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1.  Blood leukocyte Alu and LINE-1 methylation and gastric cancer risk in the Shanghai Women's Health Study 
British Journal of Cancer  2011;106(3):585-591.
Background:
Recent data suggest a link between blood leukocyte DNA methylation, and cancer risk. However, reports on DNA methylation from a prospective study are unavailable for gastric cancer.
Methods:
We explored the association between methylation in pre-diagnostic blood leukocyte DNA and gastric cancer risk in a case–control study nested in the prospective Shanghai Women's Health Study cohort. Incident gastric cancer cases (n=192) and matched controls (n=384) were included in the study. Methylation of Alu and long interspersed nucleotide elements (LINE)-1 were evaluated using bisulphite pyrosequencing. Odds ratios (ORs) and 95% confidence intervals (CI) were calculated from logistic regression adjusting for potential confounders.
Results:
Alu methylation was inversely associated with gastric cancer risk, mainly among cases diagnosed one or more years after blood collection. After excluding cases diagnosed during the first year of follow-up, the ORs for the third, second, and first quartiles of Alu methylation compared with the highest quartile were 2.43 (1.43–4.13), 1.47(0.85–2.57), and 2.22 (1.28–3.84), respectively. This association appeared to be modified by dietary intake, particularly isoflavone. In contrast, LINE-1 methylation levels were not associated with gastric cancer risk.
Conclusion:
Evidence from this prospective study is consistent with the hypothesis that DNA hypomethylation in blood leukocytes may be related to cancer risk, including risk of gastric cancer.
doi:10.1038/bjc.2011.562
PMCID: PMC3273339  PMID: 22173668
gastric cancer; DNA methylation; leukocyte
2.  Evaluation of GWAS-identified genetic variants for age at menarche among Chinese women 
Human Reproduction (Oxford, England)  2013;28(4):1135-1143.
STUDY QUESTION
Do genetic polymorphisms which influence age at menarche in women of European ancestry also influence women of Chinese ancestry?
SUMMARY ANSWER
Many genetic variants influencing age at menarche in European populations appear to impact Chinese populations in a similar manner.
WHAT IS KNOWN AND WHAT THIS PAPER ADDS
Prior genome-wide association studies have uncovered 42 SNPs associated with age at menarche in European populations. This study is the first to demonstrate that many of the genetic determinants of age at menarche are shared between European and Chinese women.
PARTICIPANTS AND SETTING
We evaluated 37 of 42 SNPs identified as associated with age at menarche from a recent, large meta-analysis, consisting primarily of women of European ancestry, in a population of 6929 Chinese women from Shanghai, China. We also constructed weighted genetic risk scores (GRSs) combining the number of effect variants for all 37 SNPs, or only the SNPs associated with age at menarche among our study population, to evaluate their joint influence on age at menarche.
MAIN RESULTS
For 32 of the 37 evaluated variants, the direction of the allele associations were the same between women of European ancestry and women of Chinese ancestry (P = 3.71 × 10−6, binomial sign test); 9 of these were statistically significant. Subjects in the highest quintile of GRSs began menarche ∼5 months later than those in the lowest quintile.
BIAS, LIMITATIONS AND GENERALIZABILITY TO OTHER POPULATIONS
Age at menarche was obtained by self-report, which can be subject to recall errors. The current analysis was restricted to loci which met or approached GWAS significance thresholds and did not evaluate loci which may act predominantly or exclusively in the Chinese population. The smaller sample size for our meta-analysis compared with meta-analyses conducted in European populations reduced the power to detect significant results.
STUDY FUNDING/COMPETING INTERESTS
This study was supported, in part, by grants from US National Institutes of Health (grants R01CA124558, R01CA090899, R01CA070867; R01CA064277 and R01CA092585 and UL1 RR024975), Ingram professorship funds and Allen Foundation funds. There are no competing interests to declare.
doi:10.1093/humrep/det011
PMCID: PMC3600840  PMID: 23406970
menarche; genome-wide association study; genetics; reproductive endocrinology
3.  Leptin Overexpression in VTA Trans-activates the Hypothalamus whereas Prolonged Leptin Action in either Region Cross-Desensitizes 
Neuropharmacology  2012;65:90-100.
High-fat feeding or CNS leptin overexpression in chow-fed rats results in a region-specific cellular leptin resistance in medial basal hypothalamic regions and the ventral tegmental area (VTA). The present investigation examined the effects of targeted chronic leptin overexpression in the VTA as compared with the medial basal hypothalamus on long-term body weight homeostasis. The study also examined if this targeted intervention conserves regional leptin sensitivity or results in localized leptin resistance. Cellular leptin resistance was assessed by leptin-stimulated phosphorylation of signal transducers and activators of transcription 3 (STAT3). Tyrosine hydroxylase was measured in hypothalamus and VTA along with brown adipose tissue uncoupling protein 1. Leptin overexpression in VTA tempered HF-induced obesity, but to a slightly lesser extent than that with leptin overexpression in the hypothalamus. Moreover, the overexpression of leptin in the VTA stimulated cellular STAT3 phosphorylation in several regions of the medial basal hypothalamus, whereas verexpression in the hypothalamus did not activate STAT3 signaling in the VTA. This unidirectional trans-stimulation did not appear to involve migration of either the vector or the gene product. Long-term leptin overexpression in either the medial basal hypothalamus or VTA caused desensitization of leptin signaling in the treated region and cross-desensitization of leptin signaling in the untreated region. These results demonstrate a role of leptin receptors in the VTA in long-term body weight regulation, but the trans-activation of the hypothalamus following VTA leptin stimulation suggests that an integrative response involving both brain regions may account for the observed physiological outcomes.
doi:10.1016/j.neuropharm.2012.09.005
PMCID: PMC3521099  PMID: 22982569
4.  Correlation between atomic structure evolution and strength in a bulk metallic glass at cryogenic temperature 
Scientific Reports  2014;4:3897.
