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1.  Overexpression of MALT1-A20-NF-κB in adult B-cell acute lymphoblastic leukemia 
Background
A20 is a dual inhibitor of NF-κB activation and apoptosis in the tumor necrosis factor receptor 1 signaling pathway, and both are related to tumorigenesis. A20 is frequently inactivated by deletions and/or mutations in several B and T cell lymphoma subtypes; however, knowledge of the role of A20 in B-cell acute lymphoblastic leukemia (B-ALL) remains limited. In this study, we characterized the A20 gene expression pattern, the expression level of its upstream regulating factor MALT1, and its downstream target NF-κB in adult B-ALL.
Methods
The expression level of MALT1, A20 and NF-κB1 was detected in peripheral blood mononuclear cells (PBMCs) from 20 patients with adult B-ALL (including 12 de novo B-ALL and 8 refractory/relapse B-ALL cases), and nine patients with B-ALL in complete remission (CR) using real-time PCR. Sixteen healthy individuals served as controls.
Results
Significant A20 overexpression was found in the B-ALL (median: 13.489) compared with B-ALL CR (median: 3.755) (P = 0.003) patients and healthy individuals (median: 8.748) (P = 0.002), while there was no significant difference in A20 expression between B-ALL CR patients and healthy individuals (P = 0.107). Interestingly, the A20 expression level in the B-ALL samples was relatively different with approximately 50% of the B-ALL cases showing a relatively high A20 expression level, while the remaining 50% cases demonstrated slight upregulation or a similar expression level as the healthy controls. However, there was no significant difference in the A20 expression level between de novo B-ALL (median 12.252) and refractory/relapse B-ALL patients (median 21.342) (P = 0.616). Similarly, a significantly higher expression level of NF-κB1 was found in the B-ALL (median 1.062) patients compared with healthy individuals (median 0.335) (P < 0.0001), while the NF-κB1 expression level was downregulated in the B-ALL CR group (median 0.339), which was significantly lower than that in those with B-ALL (P = 0.001). Moreover, the MALT1 expression level in B-ALL was upregulated (median 1.938) and significantly higher than that in healthy individuals (median 0.677) (P = 0.002) and B-ALL CR patients (median 0.153) (P = 0.008). The correlation of the expression levels of all three genes was lost in B-ALL.
Conclusions
We found that MALT1-A20-NF-κB is overexpressed in adult B-ALL, which may be related to the pathogenesis of B-ALL, and this pathway may be considered a potentially attractive target for the development of B-ALL therapeutics.
Electronic supplementary material
The online version of this article (doi:10.1186/s12935-015-0222-0) contains supplementary material, which is available to authorized users.
doi:10.1186/s12935-015-0222-0
PMCID: PMC4514975  PMID: 26213496
B-cell acute lymphoblastic leukemia; A20; MALT1; NF-κB
2.  TMEM140 is associated with the prognosis of glioma by promoting cell viability and invasion 
Background
Gliomas are the most common types of primary brain tumors in the adult central nervous system. TMEM140 is identified as an amplified gene in the human gastric cancer genome. However, the function of TMEM140 in gliomas has not been thoroughly elucidated. The aim of the current study was to determine the clinical significance of TMEM140 expression in patients with gliomas and its effect on tumor cell malignant phenotypes.
Methods
Immunohistochemical analysis and real-time reverse transcription PCR were performed to detect the expression levels of TMEM140 in 70 glioma brain tissue samples. Next, the correlation between the TMEM140 expression levels and the clinical characteristics and outcomes of glioma patients was statistically analyzed. TMEM140 expression was inhibited in two glioma cell lines (i.e., U87 and U373) using a knockdown method with small interfering RNA. Cell Counting Kit-8 and Transwell assays were used to investigate TMEM140 function during cell proliferation, invasion, and migration, respectively. Using flow cytometry and Western blot analysis, we subsequently determined the cell cycle and apoptosis profile of the TMEM140-silenced cells.
Results
TMEM140 protein expression was significantly higher in gliomas than in normal brain tissues (p < 0.0001). TMEM140 overexpression was strongly correlated with tumor size, histologic grade, and overall survival time (P < 0.05). TMEM140 decreased cell viability in vitro and dramatically decreased tumor volume in vivo. This phenomenon might be caused by G1 phase cell cycle arrest and cell apoptosis. TMEM140 silencing could suppress the viability, migration, and invasion of glioma cells.
Conclusions
Our results suggest that TMEM140 expression is a prognostic factor that might play an important role in the viability, migration, and invasion of glioma cells. This study highlights the importance of TMEM140 as a novel prognostic marker and as an attractive therapeutic target for gliomas.
doi:10.1186/s13045-015-0187-4
PMCID: PMC4511541  PMID: 26198430
TMEM140; Glioma; Cell viability; Invasion; Prognosis
3.  Mechanistic insights into metal ion activation and operator recognition by the ferric uptake regulator 
Nature Communications  2015;6:7642.
Ferric uptake regulator (Fur) plays a key role in the iron homeostasis of prokaryotes, such as bacterial pathogens, but the molecular mechanisms and structural basis of Fur–DNA binding remain incompletely understood. Here, we report high-resolution structures of Magnetospirillum gryphiswaldense MSR-1 Fur in four different states: apo-Fur, holo-Fur, the Fur–feoAB1 operator complex and the Fur–Pseudomonas aeruginosa Fur box complex. Apo-Fur is a transition metal ion-independent dimer whose binding induces profound conformational changes and confers DNA-binding ability. Structural characterization, mutagenesis, biochemistry and in vivo data reveal that Fur recognizes DNA by using a combination of base readout through direct contacts in the major groove and shape readout through recognition of the minor-groove electrostatic potential by lysine. The resulting conformational plasticity enables Fur binding to diverse substrates. Our results provide insights into metal ion activation and substrate recognition by Fur that suggest pathways to engineer magnetotactic bacteria and antipathogenic drugs.
