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1.  Serum cystatin C as a potential biomarker for the evaluation COPD 
Background: Imbalance between protease-antiprotease plays an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). Cystatin C in circulating blood is a cysteine protease inhibitor and contributes to elastolysis and tissue destruction. Objectives: The aims of the present study were to investigate whether cystatin C was a promising biomarker for the evaluation and follow-up of patients with COPD. Methods: Serum cystatin C level was determined in groups of acute exacerbation of chronic obstructive pulmonary disease (AECOPD) (n = 93), stable COPD (SCOPD) (n = 299) and healthy controls (n = 151). The influences of smoking on the level of serum cystatin C and the correlation of cystatin C with lung functional parameters were further analyzed. Results: Serum cystatin C level was significantly higher in COPD patients than that of healthy controls. Smoking increased serum cystatin C level in patients with SCOPD but not in AECOPD and control. In SCOPD group, serum cystatin C level was positively correlated with RV%TLC and negatively correlations with FEV1% predicted, FEV1%FVC, MMEF75/25% predicted, MVV% predicted and DLco% predicted. In multiple line analysis, FEV1% predicted and age were found to be independent predictors of serum cystatin C levels, but not smoking statue, sex and BMI. Conclusions: COPD had a higher level of serum cystatin C, smoking only increased cystatin C level in SCOPD. Serum cystatin C level was negatively correlated with FEV1% predicted. These results suggest that cystatin C might be a potential biomarker for lung tissue destruction and severity of COPD.
PMCID: PMC4307506  PMID: 25664059
COPD; cystatin C; cathepsins; lung function; biomarker
2.  A Corin Variant Identified in Hypertensive Patients That Alters Cytoplasmic Tail and Reduces Cell Surface Expression and Activity 
Scientific Reports  2014;4:7378.
Corin is a membrane-bound protease that regulates blood pressure by activating the natriuretic peptides. CORIN variants have been associated with hypertension and heart disease in African Americans. In this study, we conducted targeted exome sequencing and identified an insertion variant, c.102_103insA, in exon 1 of the CORIN gene. Analysis of two independent cohorts showed that the variant was preferentially present in hypertensive patients (38/795 or 4.78% vs. 4/632 or 0.63% in normal individuals, p = 4.14E-6). The insertion shifted the reading frame, resulting in a corin variant with a truncated cytoplasmic tail. In cell-based studies, the corin variant exhibited poor trafficking in the Golgi, reduced cell surface expression and zymogen activation, and low natriuretic peptide processing activity. Compared with normal individuals with the wild-type allele, individuals with the variant allele had lower levels of plasma corin [0.59 ± 0.07 ng/mL (n = 25) vs. 0.91 ± 0.02 ng/mL (n = 215), p<0.001] and higher levels of plasma N-terminal pro-atrial natriuretic peptide (NT-pro-ANP) [2.39 ± 3.6 nmol/L (n = 21) vs. 0.87 ± 0.6 nmol/L (n = 48), p = 0.005]. These results indicate that the variant altered corin structure and impaired the natriuretic peptide processing activity in vivo. The results highlight corin defects as an important underlying mechanism in hypertension.
doi:10.1038/srep07378
PMCID: PMC4260221  PMID: 25488193
3.  GENOME-WIDE ASSOCIATION STUDY META-ANALYSIS REVEALS TRANS-ETHNIC REPLICATION OF MEAN ARTERIAL AND PULSE PRESSURE LOCI 
Hypertension  2013;62(5):853-859.
We conducted a genome-wide association study meta-analysis of mean arterial pressure and pulse pressure among 26,600 East Asian participants (stage-1) followed by replication study of up to 28,783 participants (stage-2). For novel loci, statistical significance was determined by a P<5.0×10−8 in joint analysis of stage-1 and stage-2 data. For loci reported by the previous mean arterial and pulse pressure genome-wide association study meta-analysis in Europeans, evidence of trans-ethnic replication was determined by consistency in effect direction and a Bonferroni-corrected P<1.4×10−3. No novel loci were identified by the current study. Five independent mean arterial pressure variants demonstrated robust evidence for trans-ethnic replication including rs17249754 at ATP2B1 (P=7.5×10−15), rs2681492 at ATP2B1 (P=3.4×10−7), rs11191593 at NT5C2 (1.1×10−6), rs3824755 at CYP17A1 (P=1.2×10−6), and rs13149993 at FGF5 (P=2.4×10−4). Two additional variants showed suggestive evidence of trans-ethnic replication (consistency in effect direction and P<0.05), including rs319690 at MAP4 (P=0.014) and rs1173771 at NPR3 (P=0.018). For pulse pressure, robust evidence of replication was identified for 2 independent variants, including rs17249754 at ATP2B1 (P=1.2×10−5) and rs11191593 at NT5C2 (P=1.1×10−3), with suggestive evidence of replication among an additional 2 variants including rs3824755 at CYP17A1 (P=6.1×10−3) and rs2681492 at ATP2B1 (P=9.0×10−3). Replicated variants demonstrated consistency in effect sizes between East Asian and European samples, with effect size differences ranging from 0.03 to 0.24 mmHg for mean arterial pressure and from 0.03 to 0.21 mmHg for pulse pressure. In conclusion, we present the first evidence of trans-ethnic replication of several mean arterial and pulse pressure loci in an East Asian population.
doi:10.1161/HYPERTENSIONAHA.113.01148
PMCID: PMC3972802  PMID: 24001895
genetics; polymorphism; single nucleotide; blood pressure; hypertension; genome-wide association study; meta-analysis
4.  The Predictive Value of Waist-To-Height Ratio for Ischemic Stroke in a Population-Based Prospective Cohort Study among Mongolian Men in China 
PLoS ONE  2014;9(10):e110245.
