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1.  Association of interferon regulatory factor 4 gene polymorphisms rs12203592 and rs872071 with skin cancer and haematological malignancies susceptibility: a meta-analysis of 19 case–control studies 
BMC Cancer  2014;14:410.
Background
Research has indicated that the rs12203592 and rs872071 interferon regulatory factor 4 (IRF4) gene polymorphisms correlate with the risk of cancer, especially skin cancer and haematological malignancies, but the results remain controversial. To understand better the effects of these two polymorphisms on skin cancer and haematological malignancies susceptibility, a cumulative meta-analysis was performed.
Methods
We conducted a search using the PubMed and Web of Science databases for relevant case-control studies published before April 2014. Summary odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated using fixed- or random-effects models where appropriate. Heterogeneity test, publication bias test, and sensitivity analysis were also performed.
Results
In total, 11 articles comprised of 19 case–control studies were identified; five focused on the rs12203592 polymorphism with 7,992 cases and 8,849 controls, and six were on the rs872071 polymorphism with 3108 cases and 8300 controls. As for rs12203592, a significant correlation with overall skin cancer and haematological malignancies risk was found with the homozygote comparison model (OR = 1.566, 95% CI 1.087-2.256) and recessive model (OR = 1.526, 95% CI 1.107-2.104). For rs872071, a significantly elevated haematological malignancies risk was observed in all genetic models (homozygote comparison: OR = 1.805, 95% CI 1.402-2.323; heterozygote comparison: OR = 1.427, 95% CI 1.203-1.692; dominant: OR = 1.556, 95% CI 1.281-1.891; recessive: OR = 1.432, 95% CI 1.293-1.587; additive: OR = 1.349, 95% CI 1.201-1.515). Similarly, increased skin cancer and haematological malignancies risk was also identified after stratification of the SNP data by cancer type, ethnicity and source of controls for both polymorphisms.
Conclusions
Our meta-analysis indicated that the rs12203592 and rs872071 IRF4 gene polymorphisms are associated with individual susceptibility to skin cancer and haematological malignancies. Moreover, the effect of the rs12203592 polymorphism on skin cancer risk was particularly prominent among Caucasians. Further functional research should be performed to validate the association.
doi:10.1186/1471-2407-14-410
PMCID: PMC4059085  PMID: 24906573
Meta-analysis; IRF4; Interferon regulatory factor 4; Polymorphisms; rs12203592; rs872071; Cancer risk
2.  A pH and Redox Dual Responsive 4-Arm Poly(ethylene glycol)-block-poly(disulfide histamine) Copolymer for Non-Viral Gene Transfection in Vitro and in Vivo 
A novel 4-arm poly(ethylene glycol)-b-poly(disulfide histamine) copolymer was synthesized by Michael addition reaction of poly(ethylene glycol) (PEG) vinyl sulfone and amine-capped poly(disulfide histamine) oligomer, being denoted as 4-arm PEG-SSPHIS. This copolymer was able to condense DNA into nanoscale polyplexes (<200 nm in average diameter) with almost neutral surface charge (+(5–10) mV). Besides, these polyplexes were colloidal stable within 4 h in HEPES buffer saline at pH 7.4 (physiological environment), but rapidly dissociated to liberate DNA in the presence of 10 mM glutathione (intracellular reducing environment). The polyplexes also revealed pH-responsive surface charges which markedly increased with reducing pH values from 7.4–6.3 (tumor microenvironment). In vitro transfection experiments showed that polyplexes of 4-arm PEG-SSPHIS were capable of exerting enhanced transfection efficacy in MCF-7 and HepG2 cancer cells under acidic conditions (pH 6.3–7.0). Moreover, intravenous administration of the polyplexes to nude mice bearing HepG2-tumor yielded high transgene expression largely in tumor rather other normal organs. Importantly, this copolymer and its polyplexes had low cytotoxicity against the cells in vitro and caused no death of the mice. The results of this study indicate that 4-arm PEG-SSPHIS has high potential as a dual responsive gene delivery vector for cancer gene therapy.
doi:10.3390/ijms15059067
PMCID: PMC4057775  PMID: 24853287
poly(disulfide histamine); pH targeting; gene delivery; pH-responsive; cancer cells
3.  ‘Druggable’ alterations detected by Ion Torrent in metastatic colorectal cancer patients 
Oncology Letters  2014;7(6):1761-1766.
The frequency and poor prognosis of patients with metastatic colorectal cancer (mCRC) emphasizes the requirement for improved biomarkers for use in the treatment and prognosis of mCRC. In the present study, somatic variants in exonic regions of key cancer genes were identified in mCRC patients. Formalin-fixed, paraffin-embedded tissues obtained by biopsy of the metastases of mCRC patients were collected, and the DNA was extracted and sequenced using the Ion Torrent Personal Genome Machine. For the targeted amplification of known cancer genes, the Ion AmpliSeq™ Cancer Panel, which is designed to detect 739 Catalogue of Somatic Mutations in Cancer (COSMIC) mutations in 604 loci from 46 oncogenes and tumor suppressor genes using as little as 10 ng of input DNA, was used. The sequencing results were then analyzed using the Ampliseq™ Variant Caller plug-in within the Ion Torrent Suite software. In addition, Ingenuity Pathway software was used to perform a pathway analysis. The Cox regression analysis was also conducted to investigate the potential correlation between alteration numbers and clinical factors, including response rate, disease-free survival and overall survival. Among 10 specimens, 65 genetic alterations were identified in 24 genes following the exclusion of germline mutations using the SNP database, whereby 41% of the alterations were also present in the COSMIC database. No clinical factors were found to significantly correlate with the alteration numbers in the patients by statistical analysis. However, pathway analysis identified ‘colorectal cancer metastasis signaling’ as the most commonly mutated canonical pathway. This analysis further revealed mutated genes in the Wnt, phosphoinositide 3-kinase (PI3K)/AKT and transforming growth factor (TGF)-β/SMAD signaling pathways. Notably, 11 genes, including the expected APC, BRAF, KRAS, PIK3CA and TP53 genes, were mutated in at least two samples. Notably, 90% (9/10) of mCRC patients harbored at least one ‘druggable’ alteration (range, 1–6 alterations) that has been linked to a clinical treatment option or is currently being investigated in clinical trials of novel targeted therapies. These results indicated that DNA sequencing of key oncogenes and tumor suppressors enables the identification of ‘druggable’ alterations for individual colorectal cancer patients.
