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1.  Percutaneous balloon kyphoplasty for the treatment of vertebral compression fractures 
BMC Surgery  2014;14:3.
Background
Vertebral compression fractures (VCFs) constitute a major health care problem, not only because of their high incidence but also because of their direct and indirect negative impacts on both patients’ health-related quality of life and costs to the health care system. Two minimally invasive surgical approaches were developed for the management of symptomatic VCFs: balloon kyphoplasty and vertebroplasty. The purpose of this study was to evaluate the effectiveness and safety of balloon kyphoplasty in the treatment of symptomatic VCFs.
Methods
Between July 2011 and June 2012, one hundred and eighty-seven patients with two hundred and fifty-one vertebras received balloon kyphoplasty in our hospital. There were sixty-five male and one hundred and twenty-two female patients with an average age of 74.5 (range, 61 to 95 years). The pain symptoms and quality of life, were measured before operation and at one day, three months, six months and one year following kyphoplasty. Radiographic data including restoration of kyphotic angle, anterior vertebral height, and any leakage of cement were defined.
Results
The mean visual analog pain scale decreased from a preoperative value of 7.7 to 2.2 at one day (p < .05) following operation and the Oswestry Disability Index improved from 56.8 to 18.3 (p < .05). The kyphotic angle improved from a mean of 14.4° before surgery to 6.7° at one day after surgery (p < .05). The mean anterior vertebral height increased significantly from 52% before surgery to 74.5% at one day after surgery (p < .05) and 70.2% at one year follow-up. Minor cement extravasations were observed in twenty-nine out of two hundred and fifty-one procedures, including six leakage via basivertebral vein, three leakage via segmental vein and twenty leakage through a cortical defect. None of the leakages were associated with any clinical consequences.
Conclusions
Balloon kyphoplasty not only rapidly reduced pain and disability but also restored sagittal alignment in our patients at one-year follow-up. The treatment of osteoporotic vertebral compression fractures with balloon kyphoplasty is a safe, effective, and minimally invasive procedure that provides satisfactory clinical results.
doi:10.1186/1471-2482-14-3
PMCID: PMC3922728  PMID: 24423182
2.  High-Resolution Transcriptomic Analyses of Sinorhizobium sp. NGR234 Bacteroids in Determinate Nodules of Vigna unguiculata and Indeterminate Nodules of Leucaena leucocephala 
PLoS ONE  2013;8(8):e70531.
The rhizobium-legume symbiosis is a model system for studying mutualistic interactions between bacteria and eukaryotes. Sinorhizobium sp. NGR234 is distinguished by its ability to form either indeterminate nodules or determinate nodules with diverse legumes. Here, we presented a high-resolution RNA-seq transcriptomic analysis of NGR234 bacteroids in indeterminate nodules of Leucaena leucocephala and determinate nodules of Vigna unguiculata. In contrast to exponentially growing free-living bacteria, non-growing bacteroids from both legumes recruited several common cellular functions such as cbb3 oxidase, thiamine biosynthesis, nitrate reduction pathway (NO-producing), succinate metabolism, PHB (poly-3-hydroxybutyrate) biosynthesis and phosphate/phosphonate transporters. However, different transcription profiles between bacteroids from two legumes were also uncovered for genes involved in the biosynthesis of exopolysaccharides, lipopolysaccharides, T3SS (type three secretion system) and effector proteins, cytochrome bd ubiquinol oxidase, PQQ (pyrroloquinoline quinone), cytochrome c550, pseudoazurin, biotin, phasins and glycolate oxidase, and in the metabolism of glutamate and phenylalanine. Noteworthy were the distinct expression patterns of genes encoding phasins, which are thought to be involved in regulating the surface/volume ratio of PHB granules. These patterns are in good agreement with the observed granule size difference between bacteroids from L. leucocephala and V. unguiculata.
doi:10.1371/journal.pone.0070531
PMCID: PMC3732241  PMID: 23936444
3.  Robust Markers Reflecting Phylogeny and Taxonomy of Rhizobia 
PLoS ONE  2012;7(9):e44936.
Genomic ANI (Average Nucleotide Identity) has been found to be able to replace DNA-DNA hybridization in prokaryote taxonomy. The ANI of each of the core genes that has a phylogeny congruent with the reference species tree of rhizobia was compared to the genomic ANI. This allowed us to identify three housekeeping genes (SMc00019-truA-thrA) whose ANI reflected the intraspecies and interspecies genomic ANI among rhizobial strains, revealing an ANI gap (≥2%) between the inter- and intra-species comparisons. The intraspecies (96%) and interspecies (94%) ANI boundaries calculated from three genes (SMc00019-truA-thrA) provided a criterion for bacterial species definition and confirmed 621/629 of known interspecies relationships within Bradyrhizobium, Mesorhizobium, Sinorhizobium and Rhizobium. Some widely studied strains should be renamed. The SMc00019-truA-thrA ANI also correlates well with the genomic ANI of strains in Agrobacterium, Methylobacterium, Ralstonia, Rhodopseudomonas, Cupriavidus and Burkholderia, suggesting their wide applicability in other bacteria.
doi:10.1371/journal.pone.0044936
PMCID: PMC3444505  PMID: 23028691
4.  Biodiversity and Biogeography of Rhizobia Associated with Soybean Plants Grown in the North China Plain ▿ †  
Applied and Environmental Microbiology  2011;77(18):6331-6342.
