Fisetin Inhibits UVA-Induced Expression of MMP-1 and MMP-3 through the NOX/ROS/MAPK Pathway in Human Dermal Fibroblasts and Human Epidermal Keratinocytes.

Fisetin is a flavonoid found in plants and has been reported to be effective in various human diseases. However, the effective mechanisms of ultraviolet-A (UVA)-mediated skin damage are not yet clear. In this study, we investigated the protective mechanisms of fisetin regarding UVA-induced human dermal fibroblasts (HDFs) and human epidermal keratinocytes (HEKs) damages. Fisetin showed a cytoprotective effect against UVA irradiation and suppressed matrix metalloproteinases (MMPs), MMP-1, and MMP-3 expression. In addition, fisetin was rescued, which decreased mRNA levels of pro-inflammatory cytokines, reactive oxygen species production, and the downregulation of MAPK/AP-1 related protein and NADPH oxidase (NOX) mRNA levels. Furthermore, UVA-induced MMP-1 and MMP-3 were effectively inhibited by siRNAs to NOX 1 to 5 in HDFs and HEKs. These results indicate that fisetin suppresses UVA-induced damage through the NOX/ROS/MAPK pathway in HDFs and HEKs.

Protaetia brevitarsis Extract Attenuates RANKL-Induced Osteoclastogenesis by Inhibiting the JNK/NF-κB/PLCγ2 Signaling Pathway.

Protaetia brevitarsis (PB)-derived bioactive substances have been used as food and medicine in many Asian countries because of their antioxidant, antidiabetic, anti-cancer, and hepatoprotective properties. However, the effect of PB extracts (PBE) on osteoclast differentiation is unclear. In this study, we investigated the effect of PBE on RANKL-induced osteoclastogenesis in mouse bone marrow-derived macrophages (BMMs). To investigate the cytotoxicity of PBE, the viability of BMMs was confirmed via MTT assay. Tartrate-resistant acid phosphatase (TRAP) staining and pit assays were performed to confirm the inhibitory effect of PBE on osteoclast differentiation and bone resorption. The expression levels of osteoclast differentiation-related genes and proteins were evaluated using quantitative real-time PCR and Western blotting. PBE attenuated osteoclastogenesis in BMMs in TRAP and pit assays without cytotoxicity. The expression levels of osteoclast marker genes and proteins induced by RANKL were decreased after PBE treatment. PBE suppressed osteoclastogenesis by inhibiting the RANKL-induced activated JNK/NF-κB/PLCγ2 signaling pathway and the expression of NFATc1 and c-Fos. Collectively, these results suggest that PBE could be a potential therapeutic strategy or functional product for osteoclast-related bone disease.

Highly Reproducible Heterosynaptic Plasticity Enabled by MoS2/ZrO2-x Heterostructure Memtransistor.

Electrically tunable resistive switching of a polycrystalline MoS2-based memtransistor has attracted a great deal of attention as an essential synaptic component of neuromorphic circuitry because its switching characteristics from the field-induced migration of sulfur defects in the MoS2 grain boundaries can realize multilevel conductance tunability and heterosynaptic functionality. However, reproducible switching properties in the memtransistor are usually disturbed by the considerable difficulty in controlling the concentration and distribution of the intrinsically existing sulfur defects. Herein, we demonstrate reliable heterosynaptic characteristics using a memtransistor device with a MoS2/ZrO2-x heterostructure. Compared to the control device with the MoS2 semiconducting channel, the Schottky barrier height was more effectively modulated by the insertion of the insulating ZrO2-x layer below the MoS2, confirmed by an ultraviolet photoelectron spectroscopy analysis and the corresponding energy-band structures. The MoS2/ZrO2-x memtransistor accomplishes dual-terminal (drain and gate electrode) stimulated multilevel conductance owing to the tunable resistive switching behavior under varying gate voltages. Furthermore, the memtransistor exhibits long-term potentiation/depression endurance cycling over 7000 pulses and stable pulse cycling behavior by the pulse stimulus from different terminal regions. The promising candidate as an essential synaptic component of the MoS2/ZrO2-x memtransistors for neuromorphic systems results from the high recognition accuracy (∼92%) of the deep neural network simulation test, based on the training and inference of handwritten numbers (0-9). The simple memtransistor structure facilitates the implementation of complex neural circuitry.

