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1.  Isolation and Identification of miRNAs in Jatropha curcas 
MicroRNAs (miRNAs) are small noncoding RNAs that play crucial regulatory roles by targeting mRNAs for silencing. To identify miRNAs in Jatropha curcas L, a bioenergy crop, cDNA clones from two small RNA libraries of leaves and seeds were sequenced and analyzed using bioinformatic tools. Fifty-two putative miRNAs were found from the two libraries, among them six were identical to known miRNAs and 46 were novel. Differential expression patterns of 15 miRNAs in root, stem, leave, fruit and seed were detected using quantitative real-time PCR. Ten miRNAs were highly expressed in fruit or seed, implying that they may be involved in seed development or fatty acids synthesis in seed. Moreover, 28 targets of the isolated miRNAs were predicted from a jatropha cDNA library database. The miRNA target genes were predicted to encode a broad range of proteins. Sixteen targets had clear BLASTX hits to the Uniprot database and were associated with genes belonging to the three major gene ontology categories of biological process, cellular component, and molecular function. Four targets were identified for JcumiR004. By silencing JcumiR004 primary miRNA, expressions of the four target genes were up-regulated and oil composition were modulated significantly, indicating diverse functions of JcumiR004.
doi:10.7150/ijbs.3676
PMCID: PMC3303143  PMID: 22419887
Jatropha; Biofuel; miRNA; fatty acid synthesis.
2.  Mapping QTLs for oil traits and eQTLs for oleosin genes in jatropha 
BMC Plant Biology  2011;11:132.
Background
The major fatty acids in seed oil of jatropha, a biofuel crop, are palmitic acid (C16:0), stearic acid (C18:0), oleic acid (C18:1) and linoleic acid (C18:2). High oleic acid and total oil content are desirable for jatropha breeding. Until now, little was known about the genetic bases of these oil traits in jatropha. In this study, quantitative trait locus (QTL) and expression QTL analyses were applied to identify genetic factors that are relevant to seed oil traits in jatropha.
Results
Composite interval mapping identified 18 QTL underlying the oil traits. A highly significant QTL qC18:1-1 was detected at one end of linkage group (LG) 1 with logarithm of the odd (LOD) 18.4 and percentage of variance explained (PVE) 36.0%. Interestingly, the QTL qC18:1-1 overlapped with qC18:2-1, controlling oleic acid and linoleic acid compositions. Among the significant QTL controlling total oil content, qOilC-4 was mapped on LG4 a relatively high significant level with LOD 5.0 and PVE 11.1%. Meanwhile, oleosins are the major composition in oil body affecting oil traits; we therefore developed SNP markers in three oleosin genes OleI, OleII and OleIII, which were mapped onto the linkage map. OleI and OleIII were mapped on LG5, closing to QTLs controlling oleic acid and stearic acid. We further determined the expressions of OleI, OleII and OleIII in mature seeds from the QTL mapping population, and detected expression QTLs (eQTLs) of the three genes on LGs 5, 6 and 8 respectively. The eQTL of OleIII, qOleIII-5, was detected on LG5 with PVE 11.7% and overlapped with QTLs controlling stearic acid and oleic acid, implying a cis- or trans-element for the OleIII affecting fatty acid compositions.
Conclusion
We identified 18 QTLs underlying the oil traits and 3 eQTLs of the oleosin acid genes. The QTLs and eQTLs, especially qC18:1-1, qOilC-4 and qOleIII-5 with contribution rates (R2) higher than 10%, controlling oleic acid, total oil content and oleosin gene expression respectively, will provide indispensable data for initiating molecular breeding to improve seed oil traits in jatropha, the key crop for biodiesel production.
doi:10.1186/1471-2229-11-132
PMCID: PMC3195091  PMID: 21958236
3.  Restoring Eelgrass (Zostera marina L.) Habitats Using a Simple and Effective Transplanting Technique 
PLoS ONE  2014;9(4):e92982.
Eelgrass beds in coastal waters of China have declined substantially over the past 30 years. In this study, a simple new transplanting technique was developed for eelgrass (Zostera marina L.) restoration. To assist in anchoring single shoots, several rhizomes of rooted shoots were bound to a small elongate stone (50–150 g) with biodegradable thread (cotton or hemp), and then the bound packet was buried at an angle in the sediments at a depth of 2–4 cm. This stone anchoring method was used to transplant eelgrass in early November 2009 and late May 2010 in Huiquan Bay, Qingdao. The method led to high success. Three month survivorship of the transplanted shoots at the two transplant sites was >95%. From April 20 to November 19, 2012, the following characteristics of the 2009 and 2010 transplanted eelgrass beds were monitored: morphological changes, shoot density, shoot height, leaf biomass, and sediment particle size. Results showed that the sexual reproduction period of the planted eelgrass was from April to August, and vegetative reproduction reached its peak in autumn. Maximum shoot height and biomass were observed in June and July. After becoming established, the transplanted eelgrass beds were statistically equal to natural eelgrass beds nearby in terms of shoot height, biomass, and seasonal variations. This indicates that the transplant technique is effective for eelgrass restoration in coastal waters.
doi:10.1371/journal.pone.0092982
PMCID: PMC3973628  PMID: 24695414
4.  Proteolysis of the Human DNA Polymerase Delta Smallest Subunit p12 by μ-Calpain in Calcium-Triggered Apoptotic HeLa Cells 
PLoS ONE  2014;9(4):e93642.
