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author:("Wang, daping")
1.  Adoptive transfer of Tc1 or Tc17 cells elicits anti-tumor immunity against established melanoma through distinct mechanisms1 
Adoptive cell transfer (ACT) of ex vivo activated autologous tumor-reactive T cells is currently one of the most promising approaches for cancer immunotherapy. Recent studies provided some evidence that Th17/Tc17 cells may exhibit potent anti-tumor activity, but the specific mechanisms have not been completely defined. In the present study, we used a murine melanoma lung-metastasis model and tested the therapeutic effects of gp100-specific polarized Tc1 or Tc17 cells combined with autologous BMT after total TBI. BMT combined with ACT of anti-tumor (gp100-specific) Tc17 cells significantly suppressed the growth of established melanoma, whereas Tc1 cells induced long-term tumor regression. After ACT, Tc1 cells maintained their phenotype to produce IFNγ but not IL-17. However, although Tc17 cells largely preserved their ability to produce IL-17, a subset secreted IFNγ or both IFNγ and IL-17, indicating the plasticity of Tc17 cells in vivo. Furthermore, after ACT the Tc17 cells had a long-lived effector T cell phenotype (CD127hi/KLRG-1low) as compared to Tc1 cells. Mechanistically, Tc1 cells mediated anti-tumor immunity primarily through the direct effect of IFNγ on tumor cells. In contrast, despite the fact that some Tc17 cells also secreted IFNγ, Tc17-mediated anti-tumor immunity was independent of the direct effects of IFNγ on the tumor. Nevertheless, IFNγ played a critical role by creating a microenvironment that promoted Tc17-mediated anti-tumor activity. Taken together, these studies demonstrate that both Tc1 and Tc17 cells can mediate effective anti-tumor immunity through distinct effector mechanisms, but Tc1 cells are superior to Tc17 cells in mediating tumor regression.
doi:10.4049/jimmunol.1201989
PMCID: PMC3563723  PMID: 23315072
2.  Functional Networking of Human Divergently Paired Genes (DPGs) 
PLoS ONE  2013;8(10):e78896.
Divergently paired genes (DPGs), also known as bidirectional (head-to-head positioned) genes, are conserved across species and lineages, and thus deemed to be exceptional in genomic organization and functional regulation. Despite previous investigations on the features of their conservation and gene organization, the functional relationship among DPGs in a given species and lineage has not been thoroughly clarified. Here we report a network-based comprehensive analysis on human DPGs and our results indicate that the two members of the DPGs tend to participate in different biological processes while enforcing related functions as modules. Comparing to randomly paired genes as a control, the DPG pairs have a tendency to be clustered in similar “cellular components” and involved in similar “molecular functions”. The functional network bridged by DPGs consists of three major modules. The largest module includes many house-keeping genes involved in core cellular activities. This module also shows low variation in expression in both CNS (central nervous system) and non-CNS tissues. Based on analyses of disease transcriptome data, we further suggest that this particular module may play crucial roles in HIV infection and its disease mechanism.
doi:10.1371/journal.pone.0078896
PMCID: PMC3815023  PMID: 24205343
3.  LBH589 enhances T-cell activation in vivo and accelerates graft-versus-host disease in mice 
Histone deacetylase inhibitors (HDACi) are a new class of compounds that induce acetylation of histone lysine tails in chromatin and modify gene expression. The FDA approved HDACi, Vorinostat or suberoylanilide hydroxamic acid (SAHA), has been shown to inhibit tumor cell growth and the production of pro-inflammatory cytokines. In preclinical allogeneic transplantation models, SAHA induces graft-versus-host disease (GVHD) amelioration in treated mice without impairing graft-versus-leukemia (GVL). LBH589 (Panobinostat), a structurally novel cinnamic hydroxamic acid class, is an HDACi more potent than SAHA. In the current work, we tested the hypothesis that LBH589 would be highly effective in the prevention of GVHD. Using mouse model of allogeneic bone marrow transplantation (BMT), we unexpectedly found that treatment with LBH589 accelerated GVHD, in contrast to the treatment with SAHA that alleviated GVHD. Accelerated GVHD in the recipients treated with LBH589 was associated with elevated Th1 cytokines in recipient serum, enhanced CXCR3 expression on donor T cells, and T-cell infiltration in the liver. The current study highlights the distinct effects of pan HDACi on allogeneic BMT, and alerts that LBH589 (Panobinostat) could have adverse effect on GVHD, and possibly on other inflammatory diseases.
doi:10.1016/j.bbmt.2012.06.002
PMCID: PMC3417119  PMID: 22698484
4.  Distinct Genomic Aberrations between Low-Grade and High-Grade Gliomas of Chinese Patients 
PLoS ONE  2013;8(2):e57168.
