Yan Li

Capital Medical University, Peping, Beijing, China

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Publications (82)176.53 Total impact

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    ABSTRACT: IL-25 and IL-33, which belong to distinct cytokine families, induce and promote Th2-type airways inflammation. Both cytokines likely play a role in asthma, but there is paucity of direct evidence to clarify distinctions between their functions and how they might contribute to distinct "endotypes" of disease. To address this, we made a direct comparison of the effects of IL-25 and IL-33 on airways inflammation and physiology in our established murine asthma surrogate which involves per-nasal, direct airways challenge. Intranasal challenge with IL-33 or IL-25 induced inflammatory cellular infiltration, collagen deposition, airways smooth muscle hypertrophy, angiogenesis and airways hyperresponsiveness, but neither increased systemic production of IgE or IgG1 . Compared with that of IL-25, the IL-33-induced response was characterised by more sustained lay down of extracellular matrix protein, neoangiogenesis, Th2 type cytokine expression and elevation of tissue damping. Thus, both IL-25 and IL-33 may contribute significantly and independently to asthma "endotypes" when considering molecular targets for the treatment of human disease. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Immunology 03/2015; DOI:10.1111/imm.12465 · 3.74 Impact Factor
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    ABSTRACT: As a newly discovered member of the HSP70 family, heat shock protein A12B (HSPA12B) is involved in brain ischemic injury. According to our previous study, microRNA-134 (miR-134) could target HSPA12B by binding to its 3'-untranslated region (UTR). However, the regulation of miR-134 on HSPA12B and their role in protecting neuronal cells from ischemic injury are unclear. In this study, the miR-134 expression level was manipulated and the HSPA12B protein levels were also determined in oxygen-glucose deprivation (OGD)-treated primary cultured neuronal cells in vitro and mouse brain after middle cerebral artery occlusion (MCAO)-induced ischemic stroke in vivo. The results showed that miR-134 expression levels increased in primary cultured neuronal cells and mouse brain from 12h to 7 d reoxygenation/reperfusion after 1h OGD or 1h MCAO treatment. miR-134 overexpression promoted neuronal cell death and apoptosis by decreasing HSPA12B protein levels. Conversely, downregulating miR-134 reduced neuronal cell death and apoptosis by enhancing HSPA12B protein levels. Also, HSPA12B siRNA could block miR-134 inhibitor-mediated neuroprotection against OGD-induced neuronal cell injury in vitro. Taken together, miR-134 might influence neuronal cell survival against ischemic injury in primary cultured neuronal cells and mouse brain with ischemic stroke by negatively modulating HSPA12B protein expression in a posttranscriptional way.
    Brain Research 10/2014; DOI:10.1016/j.brainres.2014.09.072 · 2.83 Impact Factor
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    ABSTRACT: MicroRNAs (miRNAs) have emerged as a major regulator in neurological diseases, and understanding their molecular mechanism in modulating cerebral ischemic injury may provide potential therapeutic targets for ischemic stroke. However, as one of 19 differentially expressed miRNAs in mouse brain with middle cerebral artery occlusion (MCAO), the role of miR-134 in ischemic injury is not well understood. In this study, the miR-134 expression level was manipulated both in oxygen-glucose deprivation (OGD)-treated N2A neuroblastoma cells in vitro and mouse brain with MCAO-induced ischemic stroke in vivo, and its possible targets of heat shock protein A5 (HSPA5) and HSPA12B were determined by bioinformatics analysis and dual luciferase assay. The results showed that overexpression of miR-134 exacerbated cell death and apoptosis both in vitro and in vivo. Conversely, downregulating miR-134 levels reduced cell death and apoptosis. Furthermore, non-expression of miR-134 enhanced HSPA12B protein levels in OGD-treated N2A cells as well as in the ischemic region. It could attenuate brain infarction size and neural cell damage, and improve neurological outcomes in mice with ischemic stroke, whereas upregulation of miR-134 had the opposite effect. In addition, HSPA12B was validated to be a target of miR-134 and its short interfering RNAs (siRNAs) could block miR-134 inhibitor-induced neuroprotection in OGD-treated N2A cells. In conclusion, downregulation of miR-134 could induce neuroprotection against ischemic injury in vitro and in vivo by negatively upregulating HSPA12B protein expression.