Degradation of p12 subunit of human DNA polymerase delta (Pol δ) that results in an interconversion between Pol δ4 and Pol δ3 forms plays a significant role in response to replication stress or genotoxic agents triggered DNA damage. Also, the p12 is readily degraded by human calpain in vitro. However, little has been done for the investigation of its degree of participation in any of the more common apoptosis. Here, we first report that the p12 subunit is a substrate of μ-calpain. In calcium-triggered apoptotic HeLa cells, the p12 is degraded at 12 hours post-induction (hpi), restored thereafter by 24 hpi, and then depleted again after 36 hpi in a time-dependent manner while the other three subunits are not affected. It suggests a dual function of Pol δ by its interconversion between Pol δ4 and Pol δ3 that is involved in a novel unknown apoptosis mechanism. The proteolysis of p12 could be efficiently blocked by both calpain inhibitor ALLN and proteasome inhibitor MG132. In vitro pull down and co-immunoprecipitation assays show that the μ-calpain binds to p12 through the interaction of μ-calpain with Pol δ other three subunits, not p12 itself, and PCNA, implying that the proteolysis of p12 by μ-calpain might be through a Pol δ4/PCNA complex. The p12 cleavage sites by μ-calpain are further determined as the location within a 16-amino acids peptide 28-43 by in vitro cleavage assays. Thus, the p12/Pol δ is a target as a nuclear substrate of μ-calpain in a calcium-triggered apoptosis and appears to be a potential marker in the study of the chemotherapy of cancer therapies.
doi:10.1371/journal.pone.0093642
PMCID: PMC3972206  PMID: 24691096
5.  No Survival Improvement for Patients with Angioimmunoblastic T-Cell Lymphoma over the Past Two Decades: A Population-Based Study of 1207 Cases 
PLoS ONE  2014;9(3):e92585.
Angioimmunoblastic T-cell lymphoma (AITL) is a rare lymphoid malignancy with dismal prognosis. We conducted a large population-based study using the Surveillance, Epidemiology, and End Results (SEER) database (1973–2010) to determine the temporal survival trends and prognostic factors of AITL patients. A total of 1207 patients with AITL were included in this study, with a median age at diagnosis of 69 years. At presentation, most patients (79.5%) had an advanced-stage disease. Overall survival (OS) probabilities at 2, 5 and 10 years were 46.8%, 32.9%, and 21.9% respectively. Two-year, 5-year, and 10-year disease-specific survival (DSS) rates were 56.1%, 44.0%, and 35.9% respectively.On multivariate analysis, age older than 70 years, advanced-stage disease and male sex were identified adverse predictors for OS and DSS. We failed to find any survival differences among subgroups diagnosed in the 5 periods studied (1992 to 1998, 1999 to 2001, 2002 to 2004, 2005 to 2007, and 2008 to 2010). The current study represents the largest specific series of patients with AITL and the first investigation on temporal changes in survival of AITL patients. There has been no survival improvement for AITL patients over the past two decades. Further investigations are warranted to develop more effective treatment for AITL.
doi:10.1371/journal.pone.0092585
PMCID: PMC3961418  PMID: 24651162
6.  ALDH2 and ADH1 Genetic Polymorphisms May Contribute to the Risk of Gastric Cancer: A Meta-Analysis 
PLoS ONE  2014;9(3):e88779.
Aim
We conducted a meta-analysis of case-control studies to determine whether ALDH2, ADH1 and ADH2 genetic polymorphisms contribute to the pathogenesis of gastric cancer.
Methods
The PubMed, CISCOM, CINAHL, Web of Science, Google Scholar, EBSCO, Cochrane Library, and CBM databases were searched for relevant articles published before November 1st, 2013 without any language restrictions. Meta-analysis was conducted using the STATA 12.0 software. We calculated crude odds ratios (ORs) with their 95% confidence intervals (95%CI) to evaluate their relationships under five genetic models. Seven case-control studies with a total of 2,563 gastric cancer patients and 4,192 healthy controls met the inclusion criteria. Nine common polymorphisms were evaluated, including rs671, rs16941667 and rs886205 in the ALDH2 gene, rs1230025, rs13123099, rs698 and rs1693482 in the ADH1 gene, and rs1229984 and rs17033 in the ADH2 gene.
Results
The results of our meta-analysis suggested that ALDH2 genetic polymorphisms might be strongly correlated with an increased risk of gastric cancer (allele model: OR  = 1.21, 95%CI: 1.11∼1.32, P<0.001; dominant model: OR  = 1.23, 95%CI: 1.09∼1.39, P = 0.001; respectively), especially for rs671 polymorphism. Furthermore, we observed significant associations between ADH1 genetic polymorphisms and an increased risk of gastric cancer (allele model: OR  = 1.21, 95%CI: 1.08∼1.36, P = 0.001; dominant model: OR  = 10.52, 95%CI: 3.04∼36.41, P<0.001; respectively), especially for rs1230025 polymorphism. Nevertheless, no positive relationships were found between ADH2 genetic polymorphisms and gastric cancer risk (all P>0.05).
Conclusion
The current meta-analysis suggests that ALDH2 and ADH1 genetic polymorphisms may play crucial roles in the pathogenesis of gastric cancer. However, ADH2 genetic polymorphisms may not be important dominants of susceptibility to gastric cancer.
doi:10.1371/journal.pone.0088779
PMCID: PMC3954547  PMID: 24633362
7.  Damaging Effects of Multi-walled Carbon Nanotubes on Pregnant Mice with Different Pregnancy Times 
Scientific Reports  2014;4:4352.
