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1.  Analysis of N-glycoproteins using Genomic N-glycosite Prediction 
Journal of proteome research  2013;12(12):5609-5615.
Protein glycosylation has long been recognized as one of the most common post-translational modifications. Most membrane proteins and extracellular proteins are N-linked glycosylated and they account for the majority of current clinical diagnostic markers or therapeutic targets. Quantitative proteomic analysis of detectable N-linked glycoproteins from cells or tissues using mass spectrometry has the potential to provide biological basis for disease development and identify disease associated glycoproteins. However, the information of low abundance but important peptides is lost due to the lack of MS/MS fragmentation or low quality of MS/MS spectra for low abundant peptides. Here, we show the feasibility of formerly N-glycopeptide identification and quantification at MS1 level using genomic N-glycosite prediction (GenoGlyco) coupled with stable isotopic labeling and accurate mass matching. The GenoGlyco Analyzer software uses accurate precursor masses of detected N-deglycopeptide peaks to match them to N-linked deglycopeptides which are predicted from genes expressed in the cells. This method results in more robust glycopeptide identification compared to MS/MS based identification. Our results showed that over three times the quantity of N-deglycopeptide assignments from the same mass spectrometry data could be produced in ovarian cancer cell lines compared to a MS/MS fragmentation method. Furthermore, the method was also applied to N-deglycopeptide analysis of ovarian tumors using the identified deglycopeptides from the two ovarian cell lines as heavy standards. We show that the described method has a great potential in the analysis of detectable N-glycoproteins from cells and tissues.
doi:10.1021/pr400575f
PMCID: PMC4072220  PMID: 24164404
glycosylation; prediction; genome-wide; SILAC; accurate mass matching; ovarian cancer; mass spectrometry
2.  Endometrial regenerative cells as a novel cell therapy attenuate experimental colitis in mice 
Background
Endometrial regenerative cells (ERCs) are mesenchymal-like stem cells that can be non-invasively obtained from menstrual blood and are easily grown /generated at a large scale without tumorigenesis. We previously reported that ERCs exhibit unique immunoregulatory properties in vitro, however their immunosuppressive potential in protecting the colon from colitis has not been investigated. The present study was undertaken to determine the efficacy of ERCs in mediating immunomodulatory functions against colitis.
Methods
Colitis was induced by 4% dextran-sulfate-sodium (DSS, in drinking water) in BALB/c mice for 7 days. ERCs were cultured from healthy female menstrual blood, and injected (1 million/mouse/day, i.v.) into mice on days 2, 5, and 8 following colitis induction. Colonic and splenic tissues were collected on day 14 post-DSS-induction. Clinical signs, disease activity index (DAI), pathological and immunohistological changes, cytokine profiles and cell populations were evaluated.
Results
DSS-induced mice in untreated group developed severe colitis, characterized by body-weight loss, bloody stool, diarrhea, mucosal ulceration and colon shortening, as well as pathological changes of intra-colon cell infiltrations of neutrophils and Mac-1 positive cells. Notably, ERCs attenuated colitis with significantly reduced DAI, decreased levels of intra-colon IL-2 and TNF-α, but increased expressions of IL-4 and IL-10. Compared with those of untreated colitis mice, splenic dendritic cells isolated from ERC-treated mice exhibited significantly decreased MHC-II expression. ERC-treated mice also demonstrated much less CD3+CD25+ active T cell and CD3+CD8+ T cell population and significantly higher level of CD4+CD25+Foxp3+ Treg cells.
Conclusions
This study demonstrated novel anti-inflammatory and immunosuppressive effects of ERCs in attenuating colitis in mice, and suggested that the unique features of ERCs make them a promising therapeutic tool for the treatment of ulcerative colitis.
doi:10.1186/s12967-014-0344-5
PMCID: PMC4269937  PMID: 25475342
Endometrial regenerative cells; Colitis; Mice
3.  XGlycScan: An Open-source Software For N-linked Glycosite Assignment, Quantification and Quality Assessment of Data from Mass Spectrometry-based Glycoproteomic Analysis 
Mass spectrometry based glycoproteomics has become a major means of identifying and characterizing previously N-linked glycan attached loci (glycosites). In the bottom-up approach, several factors which include but not limited to sample preparation, mass spectrometry analyses, and protein sequence database searches result in previously N-linked peptide spectrum matches (PSMs) of varying lengths. Given that multiple PSM scan map to a glycosite, we reason that identified PSMs are varying length peptide species of a unique set of glycosites. Because associated spectra of these PSMs are typically summed separately, true glycosite associated spectra counts are lost or complicated. Also, these varying length peptide species complicate protein inference as smaller sized peptide sequences are more likely to map to more proteins than larger sized peptides or actual glycosite sequences. Here, we present XGlycScan. XGlycScan maps varying length peptide species to glycosites to facilitate an accurate quantification of glycosite associated spectra counts. We observed that this reduced the variability in reported identifications of mass spectrometry technical replicates of our sample dataset. We also observed that mapping identified peptides to glycosites provided an assessment of search-engine identification. Inherently, XGlycScan reported glycosites reduce the complexity in protein inference. We implemented XGlycScan in the platform independent Java programing language and have made it available as open source. XGlycScan's source code is freely available at https://bitbucket.org/paiyetan/xglycscan/src and its compiled binaries and documentation can be freely downloaded at https://bitbucket.org/paiyetan/xglycscan/downloads. The graphical user interface version can also be found at https://bitbucket.org/paiyetan/xglycscangui/src and https://bitbucket.org/paiyetan/xglycscangui/downloads respectively.