CDDO, a PPAR-γ ligand, inhibits TPA-induced cell migration and invasion through a PPAR-γ-independent mechanism.

Peroxisome proliferator-activated receptor-γ (PPAR-γ) acts as a key factor in breast cancer metastasis. Notably, PPAR-γ can inhibit metalloproteinase (MMP), which is involved in cancer metastasis. Our previous study revealed that PPAR-γ was related to breast cancer metastasis. The present study aimed to investigate whether the PPAR-γ ligand 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) mediated suppression of cell invasion and reduced the expression of MMP-9 in breast cancer cells. The results indicated that CDDO reduced MMP-9 expression, cell migration and invasion of breast cancer cells by inhibiting TPA-induced phosphorylation of mitogen-activated protein kinases, and downregulating the activities of activator protein-1 and nuclear factor κB. Notably, knock-out of PPAR-γ by small interfering RNA in MCF-7 cells revealed that TPA-induced MMP-9 expression occurred through a PPAR-γ-independent pathway. These data indicated that the downregulatory effect of CDDO on MMP-9 expression was affected by a mechanism independent of PPAR-γ. In conclusion, the findings of the present study suggested that CDDO may act as a key agent in the regulation of breast cancer metastasis, suggesting CDDO as a new targeted therapy for breast cancer.

Inhibition of cell invasion and migration by targeting matrix metalloproteinase-9 expression via sirtuin 6 silencing in human breast cancer cells.

Sirtuin 6 (SIRT6) regulation is involved in carcinogenesis. However, its role in breast cancer (BC) metastasis remains unclear. We investigated the effects of SIRT6 on protein kinase C activator- and cytokine-mediated cancer cell invasion and migration in MCF-7 and MDA-MB-231 cells and the association between SIRT6 and matrix metalloproteinase-9 (MMP-9) expression. To assess MMP-9 and SIRT6 expression in patients, protein levels in BC tissues were analyzed. MCF-7 and MDA-MB-231 cell viability was analyzed using MTT assays. SIRT6 was silenced in both cell lines and protein secretion, expression, and mRNA levels were analyzed. Transcription factor DNA activity was investigated using luciferase assays. Matrigel invasion assays were used to assess the effects of SIRT6 in both cell lines. SIRT6 and MMP-9 expression in cancer tissues was significantly higher than in paired normal breast tissues. 12-O-tetradecanoylphorbol-13-acetate (TPA) or tumor necrosis factor-α (TNF-α) increased MMP-9 expression and cell invasion and migration, but SIRT6 knockdown abolished these effects. SIRT6 overexpression additively increased TPA- and TNF-α-induced MMP-9 expression. SIRT6 knockdown suppressed the mitogen-activated protein kinase (MAPK) signaling pathway and thus TPA- and TNF-α-induced MMP-9 expression. SIRT6 silencing suppressed TPA- and TNF-α-induced nuclear factor-κB (NF-κB) and activator protein-1 (AP-1) expressions in both cell lines, and treatment with MAPK, NF-κB, and AP-1 inhibitors reduced MMP-9 expression. The anti-invasive effects of SIRT6 in BC cells might be mediated by suppression of MAPK phosphorylation and reduction in NF-κB and AP-1 DNA activities, leading to MMP-9 downregulation, suggesting that SIRT6 modulation has the potential to target BC metastasis.

Aurora kinase A induces migration and invasion by inducing epithelial-to-mesenchymal transition in colon cancer cells.