The mechanism by which nanoparticles cross the placental barrier was studied by using isotopic tracers. The abortion rates and other related data were counted and analysed in pregnant mice with different pregnancy times. Results showed that oxidised multi-walled carbon nanotubes (oMWCNTs) crossed the placental barrier and entered the foetus body. The abortion rates in the pregnant mice depended on pregnancy times. The abortion rates in the first-time, second-time and fourth-time pregnant mice were 70%, 40% and 50%, respectively. The maternal body weight gain was inhibited until gestational ages of 13, 10 and 11 d. oMWCNTs decreased the serum progesterone level and increased the serum oestradiol level in a dose- and time-dependent manner. However, this effect decreased with gestational age. The histology and vascular endothelial growth factor/reactive oxygen species content in the placenta showed that oMWCNTs narrowed the blood vessel and decreased the number of blood vessels in the placenta.
doi:10.1038/srep04352
PMCID: PMC3950636  PMID: 24619025
8.  The Standard, Intervention Measures and Health Risk for High Water Iodine Areas 
PLoS ONE  2014;9(2):e89608.
Our study aims to clarify the population nutrient status in locations with different levels of iodine in the water in China; to choose effective measurements of water improvement(finding other drinking water source of iodine not excess) or non-iodised salt supply or combinations thereof; to classify the areas of elevated water iodine levels and the areas with endemic goiter; and to evaluate the risk factors of water iodine excess on pregnant women, lactating women and the overall population of women. From Henan, Hebei, Shandong and Shanxi province of China, for each of 50∼99 µg/L, 100∼149 µg/L, 150∼299 µg/L, and ≥300 µg/L water iodine level, three villages were selected respectively. Students of 6–12 years old and pregnant were sampled from villages of each water-iodine level of each province, excluded iodized salt consumer. Then the children's goiter volume, the children and pregnant's urinary iodine and water iodine were tested. In addition, blood samples were collected from pregnant women, lactating women and other women of reproductive age for each water iodine level in the Shanxi Province for thyroid function tests. These indicators should be matched for each person. When the water iodine exceeds 100 µg/L; the iodine nutrient of children are iodine excessive, and are adequate or more than adequate for the pregnant women. It is reasonable to define elevated water iodine areas as locations where the water iodine levels exceed 100 µg/L. The supply of non-iodised salt alone cannot ensure adequate iodine nutrition of the residents, and water improvement must be adopted, as well. Iodine excess increases the risk of certain thyroid diseases in women from one- to eightfold.
doi:10.1371/journal.pone.0089608
PMCID: PMC3938487  PMID: 24586909
9.  Molecular Characterization and Mapping of Fgf21 Gene in a Foodfish Species Asian Seabass 
PLoS ONE  2014;9(2):e90172.
Fgf21 is a newly discovered fibroblast growth factor. It is typically induced by fasting and plays important roles in the regulation of glucose and lipid metabolisms and energy balance in mammals, whereas potential functions of this gene in teleosts are still unknown. We identified the Fgf21 gene and studied its functions in Asian seabass (Lates calcarifer). The cDNA of the Fgf21 encoded a protein with 206 amino acids. Analysis of DNA and amino acid sequences of Fgf21 genes revealed that the sequences and structure of the Fgf21 genes were highly conserved in vertebrates. Real-time PCR revealed that Fgf21 was exclusively expressed in the intestine and kidney, which was different from the expression profiles of mammals. Fgf21 was down-regulated under fasting, whereas it was significantly increased during the LPS challenge. Exogenous recombinant FGF21 significantly suppressed the appetite of Asian seabass. Our data suggest that Fgf21 plays a role in energy regulation and acute phase response in Asian seabass, and may have different functions in fish and mammals. In addition, we identified one SNP in Fgf21. By using this SNP, the gene was mapped on the linkage group 23, where a suggestive QTL for growth was mapped previously. Association mapping identified significant associations between Fgf21 genotypes at the SNP and growth traits. These results not only provide important information of the functions of Fgf21, but also suggest that the SNP in this gene can be used as a marker in selecting fast-growing individuals of Asian seabass.
doi:10.1371/journal.pone.0090172
PMCID: PMC3937445  PMID: 24587261
10.  Micro-electro-fluidic grids for nematodes: A lens-less, image-sensor-less approach for on-chip tracking of nematode locomotion 
Lab on a chip  2013;13(4):650-661.
