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1.  A literature review of indirect costs associated with stroke 
doi:10.1016/j.jstrokecerebrovasdis.2014.02.017
PMCID: PMC4383399  PMID: 24957313
stroke; ischemic stroke; hemorrhage; economic burden; indirect cost; productivity loss; cost of informal care
2.  Primary care providers' recommendations for hypertension prevention, DocStyles Survey, 2012 
Background
Healthy behaviors, including maintaining an ideal body weight, eating a healthy diet, being physically active, limiting alcohol intake, and not smoking, can help prevent hypertension. The objective of this study was to determine the prevalence of recommending these behaviors to patients by primary care providers (PCPs) and to assess what PCP characteristics, if any, were associated with making the recommendations.
Methods
DocStyles 2012, a web-based panel survey, was used to assess PCPs' demographic characteristics, health-related behaviors, practice setting, and prevalence of making selected recommendations to prevent hypertension. Logistic regression was used to calculate the odds of making all 6 recommendations, by demographic, professional, or personal health behavior characteristics.
Results
Overall, 1,253 PCPs responded to the survey (537 family physicians, 464 internists, and 252 nurse practitioners). To prevent hypertension, 89.4% recommended a healthy diet, 89.9% recommended lower salt intake, 90.3% recommended maintaining a healthy weight, 69.4% recommended limiting alcohol intake, 95.1% recommended being physically active, and 90.4% recommended smoking cessation for their patients who smoked. More than half (56.1%) of PCPs recommended all 6 healthy behaviors. PCPs' demographic characteristics and practice setting were not associated with recommending all 6. PCPs who reported participating in regular physical activity (odds ratio [OR] 1.68, 95% confidence interval [CI] 1.05−2.67) and eating healthy diet (OR 1.68, 95% CI 1.11−2.56) were more likely to offer all 6 healthy behavior recommendations than those without these behaviors.
Conclusion
Most PCPs recommended healthy behaviors to their adult patients to prevent hypertension. PCPs' own healthy behaviors were associated with their recommendations. Preventing hypertension is a multifactorial effort, and in the clinical environment, PCPs have frequent opportunities to model and promote healthy lifestyles to their patients.
doi:10.1177/2150131915568997
PMCID: PMC4466071  PMID: 25653043
Primary care providers; hypertension (high blood pressure); prevention; healthy behaviors
3.  Hypoxia-inducible miR-182 enhances HIF1α signaling via targeting PHD2 and FIH1 in prostate cancer 
Scientific Reports  2015;5:12495.
Activation of hypoxia-inducible factor 1α (HIF1α) controls the transcription of genes governing angiogenesis under hypoxic condition during tumorigenesis. Here we show that hypoxia-responsive miR-182 is regulated by HIF1α at transcriptional level. Prolyl hydroxylase domain enzymes (PHD) and factor inhibiting HIF-1 (FIH1), negative regulators of HIF1 signaling, are direct targets of miR-182. Overexpression of miR-182 in prostate cancer cells led to a reduction of PHD2 and FIH1 expression and an increase in HIF1α level either under normoxic or hypoxic condition. Consistently, inhibition of miR-182 could increase PHD2 and FIH1 levels, thereby reducing the hypoxia-induced HIF1α expression. Matrigel plug assay showed that angiogenesis was increased by miR-182 overexpression, and vice versa. miR-182 overexpression in PC-3 prostate cancer xenografts decreased PHD2 and FIH1 expression, elevated HIF1α protein levels, and increased tumor size. Lastly, we revealed that the levels of both miR-182 and HIF1α were elevated, while the expression PHD2 and FIH1 was downregulated in a mouse model of prostate cancer. Together, our results suggest that the interplay between miR-182 and HIF1α could result in a sustained activation of HIF1α pathway, which might facilitate tumor cell adaption to hypoxic stress during prostate tumor progression.
doi:10.1038/srep12495
PMCID: PMC4513346  PMID: 26205124
4.  Long noncoding RNA expression profiles in gut tissues constitute molecular signatures that reflect the types of microbes 
Scientific Reports  2015;5:11763.
The gut microbiota is commonly referred to as a hidden organ due to its pivotal effects on host physiology, metabolism, nutrition and immunity. The gut microbes may be shaped by environmental and host genetic factors, and previous studies have focused on the roles of protein-coding genes. Here we show a link between long non-coding RNA (lncRNA) expression and gut microbes. By repurposing exon microarrays and comparing the lncRNA expression profiles between germ-free, conventional and different gnotobiotic mice, we revealed subgroups of lncRNAs that were specifically enriched in each condition. A nearest shrunken centroid methodology was applied to obtain lncRNA-based signatures to identify mice in different conditions. The lncRNA-based prediction model successfully identified different gnotobiotic mice from conventional and germ-free mice, and also discriminated mice harboring transplanted microbes from fecal samples of mice or zebra fishes. To achieve optimal prediction accuracy, fewer lncRNAs were required in the prediction model than protein-coding genes. Taken together, our study demonstrated the effecacy of lncRNA expression profiles in discriminating the types of microbes in the gut. These results also provide a resource of gut microbe-associated lncRNAs for the development of lncRNA biomarkers and the identification of functional lncRNAs in host-microbes interactions.
doi:10.1038/srep11763
PMCID: PMC4485256  PMID: 26123364
5.  Non–High-Density Lipoprotein Cholesterol: Distribution and Prevalence of High Serum Levels in Children and Adolescents: United States National Health and Nutrition Examination Surveys, 2005–2010 
The Journal of pediatrics  2013;164(2):247-253.