PMCID: PMC4207213  PMID: 25346946
Bioinformatics; Peptide; Glycopeptide; Glycosite; Protein identification; Proteomics; Quality assessment
4.  M2Lite: An Open-source, Light-weight, Pluggable and Fast Proteome Discoverer MSF to mzIdentML Tool 
Journal of bioinformatics  2014;1(2):40-49.
Proteome Discoverer is one of many tools used for protein database search and peptide to spectrum assignment in mass spectrometry-based proteomics. However, the inadequacy of conversion tools makes it challenging to compare and integrate its results to those of other analytical tools. Here we present M2Lite, an open-source, light-weight, easily pluggable and fast conversion tool. M2Lite converts proteome discoverer derived MSF files to the proteomics community defined standard – the mzIdentML file format. M2Lite’s source code is available as open-source at https://bitbucket.org/paiyetan/m2lite/src and its compiled binaries and documentation can be freely downloaded at https://bitbucket.org/paiyetan/m2lite/downloads.
PMCID: PMC4206089  PMID: 25346941
Bioinformatics; Peptide identification; Proteome Discoverer; MSF; Proteomics; mzIdentML; pepXML; IDPicker
5.  Knowledge-fused differential dependency network models for detecting significant rewiring in biological networks 
BMC Systems Biology  2014;8:87.
Background
Modeling biological networks serves as both a major goal and an effective tool of systems biology in studying mechanisms that orchestrate the activities of gene products in cells. Biological networks are context-specific and dynamic in nature. To systematically characterize the selectively activated regulatory components and mechanisms, modeling tools must be able to effectively distinguish significant rewiring from random background fluctuations. While differential networks cannot be constructed by existing knowledge alone, novel incorporation of prior knowledge into data-driven approaches can improve the robustness and biological relevance of network inference. However, the major unresolved roadblocks include: big solution space but a small sample size; highly complex networks; imperfect prior knowledge; missing significance assessment; and heuristic structural parameter learning.
Results
To address these challenges, we formulated the inference of differential dependency networks that incorporate both conditional data and prior knowledge as a convex optimization problem, and developed an efficient learning algorithm to jointly infer the conserved biological network and the significant rewiring across different conditions. We used a novel sampling scheme to estimate the expected error rate due to “random” knowledge. Based on that scheme, we developed a strategy that fully exploits the benefit of this data-knowledge integrated approach. We demonstrated and validated the principle and performance of our method using synthetic datasets. We then applied our method to yeast cell line and breast cancer microarray data and obtained biologically plausible results. The open-source R software package and the experimental data are freely available at http://www.cbil.ece.vt.edu/software.htm.
Conclusions
Experiments on both synthetic and real data demonstrate the effectiveness of the knowledge-fused differential dependency network in revealing the statistically significant rewiring in biological networks. The method efficiently leverages data-driven evidence and existing biological knowledge while remaining robust to the false positive edges in the prior knowledge. The identified network rewiring events are supported by previous studies in the literature and also provide new mechanistic insight into the biological systems. We expect the knowledge-fused differential dependency network analysis, together with the open-source R package, to be an important and useful bioinformatics tool in biological network analyses.
doi:10.1186/s12918-014-0087-1
PMCID: PMC4131167  PMID: 25055984
Biological networks; Probabilistic graphical models; Differential dependency network; Network rewiring; Network analysis; Systems biology; Knowledge incorporation; Convex optimization
6.  Nonlinear System Modeling with Random Matrices: Echo State Networks Revisited 
Echo state networks (ESNs) are a novel form of recurrent neural networks (RNNs) that provide an efficient and powerful computational model approximating nonlinear dynamical systems. A unique feature of an ESN is that a large number of neurons (the “reservoir”) are used, whose synaptic connections are generated randomly, with only the connections from the reservoir to the output modified by learning. Why a large randomly generated fixed RNN gives such excellent performance in approximating nonlinear systems is still not well understood. In this brief, we apply random matrix theory to examine the properties of random reservoirs in ESNs under different topologies (sparse or fully connected) and connection weights (Bernoulli or Gaussian). We quantify the asymptotic gap between the scaling factor bounds for the necessary and sufficient conditions previously proposed for the echo state property. We then show that the state transition mapping is contractive with high probability when only the necessary condition is satisfied, which corroborates and thus analytically explains the observation that in practice one obtains echo states when the spectral radius of the reservoir weight matrix is smaller than 1.
doi:10.1109/TNNLS.2011.2178562
PMCID: PMC4107715  PMID: 24808467
Circular law; concentration of measure; echo state networks; echo state property; random matrix theory; recurrent neural networks
7.  Glycoproteomic Study Reveals Altered Plasma Proteins Associated with HIV Elite Suppressors 
Theranostics  2014;4(12):1153-1163.
