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1.  EGF-coated gold nanoparticles provide an efficient nano-scale delivery system for the molecular radiotherapy of EGFR-positive cancer 
Abstract
Purpose Radiolabeled antibodies and peptides hold promise for molecular radiotherapy but are often limited by a low payload resulting in inadequate delivery of radioactivity to tumour tissue and, therefore, modest therapeutic effect. We developed a facile synthetic method of radiolabeling indium-111 (111In) to epidermal growth factor (EGF)-gold nanoparticles (111In-EGF-Au NP) with a high payload.
Materials and methods EGF-Au NP were prepared via an interaction between gold and the disulphide bonds of EGF and radiolabeled using 111InCl3. Targeting efficiency was investigated by quantitating internalized radioactivity and by confocal imaging following exposure of MDA-MB-468 (1.3 × 106 EGFR/cell) and MCF-7 (104 EGFR/cell) cells to Cy3-EGF-Au NP. Cytotoxicity was evaluated in clonogenic assays.
Results The proportion of total administered radioactivity that was internalized by MDA-MB-468 and MCF-7 cells was 15% and 1.3%, respectively (mixing ratio of EGF:Au of 160). This differential uptake in the two cell lines was confirmed using confocal microscopy. 111In-EGF-Au NP were significantly more radiotoxic to MDA-MB-468 than MCF-7 cells with a surviving fraction of 17.1 ± 4.4% versus 89.8 ± 1.4% (p < 0.001) after exposure for 4 h.
Conclusions An 111In-labeled EGF-Au nanosystem was developed. It enabled targeted delivery of a high 111In payload specifically to EGFR-positive cancer cells leading to radiotoxicity that can be exploited for molecularly targeted radiotherapy.
doi:10.3109/09553002.2016.1145360
PMCID: PMC5116916  PMID: 26999580
Gold nanoparticles; Auger electron emitters; EGF; Indium-111; targeted radiotherapy
2.  Nanomicelles loaded with doxorubicin and curcumin for alleviating multidrug resistance in lung cancer 
Purpose
A new type of polymeric micelle (PM) was assembled using a polyethylene glycol (PEG)-linked (PEGylated) amphiphilic copolymer and d-tocopheryl PEG1000 succinate (TPGS1000). The micelles were used to deliver doxorubicin (DOX) and curcumin (CUR) for alleviating multidrug resistance (MDR) in lung cancer cells while enhancing the therapeutic efficacy of DOX.
Methods
Micelles loaded with DOX and CUR were assembled using a film-forming technique. Micelles were used to treat A549/Adr cells to find out whether micelles had the ability to reverse the MDR of A549/Adr cells. Some investigations were conducted using tumor-bearing mice to assess whether these micelles had enhanced antitumor efficacy as compared to DOX alone or the combination of DOX and CUR.
Results
Some micelles (DOX + CUR)–PMs had a small average size of about 17 nm and showed definite ability to deliver both DOX and CUR into DOX-resistant A549/Adr cells. The PMs had high cytotoxicity toward A549/Adr cells when the applied equivalent DOX dose was 1 µg/mL or higher. The cellular uptake of (DOX + CUR)–PMs into A549/Adr cells was found to be associated with an energy-dependent, caveolae-mediated, and clathrin-independent mechanism. (DOX + CUR)–PMs helped to prolong the circulation of DOX or CUR as compared to the individual administration of DOX or CUR, and they exhibited high inhibiting efficiency against the growth of tumors and were able to reduce the side effects of DOX.
Conclusion
TPGS1000 and CUR could synergistically reverse DOX-resistance of A549/Adr cells. In vivo examinations confirmed that the micelles had the capability to increase the plasma concentration of DOX or CUR, as well as to prolong their respective blood circulation. These micelles were able to significantly inhibit tumor growth in Lewis lung carcinoma tumor-bearing mice while reducing the side effects of DOX. The micelles showed potential in the treatment of lung cancer.
doi:10.2147/IJN.S118568
PMCID: PMC5098753  PMID: 27843316
synergistic effect; drug-resistance; doxorubicin; curcumin; polymeric micelles
3.  Head to Head Comparison of Two Point-of-care Platelet Function Tests Used for Assessment of On-clopidogrel Platelet Reactivity in Chinese Acute Myocardial Infarction Patients Undergoing Percutaneous Coronary Intervention 
Chinese Medical Journal  2016;129(19):2269-2274.
Background:
Platelet function tests are widely used in clinical practice to guide personalized antiplatelet therapy. In China, the thromboelastography (TEG) test has been well accepted in clinics, whereas VerifyNow, mainly used for scientific research, has not been used in routine clinical practice. The aim of the current study was to compare these two point-of-care platelet function tests and to analyze the consistency between the two tests for evaluating on-clopidogrel platelet reactivity in Chinese acute myocardial infarction patients undergoing percutaneous coronary intervention (PCI).
Methods:
A total of 184 patients admitted to Fuwai Hospital between August 2014 and May 2015 were enrolled in the study. On-clopidogrel platelet reactivity was assessed 3 days after PCI by TEG and VerifyNow using adenosine diphosphate as an agonist. Based on the previous reports, an inhibition of platelet aggregation (IPA) <30% for TEG or a P2Y12 reaction unit (PRU) >230 for VerifyNow was defined as high on-clopidogrel platelet reactivity (HPR). An IPA >70% or a PRU <178 was defined as low on-clopidogrel platelet reactivity (LPR). Correlation and agreement between the two methods were analyzed using the Spearman correlation coefficient (r) and kappa value (κ), respectively.