Objective
To explore the associations between waist-to-height ratio (WHtR), body mass index (BMI) and waist circumference (WC) and risk of ischemic stroke among Mongolian men in China.
Methods
A population-based prospective cohort study was conducted from June 2003 to July 2012 in Inner Mongolia, an autonomous region in north China. A total of 1034 men aged 20 years and older free of cardiovascular disease were included in the cohort and followed up for an average of 9.2 years. The subjects were divided into four groups by WHtR levels (WHtR<0.40, 0.40≤WHtR≤0.50, 0.500.60). The cumulative survival rates of ischemic stroke among the four groups were estimated with the Kaplan-Meier curves and compared by log-rank test. Cox proportional hazards models and Receiver Operating Characteristic (ROC) curves were employed to evaluate the associations between obesity indices and ischemic stroke.
Results
A total of 47 ischemic stroke patients were observed during the follow-up period. The cumulative incidence and incidence density of ischemic stroke were 4.55% and 507.61/100 000 person-years, respectively. After the major risk factors were adjusted, individuals with WHtR>0.60 had a 3.56-fold increased risk of ischemic stroke compared with those with 0.40≤WHtR≤0.50. Hazard ratio (HR) and 95% confidence intervals (CI) of ischemic stroke for a 1-SD increase in WHtR was 1.34(95% CI: 1.00–1.81). After adding BMI or WC to models, higher WHtR remained significantly associated with increased risk of ischemic stroke. The Kaplan-Meier survival curves showed that the cumulative survival rate in the group with WHtR>0.60 was significantly lower than in the group with 0.40≤WHtR≤0.50 (log-rank test, P = 0.025). The areas under the curve for each index were as follows: 0.586 for WHtR, 0.543 for WC; 0.566 for BMI.
Conclusions
Higher WHtR is associated with risk of ischemic stroke in Mongolian males. WHtR may be useful in predicting ischemic stroke incidence in males.
doi:10.1371/journal.pone.0110245
PMCID: PMC4212917  PMID: 25353632
5.  An update on overweight and obesity in rural Northeast China: from lifestyle risk factors to cardiometabolic comorbidities 
BMC Public Health  2014;14(1):1046.
Background
Not enough is known about the prevalence of overweight and obesity in rural China in the current decade. We aim to update our knowledge of the prevalence of obesity and its associated risk factors and comorbidities in a large population sample in rural Northeast China.
Methods
A population-based survey of 11,579 participants aged 35 years and older was conducted in rural areas of Liaoning Province during 2012–2013. Anthropometric measurements, information on health-related variables and blood biochemical indexes were collected by well-trained personnel.
Results
The prevalence of general obesity and overweight was found to be 7.8% and 37.2%, respectively. The overall prevalence of abdominal obesity was 15.1%. Female gender, ethnic minority, middle-school education and a family income of 5,000–20,000 CNY per year were found to be risk factors for general obesity, while older age, female gender, ethnic minority and longer sleep duration (>8 h/d) increased the risk of abdominal obesity, after adjusting for confounders. Overweight and obese participants had significantly higher risks to develop prehypertension, hypertension, high LDL-C and low HDL-C compared with normal weight participants, while abdominal obesity was associated with increased risks of diabetes and high TG after adjusted for multiple factors. Compared with participants with a normal BMI and no abdominal obesity, the participants classified as abdominally obese and normal BMI; as abdominally obese and overweight; and abdominally obese and generally obese each had a progressive increase in the odds of hypertension (OR: 1.961, 95% CI: 1.154 to 3.331, OR: 2.744, 95% CI: 2.126 to 3.541, and OR: 8.990, 95% CI: 5.858 to 13.795, respectively) and high TG (OR: 3.165, 95% CI: 2.183 to 4.588, OR: 3.980, 95% CI: 3.332 to 4.755, and OR: 4.340, 95% CI: 3.574 to 5.271, respectively).
Conclusions
The prevalence of obesity in rural Northeast China exhibited a remarkably increasing upwards trend. General and abdominal obesity were associated with different subtypes of cardiometabolic comorbidities, the combined effects of which on the comorbidities dramatically increased.
doi:10.1186/1471-2458-14-1046
PMCID: PMC4198624  PMID: 25293836
General obesity; Abdominal obesity; Prevalence; Risk factor; Comorbidities
6.  Associations of non-high density lipoprotein cholesterol and traditional blood lipid profiles with hyperuricemia among middle-aged and elderly Chinese people: a community-based cross-sectional study 
Background
Increased serum uric acid (SUA) is associated with dyslipidemia. However, there are conflicting data about the role of single lipid species including non-high density lipoprotein cholesterol (non-HDL-C) in promoting SUA accumulation. Here, we aimed to compare non-HDL-C with other traditional blood lipid profiles in relation to hyperuricemia in a middle-aged and elderly Chinese population.
Methods
Data was collected from 9580 participants undergoing routine physical examinations in Xiangcheng district of Suzhou. SUA, total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C), and high density lipoprotein cholesterol (HDL-C) were examined for all participants. Non-HDL-C was calculated by subtracting HDL-C from TC. The associations of blood lipid profiles with hyperuricemia were examined in men and women, respectively. The areas under Receiver Operating Characteristic (ROC) curves (AUCs) were compared to assess the discriminatory value of blood lipid parameters for predicting hyperuricemia.