doi:10.3892/ol.2014.2047
PMCID: PMC4049685  PMID: 24932229
druggable alterations; Ion Torrrent; metastasic colorectal cancer; formalin-fixed paraffin-embedded
4.  Autologous Tumor Lysate-Pulsed Dendritic Cell Immunotherapy with Cytokine-Induced Killer Cells Improves Survival in Gastric and Colorectal Cancer Patients 
PLoS ONE  2014;9(4):e93886.
Gastric and colorectal cancers (GC and CRC) have poor prognosis and are resistant to chemo- and/or radiotherapy. In the present study, the prophylactic effects of dendritic cell (DC) vaccination are evaluated on disease progression and clinical benefits in a group of 54 GC and CRC patients treated with DC immunotherapy combined with cytokine-induced killer (CIK) cells after surgery with or without chemo-radiotherapy. DCs were prepared from the mononuclear cells isolated from patients using IL-2/GM-CSF and loaded with tumor antigens; CIK cells were prepared by incubating peripheral blood lymphocytes with IL-2, IFN-γ, and CD3 antibodies. The DC/CIK therapy started 3 days after low-dose chemotherapy and was repeated 3–5 times in 2 weeks as one cycle with a total of 188.3±79.8×106 DCs and 58.8±22.3×108 CIK cells. Cytokine levels in patients' sera before and after treatments were measured and the follow-up was conducted for 98 months to determine disease-free survival (DFS) and overall survival (OS). The results demonstrate that all cytokines tested were elevated with significantly higher levels of IFN-γ and IL-12 in both GC and CRC cohorts of DC/CIK treated patients. By Cox regression analysis, DC/CIK therapy reduced the risk of post-operative disease progression (p<0.01) with an increased OS (<0.01). These results demonstrate that in addition to chemo- and/or radiotherapy, DC/CIK immunotherapy is a potential effective approach in the control of tumor growth for post-operative GC and CRC patients.
doi:10.1371/journal.pone.0093886
PMCID: PMC3974849  PMID: 24699863
5.  Cross-sectional study of the relationship of peripheral blood cell profiles with severity of infection by adenovirus type 55 
BMC Infectious Diseases  2014;14:147.
Background
The immunologic profiles of patients with human adenovirus serotype 55 (HAdV-55) infections were characterized in subjects diagnosed with silent infections (n = 30), minor infections (n = 27), severe infections (n = 34), and healthy controls (n = 30) during a recent outbreak among Chinese military trainees.
Methods
Blood was sampled at the disease peak and four weeks later, and samples were analyzed to measure changes in leukocyte and platelet profiles in patients with different severities of disease. Differential lymphocyte subsets and cytokine profiles were measured by flow cytometry and Luminex xMAP®, and serum antibodies were analyzed by ELISA and immunofluorescence staining.
Results
Patients with severe HAdV infections had higher proportions of neutrophils and reduced levels of lymphocytes (p < 0.005 for both). Patients with minor and severe infections had significantly lower platelet counts (p < 0.005 for both) than those with silent infections. The silent and minor infection groups had higher levels of dendritic cells than the severe infection group. Relative to patients with silent infections, patients with severe infections had significantly higher levels of IL-17+CD4+ cells, decreased levels of IL-17+CD8+ cells, and higher levels of IFN-γ, IL-4, IL-10, and IFN-α2 (p < 0.001 for all comparisons).
Conclusions
Patients with different severities of disease due to HAdV-55 infection had significantly different immune responses. These data provide an initial step toward the identification of patients at risk for more severe disease and the development of treatments against HAdV-55 infection.
doi:10.1186/1471-2334-14-147
PMCID: PMC4000060  PMID: 24646014
Infectious diseases; Adenovirus; Immunopathology; Outbreak
6.  Construction of Recombinant Marek's Disease Virus (rMDV) Co-Expressing AIV-H9N2-NA and NDV-F Genes under Control of MDV's Own Bi-Directional Promoter 
PLoS ONE  2014;9(3):e90677.
To qualitatively analyze and evaluate a bi-directional promoter transcriptional function in both transient and transgenic systems, several different plasmids were constructed and recombinant MDV type 1 strain GX0101 was developed to co-express a Neuraminidase (NA) gene from Avian Influenza Virus H9N2 strain and a Fusion (F) gene from the Newcastle disease virus (NDV). The two foreign genes, NDV-F gene and AIV-NA gene, were inserted in the plasmid driven in each direction by the bi-directional promoter. To test whether the expression of pp38/pp24 heterodimers are the required activators for the expression of the foreign genes, the recombinant plasmid pPpp38-NA/1.8kb-F containing expression cassette for the two foreign genes was co-transfected with a pp38/pp24 expression plasmid, pBud-pp38-pp24, in chicken embryo fibroblast (CEF) cells. Alternatively, plasmid pPpp38-NA/1.8kb-F was transfected in GX0101-infected CEFs where the viral endogenous pp38/pp24 were expressed via virus infection. The expression of both foreign genes was activated by pp38/pp24 dimers either via virus infection, or co-expression. The CEFs transfected with pPpp38-NA/1.8kb-F alone had no expression. We chose to insert the expression cassette of Ppp38-NA/1.8kb-F in the non-essential region of GX0101ΔMeq US2 gene, and formed a new rMDV named MZC13NA/F through homologous recombination. Indirect fluorescence antibody (IFA) test, ELISA and Western blot analyses indicated that F and NA genes were expressed simultaneously under control of the bi-directional promoter, but in opposite directions. The data also indicated the activity of the promoter in the 1.8-kb mRNA transcript direction was higher than that in the direction for the pp38 gene. The expression of pp38/pp24 dimers either via co-tranfection of the pBud-pp38-pp24 plasmid, or by GX0101 virus infection were critical to activate the bi-directional promoter for expression of two foreign genes in both directions. Therefore, the confirmed function of the bi-directional promoter provides better feasibilities to insert multiple foreign genes in MDV genome based vectors.
