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1.  FOXP3 is an X-linked breast cancer suppressor gene and an important repressor of the HER-2/ErbB2 oncogene 
Cell  2007;129(7):1275-1286.
The X-linked Foxp3 is a member of the forkhead/winged helix transcription factor family. Germ-line mutations cause lethal autoimmune diseases in males. Serendipitously, we observed that Foxp3sf/+ heterozygous mice developed cancer at a high rate. The majority of the cancers were mammary carcinomas in which the wild-type Foxp3 allele was inactivated and ErbB2 was over-expressed. Foxp3 bound and repressed the ErbB2 promoter. Deletion, functionally significant somatic mutations and down-regulation of the FOXP3 gene were commonly found in human breast cancer samples and correlated significantly with HER-2 over-expression, regardless of the status of HER-2 amplification. In toto, the data demonstrate that FOXP3 is an X-linked breast cancer suppressor gene and an important regulator of the HER-2/ErbB2 oncogene.
PMCID: PMC1974845  PMID: 17570480
2.  Effect of aerobic exercise and low carbohydrate diet on pre-diabetic non-alcoholic fatty liver disease in postmenopausal women and middle aged men – the role of gut microbiota composition: study protocol for the AELC randomized controlled trial 
BMC Public Health  2014;14:48.
Pre-diabetes and non-alcoholic fatty liver disease (NAFLD) are associated with an unhealthy lifestyle and pose extremely high costs to the healthcare system. In this study, we aim to explore whether individualized aerobic exercise (AEx) and low carbohydrate diet (LCh) intervention affect hepatic fat content (HFC) in pre-diabetes via modification of gut microbiota composition and other post-interventional effects.
A 6-month randomized intervention with 6-month follow-up is conducted from January 2013 to December 2015. The target sample size for intervention is 200 postmenopausal women and middle-aged men aged 50–65 year-old with pre-diabetes and NAFLD. The qualified subjects are randomized into 4 groups with 50 subjects in each group: 1 = AEx, 2 = LCh, 3 = AEx + LCh, and 4 = control. In addition, two age-matched reference groups (5 = pre-diabetes without NAFLD (n = 50) and 6 = Healthy without pre-diabetes or NAFLD (n = 50)) are included. The exercise program consists of progressive and variable aerobic exercise (intensity of 60 to 75% of initial fitness level, 3–5 times/week and 30–60 min/time). The diet program includes dietary consultation plus supplementation with a special lunch meal (40% of total energy intake/day) which aims to reduce the amount of carbohydrate consumption (30%). The control and reference groups are advised to maintain their habitual habits during the intervention. The primary outcome measures are HFC, serum metabolomics and gut microbiota composition. The secondary outcome measures include body composition and cytokines. In addition, socio-psychological aspects, social support, physical activity and diet will be performed by means of questionnaire and interview.
Specific individualized exercise and diet intervention in this study offers a more efficient approach for liver fat reduction and diabetes prevention via modification of gut microbiota composition. Besides, the study explores the importance of incorporating fitness assessment and exercise in the management of patients with pre-diabetes and fatty liver disorders. If our program is shown to be effective, it will open new strategies to combat these chronic diseases.
Trial registration
Current Controlled Trials: ISRCTN42622771.
PMCID: PMC3897962  PMID: 24438438
Liver fat content; Glucose metabolism; Lipid metabolism; Gut microbiota; Metabonomics; Human; Clinical setting
3.  Genome Sequence of Pseudomonas putida Strain SJTE-1, a Bacterium Capable of Degrading Estrogens and Persistent Organic Pollutants 
Journal of Bacteriology  2012;194(17):4781-4782.
Pseudomonas putida strain SJTE-1 can utilize 17β-estradiol and other environmental estrogens/toxicants, such as estrone, and naphthalene as sole carbon sources. We report the draft genome sequence of strain SJTE-1 (5,551,505 bp, with a GC content of 62.25%) and major findings from its annotation, which could provide insights into its biodegradation mechanisms.
PMCID: PMC3415482  PMID: 22887678
4.  Genome Sequence of Pseudomonas aeruginosa Strain SJTD-1, a Bacterium Capable of Degrading Long-Chain Alkanes and Crude Oil 
Journal of Bacteriology  2012;194(17):4783-4784.
Pseudomonas aeruginosa strain SJTD-1 can utilize long-chain alkanes, diesel oil, and crude oil as sole carbon sources. We report the draft genome sequence of strain SJTD-1 (6,074,058 bp, with a GC content of 66.83%) and major findings from its annotation, which could provide insights into its petroleum biodegradation mechanism.
PMCID: PMC3415508  PMID: 22887679
5.  FOXP3 Orchestrates H4K16 Acetylation and H3K4 Tri-Methylation for Activation of Multiple Genes through Recruiting MOF and Causing Displacement of PLU-1 
Molecular cell  2011;44(5):770-784.
