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1.  Synthesis and screening of 3-MA derivatives for autophagy inhibitors 
Autophagy  2013;9(4):595-603.
Autophagy is a conserved degradation process, which plays important pathophysiological roles. The lack of effective inhibitors of autophagy has been an obstacle in both basic research and understanding the physiological role of autophagy in disease manifestation. The most widely used inhibitor, 3-methyladenine (3-MA), is poorly soluble at room temperature and is effective only at high concentrations. In this study, we synthesized a library of small compounds by chemically modifying 3-MA and screened this library for autophagy inhibitors. Three 3-MA derivatives generated through this approach showed improved solubility and effectiveness in inhibiting autophagy. We demonstrated that chemical modification of an existing autophagy inhibitor is an effective method to generate improved autophagy inhibitors.
doi:10.4161/auto.23641
PMCID: PMC3627673  PMID: 23412639
autophagy; inhibitor; 3-MA; synthesis; derivatives
2.  Regulation of G-protein signaling via Gnas is required to regulate proximal tubular growth in the Xenopus pronephros 
Developmental biology  2013;376(1):31-42.
In the kidney, proximal tubules are very important for the reabsorption of water, ions and organic solutes from the primary urine. They are composed of highly specialized epithelial cells that are characterized by an elaborate apical brush border to increase transport efficiency. Using the pronephric kidney of Xenopus laevis we discovered that the G-protein modulator cholera toxin resulted in a dramatic reduction of the proximal tubular size. This phenotype was accompanied by changes in the cytoarchitecture characterized by ectopic expression of the distal tubular marker 4A6 and an impairment of yolk platelet degradation. In addition, cholera toxin caused edema formation. However, this phenotype was not due to kidney defects, but rather due to impaired vasculature development. Based on experiments with antisense morpholino oligomers as well as pharmacological agonists and antagonists, we could show that the complex phenotype of cholera toxin in the pronephric kidney was caused by the hyperactivation of a single G-protein alpha subunit, Gnas. This—in turn—caused elevated cAMP levels, triggered a Rapgef4-dependent signaling cassette and perturbed exo- and endocytosis. This perturbation of the secretory pathway by Ctx was not only observed in Xenopus embryos. Also, in a human proximal tubular cell line, cholera toxin or a Rapgef4-specific agonist increased uptake and decreased secretion of FITC-labeled Albumin. Based on these data we propose that the Gnas/cAMP/Rapgef4 pathway regulates the signals inducing the proliferation of proximal tubules to acquire their final organ size.
doi:10.1016/j.ydbio.2013.01.017
PMCID: PMC3767149  PMID: 23352791
Cholera toxin; Endocytosis; Exocytosis; Pronephric kidney; Xenopus; Yolk degradation
3.  Statins for the Prevention of Stroke: A Meta-Analysis of Randomized Controlled Trials 
PLoS ONE  2014;9(3):e92388.
Background
Stroke is a frequently encountered clinical event that has a detrimental impact on the quality of life. Evidence has increasingly shown that statins can substantially reduce the risk of coronary heart disease. However, it remains to be determined whether statins are definitively effective in preventing stroke.
Methods
We systematically searched the PubMed, Embase, and Central databases for studies that compared the effects of statins and placebo in patients at high risk for stroke. The outcome measures were overall incidence of stroke, incidence of fatal stroke, and incidence of hemorrhagic stroke.
Results
Eighteen randomized controlled trials satisfied all the inclusion criteria for the meta-analysis. The analysis revealed that statins reduced the overall incidence of stroke than placebo (odds ratio [OR]: 0.80; 95% confidence interval [CI]: 0.74–0.87; P<0.00001). In particular, statins showed efficacy in reducing the incidence of fatal stroke (OR: 0.90; 95% CI: 0.67–1.21; P = 0.47) and hemorrhagic stroke (OR: 0.87; 95% CI: 0.60–1.25; P = 0.45). On the contrary, they were found to increase the overall incidence of stroke (OR: 1.12; 95% CI: 0.89–1.41; P = 0.32) and fatal stroke (OR: 1.37; 95% CI: 0.93–2.03; P = 0.11) in renal transplant recipients and patients undergoing regular hemodialysis.
