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1.  Association analysis of DACT1 genetic variants and gastric cancer risk in a Chinese Han population: a case–control study 
OncoTargets and therapy  2016;9:5975-5983.
Purpose
Disheveled-binding antagonist of beta-catenin 1 (DACT1) is involved in tumorigenesis through influencing cell apoptosis and proliferation. We aimed to investigate the effect of three tag single-nucleotide polymorphisms (SNPs) in DACT1 (rs863091 C>T, rs17832998 C>T, and rs167481 C>T) on the occurrence of gastric cancer (GC), their association with specific clinical characteristics, and consideration of the functional relevance of GC-related SNPs.
Subjects and methods
In this hospital-based case–control study, the genotypes were acquired using the TaqMan-MGB method consisting of 602 cases and 602 controls. DACT1 messenger RNA level was evaluated in 76 paired tumoral and normal tissues using quantitative reverse transcription–polymerase chain reaction. Logistic regression was used to evaluate the associations among the DACT1 SNPs and GC.
Results
We found a significant association between the variant genotypes of rs863091 and decreased risk of GC (TT vs CC: P=0.009, adjusted odds ratio =0.34, 95% confidence interval =0.15–0.77; CT + TT vs CC: P=0.030, adjusted odds ratio =0.74, 95% confidence interval =0.57–0.97). In further stratified analyses, rs863091 variant genotypes were associated with a reduced risk of GC in younger individuals (<60 years) and males. No overall significant association with GC risk was observed in SNP rs17832998 or rs167481. Additionally, we assessed DACT1 messenger RNA levels in GC and found that DACT1 expressions of individuals carrying CT and TT genotypes were much higher than those with CC genotype.
Conclusion
Our findings suggest that the DACT1 rs863091 C>T polymorphism may be associated with a decreased risk of GC in the Chinese Han population and influence DACT1 expression.
Video abstract
doi:10.2147/OTT.S109899
PMCID: PMC5047710  PMID: 27729806
gastric cancer; DACT1; polymorphism; gene expression
2.  Association of metabolic syndrome with various anthropometric and atherogenic parameters in the Kazakh population in China 
Background
This study aimed to evaluate the association of the metabolic syndrome (MetS) with various anthropometric and atherogenic parameters in adult Kazakh population in China.
Methods
Four thousand ninety-four Kazakhs were recruited since 2007 to 2010. MetS and its components were confirmed according to IDF criteria. Area under the curve (AUC) of each variable was compared. Sensitivity (Sen), specificity (Spe), shortest distance in receiver’s operating characteristic curve (ROC) and cutoff of each variable to diagnose MetS were calculated.
Results
28.6 % of men and 31.0 % of women had MetS in the Kazakh population. In men, WHtR had the highest AUC value 0.821, followed by BMI (0.801), TG/HDL-C (0.792), WHR (0.776) and BAI (0.666). In women, WHtR also had the highest AUC value (0.835), following by BMI (0.789), WHR (0.778), TG/HDL-C (0.778) and BAI (0.751). WHtR had the shortest ROC distance that was 0.37 and the optimal cutoff was 0.55 in men. In women, WHtR also had the shortest ROC distance of 0.35 and the optimal cutoff was 0.54.
Conclusion
WHtR is the best predictor of MetS in both Kazakh men and women according to the IDF criteria.
doi:10.1186/s12944-016-0338-9
PMCID: PMC5035440  PMID: 27664082
Metabolic syndrome; Body mass index; Waist to height ratio; Waist to hip ratio; Body adiposity index; TG/HDL-C
3.  Optimal cutoff of the triglyceride to high-density lipoprotein cholesterol  ratio to detect cardiovascular risk factors among Han adults in Xinjiang 
Background
To determine whether TG/HDL-C ratio, which has been shown to be an indicator of the metabolic syndrome (MetS) and insulin resistance (IR), can predict cardiovascular risk factors in the Chinese Han population in Xinjiang.
Methods
The cardiovascular risk survey (CRS) was conducted from October 2007 to March 2010. A total of 14,618 representative participants were selected using a four-stage stratified sampling method. A total of 5757 Han participants were included in the study. The present statistical analysis was restricted to the 5595 Han subjects who had complete anthropometric data. The sensitivity, specificity, and distance on the receiver operating characteristic (ROC) curve in each TG/HDL level were calculated. The shortest distance in the ROC curves was used to determine the optimal cutoff of the TG/HDL-C ratio for detecting cardiovascular risk factors.
Results
The prevalence of hypertension, hypercholesterolemia, and hypertriglyceridemia was higher with higher TG/HDL-C ratio for both men and women. The TG/HDL-C ratio was positively associated with systolic blood pressure, diastolic blood pressure, and serum concentrations of total cholesterol. The optimal TG/HDL-C ratio cutoffs for predicting hypertension, dyslipidemia, diabetes, and ≥2 of these risk factors for Han adults in Xinjiang were 1.3, 1.3, 1.4, and 1.4 in men and 0.9, 1.0, 1.0, and 1.1 in women, respectively.