Objectives
To estimate age-related changes for serum concentration of non–high-density lipoprotein cholesterol (HDL-C), describe non-HDL-C distribution, and examine the prevalence of high non-HDL-C levels in children and adolescents by demographic characteristics and weight status.
Study design
Data from 7058 participants ages 6–19 years in the 2005–2010 National Health and Nutrition Examination Surveys were analyzed. A high level of non-HDL-C was defined as a non-HDL-C value ≥145mg/dL.
Results
Locally weighted scatterplot smoothing–smoothed curves showed that non-HDL-C levels increased from 101 mg/dL at age 6 to 111 mg/dL at age 10, decreased to 101 mg/dL at age 14, and then increased to 122 mg/dL at age 19 in non-Hispanic white males. Non-HDL-C levels generally were greater in female than male subjects, lower in non-Hispanic black subjects, and similar in male and slightly lower in female Mexican American subjects, compared with non-Hispanic white subjects. The overall mean was 108 (SE 0.5), and the percentiles were 67 (5th), 74 (10th), 87 (25th), 104 (50th), 123 (75th), 145 (90th), and 158 (95th) mg/dL. Mean and percentiles were greater among age groups 9–11 and 17–19 years than others and greater among non-Hispanic white than non-Hispanic black subjects. The prevalence of high non-HDL-C was 11.8% (95% CI 9.9%–14.0%) and 15.0% (95% CI 12.9%–17.3%) for the age groups 9–11 and 17–19, respectively. It varied significantly by race/ethnicity and overweight/obesity status.
Conclusion
Non-HDL-C levels vary by age, sex, race/ethnicity, and weight classification status. Evaluation of non-HDL-C in youth should account for its normal physiologic patterns and variations in demographic characteristics and weight classification.
doi:10.1016/j.jpeds.2013.08.069
PMCID: PMC4476269  PMID: 24139441
6.  Urokinase-type plasminogen activator receptor signaling is critical in nasopharyngeal carcinoma cell growth and metastasis 
Cell Cycle  2014;13(12):1958-1969.
Nasopharyngeal carcinoma (NPC) is one of the most common malignancies in southern China and Southeast Asia, with the highest metastasis rate among head and neck cancers. The mechanisms underlying NPC progression remain poorly understood. Genome-wide expression profiling on 18 NPC vs. 18 noncancerous nasopharyngeal tissues together with GeneGo pathway analysis and expression verification in NPC cells and tissues revealed a potential role of urokinase-type plasminogen activator receptor (uPAR) in NPC progression, which has not been investigated in NPC. We then observed that uPAR expression is increased in poorly differentiated, highly metastatic NPC cells compared with lowly metastatic cells or differentiated NPC cells. In vitro studies demonstrated that uPAR regulates NPC cell growth, colony formation, migration, and invasion and promotes the epithelial–mesenchymal transition (EMT). Additional tumor xenograft and spontaneous metastasis experiments revealed that uPAR promotes NPC cell growth and metastasis in vivo. The JAK–STAT pathway is involved in uPAR-regulated signaling in NPC cells as determined by immunoblotting. Moreover, uPAR-mediated growth and motility is partially abolished upon treatment with the Jak1/Jak2 inhibitor INCB018424. We suppressed uPA expression in uPAR-overexpressing NPC cells and found that uPAR-mediated cellular growth and motility is not exclusively dependent on uPA. In summary, uPAR is a significant regulator of NPC progression and could serve as a promising therapeutic target.
doi:10.4161/cc.28921
PMCID: PMC4111759  PMID: 24763226
uPAR; nasopharyngeal carcinoma; JAK; STAT; genome-wide expression profiling; tumor growth; metastasis
7.  Identification of Breast Cancer Using Integrated Information from MRI and Mammography 
PLoS ONE  2015;10(6):e0128404.
Objectives
Integration of information from corresponding regions between the breast MRI and an X-ray mammogram could benefit the detection of breast cancer in clinical diagnosis. We aimed to provide a framework of registration from breast MRI to mammography and to evaluate the diagnosis using the combined information.
Materials and Methods
43 patients with 46 lesions underwent both MRI and mammography scans, and the interval between the two examinations was around one month. The distribution of malignant to benign lesions was 31/46 based on histological results. Maximum intensity projection and thin-plate spline methods were applied for image registration for MRI to mammography. The diagnosis using integrated information was evaluated using results of histology as the reference. The assessment of annotations and statistical analysis were performed by the two radiologists.