Conclusion
The results of this analysis suggest that statins may be beneficial in reducing the overall incidence of stroke and they may decrease the risk of fatal stroke and hemorrhagic stroke. However, statins should be used with caution in patients with a history of renal transplantation, regular hemodialysis, transient ischemic attack, or stroke. Further analyses should focus on multicentre, double-blind, placebo-controlled randomized trials with data stratification according to the nature of primary diseases and dose–effect relationship, to clarify the benefits of statins in protection against stroke.
doi:10.1371/journal.pone.0092388
PMCID: PMC3958535  PMID: 24643199
4.  Monothiol glutaredoxins and A-type proteins: Partners in Fe-S cluster trafficking 
Monothiol glutaredoxins (Grxs) are proposed to function in Fe-S cluster storage and delivery, based on their ability to exist as apo monomeric forms and dimeric forms containing a subunit-bridging [Fe2S2]2+ cluster, and to accept [Fe2S2]2+ clusters from primary scaffold proteins. In addition yeast cytosolic monothiol Grxs interact with Fra2 (Fe repressor of activation-2), to form a heterodimeric complex with a bound [Fe2S2]2+ cluster that plays a key role in iron sensing and regulation of iron homeostasis. In this work, we report on in vitro UV-visible CD studies of cluster transfer between homodimeric monothiol Grxs and members of the ubiquitous A-type class of Fe-S cluster carrier proteins (NifIscA and SufA). The results reveal rapid, unidirectional, intact and quantitative cluster transfer from the [Fe2S2]2+ cluster-bound forms of A. thaliana GrxS14, S. cerevisiae Grx3, and A. vinelandii Grx-nif homodimers to A. vinelandii NifIscA and from A. thaliana GrxS14 to A. thaliana SufA1. Coupled with in vivo evidence for interaction between monothiol Grxs and A-type Fe-S cluster carrier proteins, the results indicate that these two classes of proteins work together in cellular Fe-S cluster trafficking. However, cluster transfer is reversed in the presence of Fra2, since the [Fe2S2]2+ cluster-bound heterodimeric Grx3/Fra2 complex can be formed by intact [Fe2S2]2+ cluster transfer from NifIscA. The significance of these results for Fe-S cluster biogenesis or repair and the cellular regulation of the Fe-S cluster status are discussed.
doi:10.1039/c2dt32263c
PMCID: PMC3578507  PMID: 23292141
5.  Intestinal obstruction due to migration of a thermometer from bladder to abdominal cavity: A case report 
Intraperitoneal foreign bodies such as retained surgical instruments can cause intestinal obstruction. However, intestinal obstruction due to transmural migration of foreign bodies has rarely been reported. Here, we report a case of intestinal obstruction due to a clinical thermometer which migrated from the bladder into the abdominal cavity. A 45-year-old man was admitted to our hospital with a one-year history of recurrent lower abdominal cramps. Two days before admission, the abdominal cramps aggravated. Intestinal obstruction was confirmed with upright abdominal radiography and computerized tomography scan which showed dilation of the small intestines and a thermometer in the abdominal cavity. Then laparotomy was performed. A scar was observed at the fundus of the bladder and a thermometer was adhering to the small bowels and mesentery which resulted in intestinal obstruction. Abdominal cramps were eliminated and defecation and flatus recovered soon after removal of the thermometer.
doi:10.3748/wjg.v20.i9.2426
PMCID: PMC3942848  PMID: 24605042
Intestinal obstruction; Foreign body; Thermometer; Transmural migration; Bladder
6.  New Coxsackievirus B4 Genotype Circulating in Inner Mongolia Autonomous Region, China 
PLoS ONE  2014;9(3):e90379.
Hand, foot, and mouth disease (HFMD) surveillance was initiated in the Inner Mongolia Autonomous Region of China in 2007, a crucial scrutiny for monitoring the prevalence of enterovirus serotypes associated with HFMD patients. However, this surveillance mostly focused on enterovirus 71 (EV-A71) and coxsackievirus A16; therefore, information on other enterovirus serotypes is limited. To identify the other circulating enterovirus serotypes in the HFMD outbreaks in Inner Mongolia in 2010, clinical samples from HFMD patients were investigated. Six coxsackievirus B4 (CVB4) strains were isolated and phylogenetic analyses of VP1 sequences were performed. Full-length genome sequences of two representative CVB4 isolates were acquired and similarity plot and bootscanning analyses were performed. The phylogenetic dendrogram indicated that all CVB4 strains could be divided into 5 genotypes (Genotypes I–V) with high bootstrap support (90–100%). The CVB4 prototype strain (JVB) was the sole member of genotype I. CVB4 strains belonging to genotype II, which were once common in Europe and the Americas, seemingly disappeared and gave way to genotype III and IV strains, which appear to be the dominant circulating strains in the world. All Chinese CVB4 strains belonged to Genotype V, a newly identified genotype supported by a high bootstrap value (100%), and are circulating only in mainland of China. Intertypic recombination occurred in the Chinese CVB4 strains with novel unknown serotype EV-B donor sequences. Two Chinese CVB4 strains had a virulent residue at position 129 of VP1, and one strain also had a virulent residue at position 16 of VP4. Increased surveillance is needed to monitor the emergence of new genetic lineages of enteroviruses in areas that are often associated with large-scale outbreaks. In addition, continued monitoring of enteroviruses by clinical surveillance and genetic characterization should be enhanced.