A model Zr41.25Ti13.75Ni10Cu12.5Be22.5 (at.%) bulk metallic glass (BMG) is selected to explore the structural evolution on the atomic scale with decreasing temperature down to cryogenic level using high energy X-ray synchrotron radiation. We discover a close correlation between the atomic structure evolution and the strength of the BMG and find out that the activation energy increment of the concordantly atomic shifting at lower temperature is the main factor influencing the strength. Our results might provide a fundamental understanding of the atomic-scale structure evolution and may bridge the gap between the atomic-scale physics and the macro-scale fracture strength for BMGs.
doi:10.1038/srep03897
PMCID: PMC3904144  PMID: 24469299
5.  Dietary glycemic load, glycemic index, and carbohydrates on the risk of primary liver cancer among Chinese women and men 
Annals of Oncology  2012;24(1):238-244.
Background
Dietary glycemic index (GI) and glycemic load (GL) typically have a positive relationship with obesity and diabetes, which are risk factors for liver cancer. However, studies on their association with liver cancer have yielded inconsistent results. Therefore, we assessed the association of GI, GL, and carbohydrates with liver cancer risk.
Patients and methods
A total of 72 966 women and 60 207 men from the Shanghai Women's Health Study (SWHS) and the Shanghai Men's Health Study (SMHS) were included for analysis. Food frequency questionnaire (FFQ) data were used to calculate daily dietary GI, GL, and carbohydrate intake. These values were energy adjusted and categorized into quintiles. The hazard ratios (HRs) and 95% confidence intervals (CI) were calculated with adjustment for potential confounders.
Results
After a median follow-up time of 11.2 years for the SWHS and 5.3 years for the SMHS, 139 and 208 incident liver cancer cases were identified in the SWHS and SMHS, respectively. In multivariable Cox regression models, no statistically significant trends by quintile of GI, GL, or carbohydrate intake were observed. Stratification by chronic liver disease/hepatitis, diabetes, or body mass index (BMI) did not alter the findings.
Conclusions
There is little evidence that dietary GI, GL, or carbohydrates affect the incidence of liver cancer in this Asian population.
doi:10.1093/annonc/mds287
PMCID: PMC3525137  PMID: 22898034
Chinese men and women; cohort study; diet; glycemic index; glycemic load; primary liver cancer
6.  Comparison and contrast of noise-induced hyperactivity in the dorsal cochlear nucleus and inferior colliculus 
Hearing research  2012;295(1-2):114-123.
Induction of hyperactivity in the central auditory system is one of the major physiological hallmarks of animal models of noise-induced tinnitus. Although hyperactivity occurs at various levels of the auditory system, it is not clear to what extent hyperactivity originating in one nucleus contributes to hyperactivity at higher levels of the auditory system. In this study we compared the time courses and tonotopic distribution patterns of hyperactivity in the dorsal cochlear nucleus (DCN) and inferior colliculus (IC). A model of acquisition of hyperactivity in the IC by passive relay from the DCN would predict that the two nuclei show similar time courses and tonotopic profiles of hyperactivity. A model of acquisition of hyperactivity in the IC by compensatory plasticity mechanisms would predict that the IC and DCN would show differences in these features, since each adjusts to changes of spontaneous activity of opposite polarity. To test the role of these two mechanisms, animals were exposed to an intense hyperactivity-inducing tone (10 kHz, 115 dB SPL, 4 hours) then studied electrophysiologically at three different post-exposure recovery times (from 1 to 6 weeks after exposure). For each time frame, multiunit spontaneous activity was mapped as a function of location along the tonotopic gradient in the DCN and IC. Comparison of activity profiles from the two nuclei showed a similar progression toward increased activity over time and culminated in the development of a central peak of hyperactivity at a similar tonotopic location. These similarities suggest that the shape of the activity profile is determined primarily by passive relay from the cochlear nucleus. However, the absolute levels of activity were generally much lower in the IC than in the DCN, suggesting that the magnitude of hyperactivity is greatly attenuated by inhibition.
doi:10.1016/j.heares.2012.04.003
PMCID: PMC3538909  PMID: 22521905
Inferior colliculus; dorsal cochlear nucleus; hyperactivity; noise exposure; tinnitus
7.  Involvement of miR-9/MCPIP1 axis in PDGF-BB-mediated neurogenesis in neuronal progenitor cells 
Cell Death & Disease  2013;4(12):e960-.
