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1.  Smoking and Major Depressive Disorder in Chinese Women 
PLoS ONE  2014;9(9):e106287.
Objective
To investigate the risk factors that contribute to smoking in female patients with major depressive disorder (MDD) and the clinical features in depressed smokers.
Methods
We examined the smoking status and clinical features in 6120 Han Chinese women with MDD (DSM-IV) between 30 and 60 years of age across China. Logistic regression was used to determine the association between clinical features of MDD and smoking status and between risk factors for MDD and smoking status.
Results
Among the recurrent MDD patients there were 216(3.6%) current smokers, 117 (2.0%) former smokers and 333(5.6%) lifetime smokers. Lifetime smokers had a slightly more severe illness, characterized by more episodes, longer duration, more comorbid illness (panic and phobias), with more DSM-IV A criteria and reported more symptoms of fatigue and suicidal ideation or attempts than never smokers. Some known risk factors for MDD were also differentially represented among smokers compared to non-smokers. Smokers reported more stressful life events, were more likely to report childhood sexual abuse, had higher levels of neuroticism and an increased rate of familial MDD. Only neuroticism was significantly related to nicotine dependence.
Conclusions
Although depressed women smokers experience more severe illness, smoking rates remain low in MDD patients. Family history of MDD and environmental factors contribute to lifetime smoking in Chinese women, consistent with the hypothesis that the association of smoking and depression may be caused by common underlying factors.
doi:10.1371/journal.pone.0106287
PMCID: PMC4152240  PMID: 25180682
2.  Associations of Educational Attainment, Occupation, Social Class and Major Depressive Disorder among Han Chinese Women 
PLoS ONE  2014;9(1):e86674.
Background
The prevalence of major depressive disorder (MDD) is higher in those with low levels of educational attainment, the unemployed and those with low social status. However the extent to which these factors cause MDD is unclear. Most of the available data comes from studies in developed countries, and these findings may not extrapolate to developing countries. Examining the relationship between MDD and socio economic status in China is likely to add to the debate because of the radical economic and social changes occurring in China over the last 30 years.
Principal findings
We report results from 3,639 Chinese women with recurrent MDD and 3,800 controls. Highly significant odds ratios (ORs) were observed between MDD and full time employment (OR = 0.36, 95% CI = 0.25–0.46, logP = 78), social status (OR = 0.83, 95% CI = 0.77–0.87, logP = 13.3) and education attainment (OR = 0.90, 95% CI = 0.86–0.90, logP = 6.8). We found a monotonic relationship between increasing age and increasing levels of educational attainment. Those with only primary school education have significantly more episodes of MDD (mean 6.5, P-value = 0.009) and have a clinically more severe disorder, while those with higher educational attainment are likely to manifest more comorbid anxiety disorders.
Conclusions
In China lower socioeconomic position is associated with increased rates of MDD, as it is elsewhere in the world. Significantly more episodes of MDD occur among those with lower educational attainment (rather than longer episodes of disease), consistent with the hypothesis that the lower socioeconomic position increases the likelihood of developing MDD. The phenomenology of MDD varies according to the degree of educational attainment: higher educational attainment not only appears to protect against MDD but alters its presentation, to a more anxious phenotype.
doi:10.1371/journal.pone.0086674
PMCID: PMC3909008  PMID: 24497966
3.  Childhood Sexual Abuse and the Development of Recurrent Major Depression in Chinese Women 
PLoS ONE  2014;9(1):e87569.
Background
Our prior study in Han Chinese women has shown that women with a history of childhood sexual abuse (CSA) are at increased risk for developing major depression (MD). Would this relationship be found in our whole data set?
Method
Three levels of CSA (non-genital, genital, and intercourse) were assessed by self-report in two groups of Han Chinese women: 6017 clinically ascertained with recurrent MD and 5983 matched controls. Diagnostic and other risk factor information was assessed at personal interview. Odds ratios (ORs) were calculated by logistic regression.
Results
We confirmed earlier results by replicating prior analyses in 3,950 new recurrent MD cases. There were no significant differences between the two data sets. Any form of CSA was significantly associated with recurrent MD (OR 4.06, 95% confidence interval (CI) [3.19–5.24]). This association strengthened with increasing CSA severity: non-genital (OR 2.21, 95% CI 1.58–3.15), genital (OR 5.24, 95% CI 3.52–8.15) and intercourse (OR 10.65, 95% CI 5.56–23.71). Among the depressed women, those with CSA had an earlier age of onset, longer depressive episodes. Recurrent MD patients those with CSA had an increased risk for dysthymia (OR 1.60, 95%CI 1.11–2.27) and phobia (OR 1.41, 95%CI 1.09–1.80). Any form of CSA was significantly associated with suicidal ideation or attempt (OR 1.50, 95% CI 1.20–1.89) and feelings of worthlessness or guilt (OR 1.41, 95% CI 1.02–2.02). Intercourse (OR 3.47, 95%CI 1.66–8.22), use of force and threats (OR 1.95, 95%CI 1.05–3.82) and how strongly the victims were affected at the time (OR 1.39, 95%CI 1.20–1.64) were significantly associated with recurrent MD.
