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1.  Methylation of DLEC1 Promoter Is a Predictor for Recurrence in Chinese Patients with Gastric Cancer 
Disease Markers  2014;2014:804023.
Purpose. To investigate promoter methylation in the deleted in lung and esophageal cancer 1 (DLEC1) gene in Chinese patients with gastric cancer. Methods. A total of 227 patients with gastric cancer were enrolled. The methylations of the promoter regions of DLEC1 and ACTB were determined using quantitative methylation-specific PCR. The DLEC1 methylation was compared to the clinicopathological variables of gastric cancer. Results. DLEC1 methylation was not associated with the clinicopathological variables of gastric cancer. Patients with DLEC1-hypermethylated gastric cancer had significantly higher recurrence rate than those with DLEC1-hypomethylated gastric cancer (P = 0.025; hazard ratio = 2.43). Conclusions. Methylation of DELC1 promoter may be a valuable predictor for recurrence in Chinese patients with gastric cancer.
PMCID: PMC4276360  PMID: 25574068
2.  ZEB1 Expression in Endometrial Biopsy Predicts Lymph Node Metastases in Patient with Endometrial Cancer 
Disease Markers  2014;2014:680361.
Purpose. The purpose of this study was to analyze the expression of zinc-finger E-box-binding homeobox 1 (ZEB1) in endometrial biopsy and its correlation with preoperative characteristics, including lymph node metastases in patient with endometrial cancer. Methods. Using quantitative RT-PCR, ZEB1 expressions in endometrial biopsy from 452 patients were measured. The relationship between ZEB1 expression and preoperative characteristics was analyzed. Results. ZEB1 expressions were significantly associated with subtype, grade, myometrial invasion, and lymph node metastases. Lymph node metastases could be identified with a sensitivity of 57.8% at specificity of 74.1% by ZEB1 expression in endometrial biopsy. Based on combination of preoperative characteristics and ZEB1 expression, lymph node metastases could be identified with a sensitivity of 62.1% at specificity of 96.2% prior to hysterectomy. Conclusion. ZEB1 expression in endometrial biopsy could help physicians to better predict the lymph node metastasis in patients with endometrial cancer prior to hysterectomy.
PMCID: PMC4269209  PMID: 25544793
3.  Haff disease complicated by multiple organ failure after crayfish consumption: a case study 
Haff disease is a syndrome consisting of unexplained rhabdomyolysis. Patients suffering from Haff disease report having eaten fish within 24 hours before the onset of illness. Most patients survive and recover quickly. The present study is the first report of Haff disease complicated by multiple organ failure after crayfish consumption. A 66-year-old Chinese man ate cooked crayfish on the night of June 23, 2013. He arrived at our hospital 2 days later and was admitted to the intensive care unit. After admission, the patient was diagnosed with Haff disease complicated by multiple organ failure. Despite supportive and symptomatic treatments, the condition of the patient deteriorated, and he died due to his illness.
Haff disease is a rare clinical syndrome that is sometimes misdiagnosed. Early diagnosis and proper treatment are essential to prevent progression to multiple organ failure.
PMCID: PMC4304470  PMID: 25607271
Rhabdomyolysis; Astacoidea; Eating; Case reports
4.  Review of Current Methods, Applications, and Data Management for the Bioinformatics Analysis of Whole Exome Sequencing 
Cancer Informatics  2014;13(Suppl 2):67-82.
The advent of next-generation sequencing technologies has greatly promoted advances in the study of human diseases at the genomic, transcriptomic, and epigenetic levels. Exome sequencing, where the coding region of the genome is captured and sequenced at a deep level, has proven to be a cost-effective method to detect disease-causing variants and discover gene targets. In this review, we outline the general framework of whole exome sequence data analysis. We focus on established bioinformatics tools and applications that support five analytical steps: raw data quality assessment, pre-processing, alignment, post-processing, and variant analysis (detection, annotation, and prioritization). We evaluate the performance of open-source alignment programs and variant calling tools using simulated and benchmark datasets, and highlight the challenges posed by the lack of concordance among variant detection tools. Based on these results, we recommend adopting multiple tools and resources to reduce false positives and increase the sensitivity of variant calling. In addition, we briefly discuss the current status and solutions for big data management, analysis, and summarization in the field of bioinformatics.