Results
All blood lipid parameters significantly correlated with SUA (all P values <0.001). The correlation coefficient between SUA and TG was the highest in both genders. The correlation coefficient of non-HDL-C was higher than HDL-C in males and was higher than TC and LDL-C but followed HDL-C in females. In male group, AUC of TG (0.659) was greater than that of non-HDL-C (0.595) (P values <0.001). The AUC values of HDL-C, TC and LDL-C were lower; respectively 0.581, 0.559 and 0.552. In female group, AUC was highest for TG (0.678) followed by HDL-C (0.616), non-HDL-C (0.610), LDL-C (0.559) and TC (0.557) (all P values < 0.001).
Conclusions
In both genders, serum TG has the strongest association with hyperuricemia among blood lipid parameters. Non-HDL-C is also significantly associated with hyperuricemia.
doi:10.1186/1476-511X-13-117
PMCID: PMC4115491  PMID: 25052552
Hyperuricemia; Blood lipids; Non-high density lipoprotein cholesterol
7.  Changes of HMGB1 and sRAGE during the recovery of COPD exacerbation 
Journal of Thoracic Disease  2014;6(6):734-741.
Background
Acute exacerbation of chronic obstructive pulmonary disease is associated with increased airway and systemic inflammation. However, the correlation between acute exacerbation/convalescence of chronic obstructive pulmonary disease (COPD) and simultaneous changes of high mobility group protein B1 (HMGB1) and soluble RAGE (sRAGE) levels has not been clearly clarified. The aim of this study was to assess these issues.
Methods
A total of 44 COPD patients were recruited. Following a structured interview, plasma levels of HMGB1, sRAGE, fibrinogen and serum level of high-sensitivity C-reactive protein (hsCRP) were measured in patients with acute exacerbation of COPD (AECOPD) within 24 h of hospitalization and pre-discharge (convalescence). All patients were examined with spirometry in convalescence of COPD.
Results
There was a significant decline in plasma HMGB1 (P<0.01), sRAGE (P<0.05), fibrinogen (P<0.01) and serum hsCRP (P<0.01) levels from acute exacerbation to convalescence phase of COPD. Changes of sRAGE was significantly correlated with changes of HMGB1 (r=0.4, P=0.007). COPD disease status correlated with the ratio of HMGB1/sRAGE, but not gender, age, course of disease, smoking history and FEV1% pred. Levels of HMGB1 and sRAGE were the highest in the current smoker group, and significantly decreased in ex-smoker group in both acute exacerbation and convalescence phase of COPD, however, their levels in never smoker group were higher than ex-smoker group in either phase of COPD.
Conclusions
HMGB1 and sRAGE levels were dynamically changed between exacerbation and convalescence phase of COPD, HMGB1 and sRAGE were likely not only a potential marker in COPD exacerbation but also a therapeutic target for COPD treatment.
doi:10.3978/j.issn.2072-1439.2014.04.31
PMCID: PMC4073385  PMID: 24976997
Chronic obstructive pulmonary disease (COPD); high mobility group protein B1 (HMGB1); soluble RAGE (sRAGE); biomarker; exacerbation; convalescence
8.  Preparation of North American Type II PRRSV Infectious Clone Expressing Green Fluorescent Protein 
BioMed Research International  2014;2014:368581.
Porcine reproductive and respiratory syndrome virus (PRRSV) is still one of the most important infectious diseases threatening the swine industry. To construct North American type II PRRSV infectious clone containing green fluorescent protein (GFP) gene, we amplify gfp gene, flanked by PRRSV Nsp2 gene fragments upstream and downstream, using overlap PCR method from pcDNA-EF1-GFP plasmid and FL12 plasmid containing PRRSV infectious genome as the templates. The Nsp2 fragment-flanked gfp gene was inserted into Nsp2 gene of the FL12 plasmid by Spe I and Xho I sites to generate PRRSV infectious recombinant plasmid (FL12-GFP) containing gfp gene. The recombinant PRRSV expressing GFP (PRRSV-GFP) was rescued in baby hamster kidney-21 (BHK-21) cells by transfecting PRRSV mRNA synthesized in vitro and amplified in Marc-145 cells. The PRRSV-GFP infectivity and replication capacity were identified. Results showed that, by adopting overlap PCR strategy, the gfp gene was successfully inserted into and fused with PRRSV Nsp2 gene in the PRRSV infectious clone plasmid FL-12 to generate FL12-GFP plasmid. The recombinant PRRSV-GFP was generated through transfecting PRRSV mRNA in BHK-2 cells. Like its parental virus, the recombinant PRRSV-GFP maintains its infectivity to Marc-145 cells and porcine alveolar macrophages (PAMs). This study provides essential conditions for further investigation on PRRSV.
doi:10.1155/2014/368581
PMCID: PMC4034427  PMID: 24895571
9.  A preliminary investigation on the relationship between virtues and pathological internet use among Chinese adolescents 
Background
Pathological Internet Use (PIU) has become a global issue associated with the increasing number of Internet users. Previous studies concerned both the interpersonal and intrapersonal vulnerable factors and the corresponding models. However, a limited amount of research has explored the relationship between positive factors and PIU.
Objective
The current investigation attempted to clarify the relationship between virtues and PIU among Chinese adolescents; it also sought to explore the specific contributions of the three virtues. Virtue was the core concept in positive psychology and the Values in Action Classification. A recent study demonstrated that there might be three universal virtues (relationship, vitality, and conscientiousness).
