CROSSTALK BETWEEN LYSOPHOSPATIDIC ACID (LPA) AND TRANSFORMING GROWTH FACTOR BETA (TGFβ) IN BREAST AND OVARIAN CANCER CELLS

Lysophosphatidic acid (LPA) and transforming growth factor beta (TGFβ) are platelet-derived intercellular mediators of cell proliferation and motility. LPA is a general growth, survival and motility-stimulating factor in mammalian cells. TGFβ prevents proliferation of normal epithelial cells. However, the growth-inhibitory effect of TGFβ is lost or reduced in most malignant cells. Instead, TGFβ promotes migration and invasion of advanced cancer cells. Since LPA and TGFβ are both present in the blood and tumor microenvironments, we were interested in signal integration and functional outcomes in malignant epithelial cells in an LPA and TGFβ co-stimulatory context. In a subset of breast and ovarian cancer cell lines which remain sensitive to the cytostatic effect of TGFβ, we found that LPA up-regulated expression of the cyclin-dependent kinase inhibitor p21Waf1. But this up-regulation was not observed in TGFβ-resistant ones. We examined the possibility that LPA-induced p21 might contribute to the cytostatic response to TGFβ. Indeed, TGFβ alone induced p21 expression weakly in TGFβ-sensitive cells. Serum or serum-borne LPA cooperated with TGFβ to elicit the maximal p21 induction. LPA stimulated p21 via LPA1 and LPA2 receptors and Erk-dependent activation of the CCAAT/enhancer-binding protein beta (C/EBPβ) transcription factor independent of p53. Loss or gain of p21 expression led to a shift between TGFβ sensitive and resistant phenotypes in breast and ovarian cancer cells, indicating that LPA-induced p21 is a key determinant of the growth inhibitory activity of TGFβ. The p21-stimulatory action of LPA is absent from most breast and ovarian cancer cells, leading to their resistance to TGFβ. Therefore we reveal a novel crosstalk between LPA and TGFβ that underlies TGFβ sensitive and resistant phenotypes of breast and ovarian cancer cells. In the next part of our study, we examined the role of interactions between LPA and TGFβ in regulation of tumor cell motility. LPA and, to a much less extent, TGFβ stimulate chemotactic migration and invasion of breast and ovarian cancer cells. However, when combined together with LPA, TGFβ strongly attenuated LPA-driven migration and invasion of breast and ovarian cancer cells. This inhibitory effect was most likely mediated through TGFβ downregulation of expression of LPA1, the major receptor subtype responsible for LPA-regulated cell migration. Knockdown of Smad3 or Smad4 with small hairpin RNA (shRNA) eliminated the inhibitory effects of TGFβ on the LPA1 expression and LPA-dependent cell migration. There are two potential TGFβ inhibitory elements (TIE) (-40 bp and -401 bp) present in the human LPA1 gene promoter. Deletion or point mutation of the distal TIE at around -401 bp abolished the inhibitory effect of TGFβ on the LPA1 promoter activity as revealed by luciferase assays. A DNA pull-down assay showed that the -401-TIE-E2F4/5 sequence was capable of binding Samd3, Smad4, and E2F4/5 in TGFβ-treated cells. The binding of the Smad complex to the native TIE-E2F4/5 sequences of the LPA1 gene promoter was further verified by chromatin immunoprecipitation assay. Our results identify a novel role of TGFβ in the control of LPA1 expression and LPA1-coupled biological activities, adding LPA1 to the list of TGFβ-repressed target genes

ProphetMT: a tree-based SMT-driven controlled language authoring/post-editing tools

This paper presents ProphetMT, a tree-based SMT-driven Controlled Language (CL) authoring and post-editing tool. ProphetMT employs the source-side rules in a translation model and provides them as auto-suggestions to users. Accordingly, one might say that users are writing in a ‘Controlled Language’ that is ‘understood’ by the computer. ProphetMT also allows users to easily attach structural information as they compose content. When a specific rule is selected, a partial translation is promptly generated on-the-fly with the help of the structural information. Our experiments conducted on English-to-Chinese show that our proposed ProphetMT system can not only better regularise an author’s writing behaviour, but also significantly improve translation fluency which is vital to reduce the post-editing time. Additionally, when the writing and translation process is over, ProphetMT can provide an effective colour scheme to further improve the productivity of post-editors by explicitly featuring the relations between the source and target rules

