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1.  Development and characterization of microsatellite loci for the pseudometallophyte Commelina communis (Commelinaceae)1 
Applications in Plant Sciences  2015;3(2):apps.1400098.
• Premise of the study: Microsatellite primers were developed for the pseudometallophyte Commelina communis (Commelinaceae), an important pioneer plant for phytoremediation of copper-contaminated soil. Two wild populations collected from metalliferous and nonmetalliferous sites were used to assess the polymorphism at each locus.
• Methods and Results: Based on the Fast Isolation by AFLP of Sequences COntaining repeats (FIASCO) method, a total of 34 pairs of simple sequence repeat (SSR) markers were designed. When 40 specimens from two populations were screened, 12 microsatellite loci were found to be highly polymorphic. The number of alleles per locus ranged from one to 11 and the observed and expected heterozygosity per locus ranged from 0.000 to 1.000 and from 0.195 to 0.941, respectively.
• Conclusions: These markers will be useful for examining genetic diversity, population structure, and gene flow in populations of C. communis under different edaphic conditions and guiding sustainable management plans for phytoremediation.
doi:10.3732/apps.1400098
PMCID: PMC4332143
Commelina communis; Commelinaceae; genetic diversity; microsatellites; pseudometallophyte
2.  Briarane Diterpenoids from the Gorgonian Dichotella gemmacea 
Marine Drugs  2014;12(12):6178-6189.
Seven new briarane diterpenoids, gemmacolides AS-AY (1–7), were isolated together with ten known analogues (8–17) from the South China Sea gorgonian Dichotella gemmacea. The structures of the new compounds were elucidated by the detailed analysis of spectroscopic data and comparison with reported data. The absolute configuration of compounds was determined based on electronic circular dichroism (ECD) experiments and genetic correlations as well. Compounds 15 and 16 were reported for the first time for the gorgonian. In the preliminary in vitro bioassays, compound 5 showed potential growth inhibitory activity against MG63 cells.
doi:10.3390/md12126178
PMCID: PMC4278224  PMID: 25528959
structure elucidation; briarane diterpenoids; tumor cell growth inhibitory activity; gorgonian; Dichotella gemmacea
3.  MicroRNAs in stool samples as potential screening biomarkers for pancreatic ductal adenocarcinoma cancer 
Pancreatic ductal adenocarcinoma (PDAC) accounts for approximately 90-95% exocrine malignant tumors of the pancreas. The high prevalence of metastasis and the difficulty of early diagnosis lead to a dismal prognosis. MicroRNAs (miRNAs) play a critical role in extensive biological processes. The purpose of this study was to evaluate the feasibility of stool miRNAs as novel biomarker for PDAC screening. MiRNAs were extracted from clinical specimens which included cancer and matched adjacent benign pancreatic tissues of 30 PDAC patients, pancreatic juice of 20 from the 30 PDAC patients and 10 chronic pancreatitis (CP) patients, stool samples of the 30 PDAC patients, the 10 CP patients and 15 healthy volunteers. Relative expression of a panel of 5 dysregulated miRNAs (miR-21, miR-155, miR-196a, miR-216 and miR-217) was analyzed with qRT-PCR. Receiver operating characteristic curve (ROC) analysis was performed to assess the diagnosing value of stool miRNAs in PDAC patients. The study showed that our methods of extracting and detecting miRNAs from pancreatic juice and stool specimens had high reproducibility. Compared to matched adjacent benign pancreatic tissues and pancreatic juice of CP patients, the expression of miR-21 (P = 0.0021 and P = 0.0027) as well as miR-155 (P = 0.0087 and P = 0.0067) was significantly higher and the expression of miR-216 (P < 0.0001 and P = 0.0044) was significantly lower in primary tumor tissues and pancreatic juice of PDAC patients. PDAC patients had a significantly higher stool miR-21 and miR-155 (P = 0.0049 and P = 0.0112) and lower miR-216 level (P = 0.0002) compared to normal controls. The same results were obtained in the expression levels of stool miR-21, miR-155 and miR-216 between PDAC and CP patients (P = 0.0337, P = 0.0388 and P = 0.0117, respectively). Receiver operating characteristic (ROC) analysis by using stool miRNAs expression indicated that combination of miR-21 and miR-155 had best sensitivity of 93.33% while the combination of miR-21, miR-155 and miR-216 would be best for detecting and screening PDAC with area under the curve (AUC) of 0.8667 (95% CI: 0.7722-0.9612) and a better balance of sensitivity and specificity (83.33% vs. 83.33%). Our data indicate that miRNAs could be extracted and detected from pancreatic juice and stool efficiently and reproducibly. MiR-21, miR-155 and miR-216 in stool have the potential of becoming biomarkers for screening PDAC.
PMCID: PMC4266702  PMID: 25520858
PDAC; stool; microRNA; pancreatic juice; diagnosis
4.  Auxin distribution is differentially affected by nitrate in roots of two rice cultivars differing in responsiveness to nitrogen 
Annals of Botany  2013;112(7):1383-1393.