Results:
Our results showed that VerifyNow and TEG had a moderate but significant correlation in evaluating platelet reactivity (r = −0.511). A significant although poor agreement (κ = 0.225) in identifying HPR and a significantly moderate agreement in identifying LPR (κ = 0.412) were observed between TEG and VerifyNow. By using TEG as the reference for comparison, the cutoff values of VerifyNow for the Chinese patients in this study were identified as PRU >205 for HPR and PRU <169 for LPR.
Conclusions:
By comparing VerifyNow to TEG which has been widely used in clinics, VerifyNow could be an attractive alternative to TEG for monitoring on-clopidogrel platelet reactivity in Chinese patients.
doi:10.4103/0366-6999.190664
PMCID: PMC5040010  PMID: 27647183
Blood Platelets; Clopidogrel; Thromboelastography; VerifyNow
5.  Diversity, Biogeography, and Biodegradation Potential of Actinobacteria in the Deep-Sea Sediments along the Southwest Indian Ridge 
The phylum Actinobacteria has been reported to be common or even abundant in deep marine sediments, however, knowledge about the diversity, distribution, and function of actinobacteria is limited. In this study, actinobacterial diversity in the deep sea along the Southwest Indian Ridge (SWIR) was investigated using both 16S rRNA gene pyrosequencing and culture-based methods. The samples were collected at depths of 1662–4000 m below water surface. Actinobacterial sequences represented 1.2–9.1% of all microbial 16S rRNA gene amplicon sequences in each sample. A total of 5 actinobacterial classes, 17 orders, 28 families, and 52 genera were detected by pyrosequencing, dominated by the classes Acidimicrobiia and Actinobacteria. Differences in actinobacterial community compositions were found among the samples. The community structure showed significant correlations to geochemical factors, notably pH, calcium, total organic carbon, total phosphorus, and total nitrogen, rather than to spatial distance at the scale of the investigation. In addition, 176 strains of the Actinobacteria class, belonging to 9 known orders, 18 families, and 29 genera, were isolated. Among these cultivated taxa, 8 orders, 13 families, and 15 genera were also recovered by pyrosequencing. At a 97% 16S rRNA gene sequence similarity, the pyrosequencing data encompassed 77.3% of the isolates but the isolates represented only 10.3% of the actinobacterial reads. Phylogenetic analysis of all the representative actinobacterial sequences and isolates indicated that at least four new orders within the phylum Actinobacteria were detected by pyrosequencing. More than half of the isolates spanning 23 genera and all samples demonstrated activity in the degradation of refractory organics, including polycyclic aromatic hydrocarbons and polysaccharides, suggesting their potential ecological functions and biotechnological applications for carbon recycling.
doi:10.3389/fmicb.2016.01340
PMCID: PMC5002886  PMID: 27621725
community structure; cultivation; biodegradation; marine actinobacteria; microbial diversity; pyrosequencing; Southwest Indian Ridge
6.  A Cell-type-resolved Liver Proteome* 
Molecular & Cellular Proteomics : MCP  2016;15(10):3190-3202.
Parenchymatous organs consist of multiple cell types, primarily defined as parenchymal cells (PCs) and nonparenchymal cells (NPCs). The cellular characteristics of these organs are not well understood. Proteomic studies facilitate the resolution of the molecular details of different cell types in organs. These studies have significantly extended our knowledge about organogenesis and organ cellular composition. Here, we present an atlas of the cell-type-resolved liver proteome. In-depth proteomics identified 6000 to 8000 gene products (GPs) for each cell type and a total of 10,075 GPs for four cell types. This data set revealed features of the cellular composition of the liver: (1) hepatocytes (PCs) express the least GPs, have a unique but highly homogenous proteome pattern, and execute fundamental liver functions; (2) the division of labor among PCs and NPCs follows a model in which PCs make the main components of pathways, but NPCs trigger the pathways; and (3) crosstalk among NPCs and PCs maintains the PC phenotype. This study presents the liver proteome at cell resolution, serving as a research model for dissecting the cell type constitution and organ features at the molecular level.
doi:10.1074/mcp.M116.060145
PMCID: PMC5054343  PMID: 27562671
7.  Systematic investigation of transcription factors critical in the protection against cerebral ischemia by Danhong injection 
Scientific Reports  2016;6:29823.
Systematic investigations of complex pathological cascades during ischemic brain injury help to elucidate novel therapeutic targets against cerebral ischemia. Although some transcription factors (TFs) involved in cerebral ischemia, systematic surveys of their changes during ischemic brain injury have not been reported. Moreover, some multi-target agents effectively protected against ischemic stroke, but their mechanisms, especially the targets of TFs, are still unclear. Therefore, a comprehensive approach by integrating network pharmacology strategy and a new concatenated tandem array of consensus transcription factor response elements method to systematically investigate the target TFs critical in the protection against cerebral ischemia by a medication was first reported, and then applied to a multi-target drug, Danhong injection (DHI). High-throughput nature and depth of coverage, as well as high quantitative accuracy of the developed approach, make it more suitable for analyzing such multi-target agents. Results indicated that pre-B-cell leukemia transcription factor 1 and cyclic AMP-dependent transcription factor 1, along with six other TFs, are putative target TFs for DHI-mediated protection against cerebral ischemia. This study provides, for the first time, a systematic investigation of the target TFs critical to DHI-mediated protection against cerebral ischemia, as well as reveals more potential therapeutic targets for ischemic stroke.
doi:10.1038/srep29823
PMCID: PMC4949467  PMID: 27431009
8.  Bone Marrow Mesenchymal Stem Cells (BM-MSCs) Improve Heart Function in Swine Myocardial Infarction Model through Paracrine Effects 
Scientific Reports  2016;6:28250.