Conclusions
The evaluation of TG/HDL-C ratio should be considered for one of cardiovascular risk factor predictors among Han adults in Xinjiang.
doi:10.1186/s41043-016-0067-8
PMCID: PMC5025992  PMID: 27586369
Cutoff; TG/HDL ratio; Cardiovascular risk factors; Han adults; Xinjiang
4.  Insulin post-transcriptionally modulates Bmal1 protein to affect the hepatic circadian clock 
Nature Communications  2016;7:12696.
Although food availability is a potent synchronizer of the peripheral circadian clock in mammals, the underlying mechanisms are unclear. Here, we show that hepatic Bmal1, a core transcription activator of the molecular clock, is post-transcriptionally regulated by signals from insulin, an important hormone that is temporally controlled by feeding. Insulin promotes postprandial Akt-mediated Ser42-phosphorylation of Bmal1 to induce its dissociation from DNA, interaction with 14-3-3 protein and subsequently nuclear exclusion, which results in the suppression of Bmal1 transcriptional activity. Inverted feeding cycles not only shift the phase of daily insulin oscillation, but also elevate the amplitude due to food overconsumption. This enhanced and reversed insulin signalling initiates the reset of clock gene rhythms by altering Bmal1 nuclear accumulation in mouse liver. These results reveal the molecular mechanism of insulin signalling in regulating peripheral circadian rhythms.
The effect of the liver clock is modified by food entrainment via Bmal1/Clock core machinery. Here the authors show that insulin promotes postprandial Akt-dependent phosphorylation of Bmal1, resulting in association with 14-3-3 and Bmal1 shuttling out of the nucleus, thereby disrupting Bmal1 transcriptional effects on the clock.
doi:10.1038/ncomms12696
PMCID: PMC5013695  PMID: 27576939
5.  New Bifunctional Chelator p-SCN-PhPr-NE3TA for Copper-64: Synthesis, Peptidomimetic Conjugation, Radiolabeling, and Evaluation for PET Imaging 
Inorganic chemistry  2016;55(14):6892-6901.
Bifunctional chelators play an important role in developing metallic radionuclide-based radiopharmaceuticals. In this study, a new bifunctional ligand, p-SCN-PhPr-NE3TA, was synthesized and conjugated to a very late antigen-4 targeting peptidomimetic, LLP2A, for evaluating its application in 64Cu-based positron emission tomography (PET) imaging. The new ligand exhibited strong selective coordination of Cu(II), leading to a robust Cu complex, even in the presence of 10-fold Fe(III). The LLP2A conjugate of p-SCN-PhPr-NE3TA was prepared and successfully labeled with 64Cu under mild conditions. The conjugate 64Cu-NE3TA-PEG4-LLP2A showed significantly higher specific activity, compared with 64Cu-NOTA-PEG4-LLP2A, while maintaining comparable serum stability. Subsequent biodistribution studies and PET imaging in mice bearing B16F10 xenografts confirmed its favorable in vivo performance and high tumor uptake with low background, rendering p-SCN-PhPr-NE3TA a promising bifunctional chelator for 64Cu-based radiopharmaceuticals.
Graphical Abstract
doi:10.1021/acs.inorgchem.6b00395
PMCID: PMC4949121  PMID: 27347690
6.  Synergistic Effects of Gold Nanocages in Hyperthermia and Radiotherapy Treatment 
Gold nanocages (GNCs) are a promising material that not only converts near infrared (NIR) light to heat for the ablation of tumors but also acts as a radiosensitizer. The combination of hyperthermia and radiotherapy has a synergistic effect that can lead to significant tumor cell necrosis. In the current study, we synthesized GNCs that offered the combined effects of hyperthermia and radiotherapy. This combination strategy resulted in increased tumor cell apoptosis and significant tumor tissue necrosis. We propose that GNCs can be used for clinical treatment and to potentially overcome resistance to radiotherapy by clearly increasing the antitumor effect.
doi:10.1186/s11671-016-1501-y
PMCID: PMC4889960  PMID: 27255899
Gold nanocages (GNCs); Hyperthermia; Radiosensitivity; Breast cancer; Targeted cancer therapy
7.  CD133+ cancer stem-like cells promote migration and invasion of salivary adenoid cystic carcinoma by inducing vasculogenic mimicry formation 
Oncotarget  2016;7(20):29051-29062.