As the putative center of origin for soybean and the second largest region of soybean production in China, the North China Plain covers temperate and subtropical regions with diverse soil characteristics. However, the soybean rhizobia in this plain have not been sufficiently studied. To investigate the biodiversity and biogeography of soybean rhizobia in this plain, a total of 309 isolates of symbiotic bacteria from the soybean nodules collected from 16 sampling sites were studied by molecular characterization. These isolates were classified into 10 genospecies belonging to the genera Sinorhizobium and Bradyrhizobium, including four novel groups, with S. fredii (68.28%) as the dominant group. The phylogeny of symbiotic genes nodC and nifH defined four lineages among the isolates associated with Sinorhizobium fredii, Bradyrhizobium elkanii, B. japonicum, and B. yuanmingense, demonstrating the different origins of symbiotic genes and their coevolution with the chromosome. The possible lateral transfer of symbiotic genes was detected in several cases. The association between soil factors (available N, P, and K and pH) and the distribution of genospecies suggest clear biogeographic patterns: Sinorhizobium spp. were superdominant in sampling sites with alkaline-saline soils, while Bradyrhizobium spp. were more abundant in neutral soils. This study clarified the biodiversity and biogeography of soybean rhizobia in the North China Plain.
doi:10.1128/AEM.00542-11
PMCID: PMC3187167  PMID: 21784912
5.  In Silico Analysis Reveals Sequential Interactions and Protein Conformational Changes during the Binding of Chemokine CXCL-8 to Its Receptor CXCR1 
PLoS ONE  2014;9(4):e94178.
Chemokine CXCL-8 plays a central role in human immune response by binding to and activate its cognate receptor CXCR1, a member of the G-protein coupled receptor (GPCR) family. The full-length structure of CXCR1 is modeled by combining the structures of previous NMR experiments with those from homology modeling. Molecular docking is performed to search favorable binding sites of monomeric and dimeric CXCL-8 with CXCR1 and a mutated form of it. The receptor-ligand complex is embedded into a lipid bilayer and used in multi ns molecular dynamics (MD) simulations. A multi-steps binding mode is proposed: (i) the N-loop of CXCL-8 initially binds to the N-terminal domain of receptor CXCR1 driven predominantly by electrostatic interactions; (ii) hydrophobic interactions allow the N-terminal Glu-Leu-Arg (ELR) motif of CXCL-8 to move closer to the extracellular loops of CXCR1; (iii) electrostatic interactions finally dominate the interaction between the N-terminal ELR motif of CXCL-8 and the EC-loops of CXCR1. Mutation of CXCR1 abrogates this mode of binding. The detailed binding process may help to facilitate the discovery of agonists and antagonists for rational drug design.
doi:10.1371/journal.pone.0094178
PMCID: PMC3976404  PMID: 24705928
6.  Draft Genome Sequences of Two Arcobacter Strains Isolated from Human Feces 
Genome Announcements  2014;2(2):e00113-14.
Arcobacter species are members of the family Campylobacteraceae and are considered emerging enteropathogens and potential zoonotic agents. Here, we report the draft genome sequences of two Arcobacter strains isolated from human feces in an effort to provide further genetic resources for understanding the pathogenic dynamics and diversity of this important genus.
doi:10.1128/genomeA.00113-14
PMCID: PMC3974932  PMID: 24699950
7.  Deletion of miRNAs in bone marrow prevents streptozotocin-induced murine autoimmune diabetes but deletion of miR-155 does not 
Cell Cycle  2013;12(7):1151-1152.
doi:10.4161/cc.24365
PMCID: PMC3646871  PMID: 23528982
Dicer; miRNAs; type 1 diabetes; streptozotocin; mir-155; knockout mouse
8.  ppGpp Metabolism Is Involved in Heterocyst Development in the Cyanobacterium Anabaena sp. Strain PCC 7120 
Journal of Bacteriology  2013;195(19):4536-4544.
