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Yuqing Gu, Bin Zhang, Guangliang Gu, Xiaojun Yang, Zhuyin Qian Pancreas Center, The Second Affiliated Hospital to Nanjing Medical University, Nanjing 210003, People’s Republic of ChinaCorrespondence: Zhuyin Qian Email qianzhusilver@163.comBackground: Pancreatic cancer is a devastating malignancy with poor prognosis. Metformin, a classic anti-diabetes drug, seems to improve survival of pancreatic cancer patients in some studies.Methods: Cell counting kit-8 assay was used to detect the BxPC-3 and MIAPaCa-2 cell viability after treatment with gemcitabine only or with different concentrations of metformin. The methylation state and expression level of miR-663 were detected by methylation analysis and RT-PCR. Dual-luciferase reporter gene analysis, Western blot and RT-PCR were used to confirm the target of miR-663. Moreover, xenograft experiment was also performed to validate the role of metformin in chemosensitivity in vivo.Results: We found that metformin increased the chemosensitivity of pancreatic cancer cells to gemcitabine, and epithelial–mesenchymal transition (EMT) progress caused by gemcitabine was suppressed by metformin. We further explored the possible molecular mechanisms and it was demonstrated that CpG islands of miR-663 were hypomethylated and relative expression level of miR-663 was up-regulated after treatment of metformin. miR-663, an important cancer suppressor miRNA, was confirmed to increase the chemosensitivity of pancreatic cancer cells by reversing EMT directly targeted TGF-β 1. Moreover, we identified that metformin increased the chemosensitivity through up-regulating expression of miR-663.Conclusion: We demonstrated that metformin increased the chemosensitivity of pancreatic cancer cells to gemcitabine by reversing EMT through regulation DNA methylation of miR-663.Keywords: metformin, pancreatic cancer, epithelial-mesenchymal transition; EMT, DNA methylation, miR-663

Manual portion and automatable aspects are often not explicitly differentiated and defined in most model driven software development (MDSD). This may hinder the advancement of the automation level of MDSD with problems such as defining the boundaries of automation tasks, and measuring the workload for model transformations (MT), etc. In common senses, the two parts are not distinguishable because they belong to irrespective subjective and objective conceptual areas respectively. By discussing this issue specifically for MDSD, a conceptual exclusion approach for differentiation based on an extended Entity Relationship (ER) model is proposed. A conceptual framework called MIB/CSD (manual work, inheritance, behaviorism / cardinality, static, dynamic) to implement the differentiation approach is designed. Feasibility of the differentiation work with regard to UML is discussed in both the theoretical aspect with the extended ER model and the practical aspect with some existing evidences. © 2006 IEEE.

The Unified Modeling Language (UML) is a defacto notation for model driven software development (MDSD), emphasizing on model to model refinements and transformations. However UML may not be expressive enough to describe all aspects as required by recent MDSD models. A noticeable weakness is its inability to express the ontological concepts often encountered in MDSD. In this paper, we propose an extended Entity-Relationship (ER) model called Runtime Entity-Relationship model (RER) for ontological modeling of common MDSD concepts. Different layers of the UML metamodel hierarchy are analyzed in the context of modeling the MDSD using the RER model. Modifications of the UML architecture for more precise modeling of MDSD are suggested.

The information transformation problem of model driven software development (MDSD) processes is gaining increasing attentions. In this paper, we present an indepth analysis of the major causes leading to the ambiguities of existing transformation. A metamodel based approach is then proposed to address these causes, A mechanism to generate transformation rules is devised based on a classification of the UML metamodel elements to be used in subsequent transformation processes. Some other critical issues relating to the generated transformation system are also discussed. © 2005 IEEE.