Methods
A cross-sectional sample of adolescents aged 12-17 years were recruited in 2013. A total of 674 adolescents (males = 302, females = 372; junior high school = 296, senior high school = 378) from eight junior and senior high schools in four provinces of Mainland China completed a package of psychological inventories, including the Chinese Virtues Questionnaire (CVQ) and the Adolescent Pathological Internet Use Scale (APIUS). The mean age of the current sample was 15.10 years (SD = 1.81) with an average of 5.31 years’ length (SD = 2.09) of Internet use.
Results
A total of 9.50% participants exhibited significant symptoms of PIU. Male students (Mmale = 2.50) had significantly higher scores on PIU than female students (Mfemale = 2.25). Relationship (β = -.24) and conscientiousness (β = -.21) negatively predicted PIU, whereas vitality (β = .25) positively predicted PIU. Dominance analysis further revealed that relationship and conscientiousness could explain 81% variance of PIU, and vitality only accounted for another 19%.
Conclusions
Relationship and conscientiousness were possible protective factors of pathological Internet users, while vitality was vulnerable. The results could be helpful in screening “at-risk” Internet users (low relationship and conscientiousness as well as high vitality). Future intervention strategies could focus on how to enhance relationship and conscientiousness and on how to reduce vitality.
doi:10.1186/1753-2000-8-8
PMCID: PMC3995982  PMID: 24594317
Virtue; Pathological Internet use; Vitality; Conscientiousness; Relationship
10.  Association of Biomarkers of Inflammation with Dyslipidemia and Its Components among Mongolians in China 
PLoS ONE  2014;9(2):e89023.
Objective
This study aims to examine the association between inflammatory biomarkers and dyslipidemia and its components among Mongolians in China.
Methods
Data were obtained from 2544 Mongolians via standard questionnaires and blood samples in Inner Mongolia, China. High sensitivity C-reactive protein (hsCRP), soluble intercellular adhesion molecule-1 (sICAM-1) and soluble E-selectin (sE-selectin) as well as blood lipids were examined.
Results
Individuals with dyslipidemia had higher levels of hsCRP, sICAM-1 and sE-selectin than those without dyslipidemia (all P values<0.001). Compared to the lowest quartile of inflammatory biomarkers, individuals with the highest quartile were more likely to have dyslipidemia (odds ratio, 95% confidence interval: 3.215, 2.551–4.116 for hsCRP; 1.575, 1.253–1.980 for sICAM-1; 1.495, 1.193–1.873 for sE-selectin). Moreover, hsCRP was associated with all the components of dyslipidemia, whereas, sICAM-1 was not related to high density lipoprotein cholesterol (HDL-c) or triglycerides (TAG). Additionally, sE-selectin was just associated with TAG.
Conclusion
Our study indicated that elevated plasma levels of hsCRP, sICAM-1 and sE-selectin were positively and significantly associated with increased risk of dyslipidemia among Mongolians. However, the associations were not identical for different inflammatory biomarkers with the components of dyslipidemia.
doi:10.1371/journal.pone.0089023
PMCID: PMC3928392  PMID: 24558466
11.  Glycerol Affects Root Development through Regulation of Multiple Pathways in Arabidopsis 
PLoS ONE  2014;9(1):e86269.
Glycerol metabolism has been well studied biochemically. However, the means by which glycerol functions in plant development is not well understood. This study aimed to investigate the mechanism underlying the effects of glycerol on root development in Arabidopsis thaliana. Exogenous glycerol inhibited primary root growth and altered lateral root development in wild-type plants. These phenotypes appeared concurrently with increased endogenous glycerol-3-phosphate (G3P) and H2O2 contents in seedlings, and decreased phosphate levels in roots. Upon glycerol treatment, G3P level and root development did not change in glycerol kinase mutant gli1, but G3P level increased in gpdhc1 and fad-gpdh mutants, which resulted in more severely impaired root development. Overexpression of the FAD-GPDH gene attenuated the alterations in G3P, phosphate and H2O2 levels, leading to increased tolerance to exogenous glycerol, which suggested that FAD-GPDH plays an important role in modulating this response. Free indole-3-acetic acid (IAA) content increased by 46%, and DR5pro::GUS staining increased in the stele cells of the root meristem under glycerol treatment, suggesting that glycerol likely alters normal auxin distribution. Decreases in PIN1 and PIN7 expression, β-glucuronidase (GUS) staining in plants expressing PIN7pro::GUS and green fluorescent protein (GFP) fluorescence in plants expressing PIN7pro::PIN7-GFP were observed, indicating that polar auxin transport in the root was downregulated under glycerol treatment. Analyses with auxin-related mutants showed that TIR1 and ARF7 were involved in regulating root growth under glycerol treatment. Glycerol-treated plants showed significant reductions in root meristem size and cell number as revealed by CYCB1;1pro::GUS staining. Furthermore, the expression of CDKA and CYCB1 decreased significantly in treated plants compared with control plants, implying possible alterations in cell cycle progression. Our data demonstrated that glycerol treatment altered endogenous levels of G3P, phosphate and ROS, affected auxin distribution and cell division in the root meristem, and eventually resulted in modifications of root development.
doi:10.1371/journal.pone.0086269
PMCID: PMC3899222  PMID: 24465999
12.  Association between Human Urotensin II and Essential Hypertension—A 1:1 Matched Case-Control Study 
PLoS ONE  2013;8(12):e81764.
Objective
We aimed to evaluate the controversial association between human urotensin II and essential hypertension in untreated hypertensive cases and normotensive controls.
Methods
197 newly diagnosed hypertensive patients and 197 age- and sex-matched normotensive controls were studied. Plasma urotensin II, nitric oxide metabolites, and other traditional biomarkers were examined.