When deprived of a combined-nitrogen source in the growth medium, the filamentous cyanobacterium Anabaena sp. PCC 7120 (Anabaena) can form heterocysts capable of nitrogen fixation. The process of heterocyst differentiation takes about 20 to 24 h, during which extensive metabolic and morphological changes take place. Guanosine tetraphosphate (ppGpp) is the signal of the stringent response that ensures cell survival by adjusting major cellular activities in response to nutrient starvation in bacteria, and ppGpp accumulates at the early stage of heterocyst differentiation (J. Akinyanju, R. J. Smith, FEBS Lett. 107:173–176, 1979; J Akinyanju, R. J. Smith, New Phytol. 105:117–122, 1987). Here we show that all1549 (here designated relana) in Anabaena, homologous to relA/spoT, is upregulated in response to nitrogen deprivation and predominantly localized in vegetative cells. The disruption of relana strongly affects the synthesis of ppGpp, and the resulting mutant, all1549Ωsp/sm, fails to form heterocysts and to grow in the absence of a combined-nitrogen source. This phenotype can be complemented by a wild-type copy of relana. Although the upregulation of hetR is affected in the mutant, ectopic overexpression of hetR cannot rescue the phenotype. However, we found that the mutant rapidly loses its viability, within a time window of 3 to 6 h, following the deprivation of combined nitrogen. We propose that ppGpp plays a major role in rebalancing the metabolic activities of the cells in the absence of the nitrogen source supply and that this regulation is necessary for filament survival and consequently for the success of heterocyst differentiation.
doi:10.1128/JB.00724-13
PMCID: PMC3807476  PMID: 23935047
9.  The Intracrine Renin-Angiotensin System 
The renin-angiotensin system (RAS) is one of the earliest and most extensively studied hormonal systems. The RAS is an atypical hormonal system in several ways. The major bioactive peptide of the system, angiotensin (Ang) II, is neither synthesized in, nor targets one specific organ. New research has identified additional peptides with important physiological and pathological roles. More peptides also mean newer enzymatic cascades that generate these peptides and more receptors that mediate the function. In addition, completely different roles of components that constitute the RAS have been uncovered, such as that for prorenin via the prorenin receptor. Complexity of the RAS is further enhanced by the presence of sub-systems in tissues, which act in an autocrine/paracrine manner independent of the endocrine system. The RAS seems relevant at the cellular level, wherein individual cells have a complete system, termed the intracellular RAS. Thus, from cells to tissues to the entire organism, the RAS exhibits continuity while maintaining independent control at different levels. The intracellular RAS is a relatively new concept for the RAS. The current review presents a synopsis of the literature on this system in different tissues.
doi:10.1042/CS20120089
PMCID: PMC3965264  PMID: 22590974
10.  Proteomics Analysis of the DF-1 Chicken Fibroblasts Infected with Avian Reovirus Strain S1133 
PLoS ONE  2014;9(3):e92154.
Background
Avian reovirus (ARV) is a member of the Orthoreovirus genus in the Reoviridae family. It is the etiological agent of several diseases, among which viral arthritis and malabsorption syndrome are the most commercially important, causing considerable economic losses in the poultry industry. Although a small but increasing number of reports have characterized some aspects of ARV infection, global changes in protein expression in ARV-infected host cells have not been examined. The current study used a proteomics approach to obtain a comprehensive view of changes in protein levels in host cells upon infection by ARV.
Methodology and Principal Findings
The proteomics profiles of DF-1 chicken fibroblast cells infected with ARV strain S1133 were analyzed by two-dimensional differential-image gel electrophoresis. The majority of protein expression changes (≥1.5 fold, p<0.05) occurred at 72 h post-infection. Matrix-assisted laser desorption ionization time-of-flight mass spectrometry identified 51 proteins with differential expression levels, including 25 that were upregulated during ARV infection and 26 that were downregulated. These proteins were divided into eight groups according to biological function: signal transduction, stress response, RNA processing, the ubiquitin-proteasome pathway, lipid metabolism, carbohydrate metabolism, energy metabolism, and cytoskeleton organization. They were further examined by immunoblotting to validate the observed alterations in protein expression.
Conclusion/Significance
This is the first report of a time-course proteomic analysis of ARV-infected host cells. Notably, all identified proteins involved in signal transduction, RNA processing, and the ubiquitin-proteasome pathway were downregulated in infected cells, whereas proteins involved in DNA synthesis, apoptosis, and energy production pathways were upregulated. In addition, other differentially expressed proteins were linked with the cytoskeleton, metabolism, redox regulation, and stress response. These proteomics data provide valuable information about host cell responses to ARV infection and will facilitate further studies of the molecular mechanisms underlying ARV pathogenesis.
doi:10.1371/journal.pone.0092154
PMCID: PMC3965424  PMID: 24667214
11.  Celastrol Blocks Interleukin-6 Gene Expression via Downregulation of NF-κB in Prostate Carcinoma Cells 
PLoS ONE  2014;9(3):e93151.