Highly conserved microRNA-9 (miR-9) has a critical role in various cellular processes including neurogenesis. However, its regulation by neurotropins that are known to mediate neurogenesis remains poorly defined. In this study, we identify platelet-derived growth factor-BB (PDGF-BB)-mediated upregulation of miR-9, which in turn downregulates its target gene monocyte chemotactic protein-induced protein 1 (MCPIP1), as a key player in modulating proliferation, neuronal differentiation as well as migration of neuronal progenitor cells (NPCs). Results indicate that miR-9-mediated NPC proliferation and neuronal differentiation involves signaling via the nuclear factor-kappa B (NF-κB) and cAMP response element-binding protein (CREB) pathways, and that NPC migration involves CREB but not the NF-κB signaling. These findings thus suggest that miR-9-mediated downregulation of MCPIP1 acts as a molecular switch regulation of neurogenesis.
doi:10.1038/cddis.2013.486
PMCID: PMC3877557  PMID: 24336080
neuronal progenitor cell; PDGF-BB; miR-9; MCPIP1; neurogenesis
8.  Which should be the routine cross-sectional reconstruction mode in spectral CT imaging: monochromatic or polychromatic? 
The British Journal of Radiology  2012;85(1018):e887-e890.
Objective
To provide evidence for the selection of an optimal cross-sectional reconstruction mode in spectral CT imaging of the abdomen, we compared the monochromatic images with polychromatic images.
Methods
Three phase-enhanced CT scans of the abdomen were recorded using the spectral imaging technique on 100 patients. Images were reconstructed using two modes: polychromatic and 70 keV monochromatic. The following variables were then compared: contrast-to-noise ratio (CNR) of the liver, spleen, gallbladder, kidney and pancreas, and the noise. Paired t-tests were used to compare differences between the two sets of images. Three experienced doctors graded the quality of the images with a five-point scale. The image quality scores were compared with a non-parametric rank sum test.
Results
Compared with polychromatic images, the 70 keV monochromatic mode images yielded significantly greater tissue-to-fat CNR and lower noise (p<0.001 for all comparisons). The image quality of the 70 keV monochromatic mode showed significantly better results than the polychromatic mode (p<0.001).
Conclusions
In abdominal spectral CT imaging, 70 keV monochromatic mode reconstruction images were better than those reconstructed using the polychromatic mode. The monochromatic mode may become the routine reconstruction mode for cross-sectional images.
doi:10.1259/bjr/27844842
PMCID: PMC3474011  PMID: 22723512
9.  In vitro proliferation and differentiation of hepatic oval cells and their potential capacity for intrahepatic transplantation 
Hepatic oval cells (HOCs) are recognized as facultative liver progenitor cells that play a role in liver regeneration after acute liver injury. Here, we investigated the in vitro proliferation and differentiation characteristics of HOCs in order to explore their potential capacity for intrahepatic transplantation. Clusters or scattered HOCs were detected in the portal area and interlobular bile duct in the liver of rats subjected to the modified 2-acetylaminofluorene and partial hepatectomy method. Isolated HOCs were positive for c-kit and CD90 staining (99.8% and 88.8%, respectively), and negative for CD34 staining (3.6%) as shown by immunostaining and flow cytometric analysis. In addition, HOCs could be differentiated into hepatocytes and bile duct epithelial cells after leukemia inhibitory factor deprivation. A two-cuff technique was used for orthotopic liver transplantation, and HOCs were subsequently transplanted into recipients. Biochemical indicators of liver function were assessed 4 weeks after transplantation. HOC transplantation significantly prolonged the median survival time and improved the liver function of rats receiving HOCs compared to controls (P=0.003, Student t-test). Administration of HOCs to rats also receiving liver transplantation significantly reduced acute allograft rejection compared to control liver transplant rats 3 weeks following transplantation (rejection activity index score: control=6.3±0.9; HOC=3.5±1.5; P=0.005). These results indicate that HOCs may be useful in therapeutic liver regeneration after orthotopic liver transplantation.
doi:10.1590/1414-431X20132620
PMCID: PMC3854420  PMID: 23903688
Hepatic oval cells; Proliferation; Differentiation; Liver transplantation
10.  Early maternal and paternal bonding, childhood physical abuse and adult psychopathic personality 
Psychological medicine  2010;40(6):1007-1016.
Background
A significant gap in the literature on risk factors for psychopathy is the relative lack of research on parental bonding.
Method
This study examines the cross-sectional relationship between maternal and paternal bonding, childhood physical abuse and psychopathic personality at age 28 years in a community sample of 333 males and females. It also assesses prospectively whether children separated from their parents in the first 3 years of life are more likely to have a psychopathic-like personality 25 years later.
Results
Hierarchical regression analyses indicated that: (1) poor parental bonding (lack of maternal care and low paternal overprotection) and childhood physical abuse were both associated with a psychopathic personality; (2) parental bonding was significantly associated with psychopathic personality after taking into account sex, social adversity, ethnicity and abuse; (3) those separated from parents in the first 3 years of life were particularly characterized by low parental bonding and a psychopathic personality in adulthood; and (4) the deviant behavior factor of psychopathy was more related to lack of maternal care whereas the emotional detachment factor was related to both lack of maternal care and paternal overprotection.
