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1.  Mass spectrometry of intact V-type ATPases reveals bound lipids and the effects of nucleotide binding 
Science (New York, N.Y.)  2011;334(6054):380-385.
The ability of electrospray to propel large viruses into a mass spectrometer is established and is rationalised by analogy to the atmospheric transmission of the common cold. Much less clear is the fate of membrane embedded molecular machines in the gas phase. Here we show that rotary ATPases/synthases from Thermus thermophilus and Enterococcus hirae can be maintained intact with membrane and soluble subunit interactions preserved in vacuum. Mass spectra reveal subunit stoichiometries and the identity of tightly bound lipids within the membrane rotors. Moreover subcomplexes formed in solution and gas phases reveal the regulatory effects of nucleotide binding on both ATP hydrolysis and proton translocation. Consequently we can link specific lipid and nucleotide binding with distinct regulatory roles.
doi:10.1126/science.1210148
PMCID: PMC3927129  PMID: 22021858
2.  Lack of Association between Insulin Receptor Substrate2 rs1805097 Polymorphism and the Risk of Colorectal and Breast Cancer: A Meta-Analysis 
PLoS ONE  2014;9(1):e86911.
Background
Insulin receptor substrate-2 (IRS-2), a signaling adaptor protein, was involved in two cancer-related pathways (the phosphatidylinositol 3′-kinase (PI3K) and the extracellular signal-regulated kinase (ERK) pathways). Several studies have evaluated the association between IRS2 rs1805097 (G>A) polymorphisms and the risk of colorectal and breast cancer. However, the results were inconsistent.
Methodology/Principal Findings
A meta-analysis of seven published case-control studies (4 studies with 4798 cases and 5478 controls for colorectal cancer and 3 studies with 2108 cases and 2507 controls for breast cancer) were conducted to assess the strength of association using crude odd ratios (ORs) with 95% confidence intervals (CIs). For colorectal cancer, no obvious associations were found for all genetic models (homozygote comparison OR = 0.96, 95%CI 0.85–1.08, Pheterogeneity = 0.97; heterozygote comparison: OR = 0.91, 95%CI 0.73–1.13, Pheterogeneity<0.01; dominant model: OR = 0.92, 95%CI 0.80–1.06, Pheterogeneity = 0.05; recessive model: OR = 1.02, 95%CI 0.91–1.14, Pheterogeneity = 0.60). In the subgroup analysis by ethnicity, control source and consistency of frequency with Hardy-Weinberg equilibrium (HWE), still no significant associations were observed. For breast cancer, also no obvious associations were found for all genetic models (homozygote comparison: OR = 0.95, 95%CI 0.71–1.26, Pheterogeneity = 0.10; heterozygote comparison: OR = 1.00, 95%CI 0.89–1.14, Pheterogeneity = 0.71; dominant model: OR = 0.98, 95%CI 0.87–1.10, Pheterogeneity = 0.55; recessive model: OR = 0.95, 95%CI 0.72–1.25, Pheterogeneity = 0.07). We performed subgroup analyses by sample size and did not find an association.
Conclusions
This meta-analysis indicated that IRS2 rs1805097polymorphism was not associated with colorectal and breast cancer risk.
doi:10.1371/journal.pone.0086911
PMCID: PMC3907441  PMID: 24497996
3.  Bicarbonate efflux via GABAA receptors depolarizes membrane potential and inhibits two-pore domain potassium channels of astrocytes in rat hippocampal slices 
Glia  2012;60(11):1761-1772.
Increasing evidence indicates the functional expression of ionotropic γ-aminobutyric acid receptor (GABAA-R) in astrocytes. However, it remains controversial in regard to the intracellular Cl− concentration ([Cl−]i) and the functional role of anion-selective GABAA-R in astrocytes. In gramicidin perforated-patch recordings from rat hippocampal CA1 astrocytes, GABA and GABAA-R specific agonist THIP depolarized astrocyte membrane potential (Vm), and the THIP induced currents reversed at the voltages between −75.3 to −78.3 mV, corresponding to a [Cl−]i of 3.1 – 3.9 mM that favors a passive distribution of Cl− anions across astrocyte membrane. Further analysis showed that GABAA-R induced Vm depolarization is ascribed to HCO3− efflux, while a passively distributed Cl− mediates no net flux or influx of Cl-that leads to an unchanged or hyperpolarized Vm. In addition to a rapidly activated GABAA-R current component, GABA and THIP also induced a delayed inward current (DIC) in 63% of astrocytes. The DIC became manifest after agonist withdrawal and enhanced in amplitude with increasing agonist application duration or concentrations. Astrocytic two-pore domain K+ channels (K2Ps), especially TWIK-1, appeared to underlie the DIC, because 1) acidic intracellular pH, as a result of HCO3− efflux, inhibited TWIK-1; 2) the DIC remained in the Cs+ recording solutions that inhibited conventional K+ channels and 3) the DIC was completely inhibited by 1 mM quinine but not by blockers for other cation/anion channels. Altogether, HCO3− efflux through activated GABAA-R depolarizes astrocyte Vm and induces a delayed inhibition of K2Ps K+ channels via intracellular acidification.
doi:10.1002/glia.22395
PMCID: PMC3901573  PMID: 22855415
Astrocytes; GABAA receptors; bicarbonate; TWIK-1; patch clamp; hippocampus
4.  Human Parainfluenza Virus Type 2 V Protein Inhibits TRAF6-Mediated Ubiquitination of IRF7 To Prevent TLR7- and TLR9-Dependent Interferon Induction 
Journal of Virology  2013;87(14):7966-7976.
