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1.  Forward and backward wave morphology and central pressure augmentation in men and women in the Framingham Heart Study 
Hypertension  2014;64(2):259-265.
Central pressure augmentation is associated with greater backward wave amplitude and shorter transit time and is higher in women for reasons only partially elucidated. Augmentation also is affected by left ventricular function and shapes of the forward and backward waves. The goal of this study was to examine the relative contributions of forward and backward wave morphology to central pressure augmentation in men and women. From noninvasive measurements of central pressure and flow in 7437 participants (4036 women) from 19 to 90 years of age (mean age 51 years), we calculated several variables: augmentation index, backward wave arrival time, reflection factor, forward wave amplitude, forward wave peak width and slope of the backward wave upstroke. Linear regression models for augmentation index, adjusted for height and heart rate, demonstrated non-linear relations with age (age: βx00302; =4.6±0.1%, P<0.001; age2: βx00302;=−4.2±0.1%, P<0.001) and higher augmentation in women (βx00302; =4.5±0.4%, P<0.001, model R2=0.35). Addition of reflection factor and backward wave arrival time improved model fit (R2=0.62) and reduced the age coefficients: age (βx00302; =2.3±0.1%, P<0.001) and age2 (βx00302; =−2.2±0.1%, P<0.001). Addition of width of forward wave peak, slope of backward wave upstroke and forward wave amplitude further improved model fit (R2=0.75) and attenuated the sex coefficient (βx00302;=1.9±0.2%, P<0.001). Thus, shape and amplitude of the forward wave may be important correlates of augmentation index, and part of the sex-difference in augmentation index may be explained by forward and backward wave morphology.
PMCID: PMC4184952  PMID: 24866142
augmentation index; wave reflection; pulse pressure; aortic stiffness; left ventricular contraction
2.  Givinostat inhibition of hepatic stellate cell proliferation and protein acetylation 
AIM: To explore the effect of the histone deacetylase inhibitor givinostat on proteins related to regulation of hepatic stellate cell proliferation.
METHODS: The cell counting kit-8 assay and flow cytometry were used to observe changes in proliferation, apoptosis, and cell cycle in hepatic stellate cells treated with givinostat. Western blot was used to observe expression changes in p21, p57, CDK4, CDK6, cyclinD1, caspase-3, and caspase-9 in hepatic stellate cells exposed to givinostat. The scratch assay was used to analyze the effect of givinostat on cell migration. Effects of givinostat on the reactive oxygen species profile, mitochondrial membrane potential, and mitochondrial permeability transition pore opening in JS-1 cells were observed by laser confocal microscopy.
RESULTS: Givinostat significantly inhibited JS-1 cell proliferation and promoted cell apoptosis, leading to cell cycle arrest in G0/G1 phases. Treatment with givinostat downregulated protein expression of CDK4, CDK6, and cyclin D1, whereas expression of p21 and p57 was significantly increased. The givinostat-induced apoptosis of hepatic stellate cells was mainly mediated through p38 and extracellular signal-regulated kinase 1/2. Givinostat treatment increased intracellular reactive oxygen species production, decreased mitochondrial membrane potential, and promoted mitochondrial permeability transition pore opening. Acetylation of superoxide dismutase (acetyl K68) and nuclear factor-κB p65 (acetyl K310) was upregulated, while there was no change in protein expression. Moreover, the notable beneficial effect of givinostat on liver fibrosis was also confirmed in the mouse models.
CONCLUSION: Givinostat has antifibrotic activities via regulating the acetylation of nuclear factor-κB and superoxide dismutase 2, thus inhibiting hepatic stellate cell proliferation and inducing apoptosis.
PMCID: PMC4507102  PMID: 26217084
Givinostat; Hepatic stellate cells; Histone deacetylase inhibitor; Nuclear factor-κB; Superoxide dismutase
3.  Draft Genome Sequence of the Rice Kernel Smut Tilletia horrida Strain QB-1 
Genome Announcements  2015;3(3):e00621-15.
Tilletia horrida is the most destructive fungal pathogen of rice (Oryza sativa L.). The 20,105,270-bp draft genome sequence of T. horrida strain QB-1 is reported here. Genes encoding proteins associated with key virulence factors were predicted, and this can provide information for understanding the pathogenic mechanisms in T. horrida.
PMCID: PMC4481280  PMID: 26112782
5.  Chronic NF-κB blockade improves renal angiotensin II type 1 receptor functions and reduces blood pressure in Zucker diabetic rats 
Both angiotensin II type 1 receptor (AT1R) and nuclear factor-kappa B (NF-κB) play significant roles in the pathogenesis of hypertension and type 2 diabetes. However, the role of NF-κB in perpetuating renal AT1 receptors dysfunction remains unclear. The aim of the present study to determine whether blockade of NF-κB, could reverse the exaggerated renal AT1R function, reduce inflammatory state and oxidative stress, lower blood pressure in Zucker diabetic fatty (ZDF) rats.
