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1.  Opposite Effects of Gene Deficiency and Pharmacological Inhibition of Soluble Epoxide Hydrolase on Cardiac Fibrosis 
PLoS ONE  2014;9(4):e94092.
Arachidonic acid-derived epoxyeicosatrienoic acids (EETs) are important regulators of cardiac remodeling; manipulation of their levels is a potentially useful pharmacological strategy. EETs are hydrolyzed by soluble epoxide hydrolase (sEH) to form the corresponding diols, thus altering and reducing the activity of these oxylipins. To better understand the phenotypic impact of sEH disruption, we compared the effect of EPHX2 gene knockout (EPHX2−/−) and sEH inhibition in mouse models. Measurement of plasma oxylipin profiles confirmed that the ratio of EETs/DHETs was increased in EPHX2−/− and sEH-inhibited mice. However, plasma concentrations of 9, 11, 15, 19-HETE were elevated in EPHX2−/− but not sEH-inhibited mice. Next, we investigated the role of this difference in cardiac dysfunction induced by Angiotensin II (AngII). Both EPHX2 gene deletion and inhibition protected against AngII-induced cardiac hypertrophy. Interestingly, cardiac dysfunction was attenuated by sEH inhibition rather than gene deletion. Histochemical staining revealed that compared with pharmacological inhibition, EPHX2 deletion aggravated AngII-induced myocardial fibrosis; the mRNA levels of fibrotic-related genes were increased. Furthermore, cardiac inflammatory response was greater in EPHX2−/− than sEH-inhibited mice with AngII treatment, as evidenced by increased macrophage infiltration and expression of MCP-1 and IL-6. In vitro, AngII-upregulated MCP-1 and IL-6 expression was significantly attenuated by sEH inhibition but promoted by EPHX2 deletion in cardiofibroblasts. Thus, compared with pharmacological inhibition of sEH, EPHX2 deletion caused the shift in arachidonic acid metabolism, which may led to pathological cardiac remodeling, especially cardiac fibrosis.
doi:10.1371/journal.pone.0094092
PMCID: PMC3981766  PMID: 24718617
2.  Crystal structure of NavAP, an orthologue of the NaChBac voltage-gated sodium channel 
Nature  2012;486(7401):130-134.
Voltage-gated sodium (Nav) channels are essential for the rapid depolarization of nerve and muscle1, and are important drug targets2. A family of bacterial Nav channels, exemplified by NaChBac (Na+-selective Channel of Bacteria)3, provides a good model system for structure-function analysis. Here we report the crystal structure of NavAP, a NaChBac orthologue from marine bacteria alpha proteobacterium HIMB114, at 3.05 Å resolution. The channel comprises an asymmetric tetramer. The carbonyl oxygen atoms of Thr178 and Leu179 constitute an inner site within the selectivity filter (178TLSSWE183) where a Ca2+ can bind and resides in the crystal structure. The outer mouth of the Na+ selectivity filter, defined by Ser181 and Glu183, is closed, as is the activation gate at the intracellular side of the pore. The voltage sensors adopt a depolarized conformation with all the gating charges exposing to the extracellular side. We hypothesize that NavAP is captured in an inactivated conformation. Comparison of NavAP with NavAb4 reveals significant conformational rearrangements that may underlie the electromechanical coupling mechanism of voltage-gated channels.
doi:10.1038/nature11054
PMCID: PMC3979295  PMID: 22678295
3.  Regulation of drug-induced liver injury by signal transduction pathways: critical role of mitochondria 
Drugs that cause liver injury often “stress” mitochondria and activate signal transduction pathways important in determining cell survival or death. In most cases, hepatocytes adapt to the drug-induced stress by activating adaptive signaling pathways, such as mitochondrial adaptive responses and erythroid 2-related factor 2 (Nrf-2), a transcription factor that upregulates antioxidant defenses. Due to adaptation, drugs alone rarely cause liver injury, with acetaminophen being the notable exception. Drug-induced liver injury (DILI) usually involves other extrinsic factors, such as the adaptive immune system, that cause “stressed” hepatocytes to become injured; leading to idiosyncratic DILI, the rare and unpredictable adverse drug reaction in the liver. Hepatocyte injury, due to drug and extrinsic insult, causes a second wave of signaling changes associated with adaptation, cell death, and repair. If the stress and injury reach a critical threshold, then death signaling pathways such as JNK become dominant and hepatocytes enter a failsafe mode to undergo self-destruction. DILI can be seen as an active process involving recruitment of death signaling pathways that mediate cell death rather than a passive process due to overwhelming biochemical injury. In this review, we highlight the role of signal transduction pathways, which frequently involve mitochondria, in the development of DILI.
doi:10.1016/j.tips.2013.01.009
PMCID: PMC3622802  PMID: 23453390
4.  Filtering of surface EMG using ensemble empirical mode decomposition 
Medical engineering & physics  2012;35(4):537-542.
