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Articles by W Wang
Total Records ( 25 ) for W Wang
  H Chen , W Wang , C Song , S Yu and C. Ding
 

Currently available vaccines against Mycobacterium bovis, the causative agent of tuberculosis, do not provide reliable efficacy and there is therefore a need for a novel vaccine with improved efficacy. Here, we use protein transduction technology to deliver DNA vaccines expressing mycobacterial antigens directly to target cells. We used various protein transduction domain (PTD) proteins including the VP22 conjugate from Marek's disease virus serotype 1 (MDV-1), as delivery systems for DNA constructs encoding the antigens early secretory antigenic target-6 kDa (ESAT-6) protein and culture filtrate protein 10 (CFP-10) of M. bovis. The eukaryotic expression plasmid pZ106, encoding antigens ESAT-6 and CFP-10, conjugated to various PTDs, was used to construct experimental preparations. Our findings demonstrated that VP22 alone or in combination with CFP-10:ESAT-6 fusion protein could spread into all the nuclei of the cell monolayer surrounding the transfected cells. Whereas trans-activating transcriptional PTD showed limited delivery of the fusion protein and 8R peptide was unable to deliver the fusion protein into any untransfected cells. We have demonstrated that immunization with a preparation fused to VP22 leads to a higher antibody and interferon- titer (P < 0.05). Taken together, our results demonstrated that MDV-1 VP22 serves as a potential immune enhancer in gene therapy and immunization using DNA vaccines, offering a novel approach for the prevention of M. bovis infection.

  M Saberi , D Bjelica , S Schenk , T Imamura , G Bandyopadhyay , P Li , V Jadhar , C Vargeese , W Wang , K Bowman , Y Zhang , B Polisky and J. M. Olefsky
 

The transcription factor TORC2 [transducer of regulated cAMP-responsive element-binding protein (CREB) activity 2] is a major regulator of hepatic gluconeogenesis and is increased in hyperglycemic rodent models. Because chronic hyperglycemia and increased hepatic glucose production, via increased gluconeogenesis, is a key feature of type 2 diabetes, an effective in vivo method to efficiently knock down TORC2 could provide a potential therapy for treating hyperglycemia and type 2 diabetes. To assess this, primary mouse hepatocytes, high-fat diet (HFD)-fed mice, and Zucker diabetic fatty (ZDF) rats were treated with a siRNA against TORC2 (siTORC2), which was delivered via a novel lipid nanoparticle system, or control siRNA (siCON). Compared with siCON, administration of siTORC2 resulted in highly efficient, sustained (1–3 wk) knockdown of TORC2 and its gluconeogenic target genes phosphoenolpyruvate carboxykinase and glucose-6-phophatase in primary mouse hepatocytes and in the livers of HFD-fed mice. In mice, this knockdown was specific to the liver and did not occur in kidney, skeletal muscle, or adipose tissue. In HFD-fed mice, siTORC2 reduced in vivo gluconeogenic capacity, fasting hepatic glucose production, and hyperglycemia, and led to improved hepatic and skeletal muscle insulin sensitivity. siTORC2 treatment also improved systemic hyperglycemia in ZDF rats. In conclusion, these results demonstrate the importance of TORC2 in modulating HGP in vivo and highlight a novel, liver-specific siRNA approach for the potential treatment of hyperglycemia and type 2 diabetes.

  Z Tian , T Ye , X Zhang , E Liu , W Wang , P Wang , G Liu , X Yang , G Hu and Z. Yu
 

Objective  To investigate the association between sleep duration and risk of hyperglycemia among preschool Chinese children.

Design  A population-based cross-sectional study.

Setting  Seventy-one randomly selected kindergartens in Tianjin, China.

Participants  Six hundred nineteen obese (body mass index z score ≥1.65) and 617 nonobese (body mass index z score <1.65) children aged 3 to 6 years were recruited and matched by age.

Main Exposure  Sleep duration.

Main Outcome Measures  Hyperglycemia, defined as a fasting glucose level of 100 mg/dL or higher.

Results  Obese children were more likely to have shorter sleep duration (≤8 hours) compared with their nonobese counterparts (P < .001). Compared with those who slept for 9 or 10 hours per night, those who slept for 8 hours or less had a significantly higher likelihood of having hyperglycemia, controlling for age and sex (odds ratio [OR], 1.65; 95% confidence interval [CI], 1.12-2.45). After further adjustment for other potential confounders, the association still remained statistically significant (OR, 1.64; 95% CI, 1.09-2.46). In the stratified multivariable analyses, those who were obese and slept for 8 hours or less had an increased risk of having hyperglycemia (OR, 2.12; 95% CI, 1.06-4.21) compared with those who were nonobese and slept for 9 hours or more.