Background and Aims
Although ammonium (NH4+) is the preferred form of nitrogen over nitrate (NO3−) for rice (Oryza sativa), lateral root (LR) growth in roots is enhanced by partial NO3− nutrition (PNN). The roles of auxin distribution and polar transport in LR formation in response to localized NO3− availability are not known.
Methods
Time-course studies in a split-root experimental system were used to investigate LR development patterns, auxin distribution, polar auxin transport and expression of auxin transporter genes in LR zones in response to localized PNN in ‘Nanguang’ and ‘Elio’ rice cultivars, which show high and low responsiveness to NO3−, respectively. Patterns of auxin distribution and the effects of polar auxin transport inhibitors were also examined in DR5::GUS transgenic plants.
Key Results
Initiation of LRs was enhanced by PNN after 7 d cultivation in ‘Nanguang’ but not in ‘Elio’. Auxin concentration in the roots of ‘Nanguang’ increased by approx. 24 % after 5 d cultivation with PNN compared with NH4+ as the sole nitrogen source, but no difference was observed in ‘Elio’. More auxin flux into the LR zone in ‘Nanguang’ roots was observed in response to NO3− compared with NH4+ treatment. A greater number of auxin influx and efflux transporter genes showed increased expression in the LR zone in response to PNN in ‘Nanguang’ than in ‘Elio’.
Conclusions
The results indicate that higher NO3− responsiveness is associated with greater auxin accumulation in the LR zone and is strongly related to a higher rate of LR initiation in the cultivar ‘Nanguang’.
doi:10.1093/aob/mct212
PMCID: PMC3806541  PMID: 24095838
Auxin distribution; lateral root; nitrate; rice; Oryza sativa
5.  A New Method for Computational Drug Repositioning Using Drug Pairwise Similarity 
The traditional de novo drug discovery is known as a high cost and high risk process. In response, recently there is an increasing interest in discovering new indications for known drugs—a process known as drug repositioning—using computational methods. In this study, we present a new systematic approach for identifying potential new indications of an existing drug through its relation to similar drugs. Different from the previous similarity-based methods, we adapted a novel bipartite-graph based method when considering common drug targets and their interaction information. Furthermore, we added drug structure information into the calculation of drug pairwise similarity. In cross-validation experiments, our method achieved a sensitivity of 0.77 and specificity of 0.92 (AUC = 0.888) and compared favorably to the state of the art. When compared with a control group of drug uses, our drug repositioning results were found to be significantly enriched in both the biomedical literature and clinical trials. Our results indicate that combining chemical structure and drug target information results in better prediction performance and that the proposed approach successfully captures the implicit information between drug targets.
doi:10.1109/BIBM.2012.6392722
PMCID: PMC4175719  PMID: 25264495
drug repositioning; bipartite graph; target similarity; chemical similarity; target interaction
6.  Shape-parameterized diffuse optical tomography holds promise for sensitivity enhancement of fluorescence molecular tomography 
Biomedical Optics Express  2014;5(10):3640-3659.
A fundamental approach to enhancing the sensitivity of the fluorescence molecular tomography (FMT) is to incorporate diffuse optical tomography (DOT) to modify the light propagation modeling. However, the traditional voxel-based DOT has been involving a severely ill-posed inverse problem and cannot retrieve the optical property distributions with the acceptable quantitative accuracy and spatial resolution. Although, with the aid of an anatomical imaging modality, the structural-prior-based DOT method with either the hard- or soft-prior scheme holds promise for in vivo acquiring the optical background of tissues, the low robustness of the hard-prior scheme to the segmentation error and inferior performance of the soft-prior one in the quantitative accuracy limit its further application. We propose in this paper a shape-parameterized DOT method for not only effectively determining the regional optical properties but potentially achieving reasonable structural amelioration, lending itself to FMT for comparably improved recovery of fluorescence distribution.
doi:10.1364/BOE.5.003640
PMCID: PMC4206331  PMID: 25360379
(170.3880) Medical and biological imaging; (170.6960) Tomography; (170.3010) Image reconstruction techniques
7.  Activation of Akt/mTOR Pathway Is Associated with Poor Prognosis of Nasopharyngeal Carcinoma 
PLoS ONE  2014;9(8):e106098.
