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1.  Plasma IGFBP-2 Levels after Postoperative Combined Radiotherapy and Chemotherapy Predict Prognosis in Elderly Glioblastoma Patients 
PLoS ONE  2014;9(4):e93791.
It has been found that preoperative plasma IGFBP-2 levels correlate with prognosis in glioma patients. The prognostic value of plasma IGFBP-2 after postoperative combined radiotherapy and chemotherapy in glioma patients is unknown. Plasma IGFBP-2 levels in 83 glioblastoma patients after postoperative radiotherapy plus chemotherapy were analyzed using an IGFBP-2 ELISA kit. We found that after standard therapy plasma IGFBP-2 levels significantly correlated with the patient's age (R = 0.738, P<0.001) and Karnofsky performance status (KPS, R = −0.633, P<0.05). Cox proportional hazards models were used to calculate hazard ratios (HRs) of death according to plasma IGFBP-2 levels adjusted for patient clinical characteristics. Plasma IGFBP-2 levels significantly correlated with overall survival in glioblastoma patients (multivariate HR = 1.035; 95% CI, 1.024–1.047; P<0.001). The effect of plasma IGFBP-2 levels on survival seemed to differ according to patients' age. Among patients older than 60, high plasma IGFBP-2 levels were associated with a significant increase in overall mortality (HR = 1.097; 95% CI, 1.055–1.140; P<0.001). In contrast, plasma IGFBP-2 levels conferred no significant effect on mortality among patients younger than 60. Elevated plasma IGFBP-2 levels after combined postoperative radiotherapy and chemotherapy in elderly glioblastoma patients correlate with poor KPS score and predicts poor prognosis.
doi:10.1371/journal.pone.0093791
PMCID: PMC3972244  PMID: 24690948
2.  U4 at the 3′ UTR of PB1 Segment of H5N1 Influenza Virus Promotes RNA Polymerase Activity and Contributes to Viral Pathogenicity 
PLoS ONE  2014;9(3):e93366.
The viral RNA-dependent RNA polymerase has been found to contribute to efficient replication in mammalian systems and to the high pathogenicity of H5N1 influenza A virus in humans and other mammals. The terminal untranslated regions of the viral segments perform functions such as polyadenylation and contain signals for genomic packaging and initiation of RNA synthesis. These sequences are highly conserved, apart from a U/C polymorphism at position 4 of the 3′ end, most often seen in the polymerase gene segments. However, no study has yet tested whether the untranslated regions of H5N1 make any contribution to its high pathogenicity. Herein, the association of the fourth nucleotide at the 3′ end of the untranslated region in segment 2 (PB1), of A/Vietnam/1194/2004 (H5N1), with pathogenicity was examined in mice. To this end, an RNA polymerase reporter system was constructed, and viruses with mutations at this site were rescued. Results showed the U4 in PB1 was found to contribute to greater amounts of RNA-dependent RNA polymerase activity and differentially regulate genomic transcription and replication. Although a recombinant H5N1 virus with the rarer C4 sequence in all eight segments was viable and replicated to high titers in vitro, replacing a single U4 at the 3′ termini of the PB1 gene segment enhanced viral reproduction and more pathogenesis. In this way, these data showed the importance of untranslated regions of H5N1 influenza virus to pathogenicity.
doi:10.1371/journal.pone.0093366
PMCID: PMC3968160  PMID: 24676059
3.  Development of Rapid Immunochromatographic Test for Hemagglutinin Antigen of H7 Subtype in Patients Infected with Novel Avian Influenza A (H7N9) Virus 
PLoS ONE  2014;9(3):e92306.
Background
Since human infection with the novel H7N9 avian influenza virus was identified in China in March 2013, the relatively high mortality rate and possibility of human-to-human transmission have highlighted the urgent need for sensitive and specific assays for diagnosis of H7N9 infection.
Methodology/Principal Findings
We developed a rapid diagnostic test for the novel avian influenza A (H7N9) virus using anti-hemagglutinin (HA) monoclonal antibodies specifically targeting H7 in an immunochromatographic assay system. The assay limit of detection was 103.5 pfu/ml or 103TCID50 of H7N9 virus. The assay specifically detected H7N9 viral isolates and recombinant HA proteins of H7 subtypes including H7N7 and H7N9, but did not react with non-H7 subtypes including H1N1, H3N2, H5N1, H5N9, and H9N2. The detection sensitivity was 59.4% (19/32) for H7N9 patients confirmed by RT-PCR. Moreover, the highest sensitivity of 61.5% (16/26) was obtained when testing H7N9 positive sputum samples while 35.7% (5/14) of nasopharyngeal swabs and 20% (2/10) of fecal samples tested positive. No false positive detection was found when testing 180 H7N9 negative samples.
Conclusions/Significance
Our novel rapid assay can specifically detect H7 HA antigen, facilitating rapid diagnosis for prevention and control of the on-going H7N9 epidemic.
doi:10.1371/journal.pone.0092306
PMCID: PMC3960227  PMID: 24647358
4.  Tumor-suppressive effects of CDK8 in endometrial cancer cells 
Cell Cycle  2013;12(6):987-999.