PMCID: PMC4179624  PMID: 25288881
big data; InDel; next generation sequencing; sequence alignment; SNV; whole exome sequencing; variant analysis
5.  Zuo Jin Wan reverses P-gp-mediated drug-resistance by inhibiting activation of the PI3K/Akt/NF-κB pathway 
Zuo-Jin-Wan (ZJW), a traditional Chinese medicine formula, has been identified to be effective against drug resistance in cancer. In the present study, we investigated the effect of ZJW on acquired oxaliplatin-resistant and the PI3K/Akt/NF-κB pathway in vitro.
We tested the dose–response relationship of ZJW on reversing drug-resistance by CCK-8 assay and flow cytometry analysis in vitro. The protein expression of P-gp, MRP-2, LRP, and ABCB1 mRNA expression level were evaluated by Western blot and quantitative RT-PCR. The activities of PI3K/Akt/NF-κB pathway were also examined with or without ZJW, including Akt, IκB, p65 and their phosphorylation expression.
We found that ZJW significantly enhanced the sensitivity of chemotherapeutic drugs and increased oxaliplatin (L-OHP)-induced cell apoptosis in a time- and dose-dependent manner. Moreover, both ZJW and a PI3K specific inhibitor (LY294002) suppressed phosphorylation of Akt (Ser473) and NF-κB, which is necessary in the activation of the PI3K/Akt/NF-κB pathway. The effect of ZJW in reversing drug-resistance and suppressing phosphorylation of Akt (Ser473) and NF-κB were weakened after treatment with a PI3K/Akt activator in HCT116/L-OHP cells.
Our study has provided the first direct evidence that ZJW reverses drug-resistance in human colorectal cancer by blocking the PI3K/Akt/NF-κB signaling pathway, and could be considered as a useful drug for cancer therapy.
PMCID: PMC4288643  PMID: 25085593
Drug-resistance; Akt; NF-κB; ABCB1; ZJW
6.  Reduced growth and proliferation dynamics of nasal epithelial stem/progenitor cells in nasal polyps in vitro 
Scientific Reports  2014;4:4619.
Basal cells in nasal epithelium have stemness/progenitor characters and play essential roles in the epithelial remodeling in nasal polyps (NP). We investigate whether the human nasal epithelial stem/progenitor cells (hNESPCs) from patients with NP are inherently distinct from those obtained from healthy controls. Epithelial basal cells were isolated and cultured for four passages from NP tissues and control nasal mucosa. hNESPCs from controls were stained positively with stem cell marker p63 and KRT5 and presented a consistent high Ki67 expression level over four passages. In contrast, hNESPCs from NP patients showed: i). a reduced growth and proliferation rate at each passage by evaluating colony-forming efficiency and doubling time; ii). a lower percentage of Ki67+ cells among p63+ cells in the colonies in late passages, which was also confirmed by immunostaining in the NP tissues. Thus reduced growth/proliferation dynamics in hNESPCs from NP could be an important pathological phenomenon in NP development.
PMCID: PMC3980221  PMID: 24714674
7.  The Effects of Simulated Microgravity on Intervertebral Disc Degeneration 
Astronauts experience back pain, particularly low back pain, during and after spaceflight. Recent studies have described histological and biochemical changes in rat intervertebral discs after space travel, but there is still no in vitro model to investigate the effects of microgravity on disc metabolism.
To study the effects of microgravity on disc degeneration and to establish an in vitro simulated microgravity study model
Discs were cultured in static and rotating conditions in bioreactor, and the characteristics of disc degeneration were evaluated
The mice discs were cultured in a rotating wall vessel bioreactor where the microgravity condition was simulated. Intervertebral discs were cultured in static and microgravity condition. Histology, biochemistry, and immunohistochemical assays were performed to evaluate the characteristics of the discs in microgravity condition.
Intervertebral discs cultured in rotating bioreactors were found to develop changes of disc degeneration manifested by reduced red Safranin-o staining within the annulus fibrosus, downregulated GAG content and GAG/Hypro ratio, increased MMP-3 expression, and upregulated apoptosis.
We conclude that simulated microgravity induces the molecular changes of disc degeneration. The rotating bioreactor model will provide a foundation to investigate the effects of microgravity on disc metabolism.
PMCID: PMC3612270  PMID: 23537452
intervertebral disc; microgravity; disc degeneration; apoptosis; extracellular matrix
8.  Transcriptional Events during the Recovery from MRSA Lung Infection: A Mouse Pneumonia Model 
PLoS ONE  2013;8(8):e70176.
