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Chung F.-H.,National Central University | Lee H.H.-C.,National Central University | Lee H.H.-C.,Cathay Medical Research Institute | Lee H.-C.,National Central University | Lee H.-C.,Cathay Medical Research Institute
PLoS ONE | Year: 2013

Significantly expressed genes extracted from microarray gene expression data have proved very useful for identifying genetic biomarkers of diseases, including cancer. However, deriving a disease related inference from a list of differentially expressed genes has proven less than straightforward. In a systems disease such as cancer, how genes interact with each other should matter just as much as the level of gene expression. Here, in a novel approach, we used the network and disease progression properties of individual genes in state-specific gene-gene interaction networks (GGINs) to select cancer genes for human colorectal cancer (CRC) and obtain a much higher hit rate of known cancer genes when compared with methods not based on network theory. We constructed GGINs by integrating gene expression microarray data from multiple states - healthy control (Nor), adenoma (Ade), inflammatory bowel disease (IBD) and CRC - with protein-protein interaction database and Gene Ontology. We tracked changes in the network degrees and clustering coefficients of individual genes in the GGINs as the disease state changed from one to another. From these we inferred the state sequences Nor-Ade-CRC and Nor-IBD-CRC both exhibited a trend of (disease) progression (ToP) toward CRC, and devised a ToP procedure for selecting cancer genes for CRC. Of the 141 candidates selected using ToP, ∼50% had literature support as cancer genes, compared to hit rates of 20% to 30% for standard methods using only gene expression data. Among the 16 candidate cancer genes that encoded transcription factors, 13 were known to be tumorigenic and three were novel: CDK1, SNRPF, and ILF2. We identified 13 of the 141 predicted cancer genes as candidate markers for early detection of CRC, 11 and 2 at the Ade and IBD states, respectively. © 2013 Chung et al.


Chang Y.,Chung Yuan Christian University | Yandi W.,Chung Yuan Christian University | Chen W.-Y.,National Central University | Shih Y.-J.,Chung Yuan Christian University | And 4 more authors.
Biomacromolecules | Year: 2010

This work describes a novel tunable bioadhesive hydrogel of thermoresponsive N-isopropylacrylamide (NIPAAm) containing zwitterionic sulfobetaine methacrylate (SBMA). This novel hydrogel highly regulates general bioadhesive foulants through the adsorption of plasma proteins, the adhesion of human platelets and cells, and the attachment of bacteria. In this investigation, nonionic hydrogels of polyNIPAAm, zwitterionic hydrogels of polySBMA, and three copolymeric hydrogels of NIPAAm and SBMA (poly(NIPAAm-co-SBMA)) were prepared. The copolymeric hydrogels exhibited controllable temperature-dependent swelling behaviors and showed stimuli-responsive phase characteristics in the presence of salts. The interactions of these hydrogels with biomolecules and microorganisms were demonstrated by protein adsorption, cell adhesion, and bacterial attachment, which allowed us to evaluate their bioadhesive properties. An enzyme-linked immunosorbent assay (ELISA) with monoclonal antibodies was used to measure different plasma protein adsorptions on the prepared hydrogel surfaces. At a physiological temperature, the high content of the nonionic polyNIPAAm in poly(NIPAAm-co-SBMA) hydrogel exhibits a high protein adsorption due to the interfacial exposure of polyNIPAAm-rich hydrophobic domains. A relatively high content of polySBMA in poly(NIPAAm-co-SBMA) hydrogel exhibits reduced amounts of protein adsorption due to the interfacial hydration of polySBMA-rich hydrophilic segments. The attachment of platelets and the spreading of cells were only observed on polyNIPAAm-rich hydrogel surfaces. Interestingly, the incorporation of zwitterionic SBMA units into the polyNIPAAm gels was found to accelerate the hydration of the cell-cultured surfaces and resulted in more rapid cell detachment. Such copolymer gel surface was shown to be potentially useful for triggered cell detachment. In addition, the interactions of hydrogels with bacteria were also evaluated. The polySBMA-rich hydrogels exhibited evident antimicrobial properties when they were incubated with Gram-positive bacteria (S. epidermidis) and Gram-negative bacteria (E. coli). This work shows that the bioadhesive properties of poly(NIPAAm-co-SBMA) hydrogels can be effectively controlled via regulated nonionic and zwitterionic molar mass ratios. The tunable-bioadhesive behavior of temperature-sensitive poly(NIPAAm-co-SBMA) makes this biocompatible hydrogel appropriate for biomedical applications. © 2010 American Chemical Society.


