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1.  Monochromatic energy computed tomography image for active intestinal hemorrhage: A model investigation 
AIM: To investigate the value of computed tomography (CT) spectral imaging in the evaluation of intestinal hemorrhage.
METHODS: Seven blood flow rates were simulated in vitro. Energy spectral CT and mixed-energy CT scans were performed for each rate (0.5, 0.4, 0.3, 0.2, 0.1, 0.05 and 0.025 mL/min). The detection rates and the contrast-to-noise ratios (CNRs) of the contrast agent extravasation regions were compared between the two scanning methods in the arterial phase (AP) and the portal venous phase (PVP). Comparisons of the CNR values between the PVP and the AP were made for each energy level and carried out using a completely random t test. A χ2 test was used to compare the detection rates obtained from the two scanning methods.
RESULTS: The total detection rates for energy spectral CT and mixed-energy CT in the AP were 88.57% (31/35) and 65.71% (23/35), respectively, and the difference was significant (χ2 = 5.185, P = 0.023); the total detection rates in the PVP were 100.00% (35/35) and 91.4% (32/35), respectively, and the difference was not significant (χ2 = 1.393, P = 0.238). In the AP, the CNR of the contrast agent extravasation regions was 3.58 ± 2.09 on the mixed-energy CT images, but the CNRs were 8.78 ± 7.21 and 8.83 ± 6.75 at 50 and 60 keV, respectively, on the single-energy CT images, which were significantly different (3.58 ± 2.09 vs 8.78 ± 7.21, P = 0.031; 3.58 ± 2.09 vs 8.83 ± 6.75, P = 0.029). In the PVP, the differences between the CNRs at 40, 50 and 60 keV different monochromatic energy levels and the polychromatic energy images were significant (19.35 ± 10.89 vs 11.68 ± 6.38, P = 0.010; 20.82 ± 11.26 vs 11.68 ± 6.38, P = 0.001; 20.63 ± 10.07 vs 11.68 ± 6.38, P = 0.001). The CNRs at the different energy levels in the AP and the PVP were significantly different (t = -2.415, -2.380, -2.575, -2.762, -2.945, -3.157, -3.996 and -3.189).
CONCLUSION: Monochromatic energy imaging spectral CT is superior to polychromatic energy images for the detection of intestinal hemorrhage, and the detection was easier in the PVP compared with the AP.
doi:10.3748/wjg.v21.i1.214
PMCID: PMC4284337  PMID: 25574093
Spectral imaging; Computed tomography; Monochromatic energy imaging; Small bowel bleeding
2.  Quantitative investigation of the affinity of human respiratory syncytial virus phosphoprotein C-terminus binding to nucleocapsid protein 
Virology Journal  2014;11(1):191.
Background
There are no approved small molecule drug therapies for human respiratory syncytial virus (hRSV), a cause of morbidity and mortality in at-risk newborns, the immunocompromised, and the elderly. We have investigated as a potential novel hRSV drug target the protein-protein interaction between the C-terminus of the viral phosphoprotein (P) and the viral nucleocapsid protein (N), components of the ribonucleoprotein complex that contains, replicates, and transcribes the viral RNA genome. Earlier work by others established that the 9 C-terminal residues of P are necessary and sufficient for binding to N.
Methods
We used a fluorescence anisotropy assay, surface plasmon resonance and 2-D NMR to quantify the affinities of peptides based on the C terminus of P for RNA-free, monomeric N-terminal-truncated N(13-391). We calculated the contributions to the free energies of binding of P to N(13-391) attributable to the C-terminal 11 residues, phosphorylation of the C-terminal 2 serine residues, the C-terminal Asp-Phe, and the phenyl ring of the C-terminal Phe.
Results
Binding studies confirmed the crucial role of the phosphorylated C-terminal peptide D(pS)DNDL(pS)LEDF for binding of P to RNA-free, monomeric N(13-391), contributing over 90% of the binding free energy at low ionic strength. The phenyl ring of the C-terminal Phe residue contributed an estimated -2.7 kcal/mole of the free energy of binding, the C-terminal Asp-Phe residues contributed -3.8 kcal/mole, the sequence DSDNDLSLE contributed -3.1 kcal/mole, and phosphorylation of the 2 Ser residues contributed -1.8 kcal/mole. Due to the high negative charge of the C-terminal peptide, the affinity of the P C-terminus for N(13-391) decreased as the ionic strength increased.
Conclusions
The results support the idea that the interaction of the C-terminal residues of P with N constitutes a protein-protein interaction hotspot that may be a suitable target for small-molecule drugs that inhibit viral genome replication and transcription.
doi:10.1186/s12985-014-0191-2
PMCID: PMC4239318  PMID: 25407889
Respiratory syncytial virus; Nucleocapsid; Phosphoprotein; Phosphorylation; Protein-protein interaction; Fluorescence anisotropy; Surface plasmon resonance; Nuclear magnetic resonance spectroscopy
3.  Real-Time Monitoring of New Delhi Metallo-β-Lactamase Activity in Living Bacterial Cells by 1H NMR Spectroscopy** 
Disconnections between in vitro responses and those observed in whole cells confound many attempts to design drugs in areas of serious medical need. A method based on 1D 1H NMR spectroscopy is reported that affords the ability to monitor the hydrolytic decomposition of the carbapenem antibiotic meropenem inside Escherichia coli cells expressing New Delhi metallo-β-lactamase subclass 1 (NDM-1), an emerging antibiotic-resistance threat. Cell-based NMR studies demonstrated that two known NDM-1 inhibitors, L-captopril and ethylenediaminetetraacetic acid (EDTA), inhibit the hydrolysis of meropenem in vivo. NDM-1 activity in cells was also shown to be inhibited by spermine, a porin inhibitor, although in an in vitro assay, the influence of spermine on the activity of isolated NDM-1 protein is minimal. This new approach may have generic utility for monitoring reactions involving diffusible metabolites in other complex biological matrices and whole-cell settings, including mammalian cells.