CDK8 is either amplified or mutated in a variety of human cancers, and CDK8 functions as an oncoprotein in melanoma and colorectal cancers. Previously, we reported that loss or reduction of CDK8 results in aberrant fat accumulation in Drosophila and mammals, suggesting that CDK8 plays an important role in inhibiting lipogenesis. Epidemiological studies have identified obesity and overweight as the major risk factors of endometrial cancer, thus we examined whether CDK8 regulates endometrial cancer cell growth by using several endometrial cancer cell lines, including KLE, which express low levels of CDK8, as well as AN3 CA and HEC-1A cells, which have high levels of endogenous CDK8. We observed that ectopic expression of CDK8 in KLE cells inhibited cell proliferation and potently blocked tumor growth in an in vivo mouse model. In addition, gain of CDK8 in KLE cells blocked cell migration and invasion in transwell, wound healing and persistence of migratory directionality assays. Conversely, we observed the opposite effects in all of the aforementioned assays when CDK8 was depleted in AN3 CA cells. Similar to AN3 CA cells, depletion of CDK8 in HEC-1A cells strongly enhanced cell migration in transwell assays, while overexpression of CDK8 in HEC-1A cells blocked cell migration. Furthermore, gene profiling of KLE cells overexpressing CDK8 revealed genes whose protein products are involved in lipid metabolism, cell cycle and cell movement pathways. Finally, depletion of CDK8 increased the expression of lipogenic genes in endometrial cancer cells. Taken together, these results show a reverse correlation between CDK8 levels and several key features of the endometrial cancer cells, including cell proliferation, migration and invasion as well as tumor formation in vivo. Therefore, in contrast to the oncogenic effects of CDK8 in melanoma and colorectal cancers, our results suggest that CDK8 plays a tumor-suppressive role in endometrial cancers.
doi:10.4161/cc.24003
PMCID: PMC3637357  PMID: 23454913
cyclin-dependent kinae 8 (CDK8); endometrial cancer; tumorigenesis; cell growth; cell migration
5.  SOCS3 Promoter Hypermethylation Is a Favorable Prognosticator and a Novel Indicator for G-CIMP-Positive GBM Patients 
PLoS ONE  2014;9(3):e91829.
Background
Hypermethylation of the suppressor of cytokine signaling 3(SOCS3) promoter has been reported to predict a poor prognosis in several cancers including glioblstoma multiforme (GBM). We explored the function of SOCS3 promoter hypermethylation in GBM cohorts, including analysis of the CpG island methylator phenotype (CIMP), when a large number of gene loci are simultaneously hypermethylated.
Methods
A whole genome promoter methylation profile was performed in a cohort of 33 GBM samples, with 13 long-term survivors (LTS; overall survival ≥ 18 months) and 20 short-term survivors (STS; overall survival ≤ 9 months). The SOCS3 promoter methylation status was compared between the two groups. In addition, we investigated the relationship of SOCS3 promoter methylation and G-CIMP status.
Results
Interestingly, in our present study, we found that SOCS3 promoter methylation was statistically significantly higher in the 13 LTS than that in the 20 STS. Furthermore, high SOCS3 promoter methylation detected via pyro-sequencing predicted a better prognosis in an independent cohort containing 62 GBM patients. This correlation was validated by the dataset from the Cancer Genome Atlas(TCGA) and the Chinese Cancer Genome Atlas(CGGA). In addition, we found that hypermethylation of the SOCS3 promoter was tightly associated with the G-CIMP-positive GBM patients.
Conclusions
Using a total of 359 clinical samples, we demonstrate that SOCS3 promoter hypermethylation status has a favorable prognostic value in GBM patients because of whole genome methylation status. Particularly, the hypermethylation of the SOCS3 promoter indicates positive G-CIMP status.
doi:10.1371/journal.pone.0091829
PMCID: PMC3954800  PMID: 24633048
6.  Complete Resequencing of 40 Genomes Reveals Domestication Events and Genes in Silkworm (Bombyx) 
Science (New York, N.Y.)  2009;326(5951):433-436.
A single–base pair resolution silkworm genetic variation map was constructed from 40 domesticated and wild silkworms, each sequenced to approximately threefold coverage, representing 99.88% of the genome. We identified ∼16 million single-nucleotide polymorphisms, many indels, and structural variations. We find that the domesticated silkworms are clearly genetically differentiated from the wild ones, but they have maintained large levels of genetic variability, suggesting a short domestication event involving a large number of individuals. We also identified signals of selection at 354 candidate genes that may have been important during domestication, some of which have enriched expression in the silk gland, midgut, and testis. These data add to our understanding of the domestication processes and may have applications in devising pest control strategies and advancing the use of silkworms as efficient bioreactors.
doi:10.1126/science.1176620
PMCID: PMC3951477  PMID: 19713493
7.  Molecular Subtypes of Glioblastoma Are Relevant to Lower Grade Glioma 
PLoS ONE  2014;9(3):e91216.