Conclusions  Shorter sleep duration is associated with an increased risk of having hyperglycemia among preschool Chinese children. Whether adequate sleep may help maintain euglycemia among children, especially for those who are overweight or obese, warrants further investigation.

  S. S Wu , W Wang and M. C. K. Yang
 

In the first stage of a two-stage, drop-the-losers design, a candidate for the best treatment is selected. At the second stage, additional observations are collected to decide whether the candidate is actually better than the control. The design also allows the investigator to stop the trial for ethical reasons at the end of the first stage if there is already strong evidence of futility or superiority. Two types of tests have recently been developed, one based on the combined means and the other based on the combined p-values, but corresponding interval estimators are unavailable except in special cases. The problem is that, in most cases, the interval estimators depend on the mean configuration of all treatments in the first stage, which is unknown. In this paper, we prove a basic stochastic ordering lemma that enables us to bridge the gap between hypothesis testing and interval estimation. The proposed confidence intervals achieve the nominal confidence level in certain special cases. Simulations show that decisions based on our intervals are usually more powerful than those based on existing methods.

  W Wang and S. Srivastava
 

Although the potential of biomarkers to aid in the early detection, diagnosis, prevention, and treatment of breast cancer is broadly recognized and numerous biomarker candidates have been reported in the literature, few molecular markers have been adopted into clinical use to date. To address this lack of translation of biomarkers from the bench to clinical practice, the Cancer Biomarkers Research Group in the Division of Cancer Prevention of the National Cancer Institute organized a meeting, "Strategic Discussion on Biomarkers for Breast Cancer," which was held at the Fred Hutchinson Cancer Research Center on September 14, 2008. Participants included industry leaders, basic and physician scientists, and National Cancer Institute program staff. The objectives of this strategic discussion were to define clinical uses and needed performance characteristics of biomarkers; to identify novel approaches to discover and validate breast cancer biomarkers, particularly those with improved chances of being clinically useful; and to identify candidate DNA methylation markers that could be taken forward for validation. Participants presented and recommended methylation biomarkers suitable for initiating collaborative projects to evaluate the markers for future clinical application. This commentary summarizes their discussions and recommendations and the rationale for initiating specific projects to validate DNA methylation biomarkers of breast cancer. Cancer Prev Res; 3(1); 16–24

  F Ji , W Wang , Z. L Xia , Y. J Zheng , Y. L Qiu , F Wu , W. B Miao , R. F Jin , J Qian , L Jin , Y. L Zhu and D. C. Christiani
 

Vinyl chloride (VC) was classified as a group 1 carcinogen by IARC in 1987. Although the relationship between VC exposure and liver cancer has been established, the mechanism of VC-related carcinogenesis remains largely unknown. Previous epidemiological studies have shown that VC exposure is associated with increased genotoxicity in humans. To explore chromosomal damage and its progression, and their association to genetic susceptibility, we investigated 402 workers exposed to VC, a 77 VC-exposed cohort and 141 unexposed subjects. We measured the frequencies of cytokinesis-block micronucleus (CBMN) to reflect chromosomal damage and conducted genotyping for six xenobiotic metabolisms and five DNA repair genes' polymorphism. Data indicate that 95% of the control workers had CBMN frequencies ≤3, whereas VC-exposed workers had the 3.73-fold increase compared with the controls. Among the cohort workers who were followed from 2004 to 2007, the mean CBMN frequency was higher in 2007 than in 2004 with ratio of 2.08. Multiple Poisson regression analysis showed that mean CBMN frequencies were significantly elevated for the intermediate and high exposure groups than the low. Exposed workers with CYP2E1 or XRCC1 variance showed a higher CBMN frequency than their wild-type homozygous counterparts, so did workers with GSTP1 or ALDH2 genotype. This study provides evidence that cumulative exposure dose of VC and common genetic variants in genes relevant to detoxification of carcinogens are the major factors that modulate CBMN induction in VC-exposed workers.