Aurora kinase is a family of serine/threonine kinases intimately associated with mitotic progression and the development of human cancers. Studies have shown that aurora kinases are important for the protein kinase C (PKC)-induced invasion of colon cancer cells. Recent studies have shown that aurora kinase A promotes distant metastasis by inducing epithelial-to-mesenchymal transition (EMT) in colon cancer cells. However, the role of aurora kinase A in colon cancer metastasis remains unclear. In this study, we investigated the effects of aurora kinase A on PKC-induced cell invasion, migration, and EMT in human SW480 colon cancer cells. Treatment with 12-O-tetradecanoylphorbol- 13-acetate (TPA) changed the expression levels of EMT markers, increasing α-SMA, vimentin, and MMP-9 expression and decreasing E-cadherin expression, with changes in cell morphology. TPA treatment induced EMT in a PKC-dependent manner. Moreover, the inhibition of aurora kinase A by siRNAs and inhibitors (reversine and VX-680) suppressed TPA-induced cell invasion, migration, and EMT in SW480 human colon cells. Inhibition of aurora kinase A blocked TPA-induced vimentin and MMP-9 expression, and decreased E-cadherin expression. Furthermore, the knockdown of aurora kinase A decreased the transcriptional activity of NF-κB and AP-1 in PKC-stimulated SW480 cells. These findings indicate that aurora kinase A induces migration and invasion by inducing EMT in SW480 colon cancer cells. To the best of our knowledge, this is the first study that showed aurora kinase A is a key molecule in PKC-induced metastasis in colon cancer cells. [BMB Reports 2022;55(2): 87-91].

Triptolide inhibits matrix metalloproteinase-9 expression and invasion of breast cancer cells through the inhibition of NF-κB and AP-1 signaling pathways.

Triptolide is a diterpenoid epoxide that is endogenously produced by the thunder god vine, Tripterygium wilfordii Hook F. Triptolide has demonstrated a variety of biological activities, including anticancer activities, in previous studies. Invasion and metastasis are the leading causes of mortality for patients with breast cancer, and the increased expression of matrix metalloproteinase-9 (MMP-9) has been shown to be associated with breast cancer invasion. Therefore, the aim of the present study was to investigate the effect of triptolide on 12-O-tetradecanoyl phorbol-13-acetate (TPA)-induced cell invasion and MMP-9 expression in breast cancer cells. The expression of signal molecules was examined by western blotting, zymography and quantitative polymerase chain reaction; an electrophoretic mobility gel shift assay was also used, and cell invasiveness was measured by an in vitro Matrigel invasion assay. The MCF-7 human breast cancer cell line was treated with triptolide at the highest concentrations at which no marked cytotoxicity was evident. The results demonstrated that triptolide decreased the expression of MMP-9 through inhibition of the TPA-induced phosphorylation of extracellular signal-regulated kinase (ERK) and the downregulation of nuclear factor-κB (NF-κB) and activator protein-1 (AP-1) activity. In addition, a Transwell assay revealed that triptolide reduced the ability of MCF-7 cells to invade Matrigel. These data demonstrate that the anti-invasive effect of triptolide is associated with the inhibition of ERK signaling and NF-κB and AP-1 activation, and suggest that triptolide may be a promising drug for breast cancer.

Pulse Pressure Variation is a Valuable Marker for Predicting Fluid Responsiveness in Brain-Dead Donors.

PURPOSE: Hemodynamic management in brain-dead donors (BDDs) is challenging due to hemodynamic instabilities. We compared functional parameters with traditional parameters for hemodynamic monitoring in BDDs. MATERIALS AND METHODS: Seventeen BDDs with a positive balance of >500 mL for 8 hours were included. Functional hemodynamic monitoring, including pulse pressure variation (PPV), stroke volume variation (SVV), cardiac output, and systemic vascular resistance index (SVRI) was performed in the setting of tidal volume of 6 mL/kg to 8 mL/kg and minimal positive end-expiratory pressure of 5 cm to 8 cm H2O. Responders were defined by a cardiac output increase of >15% after fluid therapy. RESULTS: Among the 17 BDDs (mean age, 46.80±13.91 years), 15 were male. Seven responders out of 17 (41.1%) had a significantly higher PPV (22.8±8.4 vs 13.4±5.9%, P = .038) and serum albumin level (3.2±0.6 vs 2.6±0.5 g/L, P = .040) at baseline than nonresponders. However, other hemodynamic markers such as SVV and SVRI were similar between groups. Traditional markers of volume status, such as heart rate, central venous pressure, hemoglobin, and serum uric acid level were also similar between the 2 groups. Hemodynamic markers including PPV, SVV, and SVRI were significantly reduced in responders. CONCLUSIONS: PPV was the most valuable hemodynamic marker for predicting volume responsiveness in BDDs.