Conclusions
In Chinese women CSA is strongly associated with recurrent MD and this association increases with greater severity of CSA. Depressed women with CSA have some specific clinical traits. Some features of CSA were associated with greater likelihood of developing recurrent MD.
doi:10.1371/journal.pone.0087569
PMCID: PMC3906190  PMID: 24489940
4.  Clinical Features of Patients with Dysthymia in a Large Cohort of Han Chinese Women with Recurrent Major Depression 
PLoS ONE  2013;8(12):e83490.
Background
Dysthymia is a form of chronic mild depression that has a complex relationship with major depressive disorder (MDD). Here we investigate the role of environmental risk factors, including stressful life events and parenting style, in patients with both MDD and dysthymia. We ask whether these risk factors act in the same way in MDD with and without dysthymia.
Results
We examined the clinical features in 5,950 Han Chinese women with MDD between 30–60 years of age across China. We confirmed earlier results by replicating prior analyses in 3,950 new MDD cases. There were no significant differences between the two data sets. We identified sixteen stressful life events that significantly increase the risk of dysthymia, given the presence of MDD. Low parental warmth, from either mother or father, increases the risk of dysthymia. Highly threatening but short-lived threats (such as rape) are more specific for MDD than dysthymia. While for MDD more severe life events show the largest odds ratio versus controls, this was not seen for cases of MDD with or without dysthymia.
Conclusions
There are increased rates of stressful life events in MDD with dysthymia, but the impact of life events on susceptibility to dysthymia with MDD differs from that seen for MDD alone. The pattern does not fit a simple dose-response relationship, suggesting that there are moderating factors involved in the relationship between environmental precipitants and the onset of dysthymia. It is possible that severe life events in childhood events index a general susceptibility to chronic depression, rather than acting specifically as risk factors for dysthymia.
doi:10.1371/journal.pone.0083490
PMCID: PMC3873934  PMID: 24386213
5.  Suicidal Risk Factors of Recurrent Major Depression in Han Chinese Women 
PLoS ONE  2013;8(11):e80030.
The relationship between suicidality and major depression is complex. Socio- demography, clinical features, comorbidity, clinical symptoms, and stressful life events are important factors influencing suicide in major depression, but these are not well defined. Thus, the aim of the present study was to assess the associations between the above-mentioned factors and suicide ideation, suicide plan, and suicide attempt in 6008 Han Chinese women with recurrent major depression (MD). Patients with any suicidality had significantly more MD symptoms, a significantly greater number of stressful life events, a positive family history of MD, a greater number of episodes, a significant experience of melancholia, and earlier age of onset. Comorbidity with dysthymia, generalized anxiety disorder (GAD), social phobia, and animal phobia was seen in suicidal patients. The present findings indicate that specific factors act to increase the likelihood of suicide in MD. Our results may help improve the clinical assessment of suicide risk in depressed patients, especially for women.
doi:10.1371/journal.pone.0080030
PMCID: PMC3842272  PMID: 24312196
6.  Clinical features and risk factors for post-partum depression in a large cohort of Chinese women with recurrent major depressive disorder 
Journal of Affective Disorders  2012;136(3):983-987.
Background
Post partum depression (PPD) is relatively common in China but its clinical characteristics and risk factors have not been studied. We set out to investigate whether known risk factors for PPD could be found in Chinese women.
Methods
A case control design was used to determine the impact of known risk factors for PPD in a cohort of 1970 Chinese women with recurrent DSM-IV major depressive disorder (MDD). In a within-case design we examined the risk factors for PPD in patients with recurrent MDD. We compared the clinical features of MDD in cases with PPD to those without MDD. Odds ratios were calculated using logistic and ordinal regression.
Results
Lower occupational and educational statuses increased the risk of PPD, as did a history of pre-menstrual symptoms, stressful life events and elevated levels of the personality trait of neuroticism. Patients with PPD and MDD were more likely to experience a comorbid anxiety disorder, had a younger age of onset of MDD, have higher levels of neuroticism and dysthymia.
Limitations
Results obtained in this clinical sample may not be applicable to PPD within the community. Data were obtained retrospectively and we do not know whether the correlations we observe have the same causes as those operating in other populations.
Conclusions
Our results are consistent with the hypothesis that the despite cultural differences between Chinese and Western women, the phenomenology and risk factors for PPD are very similar.
doi:10.1016/j.jad.2011.06.047
PMCID: PMC3315022  PMID: 21824665
Postpartum depression; Major depressive disorder; Neuroticism; Anxiety disorder
8.  Reducing Colorectal Cancer Incidence and Disparities: Performance and Outcomes of a Screening Colonoscopy Program in South Carolina 
Advances in public health  2014;2014:787282.