Paramyxovirus V proteins block Toll-like receptor 7 (TLR7)- and TLR9-dependent signaling leading to alpha interferon production. Our recent study has provided evidence that interaction of the V proteins with IRF7 is important for the blockade. However, the detailed mechanisms still remain unclear. Here we reexamined the interaction of the human parainfluenza virus type 2 (HPIV2) V protein with signaling molecules involved in TLR7/9-dependent signaling. Immunoprecipitation experiments in HEK293T cells transfected with V protein and one of the signaling molecules revealed that the V protein interacted with not only IRF7 but also TRAF6, IKKα, and MyD88. Whereas overexpression of TRAF6 markedly enhanced the level of V protein associating with IRF7, IKKα, and MyD88 in HEK293T cells, the level of V protein associating with TRAF6 was little affected by overexpression of IRF7, IKKα, and MyD88. Moreover, knockdown or knockout of endogenous TRAF6 in HEK293T or mouse embryonic fibroblast cells resulted in dissociation of the V protein from IRF7, IKKα, and MyD88. These results demonstrate that binding of the V protein to IRF7, IKKα, and MyD88 is largely indirect and mediated by endogenous TRAF6. It was found that the V protein inhibited TRAF6-mediated lysine 63 (K63)-linked polyubiquitination of IRF7, which is prerequisite for IRF7 activation. Disruption of the tryptophan-rich motif of the V protein significantly affected its TRAF6-binding efficiency, which correlated well with the magnitude of inhibition of K63-linked polyubiquitination and the resultant activation of IRF7. Taken together, these results suggest that the HPIV2 V protein prevents TLR7/9-dependent interferon induction by inhibiting TRAF6-mediated K63-linked polyubiquitination of IRF7.
doi:10.1128/JVI.03525-12
PMCID: PMC3700191  PMID: 23678181
5.  EGFRvIII Mediates Hepatocellular Carcinoma Cell Invasion by Promoting S100 Calcium Binding Protein A11 Expression 
PLoS ONE  2013;8(12):e83332.
Epidermal growth factor receptor (EGFR) is frequently aberrantly expressed in cancer, and abnormal signalling downstream of this receptor contributes to tumour growth. EGFR variant III (EGFRvIII) is the most commonly altered form of EGFR and contains a truncated ligand-binding domain. Aberrant signalling downstream of this receptor contributes to tumour invasion. We previously reported that EGFRvIII can promote hepatocellular carcinoma (HCC) invasion. However, little is known concerning the mechanisms underlying EGFRvIII-mediated increases in cell motility and invasion in HCC. In this study, we observed that S100A11 was significantly upregulated in Huh-7 cells that overexpressed EGFRvIII. Moreover, S100A11 expression was elevated in HCC tissue samples (68.6%; 35/51), and this elevation was correlated with EGFRvIII expression (p = 0.0020; n = 20). Furthermore, the overexpression of S100A11 can promote HCC cell invasiveness, whereas siRNA against S100A11 can suppress the invasiveness of HCC cells stably transfected with EGFRvIII. Additionally, STAT3 inhibitors can block S100A11 expression and S100A11 promoter activity in HCC cells with stable overexpression of EGFRvIII. Furthermore, mutation in STATx binding sites could abolish the S1000A11 promoter activity stimulation by EGFRvIII. Taken together, the results demonstrate that the EGFRvIII-STAT3 pathway promotes cell migration and invasion by upregulating S100A11.
doi:10.1371/journal.pone.0083332
PMCID: PMC3869758  PMID: 24376686
6.  The Prognostic Value of Phosphorylated AKT Expression in Non-Small Cell Lung Cancer: A Meta-Analysis 
PLoS ONE  2013;8(12):e81451.
Objectives
Phosphorylated AKT (p-AKT), constitutive activation of AKT, is a potentially interesting prognostic marker and therapeutic target in non-small cell lung cancer (NSCLC). However, the available results of p-AKT expression in NSCLC are heterogeneous. Therefore, a meta-analysis of published researches investigating the prognostic relevance of p-AKT expression in patients with NSCLC was performed.
Materials and Methods
A literature search via PubMed, EMBASE and CNKI (China National Knowledge Infrastructure) databases was conducted. Data from eligible studies were extracted and included into meta-analysis using a random effects model.