Surface electromyogram (EMG) is often corrupted by three types of noises, i.e. power line interference (PLI), white Gaussian noise (WGN), and baseline wandering (BW). A novel framework based primarily on empirical mode decomposition (EMD) was developed to reduce all the three noise contaminations from surface EMG. In addition to regular EMD, the ensemble EMD (EEMD) was also examined for surface EMG denoising. The advantages of the EMD based methods were demonstrated by comparing them with the traditional digital filters, using signals derived from our routine electrode array surface EMG recordings. The experimental results demonstrated that the EMD based methods achieved better performance than the conventional digital filters, especially when the signal to noise ratio of the processed signal was low. Among all the examined methods, the EEMD based approach achieved the best surface EMG denoising performance.
doi:10.1016/j.medengphy.2012.10.009
PMCID: PMC3769943  PMID: 23245684
Surface electromyography (EMG); Denoising; Empirical mode decomposition (EMD); Ensemble empirical mode decomposition (EEMD)
5.  An Analysis of HLA-A, -B, and -DRB1 Allele and Haplotype Frequencies of 21,918 Residents Living in Liaoning, China 
PLoS ONE  2014;9(4):e93082.
HLA-A, -B and -DRB1 allele frequencies and their haplotype frequencies in 21,918 Chinese residents living in Liaoning Province, who were registered as volunteer donors of China Marrow Donor Registry, were investigated. They are composed of 93.37% Han Chinese, 5.1% Manchus, 0.57% Mongols, 0.46% Hui persons, 0.29% Koreans and 0.14% Xibe ethnic group. In total eighteen different HLA-A alleles, forty-eight different HLA-B alleles and fourteen different HLA-DRB1 alleles have been identified. Their frequencies are in agreement with the Hardy-Weinberg equilibrium. For Han Chinese in Liaoning, 1,534 different HLA-A-B-DRB1 haplotypes were identified, with a frequency of higher than 0.01%. A*30-B*13-DRB1*07, A*02-B*46-DRB1*09 and A*02-B*13-DRB1*12 are the most frequent haplotypes among Liaoning Han. While Liaoning Han, Liaoning Manchu, Liaoning Mongol, Liaoning Hui and Liaoning Korean share the northern Han characteristic haplotypes, all minority ethnic groups with the exception of Liaoning Manchu have developed their own unique HLA profiles. This dataset characterizes the HLA allele and haplotype frequencies in the Liaoning area and suggests that it is different from those in other parts of China and ethnic groups, which implicates transplant donor searching strategies and studies on population genetics.
doi:10.1371/journal.pone.0093082
PMCID: PMC3972227  PMID: 24691290
6.  The Cytosolic DNA Sensor cGAS Forms An Oligomeric Complex with DNA and Undergoes Switch-like Conformational Changes in the Activation Loop 
Cell reports  2014;6(3):421-430.
The presence of DNA in the cytoplasm is a danger signal that triggers immune and inflammatory responses. Cytosolic DNA binds to and activates cyclic GMP-AMP (cGAMP) synthase (cGAS), which produces the second messenger cGAMP. cGAMP binds to the adaptor protein STING and activates a signaling cascade that leads to the production of type-I interferons and other cytokines. Here we report the crystal structures of human cGAS in its apo form, representing its auto-inhibited conformation, as well as cGAMP-bound and sulfate-bound forms. These structures reveal switch-like conformational changes of an activation loop that result in the rearrangement of the catalytic site. The structure of DNA-bound cGAS reveals a complex composed of dimeric cGAS bound to two molecules of DNA. Functional analyses of cGAS mutants demonstrate that both the protein-protein interface and the two DNA binding surfaces are critical for cGAS activation. These results provide new insights into the mechanism of DNA sensing by cGAS.
doi:10.1016/j.celrep.2014.01.003
PMCID: PMC3969844  PMID: 24462292
7.  Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells Alleviate Liver Fibrosis 
Stem Cells and Development  2012;22(6):845-854.