This study evaluated the efficiency, effectiveness, and racial disparities reduction potential of Screening Colonoscopies for People Everywhere in South Carolina (SCOPE SC), a state-funded program for indigent persons aged 50–64 years (45–64 years for African American (AA)) with a medical home in community health centers. Patients were referred to existing referral network providers, and the centers were compensated for patient navigation. Data on procedures and patient demographics were analyzed. Of 782 individuals recruited (71.2% AA), 85% (665) completed the procedure (71.1% AA). The adenoma detection rate was 27.8% (males 34.6% and females 25.1%), advanced neoplasm rate 7.7% (including 3 cancers), cecum intubation rate 98.9%, inadequate bowel preparation rate 7.9%, and adverse event rate 0.9%. All indicators met the national quality benchmarks. The adenoma rate of 26.0% among AAs aged 45–49 years was similar to that of older Whites and AAs. We found that patient navigation and a medical home setting resulted in a successful and high-quality screening program. The observed high adenoma rate among younger AAs calls for more research with larger cohorts to evaluate the appropriateness of the current screening guidelines for AAs, given that they suffer 47% higher colorectal cancer mortality than Whites.
doi:10.1155/2014/787282
PMCID: PMC4332847
9.  New insights into the fungal community from the raw genomic sequence data of fig wasp Ceratosolen solmsi 
BMC Microbiology  2015;15(1):27.
Background
To date, biologists have discovered a large amount of valuable information from assembled genomes, but the abundant microbial data that is hidden in the raw genomic sequence data of plants and animals is usually ignored. In this study, the richness and composition of fungal community were determined in the raw genomic sequence data of Ceratosolen solmsi (RGSD-CS).
Results
To avoid the interference from sequences of C. solmsi, the unmapped raw data (about 17.1%) was obtained by excluding the assembled genome of C. solmsi from RGSD-CS. Comparing two fungal reference datasets, internal transcribed spacer (ITS) and large ribosomal subunit (LSU) of rRNA, the ITS dataset discovered a more diverse fungal community and was therefore selected as the reference dataset for evaluating the fungal community based on the unmapped raw data. The threshold of 95% sequence identity revealed many more matched fungal reads and fungal richness in the unmapped raw data than those by identities above 95%. Based on the threshold of 95% sequence identity, the fungal community of RGSD-CS was primarily composed of Saccharomycetes (88.4%) and two other classes (Agaricomycetes and Sordariomycetes, 8.3% in total). Compared with the fungal community of other reported fig wasps, Agaricomycetes and Eurotiomycetes were found to be unique to C. solmsi. In addition, the ratio of total fungal reads to RGSD-CS was estimated to be at least 4.8 × 10−3, which indicated that a large amount of fungal data was contained in RGSD-CS. However, rarefaction measure indicated that a deeper sequencing coverage with RGSD-CS was required to discover the entire fungal community of C. solmsi.
Conclusion
This study investigated the richness and composition of fungal community in RGSD-CS and provided new insights into the efficient study of microbial diversity using raw genomic sequence data.
Electronic supplementary material
The online version of this article (doi:10.1186/s12866-015-0370-3) contains supplementary material, which is available to authorized users.
doi:10.1186/s12866-015-0370-3
PMCID: PMC4329198
Fungal community; Unmapped raw data; Fig wasp; Fungal reference datasets
10.  Rosuvastatin attenuates contrast-induced nephropathy through modulation of nitric oxide, inflammatory responses, oxidative stress and apoptosis in diabetic male rats 
Background
Contrast-induced nephropathy (CIN) is an important cause of acute renal failure. We observe the effect of rosuvastatin on preventing CIN in diabetic rats in current study.
Methods
Diabetic rats were then divided into five groups: 1 diabetic rats (D), 2 diabetic rats + contrast media (DCM), 3 diabetic rats + rosuvastatin (DR), 4 diabetic rats + contrast media + rosuvastatin (DRCM), 5 non-diabetic rat control (NDCM). Contrast-induced nephropathy was induced by intravenous injection a single dose of indomethacin (10 mg/kg), double doses of N-nitro-L-arginine methyl ester (10 mg/kg) and a single dose of high-osmolar contrast medium meglumine amidotrizoate (6 ml/kg). DR and DRCM group rats were treated with rosuvastatin (10 mg/kg/day) by gavage for 5 days. At the end of treatment, the experimental groups were sacrificed, and their renal tissues were investigated histopathologically beside assessments of functional activities, nitric oxide metabolites, and oxidative stress and apoptic markers.
Results
After 6 days, serum creatinine and urine microprotein were increased, and creatinine clearance, kidney nitrite were decreased in DCM rats compared with NDCM, D, DR and DRCM groups. Histopathology scores in group DCM were increased compared with groups NDCM, D and DR, but lower in group DRCM than in group DCM (p < 0.01). Kidney thiobarbituric acid-reacting substances (TBARS), serum malondialdehyde (MDA), and serum protein carbonyl content (PCC) were increased, and serum thiol was decreased in the DCM group compared with groups NDCM, D and DR; however, these results were reversed in group DRCM compared with group DCM. Both expression of IL-6, TNF-α and the percentage of apoptotic cells were increased in group DCM than in groups NDCM, D and DR, but they were decreased in group DRCM than in group DCM. The expression of phospho-p38, cleaved capase-3, and the Bax/Bcl-2 ratio, were increased in group DCM than in groups NDCM, D and DR, but were decreased in group DRCM than in group DCM.