Stem cells are promising for the treatment of myocardial infarction (MI) and large animal models should be used to better understand the full spectrum of stem cell actions and preclinical evidences. In this study, bone marrow mesenchymal stem cells (BM-MSCs) were transplanted into swine heart ischemia model. To detect glucose metabolism in global left ventricular myocardium and regional myocardium, combined with assessment of cardiac function, positron emission tomography-computer tomography (PET-CT) and magnetic resonance imaging (MRI) were performed. To study the changes of glucose transporters and glucose metabolism-related enzymes and the signal transduction pathway, RT-PCR, Western-blot, and immunohistochemistry were carried out. Myocardium metabolic evaluation by PET-CT showed that mean signal intensity (MSI) increased in these segments at week 4 compared with that at week 1 after BM-MSCs transplantation. Moreover, MRI demonstrated significant function enhancement in BM-MSCs group. The gene expressions of glucose transporters (GLUT1, GLUT4), glucose metabolism-related enzymes phosphofructokinase (PFK), and glyceraldehyde-3-phosphate dehydrogenase (GAPDH)) and 70-kDa ribosomal protein S6 kinase (p70s6k) in BM-MSCs injected areas were up-regulated at week 4 after BM-MSCs transplantation and this was confirmed by Western-blot and immunohistochemistry. In conclusions, BM-MSCs transplantation could improve cardiac function in swine MI model by activation of mTOR signal transduction pathway.
doi:10.1038/srep28250
PMCID: PMC4913323  PMID: 27321050
9.  Strong evidence for LncRNA ZNRD1-AS1, and its functional Cis- eQTL locus contributing more to the susceptibility of lung cancer 
Oncotarget  2016;7(24):35813-35817.
Long noncoding RNAs (IncRNAs), involved in cancer biology, contributing to essential cancer cell functions such as proliferation, invasion, and metastasis, have received increasing attention recently. Human Zinc ribbon domain containing 1 (ZNRD1) has been confirmed to be involved in carcinogenesis and development of multiple cancers. ZNRD1-AS1, a lncRNA in the upstream region of ZNRD1 which could down-regulate the expression of ZNRD1, has been identified as a possible component in carcinogenesis. The underlying relations of ZNRD1-AS1 with lung cancer development and metastasis remain obscure. In current study, we first evaluated the expression ZNRD1-AS1 and ZNRD1 among lung cancer tissues and corresponding normal tissues, which showed higher expression of ZNRD1-AS1 and lower expression of ZNRD1. To reveal the underlying mechanisms, we then investigated the associations between ZNRD1 eQTLs SNPs in ZNRD1-AS1 and risk of lung cancer in Han Chinese populations. G allele of SNP rs9261204 was significantly associated with an increased risk of lung cancer when compared with A allele (OR: 1.45; 95% CI: 1.19–1.75; P = 1.06 × 10−4). A weaker, but similar effect was also observed in bladder cancer. SNP rs3757328 was also associated with increased risk of lung cancer (OR: 1.34; 95% CI: 1.07–1.67; P = 0.011). Our findings first confirmed the contribution of LncRNA ZNRD1-AS1 to the development of lung cancer in Asian population.
doi:10.18632/oncotarget.8411
PMCID: PMC5094964  PMID: 27166266
lung cancer; LncRNA; ZNRD1-AS1; SNP; susceptibility
10.  Evaluation of 3D-CPA, HR-HPV, and TCT joint detection on cervical disease screening 
Oncology Letters  2016;12(2):887-892.
The application value of three-dimensional color power angiography (3D-CPA), high-risk human papillomavirus (HR-HPV), ThinPrep cytology test (TCT) joint detection on cervical disease screening was investigated. In total, 1,900 patients that were examined in Gynecological and Cervix Clinic of Maternal and Child Care Service Center of Xuzhou from June 2012 to March 2015 were enrolled in the present study. After admission, the patients underwent TCT, HR-HPV and 3D-CPA examinations, and vascular morphology and typing, vascularization index (VI) were recorded. Colposcopic biopsy was performed in patients with a positive outcome of any of the three indices. Pathological diagnosis was taken as the golden standard to assess the sensitivity, specificity, diagnostic rate, and Youden index of the three methods being used independently or jointly. Of the 1,900 patients, 276 cases (14.53%) were HR-HPV-positive, 214 cases (11.26%) were VI-positive and 164 cases (8.63%) were TCT-positive. A total of 418 cases were confirmed with a positive outcome of any of the three indices and a cervical biopsy was obtained. Of the 418 cases, 162 cases (38.75%) were diagnosed with chronic cervicitis, 146 cases with low-level cervical intraepithelial neoplasia (CIN) (34.93%), 104 cases (24.88%) with high level CIN, 6 cases (1.44%) with cervical cancer. Histology more than low level CIN was defined as positive: i) screening results when the three methods were used independently: HPV was confirmed with the highest sensitivity (90.63%), VI with the highest specificity (83.95%), and HPV with the highest diagnostic accuracy (83.73%); ii) screening results under HPV+TCT and HPV+TCT+VI: HPV+TCT+VI was confirmed with the highest sensitivity and specificity: sensitivity (94.53%), specificity (81.48%), diagnosis coincidence rate (89.47%) and the highest Youden index of 0.760; and iii) vascular morphology and grading were significantly different in the early stage cervical carcinoma, high level CIM, and cervicitis groups. In conclusion, the joint detection of 3D-CPA, HR-HPV, and TCT improved the sensitivity and accuracy of cervical disease screening. 3D-CPA technology may therefore be used as an auxiliary screening method for cervical cancer.