Results
A total of 1049 patients from nine studies were included in the meta-analysis. Nine studies investigated the relationship between p-AKT expression and overall survival using univariate analysis, and five of these undertook multivariate analysis. The pooled hazard ratio (HR) for overall survival was 1.49 (95% confidence interval (CI): 1.01-2.20) by univariate analysis and 1.02 (95% CI: 0.54-1.95) by multivariate analysis.
Conclusion
Our study shows that positive expression of p-AKT is associated with poor prognosis in patients with NSCLC. However, adequately designed prospective studies need to perform.
doi:10.1371/journal.pone.0081451
PMCID: PMC3857807  PMID: 24349071
7.  The crystal structures of the α-subunit of the α2β2 tetrameric Glycyl-tRNA synthetase 
Aminoacyl-tRNA synthetases (AARSs) are ligases (EC.6.1.1.-) that catalyze the acylation of amino acids to their cognate tRNAs in the process of translating genetic information from mRNA to protein. Their amino acid and tRNA specificity are crucial for correctly translating the genetic code. Glycine is the smallest amino acid and the glycyl-tRNA synthetase (GlyRS) belongs to Class II AARSs. The enzyme is unusual because it can assume different quaternary structures. In eukaryotes, archaebac-teria and some bacteria, it forms an α2 homodimer. In some bacteria, GlyRS is an α2β2 heterotetramer and shows a distant similarity to α2 GlyRSs. The human pathogen eubacterium Campylobacter jejuni GlyRS (CjGlyRS) is an α2β2 heterotetramer and is similar to Escherichia coli GlyRS; both are members of Class IIc AARSs. The two-step aminoacylation reaction of tetrameric GlyRSs requires the involvement of both α- and β-subunits. At present, the structure of the GlyRS α2β2 class and the details of the enzymatic mechanism of this enzyme remain unknown. Here we report the crystal structures of the catalytic α-subunit of CjGlyRS and its complexes with ATP, and ATP and glycine. These structures provide detailed information on substrate binding and show evidence for a proposed mechanism for amino acid activation and the formation of the glycyl-adenylate intermediate for Class II AARSs.
doi:10.1007/s10969-012-9142-6
PMCID: PMC3691008  PMID: 23054484
Gly-tRNA synthetase; Catalytic subunit; ATP binding; Glycine binding
8.  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
9.  Structure of the CRISPR Interference Complex CSM Reveals Key Similarities with Cascade 
Molecular Cell  2013;52(1):124-134.
Summary
The Clustered Regularly Interspaced Palindromic Repeats (CRISPR) system is an adaptive immune system in prokaryotes. Interference complexes encoded by CRISPR-associated (cas) genes utilize small RNAs for homology-directed detection and subsequent degradation of invading genetic elements, and they have been classified into three main types (I–III). Type III complexes share the Cas10 subunit but are subclassifed as type IIIA (CSM) and type IIIB (CMR), depending on their specificity for DNA or RNA targets, respectively. The role of CSM in limiting the spread of conjugative plasmids in Staphylococcus epidermidis was first described in 2008. Here, we report a detailed investigation of the composition and structure of the CSM complex from the archaeon Sulfolobus solfataricus, using a combination of electron microscopy, mass spectrometry, and deep sequencing. This reveals a three-dimensional model for the CSM complex that includes a helical component strikingly reminiscent of the backbone structure of the type I (Cascade) family.
Graphical Abstract
Highlights
•The CSM complex from Sulfolobus solfataricus has been purified and characterized•EM reveals a helical backbone with striking similarities to the Cascade complex•Mass spectrometry defines the subunit stoichiometry and organization of the complex•CSM subunits are modified by methylation, acetylation, and phosphorylation
doi:10.1016/j.molcel.2013.08.020
PMCID: PMC3807668  PMID: 24119402
10.  Copper Sulfide Nanoparticles as a New Class of Photoacoustic Contrast Agent for Deep Tissue Imaging at 1064-nm 
ACS nano  2012;6(8):7489-7496.
Photoacoustic tomography (PAT) is an emerging molecular imaging modality. Here, we demonstrate use of semiconductor copper sulfide nanoparticles (CuS NP) for PAT with an Nd:YAG laser at a wavelength of 1064 nm. CuS NP allowed visualization of mouse brain after intracranial injection, rat lymph nodes 12 mm below the skin after interstitial injection, and CuS NP-containing agarose gel embedded in chicken breast muscle at the depth of ~ 5 cm. This imaging approach has great potential for molecular imaging of breast cancer.
doi:10.1021/nn302782y
PMCID: PMC3429766  PMID: 22812694
photoacoustic tomography; CuS nanoparticles; 1064-nm laser; optical imaging
11.  Genetic polymorphisms of XPD and CDA and lung cancer risk 
Oncology Letters  2012;4(2):247-251.
