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Breast cancer metastasis accounts for most of the deaths from breast cancer. Since epithelial-mesenchymal transition (EMT) plays an important role in promoting metastasis of cancer, many mechanisms regarding EMT have been studied. We previously showed that Ribonucleic acid export 1 (RAE1) is dysregulated in breast cancer and its overexpression leads to aggressive breast cancer phenotypes by inducing EMT. Here, we evaluated the functional capacity of RAE1 in breast cancer metastasis by using a three-dimensional (3D) culture system and xenograft models. Furthermore, to investigate the mechanisms of RAE1-driven EMT, in vitro studies were carried out. The induction of EMT with RAE1-overexpression was confirmed under the 3D culture system and in vivo system. Importantly, RAE1 mediates upregulation of an EMT marker ZEB1, by binding to the promoter region of ZEB1. Knockdown of ZEB1 in RAE1-overexpressing cells suppressed invasive and migratory behaviors, accompanied by an increase in epithelial and a decrease in mesenchymal markers. Taken together, these data demonstrate that RAE1 contributes to breast cancer metastasis by regulating a key EMT-inducing factor ZEB1 expression, suggesting its potential as a therapeutic target.

The microbiota shields the host against infections in a process known as colonization resistance. How infections themselves shape this fundamental process remains largely unknown. Here, we show that gut microbiota from previously infected hosts display enhanced resistance to infection. This long-term functional remodeling is associated with altered bile acid metabolism leading to the expansion of taxa that utilize the sulfonic acid taurine. Notably, supplying exogenous taurine alone is sufficient to induce this alteration in microbiota function and enhance resistance. Mechanistically, taurine potentiates the microbiota's production of sulfide, an inhibitor of cellular respiration, which is key to host invasion by numerous pathogens. As such, pharmaceutical sequestration of sulfide perturbs the microbiota's composition and promotes pathogen invasion. Together, this work reveals a process by which the host, triggered by infection, can deploy taurine as a nutrient to nourish and train the microbiota, promoting its resistance to subsequent infection.

The antioxidant enzyme human extracellular superoxide dismutase (SOD3) is a promising biopharmaceutical candidate for the treatment of various diseases. To support the early development of SOD3 as a biopharmaceutical, a simple, sensitive, and rapid liquid chromatography tandem mass spectrometry procedure was developed and validated for the determination of SOD3 levels in the plasma of ICR mice. After purification with Ni-NTA magnetic beads and digestion with trypsin, SOD3 signature peptides and internal standard signature peptide (ISP) were separated via high performance liquid chromatography using a Zorbax C 18 column (2.1 × 50 mm, 3.5 μm) and a mobile phase consisting of 10 mM ammonium formate, 0.1% formic acid, and acetonitrile. The analyte and ISP were detected via a tandem mass spectrometer in electrospray ionization and multiple reaction monitoring modes to select both the signature peptide for SOD3 at m/z 669 to 969 and the ISP at m/z 655 to 941 in the positive ion mode. The calibration curves were linear (r > 0.99) between 5 and 1000 μg/mL with a lower limit of quantification of 5 μg/mL. The relative standard deviation ranged from 3.08 to 8.84% while the relative error ranged from -0.13 to -9.56%. This method was successfully applied to a preclinical pharmacokinetic study of SOD3 in male ICR mice.

Chitinase-3-like-1 (Chi3l1) is known to play a significant role in the pathogenesis of Type 2 inflammation and cancer. However, the function of Chi3l1 in T cell and its clinical implications are largely unknown. Here we show that Chi3l1 expression was increased in activated T cells, especially in Th2 cells. In addition, Chi3l1-deficient T cells are hyper-responsive to TcR stimulation and are prone to differentiating into Th1 cells. Chi3l1-deficient Th1 cells show increased expression of anti-tumor immunity genes and decreased Th1 negative regulators. Deletion of Chi3l1 in T cells in mice show reduced melanoma lung metastasis with increased IFNγ and TNFα-producing T cells in the lung. Furthermore, silencing of Chi3l1 expression in the lung using peptide-siRNA complex (dNP2-siChi3l1) efficiently inhibit lung metastasis with enhanced Th1 and CTL responses. Collectively, this study demonstrates Chi3l1 is a regulator of Th1 and CTL which could be a therapeutic target to enhance anti-tumor immunity., Chitinase-3-like-1 (Chi3l1) has been involved in inflammation and pulmonary metastasis. Here the authors show that Chi3l1 inhibits the T cell response by negatively regulating their activation and that, in a mouse model of melanoma, T cell-targeted silencing of Chi3l1 results in reduced lung metastasis.

