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1.  Expression of Stanniocalcin-1 and Stanniocalcin-2 in Laryngeal Squamous Cell Carcinoma and Correlations with Clinical and Pathological Parameters 
PLoS ONE  2014;9(4):e95466.
Background
Stanniocalcin-1 (STC1) and stanniocalcin-2 (STC2) are secreted glycoprotein hormones involved in various types of human malignancies. The roles of STC1 and STC2 in laryngeal squamous cell carcinoma (LSCC) remain unknown. We investigated correlations between STC1 and STC2 expression and clinicopathological or prognostic factors in LSCC.
Methods
Pre-surgical peripheral blood samples were collected between 2012 and 2013 from 62 patients with LSCC. Quantitative RT-PCR analysis was performed to examine mRNA levels of STC1 and STC2. Immunohistochemistry was performed to retrospectively analyze 90 paraffin-embedded LSCC tissue samples, which were obtained from patients who received surgery between 2006 and 2009. These patients did not have histories of treatment or malignancies. Univariate analysis of patient survival was performed by the Kaplan–Meier method. Multivariate analyses were performed with the Cox proportional hazards model.
Results
The relative mRNA levels of STC1 and STC2 in peripheral blood were significantly greater in LSCC patients than those of healthy volunteers (both P<0.05). STC2 protein expression in tumor tissues was associated with invasion into the thyroid cartilage, T-Stage, lymphatic metastasis, clinical stage, and pathological differentiation (all P<0.05). In addition, STC2 protein expression was an independent prognostic factor for overall survival in patients with LSCC (P = 0.025). In contrast, STC1 expression only correlated with clinical stage (P = 0.026) and was not an independent or significant prognostic factor.
Conclusions
Circulating STC1 and STC2 mRNA are potentially useful blood markers for LSCC. Our results strongly suggest that the STC2 protein, but not STC1, may be a valuable biomarker for LSCC malignancies and a prognostic marker for poor outcome following surgery. Future studies should examine STC2 as a novel molecular target for the treatment of LSCC.
doi:10.1371/journal.pone.0095466
PMCID: PMC3990672  PMID: 24743310
2.  Prognostic Role of microRNA-155 in Various Carcinomas: Results from a Meta-Analysis 
Disease markers  2013;34(6):379-386.
BACKGROUND: Recent studies have shown that microRNAs (miRNA) have prognostic values in cancers. This meta-analysis seeks to summarize the global predicting role of miR-155 for survival in patients with a variety of carcinomas.
METHODS: Eligible studies were identified through multiple search strategies. Data were extracted from studies investigating the relationship between miR-155 expression and survival in cancer patients. Combined hazard ratios (HRs) of miR-155 for outcome were analyzed.
RESULTS: A total of 16 studies dealing with various carcinomas were included for this meta-analysis. For overall survival, higher miR-155 expression could significantly predict worse outcome with the pooled HR of 2.057 (95% CI: 1.392–3.039). For relapse or progress-free survival, elevated miR-155 was also a significant predictor, with a combined HR of 1.918 (95% CI: 1.311–2.806,). In addition, subgroup analysis showed that higher expression of miR-155 had the trends to predict worse outcome in lung cancer. However, the HRs did not reach the statistical significance.
CONCLUSION: Our findings suggest that miR-155 detection has a prognostic value in cancer patients. Regularly measuring miR-155 expression may be useful in clinical practice.
doi:10.3233/DMA-130984
PMCID: PMC3810250  PMID: 23481631
miR-155; cancer; prognosis; clinical
3.  The Epithelial–Mesenchymal Transition Promotes Transdifferentiation of Subcutaneously Implanted Hepatic Oval Cells Into Mesenchymal Tumor Tissue 
Stem Cells and Development  2009;18(9):1293-1298.
Hepatic oval cells are thought to represent facultative hepatic epithelial stem cells in liver in which damage inhibits hepatocyte proliferation and liver regeneration. The LE/6 hepatic stem cell line was derived from the liver of male Sprague-Dawley rats fed a choline-deficient diet containing 0.1% ethionine. They are histochemically characterized by their expression of hepatocytic (hepPar1), cholangiocytic cytokeratin (CK19), hepatic progenitor cell (OV-6), and hematopoietic stem cell (c-kit) markers. In this study, we transplanted LE/6 cells by subcutaneous injection into adult female nude mice, and examined their engraftment and differentiation potential in the subcutaneous microenvironment in vivo. Our results demonstrated that following subcutaneous transplantation, differentiation of LE/6 cells into mesenchymal tumor tissue (MTT) was associated with reduced E-cadherin expression, upregulation of E-cadherin repressor molecules (Snail proteins), and increased expression of vimentin and N-cadherin, all of these events are characteristic of the epithelial–mesenchymal transition (EMT).
doi:10.1089/scd.2008.0321
PMCID: PMC3156617  PMID: 19226223
4.  Major complications after radiofrequency ablation for liver tumors: Analysis of 255 patients 
AIM: To investigate the major complications after radiofrequency ablation (RFA) for the treatment of liver tumors and analyze possible risk factors that precipitate these complications.