The regulation of iron levels is an important physiological process as excess cellular iron is highly toxic. Here the authors present several structures of a bacterial ferric uptake regulator (Fur) in complex with the Fe2+ transport protein operator and Fur box, shedding light on how iron promotes DNA recognition by Fur.
doi:10.1038/ncomms8642
PMCID: PMC4506495  PMID: 26134419
4.  Long-term antiviral efficacy of entecavir and liver histology improvement in Chinese patients with hepatitis B virus-related cirrhosis 
AIM: To evaluate the clinical outcomes of 240-wk treatment with entecavir (0.5 mg) in Chinese nucleoside-naive patients with cirrhosis.
METHODS: A total of 204 nucleoside-naive patients with compensated (n = 96) or decompensated (n = 108) hepatitis B virus (HBV)-induced cirrhosis at the Department of Gastroenterology of the China-Japan Union Hospital (Jilin University, Changchun, China) who were treated with entecavir (0.5 mg) for 240 wk were enrolled in this study. Liver biopsy samples obtained from 38 patients prior to treatment (baseline) and at week 240 were evaluated by different independent histopathologists. Efficacy assessments included the proportions of patients who achieved an HBV DNA level < 500 copies/mL, the association of interleukin-28B genetic variation with antivirus therapy, clinical outcomes, and histologic improvement. Changes in liver disease severity were analyzed, and liver histologic evaluation was performed in 38 patients with paired biopsies. Student t tests were used to compare the means of continuous variables between the groups, and the proportions of patients who achieved the endpoints were compared using the χ2 test.
RESULTS: At week 240, 87.5% of the patients with compensated cirrhosis and 92.6% of the patients with decompensated cirrhosis achieved a HBV DNA level < 500 copies/mL. Three patients had genotypic entecavir resistance within the 240-wk period. No significant association was observed between virologic response and interleukin-28 genotype (CT, 88.2% vs CC, 90.6%). The proportion of patients with Child-Pugh class A disease was significantly increased at week 240 (68%) from the baseline (47%; P < 0.01). The proportion of patients with Child-Pugh class B disease was significantly decreased at week 240 (25%) from the baseline (39%; P = 0.02). In the patients with paired liver biopsies, the mean reduction in the Knodell necroinflammatory score from the baseline was 3.58 ± 1.03 points (7.11 ± 1.80 vs 3.53 ± 1.35, P < 0.01). The mean reduction in Ishak fibrosis score from the baseline was 1.26 ± 0.64 points (5.58 ± 0.50 vs 4.32 ± 0.81, P < 0.01).
CONCLUSION: Entecavir is an effective treatment option for patients with HBV-related compensated or decompensated cirrhosis that can result in sustained virologic suppression and histologic improvement.
doi:10.3748/wjg.v21.i25.7869
PMCID: PMC4491974  PMID: 26167087
Decompensated cirrhosis; Hepatic function; Histologic improvement; Knodell histologic activity index score; Nucleoside analog
5.  Characteristics of A20 gene polymorphisms and clinical significance in patients with rheumatoid arthritis 
Background
There are a number of studies regarding to the susceptibility of A20 SNPs in rheumatoid arthritis (RA); however, a few of these studies have shown an association between polymorphisms in the A20 gene and RA risk in the Chinese population. The aim of this study was to investigate the characteristics of A20 gene polymorphisms, the association between polymorphisms and clinical significance in Chinese RA patients.
Methods
PCR and sequencing were used to identify A20 gene polymorphisms in peripheral blood mononuclear cells (PBMCs) (50 cases), synovial fluid (11 cases) from RA patients and PBMCs from 30 healthy individuals. Quantitative Real-time PCR (qRT-PCR) was used to analyze the A20 mRNA expression in 38 RA patients and 40 healthy individuals. Pearson’s Chi square test and two independent-samples Wilcoxon tests were used for statistical analysis.
Results
Eight single nucleotide polymorphisms (SNPs) (rs5029937, rs3799491, rs598493, rs2307859, rs146534657, rs2230926, rs661561, and rs582757) were identified in PBMCs of RA patients. One new mutation (14284 T > A) was identified in synovial fluid mononuclear cells from one RA case. rs146534657 was identified for the first time in two RA cases. Patients with rs146534657 (12411 A > G, Asn102Ser) AG genotype or rs2230926 (12486 T > G, Phe127Cys) TG genotype had poor outcome. Significantly lower A20 mRNA expression was found in PBMCs from RA patients compared with healthy individuals (p < 0.001). There was a higher A20 mRNA expression in RA patients with rs2230926 TG genotype and rs146534657 AG genotype (11.56 ± 7.39) than patients with rs2230926 TT genotype and rs146534657 AA genotype (5.63 ± 4.37) (p = 0.031).
Conclusion
Significantly lower A20 expression was found in RA patients. The polymorphisms of A20 were characterized in RA patients. We detected rs146534657 for the first time and identified a new A20 mutation (14284 T > A). A20 rs2230926 TG genotype and rs146534657 AG genotype may be related to poor outcome in RA patients.