doi:10.1002/anie.201308636
PMCID: PMC4232273  PMID: 24458501
antibiotic resistance; drug discovery; meropenem; New Delhi metallo-β-lactamase; NMR spectroscopy
4.  Effects of Tai Chi on exercise capacity and health-related quality of life in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis 
Background
Tai Chi is a traditional Chinese mind-body exercise that has been widely practiced in the People’s Republic of China for many centuries. This exercise has also been applied as a training modality in pulmonary rehabilitation programs for stable chronic obstructive pulmonary disease (COPD). This systematic review and meta-analysis aimed to assess the effects of Tai Chi on exercise capacity and health-related quality of life (HRQoL) in COPD patients.
Methods
Electronic databases (PubMed, Embase, Web of Science, The Cochrane Library, Cumulative Index to Nursing and Allied Health Literature, ClinicalTrials.gov, China National Knowledge Infrastructure, and China Biology Medicine disc) were searched. Entries published from January 1980 to March 2014 were included in the search. Eligible studies included those that involved randomized controlled trials and those that lasted for at least 12 weeks. The primary outcome measures were six-minute walking distance (6MWD), St George’s Respiratory Questionnaire (SGRQ), and Chronic Respiratory Disease Questionnaire (CRQ). Effect estimates were pooled with random-effects meta-analysis.
Results
Eleven articles involving 824 patients met the inclusion criteria. All included articles compared COPD patients in a Tai Chi group versus COPD patients in nonexercise and/or physical exercise groups. The meta-analysis showed that compared with the nonexercise group, the COPD patients practicing Tai Chi demonstrated significantly enhanced 6MWD (mean difference 35.99, 95% confidence interval [CI] 15.63–56.35, P=0.0005), decreased SGRQ total score (mean difference −10.02, 95% CI −17.59, −2.45, P=0.009), and increased CRQ total score (mean difference 0.95, 95% CI 0.22–1.67, P=0.01). Compared with the physical exercise group, the Tai Chi group showed significantly reduced SGRQ total score (mean difference −3.52, 95% CI −6.07, −0.97, P=0.007), but no statistical significance was found for 6MWD between the two groups (mean difference 13.65, 95% CI −1.06, 28.37, P=0.07) in COPD patients.
Conclusion
Preliminary evidence suggests that Tai Chi has beneficial effects on exercise capacity and HRQoL in COPD patients. This exercise can be recommended as an effective alternative training modality in pulmonary rehabilitation programs. Further studies are required to support the preliminary evidence and to observe the long-term effects of Tai Chi.
doi:10.2147/COPD.S70862
PMCID: PMC4230171  PMID: 25404855
traditional Chinese exercise; chronic obstructive pulmonary disease; six-minute walking distance; quality of life
5.  Molecular-scale Hydrophilicity Induced by Solute: Molecular-thick Charged Pancakes of Aqueous Salt Solution on Hydrophobic Carbon-based Surfaces 
Scientific Reports  2014;4:6793.
We directly observed molecular-thick aqueous salt-solution pancakes on a hydrophobic graphite surface under ambient conditions employing atomic force microscopy. This observation indicates the unexpected molecular-scale hydrophilicity of the salt solution on graphite surfaces, which is different from the macroscopic wetting property of a droplet standing on the graphite surface. Interestingly, the pancakes spontaneously displayed strong positively charged behavior. Theoretical studies showed that the formation of such positively charged pancakes is attributed to cation–π interactions between Na+ ions in the aqueous solution and aromatic rings on the graphite surface, promoting the adsorption of water molecules together with cations onto the graphite surface; i.e., Na+ ions as a medium adsorbed to the graphite surface through cation–π interactions on one side while at the same time bonding to water molecules through hydration interaction on the other side at a molecular scale. These findings suggest that actual interactions regarding carbon-based graphitic surfaces including those of graphene, carbon nanotubes, and biochar may be significantly different from existing theory and they provide new insight into the control of surface wettability, interactions and related physical, chemical and biological processes.
doi:10.1038/srep06793
PMCID: PMC4210940  PMID: 25348642
6.  Intravitreal bevacizumab and Ahmed glaucoma valve implantation in patients with neovascular glaucoma 
AIM
To explore the efficacy of preoperative intravitreal bevacizumab (IVB) injection combined with Ahmed glaucoma valve (AGV) implantation in the treatment of neovascular glaucoma (NVG).
METHODS
This retrospective study included 35 eyes from 35 patients who underwent preoperative IVB and AGV implantation for treatment of NVG. Findings such as intraocular pressure (IOP) number of anti-glaucoma medications, visual acuity (VA), surgical success rates, and complications were recorded.
