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Articles by J Chen
Total Records ( 34 ) for J Chen
  M Jiao , Y. L Zhou , H. T Li , D. L Zhang , J Chen and Y. Liang

The unfolding and refolding of two multidomain oxidoreductases, bovine liver catalase and flavoprotein bovine milk xanthine oxidase (XO), have been analyzed by fluorescence spectroscopy, circular dichroism, and activity measurements. Two intermediates, a partially folded active dimer disassembled from the native tetramer and a partially folded inactivated monomer, are found to exist in the conformational changes of catalase induced by guanidine hydrochloride (GdnHCl). Similarly, two intermediates, an active, compacted intermediate bound by flavin adenine dinucleotide (FAD) partially and an inactive flexible intermediate with FAD completely dissociated, exist in the conformational changes of XO induced by GdnHCl. The activity regains completely and an enhancement in activity compared with the native catalase or native XO is observed by dilution of catalase or XO incubated with GdnHCl at concentrations not >0.5 or 1.8 M into the refolding buffer, but the yield of reactivation for catalase or XO is zero when the concentration of GdnHCl is >1.5 or 3.0 M. The addition of FAD provides a remarkable protection against the inactivation of XO by GdnHCl under mild denaturing conditions, and the conformational change of XO is irreversible after FAD has been removed in the presence of a strong denaturing agent. These findings provide impetus for exploring the influences of cofactors such as FAD on the structure–function relationship of xanthine oxidoreductases.

  H. T Li , M Jiao , J Chen and Y. Liang

The structural integrity of the ubiquitous enzyme copper, zinc superoxide dismutase (SOD1) depends critically on the correct coordination of zinc and copper. We investigate here the roles of the stoichiometric zinc and copper ions in modulating the oxidative refolding of reduced, denatured bovine erythrocyte SOD1 at physiological pH and room temperature. Fluorescence experiment results showed that the oxidative refolding of the demetalated SOD1 (apo-SOD1) is biphasic, and the addition of stoichiometric Zn2+ into the refolding buffer remarkably accelerates both the fast phase and the slow phase of the oxidative refolding, compared with without Zn2+. Aggregation of apo-SOD1 in the presence of stoichiometric Zn2+ is remarkably slower than that in the absence of Zn2+. In contrast, the effects of stoichiometric Cu2+ on both the rates of the oxidative refolding and the aggregation of apo-SOD1 are not remarkable. Experiments of resistance to proteinase K showed that apo-SOD1 forms a conformation with low-level proteinase K resistance during refolding and stoichiometric Cu2+ has no obvious effect on the resistance to proteinase K. In contrast, when the refolding buffer contains stoichiometric zinc, SOD1 forms a compact conformation with high-level proteinase K resistance during refolding. Our data here demonstrated that stoichiometric zinc plays an important role in the oxidative refolding of low micromolar bovine SOD1 by accelerating the oxidative refolding, suppressing the aggregation during refolding, and helping the protein to form a compact conformation with high protease resistance activity.

  P Zhang , J Chen and Y. Liang

There is considerable interest in the interactions of ruthenium (Ru)(II) complexes with DNA as well as the biological impact of the interactions. Here, by using isothermal titration calorimetry, viscosity measurement, and circular dichroism, we investigated the interactions of a new Ru(II) complex, [Ru(dmp)2PMIP]2+{dmp = 2,9-dimethyl-1,10-phenanthroline, PMIP = 2-(4-methylphenyl)imidazo[4,5-f]1,10-phenanthroline}, with calf thymus DNA (CT DNA). The Ru(II) polypyridyl complex and CT DNA formed a tight 1:1 complex with a binding constant of exceeding 106 M–1 and with a binding mode of intercalation. Cell viability experiments indicated that the Ru(II) complex showed significant dose-dependent cytotoxicity to human lung tumor cell line A549. Further flow cytometry experiments showed that the cytotoxic Ru(II) complex induced apoptosis of human lung cancer cell line A549. Our data demonstrated that the Ru(II) polypyridyl complex binds to DNA and thereby induces apoptosis in tumor cells, suggesting that anti-tumor activity of the Ru(II) complex could be related to its interaction with DNA.

  G Liu , M Ding , J Chen , J Huang , H Wang , Q Jing and B. Shen

Emerging evidence suggests that specific spatio-temporal microRNA (miRNA) expression is required for heart development. In recent years, hundreds of miRNAs have been discovered. In contrast, functional annotations are available only for a very small fraction of these regulatory molecules. In order to provide a global perspective for the biologists who study the relationship between differentially expressed miRNAs and heart development, we employed computational analysis to uncover the specific cellular processes and biological pathways targeted by miRNAs in mouse heart development. Here, we utilized Gene Ontology (GO) categories, KEGG Pathway, and GeneGo Pathway Maps as a gene functional annotation system for miRNA target enrichment analysis. The target genes of miRNAs were found to be enriched in functional categories and pathway maps in which miRNAs could play important roles during heart development. Meanwhile, we developed miRHrt (, a database aiming to provide a comprehensive resource of miRNA function in regulating heart development. These computational analysis results effectively illustrated the correlation of differentially expressed miRNAs with cellular functions and heart development. We hope that the identified novel heart development-associated pathways and the database presented here would facilitate further understanding of the roles and mechanisms of miRNAs in heart development.