Nasopharyngeal carcinoma (NPC) is a malignant tumor of the head and neck region, which frequently occurs in Southeast Asia, especially in the south of China. It is known that the mammalian target of rapamycin (mTOR) pathway plays a central role in regulating cellular functions, including proliferation, growth, survival, mobility, and angiogenesis. Aberrant expression of the mTOR signaling pathway molecules has been found in many types of cancer. However, whether the alterations of p-Akt, p-p70S6K and p-4EBP1 protein expression are associated with clinicopathological features and prognostic implications in NPC have not been reported. The purposes of the present study are to investigate the association between the expression of p-Akt, p-p70S6K and p-4EBP1 proteins and clinicopathological features in NPC by immunohistochemistry. The results showed that the positive percentage of p-Akt, p-p70S6K and p-4EBP1 proteins expression in NPC (47.2%, 73.0% and 61.7%, respectively) was significantly higher than that in the non-cancerous nasopharyngeal control tissue (33.3%, 59.1% and 47.0%, respectively). There was a significantly higher positive expression of p-Akt in undifferentiated non-keratinizing nasopharyngeal carcinoma than that in differentiated non-keratinizing nasopharyngeal carcinoma (P = 0.014). Additionally, positive expression of p-p70S6K and p-4EBP1 proteins, and positive expression of either of p-Akt, p-p70S6K and p-4EBP1 were significantly correlated inversely with overall survival rates of NPC patients (P = 0.023, P = 0.033, P = 0.008, respectively). Spearman’s rank correlation test showed that expression of p-Akt in NPC was significantly associated with expression of p-p70S6K (r = 0.263, P<0.001) and p-4EBP1(r = 0.284, P<0.001). Also there was an obviously positive association between expression of p-p70S6K and p-4EBP1 proteins in NPC (r = 0.286, P<0.001). Multivariate Cox regression analysis further identified positive expression of p-4EBP1 and p-p70S6K proteins were the independent poor prognostic factors for NPC (P = 0.043, P = 0.027, respectively). Taken together, high expression of p-p70S6K and p-4EBP1 proteins may act as valuable independent biomarkers to predict a poor prognosis of NPC.
doi:10.1371/journal.pone.0106098
PMCID: PMC4148345  PMID: 25165983
8.  Effects of hypertonic saline - hydroxyethyl starch and mannitol on serum osmolality, dural tension and hemodynamics in patients undergoing elective neurosurgical procedures 
Objective: To investigate effect of equal volumes (250 ml) of 7.2% hypertonic saline - 6% hydroxyethyl starch (HS-HES) and 20% mannitol (M) on dural tension, serum osmolality and hemodynamics in patients during elective neurosurgical procedures. Material and methods: Forty ASA I-II patients scheduled for elective neurosurgical supratentorial procedures were randomly assigned to two groups. About 30 min before skull opening, patients received either HS-HES or M at infusion rate 750 ml/h. Dural tension score was used to evaluate the dural tension by neurosurgeons. Serum osmolality was tested at following time points: before, 125 ml infused, 250 ml infused, 30 min and 60 min after infusion. Hemodynamic variables were measured by FloTrac. Results: Patients who received HS-HES had a significant decrease in dural tension scores (P < 0.05) and obtained more satisfactory brain relaxation for neurosurgeon (95% vs. 75%). In HS-HES group, the peak of serum osmolality occurred earlier and hyperosmolality lasted for longer time. Transient decrease in mean arterial pressure was observed in M group at 10 min after the start infusion (P < 0.01). Heart rate significantly decreased after HS-HES infusion, whereas no significant changes were observed in M group. In HS-HES group, stroke volume variation significantly decreased from 9.7 ± 3.5 at the initiation of infusion to 6.7 ± 2.4 at 30 min after the infusion and remained decreased more than 60 min while it decreased from 6.8 ± 3.1 to 5.3 ± 1.5 in M group. Moreover, urine output in HS-HES group from initiation to 60 min after the infusion was significantly less than those in M group.Conclusion: HS-HES might be an alternative to mannitol in treatment of intracranial hypertension.
PMCID: PMC4161579  PMID: 25232419
Hypertonic saline; hydroxyethyl starch; mannitol; dural tension; neurosurgery anesthesia
9.  Increased expression of IRS-1 is associated with lymph node metastasis in nasopharyngeal carcinoma 
Nasopharyngeal carcinoma (NPC) is a head and neck malignant tumor rare throughout most of the world but common in Southeast Asia, especially in Southern China, which is with characteristics of early cervical lymph node metastasis and high incidence rate of distant metastasis. Insulin receptor substrate 1 (IRS-1) is a signaling adapter protein that is encoded by the IRS-1 gene in humans, plays an important role in the development, progression, invasion and metastasis of tumors. The aim of the present study was to investigate the association between the expression of IRS-1 protein and clinicopathological characteristics in NPC by immunohistochemistry. The results showed that the expression level of IRS-1 was significant higher in NPC than that in the control nasopharyngeal epithelia (P = 0.042). The positive percentage of IRS-1 expression in NPC with lymph node metastasis was also significantly higher than those without lymph node metastasis (P = 0.008). Positive expression of IRS-1 was proved to be the independent predicted factor for lymph node metastasis of NPC (P = 0.025) regardless of age, gender, histological type and clinical stages by multivariate logistic regression analysis. In addition, results showed higher sensitivity and agreement rate of IRS-1 for predicting lymph node metastasis of NPC patients. Taken together, high expression of IRS-1 might be closely correlated with lymph node metastasis in NPC and positive expression of IRS-1 could be used as an independent biomarker for predicting lymph node metastasis of NPC.
PMCID: PMC4203230  PMID: 25337259
Insulin receptor substrate (IRS); insulin receptor substrate 1 (IRS-1); nasopharyngeal carcinoma (NPC); metastasis; biomarker
10.  Increased Expression of Flotillin-2 Protein as a Novel Biomarker for Lymph Node Metastasis in Nasopharyngeal Carcinoma 
PLoS ONE  2014;9(7):e101676.