Both H4K16 acetylation and H3K4 tri-methylation are required for gene activation. However, it is still largely unclear how these modifications are orchestrated by transcriptional factors. Here we analyzed the mechanism of the transcriptional activation by FOXP3, an X-linked suppressor of autoimmune diseases and cancers. FOXP3 binds near transcriptional start sites of its target genes. By recruiting MOF and displacing histone H3K4 demethylase PLU-1, FOXP3 increases both H4K16 acetylation and H3K4 tri-methylation at the FOXP3-associated chromatins of multiple FOXP3-activated genes. RNAi-mediated silencing of MOF reduced both gene activation and tumor suppression by FOXP3, while both somatic mutations in clinical cancer samples and targeted mutation of FOXP3 in mouse prostate epithelial disrupted nuclear localization of MOF. Our data demonstrate a pull-push model in which a single transcription factor orchestrates two epigenetic alterations necessary for gene activation and provide a mechanism for somatic inactivation of the FOXP3 protein function in cancer cells.
PMCID: PMC3243051  PMID: 22152480
6.  Emergence and Continuous Evolution of Genotype 1E Rubella Viruses in China 
Journal of Clinical Microbiology  2012;50(2):353-363.
In China, rubella vaccination was introduced into the national immunization program in 2008, and a rubella epidemic occurred in the same year. In order to know whether changes in the genotypic distribution of rubella viruses have occurred in the postvaccination era, we investigate in detail the epidemiological profile of rubella in China and estimate the evolutionary rate, molecular clock phylogeny, and demographic history of the predominant rubella virus genotypes circulating in China using Bayesian Markov chain Monte Carlo phylodynamic analyses. 1E was found to be the predominant rubella virus genotype since its initial isolation in China in 2001, and no genotypic shift has occurred since then. The results suggest that the global 1E genotype may have diverged in 1995 and that it has evolved at a mutation rate of 1.65 × 10−3 per site per year. The Chinese 1E rubella virus isolates were grouped into either cluster 1 or cluster 2, which likely originated in 1997 and 2006, respectively. Cluster 1 viruses were found in all provinces examined in this study and had a mutation rate of 1.90 × 10−3 per site per year. The effective number of infections remained constant until 2007, and along with the introduction of rubella vaccine into the national immunization program, although the circulation of cluster 1 viruses has not been interrupted, some viral lineages have disappeared, and the epidemic started a decline that led to a decrease in the effective population size. Cluster 2 viruses were found only in Hainan Province, likely because of importation.
PMCID: PMC3264136  PMID: 22162559
7.  TLR3 deficiency impairs spinal cord synaptic transmission, central sensitization, and pruritus in mice 
The Journal of Clinical Investigation  2012;122(6):2195-2207.
Itch, also known as pruritus, is a common, intractable symptom of several skin diseases, such as atopic dermatitis and xerosis. TLRs mediate innate immunity and regulate neuropathic pain, but their roles in pruritus are elusive. Here, we report that scratching behaviors induced by histamine-dependent and -independent pruritogens are markedly reduced in mice lacking the Tlr3 gene. TLR3 is expressed mainly by small-sized primary sensory neurons in dorsal root ganglions (DRGs) that coexpress the itch signaling pathway components transient receptor potential subtype V1 and gastrin-releasing peptide. Notably, we found that treatment with a TLR3 agonist induces inward currents and action potentials in DRG neurons and elicited scratching in WT mice but not Tlr3–/– mice. Furthermore, excitatory synaptic transmission in spinal cord slices and long-term potentiation in the intact spinal cord were impaired in Tlr3–/– mice but not Tlr7–/– mice. Consequently, central sensitization–driven pain hypersensitivity, but not acute pain, was impaired in Tlr3–/– mice. In addition, TLR3 knockdown in DRGs also attenuated pruritus in WT mice. Finally, chronic itch in a dry skin condition was substantially reduced in Tlr3–/– mice. Our findings demonstrate a critical role of TLR3 in regulating sensory neuronal excitability, spinal cord synaptic transmission, and central sensitization. TLR3 may serve as a new target for developing anti-itch treatment.
PMCID: PMC3366391  PMID: 22565312
8.  A Dinucleotide Deletion in CD24 Confers Protection against Autoimmune Diseases 
PLoS Genetics  2007;3(4):e49.