METHODS: From March 2001 to April 2008, 255 patients with liver tumors (205 male, 50 female; age range, 18-89 years; mean age, 56.0 years) who received RFA were enrolled in this study. Of these patients, 212 had hepatocellular carcinoma, 39 had metastatic liver tumors and four had cholangiocellular carcinoma. One hundred and forty eight patients had a single tumor, and 107 had multiple tumors. Maximum diameter of the tumors ranged 1.3-20 cm (mean, 5.1 cm). All patients were treated with a cooled-tip perfusion electrode attached to a radiofrequency generator (Radionics, Burlington, MA, USA). RFA was performed via the percutaneous approach (n = 257), laparoscopy (n = 7), or open surgical treatment (n = 86). The major complications related to RFA were recorded. The resultant data were analyzed to determine risk factors associated these complications.
RESULTS: Among the 255 patients, 425 liver tumors were treated and 350 RFA sessions were performed. Thirty-seven (10%) major complications were observed which included 13 cases of liver failure, 10 cases of hydrothorax requiring drainage, three cases of tumor seeding, one case of upper gastrointestinal bleeding, one case of intrahepatic abscess, one case of bile duct injury, one case of cardiac arrest, and five cases of hyperglycemia. Seven patients had more than two complications. Liver failure was the most severe complication and was associated with the highest mortality. Eleven patients died due to worsening liver decompensation. Child-Pugh classification (P = 0.001) and choice of approach (P = 0.045) were related to post-treatment liver failure, whereas patient age, tumor size and number were not significant factors precipitating this complication.
CONCLUSION: RFA can be accepted as a relatively safe procedure for the treatment of liver tumors. However, attention should be paid to possible complications even though the incidences of these complications are rare. Careful patient selection and the best approach choice (percutaneous, laparoscopy, or laparotomy) will help to minimize the incidence and morbidity rate of complications which occur after RFA.
doi:10.3748/wjg.15.2651
PMCID: PMC2691498  PMID: 19496197
Complication; Hepatocellular carcinoma; Metastatic liver tumor; Radiofrequency ablation; Liver failure
5.  CDH5 is specifically activated in glioblastoma stemlike cells and contributes to vasculogenic mimicry induced by hypoxia 
Neuro-Oncology  2013;15(7):865-879.
Background
A proportion of glioblastoma stemlike cells (GSCs) expressing endothelial cell marker CDH5 (vascular-endothelial–cadherin or CD144) can transdifferentiate into endothelial cells and form blood vessels. However, the implications of CDH5 expression in gliomas and how it is regulated in GSCs remain to be clarified.
Methods
The mRNA and protein levels of CDH5 were detected in glioma samples and cultured cell lines, and the prognostic value of the CDH5 expression level for GBM patients was evaluated. Bioinformatics analysis was performed to reveal the potential functional roles of CDH5 in glioblastoma multiforme. Gene knockdown induced by short hairpin RNA, chromatin immunoprecipitation analysis, and a vasculogenic tube formation assay were performed to investigate the relationships among hypoxia, CDH5 expression level, and angiogenesis.
Results
CDH5 was overexpressed in gliomas, correlated with tumor grades, and was an independent adverse prognostic predictor for glioblastoma multiforme patients. CDH5 was specifically activated in GSCs but not in non-GSCs or neural stem cells, and CDH5+ cells could produce xenografts in immunocompromised mice. Bioinformatics analysis demonstrated that CDH5 might interact directly with hypoxia-inducible factor (HIF)2α. CDH5 expression was significantly upregulated in GSCs, but not in non-GSCs or normal neural stem cells, under a 1% O2 condition. Both HIF1α and HIF2α positively regulated CDH5 level in GSCs and could bind to the promoter of CDH5. Furthermore, CDH5 contributed to the vasculogenic mimicry of GSCs, especially under hypoxic conditions.
Conclusions
The specific expression of CDH5 in GSCs may contribute to GSC-derived neovasculogenesis in glioblastoma multiforme, especially under hypoxic conditions, revealing novel tumorigenic mechanisms contributed by GSCs.
doi:10.1093/neuonc/not029
PMCID: PMC3688011  PMID: 23645533
bioinformatics; brain tumor stem cells; cancer stem cell; hypoxia; VE-cadherin
6.  Repeated restraint stress enhances cue-elicited conditioned freezing and impairs acquisition of extinction in an age-dependent manner 
Behavioural brain research  2013;248:12-24.
Affective disorders are believed to involve dysfunction within the amygdala, a key structure for processing emotional information. Chronic stress may contribute to affective disorders such as depression and anxiety via its effects on the amygdala. Previous research has shown that chronic stress increases amygdala neuronal activity in an age-dependent manner. However, whether these distinct changes in amgydala neuronal activity are accompanied by age-dependent changes in amygdala-dependent affective behavior is unclear. In this study, we investigated how chronic stress impacts amgydala-dependent auditory fear conditioning in adolescent and adult rats in a repeated restraint model. We found that repeated restraint enhanced conditioned freezing in both adolescent and adult rats. But repeated restraint led to impaired acquisition of fear extinction only in adolescent rats. Along with previous findings, these results suggest that chronic stress may precipitate affective disorders via differential mechanisms, with different outcomes at different ages.
doi:10.1016/j.bbr.2013.03.028
PMCID: PMC3677837  PMID: 23538069
fear conditioning; fear extinction; chronic stress; repeated restraint; adolescent; amygdala
7.  Granulocyte-Macrophage Colony-Stimulating Factor Auto-Antibodies: A Marker of Aggressive Crohn’s Disease 
Inflammatory bowel diseases  2013;19(8):1671-1680.