  D Qi , K Cai , O Wang , Z Li , J Chen , B Deng , L Qian and Y. Le

Amylin is the major component of pancreatic amyloid, which is implicated in the development of type 2 diabetes. It is costored with insulin in the secretory granules of pancreatic β-cells and cosecreted with insulin following stimulation with glucose. Here, we investigate the effect of fatty acids (FAs) on amylin expression and secretion by β-cells and explore the underlying mechanisms. Palmitate and oleate dose-dependently induced amylin mRNA accumulation in murine pancreatic β-cell line MIN6 and primary pancreatic islets. the inductive effect of FAs on amylin expression is independent of glucose concentration. FAs upregulated amylin expression at the transcriptional level, and FAs must be metabolized to induce amylin expression. FAs also significantly induced human amylin promoter activation. Pretreatment of MIN6 cells with Ca2+ chelator (EGTA, BAPTA-AM) PKC inhibitor Gö-6976 or protein synthesis inhibitor cycloheximide significantly inhibited FA-induced amylin mRNA expression. Transcription factors cAMP-responsive element-binding protein, pancreatic and duodenal homeobox factor-1, and peroxisome proliferator-activated receptor were not involved in FA-induced amylin expression. Palmitate and oleate both increased amylin and insulin release from MIN6 cells and stimulated amylin expression but had no effect on insulin expression. Mice refed with Intralipid had significantly higher levels of plasma FFA, amylin, and insulin than those refed with saline. These data demonstrate that FAs differently regulate amylin and insulin expression and induce both amylin and insulin release. Ca2+ and PKC signaling pathways and de novo-synthesized protein(s) were involved in FA-induced amylin expression. Induction of amylin production and release by FA may contribute to its biological functions under physiological conditions.

  P Li , J Chen and P. Marriott

Even simple examples of finite mixture models can fail to fulfil the regularity conditions that are routinely assumed in standard parametric inference problems. Many methods have been investigated for testing for homogeneity in finite mixture models, for example, but all rely on regularity conditions including the finiteness of the Fisher information and the space of the mixing parameter being a compact subset of some Euclidean space. Very simple examples where such assumptions fail include mixtures of two geometric distributions and two exponential distributions, and, more generally, mixture models in scale distribution families. To overcome these difficulties, we propose and study an em-test statistic, which has a simple limiting distribution for examples in this paper. Simulations show that the em-test has accurate Type I errors and is more efficient than existing methods when they are applicable. A real example is included.

  X Pan , N Gong , J Zhao , Z Yu , F Gu , J Chen , X Sun , L Zhao , M Yu , Z Xu , W Dong , Y Qin , G Fei , C Zhong and T. L. Xu

Reduction of glucose metabolism in brain is one of the main features of Alzheimer’s disease. Thiamine (vitamin B1)-dependent processes are critical in glucose metabolism and have been found to be impaired in brains from patients with Alzheimer’s disease. However, thiamine treatment exerts little beneficial effect in these patients. Here, we tested the effect of benfotiamine, a thiamine derivative with better bioavailability than thiamine, on cognitive impairment and pathology alterations in a mouse model of Alzheimer’s disease, the amyloid precursor protein/presenilin-1 transgenic mouse. We show that after a chronic 8 week treatment, benfotiamine dose-dependently enhanced the spatial memory of amyloid precursor protein/presenilin-1 mice in the Morris water maze test. Furthermore, benfotiamine effectively reduced both amyloid plaque numbers and phosphorylated tau levels in cortical areas of the transgenic mice brains. Unexpectedly, these effects were not mimicked by another lipophilic thiamine derivative, fursultiamine, although both benfotiamine and fursultiamine were effective in increasing the levels of free thiamine in the brain. Most notably, benfotiamine, but not fursultiamine, significantly elevated the phosphorylation level of glycogen synthase kinase-3 and -3β, and reduced their enzymatic activities in the amyloid precursor protein/presenilin-1 transgenic brain. Therefore, in the animal Alzheimer’s disease model, benfotiamine appears to improve the cognitive function and reduce amyloid deposition via thiamine-independent mechanisms, which are likely to include the suppression of glycogen synthase kinase-3 activities. These results suggest that, unlike many other thiamine-related drugs, benfotiamine may be beneficial for clinical Alzheimer’s disease treatment.

  J Wang , J Chen , P Chang , A LeBlanc , D Li , J. L Abbruzzesse , M. L Frazier , A. M Killary and S. Sen

Development of minimally invasive biomarker assays for early detection and effective clinical management of pancreatic cancer is urgently needed to reduce high morbidity and mortality associated with this malignancy. We hypothesized that if aberrantly expressing microRNAs (miRNA) in pancreatic adenocarcinoma tissues are detected in blood plasma, then plasma profiling of these miRNAs might serve as a minimally invasive early detection biomarker assay for this malignancy. By using a modified protocol to isolate and quantify plasma miRNAs from heparin-treated blood, we show that miRNA profiling in plasma can differentiate pancreatic adenocarcinoma patients from healthy controls. We have profiled four miRNAs, miR-21, miR-210, miR-155, and miR-196a, all implicated in the development of pancreatic cancer with either proven or predicted target genes involved in critical cancer-associated cellular pathways. Of these, miR-155 has recently been identified as a candidate biomarker of early pancreatic neoplasia, whereas elevated expression of miR196a has been shown to parallel progression of disease. The results revealed a sensitivity of 64% and a specificity of 89% with the analyses of plasma levels for this panel of four miRNAs. The area under the receiver operating characteristic curve were estimated at 0.82 and 0.78 without and with leave-one-out cross-validation scheme, respectively. These observations, although a "proof of principle" finding at this time, show the feasibility of developing plasma miRNA profiling as a sensitive and specific blood-based biomarker assay for pancreatic cancer that has the potential of translation to the clinic with additional improvements in the future.