HIV elite suppressors (ES) or controllers are individuals achieving control of viremia by their natural immunological mechanisms without highly active antiretroviral therapy (HAART). Study of the mechanisms responsible for the immunological suppression of viremia in ES may lead to the detection of individuals with ES and the effective control of HIV infection. We hypothesize that plasma glycoproteins play essential roles in the immune system of ES since plasma proteins are critical and highly relevant in anti-viral immunity and most plasma proteins are glycoproteins. To examine glycoproteins associated with ES, plasma samples from ES individuals (n=20), and from individuals on HAART (n=20), with AIDS (n=20), and no HIV infection (n=10) were analyzed by quantitative glycoproteomics. We found that a number of glycoproteins changed between ES versus HAART, AIDS and HIV- individuals. In sharp contrast, the level of plasma glycoproteins in the HAART cohort showed fewer changes compared with AIDS and HIV- individuals. These results showed that although both ES and HAART effectively suppress viremia, ES appeared to profoundly affect immunologically relevant glycoproteins in plasma as consequence of or support for anti-viral immunity. Bioinformatic analysis revealed that altered proteins in ES plasma were mainly associated with inflammation. This analysis suggests that overlapping, while distinguishable, glycoprotein profiles for inflammation and immune activation appeared to be present between ES and non-ES (HAART+AIDS) cohorts, indicating different triggers for inflammation and immune activation between natural and treatment-related viral suppression.
doi:10.7150/thno.9510
PMCID: PMC4183994  PMID: 25285165
HIV; elite suppressor; HAART; AIDS; glycoprotein; glycoproteomics; inflammation; immune activation
8.  KAT5 silencing induces apoptosis of GBC-SD cells through p38MAPK-mediated upregulation of cleaved Casp9 
The poor overall prognosis of Gallbladder carcinoma (GBC) patients and the limited therapeutic regimens for these patients demonstrates the need for better therapeutic modalities, while the growing evidences have indicated that those genes contributed to epigenetic regulation may serve as therapeutic targets. The function of histone acetylation on growth and survival of GBC cells remains unknown. In present study, an RNAi screening of 16 genes involving histone acetyltransferases (HATs) was applied to GBC-SD cells and we found that KAT5 knockdown specifically inhibits the proliferation of GBC-SD cells by casp9-mediated apoptosis. Microarray data analysis showed that KAT5 RNAi may result in cleaved casp9 upregulation through p38MAPK activation in GBC-SD cells. The mRNA expression level of KAT5 was significantly upregulated in GBC tissues than in the adjacent normal tissues. In consistence with the mRNA level, the protein expression of KAT5 was markedly increased in tissues from patients with poor prognosis than those with good prognosis. These findings strongly indicated that KAT5 was implicated in GBC tumorigenesis and that its expression level was associated with the prognosis. Our work may also provide a potential therapeutic target for treatment of GBC patients.
PMCID: PMC3885462  PMID: 24427328
Gallbladder carcinoma; histone acetyltransferases; RNAi screening; KAT5; p38MAPK
9.  Endoplasmic reticulum stress, the unfolded protein response, and gene network modeling in antiestrogen resistant breast cancer 
Lack of understanding of endocrine resistance remains one of the major challenges for breast cancer researchers, clinicians, and patients. Current reductionist approaches to understanding the molecular signaling driving resistance have offered mostly incremental progress over the past 10 years. As the field of systems biology has begun to mature, the approaches and network modeling tools being developed and applied therein offer a different way to think about how molecular signaling and the regulation of critical cellular functions are integrated. To gain novel insights, we first describe some of the key challenges facing network modeling of endocrine resistance, many of which arise from the properties of the data spaces being studied. We then use activation of the unfolded protein response (UPR) following induction of endoplasmic reticulum stress in breast cancer cells by antiestrogens, to illustrate our approaches to computational modeling. Activation of UPR is a key determinant of cell fate decision making and regulation of autophagy and apoptosis. These initial studies provide insight into a small subnetwork topology obtained using differential dependency network analysis and focused on the UPR gene XBP1. The XBP1 subnetwork topology incorporates BCAR3, BCL2, BIK, NFκB, and other genes as nodes; the connecting edges represent the dependency structures amongst these nodes. As data from ongoing cellular and molecular studies become available, we will build detailed mathematical models of this XBP1-UPR network.
doi:10.1515/hmbci.2010.073
PMCID: PMC3734561  PMID: 23930139
Antiestrogen; autophagy; apoptosis; breast cancer; cell signaling; endoplasmic reticulum; estrogens; gene networks; unfolded protein response; computational modeling; mathematical modeling; systems biology
10.  Application of video-assisted thoracic surgery in the standard operation for thoracic tumors 
Cancer Biology & Medicine  2013;10(1):28-35.
Objective
To evaluate the short-term outcomes of video-assisted thoracic surgery (VATS) for thoracic tumors.
Methods
The data of 1,790 consecutive patients were retrospectively reviewed. These patients underwent VATS pulmonary resections, VATS esophagectomies, and VATS resections of mediastinal tumors or biopsies at the Cancer Institute & Hospital, Chinese Academy of Medical Sciences between January 2009 and January 2012.