    Neuroscience 07/2014; 277. DOI:10.1016/j.neuroscience.2014.06.062 · 3.33 Impact Factor
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    ABSTRACT: To determine whether within-visit blood pressure (BP) variability based on three measurements over minutes is associated with increased carotid intima-media thickness (IMT) and plaque in a general population.
    PLoS ONE 05/2014; 9(5):e97760. DOI:10.1371/journal.pone.0097760 · 3.53 Impact Factor
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    ABSTRACT: We and others previously reported that the pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and IL-6 significantly accumulate with age in mouse lung, this is accompanied by elevated phosphorylation of p38. Here, we further investigate whether aging affects activation of p38 signalling and the inflammatory reaction after exposure to lipopolysaccharide (LPS) in lungs of mice in vivo and humans ex vivo. The data showed that activation of p38 peaked at 0.5h and then rapidly declined in young (2-month-old) mouse lung, after intranasal inhalation challenge with LPS. In contract, activation of p38 peaked at 24h and was sustained longer in aged (20-month-old) mice. As well as altered p38, activations of its upstream activator MKK and downstream substrate NF-κB were also changed in lungs of aged mice, which corresponded with the absent in the early phase but delayed increases in concentrations of TNF-α, IL-1β and IL-6. Consistent with the above observations in mice, similar patterns of p38 signalling also occurred in human lungs. Compared with younger lungs from adult-middle aged subjects, the activation of p38, MKK and NF-κB, as well as the production of pro-inflammatory cytokines were significantly increased in lungs of older subjects ex vivo. Exposure of human lung cells to LPS induced rapid activation of p38, MKK and NF-κB in these cells from adultmiddle aged subjects, but not older subjects, with increases in production of the pro-inflammatory cytokines. The LPS-induced rapid activation in lung cells from adult-middle aged subjects occurred as early as 0.25h after exposure, and then declined. Compared with adult-middle aged subjects, LPS exposure did not induce marked changes in the early phase, either in the activation of p38, MKK and NF-κB, or in the production of TNF-α, IL-1β or IL-6 in lung cells from older subjects. In contrast, these changes occurred relatively late, peaked at 16h and were sustained longer in lungs of older subjects. These data support the hypothesis that the sustained activation of the p38 signalling pathway at baseline and the absence in the early phase but delayed of p38 signalling pathway response to LPS in the elderly may play important roles in increased susceptibility of aged lungs to inflammatory injury.
    Experimental gerontology 05/2014; 57. DOI:10.1016/j.exger.2014.04.017 · 3.53 Impact Factor
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    ABSTRACT: Visceral adipose tissue (VAT) is a unique pathogenic fatty deposit, in that it is closely correlated with risk of cardiovascular diseases. The present study is to investigate the usefulness of neck circumference (NC) to indicate VAT. Participants aged 35 to 75 years who had taken abdomen and neck computer tomography (CT) examination were included in this study. Neck adipose tissue, abdominal VAT and subcutaneous adipose tissue (SAT) areas, as well as sagittal abdominal diameter (SAD) were measured by CT. Body anthropometrics and metabolic parameters including blood glucose, lipid profiles and blood pressure were also measured. A lower abdomen CT examination was carried out on a total of 177 patients (87 male and 90 female) with a mean age of 59 years. Of the 177 participants, 15 men and 15 women also took a neck CT examination. With a comparable age and BMI, neck adipose area was correlated with abdominal VAT area significantly in men (r = 0.57, p = 0.028) and women (r = 0.53, p = 0.041). NC is positively correlated with VAT both in men (r = 0.49, p < 0.001) and women (r = 0.25, p = 0.012). Meanwhile, SAD is the best predictor for visceral fat both in men (r = 0.83, p < 0.001) and women (r = 0.73, p < 0.001). Body mass index (BMI), waist circumference (WC), and waist to height ratio (WHtR) correlated significantly with VAT both in men and women (r = 0.68, 0.42, 0.46 in men and 0.50, 0.23, 0.39 in women, p < 0.001), while waist hip ratio (WHR) displayed the weakest least correlation in men (r = 0.32, p = 0.001) and no correlation in women (r = 0.08, p = 0.442). Additionally, BMI was more strongly correlated with VAT than NC in both sexes (both p < 0.01). Significant correlation between NC and VAT was present in Chinese men and women, which may be accounted by the fact that neck fat area is significantly correlated with abdominal VAT. Meanwhile, SAD is the best predictor for visceral fat in the Chinese population.