  R. L. M Lett , W Wang and T. P. O`Connor
 

Neuronal connectivity is generated by the precise guidance of neuronal growth cones in response to the spatiotemporal distribution of molecular guidance cues in the developing embryo. Here we show that the class 5 semaphorin, Semaphorin 5B, is expressed in regions of the cortex and subcortex flanking the projection of and avoided by descending cortical axons, suggesting a role as a repulsive guidance cue in the formation of the internal capsule. Axons from cortical explants cultured in vitro with Semaphorin 5B-expressing cells exhibited characteristic avoidance behaviors. In organotypic slices, ectopic Semaphorin 5B expression along the presumptive internal capsule was sufficient to cause cortical axons to avoid their normal trajectory, resulting in either stalling at the boundary of Semaphorin 5B or turning into inappropriate areas of the cortex. In contrast, thalamocortical axons were not inhibited either in vitro or in slice culture by ectopic Semaphorin 5B. To further examine the function of Semaphorin 5B in situ, we knocked down its expression in the ventricular zone (VZ) at the corticostriatal angle. We found that labeled cortical fibers aberrantly navigated into the VZ where Semaphorin 5B expression was reduced. We propose that Semaphorin 5B functions to prevent corticofugal axons from abnormally projecting into germinal regions as they project to their subcortical targets.

  Z Lu , Y. P Jiang , W Wang , X. H Xu , R. T Mathias , E Entcheva , L. M Ballou , I. S Cohen and R. Z. Lin
 

Background— Phosphoinositide 3-kinase (PI3K) p110 plays a key role in insulin action and tumorigenesis. Myocyte contraction is initiated by an inward Ca2+ current (ICa,L) through the voltage-dependent L-type Ca2+ channel (LTCC). The aim of this study was to evaluate whether p110 also controls cardiac contractility by regulating the LTCC.

Methods and Results— Genetic ablation of p110 (also known as Pik3ca), but not p110β (also known as Pik3cb), in cardiac myocytes of adult mice reduced ICa,L and blocked insulin signaling in the heart. p110-null myocytes had a reduced number of LTCCs on the cell surface and a contractile defect that decreased cardiac function in vivo. Similarly, pharmacological inhibition of p110 decreased ICa,L and contractility in canine myocytes. Inhibition of p110β did not reduce ICa,L.

Conclusions— PI3K p110 but not p110β regulates the LTCC in cardiac myocytes. Decreased signaling to p110 reduces the number of LTCCs on the cell surface and thus attenuates ICa,L and contractility.

  S Hu , Z Zheng , X Yuan , W Wang , Y Song , H Sun and J. Xu
 

Background— Despite its widespread use and short-term efficacy, substantial uncertainty remains about the long-term outcomes and cost-effectiveness of off-pump coronary artery bypass (OPCAB).

Methods and Results— A retrospective review of prospectively collected data was conducted of 6665 consecutive patients undergoing isolated coronary artery bypass graft (CABG) at our institution during 1999 to 2006. All patients were followed up until September 30, 2008. Short- and long-term outcomes were compared between OPCAB and conventional CABG. The 2 main long-term outcome measures were repeat revascularization and the composite outcome of major vascular events. Cost comparison at 2 years in a propensity-matched sample during follow-up was also a study interest. The overall mean baseline age was 60.3±8.6 years, and 17.0% were women. Compared with conventional CABG, patients who underwent OPCAB had lower rates of atrial fibrillation (P=0.003) and requirements for blood transfusion (P=0.03) and ventilation time >24 hours (P<0.001). After an average of 4.5 years of follow-up, the rates of repeat revascularization (adjusted hazard ratio, 1.40; 95% confidence interval, 1.03 to 1.89) and major vascular events (adjusted hazard ratio, 1.23; 95% confidence interval, 1.09 to 1.39) were significantly higher in the OPCAB than the conventional CABG group. At 2 years, OPCAB was associated with increased additional direct costs per patient compared with conventional CABG and had a similar survival rate.

Conclusions— Compared with conventional CABG, OPCAB is associated with small short-term gain but increased long-term risks of repeat revascularization and major vascular events, especially among high-risk patients. Moreover, OPCAB consumes more resources and is less cost-effective in the long run.

  S. J Matkovich , W Wang , Y Tu , W. H Eschenbacher , L. E Dorn , G Condorelli , A Diwan , J. M Nerbonne and G. W. Dorn
 

Rationale: MicroRNA (miR)-133a regulates cardiac and skeletal muscle differentiation and plays an important role in cardiac development. Because miR-133a levels decrease during reactive cardiac hypertrophy, some have considered that restoring miR-133a levels could suppress hypertrophic remodeling.

Objective: To prevent the "normal" downregulation of miR-133a induced by an acute hypertrophic stimulus in the adult heart.