doi:10.1371/journal.pone.0090379
PMCID: PMC3940859  PMID: 24595311
7.  Streptomyces heilongjiangensis sp. nov., a novel actinomycete that produces borrelidin isolated from the root surface of soybean [Glycine max (L.) Merr] 
A borrelidin-producing actinomycete, designated strain NEAU-W2T, was isolated from the root surface of soybean [Glycine max (L.) Merr] and characterized using a polyphasic approach. The organism was found to have morphological and chemotaxonomic characteristics typical of streptomycetes. The G+C content of the DNA was 66.12 mol%. Analysis of the 16S rRNA gene sequence of strain NEAU-W2T revealed that the strain formed a distinct clade within the 16S rRNA gene sequence phylogenetic tree and showed highest similarity (99.61 %) to Streptomyces neyagawaensis ATCC 27449T. However, the DNA–DNA relatedness between strain NEAU-W2T and S. neyagawaensis ATCC 27449T was 58.51 %. Strain NEAU-W2T could also be differentiated from S. neyagawaensis ATCC 27449T and other Streptomyces species showing high 16S rRNA gene sequence similarity (98–99 %), as well as other borrelidin-producing strains, based on morphological and physiological characteristics. On the basis of its physiological and molecular properties, it is proposed that strain NEAU-W2T represents a novel Streptomyces species, Streptomyces heilongjiangensis sp. nov. The type strain is NEAU-W2T ( = CGMCC 4.7004T  = ATCC BAA-2424T  = DSM 42073T).
doi:10.1099/ijs.0.041483-0
PMCID: PMC3709533  PMID: 22707527
8.  Estrogen receptor α-coupled Bmi1 regulation pathway in breast cancer and its clinical implications 
BMC Cancer  2014;14:122.
Background
Bmi1 has been identified as an important regulator in breast cancer, but its relationship with other signaling molecules such as ERα and HER2 is undetermined.
Methods
The expression of Bmi1 and its correlation with ERα, PR, Ki-67, HER2, p16INK4a, cyclin D1 and pRB was evaluated by immunohistochemistry in a collection of 92 cases of breast cancer and statistically analyzed. Stimulation of Bmi1 expression by ERα or 17β-estradiol (E2) was analyzed in cell lines including MCF-7, MDA-MB-231, ERα-restored MDA-MB-231 and ERα-knockdown MCF-7 cells. Luciferase reporter and chromatin immunoprecipitation assays were also performed.
Results
Immunostaining revealed strong correlation of Bmi1 and ERα expression status in breast cancer. Expression of Bmi1 was stimulated by 17β-estradiol in ERα-positive MCF-7 cells but not in ERα-negative MDA-MB-231 cells, while the expression of Bmi1 did not alter expression of ERα. As expected, stimulation of Bmi1 expression could also be achieved in ERα-restored MDA-MB-231 cells, and at the same time depletion of ERα decreased expression of Bmi1. The proximal promoter region of Bmi1 was transcriptionally activated with co-transfection of ERα in luciferase assays, and the interaction of the Bmi1 promoter with ERα was confirmed by chromatin immunoprecipitation. Moreover, in breast cancer tissues activation of the ERα-coupled Bmi1 pathway generally correlated with high levels of cyclin D1, while loss of its activity resulted in aberrant expression of p16INK4a and a high Ki-67 index, which implied a more aggressive phenotype of breast cancer.
Conclusions
Expression of Bmi1 is influenced by ERα, and the activity of the ERα-coupled Bmi1 signature impacts p16INK4a and cyclin D1 status and thus correlates with the tumor molecular subtype and biologic behavior. This demonstrates the important role which is played by ERα-coupled Bmi1 in human breast cancer.
doi:10.1186/1471-2407-14-122
PMCID: PMC3939403  PMID: 24559156
Bmi1; Estrogen receptor α; p16INK4a; Cyclin D1; Breast cancer
9.  A novel reporter system for neutralizing and enhancing antibody assay against dengue virus 
BMC Microbiology  2014;14:44.
Background
Dengue virus (DENV) still poses a global public health threat, and no vaccine or antiviral therapy is currently available. Antibody plays distinct roles in controlling DENV infections. Neutralizing antibody is protective against DENV infection, whereas sub-neutralizing concentration of antibody can increase DENV infection, termed antibody-dependent enhancement (ADE). Plaque-based assay represents the most widely accepted method measuring neutralizing or enhancing antibodies.
Results
In this study, a novel reporter virus-based system was developed for measuring neutralization and ADE activity. A stable Renilla luciferase reporter DENV (Luc-DENV) that can produce robust luciferase signals in BHK-21 and K562 cells were used to establish the assay and validated against traditional plaque-based assay. Luciferase value analysis using various known DENV-specific monoclonal antibodies showed good repeatability and a well linear correlation with conventional plaque-based assays. The newly developed assay was finally validated with clinical samples from infected animals and individuals.