ProphetMT: controlled language authoring aid system description

This paper presents ProphetMT, a monolingual Controlled Language (CL) authoring tool which allows users to easily compose an in-domain sentence with the help of tree-based SMT-driven auto-suggestions. The interface also visualizes target-language sentences as they are built by the SMT system. When the user is finished composing, the final translation(s) are generated by a tree-based SMT system using the text and structural information provided by the user. With this domain-specific controlled language, ProphetMT will produce highly reliable translations. The contributions of this work are: 1) we develop a user-friendly auto-completion-based editor which guarantees that the vocabulary and grammar chosen by a user are compatible with a tree-based SMT model; 2) by applying a shift-reduce-like parsing feature, this editor allows users to write from left-to-right and generates the parsing results on the fly. Accordingly, with this in-domain composing restriction as well as the gold-standard parsing result, a highly reliable translation can be generated

Atypical sliding and Moire ferroelectricity in pure multilayer graphene

Most non-ferroelectric two-dimensional materials can be endowed with so-called sliding ferroelectricity via non-equivalent homo-bilayer stacking, which is not applicable to mono-element systems like pure graphene bilayer with inversion symmetry at any sliding vector. Herein we show first-principles evidence that multilayer graphene with N>3 can all be ferroelectric, where the polarizations of polar states stem from the symmetry breaking in stacking configurations of across-layer instead of adjacent-layer, which are electrically switchable via interlayer sliding. The non-polar states can also be electrically driven to polar states via sliding, all nearly degenerate in energy, and more diverse states with distinct polarizations will emerge in more layers. In contrast to the ferroelectric Moire domains with opposite polarization directions in twisted bilayers reported previously, the Moire pattern in some multilayer graphene systems (e.g., twisted monolayer-trilayer graphene) possess nonzero net polarizations with domains of the same direction separated by non-polar regions, which can be electrically reversed upon interlayer sliding. The distinct Moire bands of two polar states should facilitate electrical detection of such sliding Moire ferroelectricity during switching

Regulation of human glioblastoma cell death by combined treatment of cannabidiol, γ-radiation and small molecule inhibitors of cell signaling pathways

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. The challenging problem in cancer treatment is to find a way to upregulate radiosensitivity of GBM while protecting neurons and neural stem/progenitor cells in the brain. The goal of the present study was upregulation of the cytotoxic effect of γ-irradiation in GBM by non-psychotropic and non-toxic cannabinoid, cannabidiol (CBD). We emphasized three main aspects of signaling mechanisms induced by CBD treatment (alone or in combination with γ-irradiation) in human GBM that govern cell death: 1) CBD significantly upregulated the active (phosphorylated) JNK1/2 and MAPK p38 levels with the subsequent downregulation of the active phospho-ERK1/2 and phospho-AKT1 levels. MAPK p38 was one of the main drivers of CBD-induced cell death, while death levels after combined treatment of CBD and radiation were dependent on both MAPK p38 and JNK. Both MAPK p38 and JNK regulate the endogenous TRAIL expression. 2) NF-κB p65-P(Ser536) was not the main target of CBD treatment and this transcription factor was found at high levels in CBD-treated GBM cells. Additional suppression of p65-P(Ser536) levels using specific small molecule inhibitors significantly increased CBD-induced apoptosis. 3) CBD treatment substantially upregulated TNF/TNFR1 and TRAIL/TRAIL-R2 signaling by modulation of both ligand and receptor levels followed by apoptosis. Our results demonstrate that radiation-induced death in GBM could be enhanced by CBD-mediated signaling in concert with its marginal effects for neural stem/progenitor cells and astrocytes. It will allow selecting efficient targets for sensitization of GBM and overcoming cancer therapy-induced severe adverse sequelae

Test Static Tradeoff Models Against Pecking Order Models of Capital Structure in UK Firms

This paper aims at testing the static tradeoff theory and the pecking order theory against British companies during the period of 2008 to 2012. A total sample of 40 companies listed on London Stock Exchange have been established. Through panel data analysis, this study investigates which of these two theories could better explain the capital structures of companies in the United Kingdom. The empirical analysis demonstrates that the static tradeoff theory has a better explanatory power for British firms while the pecking order theory does not really work in the UK during the selected study time period. Keywords: capital structure, the static tradeoff theory, the pecking order theor