This paper reports on the development of a lens-less and image-sensor-less micro-electro-fluidic (MEF) approach for real-time monitoring of the locomotion of microscopic nematodes. The technology showed promise for overcoming the constraint of the limited field of view of conventional optical microscopy, with a relatively low cost, good spatial resolution, and high portability. The core of the device was microelectrode grids formed by orthogonally arranging two identical arrays of microelectrode lines. The two microelectrode arrays were spaced by a microfluidic chamber containing a liquid medium of interest. As a nematode (e.g., Caenorhabditis elegans) moved inside the chamber, the invasion of its body parts into some intersection regions between the microelectrodes caused changes in electrical resistance of these intersection regions. The worm's presence at or absence from a detection unit was determined by a comparison between the measured resistance variation of this unit and a pre-defined threshold resistance variation. An electronic readout circuit was designed to address all detection units and read out their individual electrical resistance. By this means, it was possible to obtain the electrical resistance profile of the whole MEF grids, and thus, the physical pattern of the swimming nematode. We studied the influence of a worm's body on the resistance of an addressed unit. We also investigated how the full-frame scanning and readout rate of the electronic circuit and the dimensions of a detection unit posed an impact on the spatial resolution of the reconstructed images of the nematode. Other important issues, such as the manufacturing induced initial non-uniformity of the grids and the electrotaxic behaviour of nematodes, were also studied. A drug resistance screening experiment was conducted by using the grids with a good resolution of 30 × 30 μm2. The phenotypic differences in the locomotion behaviours (e.g., moving speed and oscillation frequency extracted from the reconstructed images with the help of software) between the wild-type (N2) and mutant (lev-8) C. elegans worms in response to different doses of the anthelmintic drug, levamisole. The locomotive parameters obtained by the MEF grids agreed well with those obtained by optical microscopy. Therefore, this technology will benefit the whole-animal assays by providing a structurally simple, potentially cost-effective device capable of tracking the movement and phenotypes of important nematodes in various microenvironments.
doi:10.1039/c2lc41174a
PMCID: PMC3587735  PMID: 23254956
11.  Prognostic significance of the combined expression of neutral endopeptidase and dipeptidyl peptidase IV in intrahepatic cholangiocarcinoma patients after surgery resection 
OncoTargets and therapy  2014;7:297-304.
Aim
The aim of this study was to investigate the relationship between the expression of neutral endopeptidase (NEP) and dipeptidyl peptidase IV (DPP IV) proteins, and the clinical significance of the two proteins in patients with intrahepatic cholangiocarcinomas (IHCC).
Methods
Expression patterns and subcellular localizations of NEP and DPP IV proteins in 186 primary IHCC and 60 noncancerous liver tissue specimens were detected by immunohistochemistry.
Results
Both the expression of NEP and DPP IV proteins in IHCC tissues were significantly higher than those in noncancerous liver tissues (both P<0.001). Of 186 patients with IHCC, 128 (68.82%) highly expressed both NEP and DPP IV proteins. In addition, the coexpression of NEP and DPP IV proteins was significantly associated with advanced tumor stage (P=0.009), positive lymph node metastasis (P=0.016) and distant metastasis (P=0.013), and the presence of recurrence (P=0.027). Moreover, Kaplan–Meier analysis showed that IHCC patients with high NEP expression, high DPP IV expression, and combined overexpression of NEP and DPP IV proteins all had poorer overall survival and early recurrence after surgery. Furthermore, Cox analysis suggested that NEP expression, DPP IV expression, and combined expression of NEP and DPP IV proteins were all independent prognostic markers for overall survival and recurrence-free survival in patients with IHCC.
Conclusion
Our data suggest, for the first time, that both the expression of NEP and DPP IV proteins may be upregulated in human IHCC tissues and the combined expression of NEP and DPP IV proteins may play important roles in progression and prognosis of patients with IHCC.
doi:10.2147/OTT.S57355
PMCID: PMC3933717  PMID: 24570591
clinicopathological characteristics; tumor progression; prognosis
12.  G-protein-coupled receptor participates in 20-hydroxyecdysone signaling on the plasma membrane 
Background
Animal steroid hormones are conventionally known to initiate signaling via a genomic pathway by binding to the nuclear receptors. The mechanism by which 20E initiates signaling via a nongenomic pathway is unclear.
Results
We illustrate that 20E triggered the nongenomic pathway through a plasma membrane G-protein-coupled receptor (named ErGPCR) in the lepidopteran insect Helicoverpa armigera. The transcript of ErGPCR was increased at the larval molting stage and metamorphic molting stage by 20E regulation. Knockdown of ErGPCR via RNA interference in vivo blocked larval–pupal transition and suppressed 20E-induced gene expression. ErGPCR overexpression in the H. armigera epidermal cell line increased the 20E-induced gene expression. Through ErGPCR, 20E modulated Calponin nuclear translocation and phosphorylation, and induced a rapid increase in cytosolic Ca2+ levels. The inhibitors of T-type voltage-gated calcium channels and canonical transient receptor potential calcium channels repressed the 20E-induced Ca2+ increase. Truncation of the N-terminal extracellular region of ErGPCR inhibited its localization on the plasma membrane and 20E-induced gene expression. ErGPCR was not detected to bind with the steroid hormone analog [3H]Pon A.
Conclusion
These results suggest that ErGPCR participates in 20E signaling on the plasma membrane.
doi:10.1186/1478-811X-12-9
PMCID: PMC3937218  PMID: 24507557
Steroid hormones; G-protein-coupled receptors; Protein phosphorylation; Calcium influx; Signal transduction
13.  Induced effects of advanced oxidation processes 
Scientific Reports  2014;4:4018.