    BMC Public Health 04/2014; 14(1):311. DOI:10.1186/1471-2458-14-311 · 2.32 Impact Factor
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    ABSTRACT: Lifetime risk estimation is used to predict long-term cardiovascular disease (CVD) risk across the entire life span. However, most of the lifetime risk estimation came from the studies based on western population. This study aimed to assess the lifetime risk of CVD and the impact of risk factors on lifetime risk of CVD in Chinese population. Prospective population-based cohort study. The study sample came from the Chinese Multi-Provincial Cohort Study (CMCS), 21,953 participants aged 35 to 84 years without CVD at the baseline were included. The modified Kaplan-Meier method was used to calculate the lifetime risk of CVD. During follow-up years from 1992 to 2010, 1,280 participants developed acute CVD events and 1,401 died. The lifetime CVD risk, up to age 80 for men and women at age 35, were 24.4% and 20.2% respectively. A very low lifetime risk was found in individuals with an optimal profile of risk factors which modified the effect of aging. By contrast, with two or more high risk factors the lifetime risk up to age 80 reached 51.1% for men and 38.6% for women at age 35. The integrated status of major CVD risk factors can determine lifetime cardiovascular health and CVD risk in Chinese. Early prevention with a goal of all risk factors at optimal levels should become the priority of CVD prevention in the future.
    12/2013; 22(3). DOI:10.1177/2047487313516563
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    ABSTRACT: Abstract Background and aim: The miR-196a2 gene contains a C/T polymorphism (rs11614913). Its presence could change the conformation of secondary structure of miR-196a2 RNA, and directly affect the binding to target mRNAs and the miRNA maturation process. Both of which eventually alter protein expression and contributed to cancer susceptibility. This study assessed whether the rs11614913 single nucleotide polymorphism (SNP) could affect an individual's susceptibility to esophageal squamous cell carcinomas (ESCC). Methods: SNP rs11614913 was genotyped by polymerase chain reaction ligase detection reaction (PCR-LDR) in 597 ESCC patients and 597 control subjects. Results: Overall, there were no significant differences in the frequency of the miRNA-196a2 SNP rs11614913 genotype between the ESCC cases and the controls (χ(2) = 1.395, p = 0.498). The TT genotype, CT genotype and CT/TT combined genotype (dominant model) did not modify the risk of ESCC as compared with the CC genotype. Comparisons of the TT genotype to the CT/CC combined genotype did not reveal a significant association to ESCC, too. However, further analyses revealed an increased risk of ESCC in the dominant model (OR = 1.56, 95% CI = 1.08-2.26) and the allele frequency comparison (OR = 1.31, 95% CI = 1.06-1.63) in the ≤60-year-old group. Conclusions: These results suggest that the miRNA-196a2 functional polymorphism rs11614913 might be an effective genetic marker for ESCC risk assessment in individuals younger than 60 years of age from a region of high ESCC incidence in northern China.
    Biomarkers 12/2013; DOI:10.3109/1354750X.2013.866164 · 2.52 Impact Factor
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    ABSTRACT: To explore the relationship among single nucleotide polymorphism (SNP) of excision repair cross-complementing 1(ERCC1) gene, chemotherapy sensitivity and clinical outcomes of epithelial ovarian cancer (EOC) patients treated with platinum. Six tag single nucleotide polymorphisms (tagSNP;rs11615, rs3212986, rs735482, rs3212955, rs12610134 and rs3212958) were chose from ERCC1 gene. The genotypes of 6 tagSNP were determined by Snapshot method in 220 EOC patients. Primary clinical outcomes parameter contained EOC patients' responses to platinum-based chemotherapy, progression-free survival (PFS) and overall survival (OS) were analysed. The rs11615 C/T SNP of ERCC1, CC, CT and TT genotype frequencies were 53.1%, 45.6%, 1.4% in responders to platinum-based chemotherapy, while 52.0%, 35.6%, 12.3% in non-responders, respectively, in which there was significant difference between the two groups (P = 0.002) . Compared with the patients with CC genotype, the patients carrying TT genotype had a significantly poor response to platinum-based chemotherapy (OR = 6.22, 95%CI:1.12-34.42). Similarly, the genotypes frequencies distribution of rs11615 C/T SNP of ERCC1 was different between the recurrence and non-recurrence group, death and survival group (all P < 0.05). Kaplan-Meier survival analysis showed that the genotypes frequencies distribution of rs11615 C/T SNP of ERCC1 was associated with PFS and OS (P < 0.01) of EOC patients. Cox's multivariate analysis suggested that patients with TT genotype had a shorter PFS (HR = 2.19, 95%CI:1.14-4.22, P = 0.009) and OS (HR = 2.22, 95%CI:1.06-4.64, P = 0.021) compared with those carrying CC genotype [adjusting for age, International Federation of Gynecology and Obstetrics (FIGO) stage, pathological type, grade and tumor residual size]. The genotypes frequencies distribution of rs3212986, rs735482, rs3212955, rs12610134 and rs3212958 SNP of ERCC1 did not show the significant difference between the responders to platinum-based chemotherapy and non-responders. The other 5 tagSNP may not be associated with the PFS and OS of EOC patients (all P > 0.05). The rs11615 SNP of ERCC1 may become a valuable prognostic biomarker for EOC patients treated with platinum-based chemotherapy.