Community associated methicillin-resistant Staphylococcus aureus (CA-MRSA) is an emerging threat to human health throughout the world. Rodent MRSA pneumonia models mainly focus on the early innate immune responses to MRSA lung infection. However, the molecular pattern and mechanisms of recovery from MRSA lung infection are largely unknown. In this study, a sublethal mouse MRSA pneumonia model was employed to investigate late events during the recovery from MRSA lung infection. We compared lung bacterial clearance, bronchoalveolar lavage fluid (BALF) characterization, lung histology, lung cell proliferation, lung vascular permeability and lung gene expression profiling between days 1 and 3 post MRSA lung infection. Compared to day 1 post infection, bacterial colony counts, BALF total cell number and BALF protein concentration significantly decreased at day 3 post infection. Lung cDNA microarray analysis identified 47 significantly up-regulated and 35 down-regulated genes (p<0.01, 1.5 fold change [up and down]). The pattern of gene expression suggests that lung recovery is characterized by enhanced cell division, vascularization, wound healing and adjustment of host adaptive immune responses. Proliferation assay by PCNA staining further confirmed that at day 3 lungs have significantly higher cell proliferation than at day 1. Furthermore, at day 3 lungs displayed significantly lower levels of vascular permeability to albumin, compared to day 1. Collectively, this data helps us elucidate the molecular mechanisms of the recovery after MRSA lung infection.
PMCID: PMC3731344  PMID: 23936388
9.  One-Screw Fixation Provides Similar Stability to That of Two-Screw Fixation for Type II Dens Fractures 
Anterior screw fixation has been widely adopted for the treatment of Type II dens fractures. However, there is still controversy regarding whether one- or two-screw fixation is more appropriate.
We addressed three questions: (1) Do one- and two-screw fixation techniques differ regarding shear stiffness and rotational stiffness? (2) Can shear stiffness and rotational stiffness after screw fixation be restored to normal? (3) Does stiffness after screw fixation correlate with bone mineral density (BMD)?
We randomly assigned 14 fresh axes into two groups (seven axes each): one receiving one-screw fixation and another receiving two-screw fixation. Shear and torsional stiffness were measured using a nondestructive low-load test in six directions. A transverse osteotomy then was created at the base of the dens and fixed using one or two screws. Shear and torsional stiffness were tested again under the same testing conditions.
Mean stiffness in all directions after screw fixation was similar in both groups. The stiffness after one- and two-screw fixation was not restored to normal: the mean shear stiffness restored ratio was less than 50% and the mean torsional stiffness restored ratio was less than 6% in both groups. BMD did not correlate with mean stiffness after screw fixation in both groups.
One- and two-screw fixation for Type II dens fractures provide similar stability but neither restores normal shear or torsional stiffness.
Clinical Relevance
One-screw fixation might be used as an alternative to two-screw fixation. Assumed BMD should not influence surgical decision making.
PMCID: PMC3369094  PMID: 22585352
10.  Linezolid Exerts Greater Bacterial Clearance but No Modification of Host Lung Gene Expression Profiling: A Mouse MRSA Pneumonia Model 
PLoS ONE  2013;8(6):e67994.
Linezolid (LZD) is beneficial to patients with MRSA pneumonia, but whether and how LZD influences global host lung immune responses at the mRNA level during MRSA-mediated pneumonia is still unknown.
A lethal mouse model of MRSA pneumonia mediated by USA300 was employed to study the influence of LZD on survival, while the sublethal mouse model was used to examine the effect of LZD on bacterial clearance and lung gene expression during MRSA pneumonia. LZD (100mg/kg/day, IP) was given to C57Bl6 mice for three days. On Day 1 and Day 3 post infection, bronchoalveolar lavage fluid (BALF) protein concentration and levels of cytokines including IL6, TNFα, IL1β, Interferon-γ and IL17 were measured. In the sublethal model, left lungs were used to determine bacterial clearance and right lungs for whole-genome transcriptional profiling of lung immune responses.
LZD therapy significantly improved survival and bacterial clearance. It also significantly decreased BALF protein concentration and levels of cytokines including IL6, IL1β, Interferon-γ and IL17. No significant gene expression changes in the mouse lungs were associated with LZD therapy.
LZD is beneficial to MRSA pneumonia, but it does not modulate host lung immune responses at the transcriptional level.