Nasopharyngeal carcinoma (NPC) is a head and neck malignant tumor rare throughout most of the world but common in Southeast Asia, especially in Southern China. Flotillin-2 (Flot-2) is not only an important component of cellular membrane, but also involves in various cellular processes such as membrane trafficking, T cell and B cell activation, regulation of several signaling pathways associated with cell growth and malignant transformation, keeping structure and junction of epidermal cells and formation of filopodia. Although such molecular effects of Flot-2 have been reported, whether the expression of Flot-2 protein is associated with clinicopathologic implication for NPC has not been reported. The purpose of this research is to investigate the expression of Flot-2 protein in NPC and control nasopharyngeal epithelial tissues by immunohistochemistry and elucidate the association between the expression of Flot-2 protein and clinicopathological characteristics of NPC. The results showed that the positive percentage of Flot-2 expression in the NPC, nasopharyngeal epithelia with atypical hyperplasia and in the control nasopharyngeal mucosa epithelia was 88.8% (119/134), 76.9% (10/13) and 5.7% (5/88), respectively. There was significantly higher expression of Flot-2 protein in NPC and nasopharyngeal epithelia with atypical hyperplasia compared to the control nasopharyngeal mucosa epithelia (P<0.001, respectively). The positive percentage of Flot-2 protein expression in NPC patients with lymph node metastasis was significantly higher than those without lymph node metastasis. Increasing of Flot-2 expression was obviously correlated with clinical stages of NPC patients. The expression of Flot-2 was proved to be the independent predicted factor for lymph node metastasis by multivariate analysis. The sensitivity of Flot-2 for predicting lymph node metastasis of NPC patients was 93%. Taken together, our results suggest that the increased expression of Flot-2 protein is a novel higher sensitivity biomarker that can predict lymph node metastases in NPC.
doi:10.1371/journal.pone.0101676
PMCID: PMC4094483  PMID: 25014228
11.  Multiple silk coatings on biphasic calcium phosphate scaffolds: Effect on physical and mechanical properties, and in vitro osteogenic response of human mesenchymal stem cells 
Biomacromolecules  2013;14(7):2179-2188.
Ceramic scaffolds such as biphasic calcium phosphate (BCP) have been widely studied and used for bone regeneration, but their brittleness and low mechanical strength are major drawbacks. We report the first systematic study on the effect of silk coating in improving the mechanical and biological properties of BCP scaffolds, including 1) optimisation of the silk coating process by investigating multiple coatings, and 2) in vitro evaluation of the osteogenic response of human mesenchymal stem cells (hMSCs) on the coated scaffolds. Our results show that multiple silk coatings on BCP ceramic scaffolds can achieve a significant coating effect to approach the mechanical properties of native bone tissue and positively influence osteogenesis by hMSCs over an extended period. The silk coating method developed in this study represents a simple yet effective means of reinforcement that can be applied to other types of ceramic scaffolds with similar microstructure to improve osteogenic outcomes.
doi:10.1021/bm400303w
PMCID: PMC3752092  PMID: 23745709
Silk; Scaffold; Coating; Human mesenchymal stem cells (hMSCs); Osteogenic
12.  Polyethylene Glycol Electrolyte Lavage Solution versus Colonic Hydrotherapy for Bowel Preparation before Colonoscopy: A Single Center, Randomized, and Controlled Study 
This single center, randomized, and controlled study aimed to compare the effectiveness and safety of polyethylene glycol electrolyte lavage (PEG-EL) solution and colonic hydrotherapy (CHT) for bowel preparation before colonoscopy. A total of 196 eligible outpatients scheduled for diagnostic colonoscopy were randomly assigned to the PEG-EL (n = 102) or CHT (n = 94) groups. Primary outcome measures included colonic cleanliness and adverse effects. Secondary outcome measures were patient satisfaction and preference, colonoscopic findings, ileocecal arrival rate, examiner satisfaction, and cecal intubation time. The results show that PEG-EL group was associated with significantly better colonic cleanliness than CHT group, fewer adverse effects, and increased examiner satisfaction. However, the CHT group had higher patient satisfaction and higher diverticulosis detection rates. Moreover, the results showed the same ileocecal arrival rate and patient preference between the two groups (P > 0.05). These findings indicate that PEG-EL is the preferred option in patients who followed the preparation instructions completely.
doi:10.1155/2014/541586
PMCID: PMC4068103  PMID: 24995014
13.  Geniposide, the component of the Chinese herbal formula Tongluojiunao, protects amyloid-β peptide (1–42-mediated death of hippocampal neurons via the non-classical estrogen signaling pathway 
Neural Regeneration Research  2014;9(5):474-480.