  G Jin , L Xu , Y Shu , T Tian , J Liang , Y Xu , F Wang , J Chen , J Dai , Z Hu and H. Shen

Chromosome 5p15.33, containing TERT and CLPTM1L genes, was recently identified as one of the susceptible regions for lung cancer in Caucasian populations. We hypothesized that single-nucleotide polymorphisms (SNPs) identified in this region in Caucasians are also important in the development of lung cancer in Chinese population. To test this hypothesis, we genotyped two most significant SNPs reported in Caucasians, rs2736100A/C and rs402710C/T at 5p15.33, in a case–control study with 1221 non-small cell lung cancer (NSCLC) cases and 1344 cancer-free controls in a Chinese population. We found that rs2736100C allele in TERT gene was associated with a significantly increased risk of NSCLC with adjusted odds ratios of 1.26 [95% confidence interval (CI) = 1.05–1.51] and 1.31 (95% CI = 1.04–1.66) for one or two copies of the variant C allele, respectively. This significant association was more prominent among female (P for heterogeneity: 0.044), non-smokers (P for heterogeneity: 0.054) and/or the subjects with adenocarcinoma (P for heterogeneity: 0.058). However, no significant association was found between rs402710C/T and NSCLC risk. These results suggest that genetic variants in 5p15.33, especially in TERT gene, may also predispose the susceptibility of lung cancer, especially adenocarcinoma, in Chinese population.

  S. K Park , G Andreotti , A Rashid , J Chen , P. S Rosenberg , K Yu , J Olsen , Y. T Gao , J Deng , L. C Sakoda , M Zhang , M. C Shen , B. S Wang , T. Q Han , B. H Zhang , M Yeager , S. J Chanock and A. W. Hsing

Biliary tract cancer encompasses tumors of the gallbladder, bile duct and ampulla of Vater. Gallbladder cancer is more common in women, whereas bile duct cancer is more common in men, suggesting that sex hormones may play a role in the etiology of these cancers. The intracellular action of estrogens is regulated by the estrogen receptor (ESR); thus, we examined the role of common genetic variants in ESR genes on the risk of biliary tract cancers and stones in a population-based case–control study in Shanghai, China (411 cancer cases, 895 stone cases and 786 controls). We genotyped six single-nucleotide polymorphisms (SNPs), four in ESR1 (rs2234693, rs3841686, rs2228480 and rs1801132) and two in ESR2 (rs1256049 and rs4986938). In all participants, the ESR1 rs1801132 (P325P) G allele was associated with excess risks of bile duct [odds ratio (OR) = 1.7, 95% confidence interval (CI) 1.1–2.8] and ampulla of Vater cancers (OR = 2.1, 95% CI 0.9–4.9) compared with the CC genotype. The association with bile duct cancer was apparent among men (OR = 2.8, 95% CI 1.4–5.7) but not among women (P-heterogeneity = 0.01). Also, the ESR2 rs4986938 (38 bp 3' of STP) GG genotype was associated with a higher risk of bile duct cancer (OR = 3.3, 95% CI 1.3–8.7) compared with the AA genotype, although this estimate was based on a small number of subjects. None of the other SNPs examined was associated with biliary tract cancers or stones. False discovery rate-adjusted P-values were not significant (P > 0.1). No association was found for ESR1 haplotype based on four SNPs. These preliminary results suggest that variants in ESR genes could play a role in the etiology of biliary tract cancers, especially bile duct cancer in men.

  X Hu , X Xu , G Zhu , D Atzler , M Kimoto , J Chen , E Schwedhelm , N Luneburg , R. H Boger , P Zhang and Y. Chen

Background— Asymmetrical methylarginines inhibit NO synthase activity and thereby decrease NO production. Dimethylarginine dimethylaminohydrolase 1 (DDAH1) degrades asymmetrical methylarginines. We previously demonstrated that in the heart DDAH1 is predominantly expressed in vascular endothelial cells. Because an earlier study showed that mice with global DDAH1 deficiency experienced embryonic lethality, we speculated that a mouse strain with selective vascular endothelial DDAH1 deficiency (endo-DDAH1–/–) would largely abolish tissue DDAH1 expression in many tissues but possibly avoid embryonic lethality.

Methods and Results— By using the LoxP/Cre approach, we generated the endo-DDAH1–/– mice. The endo-DDAH1–/– mice had no apparent defect in growth or development compared with wild-type littermates. DDAH1 expression was greatly reduced in kidney, lung, brain, and liver, indicating that in these organs DDAH1 is distributed mainly in vascular endothelial cells. The endo-DDAH1–/– mice showed a significant increase of asymmetric dimethylarginine concentration in plasma (1.41 µmol/L in the endo-DDAH1–/– versus 0.69 µmol/L in the control mice), kidney, lung, and liver, which was associated with significantly increased systolic blood pressure (132 mm Hg versus 113 mm Hg in wild-type). The endo-DDAH1–/– mice also exhibited significantly attenuated acetylcholine-induced NO production and vessel relaxation in isolated aortic rings.

Conclusions— Our study demonstrates that DDAH1 is highly expressed in vascular endothelium and that endothelial DDAH1 plays an important role in regulating blood pressure. In the context that asymmetric methylarginines are broadly produced by many type of cells, the strong DDAH1 expression in vascular endothelium demonstrates for the first time that vascular endothelium can be an important site to actively dispose of toxic biochemical molecules produced by other types of cells.

  T. H Lee , J Chen and J. M. Miano

Rationale: We previously identified a novel serine carboxypeptidase, SCPEP1, that undergoes cleavage across all tissues where it is expressed. SCPEP1 bears the signature catalytic triad found in all serine carboxypeptidases, but its biological function is completely unknown.