Interleukin-6 (IL-6), a multifunctional cytokine, contributes to proliferation or differentiation of prostate carcinoma cells in a highly cell type-specific manner. Celastrol (3-hydroxy-24-nor-2oxo-1(10),3,5,7-friedelatetrane-29-oic acid), also named as tripterine, is extracted from root of Chinese traditional herb Tripterygiumwilfordii Hook f with potent anti-inflammatory and anti-cancer activities. In this study, we evaluated the molecular mechanisms of celastrol on cell proliferation and IL-6 gene expression in prostate carcinoma cells. 3H-thymidine incorporation and flow cytometric analysis indicated that celastrol treatments arrested the cell cycle at the G0/G1 phase, thus attenuating cell proliferation in prostate carcinoma PC-3 cells; moreover, celastrol induced cell apoptosis at higher dosage. Knockdown of IL-6 attenuated the anti-proliferative effect of celastrol on PC-3 cells. Results from ELISA and 5’-deletion transient gene expression assays indicated that celastrol treatment decreased IL-6 secretion and gene expression, and this effect is dependent on the NF-κB response element within IL-6 promoter area since mutation of the NF-κB response element from AAATGTCCCATTTTCCC to AAATGTTACATTTTCCC by site-directed mutagenesis abolished the inhibition of celastrol on the IL-6 promoter activity. Celastrol also attenuated the activation of PMA and TNFα on the gene expression and secretion of IL-6 in PC-3 cells. Immunoblot assays revealed that celastrol treatment downregulated the expressions of IKKα, p50 and p65, supporting the 5’-deletion transient gene expression assay result that celastrol blocked IL-6 expression through the NF-κB pathway in PC-3 cells. For the first time, our results concluded that celastrol attenuates PC-3 cell proliferation via downregulation of IL-6 gene expression through the NF-κB-dependent pathway.
doi:10.1371/journal.pone.0093151
PMCID: PMC3963984  PMID: 24664372
12.  Brain-Specific Phosphorylation of MeCP2 Regulates Activity-Dependent Bdnf Transcription, Dendritic Growth, and Spine Maturation 
Neuron  2006;52(2):255-269.
Summary
Mutations or duplications in MECP2 cause Rett and Rett-like syndromes, neurodevelopmental disorders characterized by mental retardation, motor dysfunction, and autistic behaviors. MeCP2 is expressed in many mammalian tissues and functions as a global repressor of transcription; however, the molecular mechanisms by which MeCP2 dysfunction leads to the neural-specific phenotypes of RTT remain poorly understood. Here, we show that neuronal activity and subsequent calcium influx trigger the de novo phosphorylation of MeCP2 at serine 421 (S421) by a CaMKII- dependent mechanism. MeCP2 S421 phosphorylation is induced selectively in the brain in response to physiological stimuli. Significantly, we find that S421 phosphorylation controls the ability of MeCP2 to regulate dendritic patterning, spine morphogenesis, and the activity-dependent induction of Bdnf transcription. These findings suggest that, by triggering MeCP2 phosphorylation, neuronal activity regulates a program of gene expression that mediates nervous system maturation and that disruption of this process in individuals with mutations in MeCP2 may underlie the neural-specific pathology of RTT.
doi:10.1016/j.neuron.2006.09.037
PMCID: PMC3962021  PMID: 17046689
13.  The Epidemic Characteristics and Changing Trend of Hemorrhagic Fever with Renal Syndrome in Hubei Province, China 
PLoS ONE  2014;9(3):e92700.
Background
Hemorrhagic fever with renal syndrome (HFRS) is caused by different hantaviruses within the Bunyaviridae family. HFRS is a fulminant, infectious disease that occurs worldwide and is endemic in all 31 provinces of China. Since the first HFRS case in Hubei Province was reported in 1957, the disease has spread across the province and Hubei has become one of the seriously affected areas in China with the greatest number of reported HFRS cases in the 1980's. However, the epidemic characteristics of HFRS in Hubei are still not entirely clear and long-term, systematic investigations of this epidemic area have been very limited.
Methods
The spatiotemporal distribution of HFRS was investigated using data spanning the years 1980 to 2009. The annual HFRS incidence, fatality rate and seasonal incidence between 1980 and 2009 were calculated and plotted. GIS-based spatial analyses were conducted to detect the spatial distribution and seasonal pattern of HFRS. A spatial statistical analysis, using Kulldorff's spatial scan statistic, was performed to identify clustering of HFRS.
Results
A total of 104,467 HFRS cases were reported in Hubei Province between 1980 and 2009. Incidence of and mortality due to HFRS declined after the outbreak in 1980s and HFRS cases have been sporadic in recent years. The locations and scale of disease clusters have changed during the three decades. The seasonal epidemic pattern of HFRS was characterized by the shift from the unimodal type (autumn/winter peak) to the bimodal type.