Results
There were 33 patients converted to open thoracotomy (OT, 1.84%). The overall morbidity and mortality rate was 2.79% (50/1790) and 0.28% (5/1790), respectively. The overall hospitalization and chest tube duration were shorter in the VATS lobectomy group (n=949) than in the open thoracotomy (OT) lobectomy group (n=753). There were no significant differences in morbidity rate, mortality rate and operation time between the two groups. In the esophageal cancer patients, no significant difference was found in the number of nodal dissection, chest tube duration, morbidity rate, mortality rate, and hospital length of stay between the VATS esophagectomy group (n=81) and open esophagectomy group (n=81). However, the operation time was longer in the VATS esophagectomy group. In the thymoma patients, there was no significant difference in the chest tube duration, morbidity rate, mortality rate, and hospital length of stay between the VATS thymectomy group (n=41) and open thymectomy group (n=41). However, the operation time was longer in the VATS group. The median tumor size in the VATS thymectomy group was comparable with that in the OT group.
Conclusions
In early-stage (I/II) non-small cell lung cancer patients who underwent lobectomies, VATS is comparable with the OT approach with similar short-term outcomes. In patients with resectable esophageal cancer, VATS esophagectomy is comparable with OT esophagectomy with similar morbidity and mortality. VATS thymectomy for Masaoka stage I and II thymoma is feasible and safe, and tumor size is not contraindicated. Longer follow-ups are needed to determine the oncologic equivalency of VATS lobectomy, esophagectomy, and thymectomy for thymoma vs. OT.
doi:10.7497/j.issn.2095-3941.2013.01.005
PMCID: PMC3643687  PMID: 23691442
Video-assisted thoracic surgery (VATS); non-small cell lung cancer (NSCLC); esophageal cancer; thymoma
11.  Impact of Lycium Barbarum Polysaccharide and Danshensu on vascular endothelial growth factor in the process of retinal neovascularization of rabbit 
AIM
To discuss the impact of Lycium Barbarum Polysaccharide (LBP) and Danshensu purified from Traditional Chinese Medicine (TCM) on vascular endothelial growth factor (VEGF) of rabbits with retinal neovascularization.
METHODS
Forty rabbits were divided into normal control group, model control group, LBP group and Danshensu group. Animals in the normal control group were fed in the normal oxygen environment. Animals in the other three groups were put into the environment with 70% oxygen for 5 days in order to build the model of oxygen-induced vascular proliferation retinopathy. And then different TCM extract was injected into the abdominal cavities of these annimals. After 7 days, the VEGF content of in the serum of rabbit was measured by double antibody sandwich method.
RESULTS
Data analysis indicated that VEGF content was as follows: Danshensu group was lower than model control group (12.92±3.84ng/L vs 19.32±4.15ng/L, P<0.05); LBP group and normal control group were lower than model control group (12.92±3.84ng/L, 9.26±1.61ng/L vs 19.32±4.15ng/L, P<0.01); total blood viscosity, plasma viscosity, cholesterol content, fibrinogen content and triacylglycerol content after peritoneal injection of LBP and Danshensu were obviously lower than before injection.
CONCLUSION
TCM extract-LBP and Danshensu can prominently reduce the content of VEGF in the process of vascular proliferative retinopathy of rabbit; can prevent the occurrence of retinal microvascular disease by improving partial oxygen-deficient environment or affecting all kinds of new growth factor.
doi:10.3980/j.issn.2222-3959.2013.01.12
PMCID: PMC3580251  PMID: 23550271
Lycium Barbarum Polysaccharide; Danshensu; vascular endothelial growth factor; retinal neovascularization; rabbit
12.  High-fat or ethinyl-oestradiol intake during pregnancy increases mammary cancer risk in several generations of offspring 
Nature communications  2012;3:1053.
Maternal exposures to environmental factors during pregnancy influence the risk of many chronic adult-onset diseases in the offspring. Here we investigate whether feeding pregnant rats a high-fat (HF)- or ethinyl-oestradiol (EE2)-supplemented diet affects carcinogen-induced mammary cancer risk in daughters, granddaughters and great-granddaughters. We show that mammary tumourigenesis is higher in daughters and granddaughters of HF rat dams and in daughters and great-granddaughters of EE2 rat dams. Outcross experiments suggest that the increase in mammary cancer risk is transmitted to HF granddaughters equally through the female or male germ lines, but it is only transmitted to EE2 granddaughters through the female germ line. The effects of maternal EE2 exposure on offspring’s mammary cancer risk are associated with changes in the DNA methylation machinery and methylation patterns in mammary tissue of all three EE2 generations. We conclude that dietary and oestrogenic exposures in pregnancy increase breast cancer risk in multiple generations of offspring, possibly through epigenetic means.
doi:10.1038/ncomms2058
PMCID: PMC3570979  PMID: 22968699
13.  Research progress on criteria for discontinuation of EGFR inhibitor therapy 
OncoTargets and therapy  2012;5:263-270.