Results
For the cranio-caudal view, the mean post-registration error between MRI and mammography was 2.2±1.9 mm. For the medio-lateral oblique view, the proposed approach performed even better with a mean error of 3.0±2.4 mm. In the diagnosis using MRI assessment with information of mammography, the sensitivity was 91.9±2.3% (29/31, 28/31), specificity 70.0±4.7% (11/15, 10/15), accuracy 84.8±3.1% (40/46, 38/46), positive predictive value 86.4±2.1% (29/33, 28/33) and negative predictive value 80.8±5.4% (11/13, 10/13).
Conclusion
MRI with the aid of mammography shows potential improvements of sensitivity, specificity, accuracy, PPV and NPV in clinical breast cancer diagnosis compared to the use of MRI alone.
doi:10.1371/journal.pone.0128404
PMCID: PMC4461246  PMID: 26056841
8.  Differences in breast cancer characteristics and outcomes between Caucasian and Chinese women in the US 
Oncotarget  2015;6(14):12774-12782.
Chinese breast cancer patients living in the United States (US) can experience different disease patterns than Caucasians, which might allow for predicting the future epidemiology of breast cancer in China. We aimed to compare the clinicopathologic characteristics and outcomes of Caucasian and Chinese female breast cancer patients residing in the US. The study cohort consisted of 3868 Chinese and 208621 Caucasian women (diagnosed from 1990 to 2009) in the US Surveillance, Epidemiology, and End Results (SEER) database. Compared with the Caucasian patients, the US-residing Chinese patients had a younger age at diagnosis and a higher family income, remained married longer, and more frequently lived in metropolitan areas. Other tumor characteristics were similarly distributed between the two races. Compared with the Caucasians, the Chinese patients had a significantly improved overall survival (OS) but similar breast cancer-specific survival (BCSS). Our analysis suggested that US-residing Chinese patients had significant differences in age, family income, marital status and area of residence, compared with their Caucasian counterparts. No significant disparities were noted in BCSS between the two races, whereas the Chinese patients had a significantly better OS. These findings warrant further investigation and should be considered in the screening and treatment of breast cancer.
PMCID: PMC4494973  PMID: 25904050
breast cancer; clinicopathological characteristics; prognosis; Chinese; Caucasian
9.  Use of Low-dose Aspirin as Secondary Prevention of Atherosclerotic Cardiovascular Disease Among US Adults (From the National Health Interview Survey, 2012) 
The American journal of cardiology  2015;115(7):895-900.
Current guidelines recommend that adults with atherosclerotic cardiovascular disease take low-dose aspirin or other antiplatelet medications as secondary prevention of recurrent cardiovascular events. Yet, no national level assessment of low-dose aspirin use for secondary prevention of cardiovascular disease has been reported among a community-based population. Using data from the 2012 National Health Interview Survey, we assessed low-dose aspirin use among those with atherosclerotic cardiovascular disease. We estimated the prevalence ratios of low-dose aspirin use, adjusting for sociodemographic status, health insurance, and cardiovascular risk factors. Among those with atherosclerotic cardiovascular disease (n=3,068), 76% had been instructed to take aspirin, and 88% of those were following this advice. Of those not advised, 11% took aspirin on this own. Overall, 70% were taking aspirin (including those who followed their health care provider's advice and those who were not advised but took aspirin on their own). Logistic regression models showed that women, non-Hispanic blacks and Hispanics, those aged 40–64 years, with a high school education or with some college, or with fewer cardiovascular disease risk factors were less likely to take aspirin than men, non-Hispanic whites, those aged ≥65 years, with a college education or higher, or with all four selected cardiovascular disease risk factors, respectively. Additional analyses conducted among those with coronary heart disease only (n=2,007) showed similar patterns. In conclusion, use of low-dose aspirin for secondary prevention was 70%, with high reported adherence to health care providers' advice to take low-dose aspirin (88%), and significant variability within subgroups.
doi:10.1016/j.amjcard.2015.01.014
PMCID: PMC4365416  PMID: 25670639
atherosclerotic cardiovascular disease; low-dose-aspirin; cardiovascular prevention; surveillance
10.  WNT5A promotes stemness characteristics in nasopharyngeal carcinoma cells leading to metastasis and tumorigenesis 
Oncotarget  2015;6(12):10239-10252.
Nasopharyngeal carcinoma (NPC) has the highest metastasis rate among head and neck cancers with unclear mechanism. WNT5A belongs to the WNT family of cysteine-rich secreted glycoproteins. Our previous high-throughput gene expression profiling revealed that WNT5A was up-regulated in highly metastatic cells. In the present study, we first confirmed the elevated expression of WNT5A in metastatic NPC tissues at both the mRNA and protein levels. We then found that WNT5A promoted epithelial-mesenchymal transition (EMT) in NPC cells, induced the accumulation of CD24-CD44+ cells and side population, which are believed to be cancer stem cell characteristics. Moreover, WNT5A promoted the migration and invasion of NPC cells in vitro, while in vivo treatment with recombinant WNT5A promoted lung metastasis. Knocking down WNT5A diminished NPC tumorigenesis in vivo. When elevated expression of WNT5A coincided with the elevated expression of vimentin in the primary NPC, the patients had a poorer prognosis. Among major signaling pathways, protein kinase C (PKC) signaling was activated by WNT5A in NPC cells. A positive feedback loop between WNT5A and phospho-PKC to promote EMT was also revealed. Taken together, these data suggest that WNT5A is an important molecule in promoting stem cell characteristics in NPC, leading to tumorigenesis and metastasis.