Conclusions
This reporter virus-based assay for neutralizing and enhancing antibody evaluation is rapid, lower cost, and high throughput, and will be helpful for laboratory detection and epidemiological investigation for DENV antibodies.
doi:10.1186/1471-2180-14-44
PMCID: PMC3930823  PMID: 24548533
Dengue virus; Neutralizing antibody; Enhancing antibody; Luciferase assay
10.  Effects of resveratrol on apoptosis in a rat model of vascular dementia 
Resveratrol is a natural polyphenol widely present in plants, particularly in the skin of red grapes and in wine. It possesses a wide range of biological effects and exhibits neuroprotective effects in numerous diseases. However, data evaluating the effects of resveratrol in vascular dementia (VaD) are lacking. In the present study, the permanent, bilateral common carotid artery occlusion rat model was used to study the effects of resveratrol on VaD. The Morris water maze was used to test the spatial learning and memory performance of the rats. The expression levels of Bax, Bcl-2, cleaved caspase-3 and cleaved poly(ADP-ribose) polymerase (PARP) in the hippocampus were measured. The results showed that resveratrol inhibited memory impairment in the VaD rat model, and attenuated the increases in the expression levels of Bax, cleaved caspase-3 and cleaved PARP and the reductions in the expression levels of Bcl-2 that were induced by VaD. These results provide a novel insight into the neuroprotective effects of resveratrol and its possible therapeutic role in VaD.
doi:10.3892/etm.2014.1542
PMCID: PMC3961111  PMID: 24660032
vascular dementia; resveratrol; apoptosis; caspase-3; poly(ADP-ribose) polymerase
11.  Lack of Association of P2RX7 Gene rs2230912 Polymorphism with Mood Disorders: A Meta-Analysis 
PLoS ONE  2014;9(2):e88575.
Background
To assess the association of P2RX7 gene rs2230912 polymorphism with mood disorders using a meta-analysis.
Methods
Data were collected from the following electronic databases: PubMed, Excerpta Medica Database, Elsevier Science Direct, Cochrane Library, and Chinese Biomedical Literature Database, with the last report up to April 1, 2013. Odds ratio (OR) with 95% confidence interval (CI) was used to assess the strength of the association. Dependent on the results of heterogeneity test among individual studies, the fixed effect model (Mantel–Haenszel) or random effect model (DerSimonian–Laird) was selected to summarize the pooled OR.
Results
We identified 13 separate studies using search (6,962 cases and 9,262 controls). We detected significant between-study heterogeneity. No significant association of this polymorphism with mood disorders was found (P>0.05). We also performed disease-specific meta-analysis in unipolar depression and bipolar disorder. No significant association of this polymorphism with unipolar depression or bipolar disorder was found (P>0.05). Additionally, we performed subgroup analysis by different types of cases. No significant association of this polymorphism with mood disorders in clinical cohorts or population-based cohorts (P>0.05). A significant association of this polymorphism with mood disorders was found for the allele contrast in family-based cohorts (OR = 1.26, 95%CI = 1.05–1.50, P = 0.01).
Conclusions
Overall, our meta-analysis suggests that P2RX7 gene rs2230912 polymorphism may not contribute to the risk of developing mood disorders using a case-control design. Given the discordance in the subgroup analysis by different types of cases, further studies based on larger sample size are still needed.
doi:10.1371/journal.pone.0088575
PMCID: PMC3922924  PMID: 24533115
12.  Sustainable, heat-resistant and flame-retardant cellulose-based composite separator for high-performance lithium ion battery 
Scientific Reports  2014;4:3935.
A sustainable, heat-resistant and flame-retardant cellulose-based composite nonwoven has been successfully fabricated and explored its potential application for promising separator of high-performance lithium ion battery. It was demonstrated that this flame-retardant cellulose-based composite separator possessed good flame retardancy, superior heat tolerance and proper mechanical strength. As compared to the commercialized polypropylene (PP) separator, such composite separator presented improved electrolyte uptake, better interface stability and enhanced ionic conductivity. In addition, the lithium cobalt oxide (LiCoO2)/graphite cell using this composite separator exhibited better rate capability and cycling retention than that for PP separator owing to its facile ion transport and excellent interfacial compatibility. Furthermore, the lithium iron phosphate (LiFePO4)/lithium cell with such composite separator delivered stable cycling performance and thermal dimensional stability even at an elevated temperature of 120°C. All these fascinating characteristics would boost the application of this composite separator for high-performance lithium ion battery.
doi:10.1038/srep03935
PMCID: PMC3909895  PMID: 24488228
13.  Decreased Expression of GATA2 Promoted Proliferation, Migration and Invasion of HepG2 In Vitro and Correlated with Poor Prognosis of Hepatocellular Carcinoma 
PLoS ONE  2014;9(1):e87505.
Background
GATA family of transcription factors are critical for organ development and associated with progression of various cancer types. However, their expression patterns and prognostic values for hepatocellular carcinoma (HCC) are still largely unknown.