Higuchi A.,National Central University | Higuchi A.,National Health Research Institute | Higuchi A.,Cathay Medical Research Institute | Ling Q.-D.,Cathay Medical Research Institute | And 4 more authors.
Chemical Reviews | Year: 2013

Millions of people lose or damage their organs or tissues due to disease, birth defects, or accidents each year. Stem cells, such as embryonic stem cells (ESC), induced pluripotent stem cells (iPSC), adult stem cells, and fetal stem cells are an attractive prospect for regenerative medicine and tissue engineering. The pluripotent nature of ESCs and iPSCs opens many avenues for potential stem cell-based regenerative therapies and the development of drug discovery platforms. Nowadays, it is difficult to find novel biomolecules for differentiation of stem cells and to find much higher efficiency of stem cell differentiation into desired lineages solely by combination of these biomolecules in culture medium. Biomaterials for stem cell culture are focused as a tool for finetuning of stem cell differentiation, because it is quite recent for researchers to realize biomaterials can guide stem cell fate of differentiation.


Chung C.A.,National Central University | Lin T.-H.,National Central University | Chen S.-D.,National Central University | Huang H.-I.,Cathay Medical Research Institute
Journal of Theoretical Biology | Year: 2010

Mathematic models help interpret experimental results and accelerate tissue engineering developments. We develop in this paper a hybrid cellular automata model that combines the differential nutrient transport equation to investigate the nutrient limited cell construct development for cartilage tissue engineering. Individual cell behaviors of migration, contact inhibition and cell collision, coupled with the cell proliferation regulated by oxygen concentration were carefully studied. Simplified two-dimensional simulations were performed. Using this model, we investigated the influence of cell migration speed on the overall cell growth within in vitro cell scaffolds. It was found that intense cell motility can enhance initial cell growth rates. However, since cell growth is also significantly modulated by the nutrient contents, intense cell motility with conventional uniform cell seeding method may lead to declined cell growth in the final time because concentrated cell population has been growing around the scaffold periphery to block the nutrient transport from outside culture media. Therefore, homogeneous cell seeding may not be a good way of gaining large and uniform cell densities for the final results. We then compared cell growth in scaffolds with various seeding modes, and proposed a seeding mode with cells initially residing in the middle area of the scaffold that may efficiently reduce the nutrient blockage and result in a better cell amount and uniform cell distribution for tissue engineering construct developments. © 2009 Elsevier Ltd. All rights reserved.


Wu C.-H.,National Central University | Lee F.-K.,Cathay General Hospital | Suresh Kumar S.,National Central University | Ling Q.-D.,Cathay Medical Research Institute | And 10 more authors.
Biomaterials | Year: 2012

Human adipose-derived stem cells (hADSCs) were purified from a suspension of human adipose tissue cells (stromal vascular fraction) by the conventional culture method and by membrane filtration through polyurethane (PU) foam membranes. hADSCs can be obtained from a suspension of human adipose tissue cells using the membrane filtration method in less than 30 min, whereas the conventional culture method requires 5-12 days. hADSCs that express the mesenchymal stem cell markers CD44, CD73, and CD90 were concentrated in the recovery solution from the PU membranes; no hADSCs were isolated in the permeate. After filtration, the cells expressing the mesenchymal stem cell markers were 3-4.5 times more concentrated than in the initial suspension of human adipose tissue cells, with the level of concentration depending on the surface modification of the PU membrane. Cells expressing the stem cell-associated marker CD34 could be successfully isolated in the recovery solutions, whereas CD34+ cells could not be purified by the conventional culture method. The hADSCs in the recovery solution demonstrated a superior capacity for osteogenic differentiation than did the cells in the suspension of human adipose tissue cells. These results suggested that the hADSCs with the capability for osteogenic differentiation adhered to the PU membranes. © 2012 Elsevier Ltd.