Tongluojiunao (TLJN) is an herbal medicine consisting of two main components, geniposide and ginsenoside Rg1. TLJN has been shown to protect primary cultured hippocampal neurons. However, its mechanism of action remains unclear. In the present study, primary cultured hippocampal neurons treated with Aβ1–42 (10 µmol/L) significantly increased the release of lactate dehydrogenase, which was markedly reduced by TLJN (2 µL/mL), specifically by the component geniposide (26 µmol/L), but not ginsenoside Rg1 (2.5 µmol/L). The estrogen receptor inhibitor, ICI182780 (1 µmol/L), did not block TLJN- or geniposide-mediated decrease of lactate dehydrogenase under Aβ1–42-exposed conditions. However, the phosphatidyl inositol 3-kinase or mitogen-activated protein kinase pathway inhibitor, LY294002 (50 µmol/L) or U0126 (10 µmol/L), respectively blocked the decrease of lactate dehydrogenase mediated by TLJN or geniposide. Therefore, these results suggest that the non-classical estrogen pathway (i.e., phosphatidyl inositol 3-kinase or mitogen-activated protein kinase) is involved in the neuroprotective effect of TLJN, specifically its component, geniposide, against Aβ1–42-mediated cell death in primary cultured hippocampal neurons.
doi:10.4103/1673-5374.130063
PMCID: PMC4153512  PMID: 25206841
nerve regeneration; neurodegeneration; Alzheimer's disease; cell culture; hippocampus; neurons; Aβ1–42; estrogen signaling pathway; phosphatidyl inositol 3-kinase pathway; mitogen-activated protein kinase pathway; Tongluojiunao injection; geniposide; ginsenoside Rg1; NSFC grant; neural regeneration
14.  Phosphorylated Mnk1 and eIF4E Are Associated with Lymph Node Metastasis and Poor Prognosis of Nasopharyngeal Carcinoma 
PLoS ONE  2014;9(2):e89220.
Nasopharyngeal carcinoma (NPC) is a head and neck malignant tumor rare throughout most of the world but common in Southeast Asia, especially in Southern China. The phosphorylation of eukaryotic translation initiation factor 4E (eIF4E) by MAP kinase-interacting kinases (Mnk) on Ser-209 promotes cellular proliferation, survival, malignant transformation and metastasis. However, whether the alterations of the expression of p-eIF4E and p-Mnk1 protein are associated with clinicopathologic/prognostic implication for NPC has not been reported. The purposes of the present study are to examine the expression of p-eIF4E and p-Mnk1 protein in NPC and non-cancerous nasopharyngeal epithelial tissues by immunohistochemistry and evaluate the association between the expression of p-eIF4E and p-Mnk1 protein and clinicopathological characteristics of NPC. The results showed that the positive percentage of p-Mnk1 and p-eIF4E proteins expression in NPC (83.5% and 75.4%, respectively) was significantly higher than that in non-cancerous nasopharyngeal epithelium (40.0% and 32.9%, respectively). The positive expression of p-eIF4E and p-Mnk1 in the NPC with cervical lymph node metastasis was significantly higher than those without lymph node metastasis. Additionally, p-eIF4E expression was more pronouncedly increased in metastatic NPC than the matched primary NPC. Increase of p-eIF4E and p-Mnk1 expression was significantly correlated inversely with overall survival. Spearman’s rank correlation test further showed that expression of p-Mnk1 was strongly positive correlated with expression of p-eIF4E in NPC. The expression of p-Mnk1 and p-eIF4E in NPC was proved to be the independent prognostic factors regardless of lymph node metastasis, clinical stages and combination of radiotherapy and chemotherapy, histological type, age and gender by multivariate analysis. Taken together, high expression of p-Mnk1 and p-eIF4E might be novel valuable biomarkers to predict poor prognosis of NPC and therapeutic targets for developing the valid treatment strategies.
doi:10.1371/journal.pone.0089220
PMCID: PMC3925237  PMID: 24551240
15.  Briarane Diterpenes from the South China Sea Gorgonian Coral, Junceella gemmacea 
Marine Drugs  2014;12(2):589-600.
Four new briarane diterpenoids, junceellolides M–P (1–4), were isolated together with seven known analogs (5–11) from the South China Sea gorgonian, Junceella gemmacea. The structures of these compounds were elucidated by detailed spectroscopic analysis and comparison with the reported data. The absolute configuration of compounds 1–3 were determined based on an ECD experiment, while the absolute configuration of compound 4 was genetically determined. All the compounds were isolated for the first time from J. gemmacea. These compounds showed no growth inhibitory activity against A549, MG63 and SMMC-7721 cell lines in an in vitro bioassay.
doi:10.3390/md12020589
PMCID: PMC3944505  PMID: 24473165
Junceella gemmacea; briarane; diterpenoid; junceellolide
16.  Integrated Analysis of Differential miRNA and mRNA Expression Profiles in Human Radioresistant and Radiosensitive Nasopharyngeal Carcinoma Cells 
PLoS ONE  2014;9(1):e87767.
Background
The purpose of this study was to identify miRNAs and genes involved in nasopharyngeal carcinoma (NPC) radioresistance, and explore the underlying mechanisms in the development of radioresistance.
Methods
We used microarrays to compare the differences of both miRNA and mRNA expression profiles in the radioresistant NPC CNE2-IR and radiosensitive NPC CNE2 cells, applied qRT-PCR to confirm the reliability of microarray data, adopted databases prediction and anticorrelated analysis of miRNA and mRNA expression to identify the miRNA target genes, and employed bioinformatics tools to examine the functions and pathways in which miRNA target genes are involved, and construct a miRNA-target gene regulatory network. We further investigated the roles of miRNA-23a and its target gene IL-8 in the NPC radioresistance.