Conclusions
Our study demonstrated that rosuvastatin treatment attenuated both inflammatory processes and apoptosis and inhibited oxidative stress and the p38 MAPK pathway in a diabetic rat model in the setting of CIN.
doi:10.1186/s12967-015-0416-1
PMCID: PMC4329210
Diabetic; Contrast-induced nephropathy (CIN); Rosuvastatin
11.  Cruciferous vegetable consumption and the risk of pancreatic cancer: a meta-analysis 
Background
Previous studies regarding the association between cruciferous vegetable intake and pancreatic cancer risk have reported inconsistent results. We conducted a meta-analysis to demonstrate the potential association between them.
Methods
A systematic literature search of papers was conducted in March 2014 using PubMed, EMBASE, and Web of Science, and the references of the retrieved articles were screened. The summary odds ratios (ORs) with 95% confidence interval (CI) for the highest versus the lowest intake of cruciferous vegetables were calculated.
Results
Four cohort and five case–control studies were eligible for inclusion. We found a significantly decreased risk of pancreatic cancer associated with the high intake of cruciferous vegetables (OR 0.78, 95% CI 0.64–0.91). Moderate heterogeneity was detected across studies (P = 0.065). There was no evidence of significant publication bias based on Begg’s funnel plot (P = 0.917) or Egger’s test (P = 0.669).
Conclusions
Cruciferous vegetable intake might be inversely associated with pancreatic cancer risk. Because of the limited number of studies included in this meta-analysis, further well-designed prospective studies are warranted to confirm the inverse association between cruciferous vegetable intake and risk of pancreatic cancer.
doi:10.1186/s12957-015-0454-4
PMCID: PMC4336706
Cruciferous vegetables; Diet; Epidemiology; Meta-analysis; Pancreatic cancer
12.  Novel Three-Component Rieske Non-Heme Iron Oxygenase System Catalyzing the N-Dealkylation of Chloroacetanilide Herbicides in Sphingomonads DC-6 and DC-2 
Applied and Environmental Microbiology  2014;80(16):5078-5085.
Sphingomonads DC-6 and DC-2 degrade the chloroacetanilide herbicides alachlor, acetochlor, and butachlor via N-dealkylation. In this study, we report a three-component Rieske non-heme iron oxygenase (RHO) system catalyzing the N-dealkylation of these herbicides. The oxygenase component gene cndA is located in a transposable element that is highly conserved in the two strains. CndA shares 24 to 42% amino acid sequence identities with the oxygenase components of some RHOs that catalyze N- or O-demethylation. Two putative [2Fe-2S] ferredoxin genes and one glutathione reductase (GR)-type reductase gene were retrieved from the genome of each strain. These genes were not located in the immediate vicinity of cndA. The four ferredoxins share 64 to 72% amino acid sequence identities to the ferredoxin component of dicamba O-demethylase (DMO), and the two reductases share 62 to 65% amino acid sequence identities to the reductase component of DMO. cndA, the four ferredoxin genes, and the two reductases genes were expressed in Escherichia coli, and the recombinant proteins were purified using Ni-affinity chromatography. The individual components or the components in pairs displayed no activity; the enzyme mixture showed N-dealkylase activities toward alachlor, acetochlor, and butachlor only when CndA-His6 was combined with one of the four ferredoxins and one of the two reductases, suggesting that the enzyme consists of three components, a homo-oligomer oxygenase, a [2Fe-2S] ferredoxin, and a GR-type reductase, and CndA has a low specificity for the electron transport component (ETC). The N-dealkylase utilizes NADH, but not NADPH, as the electron donor.
doi:10.1128/AEM.00659-14
PMCID: PMC4135782  PMID: 24928877
13.  Krt6a-Positive Mammary Epithelial Progenitors Are Not at Increased Vulnerability to Tumorigenesis Initiated by ErbB2 
PLoS ONE  2015;10(1):e0117239.
While most breast cancers are thought to arise from the luminal layer of the breast tissue, it remains unclear which specific cells in the luminal layer are the cells of origin of breast cancer. We have previously reported that WAP-positive luminal epithelial cells are at increased susceptibility to tumor initiation by ErbB2 compared to the bulk population, while the mammary cells with canonical Wnt signaling activity fail to evolve into tumors upon ErbB2 activation. Here, we used retrovirus to introduce ErbB2 into the Krt6a-positive mammary progenitor subset of the luminal epithelium and, for comparison, into the mammary luminal epithelium indiscriminately. Tumors developed from both groups of cells with a similar latency. These data indicate that the Krt6a-positive subset of mammary epithelial cells can be induced to form cancer by ErbB2 but it is not more susceptible to tumorigenesis initiated by ErbB2 than the bulk population of the luminal epithelium.
doi:10.1371/journal.pone.0117239
PMCID: PMC4311910  PMID: 25635772
14.  Conventional radiological strategy of common gastrointestinal neoplasms 
World Journal of Radiology  2015;7(1):7-16.
