High TEAD4 Expression is Associated With Aggressive Clear Cell Renal Cell Carcinoma, Regardless of YAP1 Expression.

Yes-associated protein 1 (YAP1) and transcriptional coactivator TEA domain transcription factor 4 (TEAD4) are the main effectors of the Hippo signaling pathway. Deregulation of the Hippo signaling pathway significantly impacts tumorigenesis and tumor progression. We evaluated the mRNA expression level of YAP1 and TEAD4 using the Gene Expression Profiling Interactive Analysis database and investigated the roles of YAP1 and TEAD4 in 349 surgically resected clear cell renal cell carcinoma (CCRCC) samples through immunohistochemical analysis. High YAP1 and TEAD4 expression were observed in 57 (16.3%) and 131 (37.5%) cases, respectively. High YAP1 expression was associated with a low nuclear grade only. High TEAD4 expression was significantly associated with large tumor size, high nuclear grade, lymphovascular invasion, advanced pT classification, advanced clinical stage, sarcomatous differentiation, and metastasis. CCRCC with YAP1-low/TEAD4-high expression was significantly associated with aggressive clinicopathological variables and poor outcomes. For CCRCC, higher tumor stage, sarcomatous differentiation, and metastasis were the independent prognostic factors for overall survival (OS) and disease-free survival (DFS). High TEAD4 expression was significantly associated with short OS and DFS but was not an independent prognostic factor. High TEAD4 and YAP1-low/TEAD4-high expression significantly correlated with adverse clinicopathological factors and worse OS and DFS in patients with CCRCC. YAP1 expression was not significantly associated with clinicopathological factors or patient survival. Therefore, TEAD4 plays a critical role in CCRCC tumor progression independent of YAP1 and may be a potential biomarker and therapeutic target for CCRCC.

Triphenylphosphonium conjugation to a TRAP1 inhibitor, 2-amino-6-chloro-7,9-dihydro-8H-purin-8-one increases antiproliferative activity.

Tumor-necrosis-factor-receptor associated protein 1 (TRAP1), a mitochondrial paralog of heat shock protein 90 family proteins, is overexpressed in many cancer cells and supports tumorigenesis by rewiring vital metabolic and cell death pathways. The triphenylphosphonium moiety is used to deliver therapeutic cargo to increase drug uptake into mitochondria. Various aryl- or alkyl-substituted phosphonium analogs were conjugated with TRAP1-selective inhibitors 4a-c to optimize anticancer activity. Among these various phosphonium-conjugated compounds, (6-(2-amino-9-(4-bromo-2-fluorobenzyl)-6-chloro-8-oxo-8,9-dihydro-7H-purin-7-yl)hexyl)triphenylphosphornium (6a) was identified as a potential anticancer agent. Compound 6a had IC50 values of 0.30-3.24 µM in seven different cancer cell lines and potently suppressed tumor growth without any noticeable in vivo toxicity in a nude mouse model xenografted with PC3 prostate cancer cells.

Synaptic Transistors Exhibiting Gate-Pulse-Driven, Metal-Semiconductor Transition of Conduction.

Neuromorphic devices have been investigated extensively for technological breakthroughs that could eventually replace conventional semiconductor devices. In contrast to other neuromorphic devices, the device proposed in this paper utilizes deep trap interfaces between the channel layer and the charge-inducing dielectrics (CID). The device was fabricated using in-situ atomic layer deposition (ALD) for the sequential deposition of the CID and oxide semiconductors. Upon the application of a gate bias pulse, an abrupt change in conducting states was observed in the device from the semiconductor to the metal. Additionally, numerous intermediate states could be implemented based on the number of cycles. Furthermore, each state persisted for 10,000 s after the gate pulses were removed, demonstrating excellent synaptic properties of the long-term memory. Moreover, the variation of drain current with cycle number demonstrates the device's excellent linearity and symmetry for excitatory and inhibitory behaviors when prepared on a glass substrate intended for transparent devices. The results, therefore, suggest that such unique synaptic devices with extremely stable and superior properties could replace conventional semiconducting devices in the future.

Transparent Thin-Film Silicon Solar Cells for Indoor Light Harvesting with Conversion Efficiencies of 36% without Photodegradation.