Results
The main findings were fourfold: (1) fifteen differential miRNAs and 372 differential mRNAs were identified, and the reliability of microarray data was validated for randomly selected eight miRNAs and nine genes; (2) 174 miRNA target were identified, and most of their functions and regulating pathways were related to tumor therapeutic resistance; (3) a posttranscriptional regulatory network including 375 miRNA-target gene pairs was constructed, in which the ten genes were coregulated by the six miRNAs; (4) IL-8 was a direct target of miRNA-23a, the expression levels of IL-8 were elevated in the radioresistant NPC tissues and showed inverse correlation with miRNA-23a expression, and genetic upregulation of miRNA-23a and antibody neutralization of secretory IL-8 could reduce NPC cells radioresistance.
Conclusions
We identified fifteen differential miRNAs and 372 differential mRNAs in the radioresistant NPC cells, constructed a posttranscriptional regulatory network including 375 miRNA-target gene pairs, discovered the ten target genes coregulated by the six miRNAs, and validated that downregulated miRNA-23a was involved in NPC radioresistance through directly targeting IL-8. Our data form a basis for further investigating the mechanisms of NPC radioresistance.
doi:10.1371/journal.pone.0087767
PMCID: PMC3909230  PMID: 24498188
17.  The proliferation of malignant melanoma cells could be inhibited by ranibizumab via antagonizing VEGF through VEGFR1 
Molecular Vision  2014;20:649-660.
Purpose
Angiogenesis is an important mediator in tumor progression. Vascular endothelial growth factor (VEGF) is one of the major cytokines that can influence angiogenesis. However, the potential mechanism of tumor growth inhibition through anti-VEGF agents is still unclear. This study was performed to examine whether ranibizumab could inhibit malignant melanoma growth in vitro and to determine the safety of ranibizumab on human adult retinal pigment epithelium cell line (ARPE-19 cells).
Methods
Malignant melanoma cells obtained from a clinic were cultured in vitro. VEGF concentrations secreted by malignant melanoma cells and the ARPE-19 cells were examined by enzyme-linked immunosorbent assay (ELISA). The two kinds of cells were both treated with VEGF and its antagonist, ranibizumab. The dynamic changes of the two types of cells were monitored by real-time cell electronic sensing (RT-CES) assay. The effect of ranibizumab on both types of cells was verified by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl (MTT) assay. The expression of VEGF receptor 1 (VEGFR1) RNA in uveal melanoma was further investigated through the PCR technique.
Results
The levels of VEGF secreted by malignant melanoma cells were much higher than those of ARPE-19 cells, and were markedly decreased in the action of 0.1 mg/ml ranibizumab. However, there was no obvious reduction of VEGF in the presence of ranibizumab for ARPE-19 (p>0.05). Meanwhile, RT-CES showed that the viability of malignant melanoma cells increased greatly in the presence of VEGF. When VEGF was 20 ng/ml, viability of the malignant melanoma cells increased by 40% compared with the negative control. There was no evident effect on proliferation of ARPE-19 (p>0.05). Furthermore, the growth of malignant melanoma cells was obviously inhibited after ranibizumab intervention. When ranibizumab was administered at 0.25 mg/ml, the survival rate of the malignant melanoma cells decreased to 57.5%. Nevertheless, low-dose exposure to ranibizumab had only a slight effect on the growth of ARPE-19, and PCR result demonstrated that VEGFR1 plays a role in this tumor tissue rather than VEGFR2.
Conclusions
Ranibizumab can selectively inhibit malignant melanoma cell proliferation by decreasing the expression of VEGF; the possible mechanism of the inhibitory effect may involve VEGFR1 antagonism.
PMCID: PMC4021672  PMID: 24868139
18.  Assessing the Effect of Litter Species on the Dynamic of Bacterial and Fungal Communities during Leaf Decomposition in Microcosm by Molecular Techniques 
PLoS ONE  2013;8(12):e84613.
Although bacteria and fungi are well-known to be decomposers of leaf litter, few studies have examined their compositions and diversities during the decomposition process in tropical stream water. Xishuangbanna is a tropical region preserving one of the highest floristic diversity areas in China. In this study, leaf litter of four dominant plant species in Xishuangbanna was incubated in stream water for 42 days during which samples were taken regularly. Following DNA extraction, PCR-DGGE (denaturing gradient gel electrophoresis) and clone-sequencing analyses were performed using bacterial and fungal specific primers. Leaf species have slightly influences on bacterial community rather than fungal community. The richness and diversity of bacteria was higher than that of fungi, which increased towards the end of the 42-day-incubation. The bacterial community was initially more specific upon the type of leaves and gradually became similar at the later stage of decomposition with alpha-proteobacteria as major component. Sequences affiliated to methanotrophs were obtained that indicates potentially occurrence of methane oxidation and methanogenesis. For the fungal community, sequences affiliated to Aspergillus were predominant at the beginning and then shifted to Pleosporales. Our results suggest that the microorganisms colonizing leaf biofilm in tropical stream water were mostly generalists that could exploit the resources of leaves of various species equally well.
doi:10.1371/journal.pone.0084613
PMCID: PMC3868619  PMID: 24367682
19.  Pathway-based drug repositioning using causal inference 
BMC Bioinformatics  2013;14(Suppl 16):S3.