PMCID: PMC4496352  PMID: 25823923
nasopharyngeal carcinoma; WNT5A; metastasis; tumorigenesis; PKC
11.  Copy Number Variants and Genetic Polymorphisms in TBX21, GATA3, Rorc, Foxp3 and Susceptibility to Behcet's Disease and Vogt-Koyanagi-Harada Syndrome 
Scientific Reports  2015;5:9511.
This study aimed to investigate the role of genetic variants including single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) of TBX21, GATA3, Rorc and Foxp3 genes in Behcet's disease (BD) and Vogt-Koyanagi-Harada (VKH) syndrome in a Chinese Han population. Genotyping of 25 SNPs was performed by iPLEX system (Sequenom) or polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). TaqMan real time PCR was used to assess CNVs. The expression of Rorc and Foxp3 were examined by real-time PCR and cytokine production was measured by ELISA. High Rorc CNV was associated with the susceptibility to BD (P = 8.99 × 10−8, OR = 3.0), and low Foxp3 CNV predisposed to BD in female patients (P = 1.92 × 10−5, OR = 3.1). CNVs for the investigated genes were not altered in VKH syndrome. Further functional studies demonstrated that the relative mRNA expression levels of Rorc were increased in individuals with high Rorc copy number, but not for Foxp3. Increased production of IL-1β and IL-6 was found in individuals carrying a high CNV of Rorc. Our study showed that high CNVs of Rorc and low CNVs of Foxp3 confer risk for BD but not for VKH syndrome. The tested 25 SNPs in TBX21, GATA3, Rorc and Foxp3 did not associate with BD and VKH syndrome.
doi:10.1038/srep09511
PMCID: PMC4397537  PMID: 25873156
12.  Conformational analysis of processivity clamps in solution demonstrates that tertiary structure does not correlate with protein dynamics 
Summary
The relationship between protein sequence, structure, and dynamics has been elusive. We report one of the first comprehensive analyses using an in-solution experimental approach to study how the conservation of tertiary structure correlates with protein dynamics. Hydrogen exchange measurements of eight processivity clamp proteins from different species revealed that, despite highly similar three-dimensional structures, clamp proteins display a wide range of dynamic behavior. Differences were apparent both for structurally similar domains within proteins and for corresponding domains of different proteins. Several of the clamps contained regions that underwent local unfolding with different half-lives. We also observed a conserved pattern of alternating dynamics of the α-helices lining the inner pore of the clamps as well as a correlation between dynamics and the number of salt bridges in these α-helices. Our observations reveal that tertiary structure and dynamics are not directly correlated and that primary structure plays an important role in dynamics.
doi:10.1016/j.str.2014.02.001
PMCID: PMC3984358  PMID: 24613485
hydrogen exchange mass spectrometry; DNA replication; PCNA; alpha-helix
13.  Effects of Aflatoxin B1 on T-Cell Subsets and mRNA Expression of Cytokines in the Intestine of Broilers 
This study was conducted to investigate the effects of aflatoxin B1 (AFB1) on T-cell subsets and mRNA expression of cytokines in the small intestine of broilers. One hundred and fifty-six one-day-old healthy Cobb broilers were randomly divided into control group (0 mg/kg AFB1) and AFB1 group (0.6 mg/kg AFB1) with three replicates per group and 26 birds per replicate for 21 days, respectively. At 7, 14, and 21 days of age, the duodenum, jejunum and ileum were sampled for analyzing T cell subsets (CD3+, CD3+CD4+ and CD3+CD8+) by flow cytometry as well as IL-2, IL-4, IL-6, IL-10, IL-17, IFN-γ and TNF-α mRNA expression by qRT-PCR. The percentages of T-cells in the intra-epithelial lymphocytes (IELs) and lamina propria lymphocytes (LPLs) of duodenum, jejunum and ileum in the AFB1 group showed a decreased tendency in comparison to the control group. The mRNA expression of cytokines in the three intestinal segments in the AFB1 group presented a general decline compared with the control groups. Our data demonstrated that 0.6 mg/kg AFB1 in the broilers diet could reduce the percentages of T-cell subsets and the expression level of cytokine mRNA in the small intestine, implying that the immune function of the intestinal mucosa might be affected. The reduction of cytokines mRNA expression may be closely associated with the decreased proportions of T cells subsets induced by AFB1.
doi:10.3390/ijms16046945
PMCID: PMC4424998  PMID: 25826527
aflatoxin B1; T-cell subsets; cytokine; intestinal mucosal immunity; broilers
14.  Sleep Duration and History of Stroke Among U.S. Adults 
Journal of sleep research  2014;23(5):531-537.