Objective: To begin elucidating the functions of SCPEP1 in vitro and in the vessel wall after injury.

Methods and Results: Cultured smooth muscle cells were transduced with adenovirus carrying wild-type Scpep1, a short hairpin RNA to Scpep1, or variants of Scpep1 with mutations that disrupt the catalytic triad domain or SCPEP1 cleavage. Western blotting of key growth regulators or growth and migratory responses were assessed following SCPEP1 gain- or loss-of-function in smooth muscle cells. Vascular injury-induced remodeling and cell proliferation were evaluated in wild-type or newly created Scpep1 knockout mice. Overexpression of wild-type or cleavage-defective SCPEP1, but not a catalytic triad mutant SCPEP1, promotes smooth muscle cell proliferation and migration in vitro. A short hairpin RNA to Scpep1 blunts endogenous growth, which is rescued on concurrent expression of Scpep1 carrying silent mutations that evade knockdown. SCPEP1 protein is highly expressed in the neointima of 2 models of vascular remodeling. Scpep1-null mice show decreases in medial and intimal cell proliferation as well as vessel remodeling following arterial injury.

Conclusions: SCPEP1 promotes smooth muscle cell proliferation and migration in a catalytic triad-dependent, cleavage-independent manner. SCPEP1 represents a new mediator of vascular remodeling and a potential therapeutic target for the treatment of vascular occlusive diseases.

  T Hattori , J Chen , A. M. S Harding , M. P Price , Y Lu , F. M Abboud and C. J. Benson

Rationale: Acid-sensing ion channels (ASICs) are Na+ channels that are activated by acidic pH. Their expression in cardiac afferents and remarkable sensitivity to small pH changes has made them leading candidates to sense cardiac ischemia.

Objective: Four genes encode six different ASIC subunits, however it is not yet clear which of the ASIC subunits contribute to the composition of ASICs in cardiac afferents.

Methods and Results: Here, we labeled cardiac afferents using a retrograde tracer dye in mice, which allowed for patch-clamp studies of murine cardiac afferents. We found that a higher percentage of cardiac sensory neurons from the dorsal root ganglia respond to acidic pH and generated larger currents compared to those from the nodose ganglia. The ASIC-like current properties of the cardiac dorsal root ganglia neurons from wild-type mice most closely matched the properties of ASIC2a/3 heteromeric channels. This was supported by studies in ASIC-null mice: acid-evoked currents from ASIC3–/– cardiac afferents matched the properties of ASIC2a channels, and currents from ASIC2–/– cardiac afferents matched the properties of ASIC3 channels.

Conclusions: We conclude that ASIC2a and -3 are the major ASIC subunits in cardiac dorsal root ganglia neurons and provide potential molecular targets to attenuate chest pain and deleterious reflexes associated with cardiac disease.

  A Stahl , P Sapieha , K. M Connor , J. P SanGiovanni , J Chen , C. M Aderman , K. L Willett , N. M Krah , R. J Dennison , M. R Seaward , K. I Guerin , J Hua and L. E. H. Smith

Omega3 long-chain polyunsaturated fatty acids (3-PUFAs) are powerful modulators of angiogenesis. However, little is known about the mechanisms governing 3-PUFA–dependent attenuation of angiogenesis.


This study aims to identify a major mechanism by which 3-PUFAs attenuate retinal neovascularization.

Methods and Results:

Administering 3-PUFAs exclusively during the neovascular stage of the mouse model of oxygen-induced retinopathy induces a direct neovascularization reduction of more than 40% without altering vasoobliteration or the regrowth of normal vessels. Cotreatment with an inhibitor of peroxisome proliferator-activated receptor (PPAR) almost completely abrogates this effect. Inhibition of PPAR also reverses the 3-PUFA–induced reduction of retinal tumor necrosis factor-, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, endothelial selectin, and angiopoietin 2 but not vascular endothelial growth factor.


These results identify a direct, PPAR-mediated effect of 3-PUFAs on retinal neovascularization formation and retinal angiogenic activation that is independent of vascular endothelial growth factor.

  J Le , D Zhang , S Menees , J Chen and G. Raghuveer

Background— Obesity and familial dyslipidemia in children are associated with accelerated atherosclerosis by pathological examination. We sought to determine whether these children had increased carotid artery intima-media thickness (CIMT), a measure of subclinical atherosclerosis similar to 45-year-old adults. Adult CIMT percentile tables were used for comparison because normative CIMT data for children are limited.

Methods and Results— Seventy children, ages 6 to 19 years, with obesity- and atherosclerosis-promoting risk factors such as dyslipidemia, hypertension, insulin resistance, and tobacco smoke exposure, or with familial dyslipidemia, underwent carotid artery ultrasound. Advanced "vascular age" (VA) was defined as having maximum CIMT that was ≥25th percentile for race- and sex-matched 45-year-old adults. Mean age was 13.0±3.3 years. Forty (57%) of 70 children had body mass index ≥95th percentile for age and sex. Maximum CIMT for obese children was 0.53±0.05 mm and for familial dyslipidemic children was 0.52±0.04 mm. Advanced VA was seen in 30 (75%) of obese children and 22 (73%) of familial dyslipidemic children. Thirty (75%) of obese children had >3 mutable atherosclerosis-promoting risk factors; these children had a nonsignificantly higher maximum CIMT compared with obese children with ≤3 risk factors (0.54±0.06 mm versus 0.52±0.03 mm, P=0.07). Obese children with high fasting triglyceride levels were more likely to have advanced VA.