Mesenchymal stem cells (MSCs) have been considered as an attractive tool for the therapy of diseases. Exosomes excreted from MSCs can reduce myocardial ischemia/reperfusion damage and protect against acute tubular injury. However, whether MSC-derived exosomes can relieve liver fibrosis and its mechanism remain unknown. Previous work showed that human umbilical cord-MSCs (hucMSCs) transplanted into acutely injured and fibrotic livers could restore liver function and improve liver fibrosis. In this study, it was found that transplantation of exosomes derived from hucMSC (hucMSC-Ex) reduced the surface fibrous capsules and got their textures soft, alleviated hepatic inflammation and collagen deposition in carbon tetrachloride (CCl4)-induced fibrotic liver. hucMSC-Ex also significantly recovered serum aspartate aminotransferase (AST) activity, decreased collagen type I and III, transforming growth factor (TGF)-β1 and phosphorylation Smad2 expression in vivo. In further experiments, we found that epithelial-to-mesenchymal transition (EMT)-associated markers E-cadherin-positive cells increased and N-cadherin- and vimentin-positive cells decreased after hucMSC-Ex transplantation. Furthermore, the human liver cell line HL7702 underwent typical EMT after induction with recombinant human TGF-β1, and then hucMSC-Ex treatment reversed spindle-shaped and EMT-associated markers expression in vitro. Taken together, these results suggest that hucMSC-Ex could ameliorate CCl4-induced liver fibrosis by inhibiting EMT and protecting hepatocytes. This provides a novel approach for the treatment of fibrotic liver disease.
doi:10.1089/scd.2012.0395
PMCID: PMC3585469  PMID: 23002959
8.  Heritable Multiplex Genetic Engineering in Rats Using CRISPR/Cas9 
PLoS ONE  2014;9(3):e89413.
The CRISPR/Cas9 system has been proven to be an efficient gene-editing tool for genome modification of cells and organisms. Multiplex genetic engineering in rat holds a bright future for the study of complex disease. Here, we show that this system enables the simultaneous disruption of four genes (ApoE, B2m, Prf1, and Prkdc) in rats in one-step, by co-injection of Cas9 mRNA and sgRNAs into fertilized eggs. We further observed the gene modifications are germline transmittable, and confirmed the off-target mutagenesis and mosaicism are rarely detected by comprehensive analysis. Thus, the CRISPR/Cas9 system makes it possible to efficiently and reliably generate gene knock-out rats.
doi:10.1371/journal.pone.0089413
PMCID: PMC3943732  PMID: 24598943
9.  The conformational shifts of the voltage sensing domains between NavRh and NavAb 
Cell Research  2012;23(3):444-447.
doi:10.1038/cr.2012.158
PMCID: PMC3587702  PMID: 23147793
10.  Analysis of the selectivity filter of the voltage-gated sodium channel NavRh 
Cell Research  2012;23(3):409-422.
NaChBac is a bacterial voltage-gated sodium (Nav) channel that shows sequence similarity to voltage-gated calcium channels. To understand the ion-permeation mechanism of Nav channels, we combined molecular dynamics simulation, structural biology and electrophysiological approaches to investigate the recently determined structure of NavRh, a marine bacterial NaChBac ortholog. Two Na+ binding sites are identified in the selectivity filter (SF) in our simulations: The extracellular Na+ ion first approaches site 1 constituted by the side groups of Ser181 and Glu183, and then spontaneously arrives at the energetically more favorable site 2 formed by the carbonyl oxygens of Leu179 and Thr178. In contrast, Ca2+ ions are prone to being trapped by Glu183 at site 1, which then blocks the entrance of both Na+ and Ca2+ to the vestibule of the SF. In addition, Na+ permeates through the selective filter in an asymmetrical manner, a feature that resembles that of the mammalian Nav orthologs. The study reported here provides insights into the mechanism of ion selectivity on Na+ over Ca2+ in mammalian Nav channels.
doi:10.1038/cr.2012.173
PMCID: PMC3587708  PMID: 23247626
voltage-gated ion channels; Nav channels; NaChBac; ion selectivity; permeation mechanism; structural asymmetry
11.  Multi-Scale Entropy Analysis of Different Spontaneous Motor Unit Discharge Patterns 
IEEE journal of biomedical and health informatics  2013;17(2):10.1109/JBHI.2013.2241071.