Methods and Results: miR-133a is downregulated in transverse aortic constriction (TAC) and isoproterenol-induced hypertrophy, but not in 2 genetic hypertrophy models. Using MYH6 promoter-directed expression of a miR-133a genomic precursor, increased cardiomyocyte miR-133a had no effect on postnatal cardiac development assessed by measures of structure, function, and mRNA profile. However, increased miR-133a levels increased QT intervals in surface electrocardiographic recordings and action potential durations in isolated ventricular myocytes, with a decrease in the fast component of the transient outward K+ current, Ito,f, at baseline. Transgenic expression of miR-133a prevented TAC-associated miR-133a downregulation and improved myocardial fibrosis and diastolic function without affecting the extent of hypertrophy. Ito,f downregulation normally observed post-TAC was prevented in miR-133a transgenic mice, although action potential duration and QT intervals did not reflect this benefit. miR-133a transgenic hearts had no significant alterations of basal or post-TAC mRNA expression profiles, although decreased mRNA and protein levels were observed for the Ito,f auxiliary KChIP2 subunit, which is not a predicted target.

Conclusions: These results reveal striking differences between in vitro and in vivo phenotypes of miR expression, and further suggest that mRNA signatures do not reliably predict either direct miR targets or major miR effects.

  H Ding , Y Xu , X Wang , Q Wang , L Zhang , Y Tu , J Yan , W Wang , R Hui , C. Y Wang and D. W. Wang
 

Background— Recent studies on genome-wide association have identified common variants on chromosome 9p21 associated with coronary artery disease (CAD). Given that ischemic stroke and CAD share several aspects of etiology and pathogenesis, we investigated the association of variants on chromosome 9p21 with ischemic stroke and CAD in the Chinese Han population by capturing the majority of diversity in this locus using haplotype-tagging single-nucleotide polymorphisms.

Methods and Results— We performed a shared control-cases study using 15 tagging single-nucleotide polymorphisms and 2 previously reported susceptibility single-nucleotide polymorphisms spanning 58 kb of the chromosome of 9p21 in a set of 558 patients with ischemic stroke, 510 patients with CAD, and 557 unaffected participants (controls) in the Chinese Han population. The association analyses were performed at both SNP and haplotype levels. We further verified our findings in an independent cohort of 442 ischemic stroke cases and 502 control subjects. In the first study, rs2383206, rs1004638, and rs10757278 in block 3 were significantly associated with CAD but not with ischemic stroke independent of traditional cardiovascular risk factors in additive model (P=0.002 to 0.0001, q=0.026 to 0.004). Analysis from all blocks revealed that haplotype profiles of block 3 on 9p21 were significantly different between shared control and cases of CAD (P=1.3x10–10, q=1.2x10–9) and ischemic stroke (P=1.7x10–6, q=7.7x10–6). In the expanded second case-control study, block 3 on 9p21 remained associated with ischemic stroke (P=2.6x10–4, q=6.3x10–4).

Conclusions— Our results suggest for the first time that 9p21 is a shared susceptibility locus, strongly for CAD and weakly for ischemic stroke, in a Chinese Han population.

  F Zhou , M Lu , W Wang , Z. P Bian , J. R Zhang and J. J. Zhu
  BACKGROUND:

The emergence of microfluidic immunosensors has provided a promising tool for improving clinical diagnoses. We developed an electrochemical immunoassay for the simultaneous detection of cardiac troponin I (cTnI) and C-reactive protein (CRP), based on microfluidic chips.

METHODS:

The quantitative methodology was based on ELISA in poly(dimethylsiloxane)-gold nanoparticle composite microreactors. CdTe and ZnSe quantum dots were bioconjugated with antibodies for sandwich immunoassay. After the CdTe and ZnSe quantum dots were dissolved, Cd2+ and Zn2+ were detected by square-wave anodic stripping voltammetry to enable the quantification of the 2 biomarkers. The 2 biomarkers were measured in 20 human serum samples by using the proposed method and commercially available methods.

RESULTS:

This immunosensor allowed simultaneous detection of serum cTnI and CRP. The linear range of this assay was between 0.01 and 50 µg/L and 0.5 and 200 µg/L, with the detection limits of approximately 5 amol and approximately 307 amol in 30-µL samples corresponding to cTnI and CRP, respectively. Slopes close to 1 and the correlation coefficient over 0.99 were obtained for both analytes.

CONCLUSIONS:

This strategy demonstrates a proof of principle for the successful integration of microfluidics with electrochemistry that can potentially provide an alternative to protein detection in the clinical laboratory.