Background
Recent in vivo studies showed new hopes of drug repositioning through causality inference from drugs to disease. Inspired by their success, here we present an in silico method for building a causal network (CauseNet) between drugs and diseases, in an attempt to systematically identify new therapeutic uses of existing drugs.
Methods
Unlike the traditional 'one drug-one target-one disease' causal model, we simultaneously consider all possible causal chains connecting drugs to diseases via target- and gene-involved pathways based on rich information in several expert-curated knowledge-bases. With statistical learning, our method estimates transition likelihood of each causal chain in the network based on known drug-disease treatment associations (e.g. bexarotene treats skin cancer).
Results
To demonstrate its validity, our method showed high performance (AUC = 0.859) in cross validation. Moreover, our top scored prediction results are highly enriched in literature and clinical trials. As a showcase of its utility, we show several drugs for potential re-use in Crohn's Disease.
Conclusions
We successfully developed a computational method for discovering new uses of existing drugs based on casual inference in a layered drug-target-pathway-gene- disease network. The results showed that our proposed method enables hypothesis generation from public accessible biological data for drug repositioning.
doi:10.1186/1471-2105-14-S16-S3
PMCID: PMC3853312  PMID: 24564553
20.  Developing Topic-Specific Search Filters for PubMed with Click-Through Data 
Summary
Objectives
Search filters have been developed and demonstrated for better information access to the immense and ever-growing body of publications in the biomedical domain. However, to date the number of filters remains quite limited because the current filter development methods require significant human efforts in manual document review and filter term selection. In this regard, we aim to investigate automatic methods for generating search filters.
Methods
We present an automated method to develop topic-specific filters on the basis of users’ search logs in PubMed. Specifically, for a given topic, we first detect its relevant user queries and then include their corresponding clicked articles to serve as the topic-relevant document set accordingly. Next, we statistically identify informative terms that best represent the topic-relevant document set using a background set composed of topic irrelevant articles. Lastly, the selected representative terms are combined with Boolean operators and evaluated on benchmark datasets to derive the final filter with the best performance.
Results
We applied our method to develop filters for four clinical topics: nephrology, diabetes, pregnancy, and depression. For the nephrology filter, our method obtained performance comparable to the state of the art (sensitivity of 91.3%, specificity of 98.7%, precision of 94.6%, and accuracy of 97.2%). Similarly, high-performing results (over 90% in all measures) were obtained for the other three search filters.
Conclusion
Based on PubMed click-through data, we successfully developed a high-performance method for generating topic-specific search filters that is significantly more efficient than existing manual methods. All data sets (topic-relevant and irrelevant document sets) used in this study and a demonstration system are publicly available at http://www.ncbi.nlm.nih.gov/CBBresearch/Lu/downloads/CQ_filter/
doi:10.3414/ME12-01-0054
PMCID: PMC3744813  PMID: 23666447
Information Retrieval; PubMed Search Filter; PubMed Log Analysis; Clinical Topic
21.  Systematic identification of pharmacogenomics information from clinical trials 
Journal of biomedical informatics  2012;45(5):870-878.
Recent progress in high-throughput genomic technologies has shifted pharmacogenomic research from candidate gene pharmacogenetics to clinical pharmacogenomics (PGx). Many clinical related questions may be asked such as ‘what drug should be prescribed for a patient with mutant alleles?’ Typically, answers to such questions can be found in publications mentioning the relationships of the gene–drug–disease of interest. In this work, we hypothesize that ClinicalTrials.gov is a comparable source rich in PGx related information. In this regard, we developed a systematic approach to automatically identify PGx relationships between genes, drugs and diseases from trial records in ClinicalTrials.gov. In our evaluation, we found that our extracted relationships overlap significantly with the curated factual knowledge through the literature in a PGx database and that most relationships appear on average 5 years earlier in clinical trials than in their corresponding publications, suggesting that clinical trials may be valuable for both validating known and capturing new PGx related information in a more timely manner. Furthermore, two human reviewers judged a portion of computer-generated relationships and found an overall accuracy of 74% for our text-mining approach. This work has practical implications in enriching our existing knowledge on PGx gene–drug–disease relationships as well as suggesting crosslinks between ClinicalTrials.gov and other PGx knowledge bases.
doi:10.1016/j.jbi.2012.04.005
PMCID: PMC3760158  PMID: 22546622
Text mining; Clinical outcome; Pharmacogenomics; Clinical trial
22.  Abnormality in face scanning by children with autism spectrum disorder is limited to the eye region: Evidence from multi-method analyses of eye tracking data 
Journal of Vision  2013;13(10):5.