Pyrrolidine dithiocarbamate (PDTC), a NF-κB inhibitor (150 mg/kg in drinking water)or vehicle was administered orally to 12-weeks-old ZDF rats and their respective control lean Zucker (LZ) rats for 4 weeks. Blood pressure was measured weekly by tail-cuff method. AT1R functions were determined by measuring diuretic and natriuretic responses to AT1R antagonist (candesartan; 10 μg/kg/min iv). The mRNA and protein levels of NF-κB, oxidative stress maker and AT1R were determined using quantitative real-time PCR and Western blotting, respectively. The NF-κB-DNA binding activity in renal cortex was measured by Electrophoretic mobility shift assay (EMSA).
As compared with LZ rats, ZDF rats had higher blood pressure, impaired natriuresis and diuresis, accompanied with higher levels of oxidative stress and inflammation. Furthermore, AT1R expression was higher in renal cortex from ZDF rats; candesartan induced natriresis and diuresis, which was augmented in ZDF rats. Treatment with PDTC lowered blood pressure and improved diuretic and natriuretic effects in ZDF rats; meanwhile, the increased oxidative stress and inflammation were reduced; the increased AT1R expression and augmented candesartan-mediated natriuresis and diuresis were recoverd in ZDF rats. Our further study investigated the mechanisms of PDTC on AT1R receptor expression. It resulted that PDTC inhibited NF-κB translocation from cytosol to nucleus, inhibited binding of NF-κB with AT1R promoter, therefore, reduced AT1R expression and function.
Our present study indicates blockade of NF-κB, via inhibition of binding of NF-κB with AT1R promoter, reduces renal AT1R expression and function, improves oxidative stress and inflammatory/anti-inflammatory balance, therefore, lowers blood pressure and recovers renal function in ZDF rats.
Electronic supplementary material
The online version of this article (doi:10.1186/s12933-015-0239-7) contains supplementary material, which is available to authorized users.
PMCID: PMC4465496  PMID: 26055622
Angiotensin II type 1 receptor; Inflammatory; Oxidative stress; Nuclear factor-kappa B; Hypertension
6.  Functions of Kinesin Superfamily Proteins in Neuroreceptor Trafficking 
BioMed Research International  2015;2015:639301.
Synaptic plasticity is widely regarded as the cellular basis of learning and memory. Understanding the molecular mechanism of synaptic plasticity has been one of center pieces of neuroscience research for more than three decades. It has been well known that the trafficking of α-amino-3-hydroxy-5-methylisoxazoloe-4-propionic acid- (AMPA-) type, N-methyl-D-aspartate- (NMDA-) type glutamate receptors to and from synapses is a key molecular event underlying many forms of synaptic plasticity. Kainate receptors are another type of glutamate receptors playing important roles in synaptic transmission. In addition, GABA receptors also play important roles in modulating the synaptic plasticity. Kinesin superfamily proteins (also known as KIFs) transport various cargos in both anterograde and retrograde directions through the interaction with different adaptor proteins. Recent studies indicate that KIFs regulate the trafficking of NMDA receptors, AMPA receptors, kainate receptors, and GABA receptors and thus play important roles in neuronal activity. Here we review the essential functions of KIFs in the trafficking of neuroreceptor and synaptic plasticity.
PMCID: PMC4449888  PMID: 26075252
7.  Assessment of Reproducibility – Automated and Digital Caliper ECG Measurement in the Framingham Heart Study 
Journal of electrocardiology  2014;47(3):288-293.
Digitized electrocardiography permits the rapid, automated quantification of electrocardiograms (ECGs) for analysis. Community- and population-based studies have increasingly integrated such data. Assessing the reproducibility of automated ECG measures with manual measures is a critical step in preparation for using automated measures for research purposes. We recently established an ECG repository of digitally recorded ECGs for the Framingham Heart Study and we sought to assess the reproducibility of automated and manual measures.
We selected 185 digitally recorded ECGs from routine visits of Framingham Heart Study participants spanning from 1986 to 2012. We selected the following ECG measures for their relevance to clinical and epidemiologic research: P wave duration, P wave amplitude, and PR interval in lead II; QRS duration and R wave amplitude in lead V6; and QT interval in lead V5. We obtained automated values for each waveform, and used a digital caliper for manual measurements. Digital caliper measurements were repeated in a subset (n=81) of the samples for intrarater assessment.
We calculated the intraclass correlation coefficient (ICC) values for the interrater and intrarater assessments. P wave duration had the lowest interrater ICC (r=0.46) and lowest intrarater ICC (r=0.57). R wave amplitude had the highest interrater and intrarater ICC (r=0.98) indicating excellent reproducibility. The remaining measures had interrater and intrarater ICCs of r≥0.81.
The interrater reproducibility findings for P wave amplitude, PR interval, QT interval, QRS duration, and R wave amplitude were excellent. In contrast, the reproducibility of P wave duration was more modest. These findings indicate high reproducibility of most automated and manual ECG measurements.