The clinical success of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) as therapeutic agents has prompted great interest in their further development and clinical testing for a wide variety of malignancies. However, most studies have focused on the efficacy of TKI, and few studies have been done on the criteria for their discontinuation. The current standard for drug discontinuation is “until progression”, based on change in tumor size. However, tumor size is not related to the gene expression which determines the efficacy of TKI in the final analysis, and it is also difficult to make a thorough and correct prediction based on tumor size when the TKI is discontinued. Nevertheless, clinical evaluation of the criteria for TKI discontinuation is still in its early days. Some promising findings have started to emerge. With the improving knowledge of EGFR and its inhibitors, it is expected that the criteria for discontinuation of EGFR inhibitor therapy will become clearer.
doi:10.2147/OTT.S36103
PMCID: PMC3475392  PMID: 23082072
epidermal growth factor receptor; drug discontinuation; acquired drug-resistance
14.  Inflammatory gene variants and the risk of biliary tract cancers and stones: a population-based study in China 
BMC Cancer  2012;12:468.
Background
Genetic variants in inflammation-related genes have been associated with biliary stones and biliary tract cancers in previous studies.
Methods
To follow-up on these findings, we examined 35 single nucleotide polymorphism (SNPs) in 5 genes related to inflammation (IL8, NFKBIL, RNASEL, TNF, and VEGFA) in 456 participants with incident biliary tract cancer cases (262 gallbladder, 141 extrahepatic bile duct, 53 ampulla of Vater), 982 participants with biliary stones, and 860 healthy controls in a population–based case–control study in Shanghai, China.
Results
Suggestive associations were observed for SNPs in VEGFA with biliary stones, IL8 with gallbladder and ampulla of Vater cancers, and RNASEL with ampulla of Vater cancer (false discovery rate≤0.2).
Conclusion
These findings provide additional support for the role of inflammation in biliary stones and biliary tract cancer risk and need further validation.
doi:10.1186/1471-2407-12-468
PMCID: PMC3524039  PMID: 23057767
Biliary tract cancer; Biliary stones; Inflammation; Genetic susceptibility
15.  Upregulation of tumor necrosis factor receptor-associated factor 6 correlated with synovitis severity in rheumatoid arthritis 
Arthritis Research & Therapy  2012;14(3):R133.
Introduction
Rheumatoid arthritis (RA) is a chronic inflammatory disease leading to joint destruction and disability. Focal bone erosion is due to excess bone resorption of osteoclasts. Tumor necrosis factor receptor-associated factor 6 (TRAF6) is one of the critical mediators both in inflammatory signal pathway and differentiation and resorption activity of osteoclasts. Here we aimed to investigate TRAF6 expression in RA synovium and its correlation with histological synovitis severity and radiological joint destruction in RA.
Methods
Synovitis score was determined in needle biopsied synovium from 44 patients with active RA. Synovium from nine patients with osteoarthritis (OA) and seven with orthopedic arthropathies (Orth.A) were enrolled as "less inflamed" disease controls. Serial sections were stained immunohistochemically for TRAF6 as well as CD68 (macrophage), CD3 (T cell), CD20 (B cell), CD38 (plasmocyte), CD79a (B lineage cells from pre-B cell to plasmocyte stage), and CD34 (endothelial cell). Double immunofluorescence staining of TRAF6 and CD68 were tested. Densities of positive staining cells were determined and correlated with histological disease activity (synovitis score) and radiographic joint destruction (Sharp score).
Results
TRAF6 expression was found in the intimal and subintimal area of RA synovium, with intense staining found in the endochylema and nucleus of intimal synoviocytes and subintimal inflammatory cells. Double immunofluorescence staining showed TRAF6 was expressed in most of the intimal cells and obviously expressed in CD68+ cells and some other CD68- cells in subintimal area. Synovial TRAF6 was significantly over-expressed in the RA group compared with the OA and Orth.A group (2.53 ± 0.94 vs. 0.72 ± 0.44 and 0.71 ± 0.49, P < 0.0001). Synovial TRAF6 expression in RA correlated significantly with synovitis score (r = 0.412, P = 0.006), as well as the inflammatory cell infiltration (r = 0.367, P = 0.014). Significant correlation was detected between synovial TRAF6 expression and intimal CD68+ cells, as well as the cell density of subintimal CD68+ cells, CD3+ cells, CD20+ cells, CD38+ cells, and CD79a+ cells (all P < 0.05).
Conclusions
Elevated synovial TRAF6 expression correlated with synovitis severity and CD68+ cell density in RA. It is, therefore, hypothesized that synovial TRAF6 is involved in the pathogenesis of synovial inflammation and osteoclast differentiation in RA.
doi:10.1186/ar3866
PMCID: PMC3446516  PMID: 22656185
16.  BACOM: in silico detection of genomic deletion types and correction of normal cell contamination in copy number data 
Bioinformatics  2011;27(11):1473-1480.
Motivation: Identification of somatic DNA copy number alterations (CNAs) and significant consensus events (SCEs) in cancer genomes is a main task in discovering potential cancer-driving genes such as oncogenes and tumor suppressors. The recent development of SNP array technology has facilitated studies on copy number changes at a genome-wide scale with high resolution. However, existing copy number analysis methods are oblivious to normal cell contamination and cannot distinguish between contributions of cancerous and normal cells to the measured copy number signals. This contamination could significantly confound downstream analysis of CNAs and affect the power to detect SCEs in clinical samples.