There has been considerable controversy regarding whether children with autism spectrum disorder (ASD) and typically developing children (TD) show different eye movement patterns when processing faces. We investigated ASD and age- and IQ-matched TD children's scanning of faces using a novel multi-method approach. We found that ASD children spent less time looking at the whole face generally. After controlling for this difference, ASD children's fixations of the other face parts, except for the eye region, and their scanning paths between face parts were comparable either to the age-matched or IQ-matched TD groups. In contrast, in the eye region, ASD children's scanning differed significantly from that of both TD groups: (a) ASD children fixated significantly less on the right eye (from the observer's view); (b) ASD children's fixations were more biased towards the left eye region; and (c) ASD children fixated below the left eye, whereas TD children fixated on the pupil region of the eye. Thus, ASD children do not have a general abnormality in face scanning. Rather, their abnormality is limited to the eye region, likely due to their strong tendency to avoid eye contact.
doi:10.1167/13.10.5
PMCID: PMC3739407  PMID: 23929830
autism spectrum disorder; face processing; face recognition; eye movements; eye tracking
23.  The protective effect of geniposide on human neuroblastoma cells in the presence of formaldehyde 
Background
Formaldehyde can induce misfolding and aggregation of Tau protein and β amyloid protein, which are characteristic pathological features of Alzheimer’s disease (AD). An increase in endogenous formaldehyde concentration in the brain is closely related to dementia in aging people. Therefore, the discovery of effective drugs to counteract the adverse impact of formaldehyde on neuronal cells is beneficial for the development of appropriate treatments for age-associated cognitive decline.
Methods
In this study, we assessed the neuroprotective properties of TongLuoJiuNao (TLJN), a traditional Chinese medicine preparation, against formaldehyde stress in human neuroblastoma cells (SH-SY5Y cell line). The effect of TLJN and its main ingredients (geniposide and ginsenoside Rg1) on cell viability, apoptosis, intracellular antioxidant activity and the expression of apoptotic-related genes in the presence of formaldehyde were monitored.
Results
Cell counting studies showed that in the presence of TLJN, the viability of formaldehyde-treated SH-SY5Y cells significantly recovered. Laser scanning confocal microscopy revealed that the morphology of formaldehyde-injured cells was rescued by TLJN and geniposide, an effective ingredient of TLJN. Moreover, the inhibitory effect of geniposide on formaldehyde-induced apoptosis was dose-dependent. The activity of intracellular antioxidants (superoxide dismutase and glutathione peroxidase) increased, as did mRNA and protein levels of the antiapoptotic gene Bcl-2 after the addition of geniposide. In contrast, the expression of the apoptotic-related gene - P53, apoptotic executer - caspase 3 and apoptotic initiator - caspase 9 were downregulated after geniposide treatment.
Conclusions
Our results indicate that geniposide can protect SH-SY5Y cells against formaldehyde stress through modulating the expression of Bcl-2, P53, caspase 3 and caspase 9, and by increasing the activity of intracellular superoxide dismutase and glutathione peroxidase.
doi:10.1186/1472-6882-13-152
PMCID: PMC3702466  PMID: 23815892
Formaldehyde impairment; Geniposide; Neuroprotection
24.  Perforated sarcomatoid carcinoma of the jejunum: Case report 
Oncology Letters  2013;6(2):562-564.
Sarcomatoid carcinomas exhibit features that are common to epithelial and mesenchymal tumors. These carcinomas are rare, particularly in the small intestine. In the current case report, we describe a case of an intestinal sarcomatoid carcinoma in a 70-year-old Chinese female. Sarcomatoid carcinoma was confirmed based on light microscopy and immunohistochemical observations. The patient presented with symptoms of acute abdomen, which was due to an intestinal perforation caused by sarcomatoid carcinoma of the small bowel. Patients with sarcomatoid carcinoma are usually associated with a poor prognosis. However, this patient experienced a relatively favorable prognosis, which may be attributed to low positivity for Ki67 in the tumor.
doi:10.3892/ol.2013.1378
PMCID: PMC3789042  PMID: 24137370
sarcomatoid carcinoma; small intestine; perforation
25.  Oxygen promotes biofilm formation of Shewanella putrefaciens CN32 through a diguanylate cyclase and an adhesin 
Scientific Reports  2013;3:1945.
Although oxygen has been reported to regulate biofilm formation by several Shewanella species, the exact regulatory mechanism mostly remains unclear. Here, we identify a direct oxygen-sensing diguanylate cyclase (DosD) and reveal its regulatory role in biofilm formation by Shewanella putrefaciens CN32 under aerobic conditions. In vitro and in vivo analyses revealed that the activity of DosD culminates to synthesis of cyclic diguanylate (c-di-GMP) in the presence of oxygen. DosD regulates the transcription of bpfA operon which encodes seven proteins including a large repetitive adhesin BpfA and its cognate type I secretion system (TISS). Regulation of DosD in aerobic biofilms is heavily dependent on an adhesin BpfA and the TISS. This study offers an insight into the molecular mechanism of oxygen-stimulated biofilm formation by S. putrefaciens CN32.
doi:10.1038/srep01945
PMCID: PMC3672883  PMID: 23736081

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