Electronic supplementary material
The online version of this article (doi:10.1186/s12967-015-0566-1) contains supplementary material, which is available to authorized users.
doi:10.1186/s12967-015-0566-1
PMCID: PMC4491428  PMID: 26143186
A20 gene; Polymorphism; Mutation; Rheumatoid arthritis
6.  Virulence Structure of Blumeria graminis f. sp. tritici and Its Genetic Diversity by ISSR and SRAP Profiling Analyses 
PLoS ONE  2015;10(6):e0130881.
Blumeria graminis f. sp. tritici, which causes wheat powdery mildew, is an obligate biotrophic pathogen that can easily genetically adapt to its host plant. Understanding the virulence structure of and genetic variations in this pathogen is essential for disease control and for breeding resistance to wheat powdery mildew. This study investigated 17 pathogenic populations in Sichuan, China and classified 109 isolates into two distinct groups based on pathogenicity analysis: high virulence (HV, 92 isolates) and low virulence (LV, 17 isolates). Populations from Yibin (Southern region), Xichang (Western region), and Meishan (Middle region) showed lower virulence frequencies than populations from other regions. Many of the previously known resistance genes did not confer resistance in this study. The resistance gene Pm21 displayed an immune response to pathogenic challenge with all populations in Sichuan, and Pm13, Pm5b, Pm2+6, and PmXBD maintained resistance. AMOVA revealed significantly higher levels of variation within populations and lower levels of variation among populations within regions. High levels of gene flow were detected among populations in the four regions. Closely related populations within each region were distinguished by cluster analyses using ISSR and SRAP alleles. Both ISSR and SRAP allele profiling analyses revealed high levels of genetic diversity among pathogenic populations in Sichuan. Although ISSR and SRAP profiling analysis showed similar resolutions, the SRAP alleles appeared to be more informative. We did not detect any significant association between these alleles and the virulence or pathogenicity of the pathogen. Our results suggest that ISSR and SRAP alleles are more efficient for the characterization of small or closely related populations versus distantly related populations.
doi:10.1371/journal.pone.0130881
PMCID: PMC4476801  PMID: 26098844
7.  Integration of PK/PD for dose optimization of Cefquinome against Staphylococcus aureus causing septicemia in cattle 
Cefquinome is a fourth generation cephalosporin with antimicrobial activity against gram negative and gram positive bacterial species, including Staphylococcus aureus. The aim of our study was to observe the ex-vivo activity of cefquinome against Staphylococcus aureus strains by using bovine serum from intravenously treated cattle. Cefquinome kinetics were measured by liquid chromatography and UV detection. In vitro post antibiotic effects (PAEs) and mutant prevention concentrations were determined with S. aureus strain ATCC 12598. Cefquinome exhibited time-dependent killing and produced in vitro PAEs increasing with concentration and time of exposure. A pharmacokinetic-pharmacodynamic model was established to simulate the efficacy of cefquinome for different dosage regimens. A dosage of 2 mg/kg every 12 h for 3 days was expected to reach a bactericidal activity against S. aureus in case of septicemia.
doi:10.3389/fmicb.2015.00588
PMCID: PMC4470083  PMID: 26136730
cefquinome; Staphylococcus aureus; cattle; PK/PD; septicemia
8.  Formation of active inclusion bodies induced by hydrophobic self-assembling peptide GFIL8 
Background
In the last few decades, several groups have observed that proteins expressed as inclusion bodies (IBs) in bacteria could still be biologically active when terminally fused to an appropriate aggregation-prone partner such as pyruvate oxidase from Paenibacillus polymyxa (PoxB). More recently, we have demonstrated that three amphipathic self-assembling peptides, an alpha helical peptide 18A, a beta-strand peptide ELK16, and a surfactant-like peptide L6KD, have properties that induce target proteins into active IBs. We have developed an efficient protein expression and purification approach for these active IBs by introducing a self-cleavable intein molecule.
Results
In this study, the self-assembling peptide GFIL8 (GFILGFIL) with only hydrophobic residues was analyzed, and this peptide effectively induced the formation of cytoplasmic IBs in Escherichia coli when terminally attached to lipase A and amadoriase II. The protein aggregates in cells were confirmed by transmission electron microscopy analysis and retained ~50% of their specific activities relative to the native counterparts. We constructed an expression and separation coupled tag (ESCT) by incorporating an intein molecule, the Mxe GyrA intein. Soluble target proteins were successfully released from active IBs upon cleavage of the intein between the GFIL8 tag and the target protein, which was mediated by dithiothreitol. A variant of GFIL8, GFIL16 (GFILGFILGFILGFIL), improved the ESCT scheme by efficiently eliminating interference from the soluble intein-GFIL8 molecule. The yields of target proteins at the laboratory scale were 3.0–7.5 μg/mg wet cell pellet, which is comparable to the yields from similar ESCT constructs using 18A, ELK16, or the elastin-like peptide tag scheme.
Conclusions
The all-hydrophobic self-assembling peptide GFIL8 induced the formation of active IBs in E. coli when terminally attached to target proteins. GFIL8 and its variant GFIL16 can act as a “pull-down” tag to produce purified soluble proteins with reasonable quantity and purity from active aggregates. Owing to the structural simplicity, strong hydrophobicity, and high aggregating efficiency, these peptides can be further explored for enzyme production and immobilization.
doi:10.1186/s12934-015-0270-0
PMCID: PMC4467046  PMID: 26077447
Active inclusion bodies; Hydrophobic self-assembling peptide; Intein-mediated cleavage; Expression and purification coupled tag
9.  Increased Tim-3 expression on peripheral T lymphocyte subsets and association with higher disease activity in systemic lupus erythematosus 
Diagnostic Pathology  2015;10:71.