    Zhonghua fu chan ke za zhi 11/2013; 48(11):847-852.
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    ABSTRACT: A C/T polymorphism (rs11614913) was identified in the microRNA (miRNA) 196a2 (miR-196a2) gene and was implicated in the susceptibility to cancer. Numerous studies have investigated its association with the risk of colorectal cancer (CRC). However, the results were inconsistent and inconclusive. The present meta-analysis was conducted based on the results of six published case-control studies comprising 1,754 cases and 2,430 controls (up to November, 2012). Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for the allelic and genotypic comparisons following the co-dominant, dominant and recessive genetic models. The Chi-square-based Q-test was used to assess heterogeneity. Egger's test and inverted funnel plots were used to investigate publication bias. Subgroup analysis was also performed. The results demonstrated that almost all the genetic models (except the model of CT vs. TT) indicated a significant association between rs11614913 polymorphism and CRC risk. The subgroup analysis in an Asian population also demonstrated similar results. However, there was no significant association of miR-196a2 rs11614913 polymorphism with the clinical characteristics of CRC patients. Our results confirmed the association of the polymorphism rs11614913 with the risk of CRC, but not with tumor stage and grade.
    09/2013; 1(5):737-742. DOI:10.3892/br.2013.146
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    ABSTRACT: Chronic heart failure (CHF) is a severe clinical syndrome associated with high morbidity and mortality, and with high health care expenditures. No nationwide data are currently available regarding the quality of clinical management of CHF patients in China. The aim of this study was to assess the quality of care of CHF inpatients in China. The American College of Cardiology/American Heart Association Clinical Performance Measures for Adults with Chronic Heart Failure (Inpatient Measurement Set) with slight modifications was used to measure the performance status in 612 CHF patients with acute coronary syndrome (ACS) from 65 hospitals across all regions of China. The implementation rates of guideline recommended strategies for CHF management were low. Only 57.5% of the CHF patients received complete discharge instructions, 53.6% of the patients received evaluation of left ventricular systolic function, 62.8% received an angiotensin-converting enzyme inhibitor/angiotensin receptor blocker at discharge, and 52.7% received a β-blocker at discharge, 56.3% of the smokers received smoking cessation counseling. The rate of warfarin utilization was only 9.7% in CHF patients with atrial fibrillation. Most patients (81.4%) did not receive all the first four treatments. There were marked differences in the quality of CHF management among patients with different characteristics. Performance measures provide a standardized method of assessing quality of care, and can thus highlight problems in disease management in clinical practice. The quality of care for CHF patients with ACS in China needs to be improved.