Background & Aims
Neutralizing auto-antibodies (Ab) against granulocyte-macrophage colony-stimulating factor (GM-CSF Ab) have been associated with stricturing ileal Crohn’s disease (CD) in a largely pediatric patient cohort (total 394, adult CD 57). The aim of this study was to examine this association in two independent predominantly adult inflammatory bowel disease patient cohorts.
Methods
Serum samples from 745 subjects from the NIDDK IBD Genetics Consortium and 737 patients from Australia were analyzed for GM-CSF Ab and genetic markers. We conducted multiple regression analysis with backwards elimination to assess the contribution of GM-CSF Ab levels, established CD risk alleles and smoking on ileal disease location in the 477 combined CD subjects from both cohorts. We also determined associations of GM-CSF Ab levels with complications requiring surgical intervention in combined CD subjects in both cohorts.
Results
Serum samples from CD patients expressed significantly higher concentrations of GM-CSF Ab when compared to Ulcerative Colitis or controls in each cohort. Non-smokers with ileal CD expressed significantly higher GM-CSF Ab concentrations in the Australian cohort (p= 0.002). Elevated GM-CSF Ab, ileal disease location and disease duration greater than 3 years were independently associated with stricturing/penetrating behavior and intestinal resection for CD.
Conclusions
The expression of high GM-CSF Ab is a risk marker for aggressive CD behavior and complications including surgery. Modifying factors include environmental exposure to smoking and genetic risk markers.
doi:10.1097/MIB.0b013e318281f506
PMCID: PMC3707315  PMID: 23749272
Inflammatory bowel disease; granulocyte-macrophage colony-stimulating factor antibody; Crohn’s Disease, smoking
8.  Transcriptome Analysis of Dastarcus helophoroides (Coleoptera: Bothrideridae) Using Illumina HiSeq Sequencing 
PLoS ONE  2014;9(6):e100673.
Background
Dastarcus helophoroides is known as the most valuable natural enemy insect against many large-body longhorned beetles. The molecular mechanism of its long lifespan and reproduction makes it a unique resource for genomic research. However, molecular biological studies on this parasitic beetle are scarce, and genomic information for D. helophoroides is not currently available. Thus, transcriptome information for this species is an important resource that is required for a better understanding of the molecular mechanisms of D. helophoroides. In this study, we obtained transcriptome information of D. helophoroides using high-throughput RNA sequencing.
Results
Using Illumina HiSeq 2000 sequencing, 27,543,746 clean reads corresponding to a total of 2.48 Gb nucleotides were obtained from a single run. These reads were assembled into 42,810 unigenes with a mean length of 683 bp. Using a sequence similarity search against the five public databases (NR, Swiss-Prot, GO, COG, KEGG) with a cut-off E-value of 10−5 using Blastx, a total of 31,293 unigenes were annotated with gene description, gene ontology terms, or metabolic pathways.
Conclusions
To the best of our knowledge, this is the first study on the transcriptome information of D. helophoroides. The transcriptome data presented in this study provide comprehensive information for future studies in D. helophoroides, particularly for functional genomic studies in this parasitic beetle.
doi:10.1371/journal.pone.0100673
PMCID: PMC4076278  PMID: 24979346
9.  Disorganized vascular structures in sporadic venous malformations: a possible correlation with balancing effect between Tie2 and TGF-β 
Scientific Reports  2014;4:5457.
Venous malformations (VMs) are among the most common slow-flow vascular malformations characterized by irregular venous channels, luminal thrombi, and phleboliths. To systematically manifest the disorganized vascular structures in sporadic VMs, we initially evaluated histopathological characteristics, perivascular cell coverage, adhesion molecules expression and vascular ultrastructures. Then, the expression of Tie2 and TGF-β in VMs was detected. Meanwhile, the in vitro studies were performed for mechanism investigation. Our data showed that the perivascular α-SMA+ cell coverage and expression of adhesion molecules in VMs were significantly decreased compared with those in the normal skin tissues. We also found that the expression and phosphorylation levels of Tie2 were upregulated, whereas TGF-β was downregulated in VMs, and they were negatively correlated. Moreover, the in vitro results also revealed a possible balancing effect between Tie2 and TGF-β, as demonstrated by the findings that Ang-1 (agonist of Tie2) treatment significantly downregulated TGF-β expression, and treatment with recombinant TGF-β could also suppress Tie2 expression and phosphorylation. This study provided strong evidence supporting the disorganized vascular structures and dysregulation of related molecules in sporadic VMs, and demonstrated a possible balancing effect between Tie2 and TGF-β, which might help to develop novel therapeutics for vascular disorganization-related disorders.
doi:10.1038/srep05457
PMCID: PMC4071312  PMID: 24966004
10.  Effects of Tumor Necrosis Factor-β (TNF-β) 252A>G Polymorphism on the Development of Migraine: A Meta-Analysis 
PLoS ONE  2014;9(6):e100189.
Background and Objective
Genetic factors including TNF-β have been considered as important components in the aetiology of migraine. Many studies have investigated the association between TNF-β 252A>G polymorphism and migraine risk, with debatable results. This study was designed to examine whether the TNF-β 252A>G polymorphism confers genetic susceptibility to migraine in diverse populations.