Conclusions— VA is advanced and comparable in obese children with atherosclerosis-promoting risk factors and in children with familial dyslipidemia. Advanced VA is prevalent in obese children with high fasting triglyceride levels.

  H. M Krumholz , A. R Merrill , E. M Schone , G. C Schreiner , J Chen , E. H Bradley , Y Wang , Z Lin , B. M Straube , M. T Rapp , S. L. T Normand and E. E. Drye

Background— In 2009, the Centers for Medicare & Medicaid Services is publicly reporting hospital-level risk-standardized 30-day mortality and readmission rates after acute myocardial infarction (AMI) and heart failure (HF). We provide patterns of hospital performance, based on these measures.

Methods and Results— We calculated the 30-day mortality and readmission rates for all Medicare fee-for-service beneficiaries ages 65 years or older with a primary diagnosis of AMI or HF, discharged between July 2005 and June 2008. We compared weighted risk-standardized mortality and readmission rates across Hospital Referral Regions and hospital structural characteristics. The median 30-day mortality rate was 16.6% for AMI (range, 10.9% to 24.9%; 25th to 75th percentile, 15.8% to 17.4%; 10th to 90th percentile, 14.7% to 18.4%) and 11.1% for HF (range, 6.6% to 19.8%; 25th to 75th percentile, 10.3% to 12.0%; 10th to 90th percentile, 9.4% to 13.1%). The median 30-day readmission rate was 19.9% for AMI (range, 15.3% to 29.4%; 25th to 75th percentile, 19.5% to 20.4%; 10th to 90th percentile, 18.8% to 21.1%) and 24.4% for HF (range, 15.9% to 34.4%; 25th to 75th percentile, 23.4% to 25.6%; 10th to 90th percentile, 22.3% to 27.0%). We observed geographic differences in performance across the country. Although there were some differences in average performance by hospital characteristics, there were high and low hospital performers among all types of hospitals.

Conclusions— In a recent 3-year period, 30-day risk-standardized mortality rates for AMI and HF varied among hospitals and across the country. The readmission rates were particularly high.

  G. K Mulvey , Y Wang , Z Lin , O. J Wang , J Chen , P. S Keenan , E. E Drye , S. S Rathore , S. L. T Normand and H. M. Krumholz

Background— The rankings of "America’s Best Hospitals" by U.S. News & World Report are influential, but the performance of ranked hospitals in caring for patients with routine cardiac conditions such as heart failure is not known.

Methods and Results— Using hierarchical regression models based on medical administrative data from the period July 1, 2005, to June 30, 2006, we calculated risk-standardized mortality rates and risk-standardized readmission rates for ranked and nonranked hospitals in the treatment of heart failure. The mortality analysis examined 14 813 patients in 50 ranked hospitals and 409 806 patients in 4761 nonranked hospitals. The readmission analysis included 16 641 patients in 50 ranked hospitals and 458 473 patients in 4627 nonranked hospitals. Mean 30-day risk-standardized mortality rates were lower in ranked versus nonranked hospitals (10.1% versus 11.2%, P<0.01), whereas mean 30-day risk-standardized readmission rates were no different between ranked and nonranked hospitals (23.6% versus 23.8%, P=0.40). The 30-day risk-standardized mortality rates varied widely for both ranked and nonranked hospitals, ranging from 7.9% to 12.4% for ranked hospitals and from 7.1% to 17.5% for nonranked hospitals. The 30-day risk-standardized readmission rates also spanned a large range, from 18.7% to 29.3% for ranked hospitals and from 19.2% to 29.8% for nonranked hospitals.

Conclusions— Hospitals ranked by U.S. News & World Report as "America’s Best Hospitals" in "Heart & Heart Surgery" are more likely than nonranked hospitals to have a significantly lower than expected 30-day mortality rate, but there was much overlap in performance. For readmission, the rates were similar in ranked and nonranked hospitals.

  J. S Ross , J Chen , Z Lin , H Bueno , J. P Curtis , P. S Keenan , S. L. T Normand , G Schreiner , J. A Spertus , M. T Vidan , Y Wang and H. M. Krumholz

Background— In July 2009, Medicare began publicly reporting hospitals’ risk-standardized 30-day all-cause readmission rates (RSRRs) among fee-for-service beneficiaries discharged after hospitalization for heart failure from all the US acute care nonfederal hospitals. No recent national trends in RSRRs have been reported, and it is not known whether hospital-specific performance is improving or variation in performance is decreasing.

Methods and Results— We used 2004–2006 Medicare administrative data to identify all fee-for-service beneficiaries admitted to a US acute care hospital for heart failure and discharged alive. We estimated mean annual RSRRs, a National Quality Forum-endorsed metric for quality, using 2-level hierarchical models that accounted for age, sex, and multiple comorbidities; variation in quality was estimated by the SD of the RSRRs. There were 570 996 distinct hospitalizations for heart failure in which the patient was discharged alive in 4728 hospitals in 2004, 544 550 in 4694 hospitals in 2005, and 501 234 in 4674 hospitals in 2006. Unadjusted 30-day all-cause readmission rates were virtually identical over this period: 23.0% in 2004, 23.3% in 2005, and 22.9% in 2006. The mean and SD of RSRRs were also similar: mean (SD) of 23.7% (1.3) in 2004, 23.9% (1.4) in 2005, and 23.8% (1.4) in 2006, suggesting similar hospital variation throughout the study period.