Background
Both the T cell immunoglobulin domain- and mucin domain-containing molecule-3 (Tim-3) and the death receptor Fas contribute to the pathogenesis of various autoimmune diseases, including systemic lupus erythematosus (SLE). The aim of the present study was to determine whether Tim-3 and Fas are co-expressed on certain peripheral T lymphocyte subsets, and whether this expression is associated with greater disease activity in SLE.
Methods
Peripheral blood mononuclear cells were isolated from 46 patients newly diagnosed with SLE and 28 age- and sex-matched healthy controls (HCs). Expression of Tim-3 and Fas on T subsets was analyzed by flow cytometry, while mRNA levels of the Tim-3 ligand galectin-9 and Fas ligand FasL were assayed using real-time RT-PCR.
Results
The proportions of CD3+CD4+ and CD3+CD4- T cells expressing Tim-3+ and Tim+Fas+ were significantly higher in patients than in HCs (p < 0.05), while the proportions of these subtypes expressing Fas were similar for the two groups. Patients with active SLE, as defined by their score on the SLE Disease Activity Index, had lower proportions of CD3+CD4+ T cells and higher proportions of CD3+CD4+Tim-3+ and CD3+CD4+Tim-3+Fas+ T cells than did patients with stable SLE. Serum levels of complement C3 and C4 proteins, considered as a marker of SLE activity, correlated negatively with proportions of CD3+CD4+ and CD3+CD4- T cells expressing Tim-3.
Conclusions
Expression of Tim-3 and co-expression of Tim-3 and Fas on certain peripheral T subsets are associated with disease activity in SLE patients. Future research should examine whether the same is true of other T subsets implicated in SLE, and should explore the potential role(s) of Tim-3 in the disease pathway.
Virtual slides
http://www.diagnosticpathology.diagnomx.eu/vs/1855527845145188
doi:10.1186/s13000-015-0306-0
PMCID: PMC4469310  PMID: 26076826
Systemic lupus erythematosus; Tim-3; Fas; T lymphocyte subset; Disease activity
10.  Oleanolic acid induces mitochondrial-dependent apoptosis and G0/G1 phase arrest in gallbladder cancer cells 
Oleanolic acid (OA), a naturally occurring triterpenoid, exhibits potential antitumor activity in many tumor cell lines. Gallbladder carcinoma is the most common malignancy of the biliary tract, and is a highly aggressive tumor with an extremely poor prognosis. Unfortunately, the effects of OA on gallbladder carcinoma are unknown. In this study, we investigated the effects of OA on gallbladder cancer cells and the underlying mechanism. The results showed that OA inhibits proliferation of gallbladder cancer cells in a dose-dependent and time-dependent manner on MTT and colony formation assay. A flow cytometry assay revealed apoptosis and G0/G1 phase arrest in GBC-SD and NOZ cells. Western blot analysis and a mitochondrial membrane potential assay demonstrated that OA functions through the mitochondrial apoptosis pathway. Moreover, this drug inhibited tumor growth in nude mice carrying subcutaneous NOZ tumor xenografts. These data suggest that OA inhibits proliferation of gallbladder cancer cells by regulating apoptosis and the cell cycle process. Thus, OA may be a promising drug for adjuvant chemotherapy in gallbladder carcinoma.
doi:10.2147/DDDT.S84448
PMCID: PMC4472077  PMID: 26109845
oleanolic acid; gallbladder carcinoma; apoptosis; cell cycle arrest; mitochondrial pathway
11.  Kirigami-based stretchable lithium-ion batteries 
Scientific Reports  2015;5:10988.
We have produced stretchable lithium-ion batteries (LIBs) using the concept of kirigami, i.e., a combination of folding and cutting. The designated kirigami patterns have been discovered and implemented to achieve great stretchability (over 150%) to LIBs that are produced by standardized battery manufacturing. It is shown that fracture due to cutting and folding is suppressed by plastic rolling, which provides kirigami LIBs excellent electrochemical and mechanical characteristics. The kirigami LIBs have demonstrated the capability to be integrated and power a smart watch, which may disruptively impact the field of wearable electronics by offering extra physical and functionality design spaces.
doi:10.1038/srep10988
PMCID: PMC4463940  PMID: 26066809
12.  MALAT1 promotes the proliferation and metastasis of gallbladder cancer cells by activating the ERK/MAPK pathway 
Cancer Biology & Therapy  2014;15(6):806-814.
Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), a long non-coding RNA (lncRNA), is associated with metastasis and is an independent prognostic factor for lung cancer. Recent studies have demonstrated that MALAT1 plays an important role in other malignancies. However, little is known about the role of MALAT1 in gallbladder carcinoma (GBC), which is the most common cancer of the biliary tract and has an extremely poor prognosis. In this study, we focused on the expression, biological functions and mechanism of MALAT1 in GBC and found that MALAT1 was significantly upregulated in GBC tissues compared with corresponding non-cancerous tissues. Knockdown of MALAT1 in GBC cell lines using lentivirus-mediated RNA interference significantly inhibited the proliferation and metastasis of the GBC cells both in vitro and in vivo. Furthermore, ERK/MAPK pathway was found to be inactivated in the GBC cell lines after MALAT1 knockdown. These results indicated that MALAT1 might serve as an oncogenic lncRNA that promotes proliferation and metastasis of GBC and activates the ERK/MAPK pathway
doi:10.4161/cbt.28584
PMCID: PMC4049796  PMID: 24658096
gallbladder carcinoma; MALAT1; lncRNA; ERK; MAPK; proliferation; metastasis
13.  Fitz-Hugh-Curtis syndrome: clinical diagnostic value of dynamic enhanced MSCT 
Journal of Physical Therapy Science  2015;27(6):1641-1644.