It is generally believed that susceptibility to both organ-specific and systemic autoimmune diseases is under polygenic control. Although multiple genes have been implicated in each type of autoimmune disease, few are known to have a significant impact on both. Here, we investigated the significance of polymorphisms in the human gene CD24 and the susceptibility to multiple sclerosis (MS) and systemic lupus erythematosus (SLE). We used cases/control studies to determine the association between CD24 polymorphism and the risk of MS and SLE. In addition, we also considered transmission disequilibrium tests using family data from two cohorts consisting of a total of 150 pedigrees of MS families and 187 pedigrees of SLE families. Our analyses revealed that a dinucleotide deletion at position 1527∼1528 (P1527del) from the CD24 mRNA translation start site is associated with a significantly reduced risk (odds ratio = 0.54 with 95% confidence interval = 0.34–0.82) and delayed progression (p = 0.0188) of MS. Among the SLE cohort, we found a similar reduction of risk with the same polymorphism (odds ratio = 0.38, confidence interval = 0.22–0.62). More importantly, using 150 pedigrees of MS families from two independent cohorts and the TRANSMIT software, we found that the P1527del allele was preferentially transmitted to unaffected individuals (p = 0.002). Likewise, an analysis of 187 SLE families revealed the dinucleotide-deleted allele was preferentially transmitted to unaffected individuals (p = 0.002). The mRNA levels for the dinucleotide-deletion allele were 2.5-fold less than that of the wild-type allele. The dinucleotide deletion significantly reduced the stability of CD24 mRNA. Our results demonstrate that a destabilizing dinucleotide deletion in the 3′ UTR of CD24 mRNA conveys significant protection against both MS and SLE.
Author Summary
When an individual's immune system attacks self tissues or organs, he/she develops autoimmune diseases. Although it is well established that multiple genes control susceptibility to autoimmune diseases, most of the genes remain unidentified. In addition, although different autoimmune diseases have a common immunological basis, a very small number of genes have been identified that affect multiple autoimmune diseases. Here we show that a variation in CD24 is a likely genetic factor for the risk and progression of two types of autoimmune diseases, including multiple sclerosis (MS), an organ-specific autoimmune disease affecting the central nervous system, and systemic lupus erythematosus, a systemic autoimmune disease. Our data indicated that if an individual's CD24 gene has a specific two-nucleotide deletion in the noncoding region of CD24 mRNA, his/her risk of developing MS or SLE is reduced by 2- to 3-fold. As a group, MS patients with the two-nucleotide deletion will likely have a slower disease progression. Biochemical analysis indicated that the deletion leads to rapid decay of CD24 mRNA, which should result in reduced synthesis of the CD24 protein. Our data may be useful for the treatment and diagnosis of autoimmune diseases.
PMCID: PMC1847692  PMID: 17411341
9.  Arsenite binding-induced zinc loss from PARP-1 is equivalent to zinc deficiency in reducing PARP-1 activity, leading to inhibition of DNA repair 
Toxicology and applied pharmacology  2013;274(2):313-318.
Inhibition of DNA repair is a recognized mechanism for arsenic enhancement of ultraviolet radiation-induced DNA damage and carcinogenesis. Poly(ADP-ribose) polymerase-1 (PARP-1), a zinc finger DNA repair protein, has been identified as a sensitive molecular target for arsenic. The zinc finger domains of PARP-1 protein function as a critical structure in DNA recognition and binding. Since cellular poly(ADP-ribosyl)ation capacity has been positively correlated with zinc status in cells, we hypothesize that arsenite binding-induced zinc loss from PARP-1 is equivalent to zinc deficiency in reducing PARP-1 activity, leading to inhibition of DNA repair. To test this hypothesis, we compared the effects of arsenite exposure with zinc deficiency, created by using the membrane-permeable zinc chelator TPEN, on 8-OHdG formation, PARP-1 activity and zinc binding to PARP-1 in HaCat cells. Our results show that arsenite exposure and zinc deficiency had similar effects on PARP-1 protein, whereas supplemental zinc reversed these effects. To investigate the molecular mechanism of zinc loss induced by arsenite, ICP-AES, near UV spectroscopy, fluorescence, and circular dichroism spectroscopy were utilized to examine arsenite binding and occupation of a peptide representing the first zinc finger of PARP-1. We found that arsenite binding as well as zinc loss altered the conformation of zinc finger structure which functionally leads to PARP-1 inhibition. These findings suggest that arsenite binding to PARP-1 protein created similar adverse biological effects as zinc deficiency, which establishes the molecular mechanism for zinc supplementation as a potentially effective treatment to reverse the detrimental outcomes of arsenic exposure.
PMCID: PMC3891920  PMID: 24275069
zinc deficiency; arsenite; PARP-1; DNA damage repair; zinc finger
10.  Cost-Effectiveness of Colorectal Cancer Screening Protocols in Urban Chinese Populations 
PLoS ONE  2014;9(10):e109150.