RESULTS
After AGV implantation, IOP was 18.2±4.0 mm Hg, 15.5±3.3 mm Hg and 9.8±2.6 mm Hg at 6, 12 and 36mo, significantly decreased compared with pre-IOP (P<0.01). The number of anti-glaucoma medications was 0.9±0.5, 0.8±0.9 and 0.8±0.6 at 6, 12 and 36mo, significantly decreased compared to pre-treatment (P<0.01). At last visit, there were 19 eyes with stable VA, 4 with VA improvement, 12 with diminished VA and 3 with complete loss light perception. There were 7 cases that failed during 3-year fellow up period. Cumulative probabilities of valve survival by Kaplan-Meier analysis were 82.9%, 74.1% and 71.0% at 12, 24 and 36mo, respectively. Cox stepwise regression analysis found that the survival time was significant associated with the pre-visual acuity <2/400 (P<0.05). Post-operative complications occurred in 8 eyes, of which hyphema presented in 2 eyes, choroidal effusion in 2 eyes.
CONCLUSION
The procedure of preoperative IVB and AGV implantation should be one of treatments for NVG because of its safety and effectiveness.
doi:10.3980/j.issn.2222-3959.2014.05.18
PMCID: PMC4206891  PMID: 25349803
Ahmed glaucoma valve; bevacizumab; intravitreal injection; neovascular glaucoma
7.  TET3 mediates the activation of human hepatic stellate cells via modulating the expression of long non-coding RNA HIF1A-AS1 
Activated Hepatic stellate cells (HSCs) play a critical role in liver fibrosis and a lot of efforts have been made to dissect the underlying mechanism involved in activation of HSCs. However, the underlying mechanism remains douteux up to now. In the present study, we found that TET3, one member of ten-eleven translocation (TET) protein family, reduced significantly in HSCs LX-2 activated by TGF-β1. To study the function of TET3 in activation of HSCs, knockdown was performed by RNA interference. Results showed that cell proliferation rise significantly and cell apoptosis reduce obviously after knockdown of TET3. Meanwhile, IHC showed that the expression of α-SMA rise significantly compared to control. These results indicated that TET3 is closely associated with the activation of HSCs. Further studies found that long non-coding RNA HIF1A-AS1 was reduced significantly in LX-2 cell after treatment with siRNA for TET3. The result hinted that TET3 activate HSCs through modulating the expression of HIF1A-AS1. To confirm this hypothesis, RNA interference was performed to silence the HIF1A-AS1. Results showed that HIF1A-AS1 silencing lead to enhancing in cell proliferation and declining apoptosis. Taken together, TET3 can mediate the activation of HSCs via modulating the expression of the long non-coding RNA HIF1A-AS1.
PMCID: PMC4270585  PMID: 25550811
Liver fibrosis; HSCs; TET3; long non-coding RNA; HIF1A-AS1
9.  A New Supervised Over-Sampling Algorithm with Application to Protein-Nucleotide Binding Residue Prediction 
PLoS ONE  2014;9(9):e107676.
Protein-nucleotide interactions are ubiquitous in a wide variety of biological processes. Accurately identifying interaction residues solely from protein sequences is useful for both protein function annotation and drug design, especially in the post-genomic era, as large volumes of protein data have not been functionally annotated. Protein-nucleotide binding residue prediction is a typical imbalanced learning problem, where binding residues are extremely fewer in number than non-binding residues. Alleviating the severity of class imbalance has been demonstrated to be a promising means of improving the prediction performance of a machine-learning-based predictor for class imbalance problems. However, little attention has been paid to the negative impact of class imbalance on protein-nucleotide binding residue prediction. In this study, we propose a new supervised over-sampling algorithm that synthesizes additional minority class samples to address class imbalance. The experimental results from protein-nucleotide interaction datasets demonstrate that the proposed supervised over-sampling algorithm can relieve the severity of class imbalance and help to improve prediction performance. Based on the proposed over-sampling algorithm, a predictor, called TargetSOS, is implemented for protein-nucleotide binding residue prediction. Cross-validation tests and independent validation tests demonstrate the effectiveness of TargetSOS. The web-server and datasets used in this study are freely available at http://www.csbio.sjtu.edu.cn/bioinf/TargetSOS/.
doi:10.1371/journal.pone.0107676
PMCID: PMC4168127  PMID: 25229688
10.  Enhancing protein-vitamin binding residues prediction by multiple heterogeneous subspace SVMs ensemble 
BMC Bioinformatics  2014;15(1):297.
Background
Vitamins are typical ligands that play critical roles in various metabolic processes. The accurate identification of the vitamin-binding residues solely based on a protein sequence is of significant importance for the functional annotation of proteins, especially in the post-genomic era, when large volumes of protein sequences are accumulating quickly without being functionally annotated.
Results
In this paper, a new predictor called TargetVita is designed and implemented for predicting protein-vitamin binding residues using protein sequences. In TargetVita, features derived from the position-specific scoring matrix (PSSM), predicted protein secondary structure, and vitamin binding propensity are combined to form the original feature space; then, several feature subspaces are selected by performing different feature selection methods. Finally, based on the selected feature subspaces, heterogeneous SVMs are trained and then ensembled for performing prediction.
Conclusions
The experimental results obtained with four separate vitamin-binding benchmark datasets demonstrate that the proposed TargetVita is superior to the state-of-the-art vitamin-specific predictor, and an average improvement of 10% in terms of the Matthews correlation coefficient (MCC) was achieved over independent validation tests. The TargetVita web server and the datasets used are freely available for academic use at http://csbio.njust.edu.cn/bioinf/TargetVita or http://www.csbio.sjtu.edu.cn/bioinf/TargetVita.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2105-15-297) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2105-15-297
PMCID: PMC4261549  PMID: 25189131
Protein-vitamin binding residue; Feature subspace; Heterogeneous SVM; Classifier ensemble
11.  BRAF-activated long non-coding RNA contributes to cell proliferation and activates autophagy in papillary thyroid carcinoma 
Oncology Letters  2014;8(5):1947-1952.