To determine the susceptibility genes of lung cancer, we investigated the frequency distributions of the xeroderma pigmentosum complementary group D (XPD) and cytidine deaminase (CDA) genes in patients. A case-control study was conducted involving lung cancer patients and healthy controls. The genotypic distributions of XPD exon 10 G→A (Asp312Asn) and 23 T→G (Lys751Gln), and CDA 79 A→C (Lys27Gln) and 208 G→A (Ala70Thr), were determined using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The results demonstrated that the XPD Asp312Asn genotype distribution was G/G (82.52%) and A/G (17.48%) in the lung cancer patients, and G/G (82.52%), A/G (16.50%) and A/A (10.98%) in the controls. The genotypes of Lys751Gln were T/T (83.49%) and T/G (16.50%) in the lung cancer patients, and T/T (84.47%) and T/G (15.53%) in the controls. Mutations in the XPD single nucleotide polymorphism loci did not demonstrate a significant difference between the two groups (P>0.05). The risk of lung cancer in individuals with mutations at positions 312 and 751 increased 6.13-fold (P=0.047). The CDA Lys27Gln genotype distribution was A/A (78.65%), A/C (20.39%) and C/C (0.98%) in the lung cancer patients, and A/A (79.61%), A/C (19.42%) and C/C (0.98%) in the controls (P=0.985). The CDA Ala70Thr genotype distribution was G/G (98.06%) and A/G (1.94%) in the controls, while all the genotypes were wild-type in the lung cancer patients. The difference between the lung cancer patients and the controls was not statistically significant (P=0.155). There was also no significant difference in the frequency distribution of XPD or CDA between the different pathological types (P>0.05). Our findings demonstrate that the mutation of XPD codons 312 and 751 increases the risk of lung cancer. By contrast, polymorphisms of CDA appear to have little association with lung cancer.
doi:10.3892/ol.2012.716
PMCID: PMC3402721  PMID: 22844363
genetic polymorphisms; xeroderma pigmentosum complementary group D; cytidine deaminase; lung cancer
12.  Structural and functional characterization of microcin C resistance peptidase MccF from Bacillus anthracis 
Journal of molecular biology  2012;420(0):366-383.
Microcin C (McC) is heptapeptide-adenylate antibiotic produced by Escherichia coli strains carrying the mccABCDEF gene cluster encoding enzymes, in addition to the heptapeptide structural gene mccA, necessary for McC biosynthesis and self-immunity of the producing cell. The heptapeptide facilitates McC transport into susceptible cells, where it is processed releasing a non-hydrolyzable aminoacyl adenylate that inhibits an essential aminoacyl-tRNA synthetase. The self-immunity gene mccF encodes a specialized serine-peptidase that cleaves an amide bond connecting the peptidyl or aminoacyl moieties of, respectively, intact and processed McC with the nucleotidyl moiety. Most mccF orthologs from organisms other than E. coli are not linked to the McC biosynthesis gene cluster. Here, we show that a protein product of one such gene, MccF from Bacillus anthracis (BaMccF), is able to cleave intact and processed McC and we present a series of structures of this protein. Structural analysis of apo-BaMccF and its AMP-complex reveal specific features of MccF-like peptidases that allow them to interact with substrates containing nucleotidyl moieties. Sequence analyses and phylogenetic reconstructions suggest that several distinct subfamilies form the MccF clade of the large S66 family of bacterial serine peptidases. We show that various representatives of the MccF clade can specifically detoxify non-hydrolyzable aminoacyl adenylates differing in their aminoacyl moieties. We hypothesize that bacterial mccF genes serve as a source of bacterial antibiotic resistance.
doi:10.1016/j.jmb.2012.04.011
PMCID: PMC3690760  PMID: 22516613
MccF; serine peptidase; nucleophilic elbow; catalytic triad (Ser-His-Glu); substrate binding loop
13.  Global Identification of Peptidase Specificity by Multiplex Substrate Profiling 
Nature methods  2012;9(11):1095-1100.
A simple and rapid multiplex substrate profiling method has been developed to reveal the substrate specificity of any endo- or exo-peptidase using LC-MS/MS sequencing. A physicochemically diverse library of peptides was generated by incorporating all combinations of neighbor and near-neighbor amino acid pairs into decapeptide sequences that are flanked by unique dipeptides at each terminus. Addition of a panel of evolutionarily diverse peptidases to a mixture of these tetradecapeptides generated prime and non-prime site information and substrate specificity matched or expanded upon previous substrate motifs. This method biochemically confirmed the activity of the klassevirus 3C gene responsible for polypeptide processing and allowed Granzyme B substrates to be ranked by enzymatic turnover efficiency using label-free quantitation of precursor ion abundance. Furthermore, the proteolytic secretions from a parasitic flatworm larvae and a pancreatic cancer cell line were deconvoluted in a subtractive strategy using class-specific peptidase inhibitors.
doi:10.1038/nmeth.2182
PMCID: PMC3707110  PMID: 23023596
14.  Low Dose Decitabine Treatment Induces CD80 Expression in Cancer Cells and Stimulates Tumor Specific Cytotoxic T Lymphocyte Responses 
PLoS ONE  2013;8(5):e62924.