Aqueous extract of Chrysanthemum morifolium Ramat. inhibits RANKL-induced osteoclast differentiation by suppressing the c-fos/NFATc1 pathway.

OBJECTIVE: The flower of chrysanthemum, used worldwide as a medicinal and edible product, has shown various bioactivities, such as anti-inflammatory, antioxidant, anti-tumorigenic, and hepatoprotective activities, as well as cardiovascular protection. However, the effect of Chrysanthemum morifolium Ramat. on the regulation of osteoclast differentiation has not yet been reported. In this study, we aimed to investigate the inhibitory effect of Chrysanthemum morifolium Ramat. water extract (CME) on RANKL-induced osteoclast differentiation in mouse bone marrow-derived macrophages (BMMs). STUDY DESIGN: Bone marrow-derived macrophages (BMMs) isolated from the C57BL/6 J mice. The viability of BMMs was detected with MTT assays. Inhibitory effects of CME on osteoclast differentiation and bone resorption was measured by TRAP staining and Pit assay. Osteoclast differentiation-associated gene expression were assessed by Real-time quantitative polymerase chain reaction. Intracellular signaling molecules was assessed by western blot. RESULTS: CME significantly inhibited osteoclast differentiation in BMMs without cytotoxicity, besides inhibiting MAPK/c-fos and PLCγ2/CREB activation. The inhibitory effects of CME on differentiation-related signaling molecules resulted in significant repression of NFATc1 expression, which is a key transcription factor in osteoclast differentiation, fusion, and activation. CONCLUSION: Our results confirmed the inhibition of RANKL-induced PLCγ2/CREB/c-fos/NFATc1 activation by CME during osteoclast differentiation. The findings collectively suggested CME as a traditional therapeutic agent for osteoporosis, RA, and periodontitis.

Ultra-flexible and rollable 2D-MoS2/Si heterojunction-based near-infrared photodetector via direct synthesis.

Atomic two-dimensional (2D) transition metal dichalcogenides (TMDs) have attracted significant attention for application in various optoelectronic devices such as image sensors, biomedical imaging systems, and consumer electronics and in diverse spectroscopic analyses. However, a complicated fabrication process, involving transfer and alignment of as-synthesized 2D layers onto flexible target substrates, hinders the development of flexible high-performance heterojunction-based photodetectors. Herein, an ultra-flexible 2D-MoS2/Si heterojunction-based photodetector is successfully fabricated through atmospheric-pressure plasma enhanced chemical vapor deposition, which enables the direct deposition of multi-layered MoS2 onto a flexible Si substrate at low temperature (<200 °C). The photodetector is responsive to near infrared light (λ = 850 nm), showing responsivity of 10.07 mA W-1 and specific detectivity (D*) of 4.53 × 1010 Jones. The measured photocurrent as a function of light intensity exhibits good linearity with a power law exponent of 0.84, indicating negligible trapping/de-trapping of photo-generated carriers at the heterojunction interface, which facilitates photocarrier collection. Furthermore, the photodetectors can be bent with a small bending radius (5 mm) and wrapped around a glass rod, showing excellent photoresponsivity under various bending radii. Hence, the device exhibits excellent flexibility, rollability, and durability under harsh bending conditions. This photodetector has significant potential for use in next-generation flexible and patchable optoelectronic devices.

Roles of JNK/Nrf2 Pathway on Hemin-Induced Heme Oxygenase-1 Activation in MCF-7 Human Breast Cancer Cells.