This study explores a novel application of multi-scale entropy (MSE) analysis for characterizing different patterns of spontaneous electromyogram (EMG) signals including sporadic, tonic and repetitive spontaneous motor unit discharges, and normal surface EMG baseline. Two algorithms for MSE analysis, namely the standard MSE and the intrinsic mode entropy (IMEn) (based on the recently developed multivariate empirical mode decomposition (MEMD) method), were applied to different patterns of spontaneous EMG. Significant differences were observed in multiple scales of the standard MSE and IMEn analyses (p < 0.001) for any two of the spontaneous EMG patterns, while such significance may not be observed from the single scale entropy analysis. Compared to the standard MSE, the IMEn analysis facilitates usage of a relatively low scale number to discern entropy difference among various patterns of spontaneous EMG signals. The findings from this study contribute to our understanding of the nonlinear dynamic properties of different spontaneous EMG patterns, which may be related to spinal motoneuron or motor unit health.
doi:10.1109/JBHI.2013.2241071
PMCID: PMC3831372  PMID: 24235117
Motor unit action potential; multi-scale entropy; spontaneous muscle activity; surface electromyography
12.  Multiple ITS Copies Reveal Extensive Hybridization within Rheum (Polygonaceae), a Genus That Has Undergone Rapid Radiation 
PLoS ONE  2014;9(2):e89769.
Background
During adaptive radiation events, characters can arise multiple times due to parallel evolution, but transfer of traits through hybridization provides an alternative explanation for the same character appearing in apparently non-sister lineages. The signature of hybridization can be detected in incongruence between phylogenies derived from different markers, or from the presence of two divergent versions of a nuclear marker such as ITS within one individual.
Methodology/Principal Findings
In this study, we cloned and sequenced ITS regions for 30 species of the genus Rheum, and compared them with a cpDNA phylogeny. Seven species contained two divergent copies of ITS that resolved in different clades from one another in each case, indicating hybridization events too recent for concerted evolution to have homogenised the ITS sequences. Hybridization was also indicated in at least two further species via incongruence in their position between ITS and cpDNA phylogenies. None of the ITS sequences present in these nine species matched those detected in any other species, which provides tentative evidence against recent introgression as an explanation. Rheum globulosum, previously indicated by cpDNA to represent an independent origin of decumbent habit, is indicated by ITS to be part of clade of decumbent species, which acquired cpDNA of another clade via hybridization. However decumbent and glasshouse morphology are confirmed to have arisen three and two times, respectively.
Conclusions
These findings suggested that hybridization among QTP species of Rheum has been extensive, and that a role of hybridization in diversification of Rheum requires investigation.
doi:10.1371/journal.pone.0089769
PMCID: PMC3937351  PMID: 24587023
13.  Innovative pharmaceutical development based on unique properties of nanoscale delivery formulation 
Nanoscale  2013;5(18):8307-8325.
The advent of nanotechnology has reignited interest in the field of pharmaceutical science for the development of nanomedicine. Nanomedicinal formulations are nanometer-sized carrier materials designed for increasing the drug tissue bioavailability, thereby improving the treatment of systemically applied chemotherapeutic drugs. Nanomedicine is a new approach to deliver the pharmaceuticals through different routes of administration with safer and more effective therapies compared to conventional methods. To date, various kinds of nanomaterials have been developed over the years to make delivery systems more effective for the treatment of various diseases. Even though nanomaterials have significant advantages due to their unique nanoscale properties, there are still significant challenges in the improvement and development of nanoformulations with composites and other materials. Here in this review, we highlight the nanomedicinal formulations aiming to improve the balance between the efficacy and the toxicity of therapeutic interventions through different routes of administration and how to design nanomedicine for safer and more effective ways to improve the treatment quality. We also emphasize the environmental and health prospects of nanomaterials for human health care.
doi:10.1039/c3nr01525d
PMCID: PMC3934102  PMID: 23860639
14.  Insulin induces drug resistance in melanoma through activation of the PI3K/Akt pathway 
Introduction
There is currently no curative treatment for melanoma once the disease spreads beyond the original site. Although activation of the PI3K/Akt pathway resulting from genetic mutations and epigenetic deregulation of its major regulators is known to cause resistance of melanoma to therapeutic agents, including the conventional chemotherapeutic drug dacarbazine and the Food and Drug Administration-approved mutant BRAF inhibitors vemurafenib and dabrafenib, the role of extracellular stimuli of the pathway, such as insulin, in drug resistance of melanoma remains less understood.