Hazardous organic wastes from industrial, military, and commercial activities represent one of the greatest challenges to human beings. Advanced oxidation processes (AOPs) are alternatives to the degradation of those organic wastes. However, the knowledge about the exact mechanisms of AOPs is still incomplete. Here we report a phenomenon in the AOPs: induced effects, which is a common property of combustion reaction. Through analysis EDTA oxidation processes by Fenton and UV-Fenton system, the results indicate that, just like combustion, AOPs are typical induction reactions. One most compelling example is that pre-feeding easily oxidizable organic matter can promote the oxidation of refractory organic compound when it was treated by AOPs. Connecting AOPs to combustion, it is possible to achieve some helpful enlightenment from combustion to analyze, predict and understand AOPs. In addition, we assume that maybe other oxidation reactions also have induced effects, such as corrosion, aging and passivation. Muchmore research is necessary to reveal the possibilities of induced effects in those fields.
doi:10.1038/srep04018
PMCID: PMC3916790  PMID: 24503715
14.  A comparative study between Embosphere® and conventional transcatheter arterial chemoembolization for treatment of unresectable liver metastasis from GIST 
Objective
Transcatheter arterial chemoembolization (TACE) is a standard treatment for hepatocellular carcinoma (HCC) and/or some unresectable liver metastasis tumors. Hypervascular liver metastatic lesions such as metastasis from gastrointestinal stromal tumor (GIST) are an indication for transcatheter arterial embolization (TAE). The purpose of this study was to evaluate the efficacy and safety of Embosphere®-TAE (Embo-TAE) in comparison with conventional TACE (cTACE) for the treatment of liver metastasis from GIST.
Methods
A total of 45 patients who underwent TACE between Aug 2008 and Feb 2013 were enrolled. Patients with GIST who underwent TAE with Embosphere® (n=19) were compared with controls who received cTACE (n=26). The primary end points were treatment response and treatment-related adverse events. The secondary end points were progression-free survival (PFS) and overall survival (OS).
Results
The treatment response of Embo-TAE group was significantly higher than that of the cTACE group (P<0.001). The PFS was significantly better in the Embosphere®-group than in the cTACE group (56.6 and 42.1 weeks, respectively; P=0.003). However, there was no statistically significant difference in liver toxicity between the two groups (P>0.05). The median OS in the Embo-TAE group was longer than that in the cTACE group (74.0 weeks, 95% CI: 68.2-79.8 vs. 61.7 weeks, 95% CI: 56.2-67.2 weeks) (unadjusted P=0.045). The use of Embo-TAE significantly reduced the risk of death in patients with GIST with liver metastases according to the Cox proportional hazards regression model [hazard ratio (HR): 0.149; 95% CI: 0.064-0.475].
Conclusions
TAE with Embosphere® showed better treatment response and delayed tumor progression compared with cTACE. There was no significant difference in treatment-related hepatic toxicities. Embo-TAE thus appears to be a feasible and promising approach in the treatment of liver metastasis from GIST.
doi:10.3978/j.issn.1000-9604.2014.02.11
PMCID: PMC3937743  PMID: 24653635
Transcatheter arterial chemoembolization (TACE); gastrointestinal stromal tumor (GIST); embolization
15.  EGFR gene copy number as a predictive biomarker for resistance to anti-EGFR monoclonal antibodies in metastatic colorectal cancer treatment: a meta-analysis 
Objective
The epidermal growth factor receptor (EGFR) inhibitors monoclonal antibodies (MoAbs) have already shown the therapeutic effectiveness in patients with metastatic colorectal cancer (mCRC). But many patients resist to the treatment. The aim of this meta-analysis was to assess EGFR gene copy number (GCN) as a candidate predictive biomarker for resistance to anti-EGFR MoAbs in mCRC treatment.
Methods
Systematic computerized searches of the PubMed, EMBase and Cochrane Library were performed. The primary endpoint was objective response rate (ORR). The second endpoints included progression-free survival (PFS), and overall survival (OS). The pooled odd ratio (OR) and pooled sensitivity, specificity, and summary receiver operator characteristic (SROC) for ORR were estimated. The pooled hazard ratios (HR) for PFS and OS were also calculated.
Results
Fourteen studies with 1,021 patients were included. Increased EGFR GCN was associated with increased ORR (OR=6.905; 95% CI: 4.489-10.620). It was also found in wild-type KRAS mCRC patients, with the pooled OR of 8.133 (95% CI: 4.316-15.326). GCN has medium value for predicting ORR, with the pooled sensitivity of 0.79 (95% CI: 0.73-0.84), the pooled specificity of 0.59 (95% CI: 0.55-0.62). In wild-type KRAS mCRC patients, the sensitivity and the specificity were 0.80 (95% CI: 0.70-0.87) and 0.60 (95% CI: 0.53-0.66), respectively. Increased EGFR GCN was associated with increased PFS (HR=0.557; 95% CI: 0.382-0.732) and OS (HR=0.579; 95% CI: 0.422-0.737).
Conclusions
This meta-analysis suggests that EGFR GCN represents a predictive biomarker for tumor response in mCRC patients treated with MoAbs regardless of KRAS mutation. mCRC patients with increased EGFR GCN are more likely to have a better response, PFS, and OS when treated with cetuximab or panitumumab.
doi:10.3978/j.issn.1000-9604.2014.01.10
PMCID: PMC3937753  PMID: 24653627
Metastatic colorectal cancer (mCRC); epidermal growth factor receptor (EGFR); gene copy number (GCN); meta-analysis
16.  Management of Hepatitis E Virus (HEV) Zoonotic Transmission: Protection of Rabbits against HEV Challenge following Immunization with HEV 239 Vaccine 
PLoS ONE  2014;9(1):e87600.