Results
Hypertensive patients had higher urotensin II [median (interquartile rang): 9.32 (7.86–11.52) ng/mL vs 8.52 (7.07–10.41) ng/mL] and lower nitric oxide metabolites [19.19 (2.55–38.48) µmol/L vs 23.83 (11.97–43.40) µmol/L] than normotensive controls. Urotensin II was positively correlated with systolic blood pressure (r = 0.169, P<0.001) and diastolic blood pressure (r = 0.113, P = 0.024) while negatively correlated with nitric oxide metabolites (r = −0.112, P = 0.027). In multivariate regression analysis, subjects in the highest quartile of urotensin II were more likely to have hypertension than those in the lowest quartile (OR, 2.58; 95% CI, 1.21–5.49). Sub-group analyses in 106 pairs of cases and controls with either both normal or both abnormal nitric oxide metabolites levels showed that the association between urotensin II levels and hypertension persisted (P value for trend = 0.039).
Conclusion
Human urotensin II is markedly associated with essential hypertension, and the association is independent of nitric oxide metabolites. Our results indicated that urotensin II might be an independent risk factor for essential hypertension.
doi:10.1371/journal.pone.0081764
PMCID: PMC3858253  PMID: 24339964
13.  Nucleosome-binding protein HMGN2 exhibits antitumor activity in oral squamous cell carcinoma 
Oncology Letters  2013;7(1):115-120.
Natural killer (NK) cells and cytolytic T lymphocytes (CTLs) serve as effectors in the antitumor response. High mobility group nucleosomal binding domain 2 (HMGN2) is a candidate effector molecule involved in CTL and NK cell function. In the current study, recombinant human HMGN2 was isolated and purified from transformed Escherichia coli. Tca8113 cells, an oral squamous cell carcinoma line, were treated with a variety of HMGN2 protein concentrations and cell growth was analyzed. HMGN2 significantly inhibited the growth of Tca8113 cells and was predicted to arrest cells in the S phase. Moreover, HMGN2 treatment increased the apoptosis rate of Tca8113 cells. Western blotting indicated the upregulation of p53 and Bax proteins, whereas Bcl-2 was significantly downregulated. In addition, caspase-3 was found to be activated. Furthermore, the HMGN2 protein may suppress the growth of Tca8113 cells in vivo. The results of the current study indicated that the HMGN2 protein may inhibit the growth of oral squamous cell carcinoma and HMGN2 may represent an antitumor effector molecule of CTL or NK cells.
doi:10.3892/ol.2013.1665
PMCID: PMC3861564  PMID: 24348831
HMGN2; oral squamous cell carcinoma; apoptosis; antitumor activity; cell cycle
14.  JAK1 truncating mutations in gynecologic cancer define new role of cancer-associated protein tyrosine kinase aberrations 
Scientific Reports  2013;3:3042.
Cancer-associated protein tyrosine kinase (PTK) mutations usually are gain-of-function (GOF) mutations that drive tumor growth and metastasis. We have found 50 JAK1 truncating mutations in 36 of 635 gynecologic tumors in the Total Cancer Care® (TCC®) tumor bank. Among cancer cell lines containing JAK1 truncating mutations in the Cancer Cell Line Encyclopedia databank, 68% are gynecologic cancer cells. Within JAK1 the K142, P430, and K860 frame-shift mutations were identified as hot spot mutation sites. Sanger sequencing of cancer cell lines, primary tumors, and matched normal tissues confirmed the JAK1 mutations and showed that these mutations are somatic. JAK1 mediates interferon (IFN)-γ-regulated tumor immune surveillance. Functional assays show that JAK1 deficient cancer cells are defective in IFN-γ-induced LMP2 and TAP1 expression, loss of which inhibits presentation of tumor antigens. These findings identify recurrent JAK1 truncating mutations that could contribute to tumor immune evasion in gynecologic cancers, especially in endometrial cancer.
doi:10.1038/srep03042
PMCID: PMC3807107  PMID: 24154688
15.  microRNA-449a functions as a tumor-suppressor in gastric adenocarcinoma by targeting Bcl-2 
Oncology Letters  2013;6(6):1713-1718.
microRNAs (miRNAs or miRs) may function as oncogenes or tumor suppressors. The present study identified that miR-449a was downregulated in human gastric cancer. The overexpression of miR-449a inhibited gastric adenocarcinoma cell growth and promoted cell apoptosis in the MGC-803 and SGC-7901 gastric adenocarcinoma cell lines. Subsequently, Bcl-2 was identified as a potential miR-449a target by bioinformatics analysis. It was also shown that Bcl-2 was negatively regulated by miR-449a at the post-transcriptional level, via a specific target site within the 3′-untranslated region (3′UTR), by luciferase reporter assay. The expression of miR-449a induced cell apoptosis, as observed by TdT-mediated dUTP nick end labeling and caspase 3/7 assays, and was rescued by Bcl-2 expression. Therefore, these observations indicate that miR-449a acts as a tumor suppressor by targeting the Bcl-2 gene and that it promotes gastric adenocarcinoma cell apoptosis via Bcl-2. The findings of this study contribute to or current understanding of the functions of miR-449a in gastric adenocarcinoma.
doi:10.3892/ol.2013.1609
PMCID: PMC3833858  PMID: 24260067
miR-449a; Bcl-2; gastric adenocarcinoma; caspase 3; caspase 7; apoptosis
16.  A novel hypothesis: up-regulation of HO-1 by activation of PPARγ inhibits HMGB1-RAGE signaling pathway and ameliorates the development of ALI/ARDS 
Journal of Thoracic Disease  2013;5(5):706-710.