Background
Gliomas are the most common primary malignant brain tumors in adults with great heterogeneity in histopathology and clinical course. The intent was to evaluate the relevance of known glioblastoma (GBM) expression and methylation based subtypes to grade II and III gliomas (ie. lower grade gliomas).
Methods
Gene expression array, single nucleotide polymorphism (SNP) array and clinical data were obtained for 228 GBMs and 176 grade II/II gliomas (GII/III) from the publically available Rembrandt dataset. Two additional datasets with IDH1 mutation status were utilized as validation datasets (one publicly available dataset and one newly generated dataset from MD Anderson). Unsupervised clustering was performed and compared to gene expression subtypes assigned using the Verhaak et al 840-gene classifier. The glioma-CpG Island Methylator Phenotype (G-CIMP) was assigned using prediction models by Fine et al.
Results
Unsupervised clustering by gene expression aligned with the Verhaak 840-gene subtype group assignments. GII/IIIs were preferentially assigned to the proneural subtype with IDH1 mutation and G-CIMP. GBMs were evenly distributed among the four subtypes. Proneural, IDH1 mutant, G-CIMP GII/III s had significantly better survival than other molecular subtypes. Only 6% of GBMs were proneural and had either IDH1 mutation or G-CIMP but these tumors had significantly better survival than other GBMs. Copy number changes in chromosomes 1p and 19q were associated with GII/IIIs, while these changes in CDKN2A, PTEN and EGFR were more commonly associated with GBMs.
Conclusions
GBM gene-expression and methylation based subtypes are relevant for GII/III s and associate with overall survival differences. A better understanding of the association between these subtypes and GII/IIIs could further knowledge regarding prognosis and mechanisms of glioma progression.
doi:10.1371/journal.pone.0091216
PMCID: PMC3948818  PMID: 24614622
8.  Unique genome-wide map of TCF4 and STAT3 targets using ChIP-seq reveals their association with new molecular subtypes of glioblastoma 
Neuro-Oncology  2013;15(3):279-289.
Background
Aberrant activation of beta-catenin/TCF4 and STAT3 signaling in glioblastoma multiforme (GBM) has been reported. However, the molecular mechanisms related to this process are still poorly understood.
Methods
Genome-wide screening of the binding characteristics of the transcription factors TCF4 and STAT3 in GBM cells was performed by chromatin immunoprecipitation sequencing (ChIP-seq) assay. Hierarchical clustering was used to analyze the association of TCF4 and STAT3 coregulated genes with The Cancer Genome Atlas (TCGA) GBM subtypes (classical, mesenchymal, neural, and proneural). New molecular classification of GBM was proposed and validated in Western and Asian populations.
Results
We identified 1250 overlapping putative target genes that were coregulated by TCF4 and STAT3. Further, the coregulated genes had the potential to guide TCGA GBM subtypes. Finally, we proposed a new molecular classification of GBM into 2 subtypes (proneural-like and mesenchymal-like) and showed that the new classification could be applied to both Western and Asian populations. In addition, the GBM response to temozolomide therapy differed depending on its subtype; mesenchymal-like GBM benefited, while there was no benefit for proneural-like GBM.
Conclusions
This is the first comprehensive study to combine a ChIP-seq assay of TCF4 and STAT3 and data mining of patient cohorts to derive molecular subtypes of GBM.
doi:10.1093/neuonc/nos306
PMCID: PMC3578485  PMID: 23295773
ChIP-seq; glioblastoma; molecular subtype; STAT3; TCF4
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.  Correlation of Nrf2, NQO1, MRP1, cmyc and p53 in colorectal cancer and their relationships to clinicopathologic features and survival 
Due to emergence of resistant tumor populations, prognosis for metastatic colorectal cancer (CRC) patients remains poor and five-year survival rate is still very low. To guide clinicians in selecting treatment option for CRC patients, reliable markers predictive of poor clinical outcome are desirable. This study analyzed the correlation of NF-E2-related factor 2 (Nrf2), NAD(P)H quinine oxidoreductase 1 (NQO1), multidrug resistant protein 1 (MRP1), cmyc and p53 in CRC and their relationships to Duke’s stage and clinical prognosis. 76 specimens of CRC tissues were immunohistochemically investigated using Nrf2, NQO1, MRP1, cmyc and p53 antibodies. IHC stain showed that Nrf2, NQO1, MRP1, cmyc and p53 were highly expressed in CRC tissues compared with adjacent non-tumor tissues. Significant positive correlations were found between the expression of Nrf2 and that of NQO1, MRP1, cmyc and p53. Moreover, there was significant correlation between the high level of Nrf2, NQO1, MRP1, p53 expression and Duke’s stage, as well as poor clinical prognosis. We confirmed that Nrf2, NQO1, MRP1, and p53 expression exhibits considerable heterogeneity according to CRC clinical stage and prognosis. Nrf2 is the most promising biomarker in identifying a poor prognostic group of CRC.
PMCID: PMC3971317
Colorectal cancer (CRC); NF-E2-related factor 2 (Nrf2); NAD(P)H quinine oxidoreductase 1 (NQO1); multidrug resistant protein 1 (MRP1); cmyc; p53
11.  Application of International Videoconferences for Continuing Medical Education Programs Related to Laparoscopic Surgery 
Telemedicine Journal and e-Health  2014;20(2):157-160.
