytotoxic hydroxyl radicals, killing cancer cells preferentially. When intravenously injected, PolyCAFe micelles could accumulate in tumors preferentially to remarkably suppress tumor growth, without toxicity to normal tissues. This study demonstrates the tremendous translatable potential of Nano-Fenton reactors as a new class of anticancer drugs.
Inhibition of the signal transducer and activator of transcription 3 (STAT3) signaling pathway is a novel therapeutic strategy to treat human cancers with constitutively active STAT3. During the ...screening of natural products to find STAT3 inhibitors, we identified 2′‐hydroxycinnamaldehyde (HCA) as a STAT3 inhibitor, which was isolated from the stem bark of Cinnamomum cassia. In this study, we found that HCA inhibited constitutive and inducible STAT3 activation in STAT3‐activated DU145 prostate cancer cells. HCA selectively inhibited the STAT3 activity by direct binding to STAT3, which was confirmed by biochemical methods, including a pull‐down assay with biotin‐conjugated HCA, a drug affinity responsive target stability (DARTS) experiment and a cellular thermal shift assay (CETSA). HCA inhibited STAT3 phosphorylation at the tyrosine 705 residue, dimer formation, and nuclear translocation in DU145 cells, which led to a downregulation of STAT3 target genes. The downregulation of cell cycle progression and antiapoptosis‐related gene expression by HCA induced the accumulation of cells in the G0/G1 phase of the cell cycle and then induced apoptosis. We also found that reactive oxygen species (ROS) were involved in the HCA‐induced inhibition of STAT3 activation and cell proliferation because the suppressed p‐STAT3 level was rescued by glutathione or N‐acetyl‐L‐cysteine treatment, which are general ROS inhibitors. These results suggest that HCA could be a potent anticancer agent targeting STAT3‐activated tumor cells.
2′‐Hydroxycinnamaldehyde inhibits STAT3 activation and cell proliferation through STAT3‐dependent and ROS‐dependent pathways. 2′‐Hydroxycinnamaldehyde is highly effective in prostate cancer cells with activated‐STAT3 and also suppressed DU‐145 tumor growth in an animal model. 2′‐Hydroxycinnamaldehyde has low toxicity against normal human cells and selective toxicity toward cancer cells.
Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in human cancers. Therefore, STAT3 is a therapeutic target of cancer drug discovery. We previously reported that ...natural products inhibited constitutively activated STAT3 in human prostate tumor cells. We used a dual‐luciferase assay to screen 200 natural products isolated from herbal medicines and we identified ginkgetin obtained from the leaves of Ginkgo biloba L. as a STAT3 inhibitor. Ginkgetin inhibited both inducible and constitutively activated STAT3 and blocked the nuclear translocation of p‐STAT3 in DU‐145 prostate cancer cells. Furthermore, ginkgetin selectively inhibited the growth of prostate tumor cells stimulated with activated STAT3. Ginkgetin induced STAT3 dephosphorylation at Try705 and inhibited its localization to the nucleus, leading to the inhibition of expression of STAT3 target genes such as cell survival‐related genes (cyclin D1 and survivin) and anti‐apoptotic proteins (Bcl‐2 and Bcl‐xL). Therefore, ginkgetin inhibited the growth of STAT3‐activated tumor cells. We also found that ginkgetin inhibited tumor growth in xenografted nude mice and downregulated p‐STAT3Tyr705 and survivin in tumor tissues. This is the first report that ginkgetin exerts antitumor activity by inhibiting STAT3. Therefore, ginkgetin is a good STAT3 inhibitor and may be a useful lead molecule for development of a therapeutic STAT3 inhibitor.
Ginkgetin, isolated from Ginkgo biloba, is highly effective in prostate cancer cells with activated‐STAT3. Ginkgetin has low toxicity against normal human cells and selective toxicity toward cancer cells. Ginkgetin suppressed DU‐145 tumor growth and STAT3 activities in the tumor tissues grown from DU‐145 cells in an animal model.