Suppression of inflammation in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) by activation of peroxisome proliferator-activated receptor (PPAR)-γ has been well demonstrated in animal model studies. However, the molecular mechanisms underlying this effect remain largely unknown. The induction of heme oxygenase-1 (HO-1) exerts antioxidant, anti-apoptotic, and immunomodulatory functions in various situations. Recent studies have indicated that activation of PPARγ induces expression of HO-1, suggesting that HO-1 is a downstream target of PPARγ. Meanwhile, study has shown that activation of PPARγ ameliorates inflammatory response of cells by inhibiting high mobility group box 1 (HMGB1) release. In pulmonary system, binding of HMGB1 to its receptor for advanced glycation end-products (RAGE) triggers the production of pro-inflammatory cytokines, chemokines, adhesion molecules and reactive oxygen species, promoting the development of ALI/ARDS. Based on the recent findings that induction of HO-1 protects tissues and cells from extracellular stress by reducing HMGB1 production, we propose the hypothesis that HO-1 may mediate the protective effects of PPARγ on inhibition of HMGB1-RAGE signaling pathway to attenuate the development of ALI/ARDS.
doi:10.3978/j.issn.2072-1439.2013.08.69
PMCID: PMC3815721  PMID: 24255785
Peroxisome proliferator-activated receptor (PPAR)-γ; heme oxygenase-1 (HO-1); high mobility group box 1 (HMGB1); receptor for advanced glycation end-products (RAGE); acute lung injury/acute respiratory distress syndrome (ALI/ARDS)
17.  Preventative effect of Astragalus flavescens on hepatic fibrosis in rats and its mechanism of action 
The aim of this study was to investigate the preventative effect of Astragalus flavescens on hepatic fibrosis in rats and its mechanism of action. A total of 60 rats were randomly divided into normal control, model control, high-dose treatment and low-dose treatment groups, and a hepatic fibrosis model was established. The high- and low-dose treatment groups were treated with 2 g/100 g and 0.5 g/100 g Astragalus flavescens, respectively, once a day. Eight weeks following the initiation of treatment, the liver specimens of the rats were stained and observed under a light microscope. Hepatic fibrosis indices, specifically, type III precollagen (PC III), type IV collagen (C IV), hyaluronic acid (HA) and laminin (LN), were detected. Furthermore, the expression and localization of the hepatic fibrosis-related factors transforming growth factor-β1 (TGF-β1), connective tissue growth factor (CTGF) and platelet-derived growth factor-BB (PDGF-BB) were determined. The serum levels of hepatic fibrosis indices, and the liver tissue levels of hepatic fibrosis-related factors and collagen surface density in the model control group and the high- and low-dose treatment groups were significantly higher compared with those of the normal control group (P<0.05). In addition, the values in the two treatment groups were significantly lower compared with those of the model control group (P<0.05). The present study demonstrated that Astragalus flavescens effectively prevents hepatic fibrosis in rats. A possible mechanism for this is that it may reduce the expression levels of TGF-β1, PDGF-BB and CTGF, thereby inhibiting the activation of hepatic stellate cells and specifically blocking the signal transduction pathway of hepatic fibrosis.
doi:10.3892/etm.2013.1232
PMCID: PMC3797310  PMID: 24137287
Astragalus flavescens; hepatic fibrosis; prevention; mechanism
18.  Association between Vitamin D Insufficiency and Elevated Serum Uric Acid among Middle-Aged and Elderly Chinese Han Women 
PLoS ONE  2013;8(4):e61159.
Background
Association between vitamin D insufficiency and hyperuricemia has not been reported so far. We aimed to study the association of vitamin D insufficiency with elevated serum uric acid among middle-aged and elderly Chinese Han women.
Methods
We collected data from participants residing in Jinchang district of Suzhou from January to May, 2010. Serum uric acid, 25-hydroxy vitamin D and other traditional biomarkers including fasting plasma glucose and blood lipids were determined in 1726 women aged above 30 years. Association between vitamin D insufficiency and elevated uric acid was analyzed in premenopausal and postmenopausal women, respectively.
Results
Among postmenopausal women, 25-hydroxy vitamin D level of participants with elevated uric acid was lower than that of those with normal uric acid (median [interquartile range]: 35[28–57] vs 40[32–58], µg/L; P = 0.006). Elevated uric acid was more prevalent in participants with vitamin D insufficiency compared to those without vitamin D insufficiency (16.50% vs 8.08%; P<0.001). Association between vitamin D insufficiency and elevated uric acid was not significant among premenopausal women. However, participants with vitamin D insufficiency were more likely to have elevated uric acid compared with those without vitamin D insufficiency among postmenopausal women (OR, 95% CI: 2.38, 1.47–3.87). Moreover, after excluding individuals with diabetes and/or hypertension, the association of vitamin D insufficiency with elevated uric acid was still significant (OR, 95% CI: 2.48, 1.17–5.44).