PMCID: PMC3694879  PMID: 23826353
11.  Correction: A Statistical Framework for Accurate Taxonomic Assignment of Metagenomic Sequencing Reads 
PLoS ONE  2013;8(5):10.1371/annotation/c08da7e7-60fe-4f7d-a457-299bf9f24148.
PMCID: PMC3659234
12.  Quantification of Plasma Cell-Free DNA1 in Predicting Therapeutic Efficacy of Sorafenib on Metastatic Clear Cell Renal Cell Carcinoma 
Disease markers  2013;34(2):105-111.
PURPOSE: The objective of this study is to determine whether or not plasma cfDNA levels can predict efficacy of sorafenib in patient with metastatic cRCC.
MATERIALS AND METHODS: Plasma cfDNA levels were quantified by quantitative real-time PCR at six different time-points (before treatment, 4 weeks, 8 weeks, 12 weeks, 16 weeks, and 24 weeks) in 18 metastatic cRCC patients receiving sorafenib, as assessed by CT examination according to RECIST 1.1.
RESULTS: A significantly lower plasma cfDNA level, measured from 8 weeks to 24 weeks, was found in patients with remission or stable disease than in those with progression. Higher levels in plasma cfDNA levels during the course of treatment indicated poor outcome. For predicting progression, a sensitivity of 66.7% was achieved at 100% specificity using cfDNA levels at 8 weeks.
CONCLUSIONS: Monitoring of plasma cfDNA levels during the course of sorafenib therapy could identify metastatic cRCC patients who are likely to exhibit a poor response at an early stage.
PMCID: PMC3810240  PMID: 23324577
Cell-free DNA; sorafenib; response; metastatic clear cell renal cell carcinoma
13.  Transposon integration enhances expression of stress response genes 
Nucleic Acids Research  2012;41(2):775-789.
Transposable elements possess specific patterns of integration. The biological impact of these integration profiles is not well understood. Tf1, a long-terminal repeat retrotransposon in Schizosaccharomyces pombe, integrates into promoters with a preference for the promoters of stress response genes. To determine the biological significance of Tf1 integration, we took advantage of saturated maps of insertion activity and studied how integration at hot spots affected the expression of the adjacent genes. Our study revealed that Tf1 integration did not reduce gene expression. Importantly, the insertions activated the expression of 6 of 32 genes tested. We found that Tf1 increased gene expression by inserting enhancer activity. Interestingly, the enhancer activity of Tf1 could be limited by Abp1, a host surveillance factor that sequesters transposon sequences into structures containing histone deacetylases. We found the Tf1 promoter was activated by heat treatment and, remarkably, only genes that themselves were induced by heat could be activated by Tf1 integration, suggesting a synergy of Tf1 enhancer sequence with the stress response elements of target promoters. We propose that the integration preference of Tf1 for the promoters of stress response genes and the ability of Tf1 to enhance the expression of these genes co-evolved to promote the survival of cells under stress.
PMCID: PMC3553992  PMID: 23193295
14.  Breaches of the pial basement membrane are associated with defective dentate gyrus development in mouse models of congenital muscular dystrophies 
Neuroscience letters  2011;505(1):19-24.
A subset of congenital muscular dystrophies (CMDs) has central nervous system manifestations. There are good mouse models for these CMDs that include POMGnT1 knockout, POMT2 knockout and Largemyd mice with all exhibit defects in dentate gyrus. It is not known how the abnormal dentate gyrus is formed during development. In this study, we conducted a detailed morphological examination of the dentate gyrus in adult and newborn POMGnT1 knockout, POMT2 knockout, and Largemyd mice by immunofluorescence staining and electron microscopic analyses. We observed that the pial basement membrane overlying the dentate gyrus was disrupted and there was ectopia of granule cell precursors through the breached pial basement membrane. Besides these, the knockout dentate gyrus exhibited reactive gliosis in these mouse models. Thus, breaches in the pial basement membrane are associated with defective dentate gyrus development in mouse models of congenital muscular dystrophies.
PMCID: PMC3243927  PMID: 21970971
Congenital muscular dystrophies; dentate gyrus; brain development; basement membrane
15.  A Statistical Framework for Accurate Taxonomic Assignment of Metagenomic Sequencing Reads 
PLoS ONE  2012;7(10):e46450.