Lack of immunogenicity of cancer cells has been considered a major reason for their failure in induction of a tumor specific T cell response. In this paper, we present evidence that decitabine (DAC), a DNA methylation inhibitor that is currently used for the treatment of myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) and other malignant neoplasms, is capable of eliciting an anti-tumor cytotoxic T lymphocyte (CTL) response in mouse EL4 tumor model. C57BL/6 mice with established EL4 tumors were treated with DAC (1.0 mg/kg body weight) once daily for 5 days. We found that DAC treatment resulted in infiltration of IFN-γ producing T lymphocytes into tumors and caused tumor rejection. Depletion of CD8+, but not CD4+ T cells resumed tumor growth. DAC-induced CTL response appeared to be elicited by the induction of CD80 expression on tumor cells. Epigenetic evidence suggests that DAC induces CD80 expression in EL4 cells via demethylation of CpG dinucleotide sites in the promoter of CD80 gene. In addition, we also showed that a transient, low-dose DAC treatment can induce CD80 gene expression in a variety of human cancer cells. This study provides the first evidence that epigenetic modulation can induce the expression of a major T cell co-stimulatory molecule on cancer cells, which can overcome immune tolerance, and induce an efficient anti-tumor CTL response. The results have important implications in designing DAC-based cancer immunotherapy.
doi:10.1371/journal.pone.0062924
PMCID: PMC3650049  PMID: 23671644
15.  Effects of medical adhesives in prevention of complications after endoscopic submucosal dissection 
AIM: To evaluate the use of medical adhesive spray in endoscopic submucosal dissection (ESD).
METHODS: Patients who underwent ESD between January 2009 and June 2012 (n = 173) were enrolled in the prospective randomized study. Two patients undergoing surgery due to severe intraoperative hemorrhage and failed hemostasis were excluded, and the remaining 171 patients were randomly divided into two groups: group A (medical adhesive group, n = 89) and group B (control group, n = 82). In group A, a medical adhesive spray was evenly applied after routine electrocoagulation and hemostasis using hemostatic clip after ESD. Patients in group B only treated with routine wound management. Intraoperative and postoperative data were collected and compared.
RESULTS: In all 171 patients, ESD was successfully completed. There was no significant difference in the average treatment time between groups A and B (59.4 min vs 55.0 min, respectively). The average length of hospital stay was significantly different between group A and B (8.89 d vs 9.90 d, respectively). The incidence of intraoperative perforation was 10.1% in group A and 9.8% in group B, and was not significantly different between the two groups. In all cases, perforations were successfully managed endoscopically and with conservative treatment. The incidence of postoperative delayed bleeding in group A was significantly lower than that in group B (0.00% vs 4.88%, respectively).
CONCLUSION: ESD is an effective minimally invasive treatment for gastrointestinal precancerous lesions or early-stage gastrointestinal cancer. Medical adhesive spray is effective in preventing delayed bleeding after ESD, and can thus reduce the average length of hospital stay.
doi:10.3748/wjg.v19.i17.2704
PMCID: PMC3645390  PMID: 23674879
Endoscopic submucosal dissection; Medical adhesive; Early-stage gastrointestinal cancer; Postoperative delayed bleeding; Intraoperative hemorrhage
16.  Meta-Analysis of Randomised Clinical Trials Comparing Idarubicin + Cytarabine with Daunorubicin + Cytarabine as the Induction Chemotherapy in Patients with Newly Diagnosed Acute Myeloid Leukaemia 
PLoS ONE  2013;8(4):e60699.
Background
To determine whether the use of idarubicin+cytarabine (IA) is more effective than the use of daunorubicin+cytarabine (DA) as induction chemotherapy for patients with newly diagnosed acute myeloid leukaemia.
Methods
A computer-based search was performed. Randomised trials comparing IA with DA as induction therapy for newly diagnosed AML were included in this meta-analysis. The primary outcome of interest for our analysis was survival (disease-free survival, event-free survival and overall survival); the secondary endpoint was complete remission.
Results
Ten trials with 4,060 patients were eligible for this meta-analysis. Our pooled results suggest that IA is associated with a significant advantage in CR (RR = 1·23; 95% CI = 1·07–1·41, p = 0.004), EFS (HR = 0·64; 95% CI = 0·45–0·91, p = 0.013), and OS (HR = 0·88; 95% CI = 0·81–0·95, p = 0.02) but not in DFS (HR = 0·90; 95% CI = 0·80–1·00, p = 0.06). In the subgroup analysis, age had a significant interaction with OS and CR benefits.