Conclusions
Vitamin D insufficiency was significantly associated with elevated uric acid among postmenopausal Chinese Han women. This study suggested that a clinical trial should be conducted to confirm the association of vitamin D insufficiency with hyperuricemia.
doi:10.1371/journal.pone.0061159
PMCID: PMC3621974  PMID: 23585876
19.  High frequency of HIV mutations associated with HLA-C suggests enhanced HLA-C-restricted CTL selective pressure associated with an AIDS-protective polymorphism 
Delayed HIV-1 disease progression is associated with a single nucleotide polymorphism upstream of the HLA-C gene that correlates with differential expression of the HLA-C antigen. This polymorphism was recently shown to be a marker for a protective variant in the 3′UTR of HLA-C that disrupts a microRNA binding site, resulting in enhanced HLA-C expression at the cell surface. Whether individuals with ‘high’ HLA-C expression show a stronger HLA-C-restricted immune response exerting better viral control than that of their counterparts has not been established. We hypothesised that the magnitude of the HLA-C-restricted immune pressure on HIV would be greater in subjects with highly expressed HLA-C alleles. Using a cohort derived from a unique narrow source epidemic in China, we identified mutations in HIV proviral DNA exclusively associated with HLA-C which were used as markers for the intensity of the immune pressure exerted on the virus. We found an increased frequency of mutations in individuals with highly expressed HLA-C alleles which also correlated with IFN-γ production by HLA-C-restricted CD8+ T-cells. These findings show that immune pressure on HIV is stronger in subjects with the protective genotype and highlights the potential role of HLA-C-restricted responses in HIV control. This is the first in vivo evidence supporting the protective role of HLA-C-restricted responses in non-Caucasians during HIV infection.
doi:10.4049/jimmunol.1103472
PMCID: PMC3378658  PMID: 22474021
20.  Biomarkers on melanoma patient T Cells associated with ipilimumab treatment 
Background
Ipilimumab induces long-lasting clinical responses in a minority of patients with metastatic melanoma. To better understand the mechanism(s) of action and to identify novel biomarkers associated with the clinical benefit and toxicity of ipilimumab, baseline characteristics and changes in CD4+ and CD8+ T cells from melanoma patients receiving ipilimumab were characterized by gene profiling and flow cytometry.
Methods
Microarray analysis of flow-cytometry purified CD4+ and CD8+ T cells was employed to assess gene profiling changes induced by ipilimumab. Selected molecules were further investigated by flow cytometry on pre, 3-month and 6-month post-treatment specimens.
Results
Ipilimumab up-regulated Ki67 and ICOS on CD4+ and CD8+ cells at both 3- and 6-month post ipilimumab (p ≤ 0.001), decreased CCR7 and CD25 on CD8+ at 3-month post ipilimumab (p ≤ 0.02), and increased Gata3 in CD4+ and CD8+ cells at 6-month post ipilimumab (p ≤ 0.001). Increased EOMES+CD8+, GranzymeB+EOMES+CD8+ and decreased Ki67+EOMES+CD4+ T cells at 6 months were significantly associated with relapse (all p ≤ 0.03). Decreased Ki67+CD8+ T cells were significantly associated with the development of irAE (p = 0.02). At baseline, low Ki67+EOMES+CD8+ T cells were associated with relapse (p ≤ 0.001), and low Ki67+EOMES+CD4+ T cells were associated with irAE (p ≤ 0.008).
Conclusions
Up-regulation of proliferation and activation signals in CD4+ and CD8+ T cells were pharmacodynamic markers for ipilimumab. Ki67+EOMES+CD8+ and Ki67+EOMES+CD4+T cells at baseline merit further testing as biomarkers associated with outcome and irAEs, respectively.
doi:10.1186/1479-5876-10-146
PMCID: PMC3527361  PMID: 22788688
CTLA-4; Antibody; Biomarker; Melanoma
21.  Admission clinical characteristics and early clinical outcomes among acute ischemic stroke patients 
Journal of Biomedical Research  2012;26(3):152-158.
The purpose of the present study was to investigate the association between admission clinical characteristics and outcomes at discharge among acute ischemic stroke patients in the Chinese population. A total of 2,673 patients with acute ischemic stroke were included in the present study. The clinical characteristics at admission and other study variables were collected for all patients. The study outcome was defined as neurological deficiency (National Institute of Health Stroke Scale score ≥10) at discharge or in-hospital death. Compared with the subjects without neurological deficiency at discharge or in-hospital death, the subjects with neurological deficiency at discharge or in-hospital death had a significantly higher prevalence of hyperglycemia or history of atrial fibrillation at admission. Age ≥ 80 years, hyperglycemia, hypertension, and history of atrial fibrillation were significantly associated with neurological deficiency at discharge or in-hospital death after adjustment for other variables. It is concluded that old age (≥80 years), hyperglycemia, hypertension and history of atrial fibrillation are significantly associated with neurological deficiency at discharge or in-hospital death among patients with acute ischemic stroke.
doi:10.7555/JBR.26.20110129
PMCID: PMC3596064  PMID: 23554744
acute ischemic stroke; clinical characteristics; death; neurological deficiency; discharge outcome
22.  Construction of fat1 Gene Expression Vector and Its Catalysis Efficiency in Bovine Fetal Fibroblast Cells 
The FAT-1 protein is an n-3 fatty acid desaturase, which can recognize a range of 18- and 20-carbon n-6 substrates and transform n-6 polyunsaturated fatty acids (PUFAs) into n-3 PUFAs while n-3 PUFAs have beneficial effect on human health. Fat1 gene is the coding sequence from Caenorhabditis elegans which might play an important role on lipometabolism. To reveal the function of fat1 gene in bovine fetal fibroblast cells and gain the best cell nuclear donor for transgenic bovines, the codon of fat1 sequence was optimized based on the codon usage frequency preference of bovine muscle protein, and directionally cloned into the eukaryotic expression vector pEF-GFP. After identifying by restrictive enzyme digests with AatII/XbaI and sequencing, the fusion plasmid pEF-GFP-fat1 was identified successfully. The pEF-GFP-fat1 vector was transfected into bovine fetal fibroblast cells mediated by Lipofectamine2000TM. The positive bovine fetal fibroblast cells were selected by G418 and detected by RT-PCR. The results showed that a 1,234 bp transcription was amplified by reverse transcription PCR and the positive transgenic fat1 cell line was successfully established. Then the expression level of fat1 gene in positive cells was detected using quantitative PCR, and the catalysis efficiency was detected by gas chromatography. The results demonstrated that the catalysis efficiency of fat1 was significantly high, which can improve the total PUFAs rich in EPA, DHA and DPA. Construction and expression of pEF-GFP-fat1 vector should be helpful for further understanding the mechanism of regulation of fat1 in vitro. It could also be the first step in the production of fat1 transgenic cattle.