Summary
Although short sleep duration is related to chronic conditions such as hypertension, diabetes, and obesity, the association with stroke is less well-known. Using 2006-2011 National Health Interview Surveys, we assessed the association between self-reported duration of sleep and prevalence of stroke stratifying by age and sex. Of the 154,599 participants aged 18 years or older, 29.2%, 61.8% and 9.0% reported they sleep ≤6, 7-8 and ≥9 hours per day, respectively. Corresponding age-standardized prevalence of stroke were 2.78%, 1.99% and 5.21% (P < 0.001). Logistic regression models showed a higher prevalence of stroke among those who slept ≤6 or ≥9 hours a day compared with those who slept 7-8 hours, after adjusting for sociodemographic, behavioral, and health characteristics. Further stratifying by age and sex showed that the association of duration of sleep and stroke differed among different age or sex groups. Among young adults (18-44 years), a higher prevalence of stroke was found among women with short sleep. Higher prevalence of stroke was found among middle-aged men and women reporting short or long sleep duration. Among older adults (≥65 years), higher prevalence of stroke was found only among those who slept ≥9 hours. In this national sample of adults, the association between duration of sleep and stroke varied by sex and age. Although there was an association of short sleep duration with stroke, we also observed the association of long sleep duration with stroke, especially among those aged 65 years or older.
doi:10.1111/jsr.12160
PMCID: PMC4365417  PMID: 24815229
sleep duration; stroke; age; sex; NHIS
15.  Commentary: China's changing health system: Implications for sexual and reproductive health 
Global Public Health  2014;10(2):249-251.
doi:10.1080/17441692.2014.986171
PMCID: PMC4330711  PMID: 25515316
16.  Genetic variants in the inositol phosphate metabolism pathway and risk of different types of cancer 
Scientific Reports  2015;5:8473.
Members of the inositol phosphate metabolism pathway regulate cell proliferation, migration and phosphatidylinositol-3-kinase (PI3K)/Akt signaling, and are frequently dysregulated in cancer. Whether germline genetic variants in inositol phosphate metabolism pathway are associated with cancer risk remains to be clarified. We examined the association between inositol phosphate metabolism pathway genes and risk of eight types of cancer using data from genome-wide association studies. Logistic regression models were applied to evaluate SNP-level associations. Gene- and pathway-based associations were tested using the permutation-based adaptive rank-truncated product method. The overall inositol phosphate metabolism pathway was significantly associated with risk of lung cancer (P = 2.00 × 10−4), esophageal squamous cell carcinoma (P = 5.70 × 10−3), gastric cancer (P = 3.03 × 10−2) and renal cell carcinoma (P = 1.26 × 10−2), but not with pancreatic cancer (P = 1.40 × 10−1), breast cancer (P = 3.03 × 10−1), prostate cancer (P = 4.51 × 10−1), and bladder cancer (P = 6.30 × 10−1). Our results provide a link between inherited variation in the overall inositol phosphate metabolism pathway and several individual genes and cancer. Further studies will be needed to validate these positive findings, and to explore its mechanisms.
doi:10.1038/srep08473
PMCID: PMC4329558  PMID: 25683757
17.  Increased HDAC3 and decreased miRNA-130a expression in PBMCs through recruitment HDAC3 in patients with spinal cord injuries 
The study was performed to investigate the molecular mechanism for SCI patients. The interaction between miRNA-130a and HDAC was demonstrated in PBMCs from SCI patients. Increased HDAC3 and decreased miRNA-130a were observed in PBMCs from AS patients. Next, HDAC3 loss-of-function or HAAC3 inhibition promoted the expression of miRNA-130a, and HDAC3 could be recruited to the promoter region of the gene, miRNA-130a, in PBMCs. In addition, linear regression analysis indicated that mRNA expression results were highly negative correlated between HDAC3 and miRNA-130a in PBMCs from SCI patients. Furthermore, miRNA-130a down expression increased the expression of HDAC3 in PBMCs. Loss-of-function of miRNA-130a promoted PBMCs apoptosis, but HDAC3 loss-of-function had no significant effect on the apoptotic cell. In addition, miR-130a overexpression decreased, whereas miR-130a inhibition increased, the expression of TNF-α in PBMCs. Furthermore, HDAC3 loss-of-function or HAAC3 inhibition associated with simultaneous up-regulation the expression of miR-130a and down-regulation the expression of TNF-α in PBMCs. In conclusion, HDAC3 regulated a distinct underlying molecular and pathogenic mechanism of SCI by forming a negative feedback loop with miR-130a and enhanced TNF-1α expression.
PMCID: PMC4396315  PMID: 25973054
Spinal cord injury; HDAC3; miRNA-130a; PBMCs
18.  Genetic targeting of sprouting angiogenesis using Apln-CreER 
Nature Communications  2015;6:6020.
Under pathophysiological conditions in adults, endothelial cells (ECs) sprout from pre-existing blood vessels to form new ones by a process termed angiogenesis. During embryonic development, Apelin (APLN) is robustly expressed in vascular ECs. In adult mice, however, APLN expression in the vasculature is significantly reduced. Here we show that APLN expression is reactivated in adult ECs after ischaemia insults. In models of both injury ischaemia and tumor angiogenesis, we find that Apln-CreER genetically labels sprouting but not quiescent vasculature. By leveraging this specific activity, we demonstrate that abolishment of the VEGF–VEGFR2 signalling pathway as well as ablation of sprouting ECs diminished tumour vascularization and growth without compromising vascular homeostasis in other organs. Collectively, we show that Apln-CreER distinguishes sprouting vessels from stabilized vessels in multiple pathological settings. The Apln-CreER line described here will greatly aid future mechanistic studies in both vascular developmental biology and adult vascular diseases.