Higuchi A.,National Central University | Higuchi A.,National Health Research Institute | Higuchi A.,Cathay Medical Research Institute | Ling Q.-D.,Cathay Medical Research Institute | And 4 more authors.
Chemical Reviews | Year: 2011

A scientific review presents biomaterials for the feeder-free culture of human embryonic stem cells (hESC) and induced pluripotent stem cells (iPSC). Tissue-specific stem cell niches provide crucial cell-cell contacts and paracrine signaling. The extracellular matrix ECM) keeps stem cells in the niche and serves to initiate signal transduction, while locally concentrated glycosaminoglycans (GAGs) provide soluble growth factors or cytokines. It will be highly beneficial to design, construct, and reproduce the microenvironment and niche of pluripotent stem cells in vitro with biomacromolecules and synthetic polymers. Culture materials derived from biomacromolecules and synthetic polymers have been used to support the propagation of hESCs and human iPSCs while maintaining their pluripotency.


Higuchi A.,National Central University | Higuchi A.,National Health Research Institute | Higuchi A.,Cathay Medical Research Institute | Ling Q.-D.,Cathay Medical Research Institute | And 3 more authors.
Chemical Reviews | Year: 2012

The chemical, physical, and biological characteristics of natural biopolymers, especially extracellular matrix (ECM) proteins, which are the major functional biopolymers, are discussed. The ability of these biopolymers to guide differentiation of mesenchymal stem cells (MSC) into osteogenic, chondrogenic, adipogenic, cardiomyogenic, and neural cell lineages, is also presented. Recent studies have found that patch sheets of immobilized antibodies or ligands targeting specific stem cells, which recruit the stem cells from the patient's body, are effective in gathering autologous stem cells at sites of injury. Park et al. reported that mechanical strain regulated the expression of vascular smooth muscle cell (SMC) markers in MSCs. Takahashi et al. fabricated biodegradable gelatin sponges incorporating various amounts of (β-tricalcium phosphate (βTCP) (gelatin-(βTCP)263 and investigated the in vitro osteogenic differentiation of MSCs isolated from rat bone marrow. Gil et al. found that the oligodendrocytic differentiation of hESCs was efficiently promoted by vitronectin.


Yang S.H.,Taipei Veterans General Hospital | Yang S.H.,National Yang Ming University | Huang C.-J.,Cathay Medical Research Institute | Chang S.-C.,Taipei Veterans General Hospital | And 3 more authors.
Annals of Surgical Oncology | Year: 2011

Background. An elevated plasma level of C-reactive protein (CRP) is a risk for, and prognostic factor of, colorectal cancer (CRC). In other reports of CRP concerning cardiovascular disease, CRP level correlated with its gene polymorphisms. We hypothesized that CRP polymorphisms associate risk and prognosis of CRC. Methods. This study enrolled 421 patients with CRC and 218 healthy control subjects. After preliminary studies, we selected four single nucleotide polymorphisms (SNPs) in the CRP gene: +2147A>G (rs1205), +942G>C (rs1800947), -717A>G (rs2794521), and -757T>C (rs3093059). At first, analyzing distributions of four SNPs between CRC case and non-CRC control groups was performed. Subsequently, the impacts of these SNPs with other prognostic factors of disease-free interval (DFI) and cancer-specific survival (CSS) were analyzed using uniand multivariate Cox regression analyses. Results. The case and control groups differed in the frequency of -757T>C (P = 0.002). The CRC case group had a higher percentage of the TT genotype (odds, 1.75). Regarding prognoses, multivariate analyses revealed that four factors, including stage (I, II, III), gross tumor type (polypoid, ulcerative, infiltrative), location (right, left, rectum), and -757T>C SNP (odds, 1.29; P = 0.048), correlated with DFI; two factors, including stage and +2147A>G SNP (odds, 0.71; P = 0.03), correlated with CSS. Conclusions. The -757T>C SNP is a risk for and prognostic factor of DFI; the +2147A>G SNP is a prognostic factor of CSS. CRP polymorphisms associate the risk and survival of CRC. © Society of Surgical Oncology 2011.