Abstract
Background: Continuing medical education (CME) is an effective way for practicing physicians to acquire up-to-date clinical information. Materials and Methods: We conducted four CME seminars in 2007–2010 endorsed by the Chinese Medical Association Council on Medical Education. Overseas telelectures and live case demonstrations were introduced in each seminar via telemedicine based on a digital video transport system. Network stability and packet loss were recorded. An anonymous mini-questionnaire was conducted to evaluate the satisfaction of attendees regarding the image and sound quality, content selection, and overall evaluation. Results: Four telelectures and five live case demonstrations were successfully conducted. Stability of the network was maintained during each videoconference. High-quality videos of 720×480 pixels at the rate of 30 frames per second were shown to the entire group of attendees. The time delay between Shanghai and Fukuoka, Japan, was only 0.3 s, and the packet loss was 0%. We obtained 129 valid responses to the mini-questionnaire from a total of 146 attendees. The majority of the attendees were satisfied with the quality of transmitted images and voices and with the selected contents. The overall evaluation was ranked as excellent or good. Conclusions: Videoconferences are excellent channels for CME programs associated with laparoscopic training.
doi:10.1089/tmj.2013.0070
PMCID: PMC3910541  PMID: 23758077
continuing medical education; videoconference; live case demonstration; digital video transport system; telemedicine; laparoscopic surgery
12.  Indian-Ink Perfusion Based Method for Reconstructing Continuous Vascular Networks in Whole Mouse Brain 
PLoS ONE  2014;9(1):e88067.
The topology of the cerebral vasculature, which is the energy transport corridor of the brain, can be used to study cerebral circulatory pathways. Limited by the restrictions of the vascular markers and imaging methods, studies on cerebral vascular structure now mainly focus on either observation of the macro vessels in a whole brain or imaging of the micro vessels in a small region. Simultaneous vascular studies of arteries, veins and capillaries have not been achieved in the whole brain of mammals. Here, we have combined the improved gelatin-Indian ink vessel perfusion process with Micro-Optical Sectioning Tomography for imaging the vessel network of an entire mouse brain. With 17 days of work, an integral dataset for the entire cerebral vessels was acquired. The voxel resolution is 0.35×0.4×2.0 µm3 for the whole brain. Besides the observations of fine and complex vascular networks in the reconstructed slices and entire brain views, a representative continuous vascular tracking has been demonstrated in the deep thalamus. This study provided an effective method for studying the entire macro and micro vascular networks of mouse brain simultaneously.
doi:10.1371/journal.pone.0088067
PMCID: PMC3907580  PMID: 24498247
13.  Long Non-Coding RNA H19 Promotes Glioma Cell Invasion by Deriving miR-675 
PLoS ONE  2014;9(1):e86295.
H19 RNA has been characterized as an oncogenic long non-coding RNA (lncRNA) in breast and colon cancer. However, the role and function of lncRNA H19 in glioma development remain unclear. In this study, we identified that H19/miR-675 signaling was critical for glioma progression. By analyzing glioma gene expression data sets, we found increased H19 in high grade gliomas. H19 depletion via siRNA inhibited invasion in glioma cells. Further, we found H19 positively correlated with its derivate miR-675 expression and reduction of H19 inhibited miR-675 expression. Bioinformatics and luciferase reporter assays showed that miR-675 modulated Cadherin 13 expression by directly targeting the binding site within the 3′ UTR. Finally, introduction of miR-675 abrogated H19 knockdown-induced cell invasion inhibition in glioma cells. To our knowledge, it is first time to demonstrate that H19 regulates glioma development by deriving miR-675 and provide important clues for understanding the key roles of lncRNA-miRNA functional network in glioma.
doi:10.1371/journal.pone.0086295
PMCID: PMC3900504  PMID: 24466011
14.  Induction of Neutralizing Antibodies against Four Serotypes of Dengue Viruses by MixBiEDIII, a Tetravalent Dengue Vaccine 
PLoS ONE  2014;9(1):e86573.
The worldwide expansion of four serotypes of dengue virus (DENV) poses great risk to global public health. Several vaccine candidates are under development. However, none is yet available for humans. In the present study, a novel strategy to produce tetravalent DENV vaccine based on envelope protein domain III (EDIII) was proposed. Tandem EDIIIs of two serotypes (type 1–2 and type 3–4) of DENV connected by a Gly-Ser linker ((Gly4Ser)3) were expressed in E. coli, respectively. Then, the two bivalent recombinant EDIIIs were equally mixed to form the tetravalent vaccine candidate MixBiEDIII, and used to immunize BALB/c mice. The results showed that specific IgG and neutralizing antibodies against all four serotypes of DENV were successfully induced in the MixBiEDIII employing Freund adjuvant immunized mice. Furthermore, in the suckling mouse model, sera from mice immunized with MixBiEDIII provided significant protection against four serotypes of DENV challenge. Our data demonstrated that MixBiEDIII, as a novel form of subunit vaccine candidates, might have the potential to be further developed as a tetravalent dengue vaccine in the near future.
doi:10.1371/journal.pone.0086573
PMCID: PMC3897746  PMID: 24466156
15.  Importance of Internet Surveillance in Public Health Emergency Control and Prevention: Evidence From a Digital Epidemiologic Study During Avian Influenza A H7N9 Outbreaks 
Background
Outbreaks of human infection with a new avian influenza A H7N9 virus occurred in China in the spring of 2013. Control and prevention of a new human infectious disease outbreak can be strongly affected by public reaction and social impact through the Internet and social media.