doi:10.3892/ol.2016.4677
PMCID: PMC4950101  PMID: 27446364
three-dimensional color power angiography; human papillomavirus; ThinPrep cytology test; cervical lesions; screening
11.  Does concomitant acromioplasty facilitate arthroscopic repair of full-thickness rotator cuff tears? A meta-analysis with trial sequential analysis of randomized controlled trials 
SpringerPlus  2016;5(1):685.
Purpose
To conduct a meta-analysis with randomized controlled trials (RCTs) published in full text to determine the benefits of concomitant acromioplasty in repairing full-thickness rotator cuff tears.
Methods
Literature search was performed in PubMed, Embase and the Cochrane Library from databases inception through February 2016 to identify RCTs evaluating the efficacy of performing a concomitant acromioplasty. Statistical heterogeneity among studies was quantitatively evaluated by I-squared index (I2) and trial sequential analysis (TSA) was applied to control random errors.
Results
Five RCTs totaling 523 patients were included. There was no statistically significant difference in Constant score (WMD = 1.00; 95 % CI −4.40 to 6.41; P = 0.72), University of California-Los Angeles (UCLA) score (WMD = 0.48; 95 % CI −0.79 to 1.76; P = 0.46), visual analog scale (VAS) for pain (WMD = −0.23; 95 % CI −0.58 to 0.11; P = 0.19) and re-tear rate (RR = 0.46; 95 % CI 0.14 to 1.53; P = 0.21) between acromioplasty group and the nonacromioplasty group. However, it was found to be related to a greater increase in American Shoulder and Elbow Surgeons (ASES) score (WMD = 3.02; 95 % CI 0.24 to 5.80; P = 0.03). Unfortunately, this difference was not reinforced by subsequent TSA. In addition, subgroup analysis showed no substantial difference of ASES score in patients with type-1 (WMD = −8.21; 95 % CI −23.55 to 7.14; P = 0.29), type-2 (WMD = 0.97; 95 % CI −5.10 to 7.05; P = 0.75), or type-3 (WMD = 2.32; 95 % CI −9.96 to 14.61; P = 0.71) acromion.
Conclusions
A significant higher ASES score was observed during the comparison despite lacking reinforcement by TSA. No difference was found in Constant score, UCLA score, VAS, re-tear rate and subgroup analysis did not confirm the impact of acromion type on eventual therapeutic outcome. Future studies with large number of participants, long-term follow-ups, data of patient-reported outcomes and stratification for acromion type are of the essence for demonstrating whether functional or structural differences exist in patients undergoing arthroscopic repair of full-thickness rotator cuff tears with or without acromioplasty.
doi:10.1186/s40064-016-2311-5
PMCID: PMC4899382  PMID: 27350920
Acromioplasty; Subacromial decompression (SAD); Rotator cuff; Repair; Arthroscopic; Meta-analysis; Randomized controlled trials (RCTs)
12.  Ratio of microRNA-122/155 in isoniazid-induced acute liver injury in mice 
Liver injury is a major hindrance to the treatment of tuberculosis (TB) patients due to the primary side effects associated with anti-TB drugs. Several investigations have identified sensitive biomarkers for the early diagnosis of anti-TB drug-induced liver injury (ADLI), including the use of microRNAs (miRNAs/miRs). However, the association between miR-122/155 and ADLI remains unknown. Thus, the present study used reverse transcription-quantitative polymerase chain reaction to observe changes in tissue miR-122/155 expression levels during the course of liver injury in mice. Liver injury was induced by the administration of isoniazid (INH), a first-line anti-TB drug. miR-122/155 expression levels were quantified at seven time points throughout 1 day (0.25, 0.75, 1.5, 6, 12, 18 and 24 h) based on the pharmacokinetics of INH in mice. Notably, over the timecourse of INH-induced liver injury, the tissue miR-122 expression level significantly decreased at 0.25 h, which is the peak concentration time of INH, compared with the control group (P<0.05). The change was more rapid than that of the serum aminotransferase and miR-155, which were significantly increased at 0.75 h. In addition, the pathological score correlated with the ratio of miR-122/miR-155 (r=−0.779; P<0.01). In conclusion, the miR-122/155 ratio may be utilized as a sensitive biomarker for ADLI, which could contribute to the early diagnosis of patients following anti-TB treatment.
doi:10.3892/etm.2016.3375
PMCID: PMC4950840  PMID: 27446292
antituberculosis drug-induced liver injury; epigenetics; microRNAs; microRNA-122; microRNA-155; isoniazid
13.  The transplantation of Akt-overexpressing amniotic fluid-derived mesenchymal stem cells protects the heart against ischemia-reperfusion injury in rabbits 
Molecular Medicine Reports  2016;14(1):234-242.