Objective
To investigate the effect of insulin on the response of melanoma cells to dacarbazine, and in particular, the effect of insulin on the response of melanoma cells carrying the BRAFV600E mutation to mutant BRAF inhibitors. An additional aim was to define the role of the PI3K/Akt pathway in the insulin-triggered drug resistance.
Methods
The effect of insulin on cytotoxicity induced by dacarbazine or the mutant BRAF inhibitor PLX4720 was tested by pre-incubation of melanoma cells with insulin. Cytotoxicity was determined by the MTS assay. The role of the PI3K/Akt pathway in the insulin-triggered drug resistance was examined using the PI3K inhibitor LY294002 and the PI3K and mammalian target of rapamycin dual inhibitor BEZ-235. Activation of the PI3K/Akt pathway was monitored by Western blot analysis of phosphorylated levels of Akt.
Results
Recombinant insulin attenuated dacarbazine-induced cytotoxicity in both wild-type BRAF and BRAFV600E melanoma cells, whereas it also reduced killing of BRAFV600E melanoma cells by PLX4720. Nevertheless, the protective effect of insulin was abolished by the PI3K and mTOR dual inhibitor BEZ-235 or the PI3K inhibitor LY294002.
Conclusion
Insulin attenuates the therapeutic efficacy of dacarbazine and PLX4720 in melanoma cells, which is mediated by activation of the PI3K/Akt pathway and can be overcome by PI3K inhibitors.
doi:10.2147/DDDT.S53568
PMCID: PMC3933667  PMID: 24600206
insulin; PI3K/Akt; melanoma; drug resistance; DTIC; BRAF inhibitors
15.  The geographic distribution of mammography resources in Mississippi 
OBJECTIVE: To determine whether the availability of mammography resources affected breast cancer incidence rates, stage of disease at initial diagnosis, mortality rates and/or mortality-to-incidence ratios throughout Mississippi. METHODS: Mammography facilities were geocoded and the numbers of residents residing within a thirty minute drive of a mammography facility were calculated. Other data were extracted from the Mississippi Cancer Registry, the U.S. Census, and the Mississippi Behavioral Risk Factor Surveillance Survey (BRFSS). RESULTS & DISCUSSION: There were no statistically-significant differences between breast cancer incidence rates in Black versus White females in Mississippi; however, there were significant differences in the use of mammography, percentages of advanced-stage initial diagnoses, mortality rates, and mortality-to-incidence ratios, where Black females fared worse in each category. No statistically-significant correlations were observed between breast cancer outcomes and the availability of mammography facilities. The use of mammography was negatively correlated with advanced stage of disease at initial diagnosis. By combining Black and White subsets, a correlation between mammography use and improved survival was detected; this was not apparent in either subset alone. There was also a correlation between breast cancer mortality-to-incidence ratios and the percentage of the population living below the poverty level. CONCLUSIONS: The accessibility and use of mammography resources has a greater impact on breast cancer in Mississippi than does the geographic resource distribution per se. Therefore, intensified mammography campaigns to reduce the percentage of advanced-stage breast cancers initially diagnosed in Black women, especially in communities with high levels of poverty, are warranted in Mississippi.
doi:10.5210/ojphi.v5i3.4982
PMCID: PMC3959918  PMID: 24678379
Breast Cancer; Mammography; Health Disparities; Geographic Information System (GIS)
16.  Single nucleotide polymorphism at alcohol dehydrogenase-1B is associated with risk of esophageal squamous cell carcinoma 
Background
Esophageal squamous incidence in many developed countries has increased dramatically over last decades, while the underlying mechanism of the biogenesis of ES was still unknown.
Methods
Here, we investigate 1001 subjects with esophageal cancer recruited from the affiliated hospital of Shanghai Jiao Tong University from Jan. 1, 2001 to Feb. 2, 2004. Single nucleotide polymorphism (SNP) of alcohol dehydrogenase-1B (ADH1B) was performed, and the recombinant plasimd containing ADH1B was constructed. Then, the ADH1B was purified and the enzymatic activity was assayed according to the methodology of Quayle. Furthermore, the effect of ADH1B on proliferation of human esophageal squamous cell lines was determined and the underlying mechanism of ADH1B was investigated.