Higuchi A.,National Central University | Higuchi A.,National Health Research Institute | Higuchi A.,Cathay Medical Research Institute | Tamai M.,Tokyo Institute of Technology | And 8 more authors.
Polymer Reviews | Year: 2010

The optical resolution or chiral separation of one specific enantiomer from others is in demand for the production of pharmaceuticals because many pharmaceuticals exist as stereoisomers, with each enantiomer having different biological activity. There is considerable demand for separation techniques appropriate for the large-scale resolution of chiral molecules. Chiral separation of racemic mixtures of pharmaceuticals through chiral or achiral polymeric membranes with or without a chiral selector represents a promising system for future commercial application. This article reviews several polymeric materials for the chiral separation of pharmaceuticals. Several chiral separation membranes were prepared from chiral polymers where enantioselectivity was generated from chiral carbons in the main chain. However, it is rather difficult to generate excellent chiral separation membranes from chiral polymers alone, because racemic penetrants mainly encounter the flexible side chains of the membrane polymers. Therefore, chiral separation membranes were also prepared using polymers with a chiral branch. Furthermore, several molecules have been used for specific interactions between the molecules and specific pharmaceuticals or drugs in chiral separation membranes. Cyclodextrins, crown ether derivatives, albumin, and DNA are commonly used as stereoselective ligands in chiral separation membranes. Finally, this article discusses future trends in polymeric materials for chiral separation membranes.


Lin S.-C.,Cathay General Hospital | Lin S.-C.,Cathay Medical Research Institute | Lin S.-C.,Fu Jen Catholic University | Kuo C.-C.,Cathay General Hospital | And 2 more authors.
European Journal of Clinical Investigation | Year: 2012

Background Interleukin (IL)-28 is an interferon-λ-family member involved in immunity against viral infection and tumour. We here determined the expression profiles of IL-28 and IL-28 receptor α (IL-28RA) in patients with systemic lupus erythematosus (SLE) to evaluate the possibility that IL-28 is linked to the pathogenesis of SLE. Materials and methods The serum IL-28 protein levels were determined by ELISA, and the IL-28 and IL-28RA transcript levels in peripheral blood mononuclear cells (PBMCs) and peripheral blood T cells were determined by RT-PCR. The levels in patients with SLE with the active disease activity were statistically compared with those in normal controls. Results IL-28 protein in sera and IL-28 transcripts in PBMCs and unactivated T cells were detectable only in some individuals, and IL-28 transcripts in T cells were induced by cell activation with anti-CD2, anti-CD3 and anti-CD28 antibodies. However, compared with normal controls, patients with SLE more frequently had detectable IL-28 protein in serum and had the higher IL-28 transcript levels in activated CD4 + T cells, but not activated CD8 + T cells. Two IL-28RA transcripts isoforms were detected in PBMCs and T cells, and their levels in patients with SLE were comparable with those in normal controls. Conclusions The expression of IL-28, a T-cell autocrine factor, is dysregulated in patients with SLE, supporting the possibility that IL-28 may contribute to some of the SLE pathogenesis. © 2011 The Authors. European Journal of Clinical Investigation © 2011 Stichting European Society for Clinical Investigation Journal Foundation.

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