Cancer stem cells (CSCs) have gained much attention due to their roles in the invasion and metastasis of numerous kinds of human cancers. Here, we showed that the positive expression of CD133, the stemness marker, was positively associated with vasculogenic mimicry (VM) formation, local regional recurrence, distant metastasis and poorer prognosis in salivary adenoid cystic carcinoma (ACC) specimens. Compared with CD133− ACC cells, CD133+ cancer stem-like cells had more migration and invasion capabilities, as well as more VM formation. The levels of endothelial cell marker VE-cadherin, MMP-2 and MMP-9 expression in CD133+ cancer stem-like cells and xenograft tumors of nude mice injected with CD133+ cells were significantly higher than those with CD133− cells. The data indicated that CD133+ cancer stem-like cells might contribute to the migration and invasion of ACC through inducing VM formation.
doi:10.18632/oncotarget.8665
PMCID: PMC5045377  PMID: 27074560
adenoid cystic carcinoma (ACC); salivary gland; invasion; metastasis; vasculogenic mimicry (VM)
8.  Universal Molecular Scaffold for Facile Construction of Multivalent and Multimodal Imaging Probes 
Bioconjugate chemistry  2016;27(3):515-520.
Multivalent and multimodal imaging probes are rapidly emerging as powerful chemical tools for visualizing various biochemical processes. Herein, we described a bifunctional chelator (BFC)-based scaffold that can be used to construct such promising probes concisely. Compared to other reported similar scaffolds, this new BFC scaffold demonstrated two major advantages: (1) significantly simplified synthesis due to the use of this new BFC that can serve as chelator and linker simultaneously; (2) highly effcient synthesis rendered by using either click chemistry and/or total solid-phase synthesis. In addition, the versatile utility of this molecular scaffold has been demonstrated by constructing several multivalent/multimodal imaging probes labeled with various radioisotopes, and the resulting radiotracers demonstrated substantially improved in vivo performance compared to the two individual monomeric counterparts.
Graphical Abstract
doi:10.1021/acs.bioconjchem.6b00034
PMCID: PMC4847532  PMID: 26890523
9.  Sex-Related Differences Between Patients With Symptomatic Acute Aortic Dissection 
Medicine  2016;95(11):e3100.
Abstract
We designed a retrospective cohort study to assess sex-related differences in clinical manifestations, incidence, and outcomes of patients with symptomatic acute aortic dissection (AAD).
We collected clinical data from 2010 to 2015 of 400 patients with AAD. Patients’ clinical characteristics, treatment, and outcomes were analyzed as a function of sex.
Among 400 patients with AAD, the ratio of men to women was 3.18:1; the incidence of atherosclerosis was higher in women (P = 0.02). Dysphoria (P = 0.01), focal neurological deficits (P = 0.04), and pulse deficits (P = 0.03) were more frequent in men. Imaging findings revealed that pleural effusion (P < 0.01), celiac trunk involvement (P < 0.01), and superior mesenteric artery involvement (P = 0.02) were more frequent in men. Dissection-related pneumonia (P = 0.02), pulmonary atelectasis (P = 0.01), aortic intramural hematoma (P < 0.01), ischemic electrocardiographic changes (P = 0.03), and in-hospital complications such as myocardial ischemia (P = 0.03), hypoxemia (P < 0.01), cardiac tamponade (P = 0.01) occurred more frequently in women. Women with type A dissection had higher in-hospital mortality than men (P < 0.01).
The presentation of AAD varies with a patient's sex. Women with AAD had clinical features different from men as follows: higher age of onset, more frequent inpatient complications, and higher in-hospital mortality. These findings may lead to a better understanding of aortic dissection in women that will improve their outcomes.
doi:10.1097/MD.0000000000003100
PMCID: PMC4839932  PMID: 26986151
10.  Prefrontal Hemodynamic Functions during a Verbal Fluency Task in Blepharospasm Using Multi-Channel NIRS 
PLoS ONE  2016;11(3):e0150804.
Blepharospasm (BSP) has a morbidity of 16 to 133 per million and is characterized by orbicularis oculi spasms. BSP can severely impact daily life. However, to date, its pathophysiology has not been clearly demonstrated. Near-infrared spectroscopy (NIRS) is a portable, non-invasive, and high time resolution apparatus used to measure cerebral blood flow. This study aimed to investigate the hemodynamic response patterns of BSP patients and determine whether BSP alone can be an attributional factor to influence the function of the prefrontal area using a verbal fluency task (VFT) and NIRS. Twenty-three BSP patients (10 males and 13 females) and 13 healthy controls (HC; five males and eight females) matched by gender and education were examined using NIRS. BSP patients were divided into two groups based on the presence or absence of depression and anxiety symptoms. A covariance analysis was conducted to analyze differences between the three groups and reduce the influence of different ages and educational levels. Bonferroni was used to process the post hoc test. The bilateral orbitofrontal area (ch36, 39, and 41; P<0.01) exhibited a lower activation in BSP patients without psychiatric symptoms compared with HC. This study is the first report to identify the prefrontal function in BSP using NIRS. Our findings indicate that BSP alone may cause a hypoactive hemodynamic performance in the prefrontal cortex in the absence of psychiatric symptoms. These findings provide evidence to support novel pathophysiological mechanisms of BSP.
doi:10.1371/journal.pone.0150804
PMCID: PMC4778802  PMID: 26942579
11.  Exome Sequencing in a Family Identifies RECQL5 Mutation Resulting in Early Myocardial Infarction 
Medicine  2016;95(5):e2737.