  E Lacson , W Wang , K Lester , N Ofsthun , J. M Lazarus and R. M. Hakim
 

Background and objectives: The objective of this study was to evaluate epidemiology and outcomes of a large in-center nocturnal hemodialysis (INHD) program.

Design, setting, participants, & measurements: This case-control study compared patients who were on thrice-weekly INHD from 56 Fresenius Medical Care, North America facilities with conventional hemodialysis patients from 244 facilities within the surrounding geographic area. All INHD cases and conventional hemodialysis control subjects who were active as of January 1, 2007, were followed until December 31, 2007, for evaluation of mortality and hospitalization.

Results: As of January 1, 2007, 655 patients had been on INHD for 51 ± 73 d. Patients were younger, there were more male and black patients, and vintage was longer, but they had less diabetes compared with 15,334 control subjects. Unadjusted hazard ratio was 0.59 for mortality and 0.76 for hospitalization. After adjustment for case mix and access type, only hospitalization remained significant. Fewer INHD patients were hospitalized (48 versus 59%) with a normalized rate of 9.6 versus 13.5 hospital days per patient-year. INHD patients had greater interdialytic weight gains but lower BP. At baseline, hemoglobin values were similar, whereas albumin and phosphorus values favored INHD. Mean equilibrated Kt/V was higher in INHD patients related to longer treatment time, despite lower blood and dialysate flow rates.

Conclusions: Patients who were on INHD exhibited excellent quality indicators, with better survival and lower hospitalization rates. The relative contributions of patient selection versus effect of therapy on outcomes remain to be elucidated in prospective clinical trials.

  E Lacson , W Wang , J. M Lazarus and R. M. Hakim
 

Background and objectives: Conversion from central venous catheters to a graft or a fistula is associated with lower mortality risk in long-term hemodialysis (HD) patients; however, a similar association with hospitalization risk remains to be elucidated.

Design, setting, participants, & measurements: We conducted a prospective observational study all maintenance in-center HD patients who were treated in Fresenius Medical Care, North America legacy facilities; were alive on January 1, 2007; and had baseline laboratory data from December 2006. Access conversion (particularly from a catheter to a fistula or a graft) during the 4-month period from January 1 through April 30, 2007, was linked using Cox models to hospitalization risk during the succeeding 1-year follow-up period (until April 30, 2008).

Results: The cohort (N = 79,545) on January 1, 2007 had 43% fistulas, 29% catheters, and 27% grafts. By April 30, 2007, 70,852 patients were still on HD, and among 19,792 catheters initially, only 10.3% (2045 patients) converted to either a graft or a fistula. With catheters as reference, patients who converted to grafts/fistulas had similar adjusted hazard ratios (0.69) as patients on fistulas (0.71), while patients with fistulas/grafts who converted to catheters did worse (1.22), all P < 0.0001.

Conclusions: Catheters remain associated with the greatest hospitalization risk. Conversion from a catheter to either graft or fistula had significantly lower hospitalization risk relative to keeping the catheter. Prospective studies are needed to determine whether programs that reduce catheters will decrease hospitalization risk in HD patients.

  H Xue , E Lacson , W Wang , G. C Curhan and S. M. Brunelli
 

Background and objectives: Arteriovenous fistulas (AVFs) are widely accepted as the preferred hemodialysis vascular access type. However, supporting data have failed to consider morbidity and mortality incurred during failed creation attempts and may therefore overstate potential advantages. This study compares survival, quality-adjusted survival, and costs among incident hemodialysis patients after attempted placement of AVFs or arteiovenous grafts (AVGs).

Design, setting, participants, & measurements: Analogous Markov models were created, one each for AVF and AVG. Patients entered consideration at the time of first access creation, contemporaneous with dialysis initiation. Subsequent outcomes were determined probabilistically; transition probabilities, utilities, and costs were gathered from published sources. To ensure comparability between AVFs and AVGs, the timing and likelihood of access maturation were measured in a contemporary cohort of incident hemodialysis patients.

Results: Mean (SD) overall survival was 39.2 (0.8) and 36.7 (1.0) months for AVFs and AVGs, respectively: difference (95% confidence interval [CI]) 2.6 (1.8, 3.3) months. Quality-adjusted survival was 36.1 (0.8) and 32.5 (0.9) quality-adjusted life months (QALMs) for AVFs and AVGs, respectively: difference (95% CI) 3.6 (2.8, 4.3) QALMs. The incremental cost-effectiveness ratio (95% CI) for AVFs relative to AVGs was $446 (–6023, 6994) per quality-adjusted life year saved.