Results
Logistic regression analyses revealed that subjects carrying the GG variant homozygote had a significant 2.81-fold (adjusted OR = 2.81; 95% CI = 2.18-3.62) increased risk of esophageal cancer. We found that SNP of ADH1B (GG) significantly promotes cell proliferation in ESGG. ADH1B (GG) could down-regulate endogenous ADH1B expression at posttranscriptional level. Moreover, re-expression of ADH1B in cells transfected with ADH1B (AA) significantly inhibits cell proliferation.
Conclusions
Our data implied that ADH1B (GG) could promote cell proliferation in human ESGG through regulating the enzyme activity of ADH1B. Therefore, we propose that ADH1B might be used as a therapeutic agent for human ESGG.
doi:10.1186/1475-2867-14-12
PMCID: PMC3922640  PMID: 24485404
Single nucleotide polymorphism; Alcohol dehydrogenase-1B; Esophageal squamous cell carcinoma
17.  Cyclic GMP-AMP Containing Mixed Phosphodiester Linkages Is An Endogenous High Affinity Ligand for STING 
Molecular cell  2013;51(2):10.1016/j.molcel.2013.05.022.
The presence of microbial or self DNA in the cytoplasm of mammalian cells is a danger signal detected by the DNA sensor cyclic-GMP-AMP (cGAMP) synthase (cGAS), which catalyzes the production of cGAMP that in turn serves as a second messenger to activate innate immune responses. Here we show that endogenous cGAMP in mammalian cells contains two distinct phosphodiester linkages, one between 2′-OH of GMP and 5′-phosphate of AMP, and the other between 3′-OH of AMP and 5′-phosphate of GMP. This molecule, termed 2′3′-cGAMP, is unique in that it binds to the adaptor protein STING with a much greater affinity than cGAMP molecules containing other combinations of phosphodiester linkages. The crystal structure of STING bound to 2′3′-cGAMP revealed the structural basis of this high-affinity binding and a ligand-induced conformational change in STING that may underlie its activation.
doi:10.1016/j.molcel.2013.05.022
PMCID: PMC3808999  PMID: 23747010
18.  Single-stage combined anterior retropharyngeal and posterior approach for the resection and reconstruction of C2 metastatic tumors: A case report 
This study reports the case of a 44-year-old male who had experienced severe neck pain for one month and was diagnosed with a metastatic tumor of the left C2 vertebral body and the left transverse process. The tumor was distributed to layers A–D and sectors 3–7 according to the Weinstein-Boriani-Biagini classification, and was in Category IV according to the Harrington classification system. A conventional posterior cervical approach was used to resect the left transverse process and part of the tumor in a piecemeal fashion, and spinal instrumentation was also performed. Gelfoam and absorbable hemostatic gauze were placed ventrally to the left vertebral artery and the left C3 nerve root over the tumor bed to prevent their accidental injury in the subsequent anterior approach. A high anterior retropharyngeal approach was then used to resect the tumorous C2 vertebral body by corpectomy and to perform anterior reconstruction. Six months after the surgery, the patient remained pain free. Therefore, C2 metastatic tumor resection and spinal reconstruction can be fulfilled by a single-stage combined high anterior retropharyngeal and posterior approach.
doi:10.3892/etm.2014.1493
PMCID: PMC3961110  PMID: 24660034
upper cervical spine; surgery; surgical approach
19.  Impact of Cigarette Smoking on Outcome of Hepatocellular Carcinoma after Surgery in Patients with Hepatitis B 
PLoS ONE  2014;9(1):e85077.
Background and Objectives
Cigarette smoking is a potential risk factor for hepatocellular carcinoma (HCC) initiation, partially through interaction with hepatitis B virus (HBV). We examined the hypothesis that cigarette smoking might be associated with HBV-related HCC recurrence and patient survival after curative surgery.
Patients and Methods
Data of 302 patients with HBV infection who had undergone curative resection for HCC were prospectively collected from 2008 to 2011. Smoking status and smoking quantity (pack-years, PY) were asked at admission. Factors affecting recurrence-free survival (RFS) were examined. RFS and liver-specific mortality (LSM) stratified by risk factors were compared with log-rank test.