PMCID: PMC4010803  PMID: 24792985
Electrocardiogram; reproducibility; P waves; QRS complex; QT interval
8.  Traditional Chinese Medicine Xuebijing Treatment Is Associated with Decreased Mortality Risk of Patients with Moderate Paraquat Poisoning 
PLoS ONE  2015;10(4):e0123504.
Paraquat poisoning causes multiple organ injury and high mortality due to severe toxicity and lack of effective treatment. Xuebijing (XBJ) injection, a traditional Chinese medicine preparation of five Chinese herbs (Radix Salviae Miltiorrhiae, Rhizoma Chuanxiong, Flos Carthami, Angelica Sinensis and Radix Paeoniae Rubra), has an anti-inflammatory effect and is widely used in the treatment of sepsis. This retrospective study was designed to evaluate the effects of XBJ combined with conventional therapy on mortality risk of patients with acute paraquat poisoning. Out of 68 patients, 27 were treated with conventional therapy (control group) and 41 were treated with intravenous administration of XBJ (100 ml, twice a day, up to 7 days) plus conventional therapy (XBJ group). Vital organ function, survival time within 28 days and adverse events during the treatment were reviewed. Results indicated that XBJ treatment significantly increased median survival time among patients ingesting 10-30 ml of paraquat (P=0.02) compared with the control group. After adjustment for covariates, XBJ treatment was associated significantly with a lower mortality risk (adjusted HR 0.242, 95% CI 0.113 to 0.516, P=0.001) compared with the control group. Additionally, compared with Day 1, on Day 3 the value of PaO2/FiO2 was significantly decreased, and the values of serum alanine aminotransferase, creatinine and troponin T were significantly increased in the control group (all P<0.05), but these values were significant improved in the XBJ group (all P<0.05). Only one patient had skin rash with itch within 30 minutes after injection and no severe adverse events were found in the XBJ group. In conclusion, XBJ treatment is associated with decreased mortality risk of patients with moderate paraquat poisoning, which may be attributed to improved function of vital organs with no severe adverse events.
PMCID: PMC4414552  PMID: 25923333
9.  Analyzing the gene expression profile of anaplastic histology Wilms’ tumor with real-time polymerase chain reaction arrays 
Wilms’ tumor (WT) is one of the most common malignant neoplasms of the urinary tract in children. Anaplastic histology (unfavorable histology) accounts for about 10% of whole WTs, and it is the single most important histologic predictor of treatment response and survival in patients with WT; however, until now the molecular basis of this phenotype is not very clearly.
A real-time polymerase chain reaction (PCR) array was designed and tested. Next, the gene expression profile of pediatric anaplastic histology WT and normal adjacent tissues were analyzed. These expression data were anlyzed with Multi Experiment View (MEV) cluster software further. Datasets representing genes with altered expression profiles derived from cluster analyses were imported into the Ingenuity Pathway Analysis Tool (IPA).
88 real-time PCR primer pairs for quantitative gene expression analysis of key genes involved in pediatric anaplastic histology WT were designed and tested. The gene expression profile of pediatric anaplastic histology WT is significantly different from adjacent normal controls; we identified 15 genes that are up-regulated and 16 genes that are down-regulated in the former. To investigate biological interactions of these differently regulated genes, datasets representing genes with altered expression profiles were imported into the IPA for further analysis, which revealed three significant networks: Cancer, Hematological Disease, and Gene Expression, which included 27 focus molecules and a significance score of 43. The IPA analysis also grouped the differentially expressed genes into biological mechanisms related to Cell Death and Survival 1.15E−12, Cellular Development 2.84E−11, Cellular Growth and Proliferation 2.84E-11, Gene Expression 4.43E−10, and DNA Replication, Recombination, and Repair 1.39E−07. The important upstream regulators of pediatric anaplastic histology WT were TP53 and TGFβ1 signaling (P = 1.15E−14 and 3.79E−13, respectively).
Our study demonstrates that the gene expression profile of pediatric anaplastic histology WT is significantly different from adjacent normal tissues with real-time PCR array. We identified some genes that are dysregulated in pediatric anaplastic histology WT for the first time, such as HDAC7, and IPA analysis showed the most important pathways for pediatric anaplastic histology WT are TP53 and TGFβ1 signaling. This work may provide new clues into the molecular mechanisms behind pediatric anaplastic histology WT.
Electronic supplementary material
The online version of this article (doi:10.1186/s12935-015-0197-x) contains supplementary material, which is available to authorized users.
PMCID: PMC4486424  PMID: 26136641
Pediatric anaplastic histology Wilms’ tumor; Real-time PCR array; Ingenuity pathway analysis; HDAC7; TP53; TGFβ1
10.  Association of Sex Hormones, Aging and Atrial Fibrillation in Men: The Framingham Heart Study 
Endogenous sex hormones have been related to cardiovascular outcomes and mortality. We hypothesized that sex hormones are related to atrial fibrillation (AF) in a community-based cohort of middle-aged to older men.