Conclusions: AVFs are associated with greater overall and quality-adjusted survival than AVGs. Observed differences were much less pronounced than might be expected from existing literature, suggesting that prospective identification of patients at high risk for AVF maturational failure might enable improvements in health outcomes via individualization of access planning.

  S Wu , W Wang , X Kong , L. M Congdon , K Yokomori , M. W Kirschner and J. C. Rice
 

Although the PR-Set7/Set8/KMT5a histone H4 Lys 20 monomethyltransferase (H4K20me1) plays an essential role in mammalian cell cycle progression, especially during G2/M, it remained unknown how PR-Set7 itself was regulated. In this study, we discovered the mechanisms that govern the dynamic regulation of PR-Set7 during mitosis, and that perturbation of these pathways results in defective mitotic progression. First, we found that PR-Set7 is phosphorylated at Ser 29 (S29) specifically by the cyclin-dependent kinase 1 (cdk1)/cyclinB complex, primarily from prophase through early anaphase, subsequent to global accumulation of H4K20me1. While S29 phosphorylation did not affect PR-Set7 methyltransferase activity, this event resulted in the removal of PR-Set7 from mitotic chromosomes. S29 phosphorylation also functions to stabilize PR-Set7 by directly inhibiting its interaction with the anaphase-promoting complex (APC), an E3 ubiquitin ligase. The dephosphorylation of S29 during late mitosis by the Cdc14 phosphatases was required for APCcdh1-mediated ubiquitination of PR-Set7 and subsequent proteolysis. This event is important for proper mitotic progression, as constitutive phosphorylation of PR-Set7 resulted in a substantial delay between metaphase and anaphase. Collectively, we elucidated the molecular mechanisms that control PR-Set7 protein levels during mitosis, and demonstrated that its orchestrated regulation is important for normal mitotic progression.

  M Guo , H Feng , J Zhang , W Wang , Y Wang , Y Li , C Gao , H Chen , Y Feng and Z. G. He
 

Sequence-specific DNA-binding transcription factors have widespread biological significance in the regulation of gene expression. However, in lower prokaryotes and eukaryotic metazoans, it is usually difficult to find transcription regulatory factors that recognize specific target promoters. To address this, we have developed in this study a new bacterial one-hybrid reporter vector system that provides a convenient and rapid strategy to determine the specific interaction between target DNA sequences and their transcription factors. Using this system, we have successfully determined the DNA-binding specificity of the transcription regulator Rv3133c to a previously reported promoter region of the gene Rv2031 in Mycobacterium tuberculosis. In addition, we have tested more than 20 promoter regions of M. tuberculosis genes using this approach to determine if they interact with ~150 putative regulatory proteins. A variety of transcription factors are found to participate in the regulation of stress response and fatty acid metabolism, both of which comprise the core of in vivo-induced genes when M. tuberculosis invades macrophages. Interestingly, among the many new discovered potential transcription factors, the WhiB-like transcriptional factor WhiB3 was identified for the first time to bind with the promoter sequences of most in vivo-induced genes. Therefore, this study offers important data in the dissection of the transcription regulations in M. tuberculosis, and the strategy should be applicable in the study of DNA-binding factors in a wide range of biological organisms.

  R Shoemaker , J Deng , W Wang and K. Zhang
 

In diploid mammalian genomes, parental alleles can exhibit different methylation patterns (allele-specific DNA methylation, ASM), which have been documented in a small number of cases except for the imprinted regions and X chromosomes in females. We carried out a chromosome-wide survey of ASM across 16 human pluripotent and adult cell lines using Illumina bisulfite sequencing. We applied the principle of linkage disequilibrium (LD) analysis to characterize the correlation of methylation between adjacent CpG sites on single DNA molecules, and also investigated the correlation between CpG methylation and single nucleotide polymorphisms (SNPs). We observed ASM on 23%~37% heterozygous SNPs in any given cell line. ASM is often cell-type-specific. Furthermore, we found that a significant fraction (38%~88%) of ASM regions is dependent on the presence of heterozygous SNPs in CpG dinucleotides that disrupt their methylation potential. This study identified distinct types of ASM across many cell types and suggests a potential role for CpG-SNP in connecting genetic variation with the epigenome.