Heme oxygenase-1 (HO-1) is highly induced in various human disease states, including cancer, indicating that HO-1 is an emerging target of cancer therapy. In this study, we investigated that the mechanisms of hemin-induced HO-1 expression and its signaling pathways in human breast cancer cell. We used MCF-7 cells, a human breast cancer cell line. Hemin increased HO-1 expression in MCF-7 cells in a dose- and time-dependent manner. Hemin enhanced HO-1 expression through the activation of c-Jun N-terminal kinases (JNK) signaling pathway. Hemin also induced activation of Nrf2, a major transcription factor of HO-1 expression. These responses in MCF-7 cells were completely blocked by pretreatment with brazilin, a HO-1 regulator. These results indicated that brazilin inhibits hemin-induced HO-1 expressions through inactivation of JNK/Nrf2 in MCF-7 cells. Thus, our findings suggest that HO-1 is an important anticancer-target of brazilin in human breast cancer.

Novel Exfoliation of High-Quality 2H-MoS2 Nanoflakes for Solution-Processed Photodetector.

Highly dispersive molybdenum disulfide nanoflakes (MoS2 NFs), without any phase transition during the exfoliation process, are desirable for full utilization of their semiconductor properties in practical applications. Here, we demonstrate an innovate approach for fabricating MoS2 NFs by using hydrazine-assisted ball milling via the synergetic effect of chemical intercalation and mechanical exfoliation. The NFs obtained have a lateral size of 600-800 nm, a thickness less than 3 nm, and high crystallinity in the 2H semiconducting phase. They form a stable dispersion in various solvents, which will be helpful for many applications, due to the oxygen functional group. To investigate production of a two-dimensional (2D) photodetector, 2D semiconducting MoS2, MoS2-p-Si vertical devices were fabricated, and their optical properties were characterized. The photodiode exhibited consistent responses with excellent photo-switching characteristics with wavelengths of 850, 530, and 400 nm.

One-step H2S reactive sputtering for 2D MoS2/Si heterojunction photodetector.

A technique for directly growing two-dimensional (2D) materials onto conventional semiconductor substrates, enabling high-throughput and large-area capability, is required to realise competitive 2D transition metal dichalcogenide devices. A reactive sputtering method based on H2S gas molecules and sequential in situ post-annealing treatment in the same chamber was proposed to compensate for the relatively deficient sulfur atoms in the sputtering of MoS2 and then applied to a 2D MoS2/p-Si heterojunction photodevice. X-ray photoelectron, Raman, and UV-visible spectroscopy analysis of the as-deposited Ar/H2S MoS2 film were performed, indicating that the stoichiometry and quality of the as-deposited MoS2 can be further improved compared with the Ar-only MoS2 sputtering method. For example, Ar/H2S MoS2 photodiode has lower defect densities than that of Ar MoS2. We also determined that the factors affecting photodetector performance can be optimised in the 8-12 nm deposited thickness range.

15d-PGJ2 inhibits NF-κB and AP-1-mediated MMP-9 expression and invasion of breast cancer cell by means of a heme oxygenase-1-dependent mechanism.

Activation of peroxisome proliferator-activated receptor γ (PPARγ) serves as a key factor in the proliferation and invasion of breast cancer cells and is a potential therapeutic target for breast cancer. However, the mechanisms underlying this effect remain largely unknown. Heme oxygenase-1 (HO-1) is induced and overexpressed in various cancers and is associated with features of tumor aggressiveness. Recent studies have shown that HO-1 is a major downstream target of PPARγ. In this study, we investigated the effects of induction of HO-1 by PPARγ on TPAinduced MMP-9 expression and cell invasion using MCF-7 breast cancer cells. TPA treatment increased NF-κB /AP-1 DNA binding as well as MMP-9 expression. These effects were significantly blocked by 15d-PGJ2, a natural PPARγ ligand. 15d-PGJ2 induced HO-1 expression in a dose-dependent manner. Interestingly, HO-1 siRNA significantly attenuated the inhibition of TPA-induced MMP-9 protein expression and cell invasion by 15d-PGJ2. These results suggest that 15d-PGJ2 inhibits TPA-induced MMP- 9 expression and invasion of MCF-7 cells by means of a heme oxygenase-1-dependent mechanism. Therefore, PPARγ/HO-1 signaling- pathway inhibition may be beneficial for prevention and treatment of breast cancer. [BMB Reports 2020; 53(4): 212-217].