Methods
Expression of GATA transcription factors in HCC cell lines and tissues (n = 240) were evaluated by RT-qPCR, western blot and immunohistochemistry. Cellular proliferation, migration and invasion of HepG2 was evaluated by CCK-8 kit, scratch wound assay and transwell matrigel invasion assay, respectively.
Results
GATA2 expression was decreased in HCC cell lines (p = 0.056 for mRNA, p = 0.040 for protein) and tissues (p = 1.27E-25) compared with normal hepatocytes. Decreased expression of intratumoral GATA2 protein significantly correlated with elevated alpha feto-protein (p = 2.7E-05), tumor size >5 cm (p = 0.049), absence of tumor capsule (p = 0.002), poor differentiation (p = 0.005), presence of tumor thrombi (p = 0.005) and advanced TNM stage (p = 0.001) and was associated with increased recurrence rate and decreased overall survival rate by univariate (p = 1.6E-04 for TTR, p = 1.7E-04 for OS) and multivariate analyses (HR = 0.63, 95% CI = 0.43–0.90, p = 0.012 for TTR; HR = 0.67, 95% CI = 0.47–0.95, p = 0.026 for OS). RNAi-mediated knockdown of GATA2 expression significantly enhanced proliferation, migration and invasion of HepG2 cell in vitro.
Conclusions
Decreased expression of hematopoietic factor GATA2 was associated with poor prognosis of HCC following resection.
doi:10.1371/journal.pone.0087505
PMCID: PMC3907524  PMID: 24498120
14.  Investigation of Antioxidant Interactions between Radix Astragali and Cimicifuga foetida and Identification of Synergistic Antioxidant Compounds 
PLoS ONE  2014;9(1):e87221.
The medicinal plants of Huang-qi (Radix Astragali) and Sheng-ma (Cimicifuga foetida) demonstrate significantly better antioxidant effects when used in combination than when used alone. However, the bioactive components and interactional mechanism underlying this synergistic action are still not well understood. In the present study, 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay was employed to investigate the antioxidant capacity of single herbs and their combination with the purpose of screening synergistic antioxidant compounds from them. Chromatographic isolation was performed on silica gel, Sephadex LH-20 columns and HPLC, and consequently to yield formononetin, calycosin, ferulic acid and isoferulic acid, which were identified by their retention time, UV λmax, MS and MS/MS data. The combination of isoferulic acid and calycosin at a dose ratio of 1∶1 resulted in significant synergy in scavenging DPPH radicals and ferric reducing antioxidant power (FRAP) assay. Furthermore, the protective effects of these four potential synergistic compounds were examined using H2O2-induced HepG2 Cells bioassay. Results revealed that the similar synergy was observed in the combination of isoferulic acid and calycosin. These findings might provide some theoretical basis for the purported synergistic efficiency of Huang-qi and Sheng-ma as functional foods, dietary supplements and medicinal drugs.
doi:10.1371/journal.pone.0087221
PMCID: PMC3907558  PMID: 24498048
15.  A Ser252Trp Mutation in Fibroblast Growth Factor Receptor 2 (FGFR2) Mimicking Human Apert Syndrome Reveals an Essential Role for FGF Signaling in the Regulation of Endochondral Bone Formation 
PLoS ONE  2014;9(1):e87311.
A S252W mutation of fibroblast growth factor receptor 2 (FGFR2), which is responsible for nearly two-thirds of Apert syndrome (AS) cases, causes retarded development of the skeleton and skull malformation resulting from premature fusion of the craniofacial sutures. We utilized a Fgfr2+/S252W mouse (a knock-in mouse model mimicking human AS) to demonstrate decreased bone mass due to reduced trabecular bone volume, reduced bone mineral density, and shortened growth plates in the long bones. In vitro bone mesenchymal stem cells (BMSCs) culture studies revealed that the mutant mice showed reduced BMSC proliferation, a reduction in chondrogenic differentiation, and reduced mineralization. Our results suggest that these phenomena are caused by up-regulation of p38 and Erk1/2 phosphorylation. Treatment of cultured mutant bone rudiments with SB203580 or PD98059 resulted in partial rescue of the bone growth retardation. The p38 signaling pathway especially was found to be responsible for the retarded long bone development. Our data indicate that the S252W mutation in FGFR2 directly affects endochondral ossification, resulting in growth retardation of the long bone. We also show that the p38 and Erk1/2 signaling pathways partially mediate the effects of the S252W mutation of FGFR2 on long bone development.
doi:10.1371/journal.pone.0087311
PMCID: PMC3904987  PMID: 24489893
16.  The Biological Effect of Large Single Doses: A Possible Role for Non-Targeted Effects in Cell Inactivation 
PLoS ONE  2014;9(1):e84991.
Background and Purpose
Novel radiotherapy techniques increasingly use very large dose fractions. It has been argued that the biological effect of large dose fractions may differ from that of conventional fraction sizes. The purpose was to study the biological effect of large single doses.