With the development of the Internet of Things (IoT), indoor photovoltaics are attracting considerable interest owing to their potential to benefit various IoT-related fields. Therefore, this study investigates the use of transparent hydrogenated amorphous silicon (a-Si:H) solar cells for a broad range of applications, including indoor light harvesting. High-gap triple layers were employed in the a-Si:H solar cells to obtain a high shunt resistance and high short-circuit current, JSC, and open-circuit voltage, VOC, under indoor illumination. Additionally, multiple color-adjusting layers were added without noticeable costs to the conversion efficiency. The maximum efficiency of 36.0% was obtained at a transmittance of 20.44% under white LED light (3000 lx and 0.92 mW cm-2). Furthermore, the fabricated transparent solar cells show excellent long-term performance, sustaining over 99% of original efficiency under continuous indoor light illumination for 200 h. These cells could accelerate the progress of energy harvesting in IoT applications and facilitate the construction of integrated photovoltaics.

Characterization and Preservation Performance of Multilayer Film with Insect Repellent and Antimicrobial Activities for Sliced Wheat Bread Packaging.

A multilayer film containing star anise essential oil and thymol coating layers (SAEO and TH, respectively), with insect repellent and antimicrobial properties, has been developed using bar coating and adhesive lamination processes. Our previous study reported the in vitro activities of this polypropylene film (PP)/SAEO/polyethylene terephthalate film (PET)/TH/low-density polyethylene film (LDPE) multilayer film. The current study focused on demonstrating the morphological, optical, and mechanical properties of the film, and evaluating its in vivo activities when used as a bread packaging material. The developed film was 15.03% thicker and 1.86% less transparent than the control film (without active agent coating layers: PP/PET/LDPE). While the color values of the developed film were slightly different from the control film, both films appeared similar to the naked eye. The tensile strength in the developed film was somewhat lower than that of the control film, while both films had statistically comparable values for elongation at break. During storage of sliced bread packaged in the developed film, the film both deterred insects from approaching toward and impeded the growth of microorganisms in the bread. These results suggest the potential applicability of the developed film as an active food packaging material with insect repellent and antimicrobial activities. PRACTICAL APPLICATION: A multilayer film incorporated with insect repellent and antimicrobial coating layers was applied in sliced wheat bread packaging. The developed film effectively inhibited approaches of stored-product insects to packaged bread and growth of microorganisms on the bread surface. It can be used as an active food packaging material that improves the safety and shelf-life of foods.

Development of A Comprehensive Biological Hazard-Proof Packaging Film with Insect-Repellent, Antibacterial, and Antifungal Activities.

A multifunctional film with insect-repellent and antimicrobial activities was developed. Star anise (Illicium verum Hook. f.) oil (SO) proved to be effective in repelling Plodia interpunctella (Hübner) (Lepidoptera: Pyralidae) larvae and was selected as an insect-repellent agent. Thymol, a compound that demonstrated strong growth inhibition activities against both Staphylococcus aureus and Penicillium roqueforti, was selected as an antimicrobial agent. Based on the release profile test of SO using various plastic films, polypropylene (30 µm; PP 30) and low-density polyethylene (20 µm; LDPE 20) were selected as laminated films for sustainable insect-repellent and strong antimicrobial effects, respectively. Further, polyethylene terephthalate (12 µm; PET 12) was selected as an intermediate barrier layer. Finally, structure of the multilayer film was designed as PP 30/SO/PET 12/thymol/LDPE 20. The developed film demonstrated insect-repellent activity for >3 weeks, antibacterial activity for >2 weeks, and antifungal activity for 1 week. The results indicated that the developed multilayer film structure possessed strong, sustained insect-repellent and antimicrobial effects, providing a new possibility for the industrial applications to food packaging. PRACTICAL APPLICATION: A multifunctional active packaging film with insect-repellent and antimicrobial activities was developed. Star anise oil and thymol that showed insect-repellent and antimicrobial activities (antibacterial and antifungal activities), respectively, were added in coating layers in the multilayer film structure. The developed multilayer film proved an efficient insect-repellent activity against Plodia interpunctella for >3 weeks. Also, strong antibacterial and antifungal activities of the developed multilayer film were proved against Staphylococcus aureus and Penicillium roqueforti, respectively. The developed film has a potential for the industrial use to the food packaging material.

Clinical characteristics and related risk factors of depression in patients with early COPD.