Conclusions— National mean and RSRR distributions among Medicare beneficiaries discharged after hospitalization for heart failure have not changed in recent years, indicating that there was neither improvement in hospital readmission rates nor in hospital variations in rates over this time period.

  S. L Hummel , N. P Pauli , H. M Krumholz , Y Wang , J Chen , S. L. T Normand and B. K. Nallamothu

Background— Heart transplant centers are generally considered "centers of excellence" for heart failure care. However, their overall performance has not previously been evaluated in a broad population of elderly patients with heart failure, many of whom are not transplant candidates.

Methods and Results— We identified >1 million elderly Medicare beneficiaries who were hospitalized for heart failure between 2004 and 2006 at >4500 hospitals. We calculated 30-day risk-standardized mortality rates and standardized mortality ratios as well as 30-day risk-standardized readmission rates and standardized readmission ratios at heart transplant centers and non–heart transplant hospitals using risk-standardization models that the Centers for Medicare & Medicaid Services uses for public reporting. The 30-day risk-standardized mortality rates were lower at heart transplant centers than non–heart transplant hospitals nationally (10.6% versus 11.5%, P<0.001) but were similar at peer institutions offering coronary artery bypass grafting within the same geographical region (10.6% versus 10.6%, P=0.96). The mean standardized mortality ratio for heart transplant centers was 0.9 (SD, 0.1; range, 0.7 to 1.3). No differences were noted in 30-day risk-standardized readmission rates between heart transplant centers and non–heart transplant hospitals nationally (23.6% versus 23.8%, P=0.55). The mean standardized readmission ratio for heart transplant centers was 1.0 (SD, 0.1; range, 0.8 to 1.2).

Conclusions— In elderly Medicare patients with heart failure, heart transplant centers have lower 30-day risk-standardized mortality rates than non–heart transplant hospitals nationally; however, this difference is not present in comparison with peer institutions or for 30-day risk-standardized readmission rates.

  S Gabardi , S. S Waikar , S Martin , K Roberts , J Chen , L Borgi , H Sheashaa , C Dyer , S. K Malek , S. G Tullius , N Vadivel , M Grafals , R Abdi , N Najafian , E Milford and A. Chandraker

Background and objectives: Nearly 30% of renal transplant recipients develops BK viremia, a prerequisite for BK nephropathy. Case reports have evaluated treatment options for BK virus, but no controlled studies have assessed prophylactic therapies. Fluoroquinolone antibiotics were studied for prevention of BK viremia after renal transplantation.

Design, setting, participants, & measurements: This retrospective analysis evaluated adult renal transplant recipients with at least one BK viral load (blood) between 90 and 400 days after transplantation. Six to 12 months of co-trimoxazole was used for Pneumocystis prophylaxis. In sulfa-allergic/-intolerant patients, 6 to 12 months of atovaquone with 1 month of a fluoroquinolone was used. Fluoroquinolones can inhibit BK DNA topoisomerase. The two groups studied were those that received 30 days of levofloxacin or ciprofloxacin after transplantation and those that did not. The primary endpoint was BK viremia rates at 1 year. Of note, of the 160 patients not receiving fluoroquinolone prophylaxis, 40 received a fluoroquinolone for treatment of a bacterial infection within 3 months after transplantation. Subgroup analysis evaluating these 40 patients against the 120 who had no exposure to fluoroquinolones was completed.

Results: A 1-month fluoroquinolone course after transplantation was associated with significantly lower rates of BK viremia at 1 year compared with those with no fluoroquinolone. In the subgroup analysis, exposure to fluoroquinolone for treatment of bacterial infections within 3 months after transplantation was associated with significantly lower 1-year rates of BK viremia.

Conclusions: This analysis demonstrates that fluoroquinolones are effective at preventing BK viremia after renal transplantation.

  Y. Y Teo , X Sim , R. T.H Ong , A. K.S Tan , J Chen , E Tantoso , K. S Small , C. S Ku , E. J.D Lee , M Seielstad and K. S. Chia

The Singapore Genome Variation Project (SGVP) provides a publicly available resource of 1.6 million single nucleotide polymorphisms (SNPs) genotyped in 268 individuals from the Chinese, Malay, and Indian population groups in Southeast Asia. This online database catalogs information and summaries on genotype and phased haplotype data, including allele frequencies, assessment of linkage disequilibrium (LD), and recombination rates in a format similar to the International HapMap Project. Here, we introduce this resource and describe the analysis of human genomic variation upon agglomerating data from the HapMap and the Human Genome Diversity Project, providing useful insights into the population structure of the three major population groups in Asia. In addition, this resource also surveyed across the genome for variation in regional patterns of LD between the HapMap and SGVP populations, and for signatures of positive natural selection using two well-established metrics: iHS and XP-EHH. The raw and processed genetic data, together with all population genetic summaries, are publicly available for download and browsing through a web browser modeled with the Generic Genome Browser.

  H. H Liu , P Lu , Y Guo , E Farrell , X Zhang , M Zheng , B Bosano , Z Zhang , J Allard , G Liao , S Fu , J Chen , K Dolim , A Kuroda , J Usuka , J Cheng , W Tao , K Welch , Y Liu , J Pease , S. A de Keczer , M Masjedizadeh , J. S Hu , P Weller , T Garrow and G. Peltz

Acetaminophen-induced liver toxicity is the most frequent precipitating cause of acute liver failure and liver transplant, but contemporary medical practice has mainly focused on patient management after a liver injury has been induced. An integrative genetic, transcriptional, and two-dimensional NMR-based metabolomic analysis performed using multiple inbred mouse strains, along with knowledge-based filtering of these data, identified betaine-homocysteine methyltransferase 2 (Bhmt2) as a diet-dependent genetic factor that affected susceptibility to acetaminophen-induced liver toxicity in mice. Through an effect on methionine and glutathione biosynthesis, Bhmt2 could utilize its substrate (S-methylmethionine [SMM]) to confer protection against acetaminophen-induced injury in vivo. Since SMM is only synthesized in plants, Bhmt2 exerts its beneficial effect in a diet-dependent manner. Identification of Bhmt2 and the affected biosynthetic pathway demonstrates how a novel method of integrative genomic analysis in mice can provide a unique and clinically applicable approach to a major public health problem.