doi:10.1371/journal.pone.0090677
PMCID: PMC3944216  PMID: 24599338
7.  Limitations of the BP26 Protein-Based Indirect Enzyme-Linked Immunosorbent Assay for Diagnosis of Brucellosis 
Brucellosis is a serious zoonosis that occurs worldwide, and its diagnosis is typically based on the detection of antibodies against Brucella lipopolysaccharide (LPS). However, the specificity of the LPS-based test is compromised by cross-reactivity with Escherichia coli O157:H7 and Yersinia enterocolitica O:9. Also, diagnosis based on the LPS test cannot differentiate between vaccinated and infected individuals. The detection of the 26-kDa cytosoluble protein (BP26) antibody is considered an alternative that circumvents these drawbacks because it is exclusively expressed by infectious Brucella. A BP26-based enzyme-linked immunosorbent assay (ELISA) has been tried for the diagnosis of Brucella-infected animals and humans, but a few results showed that BP26 couldn't react with all Brucella-positive sera. In order to explore whether different animals could produce antibodies against BP26 after being infected with various Brucella species, we infected sheep, goats, and beef cattle with common virulent reference Brucella species. All sera were collected from the experimental animals and tested using both LPS-based ELISAs and BP26-based ELISAs. The results showed that all Brucella-infected individuals could produce high levels of antibodies against LPS, but only B. melitensis 16M- and B. melitensis M28-infected sheep and B. melitensis 16M- and B. abortus 2308-infected goats could produce antibodies against BP26. Therefore, we concluded that the BP26-based indirect ELISA (i-ELISA) showed both Brucella species and host specificity, which obviously limits its reliability as a substitute for the traditional LPS-based ELISA for the detection of brucellosis.
doi:10.1128/CVI.00052-13
PMCID: PMC3889589  PMID: 23863503
8.  Prognostic Value of Perineural Invasion in Gastric Cancer: A Systematic Review and Meta-Analysis 
PLoS ONE  2014;9(2):e88907.
Background
The prognostic role of perineural invasion in gastric cancer is controversial. Here, we present a systemic review and meta-analysis of the association between perineural invasion and survival in resectable gastric cancer patients.
Methods
A comprehensive literature search for relevant reports published up to April 2013 was performed using PubMed, Embase, Web of Science and Wanfang Data. Studies that investigated the role of perineural invasion with a sample size greater than 100 were included and analyzed.
Results
A total of 30,590 gastric cancer patients who had undergone curative gastrectomy from twenty-four studies were included. The median rate of perineural invasion positive was 40.9% (6.8%–75.6%). Fourteen studies investigated overall survival unadjusted for other variables in 23,233 gastric cancer patients. The relative hazard estimates ranged from 0.568–7.901 with a combined random effects estimate of 2.261 (95% CI = 1.841–2.777, P = 0.000). The effect of perineural invasion on overall survival adjusted for other prognostic factors was reported in 17 studies incorporating 8,551 cases. The hazard estimates ranged from 0.420–8.110 with a pooled random effects estimates of 1.484 (95% CI = 1.237–1.781, P = 0.000). There was heterogeneity between the studies (Q = 49.22, I-squared = 67.5%, P = 0.000). Disease-free survival was investigated adjusted in four studies incorporating 9,083 cases and the pooled fixed hazard ratio estimate was 1.371(95% CI = 1.230–1.527, P = 0.000).
Conclusion
Perineural invasion is an independent prognostic factor affecting overall survival and disease-free survival of gastric cancer patients who had undergone the curative resection. This effect is independent of lymph node status, tumor size and the depth of invasion as well as a range of other biological variables on multivariate analysis. Large prospective studies are now needed to establish perineural invasion as an independent prognostic marker for gastric cancer.
doi:10.1371/journal.pone.0088907
PMCID: PMC3931634  PMID: 24586437
9.  Association between CTLA-4 60G/A and -1661A/G Polymorphisms and the Risk of Cancers: A Meta-Analysis 
PLoS ONE  2013;8(12):e83710.
Purpose
CTLA-4 is one of the most fundamental immunosuppressive cotykines which belongs to the immunoglobulin super-family, and is expressed mainly on activated T cells. Previous studies have reported the existence of CTLA4 60G/A and CTLA4 -1661A/G polymorphism in cancers. However, the effects remain conflicting. Hence, we performed a meta-analysis to investigate the association between these polymorphisms and cancer risk.
Methods
We searched the Pubmed and Web of Science databases until October 24, 2013 to obtain relevant published studies. Pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) for the relationship between CTLA4 gene polymorphisms and cancer susceptibility were calculated by stata 11 software. Heterogeneity tests, sensitivity analyses and publication bias assessments were also performed in our meta-analysis.
Results
A total of 22 articles comprising 31 case-control studies concerning the CTLA-4 60G/A and CTLA-4 -1661A/G polymorphisms were included in the meta-analysis. The pooled results suggested the CTLA-4 60G/A polymorphism was significantly associated with an increased skin cancer risk (AA vs. GG: OR = 1.32, 95%CI = 1.09-1.59; AA vs. GA+GG: OR = 1.26, 95%CI = 1.07-1.48). For CTLA-4 -1661 A/G polymorphism, the results showed that the CTLA-4 -1661A/G polymorphism was significantly associated with an increased cancer risk (GA vs. AA: OR = 1.44, 95%CI = 1.13–1.82; GA+GG vs. AA: OR = 1.35, 95%CI = 1.07–1.69; G vs. A: OR = 1.21, 95%CI = 1.01–1.47), especially in gastric cancer, breast cancer, other cancers and in Asians population subgroups.