Background and objective: Although depression is considered one of the comorbidities of COPD, the clinical characteristics of depression in patients with early COPD remain unknown. We aimed to use national-level data to identify the clinical features and risk factors of depression in patients with early COPD. Methods: We examined 7,550 subjects who were registered in the Korean National Health and Nutrition Examination Survey database of 2014 because that was the only year in which the Patient Health Questionnaire-9 for depression status was administered. Spirometry was used to identify patients with COPD whose forced expiratory volume in 1 second was 50% or more, and these patients were included in the analysis. Results: Of the 211 subjects with early COPD, 14.2% also had depression, whereas 85.8% did not. The patients with depression were predominantly living alone and had a greater prevalence of diabetes compared with the patients without depression. The overall quality of life of the subjects with depression was lower than that of those without depression, and only the quality of life index correlated significantly with depression severity. In the multivariate regression analysis, female sex (adjusted OR, 1.79; 95% CI, 1.38-2.31; p<0.01), living alone (adjusted OR, 1.86; 95% CI, 1.37-2.51; p<0.01), and low income (adjusted OR, 2.17; 95% CI, 1.55-3.04; p<0.01) were identified as significant risk factors for depression. Conclusion: In patients with early COPD, depression was associated with a low quality of life, and female sex, living alone and low income were significant risk factors for depression.

Enhanced ocular efficacy of topically-delivered dorzolamide with nanostructured mucoadhesive microparticles.

Dorzolamide eye drops are widely prescribed to reduce intraocular pressure (IOP) in the treatment of ocular hypertension and glaucoma. However, in an eye drop formulation, dorzolamide is rapidly cleared from the preocular space, hence requiring multiple daily administrations. Here, we sought to increase the preocular retention of dorzolamide using nanostructured, mucoadhesive microparticles (MUCO_NM) as carriers for topical delivery to the eye. MUCO_NM were prepared by freeze-milling dorzolamide-loaded, electrospun nanofibers composed of poly(lactic-co-glycolic acid) and polyethylene glycol. The microparticles were embedded in a rapidly-dissolving tablet of polyvinyl alcohol. To assess in vivo efficacy, the MUCO_NM were administered topically to the eyes of rabbits, and IOP was measured and compared to that in eyes treated with Trusopt®, a marketed eye drop of dorzolamide. The MUCO_NM showed a 35% greater maximum IOP decrease and a>2-fold increase in the duration of the IOP decrease, compared to Trusopt®. This enhanced efficacy was comparable to that obtained with a single administration of 4 drops of Trusopt® or 2 administrations of Trusopt® at a 4-h interval. Our findings suggest that this MUCO_NM preparation is a promising carrier for topical delivery of dorzolamide to the eye, with enhanced drug efficacy and the potential to reduce administration frequency.

Vascular Ehlers-Danlos syndrome with cryptorchidism, recurrent pneumothorax, and pulmonary capillary hemangiomatosis-like foci: A case report.

RATIONALE: Vascular Ehlers-Danlos syndrome (vEDS) is a rare autosomal dominant inherited collagen disorder caused by defects or deficiency of pro-alpha 1 chain of type III procollagen encoded by COL3A1. vEDS is characterized not only by soft tissue manifestations including hyperextensibility of skin and joint hypermobility but also by early mortality due to rupture of arteries or vital organs. Although pulmonary complications are not common, vEDS cases complicated by pneumothorax, hemothorax, or intrapulmonary hematoma have been reported. When a patient initially presents only with pulmonary complications, it is not easy for clinicians to suspect vEDS. PATIENT CONCERNS: We report a case of an 18-year-old high school student, with a past history of cryptorchidism, presenting with recurrent pneumothorax. DIAGNOSES: Routine laboratory findings were unremarkable. Chest high resolution computed tomographic scan showed age-unmatched hyperinflation of both lungs, atypical cystic changes and multifocal ground glass opacities scattered in both lower lobes. His slender body shape, hyperflexible joints, and hyperextensible skin provided clue to suspicion of a possible connective tissue disorder. INTERVENTIONS: The histological examination of the lung lesions showed excessive capillary proliferation in the pulmonary interstitium and pleura allowing the diagnosis of pulmonary capillary hemangiomatosis (PCH)-like foci. Genetic study revealed COL3A1 gene splicing site mutation confirming his diagnosis as vEDS. OUTCOMES: Although his diagnosis vEDS is notorious for fatal vascular complication, there was no evidence of such complication at presentation. Fortunately, he has been followed up for 10 months without pulmonary or vascular complications. LESSONS: To the best of our knowledge, both cryptorchidism and PCH-like foci have never been reported yet as complications of vEDS, suggesting our case might be a new variant of this condition. This case emphasizes the importance of comprehensive physical examination and history-taking, and the clinical suspicion of a possible connective tissue disorder when we encounter cases with atypical presentation and/or unique chest radiologic findings especially in young patients.

The effect of employing the p/i buffer layers and in-situ hydrogen treatment for transparent a-Si:H solar cells.