    Chinese medical journal 07/2013; 126(14):2625-31. · 1.02 Impact Factor
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    ABSTRACT: Aim: To investigate the association of tag single nucleotide polymorphisms (SNPs) in the vascular endothelial growth factor receptor 2 (VEGFR-2) gene with susceptibility to endometriosis. Methods: This study comprised 571 patients with endometriosis and 580 women in the control group. Five tag SNPs in the VEGFR-2 gene were selected using a Haploview program, and those SNPs were genotyped by a method of polymerase chain reaction and ligase detection reaction. Results: Statistical results show that there was a significant difference in the genotype and allele distribution of the 1192C/T polymorphism between the disease group and the control group (p = 0.041 and 0.017). The women carrying the T allele (C/T+T/T genotype) had a lower risk of developing endometriosis compared with the women with the C/C genotype (OR 0.75, 95% CI 0.57-0.99). There was no significant difference in the allele and genotype distribution of four other tag SNPs (1719T/A, +31C/T, IVS25-92A/G and IVS6+ 54C/T) between the disease group and the control group (all p > 0.05). Conclusions: Our results suggested that the 1192C/T polymorphisms on the VEGFR-2 gene might affect the risk of developing endometriosis in Northern Chinese women of Han ethnicity.
    Gynecologic and Obstetric Investigation 04/2013; 76(1). DOI:10.1159/000350665 · 1.25 Impact Factor
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    ABSTRACT: Aging is an inevitable process associated with immune imbalance, which is characterized by a progressive functional decline in major organs, including lung. However, effects of altered Th1/Th2 commitment on lung senescence are largely unknown. To examine effects of alter Th1/Th2 balance on lung aging, we measured proportions of Th1 and Th2 cells and expression of cytokines, chemokines, collagen deposition and other relevant physiological and pathological parameters in 2- and 20-months-old (mo) CXCR3-deficient (CXCR3(-/-)) C57BL/6J mice compared with wild-type (WT) mice. There was a significant weight-loss observed in 20-mo CXCR3(-/-) mice compared with the same aged WT group. Although lung function and structure changed with age in both groups, central airway resistance (Rn), tissue elastance (H) and damping (G) were significantly lower in 20-mo CXCR3(-/-) mice than those of WT mice. In contrast, the whole lung volume (VL), the mean linear intercept length of alveolar (Lm), and total lung collagen content were significantly elevated in 20-mo CXCR3(-/-) mice. With aging, the lungs of WT mice had typical Th1-type status (increased population of Th1 cells and concentrations of cytokine IFN-γ and CXCR3 ligands) while CXCR3(-/-) mice showed Th2-type polarization (decreased proportion of Th1 cells and concentrations of CXCR3 ligands but increased level of IL-4). Our data suggest that immune senescence is associated with lung aging, and that altered Th1/Th2 imbalance favors Th2 predominance in CXCR3(-/-) mice, which contributes to the process of accelerated lung aging in this model.
    Experimental gerontology 04/2013; DOI:10.1016/j.exger.2013.04.001 · 3.53 Impact Factor
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    ABSTRACT: Objective: The nucleotide excision repair (NER) and base excision repair (BER) pathways, two DNA repair pathways, are related to platinum resistance in cancer treatment. In this paper, we studied the association between single nucleotide polymorphisms (SNPs) of involved genes and response to platinum-based chemotherapy in epithelial ovarian cancer. Method: Eight SNPs in XRCC1 (BER), XPC and XPD (NER) were assessed in 213 patients with epithelial ovarian cancer using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and primer-introduced restriction analysis-polymerase chain reaction (PIRA-PCR) techniques. Results: The median progression-free survival (PFS) of patients carrying the Lys/Lys and Lys/Gln+Gln/Gln genotype of the XPC Lys/Gln polymorphism were 25 and 12 months, respectively (P=0.039); and the mean overall survival (OS) of patients was 31.1 and 27.8 months, respectively (P=0.048). Cox's multivariate analysis suggested that patients with epithelial ovarian cancer with the Gln allele had an increased risk of death (HR=1.75; 95% CI=1.06-2.91) compared to those with the Lys/Lys genotype. There are no associations between the XPC PAT+/-, XRCC1 Arg194Trp, Arg280His, Arg399Gln, and XPD Asp312Asn, Lys751Gln polymorphisms and the survival of patients with epithelial ovarian cancer when treated with platinum-based chemotherapy. Conclusion: Our results indicated that the XPC Lys939Gln polymorphism may correlate with clinical outcome of patients with epithelial ovarian cancer when treated with platinum-based chemotherapy in Northern China.