Method
Studies eligible for this meta-analysis were searched in the PubMed, Embase, and CNKI by using the keywords “tumor necrosis factor”, “TNF”, “252A>G”, “rs909253”, “polymorphism”, “polymorphisms”, “variant”, “SNP”, combined with “migraine” or “migraine with aura (MA)” or “migraine without aura (MO)”. Pooled ORs and 95% CI were appropriately calculated using the fixed-effect model.
Results
We finally included a total of seven studies, providing 5 557 migraineurs and 20 543 unrelated healthy controls. Meta-analysis results showed no statistical evidence of a significant association between TNF-β 252A>G polymorphism and overall migraine risk. Stratified analyses by type of migraine and gender revealed similar results. Interestingly, an OR with 95% CI representing an increased migraine risk was indicated in Asians under the recessive model (GG vs. AG + AA: OR, 1.38; 95%CI, 1.04–1.84; P for heterogeneity, 0.665).
Conclusions
Our findings appear to support the hypothesis that genetic variability of 252A>G polymorphism in TNF region may modulate risk of migraine in the population of Asian ancestry.
doi:10.1371/journal.pone.0100189
PMCID: PMC4069061  PMID: 24959879
11.  Analysis of the Transcriptome of Erigeron breviscapus Uncovers Putative Scutellarin and Chlorogenic Acids Biosynthetic Genes and Genetic Markers 
PLoS ONE  2014;9(6):e100357.
Background
Erigeron breviscapus (Vant.) Hand-Mazz. is a famous medicinal plant. Scutellarin and chlorogenic acids are the primary active components in this herb. However, the mechanisms of biosynthesis and regulation for scutellarin and chlorogenic acids in E. breviscapus are considerably unknown. In addition, genomic information of this herb is also unavailable.
Principal Findings
Using Illumina sequencing on GAIIx platform, a total of 64,605,972 raw sequencing reads were generated and assembled into 73,092 non-redundant unigenes. Among them, 44,855 unigenes (61.37%) were annotated in the public databases Nr, Swiss-Prot, KEGG, and COG. The transcripts encoding the known enzymes involved in flavonoids and in chlorogenic acids biosynthesis were discovered in the Illumina dataset. Three candidate cytochrome P450 genes were discovered which might encode flavone 6-hydroase converting apigenin to scutellarein. Furthermore, 4 unigenes encoding the homologues of maize P1 (R2R3-MYB transcription factors) were defined, which might regulate the biosynthesis of scutellarin. Additionally, a total of 11,077 simple sequence repeat (SSR) were identified from 9,255 unigenes. Of SSRs, tri-nucleotide motifs were the most abundant motif. Thirty-six primer pairs for SSRs were randomly selected for validation of the amplification and polymorphism. The result revealed that 34 (94.40%) primer pairs were successfully amplified and 19 (52.78%) primer pairs exhibited polymorphisms.
Conclusion
Using next generation sequencing (NGS) technology, this study firstly provides abundant genomic data for E. breviscapus. The candidate genes involved in the biosynthesis and transcriptional regulation of scutellarin and chlorogenic acids were obtained in this study. Additionally, a plenty of genetic makers were generated by identification of SSRs, which is a powerful tool for molecular breeding and genetics applications in this herb.
doi:10.1371/journal.pone.0100357
PMCID: PMC4067309  PMID: 24956277
12.  GADD45a Promoter Regulation by a Functional Genetic Variant Associated with Acute Lung Injury 
PLoS ONE  2014;9(6):e100169.
Rationale
Growth arrest DNA damage inducible alpha (GADD45a) is a stress-induced gene we have shown to participate in the pathophysiology of ventilator-induced lung injury (VILI) via regulation of mechanical stress-induced Akt ubiquitination and phosphorylation. The regulation of GADD45a expression by mechanical stress and its relationship with acute lung injury (ALI) susceptibility and severity, however, remains unknown.
Objectives
We examined mechanical stress-dependent regulatory elements (MSRE) in the GADD45a promoter and the contribution of promoter polymorphisms in GADD45a expression and ALI susceptibility.
Methods and Results
Initial studies in GADD45a knockout and heterozygous mice confirmed the relationship of GADD45a gene dose to VILI severity. Human lung endothelial cells (EC) transfected with a luciferase vector containing the full length GADD45a promoter sequence (−771 to +223) demonstrated a >4 fold increase in GADD45a expression in response to 18% cyclic stretch (CS, 4 h) compared to static controls while specific promoter regions harboring CS-dependent MSRE were identified using vectors containing serial deletion constructs of the GADD45a promoter. In silico analyses of GADD45a promoter region (−371 to −133) revealed a potential binding site for specificity protein 1 (SP1), a finding supported by confirmed SP1 binding with the GADD45a promoter and by the significant attenuation of CS-dependent GADD45a promoter activity in response to SP1 silencing. Separately, case-control association studies revealed a significant association of a GADD45a promoter SNP at −589 (rs581000, G>C) with reduced ALI susceptibility. Subsequently, we found allelic variation of this SNP is associated with both differential GADD45a expression in mechanically stressed EC (18% CS, 4 h) and differential binding site of interferon regulatory factor 7 (IRF7) at this site.
Conclusion
These results strongly support a functional role for GADD45a in ALI/VILI and identify a specific gene variant that confers risk for ALI.
doi:10.1371/journal.pone.0100169
PMCID: PMC4062486  PMID: 24940746
13.  Decreased pain threshold and enhanced synaptic transmission in the anterior cingulate cortex of experimental hypothyroidism mice 
Molecular Pain  2014;10:38.