During the development of an embryo, the initiation of the collinear expression of Hox genes is essential for the proper formation of the anteroposterior body axis. Retinoic acid (RA), a natural derivative of vitamin A, plays a role in vertebrate development by regulating Hox gene expression. CCCTC-binding factor (CTCF), an insulator protein that controls gene transcription, also regulates the expression of Hox genes by binding to the CTCF-binding sites (CBSs). It has been reported that upon RA signaling, retinoic acid response elements (RAREs) located in the Hox clusters become occupied. Interestingly, RAREs exist in close proximity with CBSs, and therefore when RA is bound, CTCF cannot bind. Without CTCF and its insulator activities, the repressive domain in the chromatin becomes open for gene transcription. Here, we examine the relationship between RA and CTCF during the RA-induced expression of the Hoxa cluster genes, using F9 murine embryonic teratocarcinoma cells as a model system. We treated F9 cells with RA for different time, confirmed the collinear expression of Hoxa genes, and validated CTCF-binding in F9 cells as well as in CTCF-overexpressing F9 cells, in the presence of RA. The present study suggests that RA and CTCF pose antagonistic effects on each other during vertebrate development to attain Hox gene collinearity.

The evolutionarily conserved Hox genes are organized in clusters and expressed colinearly to specify body patterning during embryonic development. Previously, Akt1 has been identified as a putative Hox gene regulator through in silico analysis. Substantial upregulation of consecutive 5' Hoxc genes has been observed when Akt1 is absent in mouse embryonic fibroblast (MEF) cells. In this study, we provide evidence that Akt1 regulates the 5' Hoxc gene expression by epigenetic modifications. Enrichment of histone H3K9 acetylation and a low level of the H3K27me3 mark were detected at the posterior 5' Hoxc loci when Akt1 is absent. A histone deacetylase (HDAC) inhibitor de-repressed 5' Hoxc gene expression when Akt1 is present, and a DNA demethylating reagent synergistically upregulated HDAC-induced 5' Hoxc gene expression. A knockdown study revealed that Hdac6 is mediated in the Hoxc12 repression through direct binding to the transcription start site (TSS) in the presence of Akt1. Co-immunoprecipitation analysis revealed that endogenous Akt1 directly interacted with Hdac6. Furthermore, exogenous Akt1 was enriched at the promoter region of the posterior Hoxc genes such as Hoxc11 and Hoxc12, not the Akt1-independent Hoxc5 and Hoxd10 loci. The regulation of the H3K27me3 mark by Ezh2 and Kdm6b at the 5' Hoxc gene promoter turned out to be Akt1 dependent. Taken together, these results suggest that Akt1 mediates the posterior 5' Hoxc gene expression through epigenetic modification such as histone methylation and acetylation, and partly through a direct binding to the promoter region of the 5' Hoxc genes and/or Hdac6 in mouse embryonic fibroblast cells.