  M Pucic , S Pinto , M Novokmet , A Knezevic , O Gornik , O Polasek , K Vlahovicek , W Wang , P. M Rudd , A. F Wright , H Campbell , I Rudan and G. Lauc
 

After performing hydrophilic interaction and weak anion exchange high-performance liquid chromatography to analyze N-glycans in the plasma of 1991 people, we identified several individuals that differed significantly from the "normal" profile of N-glycans. By performing consensus scoring of pairwise distances between vectors containing measured glycan values, we formed six groups of individuals with specific glyco-phenotypes. Some aberrations from the normal plasma protein patterns were found to be associated with clinical conditions (such as renal problems in people with increased monosialylated biantennary glycans, A2G2S1), while other substantial changes in N-glycan structure, such as the near complete absence of neutral glycans or antennary fucosylated tri- and tetraantennary glycans, were not associated with any observed adverse health outcomes. These results demonstrate the existence of specific altered glyco-phenotypes in some individuals and indicate that in some cases they might represent risk factors for the development of specific diseases.

  W Wang , R Lau , D Yu , W Zhu , A Korman and J. Weber
 

Regulatory CD4+CD25Hi T cells (Treg) and programmed death-1 (PD-1) molecule have emerged as pivotal players in immune regulation. However, the underlying mechanisms by which they impact antigen-specific CD8+ immune responses in cancer patients and how they interact with each other under physiologic conditions remain unclear. Herein, we examined the relationship of PD-1 and its abrogation to the function of Treg in patients with melanoma using short-term in vitro assays to generate melanoma-specific T cells. We identified Treg in the circulation of vaccinated melanoma patients and detected PD-1 expression on vaccine-induced melanoma antigen-specific CTLs, as well as on and within Treg from patients’ peripheral blood. Programmed death ligand (PD-L) 1 expression was also detected on patients’ Treg. PD-1 blockade promoted the generation of melanoma antigen-specific CTLs and masked their inhibition by Treg. The mechanisms by which PD-1 blockade mediated immune enhancement included direct augmentation of melanoma antigen-specific CTL proliferation, heightening their resistance to inhibition by Treg and direct limitation of the inhibitory ability of Treg. PD-1 blockade reversed the increased expression of PD-1 and PD-L1 on melanoma antigen-specific CTL by Treg, rescued INF- and IL-2 or INF- and tumor necrosis factor- co-expression and expression of IL-7 receptor by melanoma antigen-specific CTL which were diminished by Treg. PD-1 blockade also resulted in down-regulation of intracellular FoxP3 expression by Treg. These data suggest that PD-1 is importantly implicated in the regulation of Treg function in melanoma patients.

  P Gao , K Liu , L Liu , Z Wang , Z Liao , Z Xu , W Wang , X Bai , E Wang and Y. Li
 

The higher-order harmonic resonances, including second and third harmonic modes, were induced by applying alternative current signals inside a high-resolution transmission electron microscope (HRTEM), which have been used to study the mechanical properties of individual cadmium sulphide (CdS) nanowires. Young's moduli (E) and mechanical quality factors (Q) of individual CdS nanowires with diameters in the range of 50–350 nm were measured with the assistance of the mechanical resonances. The results indicate that the smooth nanowires have larger E and Q in comparison with the rough nanowires, and for the rough nanowires, E and Q increase with increasing diameters. The morphology- and size-dependent mechanical properties of CdS nanowires are directly correlated with their structure, as imaged by in situ TEM.

  B Peng , L Cao , W Wang , L Xian , D Jiang , J Zhao , Z Zhang , X Wang and L. Yu
 

Matrix metalloproteinase (MMP) 1 and MMP3 are enzymes that degrade the extracellular matrix and have been implicated to play an important role in cancer development. Many studies have been carried out on the association between polymorphisms of MMP1 –1607 1G>2G and MMP3 –1171 5A>6A and cancer risk. However, results from these studies remain inconclusive. Here, we performed a meta-analysis of >38 000 subjects to better assess the purported associations. For MMP1, –1607 2G/2G genotype carriers were found to have an increased risk of colorectal cancer [2G/2G versus 2G/1G + 1G/1G, odds ratio (OR) = 1.48, 95% confidence interval (CI) (1.26–1.74), Pheterogeneity = 0.066, I2 = 49.3%], head and neck cancer [2G/2G versus 2G/1G + 1G/1G, OR = 1.61, 95% CI (1.26–2.07), Pheterogeneity = 0.002, I2 = 64.7%] and renal cancer [2G/2G versus 2G/1G + 1G/1G, OR = 1.82, 95% CI (1.38–2.39), Pheterogeneity = 0.589, I2 = 0.0%] risk. For MMP3, no association was found between –1171 5A>6A polymorphism and cancer risk in the overall group [6A versus 5A, OR = 1.00, 95% CI (0.95–1.05), Pheterogeneity = 0.124, I2 = 24.9%] and individual cancer subgroups, but stratified analysis by smoking status showed that this polymorphism had different effects on smokers and non-smokers under recessive genetic model. In summary, our study suggests that MMP1 –1607 2G may be associated with an increased cancer risk for certain types of cancers, MMP3 –1171 5A>6A may not be a major risk factor for cancer, but it may be modified by certain environmental factors. Future studies with larger sample sizes are warranted to further evaluate these associations in more detail.