Conclusion
Our meta-analysis suggests that the CTLA-4 -1661A/G polymorphism is a potential factor for the susceptibility of cancer, especially in gastric cancer, breast cancer and other cancers, and the CTLA-4 60G/A polymorphism is significantly associated with increased skin cancer risk. The effect of the CTLA-4 -1661A/G polymorphism on cancer susceptibility especially exists in Asians and population based subjects.
doi:10.1371/journal.pone.0083710
PMCID: PMC3871533  PMID: 24376736
10.  C-reactive protein as a prognostic marker in chronic obstructive pulmonary disease 
The present study aimed to evaluate whether circulating C-reactive protein (CRP) levels are a biomarker of systemic inflammation and a significant predictor of future chronic obstructive pulmonary disease (COPD) outcome. During the study, 116 patients with stable COPD and 35 age- and gender-matched healthy subjects with normal pulmonary function were observed. Patient follow-up was also performed to evaluate the strength of the associations between CRP levels and future outcomes. The observations from the present study showed that serum CRP levels were significantly higher in stable COPD patients than in control subjects (4.48±0.83 vs. 1.01±0.27 mg/l, respectively; P<0.05). In addition, it was identified that a serum CRP concentration of >3 mg/l is a poor prognostic variable of COPD compared with a CRP concentration of ≤3 mg/l [hazard ratio (HR), 2.71; 95% confidence interval (CI), 1.05–6.99; P<0.05]. A quantitative synthesis of four studies including 1,750 COPD patients was performed and statistically similar results were obtained (HR, 1.54; 95% CI, 1.14–2.07; P<0.01). The present study showed that circulating CRP levels are higher in stable COPD patients and, therefore, may be used as a long-term predictor of future outcomes. These observations highlight the importance of high sensitivity CRP assays in patients with stable COPD.
doi:10.3892/etm.2013.1441
PMCID: PMC3881036  PMID: 24396422
C-reactive protein; chronic obstructive pulmonary disease; survival
11.  Association between Variants of the Autophagy Related Gene – IRGM and Susceptibility to Crohn’s Disease and Ulcerative Colitis: A Meta-Analysis 
PLoS ONE  2013;8(11):e80602.
Background
Polymorphisms in immunity-related GTPase family M (IRGM) gene may be associated with inflammatory bowel disease (IBD) by affecting autophagy. However, the genetic association studies on three common variants in IRGM gene (rs13361189, rs4958847 and rs10065172) have shown inconsistent results.
Methodology/ Principal Findings
The PubMed and Embase were searched up to June 5, 2013 for studies on the association between three IRGM polymorphisms and IBD risk. Data were extracted and the odd ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. Finally, we performed a meta-analysis of 25 eligible studies in 3 SNPs located at IRGM gene by using a total of 20590 IBD cases and 27670 controls. The analysis showed modest significant association for the rs13361189, rs4958847 and rs10065172 variants in Crohn’s disease (CD): the risk estimates for the allele contrast were OR=1.306 (1.200-1.420), p=5.2×10-10, OR=1.182 (1.082-1.290), p=0.0002, and OR=1.248 (1.057-1.473), p=0.009 respectively (still significant when the p value was Bonferroni adjusted to 0.017). When stratified by ethnicity, significantly increased CD risk was observed in Europeans, but not in Asians. Conversely, there was no association of rs13361189 or rs4958847 variant with risk of ulcerative colitis (UC).
Conclusions/ Significance
These results indicated that autophagy gene-IRGM polymorphisms appear to confer susceptibility to CD but not UC, especially in Europeans. Our data may provide further understanding of the role of autophagy in the pathogenesis of CD.
doi:10.1371/journal.pone.0080602
PMCID: PMC3827440  PMID: 24232856
12.  Roles of JnRAP2.6-like from the Transition Zone of Black Walnut in Hormone Signaling  
PLoS ONE  2013;8(11):e75857.
An EST sequence, designated JnRAP2-like, was isolated from tissue at the heartwood/sapwood transition zone (TZ) in black walnut (Juglans nigra L). The deduced amino acid sequence of JnRAP2-like protein consists of a single AP2-containing domain with significant similarity to conserved AP2/ERF DNA-binding domains in other species. Based on multiple sequence alignment, JnRAP2-like appears to be an ortholog of RAP2.6L (At5g13330), which encodes an ethylene response element binding protein in Arabidopsis thaliana. Real-time PCR revealed that the JnRAP2-like was expressed most abundantly in TZ of trees harvested in fall when compared with other xylem tissues harvested in the fall or summer. Independent transgenic lines over-expressing JnRAP2-like in Arabidopsis developed dramatic ethylene-related phenotypes when treated with 50 µM methyl jasmonate (MeJA). Taken together, these results indicated that JnRAP2-like may participate in the integration of ethylene and jasmonate signals in the xylem and other tissues. Given the role of ethylene in heartwood formation, it is possible JnRAP2-like expression in the transition zone is part of the signal transduction pathway leading to heartwood formation in black walnut.
doi:10.1371/journal.pone.0075857
PMCID: PMC3827044  PMID: 24265672
13.  Effects of integrin-targeted photodynamic therapy on pancreatic carcinoma cell 
AIM: To investigate the effects of photodynamic therapy with quantum dots-arginine-glycine-aspartic acid (RGD) probe as photosensitizer on the proliferation and apoptosis of pancreatic carcinoma cells.