Abstract
Coronary artery disease (CAD) including myocardial infarction (MI) is the leading cause of death worldwide and is commonly caused by the interaction between genetic factors and environmental risks. Despite intensive efforts using linkage and candidate gene approaches, the genetic etiology for the majority of families with a multigenerational early CAD /MI predisposition is unknown.
In this study, we used whole-exome sequencing of 10 individuals from 1 early MI family, in which 4 siblings were diagnosed with MI before the age of 55, to identify potential predisposing genes.
We identified a mutation in the RECQL5 gene, 1 of the 5 members of the RECQ family which are involved in the maintenance of genomic stability. This novel mutation, which is a TG insert at position 73,626,918 on the 13 chromosome and occurs before the last nucleotide of the introns 11 acceptor splice site affecting splicing of RECQL5. RT-PCR suggested the control subject had a full-length mRNA including exon 12, but the patients with RECQL5 mutation had a shorter mRNA form involving splicing of exons 11 to 13 directly, with skipping of exon 12. Quantitative RT-PCR analysis of RECQL5 exon 12 demonstrated that individuals whose genotype is mutant homozygote had only trace amounts of mRNA containing this exon and the family members who carry the heterozygous genotype had a level at 48% to 55% of the control's level.
These findings provide insight into both the pathogenesis of MI and the role of RECQL5 gene in human disease.
doi:10.1097/MD.0000000000002737
PMCID: PMC4748938  PMID: 26844521
12.  MiR-let-7a inhibits cell proliferation, migration, and invasion by down-regulating PKM2 in gastric cancer 
Oncotarget  2016;7(5):5972-5984.
In contrast to normal differentiated cells that depend on aerobicoxidation for energy production, cancer cells use aerobic glycolysis as the main source (Warburg's effect). The M2 splice isoform of pyruvate kinase (PKM2) is the key regulator for the aerobic glycolysis, high expression of PKM2 contributes to the aerobic glycolysis, promotes the growth of tumors. In the present study, we found that PKM2 was highly expressed in gastric cancer (GC) tissues and had a strongly inverse correlation with the expression of microRNA-let-7a (miR-let-7a). Furthermore, we found that the overexpression of miR-let-7a markedly suppressed the proliferation, migration, and invasion of GC cells by down-regulating the expression of PKM2. MicroRNAs (miRNAs) are important regulators play key roles in tumorigenesis and tumor progression. Although previous reports showed that let-7 family members act as tumor suppressors in many cancers. The specific regulatory mechanism of miR-let-7a to PKM2 in gastric cancer is still unclear. In this study, we revealed that miR-let-7a function as the antitumor and gene regulatory effects of PKM2 in GC cells.
doi:10.18632/oncotarget.6821
PMCID: PMC4868734  PMID: 26745603
gastric cancer; microRNA-let-7a; PKM2
13.  Anti-tumor Efficiency of Lipid-coated Cisplatin Nanoparticles Co-loaded with MicroRNA-375 
Theranostics  2016;6(1):142-154.
One of the major challenges in the hepatocellular carcinoma (HCC) treatment is its insensitivity to chemotherapeutic drugs. Here, we report the development of novel lipid-coated cisplatin nanoparticles co-loaded with microRNA-375 (NPC/miR-375) as a potential treatment for chemotherapy insensitive HCC. The NPC/miR-375 was fabricated by mixing two reverse microemulsions containing KCl solution and a highly soluble cis-diaminedihydroplatinum (II) coated with a cationic lipid layer. Subsequently, the miR-375 was incorporated into the lipid-coated cisplatin nanoparticles. The NPC/miR375 nanoparticles were expected to further decrease cell proliferation and to enhance the anti-tumor effect of cisplatin in chemotherapy resistant HCC cells. In vitro analysis of intracellular trafficking revealed that NPC/miR-375 were able to escape from the late endosomes instead of lysosomes thus avoiding degradation of the miR-375 in lysosomes. Importantly, NPC/miR-375 enhanced apoptosis and induced cell cycle arrest in HCC cells in vitro. In the double oncogenes Akt/Ras-induced primary HCC mouse model, multiple doses of NPC/miR-375 significantly inhibited tumor growth and delayed the tumor relapse. Our results indicate that cisplatin nanoparticles co-loaded with miR-375 represent a potential therapeutic agent for chemotherapy-insensitive HCC.