Amniotic fluid-derived mesenchymal stem cells (AFMSCs) are an attractive cell source for applications in regenerative medicine, due to characteristics such as proliferative capacity and multipotency. In addition, Akt, a serine-threonine kinase, maintains stem cells by promoting viability and proliferation. Whether the transplantation of Akt-overexpressing AFMSCs protects the heart against ischemia-reperfusion (I/R) injury has yet to be elucidated. Accordingly, the Akt gene was overexpressed in AFMSCs using lentiviral transduction, and Akt-AFMSCs were transplanted into the ischemic myocardium of rabbits prior to reperfusion. Any protective effects resulting from this procedure were subsequently sought after three weeks later. A histological examination revealed that there was a decrease in intramyocardial inflammation and ultrastructural damage, and an increase in capillary density and in the levels of GATA binding protein 4, connexin 43 and cardiac troponin T in the Akt-AFMSC group compared with the control group. A significant decrease in cardiomyocyte apoptosis, accompanying an increase in phosphorylated Akt and B-cell lymphoma 2 (Bcl-2) and a decrease in caspase-3, was also observed. Furthermore, the left ventricular function was markedly augmented in the Akt-AFMSC group compared with the control group. These observations suggested that the protective effect of AFMSCs may be due to the delivery of secreted cytokines, promotion of neoangiogenesis, prevention of cardiomyocyte apoptosis, transdifferentiation into cardiomyocytes and promotion of the viability of AFMSCs, which are assisted by Akt gene modification. Taken together, the results of the present study have indicated that transplantation of Akt-AFMSCs is able to alleviate myocardial I/R injury and improve cardiac function.
doi:10.3892/mmr.2016.5212
PMCID: PMC4918560  PMID: 27151366
Akt; amniotic fluid-derived mesenchymal stem cells; gene therapy; myocardial ischemia reperfusion injury
14.  G-DOC Plus – an integrative bioinformatics platform for precision medicine 
BMC Bioinformatics  2016;17:193.
Background
G-DOC Plus is a data integration and bioinformatics platform that uses cloud computing and other advanced computational tools to handle a variety of biomedical BIG DATA including gene expression arrays, NGS and medical images so that they can be analyzed in the full context of other omics and clinical information.
Results
G-DOC Plus currently holds data from over 10,000 patients selected from private and public resources including Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA) and the recently added datasets from REpository for Molecular BRAin Neoplasia DaTa (REMBRANDT), caArray studies of lung and colon cancer, ImmPort and the 1000 genomes data sets. The system allows researchers to explore clinical-omic data one sample at a time, as a cohort of samples; or at the level of population, providing the user with a comprehensive view of the data.
G-DOC Plus tools have been leveraged in cancer and non-cancer studies for hypothesis generation and validation; biomarker discovery and multi-omics analysis, to explore somatic mutations and cancer MRI images; as well as for training and graduate education in bioinformatics, data and computational sciences. Several of these use cases are described in this paper to demonstrate its multifaceted usability.
Conclusion
G-DOC Plus can be used to support a variety of user groups in multiple domains to enable hypothesis generation for precision medicine research. The long-term vision of G-DOC Plus is to extend this translational bioinformatics platform to stay current with emerging omics technologies and analysis methods to continue supporting novel hypothesis generation, analysis and validation for integrative biomedical research. By integrating several aspects of the disease and exposing various data elements, such as outpatient lab workup, pathology, radiology, current treatments, molecular signatures and expected outcomes over a web interface, G-DOC Plus will continue to strengthen precision medicine research. G-DOC Plus is available at: https://gdoc.georgetown.edu.
Electronic supplementary material
The online version of this article (doi:10.1186/s12859-016-1010-0) contains supplementary material, which is available to authorized users.
doi:10.1186/s12859-016-1010-0
PMCID: PMC4851789  PMID: 27130330
Bioinformatics; Translational research; Precision medicine; Cloud computing; Variant analysis; Next generation sequencing; Outcomes research; Genotype-phenotype integration
15.  Single Nucleotide Polymorphism rs10919543 in FCGR2A/FCGR3A Region Confers Susceptibility to Takayasu Arteritis in Chinese Population 
Chinese Medical Journal  2016;129(7):854-859.
Background:
Takayasu arteritis (TA) is a rare inflammatory arteriopathy of unknown etiology. The aim of this study was to investigate the genetic susceptibility to TA in a Chinese population.
Methods:
Four single nucleotide polymorphisms (SNPs) those locate in the IL12B region (rs56167332), the MLX region (rs665268), the FCGR2A/FCGR3A locus (rs10919543), and the HLA-B/MICA locus (rs12524487), associated with TA in different population, were genotyped in 123 Chinese TA patients and 147 healthy controls from January 2013 to August 2014. A Chi-square test was used to test for genotype/allele frequencies variants.
Results:
Among the four SNPs, rs10919543 was found to be significantly associated with TA in the studied population. The GG genotype of rs10919543 at the FCGR2A/FCGR3A locus is a high risk factor (odds ratio [OR] = 6.532, 95% confidence interval [CI] = 2.402 − 17.763, P < 0.001) for TA. Among TA patients, the level of eosinophil granulocytes (Eos) in the peripheral blood was observed to be higher in the GG group of rs10919543 (n = 23, Eos = 0.11 [0.08, 0.17] ×109/L) than the GA + AA group (n = 100, Eos = 0.08 [0.05, 0.13] ×109/L, P = 0.028). No correlation between the genotypes of the other three SNPs and TA patients was observed.