Methods and Results
We examined testosterone, estradiol, and dehydroepiandrosterone sulfate [DHEA-S]) in relation to incident AF in men participating in the Framingham Heart Study. We assessed the 10-year risk of AF in multivariable-adjusted hazard models. The cohort consisted of 1251 men (age 68.0±8.2), of whom 275 developed incident AF. We identified a significant interaction between age and testosterone, and therefore stratified men into age 55–69 (n=786), 70–79 (n=351), and ≥80 (n=114). In men 55–69 each 1-standard deviation (SD) decrease in testosterone was associated with hazard ratio (HR) 1.30 (95% confidence interval [CI], 1.07 to 1.59) for incident AF. The association between testosterone and 10-year incident AF in men 70–79 did not reach statistical significance. In men ≥80 years a 1-SD decrease in testosterone was associated with HR 3.53 (95% CI, 1.96 to 6.37) for AF risk. Estradiol was associated with incident AF (HR, 1.12; 95% CI, 1.01 to 1.26). DHEA-S had a borderline association with risk of AF that was not statistically significant (HR, 1.12; 95% CI, 0.99 to 1.28).
Testosterone and estradiol are associated with incident AF in a cohort of older men. Testosterone deficiency in men ≥80 is strongly associated with AF risk. The clinical and electrophysiologic mechanisms underlying the associations between sex hormones and AF in older men merit continued investigation.
PMCID: PMC4035016  PMID: 24610804
atrial fibrillation; sex hormones; men; aging; epidemiology
11.  Meta-analysis of the associations between TNF-α or IL-6 gene polymorphisms and susceptibility to lung cancer 
Several studies have indicated an association between tumor necrosis factor-alpha (TNF-α) or interleukin (IL)-6 gene polymorphisms and lung cancer risk. However, the conclusions remain controversial.
An English literature screening about case-control trials with regard to TNF-α (-308G/A) or IL-6 (174G/C) polymorphisms and lung cancer susceptibility was performed on PubMed, EMBASE, and EBSCO until November 2012. The pooled odds ratio (OR) and 95% confidence intervals (CI) were calculated using STATA 11.0. Sensitivity analysis was performed by sequential omission of individual studies. Publication bias was evaluated by Egger’s linear regression test and funnel plots.
Eight eligible studies, including 1,690 patients and 1,974 controls, were identified in this meta-analysis. Compared with the control, no significant association was revealed between TNF-α-308G/A (GG + GC vs. CC: OR = 1.10, 95% CI: 0.73 to 1.64; GG vs. GC + CC: OR = 1.02, 95% CI: 0.81 to 1.27; GC vs. CC: OR = 1.13, 95% CI: 0.73 to 1.77; GG vs. CC: OR = 1.04, 95% CI: 0.80 to 1.36; G vs. C: OR = 1.03, 95% CI: 0.90 to 1.18) or IL-6 174G/C (GG + GC vs. CC: OR = 1.10, 95% CI: 0.73 to 1.64; GG vs. GC + CC: OR = 1.02, 95% CI: 0.81 to 1.27; GC vs. CC: OR = 1.13, 95% CI: 0.73 to 1.77; GG vs. CC: OR = 1.04, 95% CI: 0.80 to 1.36; G vs. C: OR = 1.03, 95% CI: 0.90 to 1.18) and lung cancer risk. The pooled OR remained unchanged after removing the maximum-weight study and no publication bias was observed.
The study raises the possibility of no correlation between the polymorphisms of the two genes and lung cancer susceptibility. However, further researches with large-sample or subgroup analyses are necessary to validate the conclusions.
PMCID: PMC4438440  PMID: 25889486
Lung cancer; Tumor necrosis factor-alpha; Interleukin 6; Gene polymorphisms; Meta-analysis
12.  The impact of hemoglobin level and transfusion on the outcomes of chemotherapy in gastric cancer patients 
Objective: To examine the impact of hemoglobin levels in predicting outcomes and evaluate whether transfusion could improve the outcomes of chemotherapy on gastric cancer patients. Methods: A total 310 patients were divided into two groups: high Hb group (Hb >90 g/L) and low Hb group (Hb <90 g/L). A portion of patients in low Hb group received transfusion. The effect of hemoglobin level on the chemotherapy outcomes was determined according to the comparison between patients with high hemoglobin and patients with low hemoglobin without transfusion. The effect of transfusion on the chemotherapy outcomes was evaluated by comparing the two low groups (with and without transfusion). Results: A total of 310 patients were within the study criteria. Among them, 27.7% patients in high Hb group, 44.5% patients in low Hb without transfusion and 27.7% patients in low Hb with transfusion were followed up. The 5-years survival rates of high Hb group, low Hb group without transfusion and with transfusion were respectively 29%, 10% and 8%. The survival rate of patients in Hb group without transfusion was higher. The chemotherapy rates of patients in high Hb group, low Hb without transfusion group and with transfusion group were respectively 32.56%, 42.03% and 18.6%. Conclusion: Low nadir Hb (<90 g/L) during chemotherapy had an effect on the survival and chemotherapy response rate. The chemotherapy outcomes could not be improved through increasing Hb level by red blood cell (RBC) transfusion.