Hepatitis E virus (HEV) constitutes a significant health burden worldwide, with an estimated approximately 33% of the world’s population exposed to the pathogen. The recent licensed HEV 239 vaccine in China showed excellent protective efficacy against HEV of genotypes 1 and 4 in the general population and pregnant women. Because hepatitis E is a zoonosis, it is also necessary to ascertain whether this vaccine can serve to manage animal sources of human HEV infection. To test the efficacy of the HEV 239 vaccine in protecting animal reservoirs of HEV against HEV infection, twelve specific-pathogen-free (SPF) rabbits were divided randomly into two groups of 6 animals and inoculated intramuscularly with HEV 239 and placebo (PBS). All animals were challenged intravenously with swine HEV of genotype 4 or rabbit HEV seven weeks after the initial immunization. The course of infection was monitored for 10 weeks by serum ALT levels, duration of viremia and fecal virus excretion and HEV antibody responses. All rabbits immunized with HEV 239 developed high titers of anti-HEV and no signs of HEV infection were observed throughout the experiment, while rabbits inoculated with PBS developed viral hepatitis following challenge, with liver enzyme elevations, viremia, and fecal virus shedding. Our data indicated that the HEV 239 vaccine is highly immunogenic for rabbits and that it can completely protect rabbits against homologous and heterologous HEV infections. These findings could facilitate the prevention of food-borne sporadic HEV infection in both developing and industrialized countries.
doi:10.1371/journal.pone.0087600
PMCID: PMC3907545  PMID: 24498149
17.  A putative high affinity phosphate transporter, CmPT1, enhances tolerance to Pi deficiency of chrysanthemum 
BMC Plant Biology  2014;14:18.
Background
Inorganic phosphate (Pi) is essential for plant growth, and phosphorus deficiency is a main limiting factor in plant development. Its acquisition is largely mediated by Pht1 transporters, a family of plasma membrane-located proteins. Chrysanthemum is one of the most important ornamental plants, its productivity is usually compromised when grown in phosphate deficient soils, but the study of phosphate transporters in chrysanthemum is limited.
Results
We described the isolation from chrysanthemum of a homolog of the Phosphate Transporter 1 (PT1) family. Its predicted product is a protein with 12 transmembrane domains, highly homologous with other high affinity plant Pi transporters. Real-time quantitative PCR analysis revealed that the gene was transcribed strongly in the root, weakly in the stem and below the level of detection in the leaf of chrysanthemum plants growing in either sufficient or deficient Pi conditions. Transcript abundance was greatly enhanced in Pi-starved roots. A complementation assay in yeast showed that CmPT1 partially compensated for the absence of phosphate transporter activity in yeast strain MB192. The estimated K m of CmPT1 was 35.2 μM. Under both Pi sufficient and deficient conditions, transgenic plants constitutively expressing CmPT1 grew taller than the non-transformed wild type, produced a greater volume of roots, accumulated more biomass and took up more phosphate.
Conclusions
CmPT1 encodes a typical, root-expressed, high affinity phosphate transporter, plays an important role in coping Pi deficiency of chrysanthemum plants.
doi:10.1186/1471-2229-14-18
PMCID: PMC3890489  PMID: 24411021
Chrysanthemum morifolium; CmPT1; Functional characterization; Complementation assay; Transgenic plants
18.  Management of Postoperative Complications Following Splenectomy 
International Surgery  2013;98(1):55-60.
Complications of post-splenectomy, especially intra-abdominal hemorrhage can be fatal, with delayed or inadequate treatment having a high mortality rate. The objective of this study was to investigate the cause, prompt diagnosis, and outcome of the fatal complications after splenectomy with a focus on early diagnosis and management of hemorrhage after splenectomy. The medical files of patients who underwent splenectomy between January 1990 and March 2011 were reviewed retrospectively. The cause, characteristics, management, and outcome in patients with post-splenectomy hemorrhage were analyzed. Fourteen of 604 patients (1.19%) undergoing splenectomy had intraperitoneal hemorrhage: reoperation was performed in 13 patients, and 3 patients died after reoperation, giving the hospital a mortality rate of 21.43%; whereas, 590 of 604 patients (98%) had no hemorrhage following splenectomy, and the mortality rate (0.34%) in this group was significantly lower (P < 0.001). The complications following splenectomy, including pneumonia pancreatitis, gastric fistula, gastric flatulence, and thrombocytosis, in patients with postoperative hemorrhage were significantly higher than those without hemorrhage (P < 0.001). According to the reasons for splenectomy, 14 patients with post-splenectomy hemorrhage were grouped into two groups: splenic trauma (n = 9, group I) and portal hypertension (n = 5, group II). The median interval between splenectomy and diagnosis of hemorrhage was 15.5 hours (range, 7.25–19.5 hours). No differences were found between groups I and II in terms of incidence of postoperative hemorrhage, time of hemorrhage after splenectomy, volume of hemorrhage, and mortality of hemorrhage, except transfusion. Intra-abdominal hemorrhage after splenectomy is associated with higher hospital mortality rate and complications. Early massive intraperitoneal hemorrhage is often preceded by earlier sentinel bleeding; careful clinical inquiry and ultrasonography are the mainstays of early diagnosis.
doi:10.9738/CC63.1
PMCID: PMC3723162  PMID: 23438277
Splenectomy; Intra-abdominal hemorrhage; Postoperative complications; Splenic trauma; Portal hypertension
19.  A novel FGFR3-binding peptide inhibits FGFR3 signaling and reverses the lethal phenotype of mice mimicking human thanatophoric dysplasia 
Human Molecular Genetics  2012;21(26):5443-5455.