Colorectal cancer (CRC) takes a second and fourth position in the incidence and mortality lists respectively among all malignant tumors in urban populations in China. This study was designed to evaluate the cost-effectiveness of two different CRC screening protocols: faecal occult blood test (FOBT) alone, and FOBT plus a high-risk factor questionnaire (HRFQ) as the respective initial screens, followed by colonoscopy. We developed a Markov model to simulate the progression of a cohort of 100,000 average risk asymptomatic individuals moving through a defined series of states between the ages of 40 to 74 years. The parameters used for the modeling came from the CESP (Comparison and Evaluation of Screening Programs for Colorectal Cancer in Urban Communities in China) study and published literature. Eight CRC screening scenarios were tested in the Markov model. The cost-effectiveness of CRC screening under each scenario was measured by an incremental cost-effectiveness ratio (ICER) compared with a scenario without CRC screening. The study revealed that a combined use of FOBT and HRFQ is preferable in CRC screening programs as an initial screening instrument. Annual FOBT+HRFQ screening is recommended for those who have a negative initial result and those who have a positive result but have failed to continue to colonoscopic examination. Repeated colonoscopy (for those with a positive result in initial screening but a negative colonoscopy result) should be performed at a ten-year interval instead of one-year. Such a protocol would cost 7732 Yuan per life year saved, which is the most cost-effective option. In conclusion, the current Chinese Trial Version for CRC Screening Strategy should be revised in line with the most cost-effective protocol identified in this study.
PMCID: PMC4186806  PMID: 25285526
11.  Visceral and somatic hypersensitivity, autonomic cardiovascular dysfunction and low-grade inflammation in a subset of irritable bowel syndrome patients*  
The pathophysiology of irritable bowel syndrome (IBS) is complex and not fully understood, so the aim of this study was to evaluate whether visceral and somatic hypersensitivity, autonomic cardiovascular dysfunction, and low-grade inflammation of the gut wall are associated with diarrhea-predominant IBS (D-IBS). Sixty-two patients with D-IBS and 20 control subjects participated in the study. Using the ascending method of limits (AML) protocol, we demonstrated that D-IBS patients had significantly lower sensory thresholds compared with healthy controls (P<0.001). Using diverse methods, especially the ischemic sensitivity test, for the first time in China, we confirmed that D-IBS patients have somatic hypersensitivity. They had a significantly higher systolic blood pressure and heart rate after a cold stimulus, indicative of autonomic cardiovascular dysfunction. Compared with the control group, D-IBS patients had a significantly higher level of calprotectin (P<0.001). We also found significant correlations between visceral and somatic hypersensitivity, visceral hypersensitivity and autonomic cardiovascular dysfunction, and somatic hypersensitivity and autonomic cardiovascular dysfunction. Our findings may provide valuable suggestions for the treatment of D-IBS.
PMCID: PMC4201319  PMID: 25294380
Irritable bowel syndrome (IBS); Visceral hypersensitivity; Somatic hypersensitivity; Autonomic cardiovascular dysfunction; Low-grade inflammation
12.  Comparison of hand-sewn and stapled anastomoses in surgeries of gastrointestinal tumors based on clinical practice of China 
There is a lack of studies comparing stapled suturing and hand-sewn suturing in the surgeries of gastrointestinal tumors based on the clinical practice of Chinese surgeons.
Data were retrospectively collected from 499 patients who underwent surgery to remove gastrointestinal tumors from January 2008 to December 2009. The patients were divided into two groups according to the method of digestive tract reconstruction: 296 patients received stapled suturing and 203 patients received hand-sewn suturing. The operation time, postoperative hospital stay, postoperative recovery and complications of the patients were evaluated and compared between the two groups.
The stapling procedure took shorter operative time compared to the hand-sewn procedure for gastric carcinoma, colorectal cancer and esophageal carcinoma (P < 0.05). There was no significant difference between the two groups in postoperative hospital stay (P > 0.05). Patients receiving stapled suturing also showed shorter recovery for gastric cancer, colorectal cancer, and shorter time to recovery of normal gastrocolorectal motility compared with patients in the hand-sewn group (P < 0.05). However, there was no difference between the two groups in terms of normal time to commencing liquid diet for esophageal cancer patients (P > 0.05). We also found that the stapled procedure showed a lower incidence of anastomotic leakage, anastomotic hemorrhage and stump leakage in treating colorectal cancer or gastric carcinoma compared with the hand-sewn procedure (P < 0.05).
Application of the stapler in treating gastrointestinal tumors demonstrated better effects on patients in terms of surgical operation time, recovery time to normal functions, and occurrence of complications compared to hand-sewn anastomosis, especially in gastric carcinoma and colorectal cancer.
PMCID: PMC4194420  PMID: 25240386
Stapler; Gastrocolorectal tumor; Anastomosis; Surgery
13.  Comparison of the Effects of Acarbose and TZQ-F, a New Kind of Traditional Chinese Medicine to Treat Diabetes, Chinese Healthy Volunteers 
Ethnopharmacological Relevance. TZQ-F has been traditionally used in Traditional Chinese Medicine as a formula for the treatment of diabetes. Aim of the Study. This study aims to compare the pharmacologic effects and gastrointestinal adverse events between TZQ-F and acarbose. Methods. The double-blind randomized placebo-controlled fivefold crossover study was performed in 20 healthy male volunteers. Plasma glucose, plasma IRI, and plasma C-peptide were measured to assess the pharmacologic effects. Flatus and bowel activity were measured to assess the adverse event of gastrointestinal effect. Results. 3 and 4 tablets of TZQ decreased the Cmax of plasma glucose compared with that of the previous day and with placebo. 3 tablets also decreased Cmax of plasma C-peptide compared with placebo. 4 tablets increased Cmax of plasma insulin after breakfast and the AUC of plasma C-peptide after breakfast and dinner. 2 tablets did not decrease plasma glucose and elevated the Cmax and AUC of C-peptide after breakfast and dinner, respectively. Acarbose 50 mg decreased the Cmax of plasma insulin and C-peptide after breakfast and the Cmax of plasma glucose and C-peptide after dinner. The subjects who received TZQ did not report any abdominal adverse events. Conclusions. 3 tablets of TZQ have the same effects as the acarbose.