The advent of next-generation sequencing technologies has greatly promoted the field of metagenomics which studies genetic material recovered directly from an environment. Characterization of genomic composition of a metagenomic sample is essential for understanding the structure of the microbial community. Multiple genomes contained in a metagenomic sample can be identified and quantitated through homology searches of sequence reads with known sequences catalogued in reference databases. Traditionally, reads with multiple genomic hits are assigned to non-specific or high ranks of the taxonomy tree, thereby impacting on accurate estimates of relative abundance of multiple genomes present in a sample. Instead of assigning reads one by one to the taxonomy tree as many existing methods do, we propose a statistical framework to model the identified candidate genomes to which sequence reads have hits. After obtaining the estimated proportion of reads generated by each genome, sequence reads are assigned to the candidate genomes and the taxonomy tree based on the estimated probability by taking into account both sequence alignment scores and estimated genome abundance. The proposed method is comprehensively tested on both simulated datasets and two real datasets. It assigns reads to the low taxonomic ranks very accurately. Our statistical approach of taxonomic assignment of metagenomic reads, TAMER, is implemented in R and available at
PMCID: PMC3462201  PMID: 23049702
16.  Integrative Gene Expression Profiling Reveals G6PD-Mediated Resistance to RNA-Directed Nucleoside Analogues in B-Cell Neoplasms 
PLoS ONE  2012;7(7):e41455.
The nucleoside analogues 8-amino-adenosine and 8-chloro-adenosine have been investigated in the context of B-lineage lymphoid malignancies by our laboratories due to the selective cytotoxicity they exhibit toward multiple myeloma (MM), chronic lymphocytic leukemia (CLL), and mantle cell lymphoma (MCL) cell lines and primary cells. Encouraging pharmacokinetic and pharmacodynamic properties of 8-chloro-adenosine being documented in an ongoing Phase I trial in CLL provide additional impetus for the study of these promising drugs. In order to foster a deeper understanding of the commonalities between their mechanisms of action and gain insight into specific patient cohorts positioned to achieve maximal benefit from treatment, we devised a novel two-tiered chemoinformatic screen to identify molecular determinants of responsiveness to these compounds. This screen entailed: 1) the elucidation of gene expression patterns highly associated with the anti-tumor activity of 8-chloro-adenosine in the NCI-60 cell line panel, 2) characterization of altered transcript abundances between paired MM and MCL cell lines exhibiting differential susceptibility to 8-amino-adenosine, and 3) integration of the resulting datasets. This approach generated a signature of seven unique genes including G6PD which encodes the rate-determining enzyme of the pentose phosphate pathway (PPP), glucose-6-phosphate dehydrogenase. Bioinformatic analysis of primary cell gene expression data demonstrated that G6PD is frequently overexpressed in MM and CLL, highlighting the potential clinical implications of this finding. Utilizing the paired sensitive and resistant MM and MCL cell lines as a model system, we go on to demonstrate through loss-of-function and gain-of-function studies that elevated G6PD expression is necessary to maintain resistance to 8-amino- and 8-chloro-adenosine but insufficient to induce de novo resistance in sensitive cells. Taken together, these results indicate that G6PD activity antagonizes the cytotoxicity of 8-substituted adenosine analogues and suggests that administration of these agents to patients with B-cell malignancies exhibiting normal levels of G6PD expression may be particularly efficacious.
PMCID: PMC3407247  PMID: 22848499
17.  Functional regulatory T cells produced by inhibiting cyclic nucleotide phosphodiesterase type 3 prevent allograft rejection 
Science translational medicine  2011;3(83):83ra40.