Apelin expression is robust in embryonic but not in adult endothelial cells (ECs), where it can be reactivated by hypoxia. Liu et al. show that apelin-driven expression of Cre recombinase in mice can be used for labelling of, or gene ablation in, sprouting but not quiescent ECs in pathologies characterized by hypoxia.
doi:10.1038/ncomms7020
PMCID: PMC4309445  PMID: 25597280
19.  State Socioeconomic Indicators and Self-Reported Hypertension Among US Adults, 2011 Behavioral Risk Factor Surveillance System 
Introduction
Hypertension is the leading cause of chronic disease and premature death in the United States. To date, most risk factors for hypertension have been identified at the individual (micro) level. The association of macro-level (area) socioeconomic factors and hypertension prevalence rates in the population has not been studied extensively.
Methods
We used the 2011 Behavioral Risk Factor Surveillance System to examine whether state socioeconomic status (SES) indicators predict the prevalence of self-reported hypertension. Quintiles of state median household income, unemployment rate among the population aged 16 to 64 years, and the proportion of the population under the national poverty line were used as the proxy for state SES. Hypertension status was determined by the question “Have you ever been told by a doctor, nurse, or other health professional that you have high blood pressure?” Logistic regression was used to assess the relationship between state SES and hypertension with adjustment for individual covariates (demographic and socioeconomic factors and lifestyle behaviors).
Results
States with a median household income of $43,225 or less (odds ratio [95% confidence interval] = 1.16 [1.08–1.25]) and states with 18.7% or more of residents living below the poverty line (odds ratio [95% confidence interval] = 1.14 [1.04–1.24]) had a higher prevalence of hypertension than states with the most residents in the most advantageous quintile of the indicators.
Conclusion
The observed state SES–hypertension association indicates that area SES may contribute to the burden of hypertension in community-dwelling adults.
doi:10.5888/pcd12.140353
PMCID: PMC4344353  PMID: 25719217
20.  Interleukin-10 gene polymorphisms are associated with Behcet’s disease but not with Vogt-Koyanagi-Harada syndrome in the Chinese Han population 
Molecular Vision  2015;21:589-603.
Purpose
This study aimed to investigate the association of interleukin (IL)-10 gene polymorphisms with Behcet’s disease (BD) and Vogt–Koyanagi–Harada (VKH) syndrome in the Chinese Han population.
Methods
A two-stage association study was performed on 718 BD patients, 300 VKH patients, and 1,753 controls. Genotyping of the IL-10 gene was performed for six single nucleotide polymorphisms (SNPs), including rs1800871, rs1800872, rs1800896, rs3021094, rs3790622, and rs1554286 using PCR-restricted fragment length polymorphism or TaqMan SNP assays. Real-time PCR was performed to test the IL-10 mRNA expression of the associated polymorphisms.
Results
The first-stage result showed significantly increased frequencies of the rs1800871 T allele, rs1800872 A allele, and rs1554286 T allele in BD patients compared with controls (Pcorrected (Pcorr) = 1.82×10−5, OR = 1.837; Pcorr = 6.1×10-5, OR = 1.780; Pcorr = 3.15×10−5, OR = 1.794, respectively). There was no association of the tested six SNPs with VKH syndrome. A second-stage study was therefore performed in BD patients to validate the result of the first stage, showing a significantly increased frequency of the rs1800871 T allele (Second stage, Pcorr = 5.59×10−5, OR = 1.493; Combined data, Pcorr = 3.65×10−11, OR = 1.632). Compared to the controls, an increased frequency of the rs1800871 T allele was observed in BD patients with extraocular findings, including genital ulcers, skin lesions, and a positive pathergy test. No difference was found among the mRNA expressions of IL-10 in the peripheral blood mononuclear cells (PBMCs) of controls with different genotypes of rs1800871 after stimulation of lipopolysaccharide (LPS) or anti-CD3/CD28 antibodies.
Conclusions
The findings showed that IL-10 is a risk gene for BD but not for VKH syndrome.
PMCID: PMC4443582  PMID: 26015771
21.  Efficacy and safety of Shenyankangfu tablets for primary glomerulonephritis: study protocol for a randomized controlled trial 
Trials  2014;15:479.
Background
Chronic kidney disease is a common disease. Most chronic kidney diseases evolve from primary glomerulonephritis. Proteinuria is an independent risk factor for the progression of chronic kidney disease. The general consensus is that therapy administered to decrease proteinuria should include steroids and/or immunosuppressants, angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers. However, the side effects of, and adverse reactions to, these agents reduce the benefits to patients. In addition, the cost of these drugs is relatively high. Therefore, identification of inexpensive and effective drugs to decrease proteinuria is urgently needed. Shenyankangfu tablets have been a widely applied Chinese patent medicine for many years to decrease proteinuria. However, there is a lack of research-derived data regarding the clinical use. Therefore, we designed the present randomized controlled clinical trial to compare the efficacy and safety of Shenyankangfu tablets versus losartan potassium for control of proteinuria in patients with primary glomerulonephritis.