Results
109 were current smokers. Current smokers were not different from non-smokers in tumor burden and surgical procedure. Univariate and multivariate analysis identified that heavy smoking (PY ≥20) was the most significant factor associated with HBV-related HCC recurrence after curative surgical resection (p = 0.001), followed by anti-HBV treatment (p<0.01), current smoking (p = 0.028), surgical margin <1 cm (p = 0.048) and blood transfusion >600 ml (p = 0.028). The median RFS in non-smokers, ex-smokers and current smokers was 34 months, 24 months and 26 months, respectively (p = 0.033). Current smokers had significantly worse RFS rate and increased 5-year cumulative LSM than non-smokers (p = 0.024, and p<0.001, respectively). Heavy smokers had significantly worse RFS than non- and light smokers (0
Conclusions
Smoking history and quantity appears to be risk factors for HBV-related HCC recurrence and LSM of patients after surgery. For smokers, continued smoking postoperatively might accelerate tumor recurrence and patient death. Therefore, smoking abstinence should be strongly recommended to patients pre- and postoperatively.
doi:10.1371/journal.pone.0085077
PMCID: PMC3893178  PMID: 24454795
The Scientific World Journal  2013;2013:303656.
Smart film crack monitoring method, which can be used for detecting initiation, length, width, shape, location, and propagation of cracks on real bridges, is proposed. Firstly, the fabrication of the smart film is developed. Then the feasibility of the method is analyzed and verified by the mechanical sensing character of the smart film under the two conditions of normal strain and crack initiation. Meanwhile, the coupling interference between parallel enameled wires of the smart film is discussed, and then low-frequency detecting signal and the custom communication protocol are used to decrease interference. On this basis, crack monitoring system with smart film is designed, where the collected crack data is sent to the remote monitoring center and the cracks are simulated and recurred. Finally, the monitoring system is applied to six bridges, and the effects are discussed.
doi:10.1155/2013/303656
PMCID: PMC3893004  PMID: 24489496
PLoS ONE  2013;8(12):e84073.
Anti-apoptotic Bcl-2 family proteins, in particular, Mcl-1, are known to play a critical role in resistance of human melanoma cells to induction of apoptosis by endoplasmic reticulum stress and other agents. The present study examined whether the BH3 mimetics, Obatoclax and ABT-737, which inhibit multiple anti-apoptotic Bcl-2 family proteins, would overcome resistance to apoptosis. We report that both agents induced a strong unfolded protein response (UPR) and that RNAi knockdown of UPR signalling proteins ATF6, IRE1α and XBP-1 inhibited Mcl-1 upregulation and increased sensitivity to the agents. These results demonstrate that inhibition of anti-apoptotic Bcl-2 proteins by Obatoclax and ABT-737 appears to elicit a protective feedback response in melanoma cells, by upregulation of Mcl-1 via induction of the UPR. We also report that Obatoclax, but not ABT-737, strongly induces autophagy, which appears to play a role in determining melanoma sensitivity to the agents.
doi:10.1371/journal.pone.0084073
PMCID: PMC3868604  PMID: 24367627
PLoS ONE  2013;8(12):e82789.
Neuronal precursor cell-expressed developmentally down-regulated 4-1 (NEDD4-1) plays a great role in tumor cell growth, but its function and mechanism in cell invasive behavior are totally unknown. Here we report that NEDD4-1 regulates migration and invasion of malignant glioma cells via triggering ubiquitination of cyclic nucleotide Ras guanine nucleotide exchange factor (CNrasGEF) using cultured glioma cells. NEDD4-1 overexpression promoted cell migration and invasion, while its downregulation specifically inhibited them. However, NEDD4-1 did not affect the proliferation and apoptosis of glioma cells. NEDD4-1 physically interacted with CNrasGEF and promoted its poly-ubiquitination and degradation. Contrary to the effect of NEDD4-1, CNrasGEF downregulation promoted cell migration and invasion, while its overexpression inhibited them. Importantly, downregulation of CNrasGEF facilitated the effect of NEDD4-1-induced cell migration and invasion. Interestingly, aberrant up-regulated NEDD4-1 showed reverse correlation with CNrasGEF protein level but not with its mRNA level in glioma tissues. Combined with the in vitro results, the result of glioma tissues indicated post-translationally modification effect of NEDD4-1 on CNrasGEF. Our study suggests that NEDD4-1 regulates cell migration and invasion through ubiquitination of CNrasGEF in vitro.
doi:10.1371/journal.pone.0082789
PMCID: PMC3858320  PMID: 24340059
PLoS ONE  2013;8(12):e82616.