Long non-coding RNAs (lncRNAs) are novel regulators in cancer biology. BRAF-activated lncRNA (BANCR) is overexpressed in melanoma and has a potential functional role in melanoma cell migration. However, little is known about the role of BANCR in the development of papillary thyroid carcinoma (PTC). In the present study, BANCR expression was examined in six pairs of PTC and matched adjacent normal tissues. The results revealed that BANCR levels were significantly higher in the PTC tissues and PTC IHH-4 cells compared with the normal controls. Knockdown of BANCR in the IHH-4 cells inhibited proliferation and increased apoptosis of the cells in vitro. Further investigation of the underlying mechanisms revealed that BANCR markedly activated autophagy. Overexpression of BANCR inhibited apoptosis in the IHH-4 cells, whereas inhibition of autophagy stimulated apoptosis in the BANCR-overexpressed cells. BANCR overexpression also increased cell proliferation and the inhibition of autophagy abrogated BANCR overexpression-induced cell proliferation. In addition, the overexpression of BANCR resulted in an increase in the ratio of LC3-II/LC3-I, a marker for autophagy, while the knockdown of BANCR decreased the ratio of LC3-II/LC3-I. These results revealed that BANCR expression levels are upregulated in PTC. Additionally, BANCR increases PTC cell proliferation, which could activate autophagy.
doi:10.3892/ol.2014.2487
PMCID: PMC4186573  PMID: 25289082
long non-coding RNA; BRAF-activated long non-coding RNA; papillary thyroid carcinoma; autophagy
12.  GlnR Negatively Regulates the Transcription of the Alanine Dehydrogenase Encoding Gene ald in Amycolatopsis mediterranei U32 under Nitrogen Limited Conditions via Specific Binding to Its Major Transcription Initiation Site 
PLoS ONE  2014;9(8):e104811.
Ammonium assimilation is catalyzed by two enzymatic pathways, i.e., glutamine synthetase/glutamate synthase (GS/GOGAT) and alanine dehydrogenase (AlaDH) in Amycolatopsis mediterranei U32. Under nitrogen-rich conditions, the AlaDH pathway is the major route for ammonium assimilation, while the GS/GOGAT pathway takes over when the extracellular nitrogen supply is limited. The global nitrogen regulator GlnR was previously characterized to activate the transcription of the GS encoding gene glnA in response to nitrogen limitation and is demonstrated in this study as a repressor for the transcription of the AlaDH encoding gene ald, whose regulation is consistent with the switch of the ammonium assimilation pathways from AlaDH to GS/GOGAT responding to nitrogen limitation. Three transcription initiation sites (TISs) of ald were determined with primer extension assay, among which transcription from aldP2 contributed the major transcripts under nitrogen-rich conditions but was repressed to an undetectable level in response to nitrogen limitation. Through DNase I footprinting assay, two separate regions were found to be protected by GlnR within ald promoter, within which three GlnR binding sites (a1, b1 sites in region I and a2 site in region II) were defined. Interestingly, the major TIS aldP2 is located in the middle of a2 site within region II. Therefore, one may easily conclude that GlnR represses the transcription of ald via specific binding to the GlnR binding sites, which obviously blocks the transcription initiation from aldP2 and therefore reduces ald transcripts.
doi:10.1371/journal.pone.0104811
PMCID: PMC4140684  PMID: 25144373
13.  Correlation Between Patatin-Like Phospholipase Domain-Containing Protein 3 Gene Polymorphisms and Liver Cirrhosis in a Chinese Han Population With Chronic Hepatitis B 
Hepatitis Monthly  2014;14(8):e18943.
Background:
A single nucleotide polymorphism (SNP) of patatin-like phospholipase domain-containing 3 (PNPLA3) genes (rs738409) is associated with the severity of fibrosis and cirrhosis in patients with fatty liver disease. However, in a small group of Italian patients, there was no significant correlation between the rs738409 SNP and hepatitis B virus (HBV) infection-associated liver cirrhosis.
Objectives:
This study aimed to investigate whether PNPLA3 polymorphisms are a risk factor for liver cirrhosis in a Chinese Han population with chronic hepatitis B (CHB).
Patients and Methods:
The study population consisted of 344 Chinese Han patients with CHB, among which 203 presented with liver cirrhosis (LC group) and 141 had no sign of liver cirrhosis (CHB group). TaqMan genotyping assay was used to investigate the association of two PNPLA3 SNPs (rs738409 and rs2281135) with the risk of liver cirrhosis.
Results:
The allele and genotype distributions of PNPLA3 rs738409 and rs2281135 were not significantly different between the CHB and LC groups. After segregation on the basis of sex, no significant correlation between PNPLA3 (rs738409 and rs2281135) genotypes/alleles and liver cirrhosis was detected. Moreover, none of the haplotypes in PNPLA3 (rs738409 and rs2281135) was found to be statistically different between the two groups.
Conclusions:
Our results showed no association between PNPLA3 polymorphisms (rs738409 and rs2281135) and the susceptibility to HBV-related liver cirrhosis in a Chinese Han population.
doi:10.5812/hepatmon.18943
PMCID: PMC4199146  PMID: 25337145
Hepatitis B, Chronic; Liver Cirrhosis; Single Nucleotide Polymorphisms
14.  Smad4 Regulates Ureteral Smooth Muscle Cell Differentiation during Mouse Embryogenesis 
PLoS ONE  2014;9(8):e104503.