    Asian Pacific journal of cancer prevention: APJCP 02/2013; 14(2):941-6. DOI:10.7314/APJCP.2013.14.2.941 · 1.50 Impact Factor
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    ABSTRACT: BACKGROUND AND AIMS: Phospholipase C epsilon 1 (PLCε1) may regulate cell growth, differentiation, apoptosis and angiogenesis and play an important role in carcinogenesis and the progression of several cancers. This study was designed to validate the association of the PLCε1 rs2274223 single nucleotide polymorphism (SNP) with esophageal squamous cell carcinoma (ESCC) as identified by genome-wide association studies (GWAS) and further assess whether the rs11599672 SNP could affect an individual's susceptibility to ESCC. METHODS: These two SNPs were genotyped by polymerase chain reaction ligase detection reaction (PCR-LDR) in 527 ESCC patients and 527 controls. RESULTS: Compared with the rs2274223 SNP AA genotype, other genotypes or combined genotypes all enhanced the risk of ESCC. Further analyses showed that AG/GG genotype carriers with a family history of upper gastrointestinal cancers (UGIC) had an increased risk of ESCC than those AA genotype carriers without UGIC family history (OR = 2.10, 95% CI = 1.46-3.10). Overall, rs11599672 SNP had no influence on ESCC susceptibility. However, UGIC family history elevated the risk of ESCC for subjects with the TT genotype (OR = 1.59, 95% CI = 1.13-2.24). CONCLUSIONS: These results highlighted the role of a genetic factor in ESCC and suggested that the PLCε1 rs2274223 SNP might be an effective genetic marker to assess the risk of ESCC in individuals with a UGIC family history from a region of high incidence in northern China.
    Archives of medical research 10/2012; 43(7). DOI:10.1016/j.arcmed.2012.09.006 · 2.41 Impact Factor
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    ABSTRACT: MicroRNAs (miRNAs) bind to the 3' untranslated regions (UTRs) of messenger RNAs, where they interfere with the translation of genes that regulate cell differentiation, apoptosis, and tumorigenesis. SET8 reportedly methylates TP53 and regulates genomic stability. We analyzed a single nucleotide polymorphism (rs16917496) within the miR-502 mRNA seed region of the 3' UTR of SET8 in Chinese epithelial ovarian cancer (EOC) patients. The SET8 CC genotype was associated with a decreased risk of EOC in this case-control study. The analysis of genetic polymorphisms in miRNA binding sites may help identify subgroups of populations that are at high risk for EOC.
    Cancer Genetics 07/2012; 205(7-8):373-6. DOI:10.1016/j.cancergen.2012.04.010 · 2.42 Impact Factor
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    ABSTRACT: nm23, a tumor metastasis suppressor gene, has been linked to protection against tumorigenesis and tumor metastasis. This study evaluated whether genetic variants in the nm23 gene were associated with susceptibility to epithelial ovarian cancer (EOC) or the clinical outcome of patients. A case-control study was performed with 302 patients with epithelial ovarian cancer and 302 control women. According to the genotypes, the outcome in 213 EOC patients was compared. Progression-free survival (PFS) and overall survival (OS) were analyzed with Kaplan-Meier plots and Cox models adjusted for clinical factors. The case-control analysis showed that the rs16949649 and rs2302254 polymorphisms in the nm23 gene promoter were not associated with the risk of developing EOC. In contrast, survival analysis showed that the rs2302254 C/T polymorphism was related to the prognosis of EOC patients. Compared with patients carrying the C/C genotype, patients carrying the T/T genotype had a shorter median PFS and median OS by Kaplan-Meier plots and Cox models adjusted for clinical factors. For rs16949649 T/C polymorphisms, Kaplan-Meier analysis indicated that patients carrying the homozygous C/C genotype had shorter PFS and OS than those carrying the T allele (T/T+T/C genotype). The Cox proportional hazard model analysis suggested that this relationship was only retained in OS when adjusted for clinical factors. Our studies suggest that rs16949649 and rs2302254 polymorphisms in the nm23 gene promoter may influence the prognosis of patients with epithelial ovarian cancer.