Conclusions
Socioeconomic development has great influence on the transmission of hantaviruses to humans and new epidemic characteristics have emerged in Hubei Province. It is necessary to reinforce preventative measures against HFRS according to the newly-presented seasonal variation and to intensify these efforts especially in the urban areas of Hubei Province.
doi:10.1371/journal.pone.0092700
PMCID: PMC3962441  PMID: 24658382
14.  Increased Risk of Major Depression in the Three Years following a Femoral Neck Fracture–A National Population-Based Follow-Up Study 
PLoS ONE  2014;9(3):e89867.
Femoral neck fracture is common in the elderly, and its impact has increased in aging societies. Comorbidities, poor levels of activity and pain may contribute to the development of depression, but these factors have not been well addressed. This study aims to investigate the frequency and risk of major depression after a femoral neck fracture using a nationwide population-based study. The Taiwan Longitudinal Health Insurance Database was used in this study. A total of 4,547 patients who were hospitalized for femoral neck fracture within 2003 to 2007 were recruited as a study group; 13,641 matched non-fracture participants were enrolled as a comparison group. Each patient was prospectively followed for 3 years to monitor the occurrence of major depression. Cox proportional-hazards models were used to compute the risk of major depression between members of the study and comparison group after adjusting for residence and socio-demographic characteristics. The most common physical comorbidities that were present after the fracture were also analyzed. The incidences of major depression were 1.2% (n = 55) and 0.7% (n = 95) in the study and comparison groups, respectively. The stratified Cox proportional analysis showed a covariate-adjusted hazard ratio of major depression among patients with femoral neck fracture that was 1.82 times greater (95% CI, 1.30–2.53) than that of the comparison group. Most major depressive episodes (34.5%) presented within the first 200 days following the fracture. In conclusion, patients with a femoral neck fracture are at an increased risk of subsequent major depression. Most importantly, major depressive episodes mainly occurred within the first 200 days following the fracture.
doi:10.1371/journal.pone.0089867
PMCID: PMC3953077  PMID: 24626193
15.  Significance of DNMT3b in Oral Cancer 
PLoS ONE  2014;9(3):e89956.
The aim of this study was to explore specific molecular markers that could lead to new insights into the identification of innovative treatments. The role of DNMT3b and its predictive power in the prognosis of oral cancer were identified. Human oral cancer cell lines including SCC4 and SCC25 were selected for cellular experiments. Changes in tumor growth, aggressiveness and the responsible signaling pathway were investigated in vitro and in vivo. Furthermore, 125 oral cancer tissue specimens were analyzed using immunohistochemical staining on tissue microarray slides, and correlations calculated between the level of DNMT3b and the clinical outcome of patients. Our data revealed that inhibition of DNMT3b resulted in slower tumor growth, attenuated tumor invasion ability and epithelial mesenchymal transition, as determined by in vitro and in vivo experiments. Activated IL-6 signaling might be responsible to the induction of DNMT3b overexpression on oral cancer. Regarding clinical data, the incidence of DNMT3b immunoreactivity in oral cancer specimens was significantly higher than in non-malignant epithelium, and positively linked to expression of IL-6. Furthermore, expression of DNMT3b was significantly linked with the risk of lymph node involvement, disease recurrence and shorter survival in patients with pathological stage III-IV oral cancer. In conclusion, IL-6 –DNMT3b axis could be used to predict the prognosis of oral cancer in clinics, and targeting DNMT3b could represent a promising treatment strategy.
doi:10.1371/journal.pone.0089956
PMCID: PMC3953114  PMID: 24625449
16.  Treatment of Stress Urinary Incontinence by Cinnamaldehyde, the Major Constituent of the Chinese Medicinal Herb Ramulus Cinnamomi 
Stress urinary incontinence (SUI) is a common disorder in middle-aged women and the elderly population. Although surgical treatment of SUI has progressed, pharmacological therapies remain unelucidated. We screened potential herbal medicines against SUI with an ex vivo organ bath assay. Ramulus Cinnamomi and its major constituent cinnamaldehyde cause a high contractile force of the urethra and a low contractile force of blood vessels. Cinnamaldehyde dose-dependently reduced lipopolysaccharide-induced nitric oxide (NO) production and inducible nitric oxide synthase (iNOS) expression in RAW 264.7 cells. In the vaginal distension- (VD-) induced SUI model in mice, cinnamaldehyde significantly reversed the VD-induced SUI physical signs and reduced blood pressure. Cinnamaldehyde may offer therapeutic potential against SUI without the possible side effect of hypertension. The modulation of several SUI-related proteins including myosin, iNOS, survival motor neuron (SMN) protein, and superoxide dismutase 3 (SOD3) may play some crucial roles in the therapeutic approach against SUI. This information may offer clues to the pathogenesis of SUI and open additional avenues for potential therapy strategies.
doi:10.1155/2014/280204
PMCID: PMC3966347
17.  Snx3 regulates recycling of the transferrin receptor and iron assimilation 
Cell metabolism  2013;17(3):343-352.