Proper formation of ureteral smooth muscle cells (SMCs) during embryogenesis is essential for ureter peristalsis that propels urine from the kidney to the bladder in mammals. Currently the molecular factors that regulate differentiation of ureteral mesenchymal cells into SMCs are incompletely understood. A recent study has reported that Smad4 deficiency reduces the number of ureteral SMCs. However, its precise role in the ureteral smooth muscle development remains largely unknown. Here, we used Tbx18:Cre knock-in mouse line to delete Smad4 to examine its requirement in the development of ureteral mesenchyme and SMC differentiation. We found that mice with specific deletion of Smad4 in Tbx18-expressing ureteral mesenchyme exhibited hydroureter and hydronephrosis at embryonic day (E) 16.5, and the mutant mesenchymal cells failed to differentiate into SMCs with increased apoptosis and decreased proliferation. Molecular markers for SMCs including alpha smooth muscle actin (α-SMA) and smooth muscle myosin heavy chain (SM-MHC) were absent in the mutant ureters. Moreover, disruption of Smad4 significantly reduced the expression of genes, including Sox9, Tbx18 and Myocardin associated with SMC differentiation. These findings suggest that Smad4 is essential for initiating the SMC differentiation program during ureter development.
doi:10.1371/journal.pone.0104503
PMCID: PMC4134214  PMID: 25127126
15.  Glucose Rapidly Induces Different Forms of Excitatory Synaptic Plasticity in Hypothalamic POMC Neurons 
PLoS ONE  2014;9(8):e105080.
Hypothalamic POMC neurons are required for glucose and energy homeostasis. POMC neurons have a wide synaptic connection with neurons both within and outside the hypothalamus, and their activity is controlled by a balance between excitatory and inhibitory synaptic inputs. Brain glucose-sensing plays an essential role in the maintenance of normal body weight and metabolism; however, the effect of glucose on synaptic transmission in POMC neurons is largely unknown. Here we identified three types of POMC neurons (EPSC(+), EPSC(−), and EPSC(+/−)) based on their glucose-regulated spontaneous excitatory postsynaptic currents (sEPSCs), using whole-cell patch-clamp recordings. Lowering extracellular glucose decreased the frequency of sEPSCs in EPSC(+) neurons, but increased it in EPSC(−) neurons. Unlike EPSC(+) and EPSC(−) neurons, EPSC(+/−) neurons displayed a bi-phasic sEPSC response to glucoprivation. In the first phase of glucoprivation, both the frequency and the amplitude of sEPSCs decreased, whereas in the second phase, they increased progressively to the levels above the baseline values. Accordingly, lowering glucose exerted a bi-phasic effect on spontaneous action potentials in EPSC(+/−) neurons. Glucoprivation decreased firing rates in the first phase, but increased them in the second phase. These data indicate that glucose induces distinct excitatory synaptic plasticity in different subpopulations of POMC neurons. This synaptic remodeling is likely to regulate the sensitivity of the melanocortin system to neuronal and hormonal signals.
doi:10.1371/journal.pone.0105080
PMCID: PMC4134273  PMID: 25127258
16.  ERCC1 Cys8092Ala and XRCC1 Arg399Gln Polymorphisms Predict Progression-Free Survival after Curative Radiotherapy for Nasopharyngeal Carcinoma 
PLoS ONE  2014;9(7):e101256.
Background
Single nucleotide polymorphisms (SNPs) in DNA repair genes can alter gene expression and activity and affect response to cancer treatment and, correspondingly, survival. The present study was designed to evaluate the utility of the XRCC1 Arg399Gln and ERCC1 Cys8092Ala SNPs, measured in pretreatment biopsy samples, as predictors of response to radiotherapy in patients with non-metastatic nasopharyngeal carcinoma (NPC).
Materials and methods
The study included 75 consecutive patients with stage II-IVA-B NPC. XRCC1 Arg399Glu and ERCC1 Cys8092Ala SNPs were identified from paraffin-embedded biopsy specimens via Sanger sequencing. Expression of p53 and pAkt protein was analyzed by immunohistochemical staining. Potential relationships between genetic polymorphisms and progression-free survival (PFS) were analyzed by using a Cox proportional hazards model, the Kaplan-Meier method, and the log-rank test.
Results
Multivariate analysis showed that carriers of the ERCC1 8092 Ala/Ala genotype [hazard ratio (HR) 1.882; 95% confidence interval (CI) 1.031–3.438; P = 0.039] and heavy smokers (≥20 pack-years) carrying the XRCC1 Arg/Arg genotype (HR 2.019; 95% CI 1.010–4.036; P = 0.047) had significantly lower PFS rates. Moreover, combined positive expression of p53 and pAkt led to significantly increased PFS in subgroups carrying the XRCC1 Gln allele (HR 7.057; 95% CI 2.073–24.021; P = 0.002) or the ERCC1 Cys allele (HR 2.568; 95% CI 1.056–6.248; P = 0.038).
Conclusions
The ERCC1 Cys8092Ala polymorphism is an independent predictor of response to radiotherapy for NPC, and the XRCC1 Arg399Glu mutation combined with smoking status seems to predict PFS as well. Our results further suggest a possible correlation between these genetic polymorphisms and p53 protein status on survival.
doi:10.1371/journal.pone.0101256
PMCID: PMC4099069  PMID: 25025378
17.  A Comparative Study on Inhibition of Total Astragalus Saponins and Astragaloside IV on TNFR1-Mediated Signaling Pathways in Arterial Endothelial Cells 
PLoS ONE  2014;9(7):e101504.