    Gynecologic Oncology 06/2012; 126(3):455-9. DOI:10.1016/j.ygyno.2012.06.004 · 3.69 Impact Factor
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    ABSTRACT: Yatakemycin (YTM), an antitumor natural product, represents the most potent member of a class of potent anticancer natural products including CC-1065 and duocarmycins. Herein we describe the biosynthetic gene cluster of YTM, which was identified by genome scanning of Streptomyces sp. TP-A0356. This cluster consists of 31 open reading frames (ORFs) and was localized to a 36 kb DNA segment. Moreover, its involvement in YTM biosynthesis was confirmed by cluster deletion, gene replacement, and complementation. Inactivation of ytkT, which encodes a radical S-adenosylmethionine (SAM) protein, created a mutant strain that failed to produce YTM but accumulated a new metabolite, which was structurally elucidated as a precursor that was related to the formation of the cyclopropane ring. More importantly, biochemical characterization of the radical SAM-dependent enzyme YtkT revealed that it is a novel C-methyltransferase and contributes to an advanced intermediate during formation of the cyclopropane ring through a radical mechanism in the YTM biosynthetic pathway. On the basis of in silico analysis, genetic experiments, structure elucidation of the novel intermediate, and biochemical characterization, a biosynthetic pathway for yatakemycin was proposed, which sets the stage to further investigate the novel enzymatic mechanisms and engineer the biosynthetic machinery for the production of novel analogues.
    Journal of the American Chemical Society 05/2012; 134(21):8831-40. DOI:10.1021/ja211098r · 11.44 Impact Factor
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    ABSTRACT: Polymorphisms in DNA repair gene may alter an individual's DNA repair capacity and be associated with the risk of various cancers. This study was designed to investigate whether ERCC1 +262A/C and XPF -357A/C polymorphisms affect individual susceptibility to esophageal squamous cell carcinoma (ESCC) and gastric cardiac adenocarcinoma (GCA). In 389 ESCC patients vs. 778 healthy controls and 262 GCA patients vs. 524 healthy controls in a high incidence region of northern China, ERCC1 +262A/C polymorphism and XPF -357A/C polymorphism were genotyped by the method of polymerase chain reaction ligase detection reaction (PCR-LDR) and polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) analysis, respectively. Family history of upper gastrointestinal cancers (UGIC) may increase the risk of ESCC and GCA. Allelotype and genotype distributions of ERCC1 +262A/C and XPF -357A/C polymorphisms in ESCC and GCA patients were not significantly different from that in their respective controls (p >0.05). Compared with ERCC1 +262C/C genotype, A/A genotype decreased the risk of GCA in nonsmokers (age, gender and family history of UGIC adjusted odds ratio [OR] = 0.30, 95% confidence interval [CI] = 0.13-0.70). Neither the A/C nor the C/C genotype was associated with the overall risk of ESCC and GCA when compared with the XPF -357A/A genotype. ERCC1 +262A/A genotype may reduce the risk of GCA for nonsmokers. XPF -357A/C polymorphism was not associated with the risk of ESCC and GCA in a population of a high-incidence region in northern China.
    Archives of medical research 02/2012; 43(1):67-74. DOI:10.1016/j.arcmed.2012.01.010 · 2.41 Impact Factor
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    ABSTRACT: YM-216391, an antitumor natural product, represents a new class of cyclic peptides containing a polyoxazole-thiazole moiety. Herein we describe its gene cluster encoding the biosynthetic paradigm featuring a ribosomally synthesizing precursor peptide followed by a series of novel posttranslational modifications, which include (i) cleavage of both N-terminal leader peptide and C-terminal extension peptide and cyclization in a head-to-tail fashion, (ii) conversion of an L-Ile to D-allo-Ile, and (iii) β-hydroxylation of Phe by a P450 monooxygenase followed by further heterocyclization and oxidation to form a phenyloxazole moiety. The cluster was heterologously expressed in Streptomyces lividans to bypass difficult genetic manipulation. Deletion of the ymR3 gene, encoding a putative transcriptional regulator, increased the YM-216391 yield about 20-fold higher than the original yields for the heterologous expression of wild-type cluster, which set the stage for further combinatorial biosynthesis.
    ACS Chemical Biology 01/2012; 7(4):646-51. DOI:10.1021/cb200479f · 5.36 Impact Factor

Publication Stats

970 Citations
176.53 Total Impact Points


  • 2011–2015
    • Capital Medical University
      • Department of Neurobiology
      Peping, Beijing, China
  • 2003–2013
    • Hebei Medical University
      Chentow, Hebei, China
  • 2012
    • Shanghai Research Institute of Chemical Industry
      Shanghai, Shanghai Shi, China
  • 2004–2009
    • Roche Institute of Molecular Biology
      Nutley, New Jersey, United States