PMCID: PMC4443168  PMID: 26064334
Hemoglobin level; transfusion; chemotherapy; gastric cancer
13.  Optimizing stem cell functions and antibacterial properties of TiO2 nanotubes incorporated with ZnO nanoparticles: experiments and modeling 
To optimize mesenchymal stem cell differentiation and antibacterial properties of titanium (Ti), nano-sized zinc oxide (ZnO) particles with tunable concentrations were incorporated into TiO2 nanotubes (TNTs) using a facile hydrothermal strategy. It is revealed here for the first time that the TNTs incorporated with ZnO nanoparticles exhibited better biocompatibility compared with pure Ti samples (controls) and that the amount of ZnO (tailored by the concentration of Zn(NO3)2 in the precursor) introduced into TNTs played a crucial role on their osteogenic properties. Not only was the alkaline phosphatase activity improved to about 13.8 U/g protein, but the osterix, collagen-I, and osteocalcin gene expressions was improved from mesenchymal stem cells compared to controls. To further explore the mechanism of TNTs decorated with ZnO on cell functions, a response surface mathematical model was used to optimize the concentration of ZnO incorporation into the Ti nanotubes for stem cell differentiation and antibacterial properties for the first time. Both experimental and modeling results confirmed (R2 values of 0.8873–0.9138 and 0.9596–0.9941, respectively) that Ti incorporated with appropriate concentrations (with an initial concentration of Zn(NO3)2 at 0.015 M) of ZnO can provide exceptional osteogenic properties for stem cell differentiation in bone cells with strong antibacterial effects, properties important for improving dental and orthopedic implant efficacy.
PMCID: PMC4364596  PMID: 25792833
titanium nanotubes; ZnO nanoparticles; mesenchymal stem cells; antibacterial effect; modeling
14.  Calorie restriction inhibits ovarian follicle development and follicle loss through activating SIRT1 signaling in mice 
Silent information regulator 2 related enzyme 1 (SIRT1) is one of the key factors in the mechanism of calorie restriction (CR) extending lifespan of animals. The aim of the study is to investigate if CR prolongs ovarian lifespan in mice through activating SIRT1 signaling.
In the present study, 21 female C57BL/6 mice were divided into three groups: the control (n = 7), CR (n = 7), and SRT1720 (n = 7) groups. After the 26-week treatment, the number of ovarian follicles at each stage was counted, and Western blot was performed.
The number of surviving follicles in ovaries of the SRT1720 group was less than that of the CR group but more than that of the normal control (NC) group. The number of atretic follicles in the ovaries of the SRT1720 group was similar to that of the CR group but less than that of the NC group. The number of primordial follicles in the ovaries of the SRT1720 group was less than that of the CR group but more than that of the NC group. The numbers of primary follicles, secondary follicles, antral follicles, and corpora lutea in the SRT1720 group were similar to those in the CR group. Western blot analysis showed that the expression of SIRT1, SIRT6, FOXO3a, and NRF1 proteins was upregulated, and p53 was downregulated in both the CR group and the SRT1720 group compared to the control group.
Our results indicate that CR inhibits the activation of primordial follicles and development of follicles at different stages, thus preserving the reserve of follicle pool (at least partly) through activating SIRT1 signaling.
PMCID: PMC4367909  PMID: 25889584
Calorie restriction; Ovarian development; SIRT1 signaling; SIRT1 activator; Mice
15.  Effect of preemptive analgesia with intravenous oxycodone in the patients undergoing laparoscopic resection of ovarian tumor 
To evaluate the efficacy of preemptive intravenous oxycodone in the patients undergoing laparoscopic resection of ovarian tumor.
Sixty ASA I or II patients undergoing elective laparoscopic resection of ovarian tumor were randomly allocated to one of two groups: Group O (n=30) received intravenous oxycodone (0.1 mg·kg-1) 10 minutes before surgery over 2 minutes, and Group N (n=30) received an equivalent volume of normal saline. All patients received a standardized general anesthesia. MBP and HR at the time of arrival of the operating room (T1), 5 min before pneumoperitoneum (T2), 5 minutes (T3), 10 minutes (T4), and 15 minutes after pneumoperitoneum (T5), and VAS scores at postoperative 2, 4, 8, 12 and 24 hour were recorded. The tramadol consumption and side effects in 24 h after surgery were recorded.
VAS pain scores at 2, 4, 8 and 12 hour after operation were significantly lower in Group O (P<0.05). MBP and HR increased significantly due to pneumoperitoneum at T3, T4 and T5, compared with T1 and T2 within Group N, and were higher at T3, T4 and T5 in Group N than at the same time points in Group O. Tramadol consumption was statistically lower in Group O (P=0.0003).