  B Peng , L Cao , X Ma , W Wang , D Wang and L. Yu
 

Matrix metalloproteinase (MMP) 2, MMP7 and MMP9 are important members of the MMP family. Four polymorphisms in the promoter region of these MMPs, which are MMP2 –1306 C>T, MMP2 –735 C>T, MMP7 –181 A>G and MMP9 –1562 C>T, have been reported to be functional and may contribute to genetic susceptibility to cancers. However, the associations between these polymorphisms and cancer risk remain inconclusive due to conflicting results from different case–control studies. To better evaluate the role of these polymorphisms in cancer development, we conducted a meta-analysis that included 51 studies, with more than 40 000 subjects. The results showed that under dominant genetic model, MMP2 –1306 T was associated with lower susceptibility to lung cancer [odds ratio (OR) = 0.50, 95% confidence interval (CI) 0.43–0.59, Pheterogeneity = 0.147, I2 = 44.1%], head and neck cancer (OR = 0.53, 95% CI 0.41–0.69, Pheterogeneity = 0.974, I2 = 0.0%) and oesophageal cancer (OR = 0.67, 95% CI 0.55–0.80, Pheterogeneity = 0.593, I2 = 0.0%); MMP2-735T was associated with lower risk in lung cancer (OR = 0.65, 95%CI 0.53–0.79, Pheterogeneity = 0.42, I2 = 0.0%) and oesophageal cancer (OR = 0.84, 95% CI 0.70–0.99, Pheterogeneity = 0.206, I2 = 37.4%); MMP7 –181 AG and GG genotype carriers had an increased gastric cancer risk (OR = 1.90, 95% CI 1.43–2.51, Pheterogeneity = 0.992, I2 = 0.0%) and MMP9 –1562 C>T was not associated with cancer risk in the whole group analysis (OR = 0.99, 95% CI 0.91–1.08, Pheterogeneity = 0.419, I2 = 3.0%) and subgroup analyses. In all, our meta-analysis suggests that MMP2 –1306 C>T, MMP2 –735 C>T and MMP7 –181 A>G may play allele-specific roles in cancer development, while MMP9 –1562 C>T may not be a major risk factor for most cancer types. Large case–control studies should be performed to clarify the possible roles of these four polymorphisms in different kinds of cancer in more detail.

  N Chen , W Wang , Y Huang , P Shen , D Pei , H Yu , H Shi , Q Zhang , J Xu , Y Lv and Q. Fan
 

Background. The study was performed to investigate the prevalence, awareness and the risk factors of chronic kidney disease (CKD) in the community population in Shanghai, China.

Methods. A total of 2596 residents were randomly recruited from the community population in Shanghai, China. All were screened for albuminuria, haematuria, morning spot urine albumin-to-creatinine ratio and renal function. Serum creatinine, uric acid, cholesterol, triglyceride and haemoglobin were assessed. A simplified MDRD equation was used to estimate the glomerular filtration rate (eGFR). All studied subjects were screened by kidney ultrasound. Haematuria, if present in the morning spot urine dipstick test, was confirmed by microscopy. The associations among the demographic characteristics, health characteristics and indicators of kidney damage were examined.

Results. Two thousand five hundred and fifty-four residents (n = 2554), after giving informed consent and with complete data, were entered into this study. Albuminuria and haematuria were detected in 6.3% and 1.2% of all the studied subjects, respectively, whereas decreased kidney function was found in 5.8% of all studied subjects. Approximately 11.8% of subjects had at least one indicator of kidney damage. The rate of awareness of CKD was 8.2%. The logistic regression model showed that age, central obesity, hypertension, diabetes, anaemia, hyperuricaemia and nephrolithiasis each contributed to the development of CKD.

Conclusion. This is the first Shanghai community-based epidemiological study data on Chinese CKD patients. The prevalence of CKD in the community population in Shanghai is 11.8%, and the rate of awareness of CKD is 8.2%. All the factors including age, central obesity, hypertension, diabetes, anaemia, hyperuricaemia and nephrolithiasis are positively correlated with the development of CKD in our studied subjects.

 
 
 
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