doi:10.7150/thno.13130
PMCID: PMC4679361  PMID: 26722380
Hepatocellular Carcinoma; Co-delivery; miR-375; Cisplatin; Nanoparticles
14.  Endothelial Lipase-384A/C Polymorphism Is Associated with Acute Coronary Syndrome and Lipid Status in Elderly Uygur Patients in Xinjiang 
Objective: To explore the relationship between the endothelial lipase (EL) gene promoter −384A/C polymorphism and acute coronary syndrome (ACS) and lipid status in elderly Uygur patients in Xinjiang. Methods: The polymerase chain reaction–restriction fragment length polymorphism method was used to detect the EL gene promoter −384A/C genotype in 341 cases of elderly patients with ACS and 380 healthy subjects. Results: In an elderly Chinese Han population, the EL-384A/C genotype and allele frequency distribution were significantly different between the ACS group and the control group (p<0.05); the frequency of the CC genotype in the ACS group was significantly higher than that in the control group (p<0.05). After adjusting for gender, age, diabetes, hypertension, smoking, hyperlipidemia, and other cardiovascular risk factors, the difference remains statistically significant (p<0.05). In the ACS group, C allele carriers had significantly higher serum triglycerides, total cholesterol, and low-density lipoprotein cholesterol concentrations compared to AA genotypes (all p<0.05). Conclusion: EL-384A/C polymorphism was significantly associated with the ACS and lipids profile in an elderly Uygur population in Xinjiang.
doi:10.1089/gtmb.2014.0195
PMCID: PMC4216995  PMID: 25291260
15.  Factors Associated with Hepatitis C Knowledge Before and After an Educational Intervention among Vietnamese Americans 
BACKGROUND
Hepatitis C virus (HCV) is a major cause of chronic liver disease and cancer. Vietnamese Americans are at high risk of HCV infection, with men having the highest US incidence of liver cancer. This study examines an intervention to improve HCV knowledge among Vietnamese Americans.
STUDY
Seven Vietnamese community-based organizations in Pennsylvania and New Jersey recruited a total of 306 Vietnamese participants from 2010 to 2011.
RESULTS
Average knowledge scores for pretest and posttest were 3.32 and 5.88, respectively (maximum 10). After adjusting for confounding variables, age and higher education were positively associated with higher pretest scores and having a physician who spoke English or Vietnamese was negatively associated with higher pretest scores. Additionally, after adjusting for confounding variables, household income, education, and having an HCV-infected family member significantly increased knowledge scores.
CONCLUSIONS
Promotion and development of HCV educational programs can increase HCV knowledge among race and ethnic groups, such as Vietnamese Americans. Giving timely information to at-risk groups provides the opportunity to correct misconceptions, decrease HCV risk behaviors, and encourage testing that might improve timely HCV diagnosis and treatment.
doi:10.4137/CGast.S24737
PMCID: PMC4629630  PMID: 26561280
hepatitis C; liver cancer; Vietnamese
16.  Optimal sample volumes of human trabecular bone in μCT analysis within vertebral body and femoral head 
Trabecular bones of different skeletal sites have different bone morphologies. How to select an appropriate volume of region of interest (ROI) to reflect the microarchitecture of trabecular bone in different skeletal sites was an interesting problem. Therefore, in this study, the optimal volumes of ROI within vertebral body and femoral head, and if the relationships between volumes of ROI and microarchitectural parameters were affected by trabecular bone morphology were studied. Within vertebral body and femoral head, different cubic volumes of ROI (from (1 mm)3 to (20 mm)3) were set to compare with control groups(whole volume of trabecular bone). Five microarchitectural parameters (BV/TV, Tb.N, Tb.Th, Tb.Sp, and BS/BV) were obtained. Nonlinear curve fitting functions were used to explore the relationships between the microarchitectural parameters and the volumes of ROI. The volumes of ROI could affect the microarchitectural parameters when the volume was smaller than (8 mm)3 within the vertebral body and smaller than (13 mm)3 within the femoral head. As the volume increased, the variable tendencies of BV/TV, Tb.N, and Tb.Sp were different between these two skeletal sites. The curve fitting functions between these two sites were also different. The relationships between volumes of ROI and microarchitectural parameters were affected by the different trabecular bone morphologies within lumbar vertebral body and femoral head. When depicting the microarchitecture of human trabecular bone within lumbar vertebral body and femoral head, the volume of ROI would be larger than (8 mm)3 and (13 mm)3.
PMCID: PMC4694281  PMID: 26770381
μCT; region of interest; trabecular bone; microarchitecture; human
17.  Variation in Bordetella pertussis Susceptibility to Erythromycin and Virulence-Related Genotype Changes in China (1970-2014) 
PLoS ONE  2015;10(9):e0138941.
Objectives
To investigate changes in virulence-related genotypes and in the antimicrobial susceptibility of Bordetella pertussis isolates collected from the 1970s to 2014 in the northern part of China.
Methods
A total of 124 B. pertussis isolates from three periods, the 1970s, 2000–2008, and May 2013–Sept 2014, were typed by multilocus sequence typing (MLST) and tested for antimicrobial susceptibility and virulence-related genes. A fragment of the 23S rRNA gene from each of the 99 isolates from 2013–2014 was amplified and sequenced.