  L Zhang , J Chen , Y Wang , F Ren , W Yu and L. Cheng

Levonorgestrel (LNG), as a dedicated emergency contraception (EC) product, has been available over-the-counter in China for 10 years. Until now, only a small number of deliveries after LNG–EC failure have been documented.


This study was a prospective comparative cohort study. A group of 332 pregnant women who had used LNG–EC during the conception cycle was recruited, and matched to a group of 332 pregnant women without the exposure to LNG. Congenital malformations, perinatal complications and delivery circumstances were investigated in this study.


There were 31 pregnant women in the study group and 28 in the comparison group miscarried within 14 weeks of gestation. In the study and comparison groups, four malformations were found in each group. In the study group, both birthweight (3416 versus 3345 g, P = 0.040) and the sex ratio of birth (boys/girls, 1.14 versus 0.90, P = 0.153) were higher than in the comparison group. There were no statistically significant differences in the incidence of miscarriage or malformation or in the neonatal outcome between the two groups.


There was no association between the use of LNG–EC pills and the risk of major congenital malformations, pregnancy complications or any other adverse pregnancy outcomes in our study.

  K Wang , D Tang , M Wang , J Lu , H Yu , J Liu , B Qian , Z Gong , X Wang , J Chen , M Gu and Z. Cheng
  Kejian Wang, Ding Tang, Mo Wang, Jufei Lu, Hengxiu Yu, Jiafan Liu, Baoxiang Qian, Zhiyun Gong, Xin Wang, Jianmin Chen, Minghong Gu, and Zhukuan Cheng

MER3, a ZMM protein, is required for the formation of crossovers in Saccharomyces cerevisiae and Arabidopsis. Here, MER3, the first identified ZMM gene in a monocot, is characterized by map-based cloning in rice (Oryza sativa). The null mutation of MER3 results in complete sterility without any vegetative defects. Cytological analyses show that chiasma frequency is reduced dramatically in mer3 mutants and the remaining chiasmata distribute randomly among different pollen mother cells, implying possible coexistence of two kinds of crossover in rice. Immunocytological analyses reveal that MER3 only exists as foci in prophase I meiocytes. In addition, MER3 does not colocalize with PAIR2 at the beginning of prophase I, but locates on one end of PAIR2 fragments at later stages, whereas MER3 foci merely locate on one end of REC8 fragments when signals start to be seen in early prophase I. The normal loading of PAIR2 and REC8 in mer3...

  L Lei , Y Xiong , J Chen , J. B Yang , Y Wang , X. Y Yang , C. C. Y Chang , B. L Song , T. Y Chang and B. L. Li

High levels of the inflammatory cytokine tumor necrosis factor- (TNF-) are present in atherosclerotic lesions. TNF- regulates expression of multiple genes involved in various stages of atherosclerosis, and it exhibits proatherosclerotic and antiatherosclerotic properties. ACAT catalyzes the formation of cholesteryl esters (CE) in monocytes/macrophages, and it promotes the foam cell formation at the early stage of atherosclerosis. We hypothesize that TNF- may be involved in regulating the ACAT gene expression in monocytes/macrophages. In this article, we show that in cultured, differentiating human monocytes, TNF- enhances the expression of the ACAT1 but not ACAT2 gene, increases the cholesteryl ester accumulation, and promotes the lipid-laden cell formation. Several other proinflammatory cytokines tested do not affect the ACAT1 gene expression. The stimulation effect is consistent with a receptor-dependent process, and is blocked by using nuclear factor-kappa B (NF-kappa B) inhibitors. A functional and unique NF-kappa B element located within the human ACAT1 gene proximal promoter is required to mediate the action of TNF-. Our data demonstrate that TNF-, through the NF-kappa B pathway, specifically enhances the expression of human ACAT1 gene to promote the CE-laden cell formation from the differentiating monocytes, and our data support the hypothesis that TNF- is proatherosclerotic during early phase of lesion development.

  J Chen , E Schroth , E MacKinlay , I Fife , A Sorimachi and S. Tokonami

Naturally occurring isotopes of radon in indoor air are identified as the second leading cause of lung cancer after tobacco smoking. Winnipeg had the highest radon (222Rn) concentration among 18 Canadian cities surveyed in the past. There is great interest to know the current radon as well as thoron (220Rn) concentrations in Winnipeg homes. Therefore, radon–thoron discrimination detectors were deployed in 117 houses for a period of 3 months. The results confirmed that thoron is present at detectable levels in about half of the Winnipeg homes and radon remains significantly higher than the national average. In this study, radon concentrations ranged from 20 to 483 Bq m–3 with a geometric mean of 112 Bq m–3 and a geometric standard deviation of 2.07. It is estimated that 20% of Winnipeg homes could have radon concentrations above the Canadian indoor radon guideline of 200 Bq m–3. This conclusion is similar to the previous estimation made 20 y ago. Thoron concentrations were below the detection limit in 60 homes. Among the homes with detectable thoron concentrations, the values varied from 5 to 297 Bq m–3, the geometric mean and standard deviation were 21 Bq m–3 and 2.53, respectively.