Folate deficiency (FD) during pregnancy can cause fetal intrauterine growth restriction in pigs, of which the skeletal dysplasia is a major manifestation. Factors influencing muscle development are very important in the formation of porcine meat quality trait. However, the effect of folate deficiency on skeletal muscle development and its molecular mechanisms are unknown. The objective of this study is to determine the effect of maternal folate deficiency on the skeletal muscle transcriptome of piglets from a reciprocal cross, in which full-sibling Landrace (LR) and full-sibling Chinese local breed Laiwu (LW) pigs were used for reciprocal cross matings, and sows were fed either a folate deficient or a normal diet during early-mid gestation. In addition, the difference in the responsiveness of the piglets to folate deficiency during early-mid pregnancy between reciprocal cross groups was investigated. Longissimus dorsi (LD) muscle samples were collected from newborn piglets and a 4 × 44K Agilent porcine oligo microarray was used for transcriptome analysis of porcine LD muscle. The results showed that folate deficiency during early-mid pregnancy affected piglet body weight, LD muscle fiber number and content of intramuscular triglyceride. The microarray results indicated that 3154 genes were differentially expressed between folate deficient and normal piglets from the LR♂ × LW♀ cross, and 3885 differentially expressed genes (DEGs) in the ones from the LW♂ × LR♀ cross. From functional analyses, sow folate deficiency affected almost all biological processes in the progeny. Lipid metabolism-related genes and associated metabolic pathways were regulated extensively by folate deficiency, especially in LR♂ × LW♀ cross piglets. Most of the genes that are regulated by folate deficiency in the LD muscle of piglets were different between LR♂ × LW♀ and LW♂ × LR♀ crosses, suggesting some epigenetic effects of FD exist in genes underlying myogenesis and intramuscular fat deposition in piglets.
doi:10.1371/journal.pone.0082616
PMCID: PMC3857258  PMID: 24349320
Journal of virological methods  2012;186(1-2):126-131.
Noroviruses (NoVs) are a leading cause of epidemic acute gastroenteritis affecting millions of people worldwide. Understanding of NoV remains limited due to the lack of a cell culture system and small animal models. Currently, there are no available vaccines or antivirals against NoVs. In this study, an approach for large-scale production of anti-NoV antibodies for use as a potential treatment for NoV disease using passive immunization was evaluated. NoV-specific immunoglobulins (IgY) were produced by immunizing chickens with NoV P particles. The birds continuously produced high titers of antibodies in their eggs for at least 3 months, in which NoV-specific antibody levels reached 4.7-9.2 mg/egg yolk. The egg yolk antibodies strongly reacted with NoV P particles by both ELISA and Western blot and blocked NoV virus-like particle (VLP) and P particle binding to the histo-blood group antigen (HBGA) receptors with a BT50 of about 1:800. The blocking activity of the chicken IgY remained after an incubation at 70°C for 30 min or treatment at pH 4 to 9 for 3 h. These data suggested that chicken IgY could be a practical strategy for large-scale production of anti-NoV antibodies for potential use as passive immunization against NoV infection, as well as for diagnostic purposes.
doi:10.1016/j.jviromet.2012.07.002
PMCID: PMC3496071  PMID: 22867844
Norovirus; Immunoglobulin; IgY; Chicken; Norovirus P particle; Diarrhea
Voluntary surface electromyogram (EMG) signal is sometimes contaminated by spurious background spikes of both physiological and extrinsic or accidental origins. A novel method of muscle activity onset detection against such spurious spikes was proposed in this study based primarily on the sample entropy (SampEn) analysis of the surface EMG. The method takes advantage of the nonlinear properties of the SampEn analysis to distinguish voluntary surface EMG signals from spurious background spikes in the complexity domain. To facilitate muscle activity onset detection, the SampEn analysis of surface EMG was first performed to highlight voluntary EMG activity while suppressing spurious background spikes. Then, a SampEn threshold was optimized for muscle activity onset detection. The performance of the proposed method was examined using both semi-synthetic and experimental surface EMG signals. The SampEn based methods effectively reduced the detection error induced by spurious background spikes and achieved improved performance over the methods relying on conventional amplitude thresholding or its extended version in the Teager Kaiser Energy domain.
doi:10.1016/j.jelekin.2012.06.005
PMCID: PMC3514830  PMID: 22800657

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