METHODS: Construction of quantum dots-RGD probe as photosensitizer for integrin-targeted photodynamic therapy was accomplished. After cells were treated with photodynamic therapy (PDT), the proliferation of SW1990 cells were measured by methyl thiazolyl tetrazolium assay. Morphologic changes, cell cycle retardance and apoptosis were observed under fluoroscope and flow cytometry. The expression of myeloid cell leukemia-1 (Mcl-1), protein kinase B (Akt) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) mRNA were detected by reverse transcription-polymerase chain reaction. The amount of reactive oxygen species were also evaluated by fluorescence probe.
RESULTS: The photodynamic therapy with quantum dots-RGD probe as photosensitizer significantly inhibited cell proliferation (P < 0.01). Apoptotic cells and morphologic changes could be found under optical microscope. The FCM revealed PDT group had more significant cell apoptosis rate compared to control cells (F = 130.617, P < 0.01) and cell cycle G0/G1 and S retardance (P < 0.05) compared to control cells. The expression of Mcl-1 and Akt mRNA were down-regulated, while expression of TRAIL mRNA was up-regulated after cells treated with PDT. PDT group had more significant number of cells producing reactive oxygen species compared to control cells (F = 3262.559, P < 0.01).
CONCLUSION: The photodynamic therapy with quantum dots-RGD probe as photosensitizer significantly inhibits cell proliferation and increases apoptosis in SW1990 cells.
doi:10.3748/wjg.v19.i39.6559
PMCID: PMC3801369  PMID: 24151382
Pancreatic carcinoma; Targeted probe; Photodynamic therapy; Apoptosis; Reactive oxygen species
14.  Inflammatory Regulation by TLR3 in Acute Hepatitis1 
TLR3 is known to respond to dsRNA from viruses, apoptotic cells, and/or necrotic cells. Dying cells are a rich source of ligands that can activate TLRs, such as TLR3. TLR3 expressed in the liver is likely to be a mediator of innate activation and inflammation in the liver. The importance of this function of TLR3 during acute hepatitis has not previously been fully explored. We used the mouse model of Con A-induced hepatitis and observed a novel role for TLR3 in hepatocyte damage in the absence of an exogenous viral stimulus. Interestingly, TLR3 expression in liver mononuclear cells and sinus endothelial cells was up-regulated after Con A injection and TLR3−/− mice were protected from Con A-induced hepatitis. Moreover, splenocytes from TLR3−/− mice proliferated less to Con A stimulation in the presence of RNA derived from damaged liver tissue compared with wild-type (WT) mice. To determine the relative contribution of TLR3 expression by hematopoietic cells or nonhematopoietic to liver damage during Con A-induced hepatitis, we generated bone marrow chimeric mice. TLR3−/− mice engrafted with WT hematopoietic cells were protected in a similar manner to WT mice reconstituted with TLR3−/− bone marrow, indicating that TLR3 signaling in both nonhematopoietic and hematopoietic cells plays an important role in mediating liver damage. In summary, our data suggest that TLR3 signaling is necessary for Con A-induced liver damage in vivo and that TLR3 regulates inflammation and the adaptive T cell immune response in the absence of viral infection.
doi:10.4049/jimmunol.0901221
PMCID: PMC3787866  PMID: 19710451
15.  Botulinum Toxin Type A Therapy in Migraine: Preclinical and Clinical Trials 
Background
Botulinum toxin type A (BTX-A) has been reported to be effective for the therapy for migraine. The purpose of this study was to investigate the effect of BTX-A on the immunoreactive levels of calcitonin gene-related peptide (CGRP) and substance P (SP) in the jugular plasma and medulla oblongata of migraine in rats induced by nitroglycerin (NTG), and then to evaluate and compare the effectiveness of fixed (muscle)-sites and acupoint-sites injection of BTX-A for migraine therapy of patients in a randomly controlled trial extending over four months.
Materials and Methods
Rats with NTG-induced migraine were subcutaneously injected with vehicle or BTX-A (5 U/kg or 10 U/kg bodyweight). CGRP- and SP-like immunoreactivity (CGRP-LI and SP-LI) were determined by radioimmunoassay. In clinical trials, sixty patients respectively received BTX-A (2.5 U each site, 25 U per patient) at fixed-sites (group F, n = 30) including occipitofrontalis, corrugator supercili, temporalis and trapezius or at acupoint-sites (group A, n = 30) including EX-HN3, EX-HN5, GV20, GB8, GB20 and BL10.
Results
Local BTX-A injection suppressed NTG-induced CGRP-LI and SP-LI levels in jugular plasma and oblongata. BTX-A injection for both groups with migraine significantly reduced the attack frequency, intensity, duration and associated symptoms. The efficacy of BTX-A for migraine in group A (93% improvement) was more significant than that in group F (83% improvement) (P < 0.01).
Conclusions
The evidence that BTX-A decreases NTG-induced CGRP-LI and SP-LI levels in trigeminovascular system suggests that BTX-A attenuates migraine by suppression of neuropeptide release. BTX-A injections for migraine at acupoint-sites and fixed-sites are effective. Acupoint-sites BTX-A administration shows more efficacy for migraine than fixed-sites application.
doi:10.5812/ircmj.7704
PMCID: PMC3950781  PMID: 24693369
Botulinum Toxin Type A; Nitroglycerin; Randomized Controlled Trial
16.  A Bipartite Molecular Module Controls Cell Death Activation in the Basal Cell Lineage of Plant Embryos 
PLoS Biology  2013;11(9):e1001655.
During plant embryogenesis, once the suspensor organ of the plant embryo has fulfilled its role, it is removed by programmed cell death (PCD). The pro-death cathepsin protease NtCP14 initiates this PCD, but is inhibited by the cystatin NtCYS until the suspensor function is fulfilled.