Preemptive intravenous oxycodone was an efficient and safe method to reduce intraoperative haemodynamic effect and postoperative pain.
PMCID: PMC4476330  PMID: 26101479
Oxycodone; Preemptive analgesia; Laparoscopy; Pneumoperitoneum; Postoperative pain
16.  Association between Family History Risk Categories and Prevalence of Diabetes in Chinese Population 
PLoS ONE  2015;10(2):e0117044.
To investigate the association between different family history risk categories and prevalence of diabetes in the Chinese population.
The family history of diabetes was obtained from each subject, and an oral glucose tolerance test was performed for measuring the fasting and postload glucose and insulin levels based on a national representative cross-sectional survey of 46,239 individuals (age ≥ 20 years) in the 2007–2008 China National Diabetes and Metabolism Disorders Study. The family history risk categories of diabetes were high, moderate, and average (FH2 and FH1: at least two generations and one generation of first-degree relatives with diabetes, respectively; FH0: no first-degree relatives with diabetes).
The age- and gender-adjusted prevalence rates of diabetes were 32.7% (95% confidence interval (CI): 26.4–39.7%) in FH2, 20.1% (95% CI: 18.2–22.1%) in FH1, and 8.4% (95% CI: 7.9–8.9%) in FH0 (P < 0.0001). The calculated homeostatic model assessment-estimated insulin resistance (HOMA-IR), Matsuda insulin sensitivity index (ISI), and insulinogenic index (ΔI30/ΔG30) values showed significant trending changes among the three risk categories, with the most negative effects in FH2. Multivariate logistic regression analysis showed that the odds ratios of having diabetes were 6.16 (95% CI: 4.46–8.50) and 2.86 (95% CI: 2.41–3.39) times higher in FH2 and FH1, respectively, than in FH0 after adjustment for classical risk factors for diabetes.
Family history risk categories of diabetes have a significant, independent, and graded association with the prevalence of this disease in the Chinese population.
PMCID: PMC4321835  PMID: 25664814
17.  Early B-cell factor 3 (EBF3) is a novel tumor suppressor gene with promoter hypermethylation in pediatric acute myeloid leukemia 
Pediatric acute myeloid leukemia (AML) comprises up to 20% of all childhood leukemia. Recent research shows that aberrant DNA methylation patterning may play a role in leukemogenesis. The epigenetic silencing of the EBF3 locus is very frequent in glioblastoma. However, the expression profiles and molecular function of EBF3 in pediatric AML is still unclear.
Twelve human acute leukemia cell lines, 105 pediatric AML samples and 30 normal bone marrow/idiopathic thrombocytopenic purpura (NBM/ITP) control samples were analyzed. Transcriptional level of EBF3 was evaluated by semi-quantitative and real-time PCR. EBF3 methylation status was determined by methylation specific PCR (MSP) and bisulfite genomic sequencing (BGS). The molecular mechanism of EBF3 was investigated by apoptosis assays and PCR array analysis.
EBF3 promoter was hypermethylated in 10/12 leukemia cell lines. Aberrant EBF3 methylation was observed in 42.9% (45/105) of the pediatric AML samples using MSP analysis, and the BGS results confirmed promoter methylation. EBF3 expression was decreased in the AML samples compared with control. Methylated samples revealed similar survival outcomes by Kaplan-Meier survival analysis. EBF3 overexpression significantly inhibited cell proliferation and increased apoptosis. Real-time PCR array analysis revealed 93 dysregulated genes possibly implicated in the apoptosis of EBF3-induced AML cells.
In this study, we firstly identified epigenetic inactivation of EBF3 in both AML cell lines and pediatric AML samples for the first time. Our findings also showed for the first time that transcriptional overexpression of EBF3 could inhibit proliferation and induce apoptosis in AML cells. We identified 93 dysregulated apoptosis-related genes in EBF3-overexpressing, including DCC, AIFM2 and DAPK1. Most of these genes have never been related with EBF3 over expression. These results may provide new insights into the molecular mechanism of EBF3-induced apoptosis; however, further research will be required to determine the underlying details.
Our findings suggest that EBF3 may act as a putative tumor suppressor gene in pediatric AML.
PMCID: PMC4311429  PMID: 25609158
Early B-cell factor 3; Pediatric acute myeloid leukemia; Methylation; Tumor suppressor; Real-time PCR array
18.  Relation of Hypothyroidism and Incident Atrial Fibrillation (from the Framingham Heart Study) 
American heart journal  2013;167(1):10.1016/j.ahj.2013.10.012.
Hyperthyroidism has a well-described association with atrial fibrillation (AF). However, the relation of hypothyroidism to AF has had limited investigation. Hypothyroidism is associated with cardiovascular risk factors, subclinical cardiovascular disease and overt cardiovascular disease, all of which predispose to AF. We investigated 10-year incidence of AF in a community-dwelling cohort.