Conclusions
Findings draw attention to the importance of different components of early bonding in relation to adult psychopathy, and may have potential implications for early intervention and prevention of psychopathy.
doi:10.1017/S0033291709991279
PMCID: PMC3720131  PMID: 20441692
Abuse; bonding; maternal care; paternal overprotection; psychopathy
11.  Cigarette smoking and pancreatic cancer: an analysis from the International Pancreatic Cancer Case-Control Consortium (Panc4) 
Annals of Oncology  2011;23(7):1880-1888.
Background
To evaluate the dose–response relationship between cigarette smoking and pancreatic cancer and to examine the effects of temporal variables.
Methods
We analyzed data from 12 case–control studies within the International Pancreatic Cancer Case–Control Consortium (PanC4), including 6507 pancreatic cases and 12 890 controls. We estimated summary odds ratios (ORs) by pooling study-specific ORs using random-effects models.
Results
Compared with never smokers, the OR was 1.2 (95% confidence interval [CI] 1.0–1.3) for former smokers and 2.2 (95% CI 1.7–2.8) for current cigarette smokers, with a significant increasing trend in risk with increasing number of cigarettes among current smokers (OR = 3.4 for ≥35 cigarettes per day, P for trend <0.0001). Risk increased in relation to duration of cigarette smoking up to 40 years of smoking (OR = 2.4). No trend in risk was observed for age at starting cigarette smoking, whereas risk decreased with increasing time since cigarette cessation, the OR being 0.98 after 20 years.
Conclusions
This uniquely large pooled analysis confirms that current cigarette smoking is associated with a twofold increased risk of pancreatic cancer and that the risk increases with the number of cigarettes smoked and duration of smoking. Risk of pancreatic cancer reaches the level of never smokers ∼20 years after quitting.
doi:10.1093/annonc/mdr541
PMCID: PMC3387822  PMID: 22104574
case–control study; cigarette smoking; pancreatic cancer; pooled analysis
12.  Body mass, tobacco smoking, alcohol drinking and risk of cancer of the small intestine—a pooled analysis of over 500 000 subjects in the Asia Cohort Consortium 
Annals of Oncology  2011;23(7):1894-1898.
Background
The evidence for a role of tobacco smoking, alcohol drinking, and body mass index (BMI) in the etiology of small intestine cancer is based mainly on case–control studies from Europe and United States.
Subjects and methods
We harmonized the data across 12 cohort studies from mainland China, Japan, Korea, Singapore, and Taiwan, comprising over 500 000 subjects followed for an average of 10.6 years. We calculated hazard ratios (HRs) for BMI and (only among men) tobacco smoking and alcohol drinking.
Results
A total of 134 incident cases were observed (49 adenocarcinoma, 11 carcinoid, 46 other histologic types, and 28 of unknown histology). There was a statistically non-significant trend toward increased HR in subjects with high BMI [HR for BMI >27.5 kg/m2, compared with 22.6–25.0, 1.50; 95% confidence interval (CI) 0.76–2.96]. No association was suggested for tobacco smoking; men drinking >400 g of ethanol per week had an HR of 1.57 (95% CI 0.66–3.70), compared with abstainers.
Conclusions
Our study supports the hypothesis that elevated BMI may be a risk factor for small intestine cancer. An etiologic role of alcohol drinking was suggested. Our results reinforce the existing evidence that the epidemiology of small intestine cancer resembles that of colorectal cancer.
doi:10.1093/annonc/mdr562
PMCID: PMC3493138  PMID: 22147734
alcohol drinking; body mass index; prospective studies; small intestine cancer; tobacco smoking
13.  Short small-interfering RNAs produce interferon-α-mediated analgesia 
BJA: British Journal of Anaesthesia  2012;108(4):662-669.
Background
There is increasing interest in RNA interference in pain research using the intrathecal route to deliver small-interfering RNA (siRNA). An interferon (IFN) response is a common side-effect of siRNA. However, the IFN response in the spinal cord after intrathecal administration of siRNA remains unknown. We hypothesized that high doses of siRNAs can elicit off-target analgesia via releasing IFN-α. We investigated the IFN response and its role in regulating pain sensitivity in the spinal cords after intrathecal administration of siRNAs.
Methods
Male Sprague–Dawley rats were given intrathecal injections of non-targeting (NT) siRNAs or IFN-α and tested for complete Freund's adjuvant (CFA)-induced mechanical allodynia and heat hyperalgesia. IFN-α in the spinal cord after injection of NT siRNAs was measured by western blotting and immunohistochemical staining.
Results
IFN-α was up-regulated in the spinal cord after intrathecal treatment of NT siRNAs. Intrathecal injection of NT siRNAs, at high doses of 10 or 20 μg, reduced CFA-induced inflammatory pain (P<0.05). Intrathecal application of IFN-α inhibited pain hypersensitivity in inflamed rats and produced analgesia in naïve rats (P<0.05). Notably, the anti-nociceptive effects elicited by NT siRNAs and IFN-α were reversed by IFN-α neutralizing antibody and naloxone.