Artificial 2D van der Waals Synapse Devices via Interfacial Engineering for Neuromorphic Systems.

Despite extensive investigations of a wide variety of artificial synapse devices aimed at realizing a neuromorphic hardware system, the identification of a physical parameter that modulates synaptic plasticity is still required. In this context, a novel two-dimensional architecture consisting of a NbSe2/WSe2/Nb2O5 heterostructure placed on an SiO2/p+ Si substrate was designed to overcome the limitations of the conventional silicon-based complementary metal-oxide semiconductor technology. NbSe2, WSe2, and Nb2O5 were used as the metal electrode, active channel, and conductance-modulating layer, respectively. Interestingly, it was found that the post-synaptic current was successfully modulated by the thickness of the interlayer Nb2O5, with a thicker interlayer inducing a higher synapse spike current and a stronger interaction in the sequential pulse mode. Introduction of the Nb2O5 interlayer can facilitate the realization of reliable and controllable synaptic devices for brain-inspired integrated neuromorphic systems.

Oral administration of Ulmus davidiana extract suppresses interleukin-1ß expression in LPS-induced immune responses and lung injury.

BACKGROUND: Ulmus davidiana (UD) is a traditional Korean herb medicine that is used to treat inflammatory disorders. UD has been shown to modulate a number of inflammatory processes in vitro or in vivo studies. However, the molecular mechanisms of UD on lipopolysaccharide (LPS)-induced acute lung injury remain to be understood. OBJECTIVE: The primary objective of this study is to determine the effect of UD bark water extract on LPS-induced immune responses and lung injury using both in vitro and in vivo models. METHODS: RAW 264.7 cells and a rat model of acute lung injury (ALI) were used to study the effects of UD on several parameters. Nitrite level, lactate dehydrogenase (LDH) level, and superoxide dismutase (SOD) activities were measured. Tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and plasma transaminase activities in blood were also determined. Pathological investigations were also performed. RESULTS: LPS infusion resulted in elevated IL-1ß mRNA expression, nitrite levels, TNF-α expression, and IL-1ß expression in RAW 264.7 cells. LPS infusion also increased levels of nitrite/nitrate, total protein, LDH, and TNF-α in bronchoalveolar lavage fluid, but reduced SOD levels in ex vivo and in vivo models. UD administration ameliorated all these inflammatory markers. In particular, treatment with UD reduced LPS-induced nitrite production in RAW 264.7 cells in a dose-dependent manner. UD treatment also counteracted the LPS-induced increase in alanine aminotransferase (ALT) and aspartate transaminase (AST) activity in rat plasma, leading to a significant reduction in ALT and AST activity. CONCLUSIONS: The results revealed that UD treatment reduces LPS-induced nitrite production, IL-1ß mRNA expression, and TNF-α expression. In addition, LPS-induced decrease in SOD level is significantly elevated by UD administration. These results indicate that UD extract merits consideration as a potential drug for treating and/or preventing ALI.

Improvement of the Bias Stress Stability in 2D MoS2 and WS2 Transistors with a TiO2 Interfacial Layer.

The fermi-level pinning phenomenon, which occurs at the metal-semiconductor interface, not only obstructs the achievement of high-performance field effect transistors (FETs) but also results in poor long-term stability. This paper reports on the improvement in gate-bias stress stability in two-dimensional (2D) transition metal dichalcogenide (TMD) FETs with a titanium dioxide (TiO2) interfacial layer inserted between the 2D TMDs (MoS2 or WS2) and metal electrodes. Compared to the control MoS2, the device without the TiO2 layer, the TiO2 interfacial layer deposited on 2D TMDs could lead to more effective carrier modulation by simply changing the contact metal, thereby improving the performance of the Schottky-barrier-modulated FET device. The TiO2 layer could also suppress the Fermi-level pinning phenomenon usually fixed to the metal-semiconductor interface, resulting in an improvement in transistor performance. Especially, the introduction of the TiO2 layer contributed to achieving stable device performance. Threshold voltage variation of MoS2 and WS2 FETs with the TiO2 interfacial layer was ~2 V and ~3.6 V, respectively. The theoretical result of the density function theory validated that mid-gap energy states created within the bandgap of 2D MoS2 can cause a doping effect. The simple approach of introducing a thin interfacial oxide layer offers a promising way toward the implementation of high-performance 2D TMD-based logic circuits.