Results: We report here a statistically principled in silico approach, Bayesian Analysis of COpy number Mixtures (BACOM), to accurately estimate genomic deletion type and normal tissue contamination, and accordingly recover the true copy number profile in cancer cells. We tested the proposed method on two simulated datasets, two prostate cancer datasets and The Cancer Genome Atlas high-grade ovarian dataset, and obtained very promising results supported by the ground truth and biological plausibility. Moreover, based on a large number of comparative simulation studies, the proposed method gives significantly improved power to detect SCEs after in silico correction of normal tissue contamination. We develop a cross-platform open-source Java application that implements the whole pipeline of copy number analysis of heterogeneous cancer tissues including relevant processing steps. We also provide an R interface, bacomR, for running BACOM within the R environment, making it straightforward to include in existing data pipelines.
Availability: The cross-platform, stand-alone Java application, BACOM, the R interface, bacomR, all source code and the simulation data used in this article are freely available at authors' web site: http://www.cbil.ece.vt.edu/software.htm.
Contact: yuewang@vt.edu
Supplementary Information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btr183
PMCID: PMC3102226  PMID: 21498400
17.  DDN: a caBIG® analytical tool for differential network analysis 
Bioinformatics  2011;27(7):1036-1038.
Summary: Differential dependency network (DDN) is a caBIG® (cancer Biomedical Informatics Grid) analytical tool for detecting and visualizing statistically significant topological changes in transcriptional networks representing two biological conditions. Developed under caBIG® 's In Silico Research Centers of Excellence (ISRCE) Program, DDN enables differential network analysis and provides an alternative way for defining network biomarkers predictive of phenotypes. DDN also serves as a useful systems biology tool for users across biomedical research communities to infer how genetic, epigenetic or environment variables may affect biological networks and clinical phenotypes. Besides the standalone Java application, we have also developed a Cytoscape plug-in, CytoDDN, to integrate network analysis and visualization seamlessly.
Availability: The Java and MATLAB source code can be downloaded at the authors' web site http://www.cbil.ece.vt.edu/software.htm
Contact: yuewang@vt.edu
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btr052
PMCID: PMC3065688  PMID: 21296752
18.  Polymorphisms of estrogen receptors and risk of biliary tract cancers and gallstones: a population-based study in Shanghai, China 
Carcinogenesis  2010;31(5):842-846.
Biliary tract cancer encompasses tumors of the gallbladder, bile duct and ampulla of Vater. Gallbladder cancer is more common in women, whereas bile duct cancer is more common in men, suggesting that sex hormones may play a role in the etiology of these cancers. The intracellular action of estrogens is regulated by the estrogen receptor (ESR); thus, we examined the role of common genetic variants in ESR genes on the risk of biliary tract cancers and stones in a population-based case–control study in Shanghai, China (411 cancer cases, 895 stone cases and 786 controls). We genotyped six single-nucleotide polymorphisms (SNPs), four in ESR1 (rs2234693, rs3841686, rs2228480 and rs1801132) and two in ESR2 (rs1256049 and rs4986938). In all participants, the ESR1 rs1801132 (P325P) G allele was associated with excess risks of bile duct [odds ratio (OR) = 1.7, 95% confidence interval (CI) 1.1–2.8] and ampulla of Vater cancers (OR = 2.1, 95% CI 0.9–4.9) compared with the CC genotype. The association with bile duct cancer was apparent among men (OR = 2.8, 95% CI 1.4–5.7) but not among women (P-heterogeneity = 0.01). Also, the ESR2 rs4986938 (38 bp 3′ of STP) GG genotype was associated with a higher risk of bile duct cancer (OR = 3.3, 95% CI 1.3–8.7) compared with the AA genotype, although this estimate was based on a small number of subjects. None of the other SNPs examined was associated with biliary tract cancers or stones. False discovery rate-adjusted P-values were not significant (P > 0.1). No association was found for ESR1 haplotype based on four SNPs. These preliminary results suggest that variants in ESR genes could play a role in the etiology of biliary tract cancers, especially bile duct cancer in men.
doi:10.1093/carcin/bgq038
PMCID: PMC2864412  PMID: 20172949
19.  Androgen Receptor CAG Repeat Length and Risk of Biliary Tract Cancer and Stones 
Biliary tract cancers, encompassing cancers of the gallbladder, extrahepatic bile ducts, and ampulla of Vater, are rare but highly fatal. Gallstones represent the major risk factor for biliary tract cancer, and share with gallbladder cancer a female predominance and an association with reproductive factors and obesity. While estrogens have been implicated in earlier studies of gallbladder cancer, there are no data on the role of androgens. Since intracellular androgen activity is mediated through the androgen receptor (AR), we examined associations between AR CAG repeat length [(CAG)n] and the risk of biliary tract cancers and stones in a population-based study of 331 incident cancer cases, 837 gallstone cases, and 750 controls from Shanghai, China, where the incidence rates for biliary tract cancer are rising sharply. Men with (CAG)n>24 had a significant 2-fold risk of gallbladder cancer (odds ratio [OR]=2.00; 95% confidence interval [CI] 1.07–3.73), relative to those with (CAG)n≤22. In contrast, women with (CAG)n>24 had reduced gallbladder cancer risk (OR=0.69, 95% CI 0.43–1.09) relative to those with (CAG)n≤22; P-interaction sex=0.01), which was most pronounced for women aged 68–74 (OR=0.48, 95% CI 0.25–0.93; P-interaction age=0.02). No associations were found for bile duct cancer or gallstones. Reasons for the heterogeneity of genetic effects by gender and age are unclear but may reflect an interplay between AR and the levels of androgen as well as estrogen in men and older women. Further studies are needed to confirm these findings and clarify the mechanisms involved.