Material and Methods
Clonogenic cell survival of MCF7 and MDA-MB-231 cells was determined after direct X-ray irradiation, irradiation of feeder cells, or transfer of conditioned medium (CM). Cell-cycle distributions and the apoptotic sub-G1 fraction were measured by flow cytometry. Cytokines in CM were quantified by a cytokine antibody array. γH2AX foci were detected by immunofluorescence microscopy.
Results
The surviving fraction of MCF7 cells irradiated in vitro with 12 Gy showed an 8.5-fold decrease (95% c.i.: 4.4–16.3; P<0.0001) when the density of irradiated cells was increased from 10 to 50×103 cells per flask. Part of this effect was due to a dose-dependent transferrable factor as shown in CM experiments in the dose range 5–15 Gy. While no effect on apoptosis and cell cycle distribution was observed, and no differentially expressed cytokine could be identified, the transferable factor induced prolonged expression of γH2AX DNA repair foci at 1–12 h.
Conclusions
A dose-dependent non-targeted effect on clonogenic cell survival was found in the dose range 5–15 Gy. The dependence of SF on cell numbers at high doses would represent a “cohort effect” in vivo. These results support the hypothesis that non-targeted effects may contribute to the efficacy of very large dose fractions in radiotherapy.
doi:10.1371/journal.pone.0084991
PMCID: PMC3898915  PMID: 24465461
17.  The downregulation of PRDM1/Blimp-1 is associated with aberrant expression of miR-223 in extranodal NK/T-cell lymphoma, nasal type 
Background
The mechanism for inactivation of positive regulatory domain containing I (PRDM1), a newly identified tumour suppressor gene in extranodal NK/T-cell lymphoma, nasal type (EN-NK/T-NT) has not been well defined. The aim of the present study was to investigate the expression of PRDM1 in EN-NK/T-NT and analyse its downregulation by miRNAs.
Methods
PRDM1 and miRNA expression were evaluated in EN-NK/T-NT samples by immunohistochemical analysis, qRT-PCR, and in situ hybridisation. Luciferase assays were performed to verify the direct binding of miR-223 to the 3′-untranslated region of PRDM1 mRNA. In addition, the effect of miR-223 on PRDM1 expression was assessed in NK/T lymphoma cell lines by transfecting a miR-223 mimic or inhibitor to increase or decrease the effective expression of miR-223. Overall survival and failure-free survival in EN-NK/T-NT patients were analysed using Kaplan-Meier single-factor analysis and the log-rank test.
Results
Investigation of the downregulation of PRDM1 in EN-NK/T-NT cases revealed that PRDM1-positive staining might be a favourable predictor of overall survival and failure-free survival in EN-NK/T-NT patients. However, the negative staining of PRDM1 usually presented transcripts, suggesting a possible post-transcriptional regulation. miR-223 and its putative target gene, PRDM1, exhibited opposite patterns of expression in EN-NK/T-NT tissues and cell lines. Moreover, PRDM1 was identified as a direct target gene of miR-223 by luciferase assays. The ectopic expression of miR-223 led to the downregulation of the PRDM1 protein in the NK/T-cell lymphoma cell line, whereas a decrease in miR-223 restored the level of PRDM1 protein.
Conclusions
Our findings reveal that the downregulation of the tumour suppressor PRDM1 in EN-NK/T-NT samples is mediated by miR-223 and that PRDM1-positive staining might have prognostic value for evaluating the clinical outcome of EN-NK/T-NT patients.
doi:10.1186/1756-9966-33-7
PMCID: PMC3898819  PMID: 24438193
Extranodal NK/T-cell lymphoma; Nasal type; PRDM1; miR-223
18.  Correction: Prognostic Value of Cancer Stem Cell Marker CD133 Expression in Gastric Cancer: A Systematic Review 
PLoS ONE  2014;9(1):10.1371/annotation/80c50c32-16b8-4099-98e4-af72154192b3.
doi:10.1371/annotation/80c50c32-16b8-4099-98e4-af72154192b3
PMCID: PMC3894292
19.  A Network Pharmacology Approach to Determine Active Compounds and Action Mechanisms of Ge-Gen-Qin-Lian Decoction for Treatment of Type 2 Diabetes 
Traditional Chinese medicine (TCM) herbal formulae can be valuable therapeutic strategies and drug discovery resources. However, the active ingredients and action mechanisms of most TCM formulae remain unclear. Therefore, the identification of potent ingredients and their actions is a major challenge in TCM research. In this study, we used a network pharmacology approach we previously developed to help determine the potential antidiabetic ingredients from the traditional Ge-Gen-Qin-Lian decoction (GGQLD) formula. We predicted the target profiles of all available GGQLD ingredients to infer the active ingredients by clustering the target profile of ingredients with FDA-approved antidiabetic drugs. We also applied network target analysis to evaluate the links between herbal ingredients and pharmacological actions to help explain the action mechanisms of GGQLD. According to the predicted results, we confirmed that a novel antidiabetic ingredient from Puerariae Lobatae radix (Ge-Gen), 4-Hydroxymephenytoin, increased the insulin secretion in RIN-5F cells and improved insulin resistance in 3T3-L1 adipocytes. The network pharmacology strategy used here provided a powerful means for identifying bioactive ingredients and mechanisms of action for TCM herbal formulae, including Ge-Gen-Qin-Lian decoction.
doi:10.1155/2014/495840
PMCID: PMC3914348  PMID: 24527048
20.  Radiofrequency ablation following first-line transarterial chemoembolization for patients with unresectable hepatocellular carcinoma beyond the Milan criteria 
BMC Gastroenterology  2014;14:11.