Conclusions:
Our findings revealed unique genetic pattern in Chinese TA patients that may be partly responsible for the higher risk of TA in this population. FCGR2A/FCGR3A-related immune disorder might contribute to the etiology of TA.
doi:10.4103/0366-6999.178965
PMCID: PMC4819308  PMID: 26996483
FCGR2A; FCGR3A; Single Nucleotide Polymorphisms; Takayasu Arteritis
16.  Nuclear Protein Sam68 Interacts with the Enterovirus 71 Internal Ribosome Entry Site and Positively Regulates Viral Protein Translation 
Journal of Virology  2015;89(19):10031-10043.
ABSTRACT
Enterovirus 71 (EV71) recruits various cellular factors to assist in the replication and translation of its genome. Identification of the host factors involved in the EV71 life cycle not only will enable a better understanding of the infection mechanism but also has the potential to be of use in the development of antiviral therapeutics. In this study, we demonstrated that the cellular factor 68-kDa Src-associated protein in mitosis (Sam68) acts as an internal ribosome entry site (IRES) trans-acting factor (ITAF) that binds specifically to the EV71 5′ untranslated region (5′UTR). Interaction sites in both the viral IRES (stem-loops IV and V) and the heterogeneous nuclear ribonucleoprotein K homology (KH) domain of Sam68 protein were further mapped using an electrophoretic mobility shift assay (EMSA) and biotin RNA pulldown assay. More importantly, dual-luciferase (firefly) reporter analysis suggested that overexpression of Sam68 positively regulated IRES-dependent translation of virus proteins. In contrast, both IRES activity and viral protein translation significantly decreased in Sam68 knockdown cells compared with the negative-control cells treated with short hairpin RNA (shRNA). However, downregulation of Sam68 did not have a significant inhibitory effect on the accumulation of the EV71 genome. Moreover, Sam68 was redistributed from the nucleus to the cytoplasm and interacts with cellular factors, such as poly(rC)-binding protein 2 (PCBP2) and poly(A)-binding protein (PABP), during EV71 infection. The cytoplasmic relocalization of Sam68 in EV71-infected cells may be involved in the enhancement of EV71 IRES-mediated translation. Since Sam68 is known to be a RNA-binding protein, these results provide direct evidence that Sam68 is a novel ITAF that interacts with EV71 IRES and positively regulates viral protein translation.
IMPORTANCE The nuclear protein Sam68 is found as an additional new host factor that interacts with the EV71 IRES during infection and could potentially enhance the translation of virus protein. To our knowledge, this is the first report that describes Sam68 actively participating in the life cycle of EV71 at a molecular level. These studies will not only improve our understanding of the replication of EV71 but also have the potential for aiding in developing a therapeutic strategy against EV71 infection.
doi:10.1128/JVI.01677-15
PMCID: PMC4577883  PMID: 26202240
17.  Surgical removal and controlled trypsinization of the outer annulus fibrosus improves the bioactivity of the nucleus pulposus in a disc bioreactor culture 
Background
The maintenance of nucleus pulposus (NP) viability in vitro is difficult. The annulus fibrosus (AF) pathway reflects one nutrient transport channel and may have an important effect on NP viability in disc organ cultures. The present study describes a feasible disc pre-treatment involving the AF and investigates its efficacy in improving NP bioactivity in an in vitro disc bioreactor culture.
Methods
Rabbit discs that were randomly assigned to the experimental group (EG) were pretreated via the surgical removal and controlled trypsinization of the outer AF. The discs in the control group (CG) did not receive any special treatment. All discs were organ-cultured in a self-developed bioreactor. Solute transport into the central NP was measured using a methylene blue solution. On days 7 and 14, histological properties, cell viability, cell membrane damage, gene expression and matrix composition within the NP in these two groups were compared with each other and with the corresponding parameters of fresh NP samples. Additionally, the structures of the outer AF and the cartilage endplate (CEP) following pre-treatment were also assessed.
Results
The outer AF in the EG became disorganized, but no specific changes occurred in the CEP or the inner AF following pre-treatment. The discs in the EG exhibited increased penetration of methylene blue into the central NP. On days 7 and 14, the NP bioactivity in the EG was improved compared with that of the CG in terms of cell viability, cell membrane damage, gene expression profile and matrix synthesis. Moreover, cell viability and matrix synthesis parameters in the EG were more similar to those of fresh samples than they were to the same parameters in the CG on day 14.
Conclusions
Using this disc pre-treatment, i.e., the surgical removal and controlled trypsinization of the outer AF, NP bioactivity was better maintained for up to 14 days in an in vitro disc bioreactor culture.
doi:10.1186/s12891-016-0990-2
PMCID: PMC4802625  PMID: 27000557
Intervertebral disc; Degeneration; Organ culture; Nucleus pulposus
18.  Phylogenetic Analysis and Pathogenicity Assessment of Two Strains of Avian Influenza Virus Subtype H9N2 Isolated from Migratory Birds: High Homology of Internal Genes with Human H10N8 Virus 
Two human-infecting avian influenza viruses (AIVs), H7N9 and H10N8, have emerged in China, which further indicate that the H9N2 subtype of AIVs, as an internal gene donor, may have an important role in the generation of new viruses with cross-species transmissibility and pathogenicity. H9N2 viruses that contain such internal genes widely exist in poultry but are rarely reported in migratory birds. In this study, two strains of the H9N2 virus were isolated from fecal samples of migratory birds in 2014: one strain from Caizi Lake in Anhui Province and one from Chen Lake in Hubei Province of China. Nucleotide sequence analysis revealed high homology of all six internal genes of these two strains with the internal genes of the human H10N8 virus in Jiangxi Province, as well as with the human H7N9 virus. Phylogenetic analysis indicated a possible origin of these two strains from poultry in South China. Both of the two viruses tested could replicated in respiratory organs of infective mice without adaption, by both strains of the H9N2 AIVs from wild birds, suggesting their potential capacity for directly infecting mammals. Our findings indicate the existence of H9N2 viruses that contain internal genes highly homologous with human H10N8 or H7N9 viruses. Wild birds can contribute to the spread of the H9N2 virus that contains the “harmful” internal gene complex, leading to gene rearrangement with other influenza viruses and to the generation of new pathogenic viruses. Therefore, strengthening AIV surveillance in wild birds can promote an understanding of the presence and prevalence of viruses and provide scientific evidence for the prevention and control of AIVs and human-infecting AIVs.