SUMMARY
Sorting of endocytic ligands and receptors is critical for diverse cellular processes. The physiological significance of endosomal sorting proteins in vertebrates, however, remains largely unknown. Here we report that sorting nexin 3 (Snx3) facilitates the recycling of transferrin receptor (Tfrc), and thus is required for the proper delivery of iron to erythroid progenitors. Snx3 is highly expressed in vertebrate hematopoietic tissues. Silencing of Snx3 results in anemia and hemoglobin defects in vertebrates due to impaired transferrin (Tf)-mediated iron uptake and its accumulation in early endosomes. This impaired iron assimilation can be complemented with non-Tf iron chelates. We show that Snx3 and Vps35, a component of the retromer, interact with Tfrc to sort it to the recycling endosomes. Our findings uncover a role of Snx3 in regulating Tfrc recycling, iron homeostasis, and erythropoiesis. Thus, the identification of Snx3 provides a genetic tool for exploring erythropoiesis and disorders of iron metabolism.
doi:10.1016/j.cmet.2013.01.013
PMCID: PMC3595351  PMID: 23416069
18.  Hepatitis B Virus X Upregulates HuR Protein Level to Stabilize HER2 Expression in Hepatocellular Carcinoma Cells 
BioMed Research International  2014;2014:827415.
Hepatitis B virus- (HBV-) associated hepatocellular carcinoma (HCC) is the most common type of liver cancer. However, the underlying mechanism of HCC tumorigenesis is very complicated and HBV-encoded X protein (HBx) has been reported to play the most important role in this process. Activation of downstream signal pathways of epidermal growth factor receptor (EGFR) family is known to mediate HBx-dependent HCC tumor progression. Interestingly, HER2 (also known as ErbB2/Neu/EGFR2) is frequently overexpressed in HBx-expressing HCC patients and is associated with their poor prognosis. However, it remains unclear whether and how HBx regulates HER2 expression. In this study, our data showed that HBx expression increased HER2 protein level via enhancing its mRNA stability. The induction of RNA-binding protein HuR expression by HBx mediated the HER2 mRNA stabilization. Finally, the upregulated HER2 expression promoted the migration ability of HBx-expressing HCC cells. These findings deciphered the molecular mechanism of HBx-mediated HER2 upregulation in HBV-associated HCC.
doi:10.1155/2014/827415
PMCID: PMC3955687  PMID: 24719890
19.  Association of Lower Extremity Arterial Calcification with Amputation and Mortality in Patients with Symptomatic Peripheral Artery Disease 
PLoS ONE  2014;9(2):e90201.
Objective
The clinical implication of the coronary artery calcium score (CS) is well demonstrated. However, little is known about the association between lower extremity arterial calcification and clinical outcomes.
Methods and Results
Eighty-two patients with symptomatic peripheral artery disease (age 61.0±12.4 years) were followed for 21±11 months. CSs, ranging from the common iliac artery bifurcation to the ankle area, were analyzed through noncontrast multidetector computed tomography images retrospectively. The primary endpoints of this study were amputation and mortality. Old age, diabetes, hyperlipidemia, and end-stage renal disease were associated with higher CSs. Patients with more advanced Fontaine stages also tended to have significantly higher CSs (p = 0.03). During the follow-up period (21±11 months), 29 (35%) patients underwent amputation, and 24 (29%) patients died. Among the patients who underwent amputation, there were no significant differences in CSs between the amputated legs and the non-amputated legs. In the Cox proportional hazard model with CS divided into quartiles, patients with CS in the highest quartile had a 2.88-fold (95% confidence interval [CI] 1.18–12.72, p = 0.03) and a 5.16-fold (95% CI 1.13–21.61, p = 0.04) higher risk for amputation and all-cause mortality, respectively, than those with CS in the lowest quartile. These predictive effects remained after conventional risk factor adjustment.
Conclusion
Lower extremity arterial CSs are associated with disease severity and outcomes, including amputation and all-cause mortality, in patients with symptomatic peripheral artery disease. However, the independent predictive value needs further investigation in large scale, prospective studies.
doi:10.1371/journal.pone.0090201
PMCID: PMC3936008  PMID: 24587279
20.  Effects of hyperbaric oxygen on the osteogenic differentiation of mesenchymal stem cells 
Background
Hyperbaric oxygenation was shown to increase bone healing in a rabbit model. However, little is known about the regulatory factors and molecular mechanism involved.We hypothesized that the effect of hyperbaric oxygen (HBO) on bone formation is mediated via increases in the osteogenic differentiation of mesenchymal stem cells (MSCs) which are regulated by Wnt signaling.