Gain-of-function mutations in fibroblast growth factor receptor-3 (FGFR3) lead to several types of human skeletal dysplasia syndromes including achondroplasia, hypochondroplasia and thanatophoric dysplasia (TD). Currently, there are no effective treatments for these skeletal dysplasia diseases. In this study, we screened, using FGFR3 as a bait, a random 12-peptide phage library and obtained 23 positive clones that share identical amino acid sequences (VSPPLTLGQLLS), named as peptide P3. This peptide had high binding specificity to the extracellular domain of FGFR3. P3 inhibited tyrosine kinase activity of FGFR3 and its typical downstream molecules, extracellular signal-regulated kinase/mitogen-activated protein kinase. P3 also promoted proliferation and chondrogenic differentiation of cultured ATDC5 chondrogenic cells. In addition, P3 alleviated the bone growth retardation in bone rudiments from mice mimicking human thanatophoric dysplasia type II (TDII). Finally, P3 reversed the neonatal lethality of TDII mice. Thus, this study identifies a novel inhibitory peptide for FGFR3 signaling, which may serve as a potential therapeutic agent for the treatment of FGFR3-related skeletal dysplasia.
doi:10.1093/hmg/dds390
PMCID: PMC3657479  PMID: 23014564
20.  The Ginger-shaped Asteroid 4179 Toutatis: New Observations from a Successful Flyby of Chang'e-2 
Scientific Reports  2013;3:3411.
On 13 December 2012, Chang'e-2 conducted a successful flyby of the near-Earth asteroid 4179 Toutatis at a closest distance of 770 ± 120 meters from the asteroid's surface. The highest-resolution image, with a resolution of better than 3 meters, reveals new discoveries on the asteroid, e.g., a giant basin at the big end, a sharply perpendicular silhouette near the neck region, and direct evidence of boulders and regolith, which suggests that Toutatis may bear a rubble-pile structure. Toutatis' maximum physical length and width are (4.75 × 1.95 km) ±10%, respectively, and the direction of the +z axis is estimated to be (250 ± 5°, 63 ± 5°) with respect to the J2000 ecliptic coordinate system. The bifurcated configuration is indicative of a contact binary origin for Toutatis, which is composed of two lobes (head and body). Chang'e-2 observations have significantly improved our understanding of the characteristics, formation, and evolution of asteroids in general.
doi:10.1038/srep03411
PMCID: PMC3860288  PMID: 24336501
21.  Dispersion Estimation and Its Effect on Test Performance in RNA-seq Data Analysis: A Simulation-Based Comparison of Methods 
PLoS ONE  2013;8(12):e81415.
A central goal of RNA sequencing (RNA-seq) experiments is to detect differentially expressed genes. In the ubiquitous negative binomial model for RNA-seq data, each gene is given a dispersion parameter, and correctly estimating these dispersion parameters is vital to detecting differential expression. Since the dispersions control the variances of the gene counts, underestimation may lead to false discovery, while overestimation may lower the rate of true detection. After briefly reviewing several popular dispersion estimation methods, this article describes a simulation study that compares them in terms of point estimation and the effect on the performance of tests for differential expression. The methods that maximize the test performance are the ones that use a moderate degree of dispersion shrinkage: the DSS, Tagwise wqCML, and Tagwise APL. In practical RNA-seq data analysis, we recommend using one of these moderate-shrinkage methods with the QLShrink test in QuasiSeq R package.
doi:10.1371/journal.pone.0081415
PMCID: PMC3857202  PMID: 24349066
22.  Identification of Novel Subregions of LOH in Gastric Cancer and Analysis of the HIC1 and TOB1 Tumor Suppressor Genes in These Subregions 
Molecules and cells  2011;32(1):10.1007/s10059-011-2316-4.
Previously, we identified 3 overlapping regions showing loss of heterozygosity (LOH, R1-R3 from 11 to 30 cM) on chromosome 17 in 45 primary gastric cancers (GCs). The data indicated the presence of tumor suppressor genes (TSGs) on chromosome 17 involved in GC. Among the putative TSGs in these regions, HIC1 (in SR1) and TOB1 (in SR3) remain to be examined in GC. By immunohistochemistry (IHC), methylation-specific PCR (MSP) and western blot, we evaluated the expression and regulation status for HIC1 and TOB1 protein in GC. We narrowed down the deletion intervals on chromosome 17 and defined five smaller LOH subregions, SR1-SR5 (0.54 to 3.42 cM), in GC. We found that HIC1 had downregulated expression in 86% (91/106) and was methylated in 87% (26/30) of primary GCs. Of the primary GCs showing downregulation of HIC1 protein, 75% (18/24) had methylated HIC1 gene. TOB1 was either absent or expressed at reduced levels in 75% (73/97) of the GC samples. In addition, a general reduction was found in total and the ratio of unphosphorylated to phosphorylated TOB1 protein levels in the differentiated GC cell lines. Further analysis revealed significant simultaneous downregulation of both HIC1 and TOB1 protein in GC tissue microarray samples (67%, 52/78) and in primary GCs (65%, 11/17). These results indicate that silencing of HIC1 and TOB1 expression is a common occurrence in GC and may contribute to the development and progression of the disease.
doi:10.1007/s10059-011-2316-4
PMCID: PMC3855460  PMID: 21533545 CAMSID: cams3769
gastric cancer; HIC1; loss of heterozygosity; methylation; TOB1
23.  Nutritional assessment with different tools in leukemia patients after hematopoietic stem cell transplantation 
Objective
Correct nutritional assessment is essential for leukemia patients after hematopoietic stem cell transplantation (HSCT). This study aimed to investigate the best nutritional assessment method for leukemia patients after HSCT, and find the possible nutritional risk of the patients during the transplantation process in order to intervene in the patients with nutritional risks and undernourished patients timely, so that the entire transplantation process could be successfully completed.