Plant zygote divides asymmetrically into an apical cell that develops into the embryo proper and a basal cell that generates the suspensor, a vital organ functioning as a conduit of nutrients and growth factors to the embryo proper. After the suspensor has fulfilled its function, it is removed by programmed cell death (PCD) at the late stages of embryogenesis. The molecular trigger of this PCD is unknown. Here we use tobacco (Nicotiana tabacum) embryogenesis as a model system to demonstrate that the mechanism triggering suspensor PCD is based on the antagonistic action of two proteins: a protease inhibitor, cystatin NtCYS, and its target, cathepsin H-like protease NtCP14. NtCYS is expressed in the basal cell of the proembryo, where encoded cystatin binds to and inhibits NtCP14, thereby preventing precocious onset of PCD. The anti-cell death effect of NtCYS is transcriptionally regulated and is repressed at the 32-celled embryo stage, leading to increased NtCP14 activity and initiation of PCD. Silencing of NtCYS or overexpression of NtCP14 induces precocious cell death in the basal cell lineage causing embryonic arrest and seed abortion. Conversely, overexpression of NtCYS or silencing of NtCP14 leads to profound delay of suspensor PCD. Our results demonstrate that NtCYS-mediated inhibition of NtCP14 protease acts as a bipartite molecular module to control initiation of PCD in the basal cell lineage of plant embryos.
Author Summary
Similar to animals, plants eliminate tissues and organs that have transient function via programmed cell death (PCD). This is especially apparent during plant embryogenesis, when a plant zygote divides into an apical cell, which develops into a mature embryo, and a basal cell, which generates a single organ called the suspensor. During early seed development, the suspensor connects the embryo to the surrounding seed tissues and transports the nutrients and hormones required for its early development. Once its functions are fulfilled, the suspensor is subsequently eliminated by PCD. In this study, we answer a long-standing question in the field by elucidating the mechanism that is responsible for initiating suspensor PCD at a specific time during embryogenesis. Our findings show that in tobacco plant embryos, suspensor PCD is controlled by two antagonistically acting proteins—the pro-death cathepsin protease NtCP14 and its inhibitor cystatin NtCYS, which co-localize to the basal-most cell of the suspensor. High expression levels of NtCYS during early embryogenesis confer suspensor growth and viability by suppressing NtCP14 activity. When the suspensor ceases to grow, NtCYS expression is downregulated, leading to increased NtCP14 activity and to the initiation of PCD. The genetic modulation of this NtCYS/NtCP14 expression ratio either delays or hastens suspensor PCD, demonstrating its indispensable role in plant embryo development.
doi:10.1371/journal.pbio.1001655
PMCID: PMC3769231  PMID: 24058297
17.  IDH1/IDH2 Mutations Define the Prognosis and Molecular Profiles of Patients with Gliomas: A Meta-Analysis 
PLoS ONE  2013;8(7):e68782.
Background
Isocitrate dehydrogenase isoforms 1 and 2 (IDH1 and IDH2) mutations have received considerable attention since the discovery of their relation with human gliomas. The predictive value of IDH1 and IDH2 mutations in gliomas remains controversial. Here, we present the results of a meta-analysis of the associations between IDH mutations and both progression-free survival (PFS) and overall survival (OS) in gliomas. The interrelationship between the IDH mutations and MGMT promoter hypermethylation, EGFR amplification, codeletion of chromosomes 1p/19q and TP53 gene mutation were also revealed.
Methodology and Principal Findings
An electronic literature search of public databases (PubMed, Embase databases) was performed. In total, 10 articles, including 12 studies in English, with 2,190 total cases were included in the meta-analysis. The IDH mutations were frequent in WHO grade II and III glioma (59.5%) and secondary glioblastomas (63.4%) and were less frequent in primary glioblastomas (7.13%). Our study provides evidence that IDH mutations are tightly associated with MGMT promoter hypermethylation (P<0.001), 1p/19q codeletion (P<0.001) and TP53 gene mutation (P<0.001) but are mutually exclusive with EGFR amplification (P<0.001). This meta-analysis showed that the combined hazard ratio (HR) estimate for overall survival and progression-free survival in patients with IDH mutations was 0.33 (95% CI: 0.25–0.42) and 0.38 (95% CI: 0.21–0.68), compared with glioma patients whose tumours harboured the wild-type IDH. Subgroup analyses based on tumour grade also revealed that the presence of IDH mutations was associated with a better outcome.
Conclusion
Our study suggests that IDH mutations, which are closely linked to the genomic profile of gliomas, are potential prognostic biomarkers for gliomas.
doi:10.1371/journal.pone.0068782
PMCID: PMC3718803  PMID: 23894344
18.  Soil Microbial Biomass, Basal Respiration and Enzyme Activity of Main Forest Types in the Qinling Mountains 
PLoS ONE  2013;8(6):e67353.
Different forest types exert essential impacts on soil physical-chemical characteristics by dominant tree species producing diverse litters and root exudates, thereby further regulating size and activity of soil microbial communities. However, the study accuracy is usually restricted by differences in climate, soil type and forest age. Our objective is to precisely quantify soil microbial biomass, basal respiration and enzyme activity of five natural secondary forest (NSF) types with the same stand age and soil type in a small climate region and to evaluate relationship between soil microbial and physical-chemical characters. We determined soil physical-chemical indices and used the chloroform fumigation-extraction method, alkali absorption method and titration or colorimetry to obtain the microbial data. Our results showed that soil physical-chemical characters remarkably differed among the NSFs. Microbial biomass carbon (Cmic) was the highest in wilson spruce soils, while microbial biomass nitrogen (Nmic) was the highest in sharptooth oak soils. Moreover, the highest basal respiration was found in the spruce soils, but mixed, Chinese pine and spruce stands exhibited a higher soil qCO2. The spruce soils had the highest Cmic/Nmic ratio, the greatest Nmic/TN and Cmic/Corg ratios were found in the oak soils. Additionally, the spruce soils had the maximum invertase activity and the minimum urease and catalase activities, but the maximum urease and catalase activities were found in the mixed stand. The Pearson correlation and principle component analyses revealed that the soils of spruce and oak stands obviously discriminated from other NSFs, whereas the others were similar. This suggested that the forest types affected soil microbial properties significantly due to differences in soil physical-chemical features.
doi:10.1371/journal.pone.0067353
PMCID: PMC3696108  PMID: 23840671
19.  The effectiveness of neuroendoscopic versus non-neuroendoscopic procedures in the treatment of lateral ventricular cysts: a retrospective medical record review study 
BMC Neurology  2013;13:59.