Background
Glioma is a type of tumor that develops in the central nerve system, mainly the brain. Alterations of genomic sequence and sequence segments (such as copy number variations or CNV and copy neutral loss of heterozygosities or cnLOH) are thought to be a major determinant of the tumor grade.
Methods
We mapped genomic variations between low-grade and high-grade gliomas (LGG and HGG) in Chinese population based on Illumina’s Beadchip and validated the results using real-time qPCR.
Results
At the cytoband level, we discovered: (1) unique losses in LGG on 5q, 8p and 11q, and in HGG on 6q, 11p, 13q and 19q; (2) unique gains in the LGG on 1p and in HGG at 5p, 7p, 7q and 20q; and (3) cnLOH in HGG only on 3q, 8q, 10p, 14q, 15q, 17p, 17q, 18q and 21q. Subsequently, we confirmed well-characterized oncogenes among tumor-related loci (such as EGFR and KIT) and detected novel genes that gained chromosome sequences (such as AASS, HYAL4, NDUFA5 and SPAM1) in both LGG and HGG. In addition, we found gains, losses, and cnLOH in several genes, including VN1R2, VN1R4, and ZNF677, in multiple samples. Mapping grade-associated pathways and their related gene ontology (GO) terms, we classified LGG-associated functions as “arachidonic acid metabolism”, “DNA binding” and “regulation of DNA-dependent transcription” and the HGG-associated as “neuroactive ligand-receptor interaction”, “neuronal cell body” and “defense response to bacterium”.
Conclusion
LGG and HGG appear to have different molecular signatures in genomic variations and our results provide invaluable information for the diagnosis and treatment of gliomas in patients with variable duration or diverse tumor differentiation.
doi:10.1371/journal.pone.0057168
PMCID: PMC3579804  PMID: 23451178
5.  The Rice Genome Knowledgebase (RGKbase): an annotation database for rice comparative genomics and evolutionary biology 
Nucleic Acids Research  2012;41(D1):D1199-D1205.
Over the past 10 years, genomes of cultivated rice cultivars and their wild counterparts have been sequenced although most efforts are focused on genome assembly and annotation of two major cultivated rice (Oryza sativa L.) subspecies, 93-11 (indica) and Nipponbare (japonica). To integrate information from genome assemblies and annotations for better analysis and application, we now introduce a comparative rice genome database, the Rice Genome Knowledgebase (RGKbase, http://rgkbase.big.ac.cn/RGKbase/). RGKbase is built to have three major components: (i) integrated data curation for rice genomics and molecular biology, which includes genome sequence assemblies, transcriptomic and epigenomic data, genetic variations, quantitative trait loci (QTLs) and the relevant literature; (ii) User-friendly viewers, such as Gbrowse, GeneBrowse and Circos, for genome annotations and evolutionary dynamics and (iii) Bioinformatic tools for compositional and synteny analyses, gene family classifications, gene ontology terms and pathways and gene co-expression networks. RGKbase current includes data from five rice cultivars and species: Nipponbare (japonica), 93-11 (indica), PA64s (indica), the African rice (Oryza glaberrima) and a wild rice species (Oryza brachyantha). We are also constantly introducing new datasets from variety of public efforts, such as two recent releases—sequence data from ∼1000 rice varieties, which are mapped into the reference genome, yielding ample high-quality single-nucleotide polymorphisms and insertions–deletions.
doi:10.1093/nar/gks1225
PMCID: PMC3531066  PMID: 23193278
6.  Transposon-Derived and Satellite-Derived Repetitive Sequences Play Distinct Functional Roles in Mammalian Intron Size Expansion 
Background
Repetitive sequences (RSs) are redundant, complex at times, and often lineage-specific, representing significant “building” materials for genes and genomes. According to their origins, sequence characteristics, and ways of propagation, repetitive sequences are divided into transposable elements (TEs) and satellite sequences (SSs) as well as related subfamilies and subgroups hierarchically. The combined changes attributable to the repetitive sequences alter gene and genome architectures, such as the expansion of exonic, intronic, and intergenic sequences, and most of them propagate in a seemingly random fashion and contribute very significantly to the entire mutation spectrum of mammalian genomes.