Conclusion
Our analysis indicated that IA could improve the duration of overall survival compared to DA as induction therapy for young patients with newly diagnosed AML. Further study is needed to determine whether IA can produce clinical benefits in selected genetic or molecular subgroups of young AML patients.
doi:10.1371/journal.pone.0060699
PMCID: PMC3622517  PMID: 23593285
17.  Gambogic acid induces mitochondria-dependent apoptosis by modulation of Bcl-2 and Bax in mantle cell lymphoma JeKo-1 cells 
Objective
To study the mechanisms in gambogic acid (GA) -induced JeKo-1 human Mantle Cell Lymphoma cell apoptosis in vitro.
Methods
The proliferation of GA-treated JeKo-1 cells was measured by CCK-8 assay and Ki-67 immunocytochemical detection. Apoptosis, cell cycle and mitochondrial membrane potential were measured by flow cytometric analysis. Caspase-3, -8 and -9 were detected by colorimetric assay. Bcl-2 and Bax were analyzed by Western blotting.
Results
GA inhibited cell growth in a time- and dose- dependent manner. GA induces apoptosis in JeKo-1 cells but not in normal bone marrow cells, which was involved in reducing the membrane potential of mitochondria, activating caspases-3, -8 and -9 and decreasing the ratio of Bcl-2 and Bax without cell cycle arresting.
Conclusions
GA induced apoptosis in human MCL JeKo-1 cells by regulating Bcl-2/Bax and activating caspase-3, -8 and -9 via mitochondrial pathway without affecting cell cycle.
doi:10.3978/j.issn.1000-9604.2013.02.06
PMCID: PMC3626980  PMID: 23592899
Gambogic acid; JeKo-1 cells; cell cycle arrest, apoptosis; membrane potential of mitochondria; caspase-3; caspase-8; caspase-9; Bax; Bcl-2
18.  A PARALIND Decomposition-Based Coherent Two-Dimensional Direction of Arrival Estimation Algorithm for Acoustic Vector-Sensor Arrays 
Sensors (Basel, Switzerland)  2013;13(4):5302-5316.
In this paper, we combine the acoustic vector-sensor array parameter estimation problem with the parallel profiles with linear dependencies (PARALIND) model, which was originally applied to biology and chemistry. Exploiting the PARALIND decomposition approach, we propose a blind coherent two-dimensional direction of arrival (2D-DOA) estimation algorithm for arbitrarily spaced acoustic vector-sensor arrays subject to unknown locations. The proposed algorithm works well to achieve automatically paired azimuth and elevation angles for coherent and incoherent angle estimation of acoustic vector-sensor arrays, as well as the paired correlated matrix of the sources. Our algorithm, in contrast with conventional coherent angle estimation algorithms such as the forward backward spatial smoothing (FBSS) estimation of signal parameters via rotational invariance technique (ESPRIT) algorithm, not only has much better angle estimation performance, even for closely-spaced sources, but is also available for arbitrary arrays. Simulation results verify the effectiveness of our algorithm.
doi:10.3390/s130405302
PMCID: PMC3673138  PMID: 23604030
arbitrary array; acoustic vector-sensor; coherent angle estimation; PARALIND decomposition
19.  Absorbable implants versus metal implants for the treatment of ankle fractures: A meta-analysis 
This meta-analysis was performed to evaluate the efficiency and the safety of absorbable implants. Five major electronic databases (PubMed, Embase, Cochrane Library, SinoMed and Wanfang Data) were systematically searched for randomized controlled trials (RCTs) from their establishment to November 2012. Studies on absorbable implants and metal implants for ankle fractures were selected. The meta-analysis was performed using RevMan 5.1. Ten studies with 762 patients were included and analyzed. Compared with metal implants, absorbable implants used for the internal fixation of ankle fractures produce similar radiographic and functional outcomes (P= 0.52). Normally, removal of the internal fixation is unnecessary (P<0.0001) and the incidence of palpable implants is lower (P=0.02) for absorbable implants. No statistically significant difference was observed between the two groups with regard to foreign body reactions (P=0.07), infection (P= 0.69), osteoarthritis (P= 0.39), pain (P= 0.06), refracture (P=0.67), skin necrosis (P=0.99), deep vein thrombosis (P=0.21) and nerve injury (P=0.94). Absorbable implants used in ankle fractures rarely require reoperation and result in similar functional outcomes and complications compared with metal implants. These characteristics make them efficient and reasonably safe for the treatment of ankle fractures.
doi:10.3892/etm.2013.1017
PMCID: PMC3671805  PMID: 23737914
absorbable implant; metal implant; ankle fracture; meta-analysis
20.  The maximum standardized uptake value of 18 F-FDG PET scan to determine prognosis of hormone-receptor positive metastatic breast cancer 
BMC Cancer  2013;13:42.
Background
Whether PET scan maximum standard uptake value (SUVmax) could differentiate luminal A from luminal B and help predict the survival of metastatic breast cancer (MBC) patients with luminal subtype is still unknown and need to be investigated.