Conclusions
Our data suggest that (i) intrathecal administration of high doses of siRNA (≥10 μg) induced up-regulation of IFN-α in the spinal cord and produced analgesic effects through IFN-α, and (ii) IFN-α's analgesic effect is mediated via opioid receptors. Caution must be taken to avoid IFN-α-mediated analgesic effects of siRNAs in pain research.
doi:10.1093/bja/aer492
PMCID: PMC3303487  PMID: 22307241
analgesia; interferon; small-interfering RNA
14.  Alcohol consumption and pancreatic cancer: a pooled analysis in the International Pancreatic Cancer Case–Control Consortium (PanC4) 
Annals of Oncology  2011;23(2):374-382.
Background:
Heavy alcohol drinking has been related to pancreatic cancer, but the issue is still unsolved.
Methods:
To evaluate the role of alcohol consumption in relation to pancreatic cancer, we conducted a pooled analysis of 10 case–control studies (5585 cases and 11 827 controls) participating in the International Pancreatic Cancer Case–Control Consortium. We computed pooled odds ratios (ORs) by estimating study-specific ORs adjusted for selected covariates and pooling them using random effects models.
Results:
Compared with abstainers and occasional drinkers (<1 drink per day), we observed no association for light-to-moderate alcohol consumption (≤4 drinks per day) and pancreatic cancer risk; however, associations were above unity for higher consumption levels (OR = 1.6, 95% confidence interval 1.2–2.2 for subjects drinking ≥9 drinks per day). Results did not change substantially when we evaluated associations by tobacco smoking status, or when we excluded participants who reported a history of pancreatitis, or participants whose data were based upon proxy responses. Further, no notable differences in pooled risk estimates emerged across strata of sex, age, race, study type, and study area.
Conclusion:
This collaborative-pooled analysis provides additional evidence for a positive association between heavy alcohol consumption and the risk of pancreatic cancer.
doi:10.1093/annonc/mdr120
PMCID: PMC3265544  PMID: 21536662
alcohol drinking; case–control studies; ethanol; pancreatic cancer; pooled analysis; risk factors
15.  Metabolic syndrome and insulin resistance in relation to biliary tract cancer and stone risks: a population-based study in Shanghai, China 
British Journal of Cancer  2011;105(9):1424-1429.
Background:
Serum lipids, diabetes, and obesity, individual components of metabolic syndrome, are associated with biliary tract cancer and stone risk, but the associations of metabolic syndrome or insulin resistance with biliary tract cancers and stones are not well studied.
Methods:
In this population-based case-control study in Shanghai, China (627 biliary tract cancers, 1037 biliary stones, and 959 controls), metabolic syndrome was defined as the presence of any three of the five components, including high waist circumference, high triglycerides, low high-density lipoprotein cholesterol (HDL), high blood pressure, and diabetes. Insulin resistance and β-cell function were assessed, using homeostasis assessment models.
Results:
Metabolic syndrome was significantly associated with gallbladder cancer (odds ratio (OR)=2.75, 95% confidence interval (95% CI)=1.82–4.15) and biliary stones (OR=1.64, 95% CI=1.24–2.16), with a significant dose effect with increasing number of metabolic syndrome components (P trend <0.0001). The observed association persisted among subjects without a history of diabetes. The association between insulin resistance and gallbladder cancer was borderline (P trend=0.06). There was a significant inverse association between β-cell function and gallbladder cancer risk (P trend <0.001).
Conclusion:
Our findings suggest that metabolic syndrome and insulin resistance have a role in the aetiology of biliary tract cancers and biliary stones, and if confirmed, they imply that lifestyle control of these factors may lower the risk of biliary stones and biliary tract cancer.
doi:10.1038/bjc.2011.363
PMCID: PMC3241543  PMID: 21915122
metabolic syndrome; insulin resistance; biliary tract cancers; biliary stones
16.  Physical activity and breast cancer risk in Chinese women 
British Journal of Cancer  2011;105(9):1443-1450.
Background:
The influence of different types and intensities of physical activity on risk for breast cancer is unclear.
Methods:
In a prospective cohort of 73 049 Chinese women (40–70 years), who had worked outside the home, we studied breast cancer risk in relation to specific types of self-reported and work history-related physical activity, including adolescent and adult exercise and household activity and walking and cycling for transportation. Occupational sitting time and physical activity energy expenditure were assigned based on lifetime occupational histories.
Results:
In all, 717 incident breast cancer cases were diagnosed. Breast cancer risk was lower for women in the lowest quartile of average occupational sitting time and in the highest quartile of average occupational energy expenditure (adjusted hazard ratio (HR): 0.81 and 0.73, respectively, P⩽0.05). Adult exercise at or above the recommended level (8 metabolic equivalent (MET) h per week per year) was associated with lower risk (adjusted HR: 0.73, P<0.05) in post-menopausal women. Analysis of joint effects showed that having both an active job and exercise participation did not confer an additional benefit. Other common daily activities were not associated with lower risk.
Interpretation:
These findings suggest that both exercise and occupational activity are associated with lower breast cancer risk, which supports current health promotion campaigns promoting exercise.
doi:10.1038/bjc.2011.370
PMCID: PMC3241547  PMID: 21934685
breast cancer; physical activity; exercise; occupational; critical period
17.  In Vitro and In Vivo Characterizations of Chiglitazar, a Newly Identified PPAR Pan-Agonist 
PPAR Research  2012;2012:546548.