Background
Recent studies suggest that a combination of radiofrequency ablation (RFA) and transarterial chemoembolization (TACE) may have theoretical advantages over TACE alone for treatment of hepatocellular carcinoma (HCC). The purpose of this study was to evaluate the effectiveness and safety of radiofrequency ablation following first-line TACE treatment in the management of HCC beyond the Milan Criteria.
Methods
Forty-five patients who consecutively underwent RFA following first-line TACE treatment for HCC beyond the Milan criteria were enrolled in this study. RFA was performed within 1–2 months after TACE treatment in patients who had incomplete necrotic tumor nodules. Primary effectiveness, complications, survival rates, and prognostic factors were evaluated retrospectively.
Results
Complete ablation was achieved in 76.2% of the lesions according to 1-month follow-up computed tomography/magnetic resonance imaging evaluation. The mean follow-up period was 30.9 months (range 3–94 months). There were no major complications after RFA therapy. The median overall survival was 29 months (range 20–38 months), with 1-, 2-, and 3-year survival of 89%, 61%, and 43%, respectively. Multivariate analysis revealed that tumor diameter (P = 0.045, hazard ratio [HR] = 0.228, 95% confidence interval [CI]: 0.054-0.968) and pretreatment serum alpha-fetoprotein level (P = 0.024, HR = 2.239, 95% CI: 1.114-4.500) were independent predictors for long-term survival.
Conclusions
HCC beyond the Milan criteria can be completely and safely ablated by radiofrequency ablation following first-line TACE treatment with a low rate of complications and favorable survival outcome. Further assessment of the survival benefits of combination treatment for HCCs beyond the Milan Criteria is warranted.
doi:10.1186/1471-230X-14-11
PMCID: PMC3890612  PMID: 24410841
Hepatocellular carcinoma; Radiofrequency ablation; Transcatheter arterial chemoembolization; Milan criteria
21.  Sparsity-Regularized HMAX for Visual Recognition 
PLoS ONE  2014;9(1):e81813.
About ten years ago, HMAX was proposed as a simple and biologically feasible model for object recognition, based on how the visual cortex processes information. However, the model does not encompass sparse firing, which is a hallmark of neurons at all stages of the visual pathway. The current paper presents an improved model, called sparse HMAX, which integrates sparse firing. This model is able to learn higher-level features of objects on unlabeled training images. Unlike most other deep learning models that explicitly address global structure of images in every layer, sparse HMAX addresses local to global structure gradually along the hierarchy by applying patch-based learning to the output of the previous layer. As a consequence, the learning method can be standard sparse coding (SSC) or independent component analysis (ICA), two techniques deeply rooted in neuroscience. What makes SSC and ICA applicable at higher levels is the introduction of linear higher-order statistical regularities by max pooling. After training, high-level units display sparse, invariant selectivity for particular individuals or for image categories like those observed in human inferior temporal cortex (ITC) and medial temporal lobe (MTL). Finally, on an image classification benchmark, sparse HMAX outperforms the original HMAX by a large margin, suggesting its great potential for computer vision.
doi:10.1371/journal.pone.0081813
PMCID: PMC3879257  PMID: 24392078
22.  DNA hypomethylation within specific transposable element families associates with tissue-specific enhancer landscape 
Nature genetics  2013;45(7):10.1038/ng.2649.
Introduction
Transposable element (TE) derived sequences comprise half of our genome and DNA methylome, and are presumed densely methylated and inactive. Examination of the genome-wide DNA methylation status within 928 TE subfamilies in human embryonic and adult tissues revealed unexpected tissue-specific and subfamily-specific hypomethylation signatures. Genes proximal to tissue-specific hypomethylated TE sequences were enriched for functions important for the tissue type and their expression correlated strongly with hypomethylation of the TEs. When hypomethylated, these TE sequences gained tissue-specific enhancer marks including H3K4me1 and occupancy by p300, and a majority exhibited enhancer activity in reporter gene assays. Many such TEs also harbored binding sites for transcription factors that are important for tissue-specific functions and exhibited evidence for evolutionary selection. These data suggest that sequences derived from TEs may be responsible for wiring tissue type-specific regulatory networks, and have acquired tissue-specific epigenetic regulation.
doi:10.1038/ng.2649
PMCID: PMC3695047  PMID: 23708189
23.  RTS Noise and Dark Current White Defects Reduction Using Selective Averaging Based on a Multi-Aperture System 
Sensors (Basel, Switzerland)  2014;14(1):1528-1543.