Hox genes are responsible for encoding transcription factors that are essential for anterior-posterior body patterning at early stages of embryogenesis. However, detailed mechanisms of Hox genes are yet to be defined. Protein kinase B alpha (Akt1) was previously identified as a possible upstream regulator of Hox genes. Furthermore, the Hoxc11 gene has been upregulated in Akt1 null (Akt1-/-) mouse embryonic fibroblasts (MEFs), while repressed in wild-type MEFs. In this study, we propose to investigate the role of Gcn5, a histone acetyltransferase, in the regulation of Hoxc11 expression in MEFs. We showed that the H3 lysine 9 acetylation (H3K9ac) status has the same correlation with Hoxc11 expression and reported that Gcn5 is associated with the upregulation of Hoxc11 expression through H3K9ac in Akt1-/- MEFs. Since Hoxc11 was upregulated through histone acetylation in Akt1-/- MEFs, a functional role of Gcn5 on Hoxc11 expression was analyzed in Akt1-/- MEFs treated with Gcn5 specific inhibitor or transfected with Gcn5-small interfering RNA (Gcn5-siRNA). When the expression of Hoxc11 was analyzed using RT-PCR and real-time PCR, the Hoxc11 mRNA level was found to be similar in both Akt1-/- MEFs and control-siRNA transfected Akt1-/- MEFs. However, the Hoxc11 expression level was decreased in Gcn5-inhibited or Gcn5-knockdown Akt1-/- MEFs. Additionally, to analyze Gcn5-mediated histone acetylation status, chromatin immunoprecipitation assay was carried out in Gcn5-siRNA-transfected Akt1-/- MEFs. The H3K9ac at the Hoxc11 locus was decreased in Gcn5-knockdown Akt1-/- MEFs compared to controls. Based on these findings, we conclude that Gcn5 regulates Hoxc11 gene expression through mediating site-specific H3K9 acetylation in Akt1-/- MEFs.

The rearranged during transfection (RET) tyrosine kinase is mostly altered by fusion and it makes RET as a attractive therapeutic target for medullary thyroid cancer and non-small cell lung cancer (NSCLC). Multi-kinase inhibitors (mKIs) such as cabozantinib and vandetanib expressed poor tolerability and limited efficacy due to off-target kinase inhibitory activity in academia and clinical cases. As for selective RET inhibitor, compounds such as BLU-667 and LOXO-292 are under development, currently in clinical trials. We are currently developing potent and selective RET inhibitors to address unmet medical needs for RET-driven cancers. Our team has validated its high potency and selectivity via kinase profiling and in-vitro assay results. We also anticipate our compound to overcome certain mutation, such as V804M. Our compounds strongly suppress phosphorylation of RET in tumor cells with various RET fusions and mutations by inhibiting proliferation at below 10 nM. This potency result is higher than those of other mKIs with RET inhibitory activity. The inhibitory concentration of our compounds to VEGFR2 is more than dozens of fold compared with RET. In addition, our compounds reveal low cytotoxicity in Ba/F3 naïve cells in the 1 µM concentration. These findings lead us to conclude that our compounds can be potent and highly selective inhibitors of RET kinase, a potential novel therapeutic agents for RET-driven cancers. Citation Format: Hua Li, SeoHyun Jo, Woomi Do, Hyunkyung Kim, Hwan Kim, Kyung-ah Seo, Ji-hoon Oh, Jieun Choi, Jaeyoung Ahn, Jung Beom Son, Nam Doo Kim. Novel therapeutic agents for RET-driven cancers, which is highly potent and selective inhibitor to RET kinase [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2209.

In this short paper, we propose a hybrid TCP PEP combined XOR coding with TCP Hybla on split PEP in satellite communication. To evaluate performance of the proposed protocol we set up a test bed of satellite communication network. As a result of performance evaluation of the proposed Hybrid TCP on split PEP, the file transmission speed improved more than 40% in high error rate environment. Therefore, we can expect that the proposed Hybrid TCP, which is combined XOR coding method and TCP Hybla on the split PEP, can contribute to improve the data transmission speed in the satellite communication environments.

We propose a scheduled resource allocation mechanism using cross-layer information exchange between application layer and link layer. The positioning information of satellite communication on the move (SOTM) node and the number of sessions are exchanged between two layers. To evaluate the performance, we implement a testbed for evaluation of proposed mechanism. The results show that the performance of scheduled resource allocation mechanism improve the TCP throughput and fairness in existing disruption network.