Objective
This study aimed to investigate the potential roles of Internet surveillance in control and prevention of the human H7N9 outbreaks.
Methods
Official data for the human H7N9 outbreaks were collected via the China National Health and Family Planning Committee website from March 31 to April 24, 2013. We obtained daily posted and forwarded number of blogs for the keyword “H7N9” from Sina microblog website and a daily Baidu Attention Index (BAI) from Baidu website, which reflected public attention to the outbreak. Rumors identified and confirmed by the authorities were collected from Baidu search engine.
Results
Both daily posted and forwarded number and BAI for keyword H7N9 increased quickly during the first 3 days of the outbreaks and remained at a high level for 5 days. The total daily posted and forwarded number for H7N9 on Sina microblog peaked at 850,000 on April 3, from zero blogs before March 31, increasing to 97,726 on April 1 and to 370,607 on April 2, and remaining above 500,000 from April 5-8 before declining to 208,524 on April 12. The total daily BAI showed a similar pattern of change to the total daily posted and forwarded number over time from March 31 to April 12. When the outbreak locations spread, especially into other areas of the same province/city and the capital, Beijing, daily posted and forwarded number and BAI increased again to a peak at 368,500 and 116,911, respectively. The median daily BAI during the studied 25 days was significantly higher among the 7 provinces/cities with reported human H7N9 cases than the 2 provinces without any cases (P<.001). So were the median daily posted and forwarded number and daily BAI in each province/city except Anhui province. We retrieved a total of 32 confirmed rumors spread across 19 provinces/cities in China. In all, 84% (27/32) of rumors were disseminated and transmitted by social media.
Conclusions
The first 3 days of an epidemic is a critical period for the authorities to take appropriate action through Internet surveillance to prevent and control the epidemic, including preparation of personnel, technology, and other resources; information release; collection of public opinion and reaction; and clarification, prevention, and control of rumors. Internet surveillance can be used as an efficient and economical tool to prevent and control public health emergencies, such as H7N9 outbreaks.
doi:10.2196/jmir.2911
PMCID: PMC3906895  PMID: 24440770
influenza A virus, H7N9 subtype; Internet; surveillance; disease outbreak
16.  Inhibition of STAT3 Reduces Astrocytoma Cell Invasion and Constitutive Activation of STAT3 Predicts Poor Prognosis in Human Astrocytoma 
PLoS ONE  2013;8(12):e84723.
Astrocytoma cells characteristically possess high invasion potentials. Recent studies have revealed that knockdown of signal transducers and activators of transcription 3 (STAT3) expression by RNAi induces apoptosis in astrocytoma cell. Nevertheless, the distinct roles of STAT3 in astrocytoma’s invasion and recurrence have not been elucidated. In this study, we silenced STAT3 using Small interfering RNAs in two human glioblastoma multiforme (GBM) cell lines (U251 and U87), and investigated the effect on GBM cell adhesion and invasion. Our results demonstrate that disruption of STAT3 inhibits GBM cell’s adhesion and invasion. Knockdown of STAT3 significantly increased E-cadherin but decreased N-cadherin, vascular endothelial growth factor, matrix metalloproteinase 2 and matrix metalloproteinase 9. Additionally, expression of pSTAT3Tyr705 correlates with astrocytoma WHO classification, Karnofsky performance status scale score, tumor recurrence and survival. Furthmore, pSTAT3Tyr705 is a significant prognostic factor in astrocytoma. In conclusion, STAT3 may affect astrocytoma invasion, expression of pSTAT3Tyr705 is a significant prognostic factor in tumor recurrence and overall survival in astrocytoma patients. Therefore, STAT3 may provide a potential target for molecular therapy in human astrocytoma, and pSTAT3Tyr705could be an important biomarker for astrocytoma prognosis.
doi:10.1371/journal.pone.0084723
PMCID: PMC3875539  PMID: 24386409
17.  Association of TLR2 and TLR4 Polymorphisms with Risk of Cancer: A Meta-Analysis 
PLoS ONE  2013;8(12):e82858.
Backgrounds
The activation of Toll-like receptors (TLRs) may be an important event in the immune evasion of tumor cell. Recently, numerous studies have investigated the associations between TLR2 −196 to −174 del and two SNPs of TLR4 (rs4986790 and rs4986791) and the susceptibility to different types of cancer; however, the results remain conflicting. The aim of this study was to assess the association between TLR2 and TLR4 polymorphisms and cancer risk in a meta-analysis with eligible published studies.