PMCID: PMC3997856  PMID: 24808918
14.  Study of Burn Scar Extraction Automatically Based on Level Set Method using Remote Sensing Data 
PLoS ONE  2014;9(2):e87480.
Burn scar extraction using remote sensing data is an efficient way to precisely evaluate burn area and measure vegetation recovery. Traditional burn scar extraction methodologies have no well effect on burn scar image with blurred and irregular edges. To address these issues, this paper proposes an automatic method to extract burn scar based on Level Set Method (LSM). This method utilizes the advantages of the different features in remote sensing images, as well as considers the practical needs of extracting the burn scar rapidly and automatically. This approach integrates Change Vector Analysis (CVA), Normalized Difference Vegetation Index (NDVI) and the Normalized Burn Ratio (NBR) to obtain difference image and modifies conventional Level Set Method Chan-Vese (C-V) model with a new initial curve which results from a binary image applying K-means method on fitting errors of two near-infrared band images. Landsat 5 TM and Landsat 8 OLI data sets are used to validate the proposed method. Comparison with conventional C-V model, OSTU algorithm, Fuzzy C-mean (FCM) algorithm are made to show that the proposed approach can extract the outline curve of fire burn scar effectively and exactly. The method has higher extraction accuracy and less algorithm complexity than that of the conventional C-V model.
PMCID: PMC3913612  PMID: 24503563
15.  High Levels of BCOX1 Expression Are Associated with Poor Prognosis in Patients with Invasive Ductal Carcinomas of the Breast 
PLoS ONE  2014;9(1):e86952.
This study was to examine the breast cancer-overexpressed gene 1 (BCOX1) expression in invasive ductal carcinomas (IDC) of the breast and its value in the prognosis of the disease. The levels of BCOX1 expression in 491 paired IDC and surrounding non-tumor breast tissues as well as 40 paired fresh specimens were evaluated by tissue microarray, immunohistochemistry and quantitative RT-PCR. The potential associations of high BCOX1 expression with clinicopathological variables and the overall survival of these patients were analyzed. The relative levels of BCOX1 mRNA transcripts in the IDC breast tissues were significantly higher than that in the corresponding non-tumor tissues (P = 0.005). The anti-BCOX1 was predominantly stained in the cytoplasm of breast tissue cells and the levels of BCOX1 expression in the majority of breast cancer tissues were obviously higher than that in the corresponding non-tumor breast tissues. High levels of BCOX1 expression were found in 59.5% (292/491) of breast cancer tissues. The high BCOX1 expression was significantly associated with high histological grade (P = 0.037), positive expression of human epidermal growth factor receptor 2 (HER2, P = 0.031) and triple negative breast cancer (P = 0.027). The high BCOX1 expression in breast cancers was significantly associated with a shorter overall survival of these patients (P = 0.023), particularly in patients with triple negative breast cancer (P = 0.005). Therefore, the high BCOX1 expression may serve as a novel marker of poor prognosis and a potential therapeutic target for patients with IDC of the breast.
PMCID: PMC3904964  PMID: 24489812
16.  Transciptome Analysis of the Gill and Swimbladder of Takifugu rubripes by RNA-Seq 
PLoS ONE  2014;9(1):e85505.
The fish gill, as one of the mucosal barriers, plays an important role in mucosal immune response. The fish swimbladder functions for regulating buoyancy. The fish swimbladder has long been postulated as a homologous organ of the tetrapod lung, but the molecular evidence is scarce. In order to provide new information that is complementary to gill immune genes, initiate new research directions concerning the genetic basis of the gill immune response and understand the molecular function of swimbladder as well as its relationship with lungs, transcriptome analysis of the fugu Takifugu rubripes gill and swimbladder was carried out by RNA-Seq. Approximately 55,061,524 and 44,736,850 raw sequence reads from gill and swimbladder were generated, respectively. Gene ontology (GO) and KEGG pathway analysis revealed diverse biological functions and processes. Transcriptome comparison between gill and swimbladder resulted in 3,790 differentially expressed genes, of which 1,520 were up-regulated in the swimbladder while 2,270 were down-regulated. In addition, 406 up regulated isoforms and 296 down regulated isoforms were observed in swimbladder in comparison to gill. By the gene enrichment analysis, the three immune-related pathways and 32 immune-related genes in gill were identified. In swimbladder, five pathways including 43 swimbladder-enriched genes were identified. This work should set the foundation for studying immune-related genes for the mucosal immunity and provide genomic resources to study the relatedness of the fish swimbladder and mammalian lung.