Methods
305 MBC patients with luminal subtypes were screened with PET/CT. Eligible patients were prospectively followed up.
Results
In total, 134 patients were eligible for this study. SUVmax was significantly related to the number of metastatic sites and presence of visceral metastasis on univariate analysis. SUVmax could not effectively differentiate patients with luminal A from luminal B subtype. Although luminal subtype at diagnosis could predict the relapse-free interval, it could not predict progression-free survival (PFS) or overall survival (OS) after developing relapse. In contrast, SUVmax was predictive of both PFS and OS and this effect was maintained in multivariate COX regression model.
Conclusions
SUVmax of MBC did not correlate with molecular subtypes of primary tumor. While molecular subtype may be a valuable prognostic factor at primary diagnosis of breast cancer, the SUVmax, rather than molecular subtype, does have a potential to predict independently in multivariate analysis for the PFS and OS in patients with metastatic disease of luminal subtype.
doi:10.1186/1471-2407-13-42
PMCID: PMC3583732  PMID: 23368410
Metastatic breast cancer; Luminal subtype; PET/CT; SUVmax; Prognosis
21.  Classification and Progression Based on CFS-GA and C5.0 Boost Decision Tree of TCM Zheng in Chronic Hepatitis B 
Chronic hepatitis B (CHB) is a serious public health problem, and Traditional Chinese Medicine (TCM) plays an important role in the control and treatment for CHB. In the treatment of TCM, zheng discrimination is the most important step. In this paper, an approach based on CFS-GA (Correlation based Feature Selection and Genetic Algorithm) and C5.0 boost decision tree is used for zheng classification and progression in the TCM treatment of CHB. The CFS-GA performs better than the typical method of CFS. By CFS-GA, the acquired attribute subset is classified by C5.0 boost decision tree for TCM zheng classification of CHB, and C5.0 decision tree outperforms two typical decision trees of NBTree and REPTree on CFS-GA, CFS, and nonselection in comparison. Based on the critical indicators from C5.0 decision tree, important lab indicators in zheng progression are obtained by the method of stepwise discriminant analysis for expressing TCM zhengs in CHB, and alterations of the important indicators are also analyzed in zheng progression. In conclusion, all the three decision trees perform better on CFS-GA than on CFS and nonselection, and C5.0 decision tree outperforms the two typical decision trees both on attribute selection and nonselection.
doi:10.1155/2013/695937
PMCID: PMC3568864  PMID: 23431345
22.  The contribution of TWIK-1 channels to astrocyte K+ current is limited by retention in intracellular compartments 
TWIK-1 two-pore domain K+ channels are expressed abundantly in astrocytes. In the present study, we examined the extent to which TWIK-1 contributes to the linear current-voltage (I–V) relationship (passive) K+ membrane conductance, a dominant electrophysiological feature of mature hippocampal astrocytes. Astrocytes from TWIK-1 knockout mice have a more negative resting potential than those from wild type animals and a reduction in both inward rectification and Cs+ permeability. Nevertheless, the overall whole-cell passive conductance is not altered significantly in TWIK-1 knockout astrocytes. The expression of Kir4.1 and TREK-1, two other major astrocytic K+ channels, or of other two-pore K+ channels is not altered in TWIK-1 knockout mice, suggesting that the mild effect of TWIK-1 knockout does not result from compensation by these channels. Fractionation experiments showed that TWIK-1 is primarily localized in intracellular cytoplasmic fractions (55%) and mildly hydrophobic internal compartment fractions (41%), with only 5% in fractions containing plasma membranes. Our study revealed that TWIK-1 proteins are mainly located in the intracellular compartments of hippocampal astrocyte under physiological condition, therefore a minimal contribution of TWIK-1 channels to whole-cell currents is likely attributable to a relatively low level presence of channels in the plasma membrane.
doi:10.3389/fncel.2013.00246
PMCID: PMC3856854  PMID: 24368895
astrocytes; TWIK-1 potassium channel; patch clamp; western blot; qRT-PCR
23.  Comparison between air and carbon dioxide insufflation in the endoscopic submucosal excavation of gastrointestinal stromal tumors 
AIM: To evaluate the safety and efficacy of CO2 insufflation compared with air insufflation in the endoscopic submucosal excavation (ESE) of gastrointestinal stromal tumors.
METHODS: Sixty patients were randomized to undergo endoscopic submucosal excavation, with the CO2 group (n = 30) and the air group (n = 30) undergoing CO2 insufflation and air insufflation in the ESE, respectively. The end-tidal CO2 level (pETCO2) was observed at 4 time points: at the beginning of ESE, at total removal of the tumors, at completed wound management, and 10 min after ESE. Additionally, the patients’ experience of pain at 1, 3, 6 and 24 h after the examination was registered using a visual analog scale (VAS).