Principal findings
Our analysis is focused on evolutional features of TEs and SSs in the intronic sequence of twelve selected mammalian genomes. We divided them into four groups—primates, large mammals, rodents, and primary mammals—and used four non-mammalian vertebrate species as the out-group. After classifying intron size variation in an intron-centric way based on RS-dominance (TE-dominant or SS-dominant intron expansions), we observed several distinct profiles in intron length and positioning in different vertebrate lineages, such as retrotransposon-dominance in mammals and DNA transposon-dominance in the lower vertebrates, amphibians and fishes. The RS patterns of mouse and rat genes are most striking, which are not only distinct from those of other mammals but also different from that of the third rodent species analyzed in this study—guinea pig. Looking into the biological functions of relevant genes, we observed a two-dimensional divergence; in particular, genes that possess SS-dominant and/or RS-free introns are enriched in tissue-specific development and transcription regulation in all mammalian lineages. In addition, we found that the tendency of transposons in increasing intron size is much stronger than that of satellites, and the combined effect of both RSs is greater than either one of them alone in a simple arithmetic sum among the mammals and the opposite is found among the four non-mammalian vertebrates.
Conclusions
TE- and SS-derived RSs represent major mutational forces shaping the size and composition of vertebrate genes and genomes, and through natural selection they either fine-tune or facilitate changes in size expansion, position variation, and duplication, and thus in functions and evolutionary paths for better survival and fitness. When analyzed globally, not only are such changes significantly diversified but also comprehensible in lineages and biological implications.
doi:10.4137/EBO.S9758
PMCID: PMC3396637  PMID: 22807622
transposable elements; satellite sequences; intron size; mammalian genomes
7.  Efficient and Selective Prevention of GVHD by Antigen-Specific Induced Tregs via Linked-Suppression in Mice 
Naturally occurring regulatory T cells (nTregs) suppress the development of GVHD and may spare graft-versus-leukemia (GVL) effect. Because nTreg is a rare population in a healthy individual, the limited source and the non-selective suppression are major hurdles towards the application of nTregs in the control of clinical GVHD after allogeneic HCT. An alternative approach is to generate induced Tregs (iTregs) from naïve CD4 precursors, but the effectiveness of iTregs in the control of GVHD is highly controversial and requires further investigation. The other critical but unsolved issue on Treg therapy is how to achieve antigen (Ag)-specific tolerance that distinguishes GVHD and GVL effect. To address the important issues on the effectiveness of iTregs and Ag-specificity of Tregs, we generated Ag-specific iTregs and tested their potential in the prevention of GVHD in pre-clinical BMT model. CD4+CD25+Foxp3+ iTregs generated from OT-II TCR transgenic T cells specific for OVA target Ag efficiently prevented GVHD induced by polyclonal T effector cells (Teffs) only in the allogeneic recipients that express OVA protein but not in OVA− recipients. The efficacy of these Ag-specific iTregs was significantly higher than polyclonal iTregs. As controls, OT-II CD4+Foxp3− cells had no effect on GVHD development in OVA− recipients and exacerbated GVHD in OVA+ recipients when transplanted together with polyclonal Teffs. Because the iTregs recognize OVA whereas Teffs recognize alloAg bm12, our data reveal for the first time that Tregs prevent GVHD through a linked suppression. Mechanistically, OT-II iTregs expanded extensively, and significantly suppressed expansion and infiltration of Teffs in OVA+ but not in OVA− recipients. These results demonstrate that Ag-specific iTregs can prevent GVHD efficiently and selectively, providing a proof of principle that Ag-specific iTregs may represent a promising cell therapy for their specificity and higher efficacy in allogeneic HCT.