Methods
A prospective study was performed in 108 leukemia patients after HSCT, and different nutritional assessment methods, including nutritional risk screening 2002 (NRS2002), mini nutritional assessment (MNA), subjective globe assessment (SGA) and malnutritional universal screening tools (MUST), were used. The associations between nutritional status of these patients and nutritional assessment methods were analyzed.
Results
A total of 108 patients completed SGA, and 99 patients completed NRS2002, MNA and MUST. During the treatment process, 85.2% of the patients lost weight, wherein, 50% lost weight greater than 5%, and 42.6% had significantly reduced food intake. For nutritional risk assessment, the positive rates of NRS2002, MNA and MUST were 100%, 74.7% and 63.6%, respectively. There was a significant difference (P<0.05) among the positive rates of NRS2002, MNA and MUST. In undernutrition assessment, the positive rate of SGA (83.3%) was significantly higher than that of MNA (17.2%) (P<0.05), and the incidence rate of nutritional risk among leukemia patients ≤30 years old was greater than that of patients >30 years old (P<0.05).
Conclusions
Patients with leukemia were in poor nutritional status during and after HSCT. The leukemia patients ≤30 years old had a greater incidence rate of nutritional risk. As nutritional risk screening tool, the specificity of NRS2002 is not high, but it can be used for evaluating nutritional deficiencies. MNA is a good nutritional risk screening tool, but not an adequate tool for nutritional assessment. If assessment of undernutrition is necessary, the combination of all these screening tools and clinical laboratory indicators should be applied to improve accuracy.
doi:10.3978/j.issn.1000-9604.2013.12.09
PMCID: PMC3872547  PMID: 24385706
Nutritional screening; hematopoietic stem cell transplantation (HSCT); leukemia; nutritional risk screening 2002 (NRS2002); mini nutritional assessment (MNA); subjective globe assessment (SGA); malnutritional universal screening tools (MUST)
24.  Expression of NF-κB, CD68 and CD105 in carotid atherosclerotic plaque 
Journal of Thoracic Disease  2013;5(6):771-776.
Atherosclerotic plaque vulnerability is associated with cerebrovascular events in patients with carotid atherosclerosis. The aim of this study was to investigate the expression of inflammatory factors in carotid artherosclerotic plaques in order to explore its clinical significance in patients with carotid stenosis. Forty three patients with carotid stenosis were divided into symptomatic group (n=24) and asymptomatic group (n=19) based on clinical manifestation. All patients were treated with selective standard carotid endarterectomy (CEA); the carotid atherosclerotic plaques were removed surgically and studied pathologically to investigate the expression of nuclear factor-kappa κ (NF-κB), CD68 and CD105. The plaques were grouped into stable and unstable plaques based on thickness of the fibrous cap and the area of lipid-rich core in the plaques. The proportion of unstable plaques were significantly higher in symptomatic group than in asymptomatic group (70.8% vs. 63.2%, P=0.026). Results of immunohistochemisty staining showed that the expression of NF-κB, CD68 and CD105 in unstable plaques was higher than stable plaques (P<0.001). The association of the higher expression of these factors with instability of carotid plaque needs to be clarified in future study.
doi:10.3978/j.issn.2072-1439.2013.12.36
PMCID: PMC3886695  PMID: 24409354
Carotid stenosis; nuclear factor-kappa κ (NF-κB); CD68; CD105; vulnerable plaque
25.  Glycerol-3-Phosphate Metabolism in Wheat Contributes to Systemic Acquired Resistance against Puccinia striiformis f. sp. tritici 
PLoS ONE  2013;8(11):e81756.
Glycerol-3-phosphate (G3P) is a proposed regulator of plant defense signaling in basal resistance and systemic acquired resistance (SAR). The GLY1-encoded glycerol-3-phosphate dehydrogenase (G3PDH) and GLI1-encoded glycerol kinase (GK) are two key enzymes involved in the G3P biosynthesis in plants. However, their physiological importance in wheat defense against pathogens remains unclear. In this study, quantification analysis revealed that G3P levels were significantly induced in wheat leaves challenged by the avirulent Puccinia striiformis f. sp. tritici (Pst) race CYR23. The transcriptional levels of TaGLY1 and TaGLI1 were likewise significantly induced by avirulent Pst infection. Furthermore, knocking down TaGLY1 and TaGLI1 individually or simultaneously with barley stripe mosaic virus-induced gene silencing (BSMV-VIGS) inhibited G3P accumulation and compromised the resistance in the wheat cultivar Suwon 11, whereas the accumulation of salicylic acid (SA) and the expression of the SA-induced marker gene TaPR1 in plant leaves were altered significantly after gene silencing. These results suggested that G3P contributes to wheat systemic acquired resistance (SAR) against stripe rust, and provided evidence that the G3P function as a signaling molecule is conserved in dicots and monocots. Meanwhile, the simultaneous co-silencing of multiple genes by the VIGS system proved to be a powerful tool for multi-gene functional analysis in plants.
doi:10.1371/journal.pone.0081756
PMCID: PMC3843702  PMID: 24312351

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