Tafamidis is a first-in-class inhibitor of transthyretin amyloid fibril formation. It has been available in Argentina, Japan, and Mexico for the treatment of transthyretin amyloidosis in adult patients with early-stage symptomatic polyneuropathy. In this study, a rapid and sensitive liquid chromatography-tandem mass spectrometry method was developed and validated for the assay of tafamidis in rat plasma. The method was also assessed for its applicability to pharmacokinetic studies in rats. Tafamidis was extracted from rat plasma by the liquid-liquid extraction method using hydrochloric acid and ethyl acetate. A reversed-phase C18 column and a mobile phase consisting of 10mM ammonium formate and acetonitrile were used to achieve chromatographic separation. The flow rate for the mobile phase was set at 0.3mL/min. Tafamidis and 2-CBC, which was used as the internal standard (IS), were analyzed by multiple reaction monitoring in negative ESI mode at m/z transitions of 305.4→261.4 for tafamidis and 271.7→227.8 for the IS. The lower limit of quantification of tafamidis was obtained as 3ng/mL, and the calibration curve was linear over a concentration range of 3-3000ng/mL (R2>0.99). The validation parameters investigated, which were specificity, precision, accuracy, matrix effect, recovery, and stability, were well within acceptable limits. The method was successfully used for the evaluation of the pharmacokinetics of tafamidis in rats.

Regulatory T (Treg) cells, which express Foxp3 as a transcription factor, are subsets of CD4(+) T cells. Treg cells play crucial roles in immune tolerance and homeostasis maintenance by regulating the immune response. The primary role of Treg cells is to suppress the proliferation of effector T (Teff) cells and the production of cytokines such as IFN-γ, TNF-α, and IL-2. It has been demonstrated that Treg cells' ability to inhibit the function of Teff cells is enhanced during persistent pathogen infection and cancer development. To clarify the function of Treg cells under resting or inflamed conditions, a variety of in vitro suppression assays using mouse or human Treg cells have been devised. The main aim of this study is to develop a method to compare the differences in phenotype and suppressive function between resting and activated Treg cells. To isolate activated Treg cells, mice were infected with lymphocytic choriomeningitis virus (LCMV) clone 13 (CL13), a chronic strain of LCMV. Treg cells isolated from the spleen of LCMV CL13-infected mice exhibited both the activated phenotype and enhanced suppressive activity compared with resting Treg cells isolated from naïve mice. Here, we describe the basic protocol for ex vivo phenotype analysis to distinguish activated Treg cells from resting Treg cells. Furthermore, we describe a protocol for the measurement of the suppressive activity of fully activated Treg cells.

Coastal zone management indicators are being used as an important means of decision making in the process of policy establishment for integrated coastal management and implementation, and these indicators are very useful tools that enable the evaluation of the coastal zone management from an integrated perspective, the understanding and analysis of interactions according to each department. Accordingly, most of organizations in international society and advanced coastal states tend to develop coastal zone management indicator system in order to check current coastal environment, social and economic status, also to grasp effectiveness of the coastal zone management policy. In this research, therefore, the characteristics of coastal zone management indicator system was drawn through understanding of strength and weakness, and conducting comparative analysis of the coastal zone management indicator system according to each level having classified domestic and international coastal zone management indicator system into three aspects at large: natural and environmental aspect; social and economic aspect; and network aspect. As a result, following features were drawn as the common characteristics among the cases in the advanced coastal states: the management means for realization of sustainable coastal zone management; scientific decision making tools for various stakeholders; evaluation means for effectiveness of coastal zone integrated management; and dualization of coastal zone management indicator system; etc. Lastly, based on these common values revealed in the domestic and international coastal management indicator system, a suggestion for correct establishment of the domestic coastal management indicators was proposed in the regional aspect.

It is necessary to collect the coastal zone data, to prepare the objective analysis methods, and to build the scientific and technical support system for the efficient management of coastal zone in local aspect. This study analyzes the coastal zoning methods and the integrated methods of different kind data by case study of U.S.A coastal zone. The characteristics of coastal zone management methods in U.S.A are as follows; the concrete indices and methods of establishing coastal zone which can respond to the local values and land use, related data analysis methods for supporting spatial decision making, and establishment and administration of bureau for the spatial information construction and integration of coastal zone. This study suggest the technical implications which can build the domestic coastal zone management in local level on the basis of the common values of the coastal zoning methods and integrated methods of heterogeneous data in U.S.A.