doi:10.1016/j.bbmt.2010.12.710
PMCID: PMC3039088  PMID: 21224010
8.  LCGbase: A Comprehensive Database for Lineage-Based Co-regulated Genes 
Animal genes of different lineages, such as vertebrates and arthropods, are well-organized and blended into dynamic chromosomal structures that represent a primary regulatory mechanism for body development and cellular differentiation. The majority of genes in a genome are actually clustered, which are evolutionarily stable to different extents and biologically meaningful when evaluated among genomes within and across lineages. Until now, many questions concerning gene organization, such as what is the minimal number of genes in a cluster and what is the driving force leading to gene co-regulation, remain to be addressed. Here, we provide a user-friendly database—LCGbase (a comprehensive database for lineage-based co-regulated genes)—hosting information on evolutionary dynamics of gene clustering and ordering within animal kingdoms in two different lineages: vertebrates and arthropods. The database is constructed on a web-based Linux-Apache-MySQL-PHP framework and effective interactive user-inquiry service. Compared to other gene annotation databases with similar purposes, our database has three comprehensible advantages. First, our database is inclusive, including all high-quality genome assemblies of vertebrates and representative arthropod species. Second, it is human-centric since we map all gene clusters from other genomes in an order of lineage-ranks (such as primates, mammals, warm-blooded, and reptiles) onto human genome and start the database from well-defined gene pairs (a minimal cluster where the two adjacent genes are oriented as co-directional, convergent, and divergent pairs) to large gene clusters. Furthermore, users can search for any adjacent genes and their detailed annotations. Third, the database provides flexible parameter definitions, such as the distance of transcription start sites between two adjacent genes, which is extendable to genes that flanking the cluster across species. We also provide useful tools for sequence alignment, gene ontology (GO) annotation, promoter identification, gene expression (co-expression), and evolutionary analysis. This database not only provides a way to define lineage-specific and species-specific gene clusters but also facilitates future studies on gene co-regulation, epigenetic control of gene expression (DNA methylation and histone marks), and chromosomal structures in a context of gene clusters and species evolution. LCGbase is freely available at http://lcgbase.big.ac.cn/LCGbase.
doi:10.4137/EBO.S8540
PMCID: PMC3256993  PMID: 22267903
co-regulated genes; vertebrate; evolution; database
9.  Both Size and GC-Content of Minimal Introns Are Selected in Human Populations 
PLoS ONE  2011;6(3):e17945.
Background
We previously have studied the insertion and deletion polymorphism by sequencing no more than one hundred introns in a mixed human population and found that the minimal introns tended to maintain length at an optimal size. Here we analyzed re-sequenced 179 individual genomes (from African, European, and Asian populations) from the data released by the 1000 Genome Project to study the size dynamics of minimal introns.
Principal Findings
We not only confirmed that minimal introns in human populations are selected but also found two major effects in minimal intron evolution: (i) Size-effect: minimal introns longer than an optimal size (87 nt) tend to have a higher ratio of deletion to insertion than those that are shorter than the optimal size; (ii) GC-effect: minimal introns with lower GC content tend to be more frequently deleted than those with higher GC content. The GC-effect results in a higher GC content in minimal introns than their flanking exons as opposed to larger introns (≥125 nt) that always have a lower GC content than that of their flanking exons. We also observed that the two effects are distinguishable but not completely separable within and between populations.
Conclusions
We validated the unique mutation dynamics of minimal introns in keeping their near-optimal size and GC content, and our observations suggest potentially important functions of human minimal introns in transcript processing and gene regulation.
doi:10.1371/journal.pone.0017945
PMCID: PMC3060096  PMID: 21437290
10.  Nonsynonymous substitution rate (Ka) is a relatively consistent parameter for defining fast-evolving and slow-evolving protein-coding genes 
Biology Direct  2011;6:13.
Background
Mammalian genome sequence data are being acquired in large quantities and at enormous speeds. We now have a tremendous opportunity to better understand which genes are the most variable or conserved, and what their particular functions and evolutionary dynamics are, through comparative genomics.
Results
We chose human and eleven other high-coverage mammalian genome data–as well as an avian genome as an outgroup–to analyze orthologous protein-coding genes using nonsynonymous (Ka) and synonymous (Ks) substitution rates. After evaluating eight commonly-used methods of Ka and Ks calculation, we observed that these methods yielded a nearly uniform result when estimating Ka, but not Ks (or Ka/Ks). When sorting genes based on Ka, we noticed that fast-evolving and slow-evolving genes often belonged to different functional classes, with respect to species-specificity and lineage-specificity. In particular, we identified two functional classes of genes in the acquired immune system. Fast-evolving genes coded for signal-transducing proteins, such as receptors, ligands, cytokines, and CDs (cluster of differentiation, mostly surface proteins), whereas the slow-evolving genes were for function-modulating proteins, such as kinases and adaptor proteins. In addition, among slow-evolving genes that had functions related to the central nervous system, neurodegenerative disease-related pathways were enriched significantly in most mammalian species. We also confirmed that gene expression was negatively correlated with evolution rate, i.e. slow-evolving genes were expressed at higher levels than fast-evolving genes. Our results indicated that the functional specializations of the three major mammalian clades were: sensory perception and oncogenesis in primates, reproduction and hormone regulation in large mammals, and immunity and angiotensin in rodents.