Regulatory T cells (Tregs) manipulated ex vivo have potential as cellular therapeutics in autoimmunity and transplantation. Although it is possible to expand naturally occurring Tregs, an attractive alternative possibility, particularly suited to solid organ and bone marrow transplantation, is the stimulation of total T cell populations with defined allogeneic antigen presenting cells under conditions that lead to the generation or expansion of donor-reactive, adaptive Tregs. Here we demonstrate that stimulation of mouse CD4+ T cells by immature allogeneic dendritic cells (DCs) combined with pharmacological inhibition of phosphodiesterase 3 (PDEi) results in a functional enrichment of Foxp3+ T cells. Without further manipulation or selection, the resultant population delayed skin allograft rejection mediated by polyclonal CD4+ effectors or donor-reactive CD8+ TCR transgenic T cells and inhibited both effector cell proliferation and T cell priming for IFN-γ production. Notably, PDE inhibition also enhanced the enrichment of human Foxp3+ CD4+ T cells driven by allogeneic APC. These cells inhibited T cell proliferation in a standard in vitro mixed lymphocyte assay and importantly, attenuated the development of vasculopathy mediated by autologous PBMC in a functionally relevant humanized mouse transplant model. These data establish a method for the ex vivo generation of graft-reactive, functional mouse and human Tregs that uses a clinically approved agent, making pharmacological PDE inhibition a potential strategy for Treg-based therapies
PMCID: PMC3321352  PMID: 21593400
18.  A new method of lower extremity immobilization in radiotherapy 
We developed a new method for immobilization of the fix lower extremities by using a thermoplastic mask, a carbon fiber base plate, a customized headrest, and an adjustable angle holder. The lower extremities of 11 patients with lower extremity tumors were immobilized by this method. CT simulation was performed for each patient. For all 11 patients, the device fit was suitable and comfortable and had good reproducibility, which was proven in daily radiotherapy.
PMCID: PMC3305509  PMID: 22376892
Lower extremity; Immobilization; Radiotherapy
19.  Multicenter Clinical Study for Evaluation of Efficacy and Safety of Transdermal Fentanyl Matrix Patch in Treatment of Moderate to Severe Cancer Pain in 474 Chinese Cancer Patients 
Although a new matrix formulation fentanyl has been used throughout the world for cancer pain management, few data about its efficacy and clinical outcomes associated with its use in Chinese patients have been obtained. This study aimed to assess the efficacy and safety of the new system in Chinese patients with moderate to severe cancer pain.
A total of 474 patients with moderate to severe cancer pain were enrolled in this study and were treated with the new transdermal fentanyl matrix patch (TDF) up to 2 weeks. All the patients were asked to record pain intensity, side effects, quality of life (QOL), adherence and global satisfaction. The initial dose of fentanyl was 25 μg/h titrated with opioid or according to National Comprehensive Cancer Network (NCCN) guidelines. Transdermal fentanyl was changed every three days.
After 2 weeks. The mean pain intensity of the 459 evaluated patients decreased significantly from 5.63±1.26 to 2.03±1.46 (P<0.0001). The total remission rate was 91.29%, of which moderate remission rate 53.16%, obvious remission rate 25.49% and complete remission rate 12.64%. The rate of adverse events was 33.75%, 18.78% of which were moderate and 3.80% were severe. The most frequent adverse events were constipation and nausea. No fatal events were observed. The quality of life was remarkably improved after the treatment (P<0.0001).
The new TDF is effective and safe in treating patients with moderate to severe cancer pain, and can significantly improve the quality of life.
PMCID: PMC3551305  PMID: 23359267
Transdermal fentanyl matrix patch (TDF); Cancer pain; Efficacy; Safety; Quality of life
20.  Disease Ontology: a backbone for disease semantic integration 
Nucleic Acids Research  2011;40(Database issue):D940-D946.
The Disease Ontology (DO) database ( represents a comprehensive knowledge base of 8043 inherited, developmental and acquired human diseases (DO version 3, revision 2510). The DO web browser has been designed for speed, efficiency and robustness through the use of a graph database. Full-text contextual searching functionality using Lucene allows the querying of name, synonym, definition, DOID and cross-reference (xrefs) with complex Boolean search strings. The DO semantically integrates disease and medical vocabularies through extensive cross mapping and integration of MeSH, ICD, NCI's thesaurus, SNOMED CT and OMIM disease-specific terms and identifiers. The DO is utilized for disease annotation by major biomedical databases (e.g. Array Express, NIF, IEDB), as a standard representation of human disease in biomedical ontologies (e.g. IDO, Cell line ontology, NIFSTD ontology, Experimental Factor Ontology, Influenza Ontology), and as an ontological cross mappings resource between DO, MeSH and OMIM (e.g. GeneWiki). The DO project ( has been incorporated into open source tools (e.g. Gene Answers, FunDO) to connect gene and disease biomedical data through the lens of human disease. The next iteration of the DO web browser will integrate DO's extended relations and logical definition representation along with these biomedical resource cross-mappings.