Background
Thyroid hormones are essential for the maturation and functions of the central nervous system. Pain sensitivity is related to the thyroid status. However, information on how thyroid hormones affect pain processing and synaptic transmission in the anterior cingulate cortex (ACC) is limited. Nociceptive threshold and synaptic transmission in the ACC were detected in the experimental hypothyroidism (HT) mice.
Results
HT was induced by methimazole and potassium perchlorate in distilled drinking water for 4 weeks. The threshold of pain perception to hot insults, but not mechanical ones, decreased in hypothyroid mice. After treatment with tri-iodothyronine (T3) or thyroxine (T4) for 2 weeks, thermal pain threshold recovered. Electrophysiological recordings revealed enhanced glutamatergic synaptic transmission and reduced GABAergic synaptic transmission in the ACC. Supplementation with T3 or T4 significantly rescued this synaptic transmission imbalance. In the same model, HT caused the up-regulation of the GluR1 subunit of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor and NR2B-containing N-methyl-D-aspartate receptors, but it down-regulated γ-aminobutyric acid A receptors in the ACC. Supplementation with T3 or T4 notably recovered the levels of above proteins.
Conclusions
These results suggest that HT promotes hypersensitivity to noxious thermal, and that supplementation with T3 or T4 rescues the imbalance between excitatory and inhibitory transmission in the ACC.
doi:10.1186/1744-8069-10-38
PMCID: PMC4072477  PMID: 24943008
Thyroid hormone; Pain; Anterior cingulate cortex
14.  ABO Blood Group and Risk of Pancreatic Cancer: A Study in Shanghai and Meta-Analysis 
American Journal of Epidemiology  2013;177(12):1326-1337.
Studies over 5 decades have examined ABO blood groups and risk of pancreatic cancer in Western, Asian, and other populations, though no systematic review has been published. We studied data from 908 pancreatic cancer cases and 1,067 population controls collected during December 2006–January 2011 in urban Shanghai, China, and reviewed the literature for all studies of this association. Random-effects meta-analysis provided summary odds ratio estimates according to blood group and by populations endemic versus nonendemic for cytotoxin-associated gene A (CagA)-positive Helicobacter pylori. In our Shanghai study, versus group O, only ABO group A was associated with risk (odds ratio (OR) = 1.60, 95% confidence interval (CI): 1.27, 2.03). In 24 pooled studies, group A showed increased risk in both CagA-nonendemic and -endemic populations (ORpooled = 1.40, 95% CI: 1.32, 1.49). In nonendemic populations, groups B and AB were also associated with higher risk (OR = 1.38, 95% CI: 1.16, 1.64; and OR = 1.52, 95% CI: 1.24, 1.85, respectively). However, in CagA-endemic populations, groups B and AB were not associated with risk (OR = 1.05, 95% CI: 0.92, 1.19; and OR = 1.13, 95% CI: 0.92, 1.38, respectively). These population differences were significant. One explanation for contrasts in associations of blood groups B and AB between CagA-endemic and -nonendemic populations could involve gastric epithelial expression of A versus B antigens on colonization behaviors of CagA-positive and CagA-negative H. pylori strains.
doi:10.1093/aje/kws458
PMCID: PMC3732019  PMID: 23652164
ABO blood group system; Asia; case-control studies; meta-analysis; pancreatic neoplasms
15.  Acute administration of leptin produces anxiolytic-like effects: a comparison with fluoxetine 
Psychopharmacology  2009;207(4):535-545.
Rationale
Our previous studies in rats have shown that the adipocyte-derived hormone leptin induces antidepressant-like effects with a behavioral profile similar to selective serotonin reuptake inhibitor (SSRI) antidepressants. Acute SSRI treatment causes paradoxical anxiogenic responses, although chronic treatment has therapeutic effects on anxiety. However, the role of leptin in anxiety remains to be established.
Objectives
The scope of this study was to investigate the acute effects of leptin on anxiety-related behaviors in comparison with the SSRI antidepressant fluoxetine.
Materials and methods
Adult male C57BL/6J mice received intraperitoneal injection of leptin or fluoxetine. Thirty minutes after injection, mice were subjected to the tail suspension test (TST) and forced swim test (FST) for evaluating antidepressant activity. Anxiety-like behavior was assessed in the elevated plus maze (EPM), social interaction, and open field tests 30 min following drug treatment.
Results
While leptin and fluoxetine showed similar antidepressant-like behavioral effects in the TST and FST, they differed in the behavioral assays for anxiety. Open arm exploration in the EPM was increased by leptin but decreased by fluoxetine. Analysis of social interaction revealed that distinct social behavioral components were modulated by leptin and fluoxetine. The total time of active social behaviors was increased by leptin but reduced by fluoxetine. In addition, self-grooming, a non-social behavior, was suppressed by leptin treatment. Neither leptin nor fluoxetine produced significant effects in the open field test.