doi:10.5713/ajas.2011.11495
PMCID: PMC4093122  PMID: 25049605
fat1; Gene Expression; Catalysis Efficiency; Bovine Fetal Fibroblast Cells
23.  The Rice HGW Gene Encodes a Ubiquitin-Associated (UBA) Domain Protein That Regulates Heading Date and Grain Weight 
PLoS ONE  2012;7(3):e34231.
Heading date and grain weight are two determining agronomic traits of crop yield. To date, molecular factors controlling both heading date and grain weight have not been identified. Here we report the isolation of a hemizygous mutation, heading and grain weight (hgw), which delays heading and reduces grain weight in rice. Analysis of hgw mutant phenotypes indicate that the hemizygous hgw mutation decreases latitudinal cell number in the lemma and palea, both composing the spikelet hull that is known to determine the size and shape of brown grain. Molecular cloning and characterization of the HGW gene showed that it encodes a novel plant-specific ubiquitin-associated (UBA) domain protein localized in the cytoplasm and nucleus, and functions as a key upstream regulator to promote expressions of heading date- and grain weight-related genes. Moreover, co-expression analysis in rice and Arabidopsis indicated that HGW and its Arabidopsis homolog are co-expressed with genes encoding various components of ubiquitination machinery, implying a fundamental role for the ubiquitination pathway in heading date and grain weight control.
doi:10.1371/journal.pone.0034231
PMCID: PMC3311617  PMID: 22457828
24.  Multilayered defence in HLA-B51 associated HIV viral control 
Polymorphism in the Human Leukocyte Antigen (HLA) region of chromosome is the major source of host genetic variability in HIV-1 outcome, but there is limited understanding of the mechanisms underlying the beneficial effect of protective class I alleles such as HLA-B57, B27 and B51. Taking advantage of a unique cohort infected with clade B’ HIV-1 through contaminated blood, in which many variables, such as the length of infection, the infecting viral strain and host genetic background are controlled, we performed a comprehensive study in order to understand HLA-B51 associated HIV-1 control. We focused on the T-cell responses against three dominant HLA-B51 restricted epitopes: Gag327-345(NI9) NANPDCKTI, Pol743-751(LI9) LPPVVAKEI and Pol283-289(TI8) TAFTIPSI. Mutations in all three dominant epitopes were significantly associated with HLA-B51 in the cohort. A clear hierarchy in selection of epitope mutations was observed through epitope sequencing. L743I in Position 1 of epitope LI9 was seen in most B51+ individuals, followed by V289X in Position 8 of the TI8, then A328S in Position 2 of the NI9 epitope was also seen in some B51+individuals. Good control of viral load and higher CD4+ counts were significantly associated with at least one detectable T cell response to un-mutated epitopes, whereas lower CD4+ counts and higher viral loads were observed in patients who had developed escape mutations in all three epitopes or who lacked T-cell responses specific to these epitope(s). We propose that patients with HLA-B51 benefit from having multiple layers of effective defence against the development of immune escape mutations.
doi:10.4049/jimmunol.1100316
PMCID: PMC3166850  PMID: 21670313
25.  DNA barcoding of oomycetes with cytochrome c oxidase subunit I and internal transcribed spacer 
Molecular Ecology Resources  2011;11(6):1002-1011.
Oomycete species occupy many different environments and many ecological niches. The genera Phytophthora and Pythium for example, contain many plant pathogens which cause enormous damage to a wide range of plant species. Proper identification to the species level is a critical first step in any investigation of oomycetes, whether it is research driven or compelled by the need for rapid and accurate diagnostics during a pathogen outbreak. The use of DNA for oomycete species identification is well established, but DNA barcoding with cytochrome c oxidase subunit I (COI) is a relatively new approach that has yet to be assessed over a significant sample of oomycete genera. In this study we have sequenced COI, from 1205 isolates representing 23 genera. A comparison to internal transcribed spacer (ITS) sequences from the same isolates showed that COI identification is a practical option; complementary because it uses the mitochondrial genome instead of nuclear DNA. In some cases COI was more discriminative than ITS at the species level. This is in contrast to the large ribosomal subunit, which showed poor species resolution when sequenced from a subset of the isolates used in this study. The results described in this paper indicate that COI sequencing and the dataset generated are a valuable addition to the currently available oomycete taxonomy resources, and that both COI, the default DNA barcode supported by GenBank, and ITS, the de facto barcode accepted by the oomycete and mycology community, are acceptable and complementary DNA barcodes to be used for identification of oomycetes.
doi:10.1111/j.1755-0998.2011.03041.x
PMCID: PMC3195333  PMID: 21689384
cytochrome c oxidase subunit I; DNA barcoding; internal transcribed spacer; oomycete; species identification

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