Background
Both total astragalus saponins (AST) and it’s main component astragaloside IV (ASIV) have been used in China as cardiovascular protective medicines. However, the anti-inflammatory activities that are beneficial for cardiovascular health have never been compared directly and the molecular mechanisms remain unresolved. This study was conducted to compare the inhibitory effects of these drugs on TNFα-induced cell responses, related signaling pathways, and the underlying mechanisms in mouse arterial endothelial cells.
Methodology/Principal Findings
Real-time qRT-PCR was performed to determine the expression of cell adhesion molecule (CAM) genes. Immunofluorescent staining was used to detect the nuclear translocation of transcription factor NF-κB-p65. Western Blot analysis was used to identify TNFα-induced NF-κB-p65 phosphorylation, IκBα degradation, and caspase-3 cleavage. Cell surface proteins were isolated and TNFα receptor-1(TNFR1) expression was determined. The results suggest that both AST and ASIV attenuate TNFα-induced up-regulation of CAMs mRNA and upstream nuclear translocation and phosphorylation of NF-κB-p65. However, TNFR1-mediated IκBα degradation, cleavage of caspase-3 and apoptosis were inhibited only by AST. These differences in the actions of AST and ASIV could be explained by the presence of other components in AST, such as ASII and ASIII, which also had an inhibitory effect on TNFR1-induced IκBα degradation. Moreover, AST, but not ASIV, was able to reduce TNFR1 protein level on the cell surface. Furthermore, mechanistic investigation demonstrated that TNFR1-mediated IκBα degradation was reversed by the use of TAPI-0, an inhibitor of TNFα converting enzyme (TACE), suggesting the involvement of TACE in the modulation of surface TNFR1 level by AST.
Conclusion
ASIV was not a better inhibitor than AST, at least on the inhibition of TNFα-induced inflammatory responses and TNFR1-mediated signaling pathways in AECs. The inhibitory effect of AST was caused by the reduction of cell surface TNFR1 level, and TACE could be involved in this action.
doi:10.1371/journal.pone.0101504
PMCID: PMC4081628  PMID: 24991819
18.  The safety and efficacy of daptomycin versus other antibiotics for skin and soft-tissue infections: a meta-analysis of randomised controlled trials 
BMJ Open  2014;4(6):e004744.
Objective
Daptomycin, a cyclic lipopeptide that exhibits rapid, concentration-dependent bactericidal activity in vitro against a broad spectrum of Gram-positive pathogens, has now, since 2003, been approved in more than 70 countries and regions to treat skin and soft-tissue infections (SSTIs). The purpose of this meta-analysis was to compare the safety and efficacy of daptomycin with other antibiotics, especially with vancomycin which has long been considered the standard therapy for complicated SSTIs.
Design
Meta-analysis of randomised controlled trials (RCTs).
Data sources
We thoroughly searched PubMed, EMBASE, Cochrane Central to identify relevant RCTs. Six RCTs with a total of 1710 patients were included in this meta-analysis.
Results
The results demonstrated that the efficacy of daptomycin was at par with or maybe better than other first-line antibiotics for treating SSTIs as shown by the OR for clinical success (OR=1.05, 95% CI 0.84 to 1.31, p=0.65, I2=0%); daptomycin versus vancomycin subgroup (OR=1.19, 95% CI 0.77 to 1.83, p=0.43, I2=0%); overall microbiological success (OR=1.05, 95% CI 0.61 to 1.79, p=0.86, I2=42%); microbiological success of daptomycin versus comparators for Staphylococcus aureus (SA, OR=1.05, 95% CI 0.61 to 2.60, p=0.53, I2=47%), for methicillin-resistant S. aureus (OR=0.90, 95% CI 0.77 to 1.06, p=0.20, I2=56%). However, daptomycin tended to have a similar treatment-related adverse events (AEs) incidence in comparison with other antibiotics (OR=1.06, 95% CI 0.71 to 1.59, p=0.76, I2=41%). The trend showed that daptomycin might cause less discontinuation due to AEs and death compared with other first-line antibiotics (OR=0.71, 95% CI 0.46 to 1.10, p=0.12, I2=11%). Significantly more patients in the daptomyicn group had creatine phosphokinase elevation than those in the control group; however, it could be reversed when the therapy ended (OR=1.95, 95% CI 1.04 to 3.65, p=0.04, I2=0).
Conclusions
This meta-analysis demonstrated that the safety and efficacy of daptomycin was not inferior to that of other first-line drugs, and daptomycin tended to exhibit superior efficacy when compared with vancomycin or with comparators for SA infections; nevertheless, more high-quality RCTs are needed to draw a more credible conclusion.
doi:10.1136/bmjopen-2013-004744
PMCID: PMC4078778  PMID: 24961714
Epidemiology
19.  Ethanol at Low Concentration Attenuates Diabetes Induced Lung Injury in Rats Model 
Journal of Diabetes Research  2014;2014:107152.