Methodology/Principle Findings
A dataset composed of 14627 cases and 17438 controls from 34 publications were included in a meta-analysis to evaluate the association between overall cancer risk or cancer-specific risk and three SNPs of TLRs (TLR2 −196 to −174 del, TLR4 rs4986790 and rs4986791). The results showed that all of these three polymorphisms were significantly associated with the increased cancer risk (dominant model: OR = 1.64, 95% CI: 1.04–2.60 for TLR2 −196 to −174 del; OR = 1.19, 95% CI: 1.01–1.41 for TLR4 rs4986790; and OR = 1.47, 95% CI: 1.120–1.80 for TLR4 rs4986791; respectively). In stratified analysis, we found the effect of TLR2 −196 to −174 del on cancer risk remained significant in the subgroup of Caucasians and South Asians, but not in East Asians. However, the association between rs4986791 and cancer risk was significant in both South Asians and East Asians, but not in Caucasians. Furthermore, the association between rs4986790 and cancer risk was statistically significant in digestive cancers (dominant model: OR = 1.76, 95% CI: 1.13–2.73) and female-specific cancers (dominant model: OR = 1.50, 95% CI: 1.16–1.94). However, no significant association with risk of digestive system cancers was observed for TLR2 −196 to −174 del and TLR4 rs4986791.
Conclusions/Significance
This meta-analysis presented additional evidence for the association between TLR2 and TLR4 polymorphisms and cancer risk. Further well-designed investigations with large sample sizes are required to confirm this conclusion.
doi:10.1371/journal.pone.0082858
PMCID: PMC3869723  PMID: 24376595
18.  Identifying potential cancer driver genes by genomic data integration 
Scientific Reports  2013;3:3538.
Cancer is a genomic disease associated with a plethora of gene mutations resulting in a loss of control over vital cellular functions. Among these mutated genes, driver genes are defined as being causally linked to oncogenesis, while passenger genes are thought to be irrelevant for cancer development. With increasing numbers of large-scale genomic datasets available, integrating these genomic data to identify driver genes from aberration regions of cancer genomes becomes an important goal of cancer genome analysis and investigations into mechanisms responsible for cancer development. A computational method, MAXDRIVER, is proposed here to identify potential driver genes on the basis of copy number aberration (CNA) regions of cancer genomes, by integrating publicly available human genomic data. MAXDRIVER employs several optimization strategies to construct a heterogeneous network, by means of combining a fused gene functional similarity network, gene-disease associations and a disease phenotypic similarity network. MAXDRIVER was validated to effectively recall known associations among genes and cancers. Previously identified as well as novel driver genes were detected by scanning CNAs of breast cancer, melanoma and liver carcinoma. Three predicted driver genes (CDKN2A, AKT1, RNF139) were found common in these three cancers by comparative analysis.
doi:10.1038/srep03538
PMCID: PMC3866686  PMID: 24346768
19.  Does Nrf2 Contribute to p53-Mediated Control of Cell Survival and Death? 
Antioxidants & Redox Signaling  2012;17(12):1670-1675.
Abstract
In response to oxidative stress, the transcription factor Nrf2 is upregulated and controls activation of many genes that work in concert to defend cells from damages and to maintain cellular redox homeostasis. p53 has been regarded as the guardian of the genome through its pro-oxidant and antioxidant functions. Under low levels of reactive oxygen species (ROS), “normal” amounts of p53 upregulates expression of antioxidant genes, protecting macromolecules from ROS-induced damage. However, at high levels or extended exposure of ROS, p53 expression is enhanced, activating pro-oxidant genes and resulting in p53-dependent apoptosis. We observed a two-phase Nrf2 expression controlled by p53. (i) The induction phase: when p53 expression is relatively low, p53 enhances the protein level of Nrf2 and its target genes to promote cell survival in a p21-dependent manner. (ii) The repression phase: when p53 expression is high, the Nrf2-mediated survival response is inhibited by p53. Our observation leads to the hypothesis that the p53-mediated biphasic regulation of Nrf2 may be key for the tumor-suppressor function of p53 by coordinating cell survival and death pathways. Antioxid. Redox Signal. 17, 1670–1675.
doi:10.1089/ars.2012.4674
PMCID: PMC3474188  PMID: 22559194
20.  Procalcitonin Levels Predict Acute Kidney Injury and Prognosis in Acute Pancreatitis: A Prospective Study 
PLoS ONE  2013;8(12):e82250.
Background
Acute kidney injury (AKI) has been proposed as a leading cause of mortality for acute pancreatitis (AP) patients admitted to the intensive care unit (ICU). This study investigated the predictive value of procalcitonin (PCT) for AKI development and relevant prognosis in patients with AP, and compared PCT’s predictive power with that of other inflammation-related variables.
Methods
Between January 2011 and March 2013, we enrolled 305 cases with acute pancreatitis admitted to ICU. Serum levels of PCT, serum amyloid A (SAA), interleukin-6 (IL-6), and C reactive protein (CRP) were determined on admission. Serum PCT was tested in patients who developed AKI on the day of AKI occurrence and on either day 28 after occurrence (for survivors) or on the day of death (for those who died within 28 days).