  J Chen , R Falcomer , L Bergman , J Wierdsma and J. Ly

Soil gas radon and soil gas permeability measurements were conducted at 32 sites across the five most populated communities in the city of Ottawa where indoor radon measurements were available for 167 houses. A soil radon index (SRI) determined from the soil radon concentration and the soil gas permeability was used to characterise radon availability from soil to air. This study demonstrated that the average SRI in a community area correlates with the indoor radon potential (the percentage of homes above 200 Bq m–3) in that community. Soil gas radon concentrations together with soil gas permeability measurements can be a useful tool for the prediction of the indoor radon potential in the development of a Canadian radon risk map.

  J Chen , B Walker , A Sorimachi , H Takahashi and S. Tokonami

The alpha-track detector was well designed for long-term radon measurements in the 1992 Winnipeg case–control study. However, its diffusion characteristic for thoron in comparison to radon was yet unknown. An investigation on radon and thoron response of these detectors was undertaken. The results showed that the relative sensitivity between thoron and radon is 2 %, i.e. the detector sensitivity to radon is about 50 times higher than the sensitivity to thoron. It can be concluded that there was no significant influence of thoron on the radon measurements with these detectors.

  J Chen , J. C Dessau , E Frenette , D Moir and R. J. Cornett

Radon has been identified as the second leading cause of lung cancer after tobacco smoking. 222Rn (radon gas) and 220Rn (thoron gas) are the most common isotopes of radon. In this study, thoron exposure in Canada was assessed based on three community radon/thoron surveys conducted recently. It was confirmed that thoron was detectable in most homes and thoron progeny were present in every home surveyed. Results demonstrated that thoron concentrations varied more widely than radon. No clear correlation between 222Rn and 220Rn concentrations was observed in simultaneous measurements. It is estimated that thoron contributes to about 7 % of the radiation dose due to indoor radon exposure based on measurements in about 260 individual homes. Because indoor measurements and geological gamma-ray surveys did not support a reasonable association between 222Rn and 220Rn, thoron concentrations could not be predicted from widely available indoor radon information. In order to better assess thoron exposure in Canada and thoron risk to the Canadian population in various geographic locations, more thoron progeny measurements are required.

  J Chen , D Moir and J. Cornett

To aid in protecting patients from unnecessary exposures and to reduce radiation burdens to the public, a system for tracking a patient's medical exposure history and related radiation doses would be a useful tool. A patient-centred exposure registry, the Patient Exposure Registry (PER), is a mechanism that provides this tracking. This article outlines the objectives of the proposed Canadian PER together with considerations and preliminary design of the registry. Implementation strategy is discussed. The strategy will allow many initiatives progressing in parallel such as backward data mining and forward development in order to make this important registry a reality in the near future.

  M. A Esteban , J Xu , J Yang , M Peng , D Qin , W Li , Z Jiang , J Chen , K Deng , M Zhong , J Cai , L Lai and D. Pei

Induced pluripotent stem cell (iPS) technology appears to be a general strategy to generate pluripotent stem cells from any given mammalian species. So far, iPS cells have been reported for mouse, human, rat, and monkey. These four species have also established embryonic stem cell (ESC) lines that serve as the gold standard for pluripotency comparisons. Attempts have been made to generate porcine ESC by various means without success. Here we report the successful generation of pluripotent stem cells from fibroblasts isolated from the Tibetan miniature pig using a modified iPS protocol. The resulting iPS cell lines more closely resemble human ESC than cells from other species, have normal karyotype, stain positive for alkaline phosphatase, express high levels of ESC-like markers (Nanog, Rex1, Lin28, and SSEA4), and can differentiate into teratomas composed of the three germ layers. Because porcine physiology closely resembles human, the iPS cells reported here provide an attractive model to study certain human diseases or assess therapeutic applications of iPS in a large animal model.

  M. A Santos , M. S. Y Huen , M Jankovic , H. T Chen , A. J Lopez Contreras , I. A Klein , N Wong , J. L. R Barbancho , O Fernandez Capetillo , M. C Nussenzweig , J Chen and A. Nussenzweig

53BP1 is a well-known mediator of the cellular response to DNA damage. Two alternative mechanisms have been proposed to explain 53BP1’s interaction with DNA double-strand breaks (DSBs), one by binding to methylated histones and the other via an RNF8 E3 ligase–dependent ubiquitylation pathway. The formation of RNF8 and 53BP1 irradiation-induced foci are both dependent on histone H2AX. To evaluate the contribution of the RNF8-dependent pathway to 53BP1 function, we generated RNF8 knockout mice. We report that RNF8 deficiency results in defective class switch recombination (CSR) and accumulation of unresolved immunoglobulin heavy chain–associated DSBs. The CSR DSB repair defect is milder than that observed in the absence of 53BP1 but similar to that found in H2AX–/– mice. Moreover, similar to H2AX but different from 53BP1 deficiency, RNF8–/– males are sterile, and this is associated with defective ubiquitylation of the XY chromatin. Combined loss of H2AX and RNF8 does not cause further impairment in CSR, demonstrating that the two genes function epistatically. Importantly, although 53BP1 foci formation is RNF8 dependent, its binding to chromatin is preserved in the absence of RNF8. This suggests a two-step mechanism for 53BP1 association with chromatin in which constitutive loading is dependent on interactions with methylated histones, whereas DNA damage–inducible RNF8-dependent ubiquitylation allows its accumulation at damaged chromatin.

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