Coastal Zone is a integrated space including both coastal waters and inland. C.Z.M is a strategic practice system which can integrate and coordinate the coastal zone for preserving and making use of coastal resources. Through foreign and domestic C.Z.M Cases, this study analyzes the operating mechanism in the three aspects: role sharing among the administrative agencies, mediation and cooperation among the interested parties, and inducements of voluntary participation. And it achieves the common characteristics of C.Z.M: building the assessment system for establishing desirable policy directions, the stable support system for sustainable coastal management, the mediation system for cooperation of stakeholder, and the education system for reinforcing the management ability and inducing the voluntary participation. Finally it suggests the implications to build the coastal zone management system properly on the basis of common values in this mechanism. Key Words : Coastal Zone, C.Z.M(Coastal Zone Management), Mechanism of C.Z.M

Nelumbo nucifera semen (NNS) is a traditional herb with anti-diarrheal, anti-ganacratia, and tranquilizer-like pharmacological activities. In this study, we examined the anti-amnesic effect of NNS on rats with scopolamine-induced amnesia. Passive avoidance tests, acetylcholinesterase (ACHE) activity, and choline acetyltransferase (CHAT) expression were used to evaluate the NNS anti-amnesic effects. The rats were divided into five groups: the normal group, scopolamine-treated group (1mg/kg; control), NNS (1g/kg) and scopolamine (1mg/kg) co-treatment group, and the ARICEPT (1mg/kg) and scopolamine (1mg/kg) co-treatment group (positive control). The rats were administered the compounds orally for 14 days. The latency time of passive avoidance significantly increased by 54% in the NNS-treated group compared to the scopolamine-treated group. The ACHE activity in the NNS-treated group significantly decreased to 7.35% than that of the control group. CHAT-positive neurons increased by 51.02% in the NNS group compared to the control group. These results suggest that NNS extract improves scopolamine-induced dementia by inhibiting ACHE activity and inducing CHAT expression.

Aim: To investigate the antioxidant effects of Morinda officinalis (Morindae radix, MR) on H2O2-induced oxidative stress in cultured mouse TM3 Leydig cells. Methods: We carried out 2,2-diphenyl-1-picrylhydrazyl free radical scavenging, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, lipid peroxidation, testosterone enzyme immunoassay, superoxide dismutase (SOD), and catalase (CAT) assays in Leydig TM3 cells. Results: MR showed a 47.8% 2,2-diphenyl-1-picrylhydrazyl radical scavenging effect in TM3 cells with no significant cytotoxicity. Oxidative stress was induced in TM3 cells with 100 μmol H2O2, and treatment of the cells with 250 μg/mL MR showed the most significant protective effect (64%, P < 0.001) in the cell viability assay with a decreased lipid peroxidation level (1.75 nmol/mg protein, P < 0.05), increased testosterone production (43.5 pg/mL), and improvements in SOD activity (7.49 units of SOD/mg protein, P < 0.001) and CAT activity (74.6 units of CAT/mg protein, P < 0.001). Conclusion: These findings indicate that MR, as an antioxidant, protects functions of cultured mouse TM3 Leydig cells from H2O2-induced oxidative stress. (Asian J Androl 2008 Jul; 10: 667–674)

Rhizoctonia solani and Phytophthora capsici are two of the most destructive phytopathogens occurring worldwide and are only partly being managed by traditional control strategies. Fluorescent Pseudomonas isolates PGC1 and PGC2 were checked for the antifungal potential against R. solani and P. capsici. Both the isolates were screened for the ability to produce a range of antifungal compounds. The results of this study indicated the role of chitinase and β-1,3-glucanase in the inhibition of R. solani, however, antifungal metabolites of a non-enzymatic nature were responsible for inhibition of P. capsici. The study confirmed that multiple and diverse mechanisms are adopted by the same antagonist to suppress different phytopathogens, as evidenced in case of R. solani and P. capsici.