[Purpose] This study aimed to investigate the clinical diagnostic value of dynamic enhanced multislice computed tomography (MSCT) for Fitz-Hugh-Curtis syndrome (FHCS). [Subjects and Methods] This study retrospectively analyzed the clinical features and manifestations of scanning and dynamic enhanced MSCT in 19 patients with FHCS. [Results] MSCT scans showed different degrees of liver capsule thickness in the lesion area: seven cases of sub-capsular effusion and three cases with a small amount of pleural effusion; thickness of the liver capsular arterial phase showing significant enhancement in 17 cases, and slight enhancement in two; portal venous and delayed phase enhancement decreased with no clear boundary of the liver parenchyma; and adjacent hepatic parenchymal involvement in five cases, in which the arterial phase appeared to have patchy or triangular enhancement, and unclear portal vein and delayed phase imaging findings. MSCT revealed pelvic inflammatory disease in 14 cases, peritonitis in two, endometritis combined with bilateral ovarian abscesses in two, and a tube-ovarian abscess in one. [Conclusion] Dynamic enhanced MSCT can accurately display liver capsule lesions and possible pelvic inflammatory diseases related to FHCS, suggest the infection source, and have high application value for making early, accurate diagnoses and improved prognosis.
doi:10.1589/jpts.27.1641
PMCID: PMC4499951  PMID: 26180288
Tomography; X-ray compute; Perihepatitis
14.  IL-29/IL-28A suppress HSV-1 infection of human NT2-N neurons 
Journal of neurovirology  2011;17(3):212-219.
The newly identified cytokines, IL-28/IL-29 (also termed type III IFNs), are able to inhibit a number of viruses. Here, we examined the antiviral effects of IL-29/IL-28A against herpes simplex virus type 1 (HSV-1) in human NT2-N neurons and CHP212 neuronal cells. Both IL-29 and IL-28A could efficiently inhibit HSV-1 replication in neuronal cells, as evidenced by the reduced expression of HSV-1 DNA and proteins. This inhibitory effect of IL-29 and IL-28A against HSV-1 could be partially blocked by antibody to IL-10Rβ, one of the key receptors for IL-29 and IL-28A. To explore the underlying antiviral mechanisms employed by IL-29/IL-28A, we showed that IL-29/IL-28A could selectively induce the expression of several Toll-like receptors (TLRs) as well as activate TLR-mediated antiviral pathway, including IFN regulatory factor 7, IFN-α, and the key IFN-α stimulated antiviral genes.
doi:10.1007/s13365-011-0031-8
PMCID: PMC4444784  PMID: 21499846
IFN; HSV-1; TLR; Neuron; IRF-7
15.  Heroin Use Promotes HCV Infection and Dysregulates HCV-Related Circulating microRNAs 
Hepatitis C virus (HCV) infection is common among injection drug users (IDUs). There is accumulating evidence that circulating microRNAs (miRNAs) are associated with HCV infection and disease progression. The present study was undertaken to determine the in vivo impact of heroin use on HCV infection and HCV-related circulating miRNA expression. Using the blood specimens from four groups of the study subjects (HCV-infected individuals, heroin users with/without HCV infection, and healthy volunteers), we found that HCV-infected heroin users had significantly higher viral load than HCV-infected non-heroin users (p = 0.0004). Measurement of HCV-related circulating miRNAs in plasma showed that miRs-122, 141, 29a, 29b, and 29c were significantly increased in the heroin users with HCV infection, whereas miR-351, an HCV inhibitory miRNA, was significantly decreased in heroin users as compared to control subjects. Further investigation identified a negative correlation between the plasma levels of miR-29 family members and severity of HCV infection based on aspartate aminotransferase to platelet ratio index (APRI). In addition, heroin use and/or HCV infection also dysregulated a panel of plasma miRNAs. Taken together, these data for the first time revealed in vivo evidence that heroin use and/or HCV infection alter circulating miRNAs, which provides a novel mechanism for the impaired innate anti-HCV immunity among IDUs.
doi:10.1007/s11481-014-9577-6
PMCID: PMC4444785  PMID: 25572448
Hepatitis C virus (HCV); Injection drug users (IDUs); Circulating microRNAs
16.  Fucoxanthin: A Promising Medicinal and Nutritional Ingredient 
Fucoxanthin, an allenic carotenoid, can be isolated from edible brown seaweeds. Recent studies have reported that fucoxanthin has many physiological functions and biological properties, such as antiobesity, antitumor, antidiabetes, antioxidant, anti-inflammatory, and hepatoprotective activities, as well as cardiovascular and cerebrovascular protective effects. Therefore, fucoxanthin can be used as both medicinal and nutritional ingredient to prevent and treat chronic diseases. Although fucoxanthin possesses many medicinal ingredient and nutritional qualities, studies indicated that its structure was unstable. In this paper, we consulted the current documents and reviewed structural properties and factors affecting the stability of fucoxanthin. We also reported the metabolism, safety, pharmacological activities, and the methods of improving the bioavailability of fucoxanthin. Based on these studies providing essential background knowledge, fucoxanthin can be developed into marine drugs and nutritional products.
doi:10.1155/2015/723515
PMCID: PMC4461761  PMID: 26106437
17.  Combination of Circulating Tumor Cells with Serum Carcinoembryonic Antigen Enhances Clinical Prediction of Non-Small Cell Lung Cancer 
PLoS ONE  2015;10(5):e0126276.