This article summarizes the clinical characteristics and imaging features of common gastrointestinal (GI) neoplasms in terms of conventional radiological imaging methods. Barium studies are readily available for displaying primary malignancies and are minimally or not at all invasive. A neoplasm may be manifested as various imaging findings, including mucosal disruption, soft mass, ulcer, submucosal invasion and lumen stenosis on barium studies. Benign tumors typically appear as smoothly marginated intramural masses. Malignant neoplasms most often appear as irregular infiltrative lesions on barium examination. Tumor extension to adjacent GI segments may be indistinct on barium images. Cross-sectional images such as computed tomography and magnetic resonance imaging may provide more accurate details of the adjacent organ invasion, omental or peritoneal spread.
doi:10.4329/wjr.v7.i1.7
PMCID: PMC4295176  PMID: 25628800
Gastrointestinal; Barium enema; Computed tomography; Magnetic resonance imaging; Neoplasm
15.  Impact of enteral nutrition on energy metabolism in patients with Crohn’s disease 
AIM: To investigate the impact of enteral nutrition (EN) on the body composition and metabolism in patients with Crohn’s disease (CD).
METHODS: Sixty-one patients diagnosed with CD were enrolled in this study. They were given only EN (enteral nutritional suspension, TPF, non-elemental diet) support for 4 wk, without any treatment with corticosteroids, immunosuppressive drugs, infliximab or by surgical operation. Body composition statistics such as weight, body mass index, skeletal muscle mass (SMM), fat mass, protein mass and inflammation indexes such as C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and CD activity index (CDAI) were recorded before and after EN support.
RESULTS: The 61 patients were divided into three groups according to CDAI before and after EN support: A (active phase into remission via EN, n = 21), B (remained in active phase before and after EN, n = 19) and C (in remission before and after EN, n = 21). Patients in group A had a significant increase in SMM (22.11 ± 4.77 kg vs 23.23 ± 4.49 kg, P = 0.044), protein mass (8.01 ± 1.57 kg vs 8.44 ± 1.45 kg, P = 0.019) and decrease in resting energy expenditure (REE) per kilogram (27.42 ± 5.01 kcal/kg per day vs 22.62 ± 5.45 kcal/kg per day, P < 0.05). There was no significant difference between predicted and measured REE in active CD patients according to the Harris-Benedict equation. There was no linear correlation between the measured REE and CRP, ESR or CDAI in active CD patients.
CONCLUSION: EN could decrease the hypermetabolism in active CD patients by reducing the inflammatory response.
doi:10.3748/wjg.v21.i4.1299
PMCID: PMC4306176  PMID: 25632205
Crohn’s disease; Enteral nutrition; Body composition; Metabolism
16.  Comprehensive insights into the response of Alexandrium tamarense to algicidal component secreted by a marine bacterium 
Harmful algal blooms occur throughout the world, threatening human health, and destroying marine ecosystems. Alexandrium tamarense is a globally distributed and notoriously toxic dinoflagellate that is responsible for most paralytic shellfish poisoning incidents. The culture supernatant of the marine algicidal bacterium BS02 showed potent algicidal effects on A. tamarense ATGD98-006. In this study, we investigated the effects of this supernatant on A. tamarense at physiological and biochemical levels to elucidate the mechanism involved in the inhibition of algal growth by the supernatant of the strain BS02. Reactive oxygen species (ROS) levels increased following exposure to the BS02 supernatant, indicating that the algal cells had suffered from oxidative damage. The levels of cellular pigments, including chlorophyll a and carotenoids, were significantly decreased, which indicated that the accumulation of ROS destroyed pigment synthesis. The decline of the maximum photochemical quantum yield (Fv/Fm) and relative electron transport rate (rETR) suggested that the photosynthesis systems of algal cells were attacked by the BS02 supernatant. To eliminate the ROS, the activities of antioxidant enzymes, including superoxide dismutase (SOD) and catalase (CAT), increased significantly within a short period of time. Real-time PCR revealed changes in the transcript abundances of two target photosynthesis-related genes (psbA and psbD) and two target respiration-related genes (cob and cox). The transcription of the respiration-related genes was significantly inhibited by the treatments, which indicated that the respiratory system was disturbed. Our results demonstrate that the BS02 supernatant can affect the photosynthesis process and might block the PS II electron transport chain, leading to the production of excessive ROS. The increased ROS can further destroy membrane integrity and pigments, ultimately inducing algal cell death.
doi:10.3389/fmicb.2015.00007
PMCID: PMC4304249  PMID: 25667582
Alexandrium tamarense; algicidal bacterium; photosynthetic responses; oxidative stress; antioxidant enzyme; gene expression inhibition
17.  Early B-cell factor 3 (EBF3) is a novel tumor suppressor gene with promoter hypermethylation in pediatric acute myeloid leukemia 
Background
Pediatric acute myeloid leukemia (AML) comprises up to 20% of all childhood leukemia. Recent research shows that aberrant DNA methylation patterning may play a role in leukemogenesis. The epigenetic silencing of the EBF3 locus is very frequent in glioblastoma. However, the expression profiles and molecular function of EBF3 in pediatric AML is still unclear.