Results
Serum PCT levels were 100-fold higher in the AKI group than in the non-AKI group on the day of ICU admission (p<0.05). The area under the receiver-operating characteristic (ROC) curve of PCT for predicting AKI was 0.986, which was superior to SAA, CRP, and IL-6 (p<0.05). ROC analysis revealed all variables tested had lower predictive performance for AKI prognosis. The average serum PCT level on day 28 (2.67 (0.89, 7.99) ng/ml) was significantly (p<0.0001) lower than on the day of AKI occurrence (43.71 (19.24,65.69) ng/ml) in survivors, but the serum PCT level on death (63.73 (34.22,94.30) ng/ml) was higher than on the day of AKI occurrence (37.55 (18.70,74.12) ng/ml) in non-survivors, although there was no significant difference between the two days in the latter group (p = 0.1365).
Conclusion
Serum PCT is superior to CRP, IL-6, and SAA for predicting the development of AKI in patients with AP, and also can be used for dynamic evaluation of AKI prognosis.
doi:10.1371/journal.pone.0082250
PMCID: PMC3862675  PMID: 24349237
21.  Molecular classification of gliomas based on whole genome gene expression: a systematic report of 225 samples from the Chinese Glioma Cooperative Group 
Neuro-Oncology  2012;14(12):1432-1440.
Defining glioma subtypes based on objective genetic and molecular signatures may allow for a more rational, patient-specific approach to molecularly targeted therapy. However, prior studies attempting to classify glioma subtypes have given conflicting results. We aim to complement and validate the existing molecular classification system on a large number of samples from an East Asian population. A total of 225 samples from Chinese patients was selected for whole genome gene expression profiling. Consensus clustering was applied. Three major groups of gliomas were identified (referred to as G1, G2, and G3). The G1 subgroup correlates with a good clinical outcome, young age, and extremely high frequency of IDH1 mutations. Relative to the G1 subgroup, the G3 subgroup is correlated with a poorer clinical outcome, older age, and a very low rate of mutations in the IDH1 gene. Correlations of the G2 subgroup with respect to clinical outcome, age, and IDH1 mutation fall between the G1 and G3 subgroups. In addition, the G2 subtype was associated with a higher percentage of loss of 1p/19q when compared with G1 and G3 subtypes. Furthermore, our classification scheme was validated on 2 independent datasets derived from the cancer genome atlas (TCGA) and Rembrandt. With use of the TCGA classification system, proneural, neural, and mesenchymal, but not classical subtype, associated gene signatures were clearly defined. In summary, our results reveal that 3 main subtypes stably exist in Chinese patients with glioma. Our classification scheme may reflect the clinical and genetic alterations more clearly. Classical subtype–associated gene signature was not found in our dataset.
doi:10.1093/neuonc/nos263
PMCID: PMC3499016  PMID: 23090983
Chinese Glioma Genome Atlas; glioma; microarray; molecular classification
22.  Novel cis-Acting Element within the Capsid-Coding Region Enhances Flavivirus Viral-RNA Replication by Regulating Genome Cyclization 
Journal of Virology  2013;87(12):6804-6818.
cis-Acting elements in the viral genome RNA (vRNA) are essential for the translation, replication, and/or encapsidation of RNA viruses. In this study, a novel conserved cis-acting element was identified in the capsid-coding region of mosquito-borne flavivirus. The downstream of 5′ cyclization sequence (5′CS) pseudoknot (DCS-PK) element has a three-stem pseudoknot structure, as demonstrated by structure prediction and biochemical analysis. Using dengue virus as a model, we show that DCS-PK enhances vRNA replication and that its function depends on its secondary structure and specific primary sequence. Mutagenesis revealed that the highly conserved stem 1 and loop 2, which are involved in potential loop-helix interactions, are crucial for DCS-PK function. A predicted loop 1-stem 3 base triple interaction is important for the structural stability and function of DCS-PK. Moreover, the function of DCS-PK depends on its position relative to the 5′CS, and the presence of DCS-PK facilitates the formation of 5′-3′ RNA complexes. Taken together, our results reveal that the cis-acting element DCS-PK enhances vRNA replication by regulating genome cyclization, and DCS-PK might interplay with other cis-acting elements to form a functional vRNA cyclization domain, thus playing critical roles during the flavivirus life cycle and evolution.