Circulating tumor cells (CTCs) have emerged as a potential biomarker in the diagnosis, prognosis, treatment, and surveillance of lung cancer. However, CTC detection is not only costly, but its sensitivity is also low, thus limiting its usage and the collection of robust data regarding the significance of CTCs in lung cancer. We aimed to seek clinical variables that enhance the prediction of CTCs in patients with non-small cell lung cancer (NSCLC). Clinical samples and pathological data were collected from 169 NSCLC patients. CTCs were detected by CellSearch and tumor markers were detected using the Luminex xMAP assay. Univariate analyses revealed that histology, tumor stage, tumor size, invasiveness, tumor grade and carcinoembryonic antigen (CEA) were associated with the presence of CTCs. However, the level of CTCs was not associated with the degree of nodal involvement (N) or tumor prognostic markers Ki-67, CA125, CA199, Cyfra21-1, and SCCA. Using logistic regression analysis, we found that the combination of CTCs with tumor marker CEA has a better disease prediction. Advanced stage NSCLC patients with elevated CEA had higher numbers of CTCs. These data suggest a useful prediction model by combining CTCs with serum CEA in NSCLC patients.
doi:10.1371/journal.pone.0126276
PMCID: PMC4440620  PMID: 25996878
18.  VEGF111b, a C-terminal splice variant of VEGF-A and induced by mitomycin C, inhibits ovarian cancer growth 
Background
Alternative splicing of VEGF-A gives rise to two families – the pro-angiogenic VEGFxxx family and the anti-angiogenic VEGFxxxb family that differ by only six amino acids at their C-terminal end. The first verified and widely reported VEGFxxxb family member is VEGF165b, and here VEGF165b is a positive control.
Methords
VEGF111b mRNA was detected in ovarian cancer cell lines SKOV3 and OVCAR3 by RT-PCR. Western blot was used to detect VEGF111b and VEGF165b protein in the CMs and lysates of OVCAR3 cells. MTT and colony formation assay were used to detect the short-term and long-term proliferation inhibition ability of ovarian cancer cells with VEGF111b overexpression. Cell-cycle analysis was performed to further characterize VEGF111b inhibition effects. VEGF111b signaling on ovarian cancer cells were determined by western blot. The expression levels of Ki67, PCNA, CD31 and VEGF in VEGF111b overexpression xenograft model were detected by immunohistochemistry.
Results
Under the effect of mitomycin C, we identify a new member of VEGFxxxb family-VEGF111b in ovarian cancer cell lines. SKOV3 and OVCAR cells were transfected with empty lentivirus, VEGF111b or VEGF165b lentivirus. VEGF111b and VEGF165b overexpression inhibits proliferation of the ovarian cancer cells, but inhibition effect of VEGF111b is slightly less efficient than VEGF165b. Cell cycle analysis was further used to elucidate the mechanism involved in the inhibition effect. Further, we detected the expression of VEGF-R2 in SKOV3 and OVCAR3 cells, and shown that VEGF111b might bind to conventional VEGF-R2 with the results of reducing VEGF-R2 tyrosine phosphorylation and downstream signaling to have anti-tumor effects. In vivo VEGF111b overexpression inhibits ovarian cancer growth in xenograft mice.
Conclusion
Our results show that VEGF111b, as a new member of VEGFxxxb family, with similar properties to VEGF165b, plays potent anti-tumor effect in vitro and in vivo that can target the VEGF-R2 and its signaling pathway to inhibit ovarian tumor growth. This also opens a new avenue for treating ovarian cancer.
Electronic supplementary material
The online version of this article (doi:10.1186/s12967-015-0522-0) contains supplementary material, which is available to authorized users.
doi:10.1186/s12967-015-0522-0
PMCID: PMC4480579  PMID: 25990504
VEGF111b; Ovarian cancer; Anti-tumor; Cell cycle; VEGF-R2
19.  High density lipoprotein promotes proliferation of adipose-derived stem cells via S1P1 receptor and Akt, ERK1/2 signal pathways 
Introduction
Adipose-derived stem cells (ADSC) are non-hematopoietic mesenchymal stem cells that have shown great promise in their ability to differentiate into multiple cell lineages. Their ubiquitous nature and the ease of harvesting have attracted the attention of many researchers, and they pose as an ideal candidate for applications in regenerative medicine. Several reports have demonstrated that transplanting ADSC can promote repair of injured tissue and angiogenesis in animal models. Survival of these cells after transplant remains a key limiting factor for the success of ADSC transplantation. Circulating factors like High Density Lipoprotein (HDL) has been known to promote survival of other stems cells like bone marrow derived stem cells and endothelial progenitor cells, both by proliferation and by inhibiting cell apoptosis. The effect of HDL on transplanted adipose-derived stem cells in vivo is largely unknown.
Methods
This study focused on exploring the effects of plasma HDL on ADSC and delineating the mechanisms involved in their proliferation after entering the bloodstream. Using the MTT and BrdU assays, we tested the effects of HDL on ADSC proliferation. We probed the downstream intracellular Akt and ERK1/2 signaling pathways and expression of cyclin proteins in ADSC using western blot.