Conclusion
Our study suggests that Ka calculation, which is less biased compared to Ks and Ka/Ks, can be used as a parameter to sort genes by evolution rate and can also provide a way to categorize common protein functions and define their interaction networks, either pair-wise or in defined lineages or subgroups. Evaluating gene evolution based on Ka and Ks calculations can be done with large datasets, such as mammalian genomes.
Reviewers
This article has been reviewed by Drs. Anamaria Necsulea (nominated by Nicolas Galtier), Subhajyoti De (nominated by Sarah Teichmann) and Claus O. Wilke.
doi:10.1186/1745-6150-6-13
PMCID: PMC3055854  PMID: 21342519
11.  Therapeutic potential of human umbilical cord mesenchymal stem cells in the treatment of rheumatoid arthritis 
Arthritis Research & Therapy  2010;12(6):R210.
Introduction
Rheumatoid arthritis (RA) is a T-cell-mediated systemic autoimmune disease, characterized by synovium inflammation and articular destruction. Bone marrow mesenchymal stem cells (MSCs) could be effective in the treatment of several autoimmune diseases. However, there has been thus far no report on umbilical cord (UC)-MSCs in the treatment of RA. Here, potential immunosuppressive effects of human UC-MSCs in RA were evaluated.
Methods
The effects of UC-MSCs on the responses of fibroblast-like synoviocytes (FLSs) and T cells in RA patients were explored. The possible molecular mechanism mediating this immunosuppressive effect of UC-MSCs was explored by addition of inhibitors to indoleamine 2,3-dioxygenase (IDO), Nitric oxide (NO), prostaglandin E2 (PGE2), transforming growth factor β1 (TGF-β1) and interleukin 10 (IL-10). The therapeutic effects of systemic infusion of human UC-MSCs on collagen-induced arthritis (CIA) in a mouse model were explored.
Results
In vitro, UC-MSCs were capable of inhibiting proliferation of FLSs from RA patients, via IL-10, IDO and TGF-β1. Furthermore, the invasive behavior and IL-6 secretion of FLSs were also significantly suppressed. On the other hand, UC-MSCs induced hyporesponsiveness of T cells mediated by PGE2, TGF-β1 and NO and UC-MSCs could promote the expansion of CD4+ Foxp3+ regulatory T cells from RA patients. More importantly, systemic infusion of human UC-MSCs reduced the severity of CIA in a mouse model. Consistently, there were reduced levels of proinflammatory cytokines and chemokines (TNF-α, IL-6 and monocyte chemoattractant protein-1) and increased levels of the anti-inflammatory/regulatory cytokine (IL-10) in sera of UC-MSCs treated mice. Moreover, such treatment shifted Th1/Th2 type responses and induced Tregs in CIA.
Conclusions
In conclusion, human UC-MSCs suppressed the various inflammatory effects of FLSs and T cells of RA in vitro, and attenuated the development of CIA in vivo, strongly suggesting that UC-MSCs might be a therapeutic strategy in RA. In addition, the immunosuppressive activitiy of UC-MSCs could be prolonged by the participation of Tregs.
doi:10.1186/ar3187
PMCID: PMC3046518  PMID: 21080925
12.  A Novel Role for Minimal Introns: Routing mRNAs to the Cytosol 
PLoS ONE  2010;5(4):e10144.
Background
Introns and their splicing are tightly coupled with the subsequent mRNA maturation steps, especially nucleocytoplasmic export. A remarkable fraction of vertebrate introns have a minimal size of about 100 bp, while majority of introns expand to several kilobases even megabases in length.
Principal Findings
We carried out analyses on the evolution and function of minimal introns (50–150 bp) in human and mouse genomes. We found that minimal introns are conserved in terms of both length and sequence. They are preferentially located toward 3′ end of mRNA and non-randomly distributed among chromosomes. Both the evolutionary conservation and non-random distribution are indicative of biological relevance. We showed that genes with minimal introns have higher abundance, larger size, and tend to be universally expressed as compared to genes with only large introns and intron-less genes. Genes with minimal introns replicate earlier and preferentially reside in the vicinities of open chromatin, suggesting their unique nuclear position and potential relevance to the regulation of gene expression and transcript export.
Conclusions
Based on these observations, we proposed a nuclear-export routing model, where minimal introns play a regulatory role in selectively exporting the highly abundant and large housekeeping genes that reside at the surface of chromatin territories, and thus preventing entanglement with other genes located at the interior locations.
doi:10.1371/journal.pone.0010144
PMCID: PMC2856156  PMID: 20419085

Results 1-12 (12)