Facile fabrication of ZnO nanowire memory device based on chemically-treated surface defects.

In this study, we demonstrate a transistor-type ZnO nanowire (NW) memory device based on the surface defect states of a rough ZnO NW, which is obtained by introducing facile H2O2 solution treatment. The surface defect states of the ZnO NW are validated by photoluminescence characterisation. A memory device based on the rough ZnO NW exhibits clearly separated bi-stable states (ON and OFF states). A significant current fluctuation does not exist during repetitive endurance cycling test. Stable memory retention characteristics are also achieved at a high temperature of 85 °C and at room temperature. The surface-treated ZnO NW device also exhibits dynamically well-responsive pulse switching under a sequential pulse test configuration, thereby indicating its potential practical memory applications. The simple chemical treatment strategy can be widely used for modulating the surface states of diverse low-dimensional materials.

Effects of phased education on attitudes toward organ donation and willingness to donate after brain death in an Asian country.

BACKGROUND/OBJECTIVE: This study aims to investigate the effects of phased education on attitudes toward organ donation and willingness to donate after brain death. METHODS: A survey was conducted using a questionnaire to examine attitudes toward organ donation of the families of patients admitted to a surgical intensive care unit (SICU) between March 1, 2014 and September 30, 2016. RESULTS: Ninety-two people voluntarily participated in this survey. Before reviewing the educational material, 75.0% had a positive attitude toward organ donation, 60.9% were willing to donate their own organs, and 38.0% were willing to donate a family member's organs. After reviewing the educational material, these figures increased to 92.4%, 80.4%, and 56.5%, respectively. Before receiving an education, there was a significant difference in consistency between people's attitudes and willingness to donate their own organs, versus donating a family member's organs (79.3% vs 54.3%, p < 0.001). With phased education, these percentages increased from 79.3% to 85.9% with regard to donating one's own organs, and from 54.3% to 64.1% with regard to donating a family member's organs. CONCLUSION: Phased education was effective overall, but it had a limited effect on changing the willingness to donate a family member's organs. It increased the consistency between people's attitudes toward organ donation and willingness to donate their own, or a family member's organs.

Schedule-dependent synergistic effects of 5-fluorouracil and selumetinib in KRAS or BRAF mutant colon cancer models.

Combination of MEK inhibitor and 5-FU had showed limited efficacy in clinical trials. We previously reported that acquired resistance to 5-FU was related with continued activation of salvage pathway. Here we investigated whether combination of 5-FU and a MEK inhibitor had treatment sequence-dependent synergistic effects in KRAS or BRAF mutant colon cancer models. Treatment with 5-FU followed by selumetinib (FS) induced highest cell death and synergy compared with reverse (SF) and concomitant (cFS) treatment in six cell lines. SF or cFS combination induced synergy in 1 or 2 cell lines, respectively, in which the synergy was less than that by FS combination. FS enhanced apoptosis and decreased anchorage-independent growth. Induction of thymidine kinase 1, a rate-limiting enzyme in salvage pathway, by 5-FU was abrogated by subsequent treatment with selumetinib, and ERK reactivation after selumetinib was prohibited by pretreatment with 5-FU. FS altered mRNA expression in groups of genes distinct from SF. Administration of 5-FU (10 or 30 mg/kg/day) for 7 days, followed by selumetinib (10 or 25 mg/kg/day) for another 7 days, in colo205 and HCT8 xenograft models significantly decreased tumor growth compared with a single agent. However, co-administration in the reverse sequence did not show the difference in tumor size compared with the treatment of single agent. Decreased expression of Ki67 was observed in tumors from mice treated with FS. Our results suggest that sequential administration of 5-FU plus selumetinib would be a promising strategy for patients having KRAS or BRAF mutant colon cancers.