Results
Our study found that HDL promotes proliferation of ADSC, by binding to sphingosine-1- phosphate receptor-1(S1P1) on the cell membrane. This interaction led to activation of intracellular Akt and ERK1/2 signaling pathways, resulting in increased expression of cyclin D1 and cyclin E, and simultaneous reduction in expression of cyclin-dependent kinase inhibitors p21 and p27, therefore promoting cell cycle progression and cell proliferation.
Conclusions
These studies raise the possibility that HDL may be a physiologic regulator of stem cells and increasing HDL concentrations may be valuable strategy to promote ADSC transplantation.
Electronic supplementary material
The online version of this article (doi:10.1186/s13287-015-0090-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s13287-015-0090-5
PMCID: PMC4453044  PMID: 25976318
20.  Differential Gene Expression in Ovaries of Qira Black Sheep and Hetian Sheep Using RNA-Seq Technique 
PLoS ONE  2015;10(3):e0120170.
The Qira black sheep and the Hetian sheep are two local breeds in the Northwest of China, which are characterized by high-fecundity and low-fecundity breed respectively. The elucidation of mRNA expression profiles in the ovaries among different sheep breeds representing fecundity extremes will helpful for identification and utilization of major prolificacy genes in sheep. In the present study, we performed RNA-seq technology to compare the difference in ovarian mRNA expression profiles between Qira black sheep and Hetian sheep. From the Qira black sheep and the Hetian sheep libraries, we obtained a total of 11,747,582 and 11,879,968 sequencing reads, respectively. After aligning to the reference sequences, the two libraries included 16,763 and 16,814 genes respectively. A total of 1,252 genes were significantly differentially expressed at Hetian sheep compared with Qira black sheep. Eight differentially expressed genes were randomly selected for validation by real-time RT-PCR. This study provides a basic data for future research of the sheep reproduction.
doi:10.1371/journal.pone.0120170
PMCID: PMC4366253  PMID: 25790350
21.  Acinetobacter calcoaceticus from a fatal case of pneumonia harboring blaNDM-1 on a widely distributed plasmid 
BMC Infectious Diseases  2015;15:131.
Background
We have recovered one blaNDM-1-harboring bacterial strain, designated as XM1570, from a sputum sample obtained from a fatal case of pneumonia in China.
Methods
Biochemical profiling, 16S rRNA sequencing and antimicrobial susceptibility testing were performed. Conjugation experiments were conducted to determine transmissibility of resistance. Pulsed-field gel electrophoresis and whole genome sequencing were performed to identify strain-specific features.
Results
The isolate XM1570 was identified as Acinetobacter calcoaceticus. Whole genome sequencing identified two plasmids, pXM1 and pXM2. Comparative analysis showed >99% similarity between XM1570 and A. calcoaceticus PHEA-2. Plasmid pXM1 carried the carbapenemase gene blaNDM-1 and displayed high homology with previously described plasmids isolated from different Acinetobacter spp., which were collected from human or livestock distributed in China and worldwide. The blaNDM-1 gene was located on this conjugative plasmid in a transposon-like region flanked by two copies of the insertion sequence ISAba125; and resistance to all tested β-lactams was observed. Transferability of resistance from pXM1 to the transconjugants was identified. Plasmid pXM2 had an insertion sequence ISAba125 and a −35 region of the blaNDM-1 gene promoter but the blaNDM-1 gene was not present. A chromosomally located carbapenemase-encoding gene blaOXA-75 was detected; however, this gene was interrupted by an insertion sequence ISAba22 belonging to IS3 family.
Conclusions
Location of blaNDM-1 on different self-transmissible plasmids could facilitate geographically broad dissemination and host range expansion of the blaNDM-1 gene via horizontal gene transfer. Our findings of this normally environmental species A. calcoaceticus XM1570 further underline the significant clinical challenge and the essential need for surveillance including molecular methods and plasmid analyses.
Electronic supplementary material
The online version of this article (doi:10.1186/s12879-015-0870-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s12879-015-0870-7
PMCID: PMC4373515  PMID: 25881070
A. calcoaceticus; Type IV secretion system; blaNDM-1; ISAba125
22.  Effect of mir-16 on proliferation and apoptosis in human A549 lung adenocarcinoma cells 
Objective: To investigate the expression of mir-16 in lung adenocarcinoma cancer line and to observe the effect of mir-16 on the biological behaviors of human lung adenocarcinoma cancer A549 cell. Methods the expression of mir-16 in A549 cells was examined by quantitative real-time (qRT)-PCR. mir-16 minics was chemically synthesized and transfected into A549 cells by Lipofectamine 2000. The cell cycle and apoptosis changes were assayed by flow cytometry, the cell proliferation was measured by MTS assay. The wild-type and mutant wip1 3’-UTR luciferase reporter rectors were constructed. The relative activity of renila luciferase was detected to confirm the binding site of mir-16 on wip1 mRNA. Results, the expression of mir-16 is reduced in A549 cell compared with the normal bronchial epithelial cell. Transfection of mir-16 minics significantly suppressed the luciferase reporter containing wild type not mutant wip1 3’-UTR. Furthermore enforced expression of mir-16 lead to reduced A549 cell proliferation and promote apoptosis. Conclusion Therapeutic strategies to resume miRNA-16 expression may be benefit to patients with NSCLC in the feature.