The circular waveguide aperture or open-end radiator, one of the canonical antenna elements, can be filled with a dielectric material for miniaturization. With dielectric filling, the aperture ...reflection increases and impedance matching is necessary. This paper presents a simple but innovative simulation-based approach to the aperture matching of a dielectric-filled circular waveguide aperture. By properly loading the aperture with two- or three-section dielectric rings, the impedance matching is possible over a wide frequency range starting slightly above the TE
-mode cutoff and continuing upward. The material for the aperture matching is the same as that filling the waveguide. The proposed matching structure is analyzed and optimized using a simulation tool for the dielectric constant
of the filling material ranging from 1.8 to 10. For
≥ 5, the unmatched reflection coefficient ranges from -6.0 dB to -0.9 dB while the matched reflection coefficient is from -20.4 dB to -10.0 dB. The impedance matching has been achieved over more than an octave bandwidth.
The triglyceride glucose (TyG) index has been suggested as a simple surrogate marker of insulin resistance. However, there are limited data regarding the association between the TyG index and ...arterial stiffness in adults. Therefore, we evaluated the relationship between the TyG index and arterial stiffness as measured based on brachial ankle pulse wave velocity (baPWV) in Korean adults.
A total of 3587 subjects were enrolled in this study. Anthropometric and cardiovascular risk factors were measured. The TyG index was calculated as lnfasting triglycerides(mg/dl) × fasting glucose(mg/dl)/2, and the insulin resistance index of homeostasis model assessment (HOMA-IR) was estimated. Arterial stiffness was determined by measuring baPWV.
The subjects were stratified into four groups based on the TyG index. There were significant differences in cardiovascular parameters among the groups; the mean baPWV increased significantly with increasing TyG index. According to the logistic regression analysis after adjusting for multiple risk factors, the odds ratio (95% CI) for increased baPWV (> 75th percentile) for the highest and lowest quartiles of the TyG index was 2.92 (1.92-4.44) in men and 1.84 (1.15-2.96) in women, and the odds ratio for increased baPWV for the highest and lowest quartiles of the HOMA-IR was 1.80 (1.17-2.78) in men and 1.46 (1.06-2.47) in women, respectively.
The TyG index is more independently associated with increased arterial stiffness than HOMA-IR in Korean adults.
ZnSe/ZnS core/shell quantum dots (QDs) with efficient blue emission are in situ synthesized using a novel microfluidic reaction system. This advances research on both simple one‐step synthesis of ...core/shell QDs and their production using thermoplastic‐based microfluidic reaction systems. Furthermore, QD light‐emitting diodes (LEDs) are demonstrated using ZnSe/ZnS QDs as wavelength converters.
Signal transducer and activator of transcription 3 (STAT3) is aberrantly activated in many human cancers. We tried to find STAT3 inhibitors from natural sources and found that Xanthium fruit extracts ...decreased phosphorylation of STAT3‐Y705. 8‐Epi‐xanthatin (EXT) was isolated from the extracts. When DU145 cancer cells were treated with EXT, p‐STAT3‐Y705 was decreased with an IC50 of 3.2 μM. EXT decreased the expression of STAT3 target genes, such as cyclin A, cyclin D1, and BCL‐2, and induced PARP cleavage, indicating apoptotic cell death. Downregulation of EXT‐induced p‐STAT3‐Y705 was rescued by pretreating DU145 cells with antioxidants, such as N‐acetyl‐L‐cysteine (NAC), indicating that reactive oxygen species (ROS) were involved in the EXT‐induced inhibition of STAT3 activation. Furthermore, we proved the association of EXT with STAT3 protein by using a drug affinity responsive target stability (DARTS) assay and a cellular thermal shift assay (CETSA). EXT inhibited proliferation of DU145 cells with a GI50 of 6 μM and reduced tumor growth in mice xenografted with DU145 cells. Immunoblotting showed that phosphorylation of STAT3‐Y705 was lower in EXT‐treated tumor tissue than in control tissues. Collectively, we found that EXT binds to, and inhibits, STAT3 activation and could be a lead compound for anticancer therapy.
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