doi:10.3389/fmicb.2016.00057
PMCID: PMC4770023  PMID: 26973600
influenza virus; H9N2; H10N8; H7N9; migratory birds; phylogenetic analysis; pathogenicity
19.  Dynamic Compression Effects on Immature Nucleus Pulposus: a Study Using a Novel Intelligent and Mechanically Active Bioreactor 
Background: Previous cell culture and animal in vivo studies indicate the obvious effects of mechanical compression on disc cell biology. However, the effects of dynamic compression magnitude, frequency and duration on the immature nucleus pulposus (NP) from an organ-cultured disc are not well understood.
Objective: To investigate the effects of a relatively wide range of compressive magnitudes, frequencies and durations on cell apoptosis and matrix composition within the immature NP using an intelligent and mechanically active bioreactor.
Methods: Discs from the immature porcine were cultured in a mechanically active bioreactor for 7 days. The discs in various compressive magnitude groups (0.1, 0.2, 0.4, 0.8 and 1.3 MPa at a frequency of 1.0 Hz for 2 hours), frequency groups (0.1, 0.5, 1.0, 3.0 and 5.0 Hz at a magnitude of 0.4 MPa for 2 hours) and duration groups (1, 2, 4 and 8 hours at a magnitude of 0.4 MPa and frequency of 1.0 Hz) experienced dynamic compression once per day. Discs cultured without compression were used as controls. Immature NP samples were analyzed using the TUNEL assay, histological staining, glycosaminoglycan (GAG) content measurement, real-time PCR and collagen II immunohistochemical staining.
Results: In the 1.3 MPa, 5.0 Hz and 8 hour groups, the immature NP showed a significantly increase in apoptotic cells, a catabolic gene expression profile with down-regulated matrix molecules and up-regulated matrix degradation enzymes, and decreased GAG content and collagen II deposition. In the other compressive magnitude, frequency and duration groups, the immature NP showed a healthier status regarding NP cell apoptosis, gene expression profile and matrix production.
Conclusion: Cell apoptosis and matrix composition within the immature NP were compressive magnitude-, frequency- and duration-dependent. The relatively high compressive magnitude or frequency and long compressive duration are not helpful for maintaining the healthy status of an immature NP.
doi:10.7150/ijms.13747
PMCID: PMC4773287  PMID: 26941583
intervertebral disc degeneration; immature; nucleus pulposus; organ culture; bioreactor; dynamic compression.
20.  Role of the ERK1/2 Signaling Pathway in Osteogenesis of Rat Tendon-Derived Stem Cells in Normoxic and Hypoxic Cultures 
Background: Ectopic ossification and increased vascularization are two common phenomena in the chronic tendinopathic tendon. The increased vascularization usually leads to an elevated local oxygen tension which is one of micro-environments that can influence differentiate status of stem cells.
Objective: This study aimed to investigate the osteogenesis capacity of rat tendon-derived stem cells TDSCs (rTDSCs) in normoxic and hypoxic cultures, and to study the role of ERK1/2 signaling pathway in this process.
Methods: rTDSCs were subjected to osteogenesis inductive culture in hypoxic (3% O2) and normoxic (20% O2) conditions. The inhibitor U0126 was added along with culture medium to determine the role of ERK1/2 signaling pathway. Cell viability, cell proliferation, alizarin red staining, alkaline phosphatase (AKP) activity, gene expression (ALP, osteocalcin, collagen I and RUNX2) and protein expression (p-ERK1/2 and RUNX2) of osteogenic-cultured rTSDCs were analyzed in this study.
Results: Hypoxic and normoxic culture had no effects on cell viability of rTDSCs, whereas the proliferation potential of rTDSCs was significantly increased in hypoxic culture. The osteogenesis capacity of rTDSCs in normoxic culture was significantly promoted compared with hypoxic culture, which was reflected by an increased alizarin red staining intensity, an elevated ALP activity, and the up-regulated gene (ALP, osteocalcin, collagen I and RUNX2) or protein (RUNX2) expression of osteogenic makers. However, the osteogenesis capacity of rTDSCs in both hypoxic and normoxic cultures was attenuated by the inhibitor U0126.
Conclusion: Normoxic culture promotes osteogenic differentiation of rTDSCs compared with the hypoxic culture, and the ERK1/2 signaling pathway is involved in this process.
doi:10.7150/ijms.16045
PMCID: PMC4974911  PMID: 27499695
tendinopathy; tendon-derived stem cells; hypoxic; normoxic; osteogenesis.
21.  MicroRNA-126 inhibits proliferation and metastasis by targeting pik3r2 in prostate cancer 
Molecular Medicine Reports  2015;13(2):1204-1210.