Among 6,653 Framingham heart Study participants, 5,069 participants, 52% woman, mean age 57±12, were eligible after excluding those with missing thyroid stimulating hormone (TSH), TSH <0.45 μU/L (hyperthyroid), TSH >19.9 μU/L or prevalent AF. TSH was categorized by range (≥0.45 to <4.5, 4.5 to <10.0, 10.0 to ≤19.9 μU/L) and by quartiles. We examined the associations between TSH and 10-year risk of AF using multivariable-adjusted Cox proportional hazards analysis.
Over 10-year follow-up, we observed 277 cases of incident AF. A 1-standard deviation (SD) increase in TSH was not associated with increased risk of AF (hazard ratio 1.01, 95% confidence interval 0.90 to 1.14, p=0.83). In categorical analysis, employing TSH ≥0.45 to <4.5 μU/L as the referent (equivalent to euthyroid state), we found no significant association between hypothyroidism and 10-year AF risk. Comparing the highest (2.6
In conclusion, we did not identify a significant association between hypothyroidism and 10-year risk of incident AF in a community-based study.
PMCID: PMC3868014  PMID: 24332151
Atrial fibrillation; hypothyroidism; risk factors; cohort study
Polo-like kinase 1 (PLK1) is highly expressed in many cancers and therefore a biomarker of transformation and potential target for the development of cancer-specific small molecule drugs. RO3280 was recently identified as a novel PLK1 inhibitor; however its therapeutic effects in leukemia treatment are still unknown. We found that the PLK1 protein was highly expressed in leukemia cell lines as well as 73.3% (11/15) of pediatric acute myeloid leukemia (AML) samples. PLK1 mRNA expression was significantly higher in AML samples compared with control samples (82.95 ± 110.28 vs. 6.36 ± 6.35; p < 0.001). Kaplan-Meier survival analysis revealed that shorter survival time correlated with high tumor PLK1 expression (p = 0.002). The 50% inhibitory concentration (IC50) of RO3280 for acute leukemia cells was between 74 and 797 nM. The IC50 of RO3280 in primary acute lymphocytic leukemia (ALL) and AML cells was between 35.49 and 110.76 nM and 52.80 and 147.50 nM, respectively. RO3280 induced apoptosis and cell cycle disorder in leukemia cells. RO3280 treatment regulated several apoptosis-associated genes. The regulation of DCC, CDKN1A, BTK, and SOCS2 was verified by western blot. These results provide insights into the potential use of RO3280 for AML therapy; however, the underlying mechanisms remain to be determined.
PMCID: PMC4307303  PMID: 25574601
RO3280; pediatric acute myeloid leukemia (AML); polo-like kinase 1 (PLK1); apoptosis; oncogene target
Saudi Medical Journal  2015;36(4):437-441.
To evaluate the efficacy of preemptive intravenous oxycodone on low-dose bupivacaine spinal anesthesia with intrathecal sufentanil in patients undergoing transurethral resection of the prostate (TURP).
In this randomized, double-blinded, placebo-controlled trial, 60 patients undergoing TURP were allocated into 2 groups: oxycodone group (group O, n=30) and a normal saline group (group N, n=30). Oxycodone 0.1 mg/kg, or normal saline 0.1 ml/kg was administered intravenously 10 minutes before surgical procedures in group O, or in group N. All patients received sufentanil 5 µg + bupivacaine 0.5% (0.8 ml) + normal saline 0.7 ml - in total, bupivacaine 0.25% (1.6 ml) intrathecally. Spinal block characteristics, hemodynamic values, the perioperative analgesic requirements, visual analogue scale (VAS) scores, Ramsay sedation scale, and side effects were assessed. The study was carried out at the First Hospital of Jilin University, Jilin, China between March and September 2014.
The time to 2-segment regression of sensory block, full recovery of sensory block, and first analgesic request was longer in group O. Fewer patients required postoperative analgesics, and the VAS pain scores at 4, 8, 16, and 24 hour after operation were significantly lower in group O.
Preemptive intravenous oxycodone was an efficient and safe method to decrease postoperative pain and reduce tramadol analgesia in patients under low-dose dilute bupivacaine spinal anesthesia combined with intrathecal sufentanil.
PMCID: PMC4404477  PMID: 25828280
Scientific Reports  2014;4:7167.
Wnt4 gene plays a role in developmental processes in mammals. However, little is known regarding its function in teleosts. We cloned and characterized the full-length half-smooth tongue sole (Cynoglossus semilaevis) wnt4a gene (CS-wnt4a). CS-wnt4a cDNA was 1746 bp in length encoding 353aa. CS-wnt4a expression level was highest in the testis, and gradually increased in the developing gonads until 1 year of age. In situ hybridization revealed that CS-wnt4a expression level was highest in stage II oocytes and sperm in the adult ovary and testis, respectively. CS-wnt4a expression level was significantly up-regulated in the gonads after exposure to high temperature. The level of methylation of the CS-wnt4a first exon was negatively correlated with the expression of CS-wnt4a. The branch-site model suggested that vertebrate wnt4a differed significantly from that of wnt4b, and that the selective pressures differed between ancestral aquatic and terrestrial organisms. Two positively selected sites were found in the ancestral lineages of teleost fish, but none in the ancestral lineages of mammals. One positively selected site was located on the α-helices of the 3D structure, the other on the random coil. Our results are of value for further study of the function of wnt4 and the mechanism of selection.