Methods
Twelve human acute leukemia cell lines, 105 pediatric AML samples and 30 normal bone marrow/idiopathic thrombocytopenic purpura (NBM/ITP) control samples were analyzed. Transcriptional level of EBF3 was evaluated by semi-quantitative and real-time PCR. EBF3 methylation status was determined by methylation specific PCR (MSP) and bisulfite genomic sequencing (BGS). The molecular mechanism of EBF3 was investigated by apoptosis assays and PCR array analysis.
Results
EBF3 promoter was hypermethylated in 10/12 leukemia cell lines. Aberrant EBF3 methylation was observed in 42.9% (45/105) of the pediatric AML samples using MSP analysis, and the BGS results confirmed promoter methylation. EBF3 expression was decreased in the AML samples compared with control. Methylated samples revealed similar survival outcomes by Kaplan-Meier survival analysis. EBF3 overexpression significantly inhibited cell proliferation and increased apoptosis. Real-time PCR array analysis revealed 93 dysregulated genes possibly implicated in the apoptosis of EBF3-induced AML cells.
Conclusion
In this study, we firstly identified epigenetic inactivation of EBF3 in both AML cell lines and pediatric AML samples for the first time. Our findings also showed for the first time that transcriptional overexpression of EBF3 could inhibit proliferation and induce apoptosis in AML cells. We identified 93 dysregulated apoptosis-related genes in EBF3-overexpressing, including DCC, AIFM2 and DAPK1. Most of these genes have never been related with EBF3 over expression. These results may provide new insights into the molecular mechanism of EBF3-induced apoptosis; however, further research will be required to determine the underlying details.
Our findings suggest that EBF3 may act as a putative tumor suppressor gene in pediatric AML.
doi:10.1186/s13046-014-0118-1
PMCID: PMC4311429  PMID: 25609158
Early B-cell factor 3; Pediatric acute myeloid leukemia; Methylation; Tumor suppressor; Real-time PCR array
18.  Identification and validation of the methylation biomarkers of non-small cell lung cancer (NSCLC) 
Clinical Epigenetics  2015;7(1):3.
Background
DNA methylation was suggested as the promising biomarker for lung cancer diagnosis. However, it is a great challenge to search for the optimal combination of methylation biomarkers to obtain maximum diagnostic performance.
Results
In this study, we developed a panel of DNA methylation biomarkers and validated their diagnostic efficiency for non-small cell lung cancer (NSCLC) in a large Chinese Han NSCLC retrospective cohort. Three high-throughput DNA methylation microarray datasets (458 samples) were collected in the discovery stage. After normalization, batch effect elimination and integration, significantly differentially methylated genes and the best combination of the biomarkers were determined by the leave-one-out SVM (support vector machine) feature selection procedure. Then, candidate promoters were examined by the methylation status determined single nucleotide primer extension technique (MSD-SNuPET) in an independent set of 150 pairwise NSCLC/normal tissues. Four statistical models with fivefold cross-validation were used to evaluate the performance of the discriminatory algorithms. The sensitivity, specificity and accuracy were 86.3%, 95.7% and 91%, respectively, in Bayes tree model. The logistic regression model incorporated five gene methylation signatures at AGTR1, GALR1, SLC5A8, ZMYND10 and NTSR1, adjusted for age, sex and smoking, showed robust performances in which the sensitivity, specificity, accuracy, and area under the curve (AUC) were 78%, 97%, 87%, and 0.91, respectively.
Conclusions
In summary, a high-throughput DNA methylation microarray dataset followed by batch effect elimination can be a good strategy to discover optimal DNA methylation diagnostic panels. Methylation profiles of AGTR1, GALR1, SLC5A8, ZMYND10 and NTSR1, could be an effective methylation-based assay for NSCLC diagnosis.
Electronic supplementary material
The online version of this article (doi:10.1186/s13148-014-0035-3) contains supplementary material, which is available to authorized users.
doi:10.1186/s13148-014-0035-3
PMCID: PMC4318209  PMID: 25657825
Non-small cell lung cancer; DNA methylation; Biomarker; Batch effect elimination; Diagnosis
19.  Aged Mice are Unable to Mount an Effective Myeloid Response to Sepsis 
Journal of immunology (Baltimore, Md. : 1950)  2013;192(2):10.4049/jimmunol.1302109.
The elderly have increased morbidity and mortality following sepsis; however, the cause(s) remain unclear. We hypothesized that these poor outcomes are due in part to defects in innate immunity, rather than to an exaggerated early inflammatory response. Juvenile (6–12 weeks) or aged (20–24 months) mice underwent polymicrobial sepsis and subsequently, the aged mice had increased mortality and defective peritoneal bacterial clearance compared to young mice. No differences were found in the magnitude of the plasma cytokine responses. Although septic aged mice displayed equivalent or increased numbers of circulating, splenic and bone marrow myeloid cells, some of these cells exhibited decreased phagocytosis, reactive oxygen species production and chemotaxis. Blood leukocyte gene expression was less altered in aged versus young mice one day after sepsis. Aged mice had a relative inability to upregulate gene expression of pathways related to ‘PMN-mediated protective immunity’, ‘chemokine/chemokine receptor binding’ and ‘responses to exogenous molecules’. Expression of most MHC genes remained more down-regulated in aged mice at day three. Despite their increased myeloid response to sepsis, the increased susceptibility of aged mice to sepsis appears not to be due to an exaggerated inflammatory response, but rather, a failure to mount an effective innate immune response.
doi:10.4049/jimmunol.1302109
PMCID: PMC3884685  PMID: 24337739
20.  Blood pressure decrease correlates with tau pathology and memory decline in hypertensive elderly 
Neurobiology of aging  2013;35(1):64-71.