PMCID: PMC3894188  PMID: 24454879
17.  P16 and P53 Play Distinct Roles in Different Subtypes of Breast Cancer 
PLoS ONE  2013;8(10):e76408.
Breast cancers are heterogeneous and complex diseases, and subtypes of breast cancers may involve unique molecular mechanisms. The p16INK4a and p53 pathways are two of the major pathways involved in control of the cell cycle. They also play key roles in tumorigenesis. However, whether the roles of these pathways differ in the subtypes of breast cancer is unclear. Therefore, p16 and p53 expression were investigated in different breast cancer subtypes to ascertain their contributions to these cancers. A total of 400 cases of non-invasive ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC), including the major molecular subtypes luminal-A, luminal-B, Her-2, and triple-negative subtypes, and 50 cases of normal controls were compared. Luminal-A cancers expressed the lowest level of p16 among the subtypes in DCIS, and the level of p16 expression was up-regulated in the luminal-A of IDC (P<0.008). Triple-negative breast cancers were characterized by a correlation of p53 overexpression with a high level of p16 expression. Luminal lesion types with high p16 expression in DCIS were found to be more likely to develop into aggressive breast cancers, possibly promoted by p53 dysfunction. Taken together, the present study suggest that p16 expression in luminal-A breast cancers is associated with their progression from DCIS to IDC, and both p53 and p16 expressions are important for the development of triple-negative breast cancers in DCIS and IDC.
PMCID: PMC3795768  PMID: 24146864
18.  Overexpression of TROP2 Predicts Poor Prognosis of Patients with Cervical Cancer and Promotes the Proliferation and Invasion of Cervical Cancer Cells by Regulating ERK Signaling Pathway 
PLoS ONE  2013;8(9):e75864.
Overwhelming evidence has demonstrated that the aberrant expression of the human trophoblast cell-surface antigen (TROP2) was associated with tumor aggressiveness and poor prognosis in a variety of human cancers, however the roles of TROP2 in cervical cancer have not been investigated. The purpose of our study was to elucidate the prognostic significance of TROP2 expression in patients with cervical cancer and determine its effect on tumor progression. Immunohistochemistry assay showed that 88.7% (94/106 cases) of cervical cancer specimens were positively stained with TROP2, and the overexpression of TROP2 was closely related with FIGO stage, histological grades, lymphatic metastasis, invasive interstitial depth and high expression of Ki-67. Patients with TROP2-positive staining exhibited a significantly decreased overall survival and progression free survival; it was also an independent predictor for prognosis according to multivariate analysis. Moreover, down-regulation of TROP2 mediated by siRNA in Siha and CaSki cells resulted in a strong inhibition of proliferation and invasion, TROP2 abrogation also elevated the apoptotic ratio and caused G1 arrest. Conversely, enforced expression of TROP2 in HeLa and C33A cells remarkably promoted cell growth, migration and invasion. In addition, the tumorigenic function of TROP2 was associated with the increased expressions of cyclin D1, cyclin E, CDK2 and CDK4 but reduced expression of p27 and E-cadherin via the activation of Erk1/2 signaling pathway. Furthermore, the inhibition of TROP2 expression in cervical cancer cell lines enhances sensitivity to cisplatin. The present study suggest that overexpression of TROP2 may play crucial roles in the development and pathogenesis of human cervical cancer, therefore, TROP2 may represent a prospective prognostic indicator and a potential therapeutic target of cervical cancer.
PMCID: PMC3785439  PMID: 24086649
19.  Gene Silencing of Porcine MUC13 and ITGB5: Candidate Genes towards Escherichia coli F4ac Adhesion 
PLoS ONE  2013;8(7):e70303.
Integrin beta-5 (ITGB5) and mucin 13 (MUC13) genes are highly expressed on the apical surface of intestinal epithelia and are thought to be candidate genes for controlling the expression of the receptor for enterotoxigenic Escherichia coli (ETEC) F4ac. Human MUC13 protein has an expected role in protecting intestinal mucosal surfaces and porcine ITGB5 is a newly identified potential receptor for ETEC F4ac.
Methodology/Principal Findings
To test the hypothesis that ITGB5 and MUC13 both play key roles in protection of the intestinal mucosa against pathogenic bacterium, porcine intestinal epithelial cells (IPEC-J2) were transfected with ITGB5-targeting, MUC13-targeting or negative control small interfering RNA (siRNA), respectively. Firstly, we measured mRNA expression levels of mucin genes (MUC4, MUC20), pro-inflammatory genes (IL8, IL1A, IL6, CXCL2), anti-inflammatory mediator SLPI, and PLAU after RNAi treatments with and without ETEC infection. Secondly, we compared the adhesions of ETEC to the pre- and post-knockdown IPEC-J2 cells of ITGB5 and MUC13, respectively. We found that ITGB5 and MUC13 knockdown both had small but significant effects in attenuating the inflammation induced by ETEC infection, and both increased bacterial adhesion in response to F4ac ETEC exposure.