PMCID: PMC3245088  PMID: 22080554
21.  Adenovirus-mediated expression of growth and differentiation factor-5 promotes chondrogenesis of adipose stem cells 
The repair of articular cartilage injuries is impeded by the avascular and non-innervated nature of cartilage. Transplantation of autologous chondrocytes has a limited ability to augment the repair process due to the highly differentiated state of chondrocytes and the risks of donor-site morbidity. Mesenchymal stem cells can undergo chondrogenesis in the presence of growth factors for cartilage defect repair. Growth and differentiation factor-5 (GDF5) plays an important role in chondrogenesis. In this study, we examined the effects of GDF5 on chondrogenesis of adipose-derived stem cells (ADSCs) and evaluate the chondrogenic potentials of GDF5 genetically engineered ADSCs using an in vitro pellet culture model. Rat ADSCs were grown as pellet cultures and treated with chondrogenic media (CM). Induction of GDF5 by an adenovirus (Ad-GDF5) was compared with exogenous supplementation of GDF5 (100 ng/ml) and transforming growth factor-β (TGF-β1; 10 ng/ml). The ADSCs underwent chondrogenic differentiation in response to GDF5 exposure as demonstrated by production of proteoglycan, and up-regulation of collagen II and aggrecan at the protein and mRNA level. The chondrogenic potential of a one-time infection with Ad-GDF5 was weaker than exogenous GDF5, but equal to that of TGF-β1. Stimulation with growth factors or CM alone induced transient expression of the mRNA for collagen X, indicating a need for optimization of the CM. Our findings indicate that GDF5 is a potent inducer of chondrogenesis in ADSCs, and that ADSCs genetically engineered to express prochondrogenic growth factors, such as GDF5, may be a promising therapeutic cell source for cartilage tissue engineering.
PMCID: PMC3034080  PMID: 18569021
Growth factors; chondrogenesis; GDF5; gene therapy; stem cells; cartilage
22.  Therapeutic effects of adenovirus-mediated growth and differentiation factor-5 in a mice disc degeneration model induced by annulus needle puncture 
The therapeutic strategies that have thus far been employed for the treatment of intervertebral disc degeneration (IDD) have focused on relieving the symptoms, while reversal of the degeneration remains an important challenge for the effective treatment of IDD. Growth and differentiation factor-5 (GDF5), of which deficiency leads to early disc degeneration changes, has the potential to increase proliferation of disc cells and expression of extracellular matrix proteins.
To develop a lumbar disc degeneration model in mice and determine the effect of adenoviral GDF5 gene therapy.
Compare the degeneration changes of discs punctured by different size needles to develop a mice lumbar disc degeneration model. Evaluate the effects of in vivo gene therapy for the mice disc degeneration model by an adenoviral vector carrying GDF5 gene.
A lumbar disc degeneration model was developed by needle punctures to the discs in Balb/c mice. Afterwards, a gene therapy treatment to disc degeneration was evaluated. Two of the mice lumbar discs were randomly chosen to be punctured by a 30- gauge needle and then injected with adenovirus that had been engineered to express either the luciferase gene (Ad-Luc) or the GDF5 gene (Ad-GDF5). Animals were analyzed by bioluminescent imaging, radiographic and MRI scanning, then sacrificed at 1-, 2-, 4-, or 8- week post operation and subjected to histological and biochemical assays.
By the detection of T2-weighted MRI scanning and histological study, the degeneration was found in all of the discs punctured by different size needles. But the development of the degeneration in the discs injured by 30-gauge needle was more reliable and moderate compared with other groups. The detection of luciferase activity by bioluminescent imaging revealed that adenovirus survived and the introduced genes were expressed over 6 weeks after injection. There were no T2-weighted MRI signals in either the Ad-Luc or Ad-GDF5 injected mice up to 4 weeks post operation. At 6 and 8 weeks, T2-weighted signals were detected in the Ad-GDF5 group, but none in the Ad-Luc control group. The percent disc height index (%DHI) was significantly decreased (~ 20%) by 1 week following injury in both groups, indicating the development of disc degeneration. At 2 weeks, the %DHI in the mice injected with Ad-GDF5 increased significantly compared with that of the mice injected with Ad-Luc group; the increase was sustained for the rest of experiment period. The disc histology treated with Ad-GDF5 was improved compared with that in control group. Glycosaminoglycan (GAG) levels were significantly decreased in the Ad-Luc injection group since 2 weeks after injury, and the DNA content had diminished by 4 weeks after the operation. In contrast, in the discs injected with Ad-GDF5, there was no decrease in the GAG and DNA levels following injury throughout the 8 weeks treatment period.