Methods
The phenotypic characterization of the MSCs was analyzed by flow cytometric analysis. To investigate the effects of HBO on Wnt signaling and osteogenic differentiation of MSCs, mRNA and protein levels of Wnt3a, beta-catenin, GSK-3beta, Runx 2, as well as alkaline phosphatase activity, calcium deposition, and the intensity of von Kossa staining were analyzed after HBO treatment. To investigate the effects of HBO on Wnt processing and secretion, the expression of Wntless and vacuolar ATPases were quantified after HBO treatment.
Results
Cells expressed MSC markers such as CD105, CD146, and STRO-1. The mRNA and protein levels of Wnt3a, β-catenin, and Runx 2 were up-regulated, while GSK-3β was down-regulated after HBO treatment. Western blot analysis showed an increased β-catenin translocation with a subsequent stimulation of the expression of target genes after HBO treatment. The above observation was confirmed by small interfering (si)RNA treatment. HBO significantly increased alkaline phosphatase activity, calcium deposition, and the intensity of von Kossa staining of osteogenically differentiated MSCs. We further showed that HBO treatment increased the expression of Wntless, a retromer trafficking protein, and vacuolar ATPases to stimulate Wnt processing and secretion, and the effect was confirmed by siRNA treatment.
Conclusions
HBO treatment increased osteogenic differentiation of MSCs via regulating Wnt processing, secretion, and signaling.
doi:10.1186/1471-2474-15-56
PMCID: PMC3938030  PMID: 24568330
Hyperbaric oxygen; Mesenchymal stem cells; Wntless; Retromer trafficking protein; Vacuolar ATPases
21.  Trichostatin A Suppresses EGFR Expression through Induction of MicroRNA-7 in an HDAC-Independent Manner in Lapatinib-Treated Cells 
BioMed Research International  2014;2014:168949.
Lapatinib, a dual EGFR/HER2 tyrosine kinase inhibitor, has been shown to improve the survival rate of patients with advanced HER2-positive breast cancers. However, the off-target activity of lapatinib in inducing EGFR expression without tyrosine kinase activity was demonstrated to render HER2-negative breast cancer cells more metastatic, suggesting a limitation to the therapeutic effectiveness of this dual inhibitor in HER2-heterogeneous tumors. Therefore, targeting EGFR expression may be a feasible approach to improve the anticancer efficiency of lapatinib-based therapy. Inhibition of HDAC has been previously reported to epigenetically suppress EGFR protein expression. In this study, however, our data indicated that treatment with HDAC inhibitors trichostatin A (TSA), but not suberoylanilide hydroxamic acid (SAHA) or HDAC siRNA, can attenuate both protein and mRNA expressions of EGFR in lapatinib-treated triple-negative breast cancer cells, suggesting that TSA may suppress EGFR expression independently of HDAC inhibition. Nevertheless, TSA reduced EGFR 3′UTR activity and induced the gene expression of microRNA-7, a known EGFR-targeting microRNA. Furthermore, treatment with microRNA-7 inhibitor attenuated TSA-mediated EGFR suppression. These results suggest that TSA induced microRNA-7 expression to downregulate EGFR expression in an HDAC-independent manner.
doi:10.1155/2014/168949
PMCID: PMC3950925
22.  A prospective study of age trends of high-risk human papillomavirus infection in rural China 
Background
In China, high-risk human papillomavirus (HR-HPV) prevalence is unexpectedly high in older women, but the possible reasons have not been well studied yet. This study investigated the age trends of HR-HPV infection in a prospective study.
Methods
A total of 7397 women aged 25-65 years without cervical precancer or cancer were evaluated during 2010-2011 with a stratified sample of 2791 women re-evaluated after one year. Test results for careHPV and careHPV16/18/45 were used to describe the HR-HPV prevalence, incidence and clearance. Risk factors associated with HR-HPV infections were explored using a logistic regression model.
Results
The overall HR-HPV prevalence was 13.1% at baseline, with a peak of 19.3% in women aged 55-59 years. The prevalence of HR-HPV (p for trends < 0.001), HPV16/18/45 (p for trends = 0.002), and HR-HPV other than HPV16/18/45 (p for trends = 0.002) generally increased with increasing age. Number of infections that cleared was generally greater than number of incident infections within age groups. One-year clearance rate decreased with increasing age (p for trends < 0.001), however, incidence rate was unrelated to age (p for trends = 0.159). Risk factors that associated with HR-HPV infection differed between younger and older women.