Results
All isolates from 2000–2008 and 2013–2014 were identified as ST2, whereas isolates from the 1970s were ST1. PtxA2/ptxC1/ptxP1/prn1/fim2-1/fim3-1/tcfA2, which was the same as the vaccine strain, was the only type in the 1970s. During the 2000s and 2013–2014, the virulence type ptxA1/ptxC1/ptxP1/prn1/fim2-1/fim3-1/tcfA2 was dominant, with frequencies of 68.4% and 91.9%, respectively. Nine ptxP3 strains, which were more virulent, were detected after 2000. All 124 isolates were susceptible to levofloxacin, sulphamethoxazole/trimethoprim and tetracycline. The isolates from the 1970s and 2000–2008 were susceptible to all tested macrolides, whereas 91.9% of the 2013–2014 isolates were highly resistant (minimal inhibitory concentration, MIC >256 μg/ml). No ptxP3 strain was resistant to macrolides. All erythromycin-resistant strains except for one had the A2047G mutation in the 23S rRNA gene.
Conclusions
Macrolide resistance of the B. pertussis population has been a serious problem in the northern part of China. Because most of the epidemic clone of the pathogen expresses the same antigen profiles as the vaccine strain, except ptxA, improvements in immunization strategies may prevent the spread of infection and drug resistance.
doi:10.1371/journal.pone.0138941
PMCID: PMC4583996  PMID: 26406905
18.  Prevalence of Congenital Heart Disease in Xinjiang Multi-Ethnic Region of China 
PLoS ONE  2015;10(8):e0133961.
Background
The prevalence and risk factors of congenital heart disease among Xinjiang, northwestern part of China is currently unknown.
Methods
This multiple-ethnic, community-based, cross-sectional study was conducted to estimate the prevalence and distribution of congenital heart disease (CHD) in Xinjiang, northwestern part of China. Four major ethnics, Uygur, Han, Kazak, and Hui children in this region were investigated during February 2010 and May 2012.
Results
A total of 14,530 children (0–18 yr) were examined. Of these children, 240 (boys, 43.8%, and girls, 56.3%) were identified with CHD, giving an overall prevalence of 16.5‰ (17.7‰ in Uygur, 6.9‰ in Han, 11.4‰ in Kazak, and 38.1‰ in Hui Chinese, respectively). Ventricular septal defect (VSD, 29.2%), atrial septal defect (ASD, 20.8%), patent ductus arteriosus (PDA, 13.7%), acleistocardia (13.7%), Bicuspid aortic valve (7.9%), pulmonary valve stenosis (5.4%), and tetralogy of fallot (TOF, 4.2%) were common cyanotic and cyanotic defects observed. Compared to non-CHD children, children with CHD had a higher percentage of history of abortion, CHD history of family, consanguinity and premature birth (all P<0.05). In CHD children, 24% of mothers caught a cold, 10% had a febrile illness and 6.7% received antibiotic treatment during the first trimester of pregnancy, that were higher than non-CHD group (all P<0.05).
Conclusion
The overall prevalence of CHD in four ethnic children at ages 0–18 yr in Xinjiang was 16.5‰. VSD, ASD and TOF were the most common acyanotic and cyanotic congenital heart defects, respectively. This study also identified some modifiable risk factors that may contribute to the incidence of CHD among the 4 ethnic groups.
doi:10.1371/journal.pone.0133961
PMCID: PMC4552834  PMID: 26317413
19.  Characterization and comparative profiling of the small RNA transcriptomes in two phases of flowering in Cymbidium ensifolium 
BMC Genomics  2015;16(1):622.
Background
Cymbidium ensifolium is one of the most important ornamental flowers in China, with an elegant shape, beautiful appearance, and a fragrant aroma. Its unique flower shape has long attracted scientists. MicroRNAs (miRNAs) are critical regulators in plant development and physiology, including floral development. However, to date, few studies have examined miRNAs in C. ensifolium.
Results
In this study, we employed Solexa technology to sequence four small RNA libraries from two flowering phases to identify miRNAs related to floral development. We identified 48 mature conserved miRNA and 71 precursors. These conserved miRNA belonged to 20 families. We also identified 45 novel miRNA which includes 21 putative novel miRNAs*, and 28 hairpin forming precursors. Two trans-acting small interfering RNAs (ta-siRNAs) were identified, one of which was homologous to TAS3a1. TAS3a1 belongs to the TAS3 family, which has been previously reported to target auxin response factors (ARF) and be involved in plant growth and floral development. Moreover, we built a C. ensifolium transctriptome database to identify genes targeted by miRNA, which resulted in 790 transcriptomic target unigenes. The target unigenes were annotated with information from the non-redundant (Nr), gene ontology database (GO), eukaryotic orthologous groups (KOGs) and Kyoto encyclopedia of genes and genomes (KEGG) database. The unigenes included MADS-box transcription factors targeted by miR156, miR172 and miR5179, and various hormone responding factors targeted by miR159. The MADS-box transcription factors are well known to determine the identity of flower organs and hormone responding factors involved in floral development. In expression analysis, three novel and four conserved miRNA were differentially expressed between two phases of flowering. The results were confirmed by RNA-seq and qRT-PCR. The differential expression of two miRNA, miR160 and miR396, targeted ARFs and growth regulating factor (GRF), respectively. However, most of these small RNA were clustered in the uncharacterized group, which suggests there may be many novel small non-coding RNAs yet to be discovered.