Conclusions
In contrast to anxiogenic-like effects induced by acute fluoxetine, leptin elicits anxiolytic-like effects after acute administration. These results suggest that leptin has both antidepressant-like and anxiolytic-like properties.
doi:10.1007/s00213-009-1684-3
PMCID: PMC4057895  PMID: 19823809
Leptin; Fluoxetine; Anxiety; Depression; Tail suspension; Forced swim; Elevated plus maze; Social interaction
16.  Genome Sequence of the ε-Poly-l-Lysine-Producing Strain Streptomyces albulus NK660, Isolated from Soil in Gutian, Fujian Province, China 
Genome Announcements  2014;2(3):e00532-14.
We determined the complete genome sequence of a soil bacterium, Streptomyces albulus NK660. It can produce ε-poly-l-lysine, which has antimicrobial activity against a spectrum of microorganisms. The genome of S. albulus NK660 contains a 9,360,281-bp linear chromosome and a 12,120-bp linear plasmid.
doi:10.1128/genomeA.00532-14
PMCID: PMC4056293  PMID: 24926050
17.  Age-related homeostatic mid-channel proteolysis of neuronal L-type voltage-gated Ca2+ channels 
Neuron  2014;82(5):1045-1057.
SUMMARY
Neural circuitry and brain activity depend critically on proper function of voltage-gated calcium channels (VGCCs), whose activity must be tightly controlled. We show that the main body of the pore-forming α1 subunit of neuronal L-type VGCCs, Cav1.2, is proteolytically cleaved, resulting in Cav1.2 fragment-channels that separate but remain on the plasma membrane. This “gmid-channel” proteolysis is regulated by channel activity, involves the Ca2+-dependent protease calpain and the ubiquitin-proteasome system, and causes attenuation and biophysical alterations of VGCC currents. Recombinant Cav1.2 fragment-channels mimicking the products of mid-channel proteolysis do not form active channels on their own, but when properly paired, produce currents with distinct biophysical properties. Mid-channel proteolysis increases dramatically with age and can be attenuated with an L-type VGCC blocker in vivo. Mid-channel proteolysis represents a novel form of homeostatic negative-feedback processing of VGCCs that could profoundly affect neuronal excitability, neurotransmission, neuroprotection, and calcium signaling in physiological and disease states.
doi:10.1016/j.neuron.2014.04.017
PMCID: PMC4052215  PMID: 24908485
18.  PIK3CA and TP53 Gene Mutations in Human Breast Cancer Tumors Frequently Detected by Ion Torrent DNA Sequencing 
PLoS ONE  2014;9(6):e99306.
Breast cancer is the most common malignancy and the leading cause of cancer deaths in women worldwide. While specific genetic mutations have been linked to 5–10% of breast cancer cases, other environmental and epigenetic factors influence the development and progression of the cancer. Since unique mutations patterns have been observed in individual cancer samples, identification and characterization of the distinctive breast cancer molecular profile is needed to develop more effective target therapies. Until recently, identifying genetic cancer mutations via personalized DNA sequencing was impractical and expensive. The recent technological advancements in next-generation DNA sequencing, such as the semiconductor-based Ion Torrent sequencing platform, has made DNA sequencing cost and time effective with more reliable results. Using the Ion Torrent Ampliseq Cancer Panel, we sequenced 737 loci from 45 cancer-related genes to identify genetic mutations in 105 human breast cancer samples. The sequencing analysis revealed missense mutations in PIK3CA, and TP53 genes in the breast cancer samples of various histologic types. Thus, this study demonstrates the necessity of sequencing individual human cancers in order to develop personalized drugs or combination therapies to effectively target individual, breast cancer-specific mutations.
doi:10.1371/journal.pone.0099306
PMCID: PMC4053449  PMID: 24918944
19.  Metastasis, Risk Factors and Prognostic Significance of Splenic Hilar Lymph Nodes in Gastric Adenocarcinoma 
PLoS ONE  2014;9(6):e99650.
Background
The metastatic rate and risk factors of splenic hilar (No.10) lymph nodes (LNs) in gastric adenocarcinoma were still variable and uncertain, and the prognostic significance of No.10 LNs was also controversial. The aim of this retrospective study was to analyze the metastatic rate, risk factors and prognostic significance of No.10 LNs in gastric adenocarcinoma.
Methods
From August 2007 to December 2011, 205 patients who were diagnosed with primary gastric adenocarcinoma and underwent total or proximal gastrectomy plus No.10 LNs dissection in West China Hospital were enrolled. Clinicopathological features and survival outcomes were retrospectively analyzed.
Results
Mean numbers of harvested LNs and metastatic LNs were 34.8±12.6 (15–73) and 8.7±10.8 (0–67), respectively. The proportion of cases with positive No.10 LNs was 8.8% (18/205). In all 204 dissected No.10 LNs, 47 LNs (23.0%) were metastatic. In 52.2% (107/205) patients, the dissected splenic hilar tissues were histologically determined as only fat tissues but without LNs structure. Histological evidence of LNs structure was found in 98 (47.8%) patients with 18.4% (18/98) metastatic No.10 LNs. In multivariate logistic regression analysis, metastasis of No.10 LNs was significantly correlated with No.4sa LNs (p = 0.010) and pN stage (p = 0.012). Regarding survival analysis, 199 (97.1%) patients were followed up (0.6–74.8 months). In all patients with R0 resection, metastatic No.10 LNs caused significantly worse prognosis both in Kaplan-Meier (p = 0.006) and Cox regression analysis (p = 0.031).