Background
The aim of this study was to assess the effectiveness of neuroendoscopy compared with non-neuroendoscopic procedures for treating patients with arachnoid membrane cysts in the lateral ventricles.
Methods
The medical records of 28 patients with arachnoid membrane cysts in the lateral ventricles who were treated with neuroendoscopy and 39 such patients treated with non-neuroendoscopic techniques using classic treatment procedures were reviewed. The neuroendoscopic approach combined craniotomy, corticectomy, lesion resection and cyst ventriculostomy or cyst cisternostomy to restore normal cerebrospinal fluid circulation. The non-neuroendoscopic techniques included craniotomy, corticectomy, and lesion resection performed under a microscope. Clinical outcomes of symptoms and cyst size change on imaging were compared between the two treatment groups during follow-up (range: 1–5 years).
Results
Patients in the neuroendoscopy group had significantly less blood loss (P < 0.001) and shorter operative time (P < 0.001), better marked improvement in symptoms (64.3% vs. 5.1%, respectively), and a higher total resection rate (92.9% vs. 66.7%; P = 0.011) compared with the patients in the non-neuroendoscopy group. In the neuroendoscopy group there was no cyst recurrence whereas in the non-neuroendoscopy group 8 (20.5%) patients had cyst recurrence. However, all patients in the neuroendoscopy group had postoperative transient fever and 8 (28.6%) patients had subdural fluid accumulation which was treated and subsequently resolved during follow-up. These symptoms did not occur in the non-neuroendoscopy group.
Conclusion
We found that neuroendoscopic therapy for arachnoid cysts in the lateral ventricles was more efficacious than non-neuroendoscopic methods. Our results indicate that neuroendoscopy may produce better clinical outcomes than non-neuroendoscopic procedures in treating patients with arachnoid cysts in the lateral ventricles.
doi:10.1186/1471-2377-13-59
PMCID: PMC3684506  PMID: 23763938
Neuroendoscope; Lateral ventricle; Arachnoid cyst; Intracranial lesion
20.  Complete Genome Sequence of a Recombinant Marek's Disease Virus Field Strain with One Reticuloendotheliosis Virus Long Terminal Repeat Insert 
Journal of Virology  2012;86(24):13818-13819.
Marek's disease virus (MDV) Chinese strain GX0101, isolated in 2001 from a vaccinated flock of layer chickens with severe tumors, was the first reported recombinant MDV field strain with one reticuloendotheliosis virus (REV) long terminal repeat (LTR) insert. GX0101 belongs to very virulent MDV (vvMDV) but has higher horizontal transmission ability than the vvMDV strain Md5. The complete genome sequence of GX0101 is 178,101 nucleotides (nt) and contains only one REV-LTR insert at a site 267 nt upstream of the sorf2 gene. Moreover, GX0101 has 5 repeats of a 217-nt fragment in its terminal repeat short (TRS) region and 3 repeats in internal repeat short (IRS) region, compared to the other 10 strains with only 1 or 2 repeats in both TRS and IRS.
doi:10.1128/JVI.02583-12
PMCID: PMC3503109  PMID: 23166235
21.  Genetic polymorphisms of DNA double-strand break repair pathway genes and glioma susceptibility 
BMC Cancer  2013;13:234.
Background
Genetic variations in DNA double-strand break repair genes can influence the ability of a cell to repair damaged DNA and alter an individual’s susceptibility to cancer. We studied whether polymorphisms in DNA double-strand break repair genes are associated with an increased risk of glioma development.
Methods
We genotyped 10 potentially functional single nucleotide polymorphisms (SNPs) in 7 DNA double-strand break repair pathway genes (XRCC3, BRCA2, RAG1, XRCC5, LIG4, XRCC4 and ATM) in a case–control study including 384 glioma patients and 384 cancer-free controls in a Chinese Han population. Genotypes were determined using the OpenArray platform.
Results
In the single-locus analysis there was a significant association between gliomas and the LIG4 rs1805388 (Ex2 +54C>T, Thr9Ile) TT genotype (adjusted OR, 3.27; 95% CI, 1.87-5.71), as well as the TC genotype (adjusted OR, 1.62; 95% CI, 1.20-2.18). We also found that the homozygous variant genotype (GG) of XRCC4 rs1805377 (IVS7-1A>G, splice-site) was associated with a significantly increased risk of gliomas (OR, 1.77; 95% CI, 1.12-2.80). Interestingly, we detected a significant additive and multiplicative interaction effect between the LIG4 rs1805388 and XRCC4 rs1805377 polymorphisms with an increasing risk of gliomas. When we stratified our analysis by smoking status, LIG4 rs1805388 was associated with an increased glioma risk among smokers.
Conclusions
These results indicate for the first time that LIG4 rs1805388 and XRCC4 rs1805377, alone or in combination, are associated with a risk of gliomas.
doi:10.1186/1471-2407-13-234
PMCID: PMC3655843  PMID: 23663450
DNA double-strand breaks (DSBs); Single nucleotide polymorphisms (SNPs); Glioma; Susceptibility
22.  STAT1, NF-κB and ERKs play a role in the induction of lipocalin-2 expression in adipocytes★ 
Molecular Metabolism  2013;2(3):161-170.