Our current study first reported that ITGB5 and MUC13 are important adhesion molecules of mucosal epithelial signaling in response to Escherichia coli in pigs. These data suggest that both ITGB5 and MUC13 play key roles in defending the attachment and adhesion of ETEC to porcine jejunal cells and in maintaining epithelial barrier and immunity function.
PMCID: PMC3726385  PMID: 23922972
20.  Effects of Outdoor and Indoor Air Pollution on Respiratory Health of Chinese Children from 50 Kindergartens 
Journal of Epidemiology  2013;23(4):280-287.
Concentrations of ambient air pollution and pollutants in China have changed considerably during the last decade. However, few studies have evaluated the effects of current ambient air pollution on the health of kindergarten children.
We studied 6730 Chinese children (age, 3–7 years) from 50 kindergartens in 7 cities of Northeast China in 2009. Parents or guardians completed questionnaires that asked about the children’s histories of respiratory symptoms and risk factors. Three-year concentrations of particles with an aerodynamic diameter ≤10 µm (PM10), sulfur dioxide (SO2), and nitrogen dioxides (NO2) were calculated at monitoring stations in 25 study districts. A 2-stage regression approach was used in data analyses.
The prevalence of respiratory symptoms was higher among children living near a busy road, those living near chimneys or a factory, those having a coal-burning device, those living with smokers, and those living in a home that had been recently renovated. Among girls, PM10 was associated with persistent cough (odds ratio [OR]PM10 = 1.44; 95% CI, 1.18–1.77), persistent phlegm (ORPM10 = 1.36; 95% CI, 1.02–1.81), and wheezing (ORPM10 = 1.31; 95% CI, 1.04–1.65). NO2 concentration was associated with increased prevalence of allergic rhinitis (OR = 1.96; 95% CI, 1.27–3.02) among girls. In contrast, associations of respiratory symptoms with concentrations of PM10, SO2, and NO2 were not statistically significant among boys.
Air pollution is particularly important in the development of respiratory morbidity among children. Girls may be more susceptible than boys to air pollution.
PMCID: PMC3709542  PMID: 23728483
air pollution; children; respiratory diseases, China
21.  Two cases of a rare association: double aortic arch with tetralogy of Fallot 
Two cases of asymptomatic double aortic arch with tetralogy of Fallot are reported. One presented with a non-dominant left arch and left-sided descending thoracic aorta and the other with a non-dominant left arch, a right-sided descending thoracic aorta and a patent ductus arteriosus. One-stage operation was performed and both patients were discharged free of symptoms and signs related to the double aortic arch and tetralogy of Fallot after the operation. A preoperative recognition of DAA is important, especially in echocardiographic investigation.
PMCID: PMC3599920  PMID: 23497578
Double aortic arch; Tetralogy of Fallot; Congenital heart disease
22.  Promoter Hypermethylation of ARID1A Gene Is Responsible for Its Low mRNA Expression in Many Invasive Breast Cancers 
PLoS ONE  2013;8(1):e53931.
ARID1A (AT-rich interactive domain 1A) has recently been identified as a tumor suppressor gene. Its mRNA expression is significantly low in many breast cancers; this is often associated with more aggressive phenotypes. However, the underlying molecular mechanism for its low expression has not been fully understood. This study was undertaken to evaluate the contribution of gene copy number variation, mutations, promoter methylation and histone modification to ARID1A’s low expression. 38 pairs of breast invasive ductal carcinomas and their normal breast tissue counterparts from the same patients were randomly selected for gene expression and copy number variation detection. Promoter methylation and histone modification levels were evaluated by MeDIP-qPCR and ChIP-qPCR, respectively. PCR product Sanger sequencing was carried out to detect the exon mutation rate. Twenty-two out of 38 invasive ductal carcinomas in the study (57.9%) revealed ARID1A mRNA low expression by realtime RT-PCR. The relative promoter methylation level was, significantly higher in ARID1A mRNA low expression group compared with its high expression group (p<0.001). In the low expression group, nineteen out of 22 invasive ductal carcinomas (86.4%) exhibited ARID1A promoter hypermthylation. In addition, the promoter hypermethylation was accompanied with repressive histone modification (H3K27Me3). Although five out of 38 invasive ductal carcinomas (13.2%) exhibited loss of ARID1A gene copy number by realtime PCR and nine exon novel mutations are seen from eight out of 33 invasive ductal carcinomas (24.2%), there was no statistically significant difference in both ARID1A mRNA low and high expression groups (p = 0.25,and p = 0.68, respectively). We demonstrate that promoter hypermethylation was the main culprit for ARID1A mRNA low expression in invasive ductal carcinomas. The influence of mutation and copy number variation on the expression were statistically insignificant at mRNA level, and were, therefore, not considered the main causes for ARID1A mRNA low expression in invasive breast cancer.