Conclusion
Our study provides a diverse set of miRNAs related to cymbidium floral development and serves as a useful resource for investigating miRNA-mediated regulatory mechanisms of floral development.
Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-1764-1) contains supplementary material, which is available to authorized users.
doi:10.1186/s12864-015-1764-1
PMCID: PMC4546042  PMID: 26289943
20.  Pharmacokinetics and distributions of bevacizumab by intravitreal injection of bevacizumab-PLGA microspheres in rabbits 
AIM
To investigate the pharmacokinetics and distributions of bevacizumab by intravitreal injection of prepared bevacizumab-poly (L-lactic-co-glycolic acid) (PLGA) microspheres in rabbits, to provide evidence for clinical application of this kind of bevacizumab sustained release dosage form.
METHODS
Bevacizumab was encapsulated into PLGA microsphere via the solid-in-oil-in-hydrophilic oil (S/O/hO) method. Fifteen healthy New Zealand albino-rabbits were used in experiments. The eyes of each rabbit received an intravitreal injection. The left eyes were injected with prepared bevacizumab-PLGA microspheres and the right eyes were injected with bevacizumab solution. After intravitreal injection, rabbits were randomly selected at days 3, 7, 14, 28 and 42 respectively, three animals each day. Then we used immunofluorescence staining to observe the distribution and duration of bevacizumab in rabbit eye tissues, and used the sandwich ELISA to quantify the concentration of free bevacizumab from the rabbit aqueous humor and vitreous after intravitreal injection.
RESULTS
The results show that the concentration of bevacizumab in vitreous and aqueous humor after administration of PLGA formulation was higher than that of bevacizumab solution. The T1/2 of intravitreal injection of bevacizumab-PLGA microspheres is 9.6d in vitreous and 10.2d in aqueous humor, and the T1/2 of intravitreal injection of soluble bevacizumab is 3.91d in vitreous and 4.1d in aqueous humor. There were statistical significant difference for comparison the results of the bevacizumab in vitreous and aqueous humor between the left and right eyes (P<0.05). The AUC0-t of the sustained release dosage form was 1-fold higher than that of the soluble form. The relative bioavailability was raised significantly. The immunofluorescence staining of PLGA-encapsulated bevacizumab (b-PLGA) in rabbit eye tissues was still observed up to 42d. It was longer than that of the soluble form.
CONCLUSION
The result of this study shows the beneficial effects of PLGA in prolonging the residency of bevacizumab in the vitreous. And the drug delivery system may have potential as a treatment modality for related disease.
doi:10.3980/j.issn.2222-3959.2015.04.02
PMCID: PMC4539635  PMID: 26309857
bevacizumab-PLGA microspheres; intravitreal injection; sustained release; pharmacokinetic; immunohistochemistry
21.  FrzA gene protects cardiomyocytes from H2O2-induced oxidative stress through restraining the Wnt/Frizzled pathway 
Background
Lately, there is accumulating evidence that the Wnt/Frizzled pathway is reactivated after myocardial infarction, the inhibition of the pathway is beneficial since it reduce of myocardial apoptosis and prevents heart failure. FrzA/Sfrp-1, a secreted frizzled-related protein and antagonist for the wnt/frizzled pathway. We assessed the hypothesis that FrzA protects cardiomyocytes from H2O2-Induced Oxidative damage through the inhibition of Wnt/Frizzled pathway activity.
Methods
We used a recombinant AAV9 vector to deliver FrzA gene into neonatal rat ventricle myocytes and developed an oxidative stress model using H2O2. The cell vitality was measured by MTT colorimetric assay. Western blot and RT-PCR were used to evaluate the expressions of Dvl-1, β-catenin, c-Myc, Bax and Bcl-2. Flow cytometry analysis of cardiomyocytes apoptosis.
Results
We confirmed that Wnt/frizzled pathway is involved in H2O2-induced apoptosis in cardiomyocytes. Compared with controls, H2O2 induced the upregulation of Dvl-1, β-catenin, and c-Myc. FrzA suppressed the expression of Dvl-1, β-catenin, c-Myc and the activity of the Wnt/frizzled pathway. Furthermore, FrzA over-expression decreased the apoptotic rate, and the Bax/Bcl-2 ratio in cardiomyocytes treated with H2O2.