RESULTS: Both the CO2 group and air group were similar in mean age, sex, body mass index (all P > 0.05). There were no significant differences in PetCO2 values before and after the procedure (P > 0.05). However, the pain scores after the ESE at different time points in the CO2 group decreased significantly compared with the air group (1 h: 21.2 ± 3.4 vs 61.5 ± 1.7; 3 h: 8.5 ± 0.7 vs 42.9 ± 1.3; 6 h: 4.4 ± 1.6 vs 27.6 ± 1.2; 24 h: 2.3 ± 0.4 vs 21.4 ± 0.7, P < 0.05). Meanwhile, the percentage of VAS scores of 0 in the CO2 group after 1, 3, 6 and 24 h was significantly higher than that in the air group (60.7 ± 1.4 vs 18.9 ± 1.5, 81.5 ± 2.3 vs 20.6 ± 1.2, 89.2 ± 0.7 vs 36.8 ± 0.9, 91.3 ± 0.8 vs 63.8 ± 1.3, respectively, P < 0.05). Moreover, the condition of the CO2 group was better than that of the air group with respect to anal exsufflation.
CONCLUSION: Insufflation of CO2 in the ESE of gastrointestinal stromal tumors will not cause CO2 retention and it may significantly reduce the level of pain, thus it is safe and effective.
doi:10.3748/wjg.v18.i48.7296
PMCID: PMC3544033  PMID: 23326136
Carbon dioxide insufflation; Endoscopic submucosal excavation; Gastrointestinal tract; Stromal tumor; Treatment
24.  The Prognostic Significance of the Serum p53 Protein Concentration in Chinese Patients with Non-Hodgkin Lymphoma 
Turkish Journal of Haematology  2012;29(4):376-384.
Objective: To investigate the prognostic significance of cytogenetic abnormalities, staging, patient factors, and the serum p53 protein concentration in Chinese non-Hodgkin lymphoma (NHL) patients.
Material and Methods: The study included 43 patients with NHL that were identified between August 2003 and December 2008. Patient clinical characteristics patients were determined based on morphological, immunohistochemical, and cytogenetic analysis, and the serum p53 protein concentration was measured quantitatively.
Results: Following conventional chemotherapy, the complete/partial remission (CR/PR) rate was significantly higher and overall survival (OS) was significantly longer in the patients with early-stage (stage I-II) lymphoma, normal karyotype, and a low serum p53 protein concentration than in those with advanced-stage (stage III-IV) lymphoma, cytogenetic abnormalities, and a high serum p53 protein concentration (≥0.35 U/mL). Bone marrow infiltration was also a predictor of poor response and OS. There weren’t any significant differences in disease remission between the male and female patients, older and younger patients (aged <70 years vs. ≥70 years), or B-cell lymphoma and T-cell lymphoma patients.
Conclusion: Staging is an effective means of assessing the severity of NHL. Cytogenetic examination can provide useful information for diagnosis, staging, and prognostication. The serum p53 protein level may be a potential prognostic marker in patients with NHL.
Conflict of interest:None declared.
doi:10.5505/tjh.2012.57338
PMCID: PMC3781622  PMID: 24385725
non-Hodgkin lymphoma; p53 protein; Karyotype
25.  Analysis of the expression of the Notch3 receptor protein in adult lung cancer 
Oncology Letters  2012;5(2):499-504.
Abnormalities in the Notch signaling system are considered to play a role in the tumorigenesis of bronchiogenic carcinoma. The present study aimed to investigate the expression of Notch3 in adult lung cancer patients and its role in the pathogenesis of primary bronchiogenic carcinoma. The expression of the Notch3 protein in lung squamous cell carcinoma, adenocarcinoma, small cell carcinoma and corresponding non-tumor tissues was detected by immunohistochemistry. To investigate the expression of Notch3 in adenocarcinoma tissues, Notch3 mRNA and protein expression were measured with reverse transcription polymerase chain reaction (RT-PCR) and western blot analysis, respectively. It was demonstrated that Notch3 had a stronger positive degree of expression in lung squamous cell carcinoma and adenocarcinoma compared with the corresponding non-tumor tissue (P<0.01). The expression of Notch3 in small cell carcinoma tissue was lower compared with that of the corresponding non-tumor tissue (P<0.01). The expression of Notch3 in the lung adenocarcinoma group was the highest of the three lung carcinoma groups (P<0.01). RT-PCR revealed that the expression of Notch3 mRNA in the lung adenocarcinoma group was higher than that of the normal lung group, but there was no statistically significant difference (P=0.05). The expression of Notch1 protein in the lung adenocarcinoma group was significantly higher compared with the normal lung group (P<0.01), as shown by western blot analysis. Notch3 may be involved in the pathogenesis of bronchogenic carcinoma, in particular in the promotion of the lung cancer oncogene, and a difference in its expression may exist in the various pathological types.
doi:10.3892/ol.2012.1033
PMCID: PMC3573152  PMID: 23420695
bronchiogenic carcinoma; Notch3; lung cancer

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