doi:10.1158/1055-9965.EPI-09-0973
PMCID: PMC2837546  PMID: 20200439
Biliary Tract Cancer; Gallstones; Androgen Receptor; Gallbladder Neoplasms
20.  Sorafenib extends the survival time of patients with multiple recurrences of hepatocellular carcinoma after liver transplantation 
Acta Pharmacologica Sinica  2010;31(12):1643-1648.
Aim:
To determine the efficacy and toxicities of sorafenib in the treatment of patients with multiple recurrences of hepatocellular carcinoma (HCC) after liver transplantation in a Chinese population.
Methods:
Twenty patients with multiple recurrences of HCC after liver transplantation were retrospectively studied. They received either transarterial chemoembolization (TACE) or TACE combined with sorafenib.
Results:
The median survival times (MST) after multiple recurrences was 14 months (TACE+sorafenib group) and 6 months (TACE only group). The difference was significant in MST between the two groups (P=0.005). The TACE + sorafenib group had more stable disease (SD) patients than the TACE group. The most frequent adverse events of sorafenib were hand–foot skin reaction and diarrhea. In the univariate analysis, preoperative bilirubin and CHILD grade are found to be significantly associated with tumor-free survival time, the survival time after multiple recurrences and overall survival time. TACE+sorafenib group showed a better outcome than single TACE treatment group. In the multivariate COX regression modeling, the preoperative high CHILD grade was found to be a risk factor of tumor-free survival time. In addition, the preoperative high bilirubin grade was also found to be a risk factor of survival time after recurrence and overall survival time. Furthermore, survival time after recurrence and overall survival time were also associated with therapeutic schedule, which was indicated by the GROUP.
Conclusion:
Treatment with TACE and sorafenib is worthy of further study and may have more extensive application prospects.
doi:10.1038/aps.2010.124
PMCID: PMC4002938  PMID: 21102481
hepatocellular carcinoma; sorafenib; transarterial chemoembolization; survival analysis; molecular targeted therapy
21.  Novel Function of CD81 in Controlling Hepatitis C Virus Replication▿ † 
Journal of Virology  2010;84(7):3396-3407.
The mechanisms of hepatitis C virus (HCV) replication remain poorly understood, and the cellular factors required for HCV replication are yet to be completely defined. CD81 is known to mediate HCV entry. Our study uncovered an unexpected novel function of CD81 in the HCV life cycle that is important for HCV RNA replication. HCV replication occurred efficiently in infected cells with high levels of CD81 expression. In HCV-infected or RNA-transfected cells with low levels of CD81 expression, initial viral protein synthesis occurred normally, but efficient replication failed to proceed. The aborted replication could be restored by the transient transfection of a CD81 expression plasmid. CD81-dependent replication was demonstrated with both an HCV infectious cell culture and HCV replicon cells of genotypes 1b and 2a. We also showed that CD81 expression is positively correlated with the kinetics of HCV RNA synthesis but inversely related to the kinetics of viral protein production, suggesting that CD81 may control viral replication by directing viral RNA template function to RNA replication. Thus, CD81 may be necessary for the efficient replication of the HCV genome in addition to its role in viral entry.
doi:10.1128/JVI.02391-09
PMCID: PMC2838140  PMID: 20089661
22.  Polymorphisms of Genes in the Lipid Metabolism Pathway and the Risk of Biliary Tract Cancers and Stones: A Population-based Case-Control Study in Shanghai, China 
Biliary tract cancers, encompassing the gallbladder, extrahepatic bile duct, and ampulla of Vater, are uncommon, yet highly fatal malignancies. Gallstones, the primary risk factor for biliary cancers, are linked with hyperlipidemia. We examined the associations of 12 single nucleotide polymorphisms (SNPs) of five genes in the lipid metabolism pathway with the risks of biliary cancers and stones in a population-based case-control study in Shanghai, China. We included 235 gallbladder, 125 extrahepatic bile duct, and 46 ampulla of Vater cancer cases, 880 biliary stone cases, and 779 population controls. Subjects completed an in-person interview and gave blood. Genotyping was conducted by Taqman assay using DNA from buffy coats. The effects of APOE IVS1+69 (rs440446) and APOB IVS6+360C>T (rs520354) markers were limited to men. Men carrying the G allele of APOE IVS1+69 had a 1.7-fold risk of stones (95% confidence interval (CI) =1.2–2.4), a 1.8–fold risk of gallbladder cancer (95% CI=1.0–3.3), a 3.7–fold risk of bile duct cancer (95% CI=2.0–7.0), and a 4-fold risk of ampullary cancer (95% CI=1.4–12.4). Male carriers of the T allele of APOB IVS6+360C>T had a 2-fold risk of bile duct cancer (95% CI=1.2–3.4). The APOB T-T haplotype (APOB IVS6+360C>T, EX4+56C>T) was associated with a 1.6-fold risk of bile duct cancer (95% CI=1.1–2.3). Male and female carriers of the T allele of LDLR IVS9-30C>T (rs1003723) had 1.5-fold risks of bile duct cancer. Our findings suggest that gene variants in the lipid metabolism pathway contribute to the risk of biliary tract stones and cancers, particularly of the bile duct.