Conclusions
The greater HR-HPV prevalence in older versus younger women in rural China may be explained by a cohort effect, higher than expected incidence, and/or poorer clearance at older age.
doi:10.1186/1471-2334-14-96
PMCID: PMC3936871  PMID: 24559293
Human papillomavirus; Infection; Age; Risk factor; Cohort effect
23.  Topoisomerase Inhibitors Modulate Gene Expression of B-Cell Translocation Gene 2 and Prostate Specific Antigen in Prostate Carcinoma Cells 
PLoS ONE  2014;9(2):e89117.
Camptothecin (CPT) and doxorubicin (DOX) have been demonstrated to have potent anti-tumor activity. The B-cell translocation gene 2 (BTG2) is involved in the regulation of cell cycle progression. We evaluated the molecular mechanisms of CPT and DOX on cell proliferation and the expressions of BTG2 and prostate specific antigen (PSA) in prostate carcinoma cells. Our results indicated that CPT or DOX treatments induced Go/G1 cell cycle arrest in LNCaP cells and apoptosis at higher dosage. Immunoblot and transient gene expression assay indicated that CPT or DOX treatments induced p53 and BTG2 gene expression, with the later effect dependent on the p53 response element within BTG2 promoter area since mutation of the p53 response element from GGGAAAGTCC to GGAGTCC or from GGCAGAGCCC to GGCACC by site-directed mutagenesis abolished the stimulation of CPT or DOX on the BTG2 promoter activity, which is also supported by our results that cotreatments of pifithrin-α, an inhibitor of p53 dependent transcriptional activation, blocked the induction of CPT or DOX on BTG2 gene expression. CPT or DOX also downregulated the protein expressions of androgen receptor (AR) and PSA. Transient gene expression assays suggested that CPT or DOX’s attenuation of PSA promoter activity is dependent on both the androgen and p53 response elements within of the PSA promoter. Our results indicated that CPT and DOX attenuate cell proliferation via upregulation of BTG2 gene expression through the p53-dependent pathway. The CPT and DOX block the PSA gene expression by upregulation of p53 activity and downregulation of androgen receptor activity.
doi:10.1371/journal.pone.0089117
PMCID: PMC3930641  PMID: 24586533
24.  Draft Genome Sequence of Arcobacter cibarius Strain LMG21996T, Isolated from Broiler Carcasses 
Genome Announcements  2014;2(1):e00034-14.
The draft genome sequence of Arcobacter cibarius strain LMG21996T, isolated from chicken carcasses, is reported here. The draft genome consists of 2.2 Mbp, with a 27.12% G+C content. A total of 2,179 protein-coding genes, 46 tRNA genes, and 15 rRNAs have been identified and annotated.
doi:10.1128/genomeA.00034-14
PMCID: PMC3931353  PMID: 24558232
25.  Fibrin glue-assisted for the treatment of corneal perforations using glycerin-cryopreserved corneal tissue 
AIM
To evaluate the outcomes and safety of lamellar keratoplasty (LK) assisted by fibrin glue in corneal perforations.
METHODS
Six eyes of 6 patients affected by different corneal pathologies (2 posttraumatic corneal scar and 3 bacterial keratitis) underwent LK procedures by using fibrin glue. The mean corneal perforation diameter was 1.35±0.64mm (range, 0.7-2.5mm), and the greatest diameter of the ulcerative stromal defect was 2.47±0.77mm in average (range, 1.5-3.5mm). The donor corneal lamella diameters were 0.20-mm larger and thicker than the recipient to restore a physiologic corneal thickness and shape: mean donor diameter was 8.34±0.28mm (range, 8.2-8.7mm) and mean thickness was 352±40.27mm (range, 220-400mm). Mean follow-up was 7.33±1.97 months (range, 6-11 months). Postoperatively, the graft status, graft clarity, anterior chamber response, the visual prognosis, intraocular pressures, and postoperative complications were recorded.
RESULTS
All the corneal perforations were successfully healed after the procedure. The best-corrected visual acuity (BCVA) ranged from 20/1 000 to 20/50 in their initial presentation, and from 20/100 to 20/20 in their last visit, showed increase in all the patients. No major complications such as graft dislocation and graft failure were noted. Neovascularization developed in the superficial stroma of donor graft in 1 case. High intraocular pressure developed on day 2 after surgery, while was remained in normal range after application of anti-glaucomatous eyedrops for 1 week in 1 case.
CONCLUSION
Fibrin glue-assisted sutureless LK is valuable for maintaining the ocular integrity in the treatment of corneal perforations.
doi:10.3980/j.issn.2222-3959.2014.01.11
PMCID: PMC3949460  PMID: 24634865
fibrin glue corneal perforation; lamellar keratoplasty

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