Methods/design
This study will be a multicenter, prospective, double-blind, double-dummy, randomized controlled clinical trial. We will enroll 720 patients diagnosed with primary glomerulonephritis. The eligible patients will be randomly divided into the following groups at a 1:1:1:1:1 ratio: Shenyankangfu tablets group, losartan potassium 50 mg group, losartan potassium 100 mg group, Shenyankangfu tablets + losartan potassium 50 mg group, and Shenyankangfu tablets + losartan potassium 100 mg group. All groups will be followed up for 48 weeks; follow-up visits will be performed, at weeks 0, 4, 8, 12, 24, 36, and 48. The primary efficacy outcome will be the post-treatment change in the 24-hour proteinuria level, and the secondary efficacy outcomes will be the post-treatment changes in the serum creatinine level, estimated glomerular filtration rate, traditional Chinese medicine syndrome score, and serum albumin level.
Discussion
The results of this trial will provide solid data for use in evidence-based medicine with respect to the efficacy and safety of Shenyankangfu tablets for control of proteinuria in patients with primary glomerulonephritis compared to those of losartan potassium. Moreover, we infer that therapy comprising Shenyankangfu tablets + losartan potassium can decrease proteinuria to a larger extent than Shenyankangfu tablets or losartan potassium can alone.
Trial registration
This trial was registered on 12 February 2014 at ClinicalTrials.gov (ID number NCT02063100).
Electronic supplementary material
The online version of this article (doi:10.1186/1745-6215-15-479) contains supplementary material, which is available to authorized users.
doi:10.1186/1745-6215-15-479
PMCID: PMC4289030  PMID: 25480673
Glomerulonephritis; Proteinuria; Shenyankangfu tablets; Losartan; Efficacy; Safety; Randomized controlled trial; Double-blind
22.  Developmental changes in cell proliferation and apoptosis in the normal duck bursa of Fabricius 
Journal of Veterinary Science  2014;15(4):465-474.
The aim of this work was to investigate developmental changes in cell proliferation and apoptosis in normal duck bursa of Fabricius using flow cytometry and immunohistochemistry. Studies were carried out on Tianfu ducks on days 24 and 27 of embryogenesis (E24 and E27) along with days 20, 70, and 200 of postnatal development (P20, P70, and P200). Results showed that the percentage of G0/G1 bursa cells significantly increased between E24 and P200 while the percentage of cells in the S phase or G2 + M phase as well as the proliferating index obviously decreased during the same period. Proliferation cell nuclear antigen was detected in lymphocyte and interfollicular epithelium. The proliferative lymphocyte density tended to decrease from E24 to P200. Apoptotic bodies in macrophages, free apoptotic bodies, or nuclei with condensed chromatin in lymphocytes in follicles were identified by transferase-mediated dUTP nick-end labeling. Both flow cytometry and microscopic analysis reveal that the proportion of apoptotic cells and apoptotic lymphocyte density increased from E24 to P20, fell on P70, then rose again on P200. Our foundings demonstrate that cell proliferation decreases and apoptosis increases with age. These changes may account for duck bursa development and involution.
doi:10.4142/jvs.2014.15.4.465
PMCID: PMC4269588  PMID: 24962417
apoptosis; bursa of Fabricius; development; duck; proliferation
23.  Protective Roles of Sodium Selenite against Aflatoxin B1-Induced Apoptosis of Jejunum in Broilers 
The effects of aflatoxin B1 (AFB1) exposure and sodium selenite supplementation on cell apoptosis of jejunum in broilers were studied. A total of 240 one-day-old male AA broilers were randomly assigned four dietary treatments containing 0 mg/kg of AFB1 (control), 0.3 mg/kg AFB1 (AFB1), 0.4 mg/kg supplement Se (+ Se) and 0.3 mg/kg AFB1 + 0.4 mg/kg supplement Se (AFB1 + Se), respectively. Compared with the control broilers, the number of apoptotic cells, the expression of Bax and Caspase-3 mRNA were significantly increased, while the expression of Bcl-2 mRNA and the Bcl-2/Bax ratio were significantly decreased in AFB1 broilers. The number of apoptotic cells and the expression of Caspase-3 mRNA in AFB1 + Se broilers were significantly higher than those in the control broilers, but significantly lower than those in AFB1 broilers. There were no significant changes in the expression of Bax mRNA between AFB1 + Se and control broilers; the expression of Bcl-2 mRNA and the Bcl-2/Bax ratio in AFB1 + Se broilers were significantly lower than those in the control broilers, but significantly higher than those in AFB1 broilers. In conclusion, 0.3 mg/kg AFB1 in the diet can increase cell apoptosis, decrease Bcl-2 mRNA expression, and increase of Bax and Caspase-3 mRNA expression in broiler’s jejunum. However, supplementation of dietary sodium selenite at the concentration of 0.4 mg/kg Se may ameliorate AFB1-induced apoptosis by increasing Bcl-2 mRNA expression, and decreasing Bax and Caspase-3 mRNA expression.
doi:10.3390/ijerph111213130
PMCID: PMC4276667  PMID: 25526081
aflatoxin B1; apoptosis; TUNEL; Bcl-2; Bax; Caspase-3
24.  Impact of type 2 diabetes mellitus on the prognosis of early stage triple-negative breast cancer in People’s Republic of China 
OncoTargets and therapy  2014;7:2147-2154.