Solid rationales are still present for the identification of synthetic ligands to simultaneously target multiple PPAR subtypes for the treatment of T2DM. The purpose of this study was to characterize the in vitro and in vivo differential effects of chiglitazar, a non-TZD type of PPAR pan-agonist currently in phase III clinic development in China, from PPARγ-selective agonist like rosiglitazone. Chiglitazar showed transactivating activity in each PPARα, γ, and δ subtype and upregulated the expression of PPARα and/or PPARδ downstream genes involved in the key processes of lipid metabolism and thermogenesis. Comparable blood glucose lowering effect was observed between chiglitazar and rosiglitazone, but chiglitazar did not significantly increase the body weight in KKAy and fat pad weight in db/db mice. Chiglitazar had high distribution in liver, pancreas, and skeleton muscles but was less present in kidney, heart, and adipose in rats. Heart weight increase was not observed in rats treated with chiglitazar for 6 months at a dose as high as 45 mg kg−1. The in vitro and in vivo differential features of chiglitazar are informative and encouraging for the further development of this synthetic ligand for the potential use in T2DM.
doi:10.1155/2012/546548
PMCID: PMC3486420  PMID: 23150725
18.  Interaction of fibrin with VE-cadherin and anti-inflammatory effect of fibrin-derived fragments 
Summary
Background
The interaction of fibrin βN-domain with VE-cadherin on endothelial cells was implicated in transendothelial migration of leukocytes and theβ15-42 fragment representing part of this domain was shown to inhibit this process. However, our previous study revealed that only a dimeric (β15-66)2 fragment corresponding to the full-length βN-domain and mimicking its dimeric arrangement in fibrin bound to VE-cadherin.
Objective
To test our hypothesis that dimerization of β15-42-containing fragments increases their affinity to VE-cadherin and ability to inhibit transendothelial migration of leukocytes.
Methods
Interaction of β15-42-containing fragments with VE-cadherin was characterized by ELISA and surface plasmon resonance. Inhibitory effect of such fragments was tested in vitro using leukocyte transendothelial migration assay and in vivo using mouse models of peritonitis and myocardial ischemia-reperfusion injury.
Results
First, we prepared the monomeric β15-42 and β15-64 fragments and their dimeric forms, (β15-44)2 and (β15-66)2, and studied their interaction with fibrin-binding domain of VE-cadherin, VE-cad(3). The experiments revealed that both dimeric fragments bound to VE-cad(3) with high affinity while the affinities of monomeric β15-42 and β15-64 were significantly lower. Next, we tested the ability of these fragments to inhibit leukocyte transmigration in vitro and infiltration into the inflamed peritoneum in vivo and found that the inhibitory effects of the dimers on these processes were also superior. Furthermore, dimeric (β15-44)2 significantly reduced myocardial injury induced by ischemia-reperfusion.
Conclusion
The results confirm our hypotheses and indicate that dimeric (β15-66)2 and (β15-44)2, which exhibited much higher affinity to VE-cadherin, are highly effective in suppressing inflammation by inhibiting leukocyte transmigration.
doi:10.1111/j.1538-7836.2011.04438.x
PMCID: PMC3166367  PMID: 21752185
fibrinogen; fibrin; inflammation; leukocytes; transendothelial migration; VE-cadherin
19.  Isolation and biological characterization of chicken amnion epithelial cells 
Amniotic epithelial cells (AECs) express Oct4, Nanog and Sox-2, which are necessary for maintaining the undifferentiated state of pluripotent stem cells. AECs additionally express CK19, which is a specific marker of epithelial cells, both in vivo and in vitro. In this research, we investigated the biological characteristics and potential for cell therapy of AECs from 6-day-old chicken embryos. We induced the AECs to differentiate into pancreatic islet-like cells (endoderm), adipocytes and osteoblasts (mesoderm) and neural-like cells (ectoderm), and used immunofluorescence and RT-PCR to detect the expression of AECs specific markers. To assess the differentiation capacity of AECs, passage 3 cells were induced to differentiate into adipocytes, osteoblasts, pancreatic islet-like cells and neural-like cells. The AEC markers, Oct-4, Nanog, Sox-2 and CK19, were all positively expressed. Cloning efficiency decreased with increasing passage number. Passage 3 AECs were successfully induced to differentiate into pancreatic islet-like cells, osteoblasts, adipocytes, and neural-like cells. These results suggested that AECs isolated from chicken embryos exhibited the characteristics of the multipotent stem cells. AECs may therefore be ideal candidates for cellular transplantation therapy and tissue engineering.
doi:10.4081/ejh.2012.e33
PMCID: PMC3493979  PMID: 23027349
chicken; AECs; biological research; differentiation capacity.
20.  Plasma pepsinogens, antibodies against Helicobacter pylori, and risk of gastric cancer in the Shanghai Women's Health Study Cohort 
British Journal of Cancer  2011;104(9):1511-1516.
Background:
Circulating pepsinogens can indicate atrophic gastritis, a precursor of gastric cancer. We tested the association between gastric cancer and plasma pepsinogens and antibodies against Helicobacter pylori in a case–control study nested in a prospective cohort.
Methods:
We selected 141 gastric cancer cases and 282 incidence-density sampled controls. Plasma concentrations of pepsinogens 1 and 2 were measured using ELISA kits, and anti-H. pylori antibodies were measured using a kit specific to Chinese strains. Associations were estimated using conditional logistic regression models adjusted for potential confounders.