Lipocalin-2 (LCN2) is induced in conditions of obesity and Type 2 diabetes (T2DM). IFNγ and TNFα induce LCN2 expression in adipocytes in a manner that is dependent on transcription. The effects of these cytokines are additive. IFNγ induced STAT1 and TNFα induced NF-κB play a role in the induction of LCN2. In the LCN2 promoter, one NF-κB binding site and four STAT1 binding sites were identified by in silico and in vitro approaches. MAPK (ERKs 1 and 2) activation was required for the IFNγ and TNFα induction of LCN2 expression, but did not affect the nuclear translocation or DNA binding activity of STAT1 or NF-κB. The NF-κB binding site and the STAT1 binding sites we identified in vitro were confirmed by in vivo studies. Transfection of a LCN2 promoter/luciferase reporter construct confirmed acute activation by IFNγ and TNFα. Our studies identify mechanisms involved in the actions of cytokines secreted from immune cells in adipose tissue that induce LCN2 expression in conditions of obesity and T2DM.
doi:10.1016/j.molmet.2013.04.003
PMCID: PMC3773839  PMID: 24049731
Lipocalin-2; STAT1; NF-κB; ERKs; Adipocyte; TNFα; IFNγ
23.  Efficacy and safety of percutaneous microwave coagulation therapy followed by 125I seed brachytherapy for VX2 hepatic tumors in a rabbit model 
The aim of this study was to evaluate the efficacy and safety of percutaneous microwave coagulation therapy (PMCT) followed by 125I seed brachytherapy for VX2 liver cancer in rabbits. Eighty New Zealand rabbits were injected with suspensions of VX2 tumor cells to create an animal model. The rabbits were randomly divided into 4 groups (n=20); the control, PMCT, 125I seed brachytherapy and combination groups. Group A was treated with PMCT at 40 W for 120 sec, group B was treated with 125I seed brachytherapy and group C was treated with PMCT followed by 125I seed brachytherapy. Group D were not treated and served as the control group. At 21 days after treatment, the rabbits were sacrificed for pathological assessment. The complete tumor necrosis rate was 19 out of 20 tumors (95%) in group C, 6 (30%) in group A, 0 (0%) in group B and 0 (0%) in the control group. The complete tumor necrosis rate was observed to be significantly different between groups C and A, and between groups C and B (P<0.01). No intraheptic metastasis occurred in group C, compared with an incidence of 7 (35%) in group A, 2 (10%) in group B and 20 (100%) in the control group. Between groups C and A, and between groups C and D, the intraheptic metastasis rate was statistically significant (P<0.01). PMCT followed by 125I seed brachytherapy increased the rate of carcinoma necrosis and decreased carcinoma metastasis in the VX2 rabbit model. This combined treatment is a safe, effective and minimally invasive therapeutic option for liver cancer.
doi:10.3892/etm.2013.1088
PMCID: PMC3735553  PMID: 23935738
liver cancer; microwave; 125I seed; computed tomography; animal model
24.  Neuropeptide S Facilitates Mice Olfactory Function through Activation of Cognate Receptor-Expressing Neurons in the Olfactory Cortex 
PLoS ONE  2013;8(4):e62089.
Neuropeptide S (NPS) is a newly identified neuromodulator located in the brainstem and regulates various biological functions by selectively activating the NPS receptors (NPSR). High level expression of NPSR mRNA in the olfactory cortex suggests that NPS-NPSR system might be involved in the regulation of olfactory function. The present study was undertaken to investigate the effects of intracerebroventricular (i.c.v.) injection of NPS or co-injection of NPSR antagonist on the olfactory behaviors, food intake, and c-Fos expression in olfactory cortex in mice. In addition, dual-immunofluorescence was employed to identify NPS-induced Fos immunereactive (-ir) neurons that also bear NPSR. NPS (0.1–1 nmol) i.c.v. injection significantly reduced the latency to find the buried food, and increased olfactory differentiation of different odors and the total sniffing time spent in olfactory habituation/dishabituation tasks. NPS facilitated olfactory ability most at the dose of 0.5 nmol, which could be blocked by co-injection of 40 nmol NPSR antagonist [D-Val5]NPS. NPS administration dose-dependently inhibited food intake in fasted mice. Ex-vivo c-Fos and NPSR immunohistochemistry in the olfactory cortex revealed that, as compared with vehicle-treated mice, NPS markedly enhanced c-Fos expression in the anterior olfactory nucleus (AON), piriform cortex (Pir), ventral tenia tecta (VTT), the anterior cortical amygdaloid nucleus (ACo) and lateral entorhinal cortex (LEnt). The percentage of Fos-ir neurons that also express NPSR were 88.5% and 98.1% in the AON and Pir, respectively. The present findings demonstrated that NPS, via selective activation of the neurons bearing NPSR in the olfactory cortex, facilitates olfactory function in mice.
doi:10.1371/journal.pone.0062089
PMCID: PMC3628337  PMID: 23614017
25.  Identification of STAT target genes in adipocytes 
JAK-STAT  2013;2(2):e23092.
Adipocytes play important roles in lipid storage, energy homeostasis and whole body insulin sensitivity. Studies in the last two decades have identified the hormones and cytokines that activate specific STATs in adipocytes in vitro and in vivo. Five of the seven STAT family members are expressed in adipocyte (STATs 1, 3, 5A, 5B and 6). Many transcription factors, including STATs, have been shown to play an important role in adipose tissue development and function. This review will summarize the importance of adipocytes, indicate the cytokines and hormones that utilize the JAK-STAT signaling pathway in fat cells and focus on the identification of STAT target genes in mature adipocytes. To date, specific target genes have been identified for STATs, 1, 5A and 5B, but not for STATs 3 and 6.
doi:10.4161/jkst.23092
PMCID: PMC3710315  PMID: 24058802
adipocytes; STAT; adipocyte; adipose tissue; transcription

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