Conclusions
Although the metastatic rate of No.10 LNs was 8.8%, dissection of No.10 LNs might be meaningful due to the poor prognosis of positive cases. And attentions should be also paid to its correlated factors including pN stage and No.4sa LNs.
doi:10.1371/journal.pone.0099650
PMCID: PMC4051839  PMID: 24915065
20.  Hypothalamus-adipose tissue crosstalk: neuropeptide Y and the regulation of energy metabolism 
Neuropeptide Y (NPY) is an orexigenic neuropeptide that plays a role in regulating adiposity by promoting energy storage in white adipose tissue and inhibiting brown adipose tissue activation in mammals. This review describes mechanisms underlying NPY’s effects on adipose tissue energy metabolism, with an emphasis on cellular proliferation, adipogenesis, lipid deposition, and lipolysis in white adipose tissue, and brown fat activation and thermogenesis. In general, NPY promotes adipocyte differentiation and lipid accumulation, leading to energy storage in adipose tissue, with effects mediated mainly through NPY receptor sub-types 1 and 2. This review highlights hypothalamus-sympathetic nervous system-adipose tissue innervation and adipose tissue-hypothalamus feedback loops as pathways underlying these effects. Potential sources of NPY that mediate adipose effects include the bloodstream, sympathetic nerve terminals that innervate the adipose tissue, as well as adipose tissue-derived cells. Understanding the role of central vs. peripherally-derived NPY in whole-body energy balance could shed light on mechanisms underlying the pathogenesis of obesity. This information may provide some insight into searching for alternative therapeutic strategies for the treatment of obesity and associated diseases.
doi:10.1186/1743-7075-11-27
PMCID: PMC4066284  PMID: 24959194
Adipose tissue; Hypothalamus; neuropeptide Y; Obesity; Sympathetic nervous system; Thermogenesis
21.  Fucoidan Can Function as an Adjuvant In Vivo to Enhance Dendritic Cell Maturation and Function and Promote Antigen-Specific T Cell Immune Responses 
PLoS ONE  2014;9(6):e99396.
Fucoidan, a sulfated polysaccharide purified from brown algae, has a variety of immune-modulation effects, including promoting antigen uptake and enhancing anti-viral and anti-tumor effects. However, the effect of fucoidan in vivo, especially its adjuvant effect on in vivo anti-tumor immune responses, was not fully investigated. In this study, we investigated the effect of fucoidan on the function of spleen dendritic cells (DCs) and its adjuvant effect in vivo. Systemic administration of fucoidan induced up-regulation of CD40, CD80 and CD86 expression and production of IL-6, IL-12 and TNF-α in spleen cDCs. Fucoidan also promoted the generation of IFN-γ-producing Th1 and Tc1 cells in an IL-12-dependent manner. When used as an adjuvant in vivo with ovalbumin (OVA) antigen, fucoidan promoted OVA-specific antibody production and primed IFN-γ production in OVA-specific T cells. Moreover, fucoidan enhanced OVA-induced up-regulation of MHC class I and II on spleen cDCs and strongly prompted the proliferation of OVA-specific CD4 and CD8 T cells. Finally, OVA immunization with fucoidan as adjuvant protected mice from the challenge with B16-OVA tumor cells. Taken together, these results suggest that fucoidan can function as an adjuvant to induce Th1 immune response and CTL activation, which may be useful in tumor vaccine development.
doi:10.1371/journal.pone.0099396
PMCID: PMC4049775  PMID: 24911024
22.  Adherence to and effectiveness of an individually tailored home-based exercise program for frail older adults, driven by mobility monitoring: design of a prospective cohort study 
BMC Public Health  2014;14:570.
Background
With the number of older adults in society rising, frailty becomes an increasingly prevalent health condition. Regular physical activity can prevent functional decline and reduce frailty symptoms. In particular, home-based exercise programs can be beneficial in reducing frailty of older adults and fall risk, and in improving associated physiological parameters. However, adherence to home-based exercise programs is generally low among older adults. Current developments in technology can assist in enlarging adherence to home-based exercise programs. This paper presents the rationale and design of a study evaluating the adherence to and effectiveness of an individually tailored, home-based physical activity program for frail older adults driven by mobility monitoring through a necklace-worn physical activity sensor and remote feedback using a tablet PC.
Methods/design
Fifty transitionally frail community-dwelling older adults will join a 6-month home-based physical activity program in which exercises are provided in the form of exercise videos on a tablet PC and daily activity is monitored by means of a necklace-worn motion sensor. Participants exercise 5 times a week. Exercises are built up in levels and are individually tailored in consultation with a coach through weekly telephone contact.
Discussion
The physical activity program driven by mobility monitoring through a necklace-worn sensor and remote feedback using a tablet PC is an innovative method for physical activity stimulation in frail older adults. We hypothesize that, if participants are sufficiently adherent, the program will result in higher daily physical activity and higher strength and balance assessed by physical tests compared to baseline. If adherence to and effectiveness of the program is considered sufficient, the next step would be to evaluate the effectiveness with a randomised controlled trial. The knowledge gained in this study can be used to develop and fine-tune the application of innovative technology in home-based exercise programs.
Trial registration
Nederlands Trial Register (NTR); trial number 4265. The study was prospectively registered (registration date 14/11/2013).
doi:10.1186/1471-2458-14-570
PMCID: PMC4066276  PMID: 24908049
Home-based physical activity program; Remote coaching; Daily activity; Objective measurement; Frail older adults
23.  Expression Pattern of Long Non-Coding RNAs in Renal Cell Carcinoma Revealed by Microarray 
PLoS ONE  2014;9(6):e99372.