Results:
Gastric cancer subjects were more likely to be anti-H. pylori positive than controls, 97 vs 92%. A plasma pepsinogen 1 (PG1) concentration <50 ng ml–1 (15% of cases) was associated with a significantly increased risk of gastric cancer (OR 4.23; (95% CI: 1.86–9.63), whereas a plasma pepsinogen 2 (PG2) concentration >6.6 ng ml–1 (75% of cases) was also associated with a significantly increased risk of gastric cancer (OR 3.62; (95% CI: 1.85–7.09). We also found that the PG1 : 2 ratio had a nearly linear association with gastric cancer risk.
Conclusion:
Lower plasma PG1 : 2 ratios are associated with a higher risk of gastric cancer. Furthermore, it appears that circulating pepsinogens 1 and 2 may be independently associated with the risk of gastric cancer.
doi:10.1038/bjc.2011.77
PMCID: PMC3101941  PMID: 21407214
gastric cancer; pepsinogens; Helicobacter pylori; cohort; China
21.  Association of CDX1 binding site of periostin gene with bone mineral density and vertebral fracture risk 
Osteoporosis International  2012;23(7):1877-1887.
Summary
Periostin (POSTN) as a regulator of osteoblast differentiation and bone formation may affect susceptibility to osteoporosis. This study suggests POSTN as a candidate gene for bone mineral density (BMD) variation and vertebral fracture risk, which could better our understanding about the genetic pathogenesis of osteoporosis and will be useful in clinic in the future.
Introduction
The genetic determination of osteoporosis is complex and ill-defined. Periostin (POSTN), an extracellular matrix secreted by osteoblasts and a regulator of osteoblast differentiation and bone formation, may affect susceptibility to osteoporosis.
Methods
We adopted a tag-single nucleotide polymorphism (SNP) based association method followed by imputation-based verification and identification of a causal variant. The association was investigated in 1,572 subjects with extreme-BMD and replicated in an independent population of 2,509 subjects. BMD was measured by dual X-ray absorptiometry. Vertebral fractures were identified by assessing vertebral height from X-rays of the thoracolumbar spine. Association analyses were performed with PLINK toolset and imputation analyses with MACH software. The top imputation finding was subsequently validated by genotyping. Interactions between POSTN and another BMD-related candidate gene sclerostin (SOST) were analyzed using MDR program and validated by logistical regression analyses. The putative transcription factor binding with target sequence was confirmed by electrophoretic mobility shift assay (EMSA).
Results
Several SNPs of POSTN were associated with BMD or vertebral fractures. The most significant polymorphism was rs9547970, located at the −2,327 bp upstream (P = 6.8 × 10−4) of POSTN. Carriers of the minor allele G per copy of rs9547970 had 1.33 higher risk of vertebral fracture (P = 0.007). An interactive effect between POSTN and SOST upon BMD variation was suggested (P < 0.01). A specific binding of CDX1 to the sequence of POSTN with the major allele A of rs9547970 but not the variant G allele was confirmed by EMSA.
Conclusions
Our results suggest POSTN as a candidate gene for BMD variation and vertebral fracture risk.
Electronic supplementary material
The online version of this article (doi:10.1007/s00198-011-1861-1) contains supplementary material, which is available to authorized users.
doi:10.1007/s00198-011-1861-1
PMCID: PMC3368110  PMID: 22215184
Association; BMD; CDX1; Periostin; Vertebral fracture
22.  Association of genetic variation in FTO with risk of obesity and type 2 diabetes with data from 96,551 East and South Asians 
Diabetologia  2011;55(4):981-995.
Aims/hypothesis
FTO harbours the strongest known obesity-susceptibility locus in Europeans. While there is growing evidence for a role for FTO in obesity risk in Asians, its association with type 2 diabetes, independently of BMI, remains inconsistent. To test whether there is an association of the FTO locus with obesity and type 2 diabetes, we conducted a meta-analysis of 32 populations including 96,551 East and South Asians.
Methods
All studies published on the association between FTO-rs9939609 (or proxy [r2 > 0.98]) and BMI, obesity or type 2 diabetes in East or South Asians were invited. Each study group analysed their data according to a standardised analysis plan. Association with type 2 diabetes was also adjusted for BMI. Random-effects meta-analyses were performed to pool all effect sizes.
Results
The FTO-rs9939609 minor allele increased risk of obesity by 1.25-fold/allele (p = 9.0 × 10−19), overweight by 1.13-fold/allele (p = 1.0 × 10−11) and type 2 diabetes by 1.15-fold/allele (p = 5.5 × 10−8). The association with type 2 diabetes was attenuated after adjustment for BMI (OR 1.10-fold/allele, p = 6.6 × 10−5). The FTO-rs9939609 minor allele increased BMI by 0.26 kg/m2 per allele (p = 2.8 × 10−17), WHR by 0.003/allele (p = 1.2 × 10−6), and body fat percentage by 0.31%/allele (p = 0.0005). Associations were similar using dominant models. While the minor allele is less common in East Asians (12–20%) than South Asians (30–33%), the effect of FTO variation on obesity-related traits and type 2 diabetes was similar in the two populations.