The dysregulation of miR-126 has been reported to correlate with the progression of several cancer types. The present study demonstrated that miR-126 was significantly downregulated in prostate cancer (PCa) tissues compared with normal prostate tissues. In vitro and in vivo studies indicated that forced overexpression of miR-126 significantly suppressed the proliferation of PCa cell lines. Additionally, a Transwell assay showed that enhanced expression of miR-126 inhibited metastasis in PCa in vitro. Furthermore, pik3r2 was confirmed to be a direct target of miR-126 in PCa. It was also shown that pik3r2 was upregulated in PCa tissues and this inversely correlated with miR-126 in PCa tissues. In conclusion, these results revealed that aberrant expression of miR-126 promoted the progression of PCa and may serve as a novel therapeutic biomarker for PCa.
doi:10.3892/mmr.2015.4661
PMCID: PMC4732865  PMID: 26677064
prostate cancer; miR-126; pik3r2; proliferation; metastasis
22.  Current Status of Research on Osteoporosis after Solid Organ Transplantation: Pathogenesis and Management 
BioMed Research International  2015;2015:413169.
Improved survival following organ transplantation has brought to the forefront some long-term complications, among which osteoporosis and associated fractures are the major ones that adversely affect the quality of life in recipients. The pathogenesis of osteoporosis in transplant recipients is complex and multifactorial which may be related to increased bone resorption, decreased bone formation, or both. Studies have shown that the preexisting underlying metabolic bone disorders and the use of immunosuppressive agents are the major risk factors for osteoporosis and fractures after organ transplantation. And rapid bone loss usually occurs in the first 6–12 months with a significant increase in fracture risk. This paper will provide an updated review on the possible pathogenesis of posttransplant osteoporosis and fractures, the natural history, and the current prevention and treatment strategies concerning different types of organ transplantation.
doi:10.1155/2015/413169
PMCID: PMC4662986  PMID: 26649301
23.  Production of Human Albumin in Pigs Through CRISPR/Cas9-Mediated Knockin of Human cDNA into Swine Albumin Locus in the Zygotes 
Scientific Reports  2015;5:16705.
Precise genome modification in large domesticated animals is desirable under many circumstances. In the past it is only possible through lengthy and burdensome cloning procedures. Here we attempted to achieve that goal through the use of the newest genome-modifying tool CRISPR/Cas9. We set out to knockin human albumin cDNA into pig Alb locus for the production of recombinant human serum albumin (rHSA). HSA is a widely used human blood product and is in high demand. We show that homologous recombination can occur highly efficiently in swine zygotes. All 16 piglets born from the manipulated zygotes carry the expected knockin allele and we demonstrated the presence of human albumin in the blood of these piglets. Furthermore, the knockin allele was successfully transmitted through germline. This success in precision genomic engineering is expected to spur exploration of pigs and other large domesticated animals to be used as bioreactors for the production of biomedical products or creation of livestock strains with more desirable traits.
doi:10.1038/srep16705
PMCID: PMC4642324  PMID: 26560187
24.  Risk factors of fatigue status among Chinese adolescents 
In recent years, fatigue is common among adolescents. The aim of this study is to evaluate fatigue status and find related factors of fatigue among students ranged from 13-26 years from Wuhu, China. This is a case-control, cross-sectional observational study. The students from six middle schools (high school? 26 years old?) in Wuhu city were recruited, Self-Rating Fatigue Scale (SFS) was used to measure the fatigue status among students ranged from 13-26 years, and some demographic characteristics of students also was determined. A total of 726 students are included in our study. A significant difference was observed between fatigue status and grade, a balanced diet, the partial eclipse, picky for food, lack of sleep, excessive fatigue, drinking (P < 0.05). The risk factors of fatigue status include myopia, partial eclipse, picky for food, lacking of sleep, drinking; grade while a balanced diet is the protective factor of fatigue. Therefore, the school should pay more attention to the fatigue among students in middle school in China, and take some properly measures to reduce the fatigue.
PMCID: PMC4694489  PMID: 26770589
China; adolescents; fatigue status; influencing factors; recurrent and chronic pain
25.  SNP2Structure: A Public and Versatile Resource for Mapping and Three-Dimensional Modeling of Missense SNPs on Human Protein Structures 
One of the long-standing challenges in biology is to understand how non-synonymous single nucleotide polymorphisms (nsSNPs) change protein structure and further affect their function. While it is impractical to solve all the mutated protein structures experimentally, it is quite feasible to model the mutated structures in silico. Toward this goal, we built a publicly available structure database resource (SNP2Structure, https://apps.icbi.georgetown.edu/snp2structure) focusing on missense mutations, msSNP. Compared with web portals with similar aims, SNP2Structure has the following major advantages. First, our portal offers direct comparison of two related 3D structures. Second, the protein models include all interacting molecules in the original PDB structures, so users are able to determine regions of potential interaction changes when a protein mutation occurs. Third, the mutated structures are available to download locally for further structural and functional analysis. Fourth, we used Jsmol package to display the protein structure that has no system compatibility issue. SNP2Structure provides reliable, high quality mapping of nsSNPs to 3D protein structures enabling researchers to explore the likely functional impact of human disease-causing mutations.
doi:10.1016/j.csbj.2015.09.002
PMCID: PMC4759123  PMID: 26949480
Active site mutations; Protein structure; Molecular modeling; Disease causing SNPs; SNP database

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