In this study, we describe the effects of various thicknesses of triple p/i buffer layers and hydrogen treatment on various performances in the fabrication of transparent a-Si:H solar cells. For the increment of buffer layer thickness, V(oc) increases steadily and J(sc) firstly increases and then decreases. The triple buffer layers also enhance the transmittance as well as conversion efficiency. For hydrogen plasma treatment, overall performances were enhanced with plasma power due to the passivation of dangling bonds at p/i interface. Therefore, the usage of triple buffer layers with proper treatment is beneficial to obtaining transparent a-Si:H solar cells with high quality.

The radio-sensitizing effect of xanthohumol is mediated by STAT3 and EGFR suppression in doxorubicin-resistant MCF-7 human breast cancer cells.

BACKGROUND: Chemotherapeutic drug resistance remains a clinical obstacle in cancer management. Drug-resistant cancer cells usually exhibit cross-resistance to ionizing radiation, which has devastating consequences for patients. With a better understanding of the molecular mechanisms, it will be possible to develop strategies to overcome this cross-resistance and to increase therapeutic sensitivity. METHODS: Natural and synthetic flavonoid compounds including xanthohumol, the principal flavonoid in hops, were investigated for its radio-sensitizing activity on human breast cancer MCF-7 and adriamycin-resistant MCF-7 (MCF-7/ADR) cells. Chemo-sensitizing or radio-sensitizing effect was analyzed by tetrazolium-based colorimetric assay and flow cytometry. Western blot analysis, confocal microscopy, gene silencing with siRNA transfection and luciferase reporter gene assay were performed to examine signaling molecule activation. RESULTS: Among the tested flavonoid compounds, pretreatment of the cells with xanthohumol significantly sensitized MCF-7/ADR cells to the radiation treatment by inducing apoptosis. In MCF-7/ADR cells, treatment with xanthohumol alone or with gamma-rays significantly decreased levels of anti-apoptotic proteins. Multi-drug resistance 1 (MDR1), epidermal growth factor receptor (EGFR) and signal transducer and activator of transcription 3 (STAT3) expression levels in MCF-7/ADR cells were suppressed by xanthohumol treatment. In addition, xanthohumol treatment increased death receptor (DR)-4 and DR5 expression. The xanthohumol-induced changes of these resistance-related molecules in MCF-7/ADR cells were synergistically increased by gamma-ray treatment. CONCLUSIONS: Xanthohumol restored sensitivity of MCF-7/ADR cells to doxorubicin and radiation therapies. GENERAL SIGNIFICANCE: Our results suggest that xanthohumol may be a potent chemo- and radio-sensitizer, and its actions are mediated through STAT3 and EGFR inhibition.

Induction of p53-independent apoptosis by a novel synthetic hexahydrocannabinol analog is mediated via Sp1-dependent NSAID-activated gene-1 in colon cancer cells.

Nonsteroidal anti-inflammatory drug (NSAID)-activated gene-1 (NAG-1) has received greater attention as a novel molecular target for anti-cancer therapeutics in recent years. We identified a novel synthetic hexahydrocannabinol analog, LYR-8 [(1-((9S)-1-hydroxy-6,6,9-trimethyl-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-2-yl)ethanone)], as a potent NAG-1 and apoptosis inducer in a panel of human cancer cells. LYR-8 did not possess any affinity for cannabinoid receptor CB(1) or CB(2), which eliminates the concern about potential psychoactive side effects. LYR-8 dramatically induced NAG-1 expression and apoptosis in HCT116 (wild-type p53) and HT29 (mutant p53) colon cancer cells. The NAG-1 expression by LYR-8 was not blocked by pifithrin-alpha, a specific p53 inhibitor, which was different from doxorubicin that induced p53-dependent NAG-1 transcriptional activity. The induction of NAG-1 promoter activity by LYR-8 was strongly correlated with increased Sp1 activation as noted in various luc-promoter activities. Furthermore, pretreatment with the specific Sp1 inhibitor mithramycin A completely reversed the LYR-8-induced NAG-1 expression in both HCT116 and HT29 cells. Knockdown of NAG-1 using siRNA significantly reversed LYR-8-induced cell death in both wild-type and mutant p53-expressing colon cancer cells. Furthermore, sensitization with NAG-1 inducer sulindac sulfide synergized LYR-8-induced cell death in both colon cancer cells. These results suggest that induction of NAG-1 via Sp1 activation is a promising therapeutic approach in cancer treatment, and that a novel compound like LYR-8 could be a potent chemotherapeutic agent for colon cancers including p53-mutated cancer.