PMCID: PMC3549982  PMID: 23349767
23.  Epidemiology of general obesity, abdominal obesity and related risk factors in urban adults from 33 communities of northeast china: the CHPSNE study 
BMC Public Health  2012;12:967.
Obesity increases the risk of many diseases. However, there has been little literature about the epidemiology of obesity classified by body mass index (BMI) or waist (abdominal obesity) among urban Chinese adults. This study is to fill the gap by assessing the prevalence of obesity and associated risk factors among urban Chinese adults.
A representative sample of 25,196 urban adults aged 18 to 74 years in Northeast China was selected and measurements of height, weight and waist circumference (WC) were taken from 2009–2010. Definitions of overweight and obesity by the World Health Organization (WHO) were used.
The overall prevalence rates of general obesity and overweight classified by BMI were 15.0% (15.7% for men and 14.3% for women, p<0.01) and 19.2% (20.8% for men and 17.7% for women, p<0.01), respectively, and the overall prevalence rate of abdominal obesity was 37.6% (31.1% for men and women 43.9% for women, p<0.01). Multivariable logistic regression showed that the elderly and those who had a history of parental obesity, alcohol drinking, or former cigarette smoking were at high risk of obesity classified by BMI or WC, whereas those with a higher level of education, higher family income, or a healthy and balanced diet were at low risk of obesity. Analysis stratified by gender showed that men with a higher level education level, a white-collar job, a cadre job, or higher family income were the high risk group, and women with a higher level of education or higher family income were the low risk group.
Obesity and overweight have become epidemic in urban populations in China; associations of risk factors with obesity differ between men and women.
PMCID: PMC3509037  PMID: 23146089
General obesity; Abdominal obesity; Risk factors; Gender difference; Chinese urban adults
24.  Skull base metastases from a malignant solitary fibrous tumor of the liver. A case report and literature review 
Diagnostic Pathology  2011;6:127.
Solitary fibrous tumors (SFTs) of the liver are rarely described; only 38 cases have been reported in literature, most of which have shown benign clinical characteristics, and only 3 of these cases exhibited malignant variants. In this study, we present a 24-year-old woman with a 1-month history of a rapidly enlarging abdominal mass and a CT showing an exophytic heterogeneous liver mass with a firm parietal bone mass. The patient underwent a transcatheter arterial chemoembolization (TACE) before operation, and an extended right hepatectomy and craniectomy with a negative margin was performed under general anesthesia. The masses showed histological features of oval spindle cells haphazardly arranged in the classic short-storiform or so-called patternless pattern of solitary fibrous tumors. The tumor cells showed positive immunohistochemical reactions to CD34 and bcl-2. The tumor recurred in the residual liver 2 months after operation, metastatic osteoblastic lesions in the thoracic and lumbar vertebrae were identified 3 months after the operation, and lumbar vertebrae metastasis 7 months after operation paralyzed the patient. The patient underwent percutaneous ethanol injection therapy (PEI) and chemotherapy, but the patient died because of the uncontrolled tumor 16 months after the initial operation. To our knowledge, this is the first case of malignant solitary fibrous liver tumors with skeletal metastasis.
PMCID: PMC3260251  PMID: 22192457
Solitary fibrous tumor; Liver
25.  Effect of 2, 5-Substituents on the Stability of Cyclic Nitrone Superoxide Spin Adducts: A Density Functional Theory Approach 
Free radical research  2010;44(7):751-778.
To design efficient spin traps for superoxide radicals, interest in the elucidation of substituent effects on the stability of superoxide spin adducts has become a necessary priority. In the present study, five cyclic nitrone superoxide spin adducts, i.e. DMPO-OOH, M3PO-OOH, EMPO-OOH, DEPMPO-OOH, and DEPDMPO-OOH, were chosen as model compounds to investigate the effect of 2,5-subsitituents on their stability, through structural analysis and decay thermodynamics using density functional theory (DFT) calculations. Analysis of the optimized geometries reveals that none of the previously proposed stabilizing factors, including intramolecular H-bonds, intramolecular nonbonding interactions, bulky steric protection, nor the C(2)–N(1) bond distance can be used to clearly explain the effect of 2,5-substituents on the stability of the spin adducts. Additionally the effect of the 2,5-substituents on the stability of the superoxide spin adducts cannot be simply clarified by Milliken charges on both atoms (nitroxyl nitrogen and nitroxyl oxygen). Subsequent study found that spin densities on the nitroxyl nitrogen and oxygen are well correlated with the half-life times of the spin adducts, and consequently are the proper parameters to characterize the effect of 2,5-substituents on their stability. Examination of the decomposition thermodynamics further supports the effect of the substituents on the persistence of cyclic nitrone superoxide spin adducts.
PMCID: PMC3074479  PMID: 20370568

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