Background
Type 2 diabetes mellitus (T2DM) is one of the most common chronic metabolic diseases. Increased cause-specific mortality and decreased disease-free survival (DFS) have been reported among cancer patients with T2DM compared with patients without T2DM, even after adjustments of other comorbidities. However, less is known about the impact of T2DM and other comorbidities on DFS in Chinese patients with early stage triple-negative breast cancer (TNBC).
Patients and methods
We assessed patients who were newly diagnosed with early stage primary TNBC at the Department of Breast Surgery, Fudan University, from 2003 to 2011. Of the 1,100 TNBC patients, 865 female patients had invasive and early stage TNBC. The association of the variables in the T2DM and non-T2DM groups was compared using the Pearson’s chi-square and independent t-tests. DFS was estimated using the Kaplan–Meier method. The effects of T2DM and other possible risk factors on DFS were assessed by Cox proportional hazards regression using univariate or multivariate analysis.
Results
A total of 865 early stage primary TNBC cases were studied, including 104 (12.02%) subjects with T2DM. Metastatic or recurrent disease was detected in 24 (23.08%) patients in the T2DM group and 35 (4.60%) patients in the non-T2DM group. Patients with T2DM exhibited a significantly lower DFS than patients without T2DM (log-rank P<0.001). Similar results were observed when patients with positive lymph nodes were compared with patients with negative lymph nodes (log-rank P=0.003). T2DM was independently associated with a lower DFS after adjustments of other variables (adjusted hazard ratio, 7.719; 95% confidence interval, 4.304–13.843; P<0.001) and adjustments of lymph node positivity (adjusted hazard ratio, 2.407; 95% confidence interval, 1.391–4.166; P=0.002). The DFS rates at 2 years for the T2DM group and the non-T2DM group were 78% and 97%, respectively. The prognostic influence of T2DM was consistent across the subgroups, including subgroups by age (>50 or ≤50), menopausal status (post- or premenopausal), tumor size (>5 cm or ≤5 cm), lymph node involvement (positive or negative), and adjuvant chemotherapy (received or not) using the Kaplan–Meier method (log-rank P<0.05).
Conclusion
In the People’s Republic of China, T2DM is an independent prognostic risk factor that indicates an increased likelihood of recurrence and metastasis in patients with early stage TNBC. The presence of T2DM should be taken into account when evaluating the risk for an early stage TNBC patient. More effective therapeutic regimens are needed for early stage TNBC patients with T2DM.
doi:10.2147/OTT.S71095
PMCID: PMC4251575  PMID: 25473296
disease-free survival; hyperglycemia; highly aggressive breast cancer
25.  Synbindin in Extracellular Signal-Regulated Protein Kinase Spatial Regulation and Gastric Cancer Aggressiveness 
Background
The molecular mechanisms that control the aggressiveness of gastric cancer (GC) remain poorly defined. Here we show that synbindin contributes to the aggressiveness of GC by activating extracellular signal-regulated protein kinase (ERK) signaling on the Golgi apparatus.
Methods
Expression of synbindin was examined in normal gastric mucosa (n = 44), intestinal metaplastic gastric mucosa (n = 66), and GC tissues (n=52), and the biological effects of synbindin on tumor growth and ERK signaling were detected in cultured cells, nude mice, and human tissue samples. The interaction between synbindin and mitogen-activated protein kinase kinase (MEK1)/ERK was determined by immunofluorescence and fluorescence resonance energy transfer assays. The transactivation of synbindin by nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) was detected using luciferase reporter assay and chromatin immunoprecipitation.
Results
High expression of synbindin was associated with larger tumor size (120.8 vs 44.8cm3; P = .01), advanced tumor node metastasis (TNM) stage (P = .003), and shorter patient survival (hazard ratio = 1.51; 95% confidence interval [CI] = 1.01 to 2.27; P = .046). Synbindin promotes cell proliferation and invasion by activating ERK2 on the Golgi apparatus, and synbindin is directly transactivated by NF-κB. Synbindin expression level was statistically significantly higher in human GCs with activated ERK2 than those with low ERK2 activity (intensity score of 11.5, 95% CI = 10.4 to 12.4 vs intensity score of 4.6, 95% CI 3.9 to 5.3; P < .001). Targeting synbindin in xenograft tumors decreased ERK2 phosphorylation and statistically significantly reduced tumor volume (451.2mm3, 95% CI = 328.3 to 574.1 vs 726.1mm3, 95% CI = 544.2 to 908.2; P = .01).
Conclusions
Synbindin contributes to malignant phenotypes of GC by activating ERK on the Golgi, and synbindin is a potential biomarker and therapeutic target for GC.
doi:10.1093/jnci/djt271
PMCID: PMC4042874  PMID: 24104608

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