Inhibitory effects of clotrimazole on TNF-alpha-induced adhesion molecule expression and angiogenesis.

Cell adhesion molecules play a pivotal role in chronic inflammation and pathological angiogenesis. In the present study, we investigated the inhibitory effects of clotrimazole (CLT) on tumor necrosis factor (TNF)-alpha-induced changes in adhesion molecule expression. CLT dose-dependently inhibited monocyte chemoattractant protein-1 (MCP-1), intercellular cell adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) expressions in TNF-alpha-stimulated HT29 colonic epithelial cells. This inhibitory action of CLT correlated with a significant reduction in TNF-alpha-induced adhesion of monocytes to HT29 cells, which was comparable to the inhibitory effects of anti-ICAM-1 and VCAM-1 monoclonal antibodies on monocyte-epithelial adhesion. These inhibitory actions of CLT were, at least in part, attributable to the inhibition of redox sensitive NF-kappaB activation, as CLT inhibited TNF-alpha-induced ROS generation as well as NF-kappaB nuclear translocation and activation in HT29 cells. Furthermore, the inhibition of TNF-alpha-induced monocyte adhesion was also mimicked by the specific NF-kappaB inhibitor, pyrrolidine dithiocarbamate (PDTC). Inflammatory mediators including TNF-alpha have known to promote angiogenesis, which in turn further contributes to inflammatory pathology. Therefore, we additionally evaluated whether CLT modulates TNF-alpha-induced angiogenesis using in vivo chick chorioallantoic membrane (CAM) assay. The CAM assay showed that CLT dose-dependently attenuated TNF-alpha-induced angiogenesis, and the effect was correlated with decreased inflammation of the CAM tissue. In conclusion, our results suggest that CLT can inhibit TNF-alpha-triggered expression of adhesion molecules, ICAM-1 and VCAM-1, and angiogenesis during inflammation.

Optimum conditions for production and purification of human papillomavirus type 16 L1 protein from Saccharomyces cerevisiae.

Several prophylactic human papillomavirus (HPV) vaccines have been developed based on virus-like particles (VLPs) made from viral L1 proteins. A substantial number of VLPs is necessary for biochemical characterization and diagnostic test development. To establish the optimum conditions for production and purification of HPV L1 in the yeast expression system we varied the amount and nature of the carbon source and evaluated HPV 16 L1 recovery by three purification methods. Maximally threefold more HPV 16 L1 was produced with a 4% carbon source than with a 2% carbon source. In addition, the productivity of HPV 16 L1 varied by 25% depending on the combination of glucose and galactose in the 4% carbon source. We introduced an ammonium sulfate precipitation step in place of the ultracentrifugation using a sucrose cushion routinely used for HPV L1 purification, and optimized the purification by cation-exchange chromatography. Overall L1 protein recovery using the ammonium sulfate precipitation method was 30%, the highest recovery achieved so far. The purified HPV 16 L1 protein successfully self-assembled into VLPs. Purification by ammonium sulfate precipitation was maximally 15 times greater than ultracentrifugation on a sucrose cushion. We anticipate that our procedures for production and purification will reduce the cost, time and labor involved in obtaining sufficient yields of VLPs.

Anti-inflammatory constituents isolated from Clerodendron trichotomum Tunberg Leaves (CTL) inhibits pro-inflammatory gene expression in LPS-stimulated RAW 264.7 macrophages by suppressing NF-kappaB activation.

Clerodendron trichotomum Tunberg Leaves (CTL) have been used for centuries in Chinese folk medicine for their anti-inflammatory properties. To investigate the molecular mechanism of anti-inflammation by CTL, we analyzed the regulation of TNF-alpha expression in RAW 264.7 cells, a key step in inflammation. The effect of CTL on the production and expression of tumor necrosis factor-alpha (TNF-alpha) was determined by enzyme-linked immunosorbent assay (ELISA) and reverse transcription polymerase chain reaction (RT-PCR). CTL inhibited the production and expression of TNF-alpha in LPS-stimulated RAW 264.7 cells in a dose-dependent manner. In addition, activation of NF-kappaB, which controls TNF-alpha expression, was inhibited in LPS-stimulated RAW 264.7 cells by CTL in a dose-dependent manner, as demonstrated by an electro phoretic mobility shift assay (EMSA). Furthermore, CTL inhibited activation of NF-kappaB through inhibition IkappaB degradation, as demonstrated by an western blot analysis of IkappaB-alpha. These results suggest that CTL inhibits the expression of the pro-inflammation gene through the inhibition of NF-kappaB dependent pathway in RAW 264.7 cells.