PMCID: PMC4443046  PMID: 26064212
Mir-16; lung adenocarcinoma; apoptosis
23.  Trop2 inhibition suppresses the proliferation and invasion of laryngeal carcinoma cells via the extracellular signal-regulated kinase/mitogen-activated protein kinase pathway 
Molecular Medicine Reports  2015;12(1):865-870.
The cell surface glycoprotein Trop2 is overexpressed in various types of epithelial cancer. Laryngeal carcinoma is one of the most common types of head and neck cancer and in a previous study, the expression of Trop2 in laryngeal squamous cell carcinoma (LSCC) was identified as an independent prognostic factor. However, the biological significance of Trop2 in LSCC development remains unclear. In the current study, Trop2 protein expression in fresh LSCC tissue and paracancerous tissue was investigated using western blotting. Trop2 in the Hep2 laryngeal cell line was subsequently suppressed by transfection with small interfering RNA (siRNA). The effects of knockdown of Trop2 on cell viability, migration, invasiveness and ERK/MAPK pathway activity were investigated in the current study. The expression of Trop2 in fresh LSCC tissue was demonstrated to be significantly greater than that in paracancerous tissue. Trop2 expression was also identified to be required for proliferation, migration and invasiveness of Hep2 laryngeal carcinoma cells, as all were blocked by siRNA-mediated Trop2 inhibition. Notably, the ERK/MAPK signaling pathway and cell cycle factor, cyclin D1, were identified to be suppressed following the knockdown of Trop2 in Hep2 cells. These observations suggest that Trop2 serves an oncogenic role in LSCC and has potential as a therapeutic target.
doi:10.3892/mmr.2015.3485
PMCID: PMC4438912  PMID: 25779928
laryngeal carcinoma; Trop2; invasion; proliferation
24.  ALDH2 is the major genetic determinant of “daily maximum drinks” in a GWAS study of an isolated rural Chinese sample 
Alcohol dependence (AD) is a moderately heritable phenotype with a small number of known risk genes mapped via linkage or candidate gene studies. We considered 313 males from among 600 members of documented, extended pedigrees in which AD segregates collected in Northern Hunan Province, China. A joint analysis of both males and females could not be performed as the difference in alcohol consumption variance was too large. Genome-wide association analyses were performed for approximately 300,000 single nucleotide polymorphisms (SNPs). Significant associations found in the ALDH2 region for AD (minimum p = 4.73×10-8) and two AD-related phenotypes: flushing response (minimum p = 4.75×10-26) and maximum drinks in a 24-hour period (minimum p = 1.54×10-16). Association of previous candidate SNP, rs10774610 in CCDC63, was confirmed but resulted from linkage disequilibrium with ALDH2. ALDH2 is strongly associated with flushing response, AD, and maximum drinks in males, with nonsynonymous SNP rs671 explaining 29.2%, 7.9% and 22.9% of phenotypic variation, respectively, in this sample. When rs671 was considered as a candidate SNP in females, it explained 23.6% of the variation in flushing response, but alcohol consumption rates were too low among females – despite familial enrichment for AD – for an adequate test of association for either AD or maximum drinks. These results support a mediating effect of aldehyde dehydrogenase deficiency on alcohol consumption in males and a secondary, culturally-mediated limitation on alcohol consumption by females that should be appropriately modeled in future studies of alcohol consumption in populations where this may be a factor.
doi:10.1002/ajmg.b.32213
PMCID: PMC4149216  PMID: 24277619
Alcohol Dependence; Maximum Drinks; Flushing Response; Genome-Wide Association; Aldehyde Dehydrogenase
25.  Prognostic role of YB-1 expression in breast cancer: a meta-analysis 
Objective: In published studies, Y-box binding protein-1 (YB-1) correlated with the prognosis of patients with breast cancer (BC), but the specific role of YB-1 is still unclear. Our study aimed to evaluate the prognostic value of YB-1 in BC patients using meta-analysis based on the published studies. Methods: We searched the relevant literatures deadline for June 2014 in databases, including PubMed, Embase, Medline and Cochrane library, and finally 8 studies were included in our study. Our study contained 1094 BC patients with 398 YB-1 positive and 696 YB-1 negative. Results: Our results showed that YB-1 abnormal expression did not correlated with the lymph node status [OR = 1.258, 95% CI = 0.895-1.769, P = 0.186], high histological grade [OR = 2.709, 95% CI = 0.861-8.530, P = 0.089], histological type [OR = 0.837, 95% CI = 0.526-1.331, P = 0.452], P53 status [OR = 2.006, 95% CI 0.686-5.865, P = 0.203] and PR [OR = 0.607, 95% CI = 0.347-1.061, P = 0.080] in BC patients. But YB-1 over-expression was associated with other unfavorable factors: ER negativity [OR = 0.604, 95% CI = 0.388-0.941, P = 0.026], HER2 positivity [OR = 3.841, 95% CI = 2.637-5.594, P = 0.000], and high tumorous T stage [OR = 2.169, 95% CI = 1.295-3.632, P = 0.003]. In addition, our data suggested that high YB-1 expression had an adverse impact on 5-year OS [RR = 2.767, 95% CI = 2.054-3.727, P = 0.000] in BC patients. Conclusions: Our findings implied that YB-1 might a novel biomarker to predict the prognosis of BC, and could be a potential direction for developing diagnostic and therapeutic approaches in BC.
PMCID: PMC4402753  PMID: 25932106
YB-1; breast cancer; prognosis; meta-analysis

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