Background
Recent large-scale transcriptome analyses have found large numbers of transcripts, including that of long non-coding RNAs (lncRNAs), which are aberrant in various diseases, especially cancers. However, it is not clear whether lncRNAs are involved specifically in renal cell carcinoma (RCC). We investigated the expression patterns of lncRNAs in five RCC tumor samples (T) relative to those of matched adjacent non-tumor tissues (N) via microarray.
Methods
A microarray with 33,045 lncRNA probes and 30,215 mRNA probes was used to identify deregulated lncRNAs in five RCC patients. Furthermore, we confirmed the relative expression levels of AK096725 and ENST00000453068 in 70 paired samples by quantitative reverse transcription polymerase chain reaction (qRT-PCR).
Results
The lncRNA microarray revealed 27,279 lncRNAs in RCC samples, of which 480 were significantly upregulated (P<0.05; T/N>1.5) and 417 were significantly downregulated (P<0.05; N/T>1.5) compared with the matched non-tumor samples. In addition, 19,995 mRNAs were detected, of which 458 were significantly upregulated (P<0.05; T/N>1.5) and 413 were significantly downregulated (P<0.05; N/T>1.5). The expression level changes of AK096725 (P = 0.043) and ENST00000453068 (P<0.001) in 70 paired samples were in accord with the microarray data.
Conclusions
The study uncovered expression patterns of lncRNAs in 5 RCC patients, as well as a number of aberrant lncRNAs and mRNAs in tumor samples compared with the non-tumor tissues. The revelation of an association between AK096725 expression and RCC is especially noteworthy. These findings may help to find new biomarkers in RCC.
doi:10.1371/journal.pone.0099372
PMCID: PMC4048223  PMID: 24905231
24.  Structure-Function Relationship of SW-AT-1, a Serpin-Type Protease Inhibitor in Silkworm 
PLoS ONE  2014;9(6):e99013.
Although SW-AT-1, a serpin-type trypsin inhibitor from silkworm (Bombyx mori), was identified in previous study, its structure-function relationship has not been studied. In this study, SW-AT-1 was cloned from the body wall of silkworm and expressed in E. coli. rSW-AT-1 inhibited both trypsin and chymotrypsin in a concentration-dependent manner. The association rate constant for rSW-AT-1 and trypsin is 1.31×10−5 M−1s−1, for rSW-AT-1 and chymotrpsin is 2.85×10−6 M−1s−1. Circular dichroism (CD) assay showed 33% α-helices, 16% β-sheets, 17% turns, and 31% random coils in the secondary structure of the protein. Enzymatic and CD analysis indicated that rSW-AT-1 was stable at wide pH range between 4–10, and exhibited the highest activity at weakly acidic or alkaline condition. The predicted three-dimensional structure of SW-AT-1 by PyMOL (v1.4) revealed a deductive reactive centre loop (RCL) near the C-terminus, which was extended from the body of the molecule. In addition to trypsin cleavage site in RCL, matrix-assisted laser desorption ionization time of flight mass spectrometry indicated that the chymotrypsin cleavage site of SW-AT-1 was between F336 and T337 in RCL. Directed mutagenesis indicated that both the N- and C-terminal sides of RCL have effects on the activity, and G327 and E329 played an important role in the proper folding of RCL. The physiological role of SW-AT-1 in the defense responses of silkworm were also discussed.
doi:10.1371/journal.pone.0099013
PMCID: PMC4047069  PMID: 24901510
25.  Identification of Maize Long Non-Coding RNAs Responsive to Drought Stress 
PLoS ONE  2014;9(6):e98958.
Long non-coding RNAs (lncRNAs) represent a class of riboregulators that either directly act in long form or are processed to shorter miRNAs and siRNAs. Emerging evidence shows that lncRNAs participate in stress responsive regulation. In this study, to identify the putative maize lncRNAs responsive to drought stress, 8449 drought responsive transcripts were first uploaded to the Coding Potential Calculator website for classification as protein coding or non-coding RNAs, and 1724 RNAs were identified as potential non-coding RNAs. A Perl script was written to screen these 1724 ncRNAs and 664 transcripts were ultimately identified as drought-responsive lncRNAs. Of these 664 transcripts, 126 drought-responsive lncRNAs were highly similar to known maize lncRNAs; the remaining 538 transcripts were considered as novel lncRNAs. Among the 664 lncRNAs identified as drought responsive, 567 were upregulated and 97 were downregulated in drought-stressed leaves of maize. 8 lncRNAs were identified as miRNA precursor lncRNAs, 62 were classified as both shRNA and siRNA precursors, and 279 were classified as siRNA precursors. The remaining 315 lncRNAs were classified as other lncRNAs that are likely to function as longer molecules. Among these 315 lncRNAs, 10 are identified as antisense lncRNAs and 7 could pair with 17 CDS sequences with near-perfect matches. Finally, RT-qPCR results confirmed that all selected lncRNAs could respond to drought stress. These findings extend the current view on lncRNAs as ubiquitous regulators under stress conditions.
doi:10.1371/journal.pone.0098958
PMCID: PMC4044008  PMID: 24892290

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