PMCID: PMC4241513  PMID: 25418599
Papillary thyroid cancer (PTC) is the most common epithelial thyroid tumor, accounting for more than 80% of all thyroid cancers. Although PTC shows an indolent character and excellent prognosis, patients with aggressive characteristics are more likely to have a disease recurrence and die in the end. The aim of this study was to analyze BRAFV600E mutation and methylation levels of CpG sites in the promoters of CDH1, DAPK, RARβ and RUNX3 genes in a cohort of PTCs, and investigate their association with tumor recurrence. In this study, we used pyrosequencing method to individually quantified methylation levels at multiple CpG sites within each gene promoter, and detect BRAFV600E mutation in 120 PTCs and 23 goiter tissues as normal control. Moreover, appropriate cut-off values for each CpG site were set up to predict disease recurrence. Our data showed that overall average methylation levels of CDH1 and RUNX3 genes were significantly higher in PTCs than that in control subjects. Conversely, overall average methylation levels of DAPK promoter were significantly lower in PTCs than that in control subjects. Moreover, BRAFV600E mutation and overall average methylation levels of all these genes were not significant difference between recurrent and non-recurrent cases. However, we found that hypermethylation of RUNX3 at CpG sites -1397, -1406, -1415 and -1417 significantly increased the risk of of disease recurrence by using appropriate site-specific cut-off values. Collectively, our findings suggest RUNX3 site-specific hypermethylation may offer value in predicting or monitoring postoperative recurrence of PTC patients.
PMCID: PMC4266707  PMID: 25520863
Papillary thyroid cancer (PTC); tumor recurrence; RUNX3; promoter hypermethylation; pyrosequencing
PLoS ONE  2014;9(11):e112626.
Antibiotic-resistant bacteria and genes are recognized as new environmental pollutants that warrant special concern. There were few reports on veterinary antibiotic-resistant bacteria and genes in China. This work systematically analyzed the prevalence and distribution of sulfonamide resistance genes in soils from the environments around poultry and livestock farms in Jiangsu Province, Southeastern China. The results showed that the animal manure application made the spread and abundance of antibiotic resistance genes (ARGs) increasingly in the soil. The frequency of sulfonamide resistance genes was sul1 > sul2 > sul3 in pig-manured soil DNA and sul2 > sul1 > sul3 in chicken-manured soil DNA. Further analysis suggested that the frequency distribution of the sul genes in the genomic DNA and plasmids of the SR isolates from manured soil was sul2 > sul1 > sul3 overall (p<0.05). The combination of sul1 and sul2 was the most frequent, and the co-existence of sul1 and sul3 was not found either in the genomic DNA or plasmids. The sample type, animal type and sampling time can influence the prevalence and distribution pattern of sulfonamide resistance genes. The present study also indicated that Bacillus, Pseudomonas and Shigella were the most prevalent sul-positive genera in the soil, suggesting a potential human health risk. The above results could be important in the evaluation of antibiotic-resistant bacteria and genes from manure as sources of agricultural soil pollution; the results also demonstrate the necessity and urgency of the regulation and supervision of veterinary antibiotics in China.
PMCID: PMC4236111  PMID: 25405870
PLoS ONE  2014;9(11):e111737.
A monoclonal antibody (McAb) against non-structural protein (NSP) 3B of foot-mouth-disease virus (FMDV) (3B4B1) was generated and shown to recognize a conserved epitope spanning amino acids 24–32 of 3B (GPYAGPMER) by peptide screening ELISA. This epitope was further shown to be a unique and predominant B cell epitope in 3B2, as sera from animals infected with different serotypes of FMDV blocked the ability of McAb 3B4B1 to bind to NSP 2C3AB. Also, a polyclonal antibody against NSP 2C was produced in a rabbit vaccinated with 2C epitope regions expressed in E. coli. Using McAb 3B4B1 and the 2C polyclonal antibody, a solid-phase blocking ELISA (SPB-ELISA) was developed for the detection of antibodies against NSP 2C3AB to distinguish FMDV-infected from vaccinated animals (DIVA test). The parameters for this SPB-ELISA were established by screening panels of sera of different origins. Serum samples with a percent inhibition (PI) greater than or equal to 46% were considered to be from infected animals, and a PI lower than 46% was considered to indicate a non-infected animal. This test showed a similar performance as the commercially available PrioCHECK NS ELISA. This is the first description of the conserved and predominant GPYAGPMER epitope of 3B and also the first report of a DIVA test for FMDV NSP 3B based on a McAb against this epitope.
PMCID: PMC4219772  PMID: 25369323

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