In hypertension, cerebral blood flow regulation limits are changed, and the threshold for blood pressure at which perfusion is safely maintained is higher. This shift may increase the brain's vulnerability to lower blood pressure in subjects with vascular disease. We investigated whether longitudinal reduction in mean arterial pressure (MAP) was related to changes in CSF biomarkers of Alzheimer's disease in a group of cognitively healthy elderly with and without hypertension (HTN). The relationships between MAP, memory decline and hippocampal atrophy were also examined. Seventy-seven subjects (age 63.4±9.4, range 44-86 years; education 16.9±2.1, range 10-22 years; 60% women) were assessed twice, 2±0.5 years apart. At both time points, all subjects underwent full medical and neuropsychological evaluations, lumbar punctures and MRI examinations. Twenty-five subjects had HTN. Hypertensive and normotensive subjects did not differ in their CSF biomarkers, hippocampal volumes or memory scores at baseline. In the entire study group, the increase in p-tau181 was associated with a decline in verbal episodic memory (ß=−.30, p=.01) and hippocampal volume reduction (ß=−.27, p=.02). However, longitudinal decrease in MAP was related to memory decline (β=0.50, p=.01) and an increase in p-tau181 (β=−0.50, p=.01) only in subjects with hypertension. Our findings suggest that the hypertensive group may be sensitive to blood pressure reductions.
doi:10.1016/j.neurobiolaging.2013.06.011
PMCID: PMC3799812  PMID: 23969178
21.  Human bocavirus 1 infects commercially-available primary human airway epithelium cultures productively 
Journal of virological methods  2013;195:10.1016/j.jviromet.2013.10.012.
Human bocavirus 1 (HBoV1), a human parvovirus, belongs to the genus Bocavirus of the Parvoviridae family. It causes wheezing in young children with acute respiratory tract infections. HBoV1 has been shown to infect polarized human airway epithelium (HAE) made in house, and induces airway epithelial damage. In this study, two commercially-available HAE cultures, EpiAirway and MucilAir HAE, were examined for HBoV1 infection. Both HAE cultures support fully productive HBoV1 infection. Infected EpiAirway and MucilAir HAE cultures showed loss of cilia, disruption of the tight junction barrier, and a significant decrease in transepithelial electrical resistance. Notably, HBoV1 persistent infection was demonstrated by maintaining HBoV1-infected EpiAirway HAE for as long as 50 days. After 2 days post-infection, progeny virus was produced consistently daily at a level of over 2 × 108 viral genome copies per culture (0.6 cm2). This study is the first to use commercial sources of HAE cultures for HBoV1 infection. The availability of these cultures will enable a wide range of laboratories to study HBoV1 infection.
doi:10.1016/j.jviromet.2013.10.012
PMCID: PMC3855471  PMID: 24134939
22.  Toll-like receptor 7-stimulated tumor necrosis factor α causes bone marrow damage in systemic lupus erythematosus 
Objective
To define the pathogenesis of bone marrow (BM) involvement in systemic lupus erythematosus (SLE).
Methods
Tumor necrosis factor-α (TNFα), cell death, and cellular damage in BM from SLE patients, controls, and mice with pristane-induced lupus were analyzed morphologically and using immunohistochemistry. The pathogenesis of BM abnormalities was studied in wild-type, and TNFα-, TLR7-, and interferon-α receptor-deficient, along with B cell-deficient (µmt) mice treated with pristane. Flow cytometry was used to examine TNFα production (intracellular staining) and plasma cell/plasmablast development. CXCL12 expression was determined by quantitative PCR.
Results
SLE patients’ BM exhibited striking death of niche and hematopoietic cells associated with TNFα over-production. BM from mice with an IFN-I-mediated lupus syndrome induced by pristane showed similar abnormalities. TNFα was produced mainly by BM neutrophils, many with phagocytosed nuclear material (LE cells). TNFα production was abolished in TLR7−/− and µmt mice but was restored in µmt mice by infusing normal plasma. Pristane-treated wild-type- and IFNAR−/− mice developed anemia, BM hypocellularity, and extramedullary hematopoiesis, which were absent in TLR7−/− and TNFα−/− mice. Additionally, CXCL12, which is produced by stromal cells and mediates homing of hematopoietic cells and plasmablasts, was decreased in BM from pristane-treated wild-type mice but normal in TNFα−/− mice.