Conclusions/interpretation
FTO is associated with increased risk of obesity and type 2 diabetes, with effect sizes similar in East and South Asians and similar to those observed in Europeans. Furthermore, FTO is also associated with type 2 diabetes independently of BMI.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-011-2370-7) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
doi:10.1007/s00125-011-2370-7
PMCID: PMC3296006  PMID: 22109280
Asians; FTO; Meta-analysis; Obesity; Type 2 diabetes
23.  Pro-opiomelanocortin Gene Transfer to the NTS but not ARC Ameliorates Chronic Diet-Induced Obesity 
Neuroscience  2010;169(4):1662-1671.
Short-term pharmacological melanocortin activation deters diet-induced obesity (DIO) effectively in rodents. However, whether central pro-opiomelanocortin (POMC) gene transfer targeted to the hypothalamus or hindbrain nucleus of the solitary track (NTS) can combat chronic dietary obesity has not been investigated. Four-week-old Sprague Dawley rats were fed a high fat diet for five months, and then injected with either the POMC or control vector into the hypothalamus or NTS, and body weight and food intake recorded for 68 days. Insulin sensitivity, glucose metabolism and adrenal indicators of central sympathetic activation were measured, and voluntary wheel running (WR) assessed. Whereas the NTS POMC-treatment decreased cumulative food consumption and caused sustained weight reduction over 68 days, the hypothalamic POMC-treatment did not alter cumulative food intake and produced weight loss only in the first 25 days. At death, only the NTS-POMC rats had a significant decrease in fat mass. They also displayed enhanced glucose tolerance, lowered fasting insulin and increased QUICK value, and elevated adrenal indicators of central sympathetic activation. Moreover, the NTS-POMC animals exhibited a near 20% increase in distance ran relative to the respective controls, but the ARC-POMC rats did not. In conclusion, POMC gene transfer to the NTS caused modest anorexia, persistent weight loss, improved insulin sensitivity, and increased propensity for WR in DIO rats. These metabolic improvements may involve stimulation of energy expenditure via centrally regulated sympathetic outflow. The similar POMC treatment in the hypothalamus had minimal long-term physiological or metabolic impact. Thus, melanocortin activation in the brainstem NTS region effectively ameliorates chronic dietary obesity whilst that in the hypothalamus fails to do so.
doi:10.1016/j.neuroscience.2010.06.001
PMCID: PMC2924636  PMID: 20538045
ARC; NTS; dietary obesity; voluntary wheel running; melanocortin
24.  Diabetes in relation to biliary tract cancer and stones: a population-based study in Shanghai, China 
British Journal of Cancer  2010;103(1):115-119.
Background:
Biliary tract cancers are rare but fatal malignancies. Diabetes has been related to biliary stones, but its association with biliary tract cancers is less conclusive.
Methods:
In a population-based case–control study of 627 cancers, 1037 stones, and 959 controls in Shanghai, China, we examined the association between diabetes and the risks of biliary tract cancer and stones, as well as the effect of potential mediating factors, including serum lipids and biliary stones (for cancer), contributing to the causal pathway from diabetes to biliary diseases.
Results:
Independent of body mass index (BMI), diabetes was significantly associated with gallbladder cancer and biliary stones ((odds ratio (OR) (95% confidence interval)=2.6 (1.5–4.7) and 2.0 (1.2–3.3), respectively). Biliary stones and low serum levels of high-density lipoprotein (HDL) were significant mediators of the diabetes effect on gallbladder cancer risk, accounting for 60 and 17% of the diabetes effect, respectively. High-density lipoprotein was also a significant mediator of the diabetes effect on biliary stones, accounting for 18% of the diabetes effect.
Conclusions:
Independent of BMI, diabetes is a risk factor for gallbladder cancer, but its effect is mediated in part by biliary stones and serum HDL levels, suggesting that gallbladder cancer risk may be reduced by controlling diabetes, stones, and HDL levels.
doi:10.1038/sj.bjc.6605706
PMCID: PMC2905288  PMID: 20517308
diabetes; biliary tract cancers; biliary stones; mediation modelling
25.  Reproductive factors and risks of biliary tract cancers and stones: a population-based study in Shanghai, China 
British Journal of Cancer  2010;102(7):1185-1189.
Background:
Parity has been linked to gallbladder cancer and gallstones, but the effects of other reproductive factors are less clear.
Methods:
We examined 361 incident biliary tract cancer cases, 647 biliary stone cases, and 586 healthy women in a population-based study in Shanghai.
Results:
The effects of parity (odds ratios, OR⩾3 vs 1 child=2.0, 95% confidence interval (CI) 0.7–5.1), younger age at first birth (ORper 1-year decrease=1.2, 95% CI 0.99–1.6), and older age at menarche (ORper 1-year increase=1.4, 95% CI 1.1–1.8) on gallbladder cancer risk were more pronounced among women with stones, but the interactions were not significant.
Conclusion:
Our results provide support for high parity, younger age at first birth, and late age at menarche in the development of gallbladder cancer, particularly among women with biliary stones.
doi:10.1038/sj.bjc.6605597
PMCID: PMC2853091  PMID: 20216539
reproductive factors; gallstones; biliary tract cancer

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