In extremely low-light conditions, random telegraph signal (RTS) noise and dark current white defects become visible. In this paper, a multi-aperture imaging system and selective averaging method which removes the RTS noise and the dark current white defects by minimizing the synthetic sensor noise at every pixel is proposed. In the multi-aperture imaging system, a very small synthetic F-number which is much smaller than 1.0 is achieved by increasing optical gain with multiple lenses. It is verified by simulation that the effective noise normalized by optical gain in the peak of noise histogram is reduced from 1.38e- to 0.48e- in a 3 × 3-aperture system using low-noise CMOS image sensors based on folding-integration and cyclic column ADCs. In the experiment, a prototype 3 × 3-aperture camera, where each aperture has 200 × 200 pixels and an imaging lens with a focal length of 3.0 mm and F-number of 3.0, is developed. Under a low-light condition, in which the maximum average signal is 11e- per aperture, the RTS noise and dark current white defects are removed and the peak signal-to-noise ratio (PSNR) of the image is increased by 6.3 dB.
doi:10.3390/s140101528
PMCID: PMC3926624  PMID: 24441768
noise reduction; multi-aperture; random telegraph signal (RTS) noise; dark current white defect
24.  Protective Effects of p38 MAPK Inhibitor SB202190 against Hippocampal Apoptosis and Spatial Learning and Memory Deficits in a Rat Model of Vascular Dementia 
BioMed Research International  2013;2013:215798.
Vascular dementia (VaD) is a common age-related neurodegenerative disease resulting from chronic hypoxia. In the present study, we examined the protective effects of p38 MAPK inhibitor SB202190 against hippocampal apoptosis and spatial learning and memory deficits in a chronic hypoperfusion rat model of VaD established by permanent bilateral carotid occlusion (2-VO). Sixty rats were randomly divided into sham-operated, VaD model, and VaD plus SB202190 groups (n = 20/group). After sham/2-VO surgery, rats were administered 0.1% DMSO (sham-operated and VaD groups) or SB202190 by intracerebroventricular injection. One week after inhibitor/vehicle treatment, hippocampal p38 MAPK phosphorylation was higher in the model group than in the SB202190 group (P < 0.01). Compared to the model group, the SB202190 group exhibited significantly shorter escape latencies in the Morris water maze hidden platform trials (P < 0.01) and longer times in the original platform quadrant during probe trials (P < 0.01). The SB202190 group also showed significantly reduced neuronal apoptosis in the hippocampus compared to VaD model rats (P < 0.01) as well as higher (antiapoptotic) Bcl-2 expression and lower (proapoptotic) caspase-3 expression (P < 0.01 for both). In conclusion, blockade of the p38 MAPK signaling pathway by SB202190 following permanent 2-OV reduced apoptosis of hippocampal neurons and rescued spatial learning and memory deficits.
doi:10.1155/2013/215798
PMCID: PMC3886604  PMID: 24455679
25.  Modified McKeown Minimally Invasive Esophagectomy for Esophageal Cancer: A 5-Year Retrospective Study of 142 Patients in a Single Institution 
PLoS ONE  2013;8(12):e82428.
Background
To achieve decreased invasiveness and lower morbidity, minimally invasive esophagectomy (MIE) was introduced in 1997 for localized esophageal cancer. The combined thoracoscopic-laparoscopic esophagectomy (left neck anastomosis, defined as the McKeown MIE procedure) has been performed since 2007 at our institution. From 2007 to 2011, our institution subsequently evolved as a high-volume MIE center in China. We aim to share our experience with MIE, and have evaluated the outcomes of 142 patients.
Methods
We retrospectively reviewed 142 consecutive patients who had presented with esophageal cancer undergoing McKeown MIE from July 2007 to December 2011. The procedure, surgical outcomes, disease-free and overall survival of these cases were assessed.
Results
The average total procedure time was 270.5±28.1 min. The median operation time for thoracoscopy was 81.5±14.6 min and for laparoscopy was 63.8±9.1 min. The average blood loss associated with thoracoscopy was 123.8±39.2 ml, and for laparoscopic procedures was 49.9±14.3 ml. The median number of lymph nodes retrieved was 22.8. The 30 day mortality rate was 0.7%. Major surgical complications occurred in 24.6% and major non-surgical complications occurred in 18.3% of these patients. The median DFS and OS were 36.0±2.6 months and 43.0±3.4 months respectively.
Conclusions
Surgical and oncological outcomes following McKeown MIE for esophageal cancer were acceptable and comparable with those of open-McKeown esophagectomy. The procedure was both feasible and safe – properties that can be consolidated by experience.
doi:10.1371/journal.pone.0082428
PMCID: PMC3869695  PMID: 24376537

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