Conclusion
Although autoantibodies and glomerulonephritis are IFN-I dependent, lupus-associated BM abnormalities were TLR7- and TNFα-driven, but IFN-I-independent, suggesting that lupus is a disorder of innate immunity in which TLR7 activation by phagocytosed nuclei causes relentless IFN-I and TNFα production mediating glomerulonephritis and hematologic involvement, respectively.
doi:10.1002/art.38189
PMCID: PMC3990233  PMID: 24449581
23.  Analysis of Ordinal Outcomes with Longitudinal Covariates Subject to Missingness 
Journal of applied statistics  2013;41(5):1040-1052.
We propose a mixture model for data with an ordinal outcome and a longitudinal covariate that is subject to missingness. Data from a tailored telephone delivered, smoking cessation intervention for construction laborers are used to illustrate the method, which considers as an outcome a categorical measure of smoking cessation, and evaluates the effectiveness of the motivational telephone interviews on this outcome. We propose two model structures for the longitudinal covariate, for the case when the missing data are missing at random, and when the missing data mechanism is non-ignorable. A generalized EM algorithm is used to obtain maximum likelihood estimates.
doi:10.1080/02664763.2013.859236
PMCID: PMC4002054  PMID: 24791038
ordinal outcomes; longitudinal covariates; missingness
24.  Mitochondrial Polymorphism A10398G and Haplogroup I Are Associated With Fuchs' Endothelial Corneal Dystrophy 
Purpose.
We investigated whether mitochondrial DNA (mtDNA) variants affect the susceptibility of Fuchs endothelial corneal dystrophy (FECD).
Methods.
Ten mtDNA variants defining European haplogroups were genotyped in a discovery dataset consisting of 530 cases and 498 controls of European descent from the Duke FECD cohort. Association tests for mtDNA markers and haplogroups were performed using logistic regression models with adjustment of age and sex. Subset analyses included controlling for additional effects of either the TCF4 SNP rs613872 or cigarette smoking. Our replication dataset was derived from the genome-wide association study (GWAS) of the FECD Genetics Consortium, where genotypes for three of 10 mtDNA markers were available. Replication analyses were performed to compare non-Duke cases to all GWAS controls (GWAS1, N = 3200), and to non-Duke controls (GWAS2, N = 3043).
Results.
The variant A10398G was significantly associated with FECD (odds ratio [OR] = 0.72; 95% confidence interval [CI] = [0.53, 0.98]; P = 0.034), and remains significant after adjusting for smoking status (min P = 0.012). This variant was replicated in GWAS1 (P = 0.019) and GWAS2 (P = 0.036). Haplogroup I was significantly associated with FECD (OR = 0.46; 95% CI = [0.22, 0.97]; P = 0.041) and remains significant after adjusting for the effect of smoking (min P = 0.008) or rs613872 (P = 0.034).
Conclusions.
The 10398G allele and Haplogroup I appear to confer significant protective effects for FECD. The effect of A10398G and Haplogroup I to FECD is likely independent of the known TCF4 variant. More data are needed to decipher the interaction between smoking and mtDNA haplogroups.
The nine European mitochondrial haplogroups were investigated for the susceptibility of Fuchs endothelial corneal dystrophy (FECD). A10398G and Haplogroup I were found significantly decreasing the risk of FECD.
doi:10.1167/iovs.13-13517
PMCID: PMC4109404  PMID: 24917144
mitochondrial haplogroup; genetic association; oxidative stress; TCF4; smoking
25.  Molecular Targeting of the Oncoprotein PLK1 in Pediatric Acute Myeloid Leukemia: RO3280, a Novel PLK1 Inhibitor, Induces Apoptosis in Leukemia Cells 
Polo-like kinase 1 (PLK1) is highly expressed in many cancers and therefore a biomarker of transformation and potential target for the development of cancer-specific small molecule drugs. RO3280 was recently identified as a novel PLK1 inhibitor; however its therapeutic effects in leukemia treatment are still unknown. We found that the PLK1 protein was highly expressed in leukemia cell lines as well as 73.3% (11/15) of pediatric acute myeloid leukemia (AML) samples. PLK1 mRNA expression was significantly higher in AML samples compared with control samples (82.95 ± 110.28 vs. 6.36 ± 6.35; p < 0.001). Kaplan-Meier survival analysis revealed that shorter survival time correlated with high tumor PLK1 expression (p = 0.002). The 50% inhibitory concentration (IC50) of RO3280 for acute leukemia cells was between 74 and 797 nM. The IC50 of RO3280 in primary acute lymphocytic leukemia (ALL) and AML cells was between 35.49 and 110.76 nM and 52.80 and 147.50 nM, respectively. RO3280 induced apoptosis and cell cycle disorder in leukemia cells. RO3280 treatment regulated several apoptosis-associated genes. The regulation of DCC, CDKN1A, BTK, and SOCS2 was verified by western blot. These results provide insights into the potential use of RO3280 for AML therapy; however, the underlying mechanisms remain to be determined.
doi:10.3390/ijms16011266
PMCID: PMC4307303  PMID: 25574601
RO3280; pediatric acute myeloid leukemia (AML); polo-like kinase 1 (PLK1); apoptosis; oncogene target

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