Conclusions
FrzA, through the inhibition of Wnt/Frizzled pathway activity reduced H2O2-induced cardiomyocytes apoptosis and could be a potential therapeutic target for prevention of cardiac oxidative damage.
doi:10.1186/s12944-015-0088-0
PMCID: PMC4539933  PMID: 26282432
FrzA; Wnt/frizzled pathway; Oxidative stress; Cardiomyocytes; Apoptosis
22.  Serum miR-26a as a diagnostic and prognostic biomarker in cholangiocarcinoma 
Oncotarget  2015;6(21):18631-18640.
In order to determine the diagnostic and prognostic value of miR-26a in Cholangiocarcinoma (CCA), we compared miR-26a levels in serum from 66 CCA patients and 66 healthy controls, which was followed by serum analysis between the pre-operative serum and post-operative serum of these CCA patients. We found the concentration levels of miR-26a in serum of CCA patients were significantly higher than that from healthy controls (P < 0.01). Furthermore, the concentration levels of miR-26a in the post-operative serum were significantly reduced when compared to the pre-operative serum (P < 0.001). High miR-26a in serum was correlated significantly with clinical stage, distant metastasis, differentiation status, and poor survival of CCA patients. More importantly, serum miR-26a was an independent prognostic marker for CCA. In conclusion, our results suggested that miR-26a in serum might be a potential and useful noninvasive biomarker for the early detection of CCA.
PMCID: PMC4621915  PMID: 26087181
serum miR-26a; diagnostic; prognosis; cholangiocarcinoma
23.  Targeted delivery of chemically modified anti-miR-221 to hepatocellular carcinoma with negatively charged liposomes 
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death. Gene therapy was established as a new strategy for treating HCC. To explore the potential delivery system to support the gene therapy of HCC, negatively charged liposomal delivery system was used to deliver miR-221 antisense oligonucleotide (anti-miR-221) to the transferrin (Tf) receptor over expressed HepG2 cells. The liposome exhibited a mean particle size of 122.5 nm, zeta potential of −15.74 mV, anti-miR-221 encapsulation efficiency of 70%, and excellent colloidal stability at 4°C. Anti-miR-221-encapsulated Tf-targeted liposome demonstrated a 15-fold higher delivery efficiency compared to nontargeted liposome in HepG2 cells in vitro. Anti-miR-221 Tf-targeted liposome effectively delivered anti-miR-221 to HepG2 cells, upregulated miR-221 target genes PTEN, P27kip1, and TIMP3, and exhibited greater silencing efficiency over nontargeted anti-miR-221 liposome. After intravenous injection into HepG2 tumor-bearing xenografted mice with Cy3-labeled anti-miR-221 Tf-targeted liposome, Cy3-anti-miR-221 was successfully delivered to the tumor site and increased the expressions of PTEN, P27kip1, and TIMP3. Our results demonstrate that the Tf-targeted negatively charged liposome could be a potential therapeutic modality in the gene therapy of human HCC.
doi:10.2147/IJN.S79598
PMCID: PMC4524461  PMID: 26251599
transferrin; gene; HCC; target delivery system; anionic liposome
24.  Multiple Hemolymphangioma of the Visceral Organs 
Medicine  2015;94(27):e1126.
Abstract
Hemolymphangioma is a rare disease with malformation of both lymphatic and vascular vessels. Few cases of hemolymphangioma occurring in the rectum, small intestine, pancreas, esophagus, and other organs have been reported. Nevertheless, multiple hemolymphangioma of the visceral organs are extremely rare. We report a 25-year-old female with a significantly enlarged spleen full of multiple-rounded lesions. Curiously, the splenic flexure and even retroperitoneum had many lesions. The patient recovered well after splenectomy and the pathologic diagnosis of spleen was hemolymphangioma with abnormal lymphatic and blood vessels with polycystic spaces.
Usually, it is hard to cure this disease. We should take much more consideration into the diagnosis, treatment, and even pathogenesis, even though it is a benign lesion.
doi:10.1097/MD.0000000000001126
PMCID: PMC4504602  PMID: 26166115
25.  Multiple Hemolymphangioma of the Visceral Organs 
Medicine  2015;94(27):e1126.
Abstract
Hemolymphangioma is a rare disease with malformation of both lymphatic and vascular vessels. Few cases of hemolymphangioma occurring in the rectum, small intestine, pancreas, esophagus, and other organs have been reported. Nevertheless, multiple hemolymphangioma of the visceral organs are extremely rare. We report a 25-year-old female with a significantly enlarged spleen full of multiple-rounded lesions. Curiously, the splenic flexure and even retroperitoneum had many lesions. The patient recovered well after splenectomy and the pathologic diagnosis of spleen was hemolymphangioma with abnormal lymphatic and blood vessels with polycystic spaces.
Usually, it is hard to cure this disease. We should take much more consideration into the diagnosis, treatment, and even pathogenesis, even though it is a benign lesion.
doi:10.1097/MD.0000000000001126
PMCID: PMC4504602  PMID: 26166115

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