To observe the changes of lung injury when diabetic rats were treated with low concentration of ethanol (EtOH) and analyze the related mechanisms, male Sprague-Dawley (SD) rats were divided into control, diabetic (DM), and EtOH+DM groups. Diabetic rat was mimicked by injection of streptozotocin intraperitoneally. Fasting blood glucose (FBG) level, lung weight (LW), body weight (BW), and LW/BW were measured. The changes of lung tissue and Type II alveolar cell were detected. Pulmonary malondialdehyde (MDA) content and superoxide dismutase (SOD) activity were measured; meanwhile, ALDH2 mRNA and protein expressions were detected by RT-PCR and western blotting, respectively. Compared with control group, in DM group, SOD activity was decreased; FBG level, LW/BW, MDA content, ALDH2 mRNA, and protein expressions were decreased. Compared with DM group, in EtOH+DM group, SOD activity, ALDH2 mRNA, and protein expressions were increased; LW/BW and MDA content were decreased. The structures of lung tissue and lamellar bodies were collapsed in DM group; the injury was attenuated in EtOH+DM group. Our findings suggested that, in diabetic rat, pulmonary ALDH2 expression was decreased accompanying lung injury. EtOH at low concentration decreased diabetes induced lung injury through activating ALDH2 expression.
doi:10.1155/2014/107152
PMCID: PMC4082928  PMID: 25019090
20.  Two-year prospective case-controlled study of a case management program for community-dwelling individuals with schizophrenia 
Shanghai Archives of Psychiatry  2014;26(3):119-128.
Background
A community-based rehabilitation program is an essential element of the comprehensive treatment of individuals with schizophrenia.
Objective
Assess the long-term effects of a community-based case management program for providing rehabilitations services to individuals with schizophrenia.
Methods
A total of 730 community-residing participants who met ICD-10 diagnostic criteriafor schizophrenia were enrolled, 380 in the case management group and 350 in the control group from two districts in Shanghai. Case management involved monthly training visits with patients and their co-resident family members that focused on encouraging medication adherence. Participants were assessed every three months for 24 months with the Camberwell Assessment of Need (CAN), Positive and Negative Syndrome Scale (PANSS), WHO-Disability Assessment Scale (WHO-DAS), and the Quality of Life Scale (QOLS). Level of discomfort due to side-effects was also assessed every three months. Individuals who discontinued their antipsychotic medication without physician approval for one month or longer at any time during follow-up were classified as ‘self-determined medication discontinuation’.
Results
Compared to the treatment as usual group (i.e., follow-up management every 3 months), by the end of the two-year follow-up those who participated in the case management program had significantly lower rates of medication discontinuation, significantly less severe negative symptoms, lower relapse rates and lower rehospitalization rates. Other factors that had an independent effect on discontinuation of medication included educational level (those with more education had higher discontinuation rates), lack of family supervision of medication, higher dosages of medication, and greater medication-related discomfort.
Conclusions
Case management is a feasible and effective long-term method for improving the rehabilitation outcomes of community residents with schizophrenia. Our results highlight the need to involve family members in the management of patients’ medication, to use the minimum effective dosage of medication, and to aggressively manage all side-effects.
doi:10.3969/j.issn.1002-0829.2014.03.003
PMCID: PMC4118008  PMID: 25114486
schizophrenia; community-based rehabilitation; case management; discontinuation rate; social function
21.  sA population-based study of macular choroidal neovascularization using optical coherence tomography in Eastern China 
The aim of the present study was to investigate the pathomorphological and functional variations of choroidal neovascularization (CNV) in age-related macular degeneration (AMD) in a Chinese population using optical coherence tomography (OCT). This population-based study enrolled 59 patients (age, >45 years; eyes, 70) with early and intermediate-stage AMD from Youyi Road Community, Baoshan District, Shanghai, China. Comprehensive standardized ophthalmic examinations included visual acuity, anterior segment analysis using a slit lamp, dilated fundus evaluation by direct ophthalmoscopy, 90D handheld lens analysis, fundus photography, fundus fluorescein angiography (FFA) and fast optic disk scans using OCT. The macular CNV characteristic profiles in early and intermediate-stage AMD were determined by OCT. Data were obtained on the first visit and the follow-up period ranged between 6 and 24 months, where FFA and OCT outcomes of early and intermediate-stage AMD patients were analyzed. Three profiles of early and intermediate-stage AMD were created from the OCT and FFA results, each with a different prognosis. Firstly, drusens with unclear boundaries and evident pigment proliferation, as well as hypofluorescence around the drusens, was observed via FFA. A slight small arch field located in the retinal pigment epithelium (RPE)/choriocapillary layer (CCL) was shown on OCT scans, indicating exudative AMD. Secondly, RPE detachments of >1 pupillary distance, without CNV in the macular area, indicated geographic chorioretinitis atrophy. Finally, drusens with clear boundaries and few pigment proliferations and no certain surrounding fluorescence was observed via FFA, while a clear RPE/CCL band on the OCT scans indicated slow progress. The results of the present study demonstrated that combined OCT and FFA was the most efficient method for identifying CNV and diagnosing AMD. If the two techniques are not available concurrently, then OCT is a safer and more reliable technique to follow-up early and intermediate-stage AMD patients.
doi:10.3892/etm.2014.1731
PMCID: PMC4079400  PMID: 25009585
age-related macular degeneration; choroidal neovascularization; optic coherence tomography; population-based study; Eastern China
22.  BRAF-activated long non-coding RNA contributes to colorectal cancer migration by inducing epithelial-mesenchymal transition 
Oncology Letters  2014;8(2):869-875.