doi:10.1128/JVI.00243-13
PMCID: PMC3676100  PMID: 23576500
23.  EGFR Mutations in Surgically Resected Fresh Specimens from 697 Consecutive Chinese Patients with Non-Small Cell Lung Cancer and Their Relationships with Clinical Features 
We aimed to reveal the true status of epidermal growth factor receptor (EGFR) mutations in Chinese patients with non-small cell lung cancer (NSCLC) after lung resections. EGFR mutations of surgically resected fresh tumor samples from 697 Chinese NSCLC patients were analyzed by Amplification Refractory Mutation System (ARMS). Correlations between EGFR mutation hotspots and clinical features were also explored. Of the 697 NSCLC patients, 235 (33.7%) patients had tyrosine kinase inhibitor (TKIs) sensitive EGFR mutations in 41 (14.5%) of the 282 squamous carcinomas, 155 (52.9%) of the 293 adenocarcinomas, 34 (39.5%) of the 86 adenosquamous carcinomas, one (9.1%) of the 11 large-cell carcinomas, 2 (11.1%) of the 18 sarcomatoid carcinomas, and 2 (28.6%) of the 7 mucoepidermoid carcinomas. TKIs sensitive EGFR mutations were more frequently found in female patients (p < 0.001), non-smokers (p = 0.047) and adenocarcinomas (p < 0.001). The rates of exon 19 deletion mutation (19-del), exon 21 L858R point mutation (L858R), exon 21 L861Q point mutation (L861Q), exon 18 G719X point mutations (G719X, including G719C, G719S, G719A) were 43.4%, 48.1%, 1.7% and 6.8%, respectively. Exon 20 T790M point mutation (T790M) was detected in 3 squamous carcinomas and 3 adenocarcinomas and exon 20 insertion mutation (20-ins) was detected in 2 patients with adenocarcinoma. Our results show the rates of EGFR mutations are higher in all types of NSCLC in Chinese patients. 19-del and L858R are two of the more frequent mutations. EGFR mutation detection should be performed as a routine postoperative examination in Chinese NSCLC patients.
doi:10.3390/ijms141224549
PMCID: PMC3876127  PMID: 24351833
EGFR mutations; NSCLC; targeted therapy; ARMS; surgery; fresh tumor specimens
24.  Presep: Predicting the Propensity of a Protein Being Secreted into the Supernatant when Expressed in Pichia pastoris 
PLoS ONE  2013;8(11):e79749.
Pichia pastoris is commonly used for the production of recombinant proteins due to its preferential secretion of recombinant proteins, resulting in lower production costs and increased yields of target proteins. However, not all recombinant proteins can be successfully secreted in P. pastoris. A computational method that predicts the likelihood of a protein being secreted into the supernatant would be of considerable value; however, to the best of our knowledge, no such tool has yet been developed. We present a machine-learning approach called Presep to assess the likelihood of a recombinant protein being secreted by P. pastoris based on its pseudo amino acid composition (PseAA). Using a 20-fold cross validation, Presep demonstrated a high degree of accuracy, with Matthews correlation coefficient (MCC) and overall accuracy (Q2) scores of 0.78 and 95%, respectively. Computational results were validated experimentally, with six β-galactosidase genes expressed in P. pastoris strain GS115 to verify Presep model predictions. A strong correlation (R2 = 0.967) was observed between Presep prediction secretion propensity and the experimental secretion percentage. Together, these results demonstrate the ability of the Presep model for predicting the secretion propensity of P. pastoris for a given protein. This model may serve as a valuable tool for determining the utility of P. pastoris as a host organism prior to initiating biological experiments. The Presep prediction tool can be freely downloaded at http://www.mobioinfor.cn/Presep.
doi:10.1371/journal.pone.0079749
PMCID: PMC3836778  PMID: 24278168
25.  Expression of hypoxia-related markers in inflammatory myofibroblastic tumors of the head and neck 
Background
The etiology of inflammatory myofibroblastic tumors (IMTs) is controversial and the prognosis is unpredictable. Previous studies have not investigated the expression of hypoxia-related markers in IMTs.
Methods
Between 2002 and 2012, 12 consecutive patients with histologically proven IMTs were enrolled in the study. Immunohistochemistry was used to detect GLUT-1, HIF-1α, PI3K, and p-Akt expression in paraffin-embedded tumor specimens. Associations among GLUT-1, HIF-1α, PI3K, and p-Akt protein expression and clinical parameters were investigated.
Results
The mean duration of follow-up was 52.1 months (range, 11 to 132 months). Six patients had local recurrence. GLUT-1, HIF-1α, PI3K, and p-Akt expression were detected in 41.7%, 50.0%, 33.3%, and 41.7% of patients, respectively. Fisher’s exact test revealed significant correlations between recurrence of IMT and PI3K expression (P = 0.01) and p-Akt expression (P = 0.015). Univariate analyses revealed significant correlations between survival and GLUT-1 expression (P = 0.028), PI3K expression (P = 0.006), and p-Akt expression (P = 0.028). Multivariate analysis did not show a significant relationship between survival and GLUT-1, HIF-1α, PI3K, or p-Akt. Spearman rank correlation analysis showed significant correlations between HIF-1α and PI3K expression (r = 0.707, P = 0.01) and between p-Akt and PI3K expression (r = 0.837, P = 0.001).
Conclusions
Although our results are inconclusive owing to the small sample size, they suggest that PI3K and p-Akt expression may play a role in the recurrence of IMTs of the head and neck.
doi:10.1186/1477-7819-11-294
PMCID: PMC3842822  PMID: 24245510
Glucose transporter-1; Hypoxia-inducible factor 1α; Inflammatory myofibroblastic tumor; PI3K/Akt pathway; Prognosis; Recurrence

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