Disc degeneration animal model can be developed by using needle puncture to the discs in mice. The adenovirus is an effective vehicle for gene delivery with rapid and prolonged expression of target protein, and resulting improvement in markers of disc degeneration. Ad-GDF5 gene therapy could restore the functions of injured discs and has the potential to be an effective treatment.
PMCID: PMC2818300  PMID: 19926342
Intervertebral disc; degeneration; gene therapy; growth factor
23.  Mesenchymal Stem Cells Prevent the Rejection of Fully Allogenic Islet Grafts by the Immunosuppressive Activity of Matrix Metalloproteinase-2 and -9 
Diabetes  2009;58(8):1797-1806.
Mesenchymal stem cells (MSCs) are known to be capable of suppressing immune responses, but the molecular mechanisms involved and the therapeutic potential of MSCs remain to be clarified.
We investigated the molecular mechanisms underlying the immunosuppressive effects of MSCs in vitro and in vivo.
Our results demonstrate that matrix metalloproteinases (MMPs) secreted by MSCs, in particular MMP-2 and MMP-9, play an important role in the suppressive activity of MSCs by reducing surface expression of CD25 on responding T-cells. Blocking the activity of MMP-2 and MMP-9 in vitro completely abolished the suppression of T-cell proliferation by MSCs and restored T-cell expression of CD25 as well as responsiveness to interleukin-2. In vivo, administration of MSCs significantly reduced delayed-type hypersensitivity responses to allogeneic antigen and profoundly prolonged the survival of fully allogeneic islet grafts in transplant recipients. Significantly, these MSC-mediated protective effects were completely reversed by in vivo inhibition of MMP-2 and MMP-9.
We demonstrate that MSCs can prevent islet allograft rejection leading to stable, long-term normoglycemia. In addition, we provide a novel insight into the mechanism underlying the suppressive effects of MSCs on T-cell responses to alloantigen.
PMCID: PMC2712800  PMID: 19509016
24.  Xyloccensin L 
The title compound, C32H40O10, also known as xyloccensin L [systematic name: (1R,4aR,4bS,5aR,6aR,9R,10S,10aS,10bR,2aR,13R)-1-(furan-3-yl)-6a-hy­droxy-10-(2-meth­oxy-2-oxoeth­yl)-9,10a,12a-trimethyl-3-oxododeca­hydro-1H,3H,5aH-6,9-methano­isochromeno[6,5-f]oxireno[g]chromen-13-yl (2E)-2-methyl­but-2-enoate], is a limonoid with a C1—C29 oxygen bridge: this is the first report of the X-ray crystal structure of such a limonoid. Two fused pyran rings and two cyclo­hexane rings adopt boat conformations, while another cyclo­hexane ring and the d-lactone ring are in half-chair conformations. The mol­ecular structure is stabilized by intra­molecular O—H⋯O hydrogen bonding.
PMCID: PMC3007225  PMID: 21588402
25.  GATA-2 Reinforces Megakaryocyte Development in the Absence of GATA-1▿ †  
Molecular and Cellular Biology  2009;29(18):5168-5180.
GATA-2 is an essential transcription factor that regulates multiple aspects of hematopoiesis. Dysregulation of GATA-2 is a hallmark of acute megakaryoblastic leukemia in children with Down syndrome, a malignancy that is defined by the combination of trisomy 21 and a GATA1 mutation. Here, we show that GATA-2 is required for normal megakaryocyte development as well as aberrant megakaryopoiesis in Gata1 mutant cells. Furthermore, we demonstrate that GATA-2 indirectly controls cell cycle progression in GATA-1-deficient megakaryocytes. Genome-wide microarray analysis and chromatin immunoprecipitation studies revealed that GATA-2 regulates a wide set of genes, including cell cycle regulators and megakaryocyte-specific genes. Surprisingly, GATA-2 also negatively regulates the expression of crucial myeloid transcription factors, such as Sfpi1 and Cebpa. In the absence of GATA-1, GATA-2 prevents induction of a latent myeloid gene expression program. Thus, GATA-2 contributes to cell cycle progression and the maintenance of megakaryocyte identity of GATA-1-deficient cells, including GATA-1s-expressing fetal megakaryocyte progenitors. Moreover, our data reveal that overexpression of GATA-2 facilitates aberrant megakaryopoiesis.
PMCID: PMC2738300  PMID: 19620289

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