Long non-coding RNAs (lncRNAs) are recently identified regulators in tumorigenesis and tumour progression. BRAF-activated lncRNA (BANCR) is overexpressed in melanoma and has a potential functional role in melanoma cell migration. However, little is known concerning the role of BANCR in the development of colorectal cancer (CRC). The current study examined BANCR expression in 60 pairs of CRC and matched adjacent normal tissues. The quantitative polymerase chain reaction results showed that BANCR was frequently overexpressed in cancer tissues and this overexpression was found to significantly correlate with lymph node metastasis and tumour stage. The ectopic expression of BANCR contributed to the migration of human CRC Caco-2 cells, whereas knockdown of BANCR inhibited the migration of the HCT116 cells in vitro. Further investigation into the underlying mechanisms responsible for the migratory effects revealed that BANCR induced the epithelial-mesenchymal transition (EMT) through an MEK/extracellular signal-regulated kinase-dependent mechanism as treatment with the MEK inhibitor, U0126 decreased migration and reversed the EMT in the BANCR-overexpressed HCT116 cells. These results revealed the significance of BANCR in the molecular etiology of CRC and implied the potential application of BANCR in the therapeutic treatment of CRC.
doi:10.3892/ol.2014.2154
PMCID: PMC4081361  PMID: 25013510
extracellular signal-regulated kinase; colorectal cancer; long non-coding RNA; BRAF-activated long non-coding RNA; migration; epithelial-mesenchymal transition
23.  A simple model of radial nerve injury in the rhesus monkey to evaluate peripheral nerve repair 
Neural Regeneration Research  2014;9(10):1041-1046.
Current research on bone marrow stem cell transplantation and autologous or xenogenic nerve transplantation for peripheral nerve regeneration has mainly focused on the repair of peripheral nerve defects in rodents. In this study, we established a standardized experimental model of radial nerve defects in primates and evaluated the effect of repair on peripheral nerve injury. We repaired 2.5-cm lesions in the radial nerve of rhesus monkeys by transplantation of autografts, acellular allografts, or acellular allografts seeded with autologous bone marrow stem cells. Five months after surgery, regenerated nerve tissue was assessed for function, electrophysiology, and histomorphometry. Postoperative functional recovery was evaluated by the wrist-extension test. Compared with the simple autografts, the acellular allografts and allografts seeded with bone marrow stem cells facilitated remarkable recovery of the wrist-extension functions in the rhesus monkeys. This functional improvement was coupled with radial nerve distal axon growth, a higher percentage of neuron survival, increased nerve fiber density and diameter, increased myelin sheath thickness, and increased nerve conduction velocities and peak amplitudes of compound motor action potentials. Furthermore, the quality of nerve regeneration in the bone marrow stem cells-laden allografts group was comparable to that achieved with autografts. The wrist-extension test is a simple behavioral method for objective quantification of peripheral nerve regeneration.
doi:10.4103/1673-5374.133166
PMCID: PMC4146303  PMID: 25206757
nerve regeneration; peripheral nerve injury; rhesus monkeys; bone marrow stem cells; allogeneic nerve; transplantation; wrist-extension test; electrophysiology; neurological function; NSFC grant; neural regeneration
24.  Porcine circovirus type 2 in China: an update on and insights to its prevalence and control 
Virology Journal  2014;11:88.
Currently, porcine circovirus type 2 (PCV2) is considered the major pathogen of porcine circovirus associated-diseases (PCVAD) that causes large economic losses for the swine industry in the world annually, including China. Since the first report of PCV2 in 1998, it has been drawing tremendous attention for the government, farming enterprises, farmers, and veterinary practitioners. Chinese researchers have conducted a number of molecular epidemiological work on PCV2 by molecular approaches in the past several years, which has resulted in the identification of novel PCV2 genotypes and PCV2-like agents as well as the description of new prevalence patterns. Since late 2009, commercial PCV2 vaccines, including the subunit vaccines and inactivated vaccines, have already been used in Chinese swine farms. The aim of this review is to update the insights into the prevalence and control of PCV2 in China, which would contribute to understanding the epidemiology, control measures and design of novel vaccines for PCV2.
doi:10.1186/1743-422X-11-88
PMCID: PMC4031328  PMID: 24885983
Porcine circovirus type 2; Prevalence; Control; PCV2 vaccines; Update; China
25.  C-Reactive Protein as a Prognostic Factor for Human Osteosarcoma: A Meta-Analysis and Literature Review 
PLoS ONE  2014;9(5):e94632.
Background
Osteosarcoma is the most common primary bone cancer in growing adolescents and young adults. The prognostic role of C-reactive protein (CRP) in patients with osteosarcoma is not fully investigated. The purpose of this study is to perform a meta-analysis and literature review on the role of CRP in osteosarcoma and to assess the potential role of serum CRP as a prognostic factor for patients with osteosarcoma.
Methods
A detailed literature search was made in Medline for related research publications written in English. Methodological quality of the studies was also evaluated. The data were extracted and assessed by two reviewers independently. Analysis of pooled data were performed, risk ratio (RR) and corresponding confidence intervals (CIs) were calculated and summarized respectively.
Results
Final analysis of 397 patients from 2 eligible studies was performed. Combined RR of CRP expression suggested that the raised serum CRP level had an adverse prognostic effect on overall survival of patients with osteosarcoma (n = 397 in 2 studies; RR = 0.35; 95% CI: 0.18–0.68; p = 0.002). In the uni- and multivariate survival analysis, response rate and CRP levels were the only independent prognostic variables.
Conclusions
The results of this meta-analysis suggest that CRP expression confers a worse prognosis in patients with osteosarcoma. Large prospective studies are necessary to provide solid data to confirm the prognostic significance of CRP.
doi:10.1371/journal.pone.0094632
PMCID: PMC4011684  PMID: 24800842

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