doi:10.1158/1055-9965.EPI-07-2704
PMCID: PMC2897750  PMID: 18296645
single nucleotide polymorphisms; lipid metabolism; gallstones; biliary tract cancer
24.  Serum Lipid Levels and the Risk of Biliary Tract Cancers and Biliary Stones: A Population-based Study in China 
Biliary tract cancers, encompassing the gallbladder, extrahepatic bile ducts, and ampulla of Vater, are rare, but highly fatal malignancies. Gallstones, the predominant risk factor for biliary cancers, are linked with hyperlipidemia. As part of a population-based case-control study conducted in Shanghai, China, we examined the associations of serum lipid levels with biliary stones and cancers. We included 460 biliary cancer cases (264 gallbladder, 141 extrahepatic bile duct, and 55 ampulla of Vater), 981 biliary stone cases, and 858 healthy individuals randomly selected from the population. Participants completed an in-person interview and gave overnight fasting blood samples. Participants in the highest quintile of triglycerides (≥ 160 mg/dl) had a 1.4-fold risk of biliary stones (95% CI=1.1-1.9), a 1.9-fold risk of gallbladder cancer (95% CI=1.3-2.8), and a 4.8-fold risk of bile duct cancer (95% CI=2.8-8.1), compared to the reference group (third quintile: 90-124 mg/dl). Participants in the lowest quintile of high-density lipoprotein (HDL) (< 30 mg/dl) had a 4.2-fold risk of biliary stones (95% CI=3.0-6.0), an 11.6-fold risk of gallbladder cancer (95% CI=7.3-18.5), and a 16.8-fold risk of bile duct cancer (95% CI=9.1-30.9), relative to the reference group (third quintile: 40-49 mg/dl). In addition, total cholesterol, low-density lipoprotein (LDL) and apolipoprotein A (apo A) were inversely associated with biliary stones; whereas low levels as well as high levels of total cholesterol, LDL, apo A, and apolipoprotein B (apo B) were associated with excess risks of biliary tract cancers. Our findings support a role for serum lipids in gallstone development and biliary carcinogenesis.
doi:10.1002/ijc.23307
PMCID: PMC2860727  PMID: 18076041
serum lipid levels; gallstones; biliary tract cancer
25.  Variants in hormone-related genes and the risk of biliary tract cancers and stones: a population-based study in China 
Carcinogenesis  2009;30(4):606-614.
Biliary tract cancers, encompassing gallbladder, extrahepatic bile duct and ampulla of Vater cancers, are uncommon but often fatal malignancies. Hormone-related factors, including parity, oral contraceptive use, obesity, and gallstones, have been implicated in the etiology of these cancers. To further clarify the role of hormones in biliary tract cancers and biliary stones, we genotyped 18 single-nucleotide polymorphisms (SNPs) in nine genes involved in steroid hormone biosynthesis, metabolism and transport in a population-based case-control study in Shanghai, China. This study included subjects who completed an interview and provided blood, which totaled 411 biliary tract cancer and 893 biliary stone patients and 786 healthy Shanghai residents. The CYP1A1 IVS1 + 606 (rs2606345) T allele was associated with gallbladder [odds ratio (OR) = 2.0, 95% confidence interval (CI), 1.3–3.0] and bile duct cancers (OR = 1.8, 95% CI = 1.1–3.1), whereas the CYP1A1 Ex7 + 131 (rs1048943) G allele was associated with ampulla of Vater cancer (OR = 2.9, 95% CI = 1.5–5.4). After taking into account multiple comparisons for SNPs within each gene, CYP1A1 was significantly associated with gallbladder (P = 0.004) and ampulla of Vater cancers (P = 0.01), but borderline with bile duct cancer (P = 0.06). The effect of CYP1A1 IVS1 + 606 on gallbladder cancer was more pronounced among non-obese (body mass index < 23) (OR = 3.3, 95% CI = 1.8–6.1; P interaction = 0.001). Among women taking oral contraceptives, the effect of SHBG Ex8 + 6 (rs6259) on gallbladder cancer (OR = 6.7, 95% CI = 2.2–20.5; P interaction = 0.001) and stones (OR = 2.3, 95% CI = 1.1–4.9; P-interaction = 0.05) was statistically significant. Our findings suggest that common variants in hormone-related genes contribute to the risk of biliary tract cancers and stones, possibly by modulating hormone metabolism.
doi:10.1093/carcin/bgp024
PMCID: PMC2664453  PMID: 19168589

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