The Web Services descriptions such as DAML-S/OWL-S, BPEL4WS and WSMF focusing on the functional aspects of Web Services have limitations for the representation of the conceptual and semantic capabilities of Web Services, although WSMF is based on ontology and can represent the goal of Web Services. This paper proposes the new description formalism based on the competence ontology that can represent both functional and semantic aspects of Web Services. This paper also presents the integration and the composition of Web Services by means of Data Mediator(D-Mediator) and Control Mediator(C-Mediator) to mediate compositional in compatibility between heterogeneous Web Services.

A non-glycosidic iridoid, campsinol (1), and two iridoid glucosides, 7-O-(Z)-p-coumaroylcachineside V (2) and 7-O-(E)-p-coumaroylcachineside I (3), were isolated from the fresh flowers of Campsis grandiflora along with five known iridoid glycosides, ixoroside (4), campsiside (5), cachineside I (6), 5-hydroxycampenoside (7), and 5-hydroxycampsiside (8), and two known phenylpropanoid glycosides, acteoside (9) and leucosceptoside A (10). The structures of these compounds were determined based on the NMR and Mass spectroscopic data and other chemical evidences.

Photocurable and highly condensed fluorinated methacrylate oligosiloxane, with a low dielectric constant (kappa = 2.54), was prepared by a nonhydrolytic sol-gel condensation reaction. The oligosiloxane resin was then spin-coated, photocured, and thermally baked in order to fabricate a fluorinated methacrylate hybrid material (FM hybrimer) thin film. This study investigated the application of this FM hybrimer film as a low-kappa passivation layer in LCD-based thin film transistors (TFT). It was found that a dielectric constant as low as kappa = 2.54 could be obtained, without introducing pores in the dense FM hybrimer films. This study compares FM hybrimer film characteristics with those required for passivation layers in LCD-TFTs, including thermal stability, optical transmittance, hydrophobicity, gap fill, and planarization effects as well as electrical insulation.

itor> Meeting abstracts - A single PDF containing all abstracts in this Supplement is available here http://www. biomedcentral.co m/content/pdf/14 71-2202-8-S2-in fo.pdf

In this study, indium tin oxide (ITO) films were deposited at 300°C on glass substrates by low-frequency (60 Hz) magnetron sputtering technique. The influence of oxygen flow rate on the structural, electrical and optical properties of ITO thin films was investigated. The oxygen flow rate was varied from 0 to 8 sccm. We obtained the most superior property of ITO films at oxygen flow rate of 0.5 sccm. The films are found to show preferential orientation both (222) and (400) planes in the XRD patterns. The resistivity of the films with the thickness of 140 nm is 2.1 × 10−4 ohm · cm with 88% optical average transmittance in visible range (500–800 nm). Therefore, we conclude that transparent conducting ITO films prepared by low-frequency magnetron sputtering can be applied for various flat panel displays.

Key Points: • Antarctic meltwater forcing induces an overall global cooling but regional warming in East Asia • Antarctic meltwater forcing can shift the Intertropical Convergence Zone northward and suppress convection over the Western North Pacific • Suppressed convection in the Western North Pacific is responsible for the regional warming of East Asia via atmospheric teleconnection. In recent decades, Antarctic ice sheet/shelf melting has been accelerated, releasing freshwater into the Southern Ocean. It has been suggested that the meltwater flux could lead to cooling in the Southern Hemisphere, which would retard global warming and further induce a northward shift of the Intertropical Convergence Zone (ITCZ). In this study, we use experimental ensemble climate simulations to show that Antarctic meltwater forcing has distinct regional climate impacts over the globe, leading in particular to regional warming in East Asia, which offsets the global cooling effect by the meltwater forcing. It is suggested that Antarctic meltwater forcing leads to a negative precipitation anomaly in the Western North Pacific (WNP) via cooling in the tropics and the northward shift of the ITCZ. This suppressed convection in WNP induces an anticyclonic flow over the North Pacific, which leads to regional warming in East Asia. This hypothesis is supported by analyses of interensemble spread and long-term control simulations.