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1.  Complete Genome Sequence of Klebsiella pneumoniae Sequence Type 17, a Multidrug-Resistant Strain Isolated during Tigecycline Treatment 
Genome Announcements  2014;2(6):e01337-14.
Klbesiella pneumoniae is one of the most important human pathogens and frequently causes many diseases. To facilitate the comparative genome analysis in tigecycline resistance mechanism, we report the complete chromosomal sequence of a multidrug-resistance K. pneumoniae strain before tigecycline treatment for reference genome.
doi:10.1128/genomeA.01337-14
PMCID: PMC4276827  PMID: 25540349
2.  Suv39h1 Mediates AP-2α-Dependent Inhibition of C/EBPα Expression during Adipogenesis 
Molecular and Cellular Biology  2014;34(12):2330-2338.
Previous studies have shown that CCAAT/enhancer-binding protein α (C/EBPα) plays a very important role during adipocyte terminal differentiation and that AP-2α (activator protein 2α) acts as a repressor to delay the expression of C/EBPα. However, the mechanisms by which AP-2α prevents the expression of C/EBPα are not fully understood. Here, we present evidence that Suv39h1, a histone H3 lysine 9 (H3K9)-specific trimethyltransferase, and G9a, a euchromatic methyltransferase, both interact with AP-2α and enhance AP-2α-mediated transcriptional repression of C/EBPα. Interestingly, we discovered that G9a mediates dimethylation of H3K9, thus providing the substrate, which is methylated by Suv39h1, to H3K9me3 on the C/EBPα promoter. The expression level of AP-2α was consistent with enrichment of H3K9me2 and H3K9me3 on the C/EBPα promoter in 3T3-L1 preadipocytes. Knockdown of Suv39h markedly increased C/EBPα expression and promoted adipogenesis. Conversely, ectopic expression of Suv39h1 delayed C/EBPα expression and impaired the accumulation of triglyceride, while simultaneous knockdown of AP-2α or G9a partially rescued this process. These findings indicate that Suv39h1 enhances AP-2α-mediated transcriptional repression of C/EBPα in an epigenetic manner and further inhibits adipocyte differentiation.
doi:10.1128/MCB.00070-14
PMCID: PMC4054298  PMID: 24732798
3.  Molecular Actions of Ovarian Cancer G Protein-Coupled Receptor 1 Caused by Extracellular Acidification in Bone 
Extracellular acidification occurs under physiologic and pathologic conditions, such as exercise, ischemia, and inflammation. It has been shown that acidosis has various adverse effects on bone. In recent years there has been increasing evidence which indicates that ovarian cancer G protein-coupled receptor 1 (OGR1) is a pH-sensing receptor and mediates a variety of extracellular acidification-induced actions on bone cells and other cell types. Recent studies have shown that OGR1 is involved in the regulation of osteoclast differentiation, survival, and function, as well as osteoblast differentiation and bone formation. Moreover, OGR1 also regulates acid-induced apoptosis of endplate chondrocytes in intervertebral discs. These observations demonstrate the importance of OGR1 in skeletal development and metabolism. Here, we provide an overview of OGR1 regulation ofosteoclasts, osteoblasts, and chondrocytes, and the molecular actions of OGR1 induced by extracellular acidification in the maintenance of bone health.
doi:10.3390/ijms151222365
PMCID: PMC4284713  PMID: 25479080
extracellular acidification; OGR1; osteoclasts; osteoblasts; endplate chondrocytes
4.  The Simultaneous Electrochemical Detection of Catechol and Hydroquinone with [Cu(Sal-β-Ala)(3,5-DMPz)2]/SWCNTs/GCE 
Sensors (Basel, Switzerland)  2014;14(12):22274-22284.
A glassy carbon electrode was modified with a copper(II) complex [Cu(Sal-β-Ala) (3,5-DMPz)2] (Sal = salicylaldehyde, β-Ala = β-alanine, 3,5-DMPz = 3,5-dimethylpyrazole) and single-walled carbon nanotubes (SWCNTs). The modified electrode was used to detect catechol (CT) and hydroquinone (HQ) and exhibited good electrocatalytic activities toward the oxidation of CT and HQ. The peak currents were linear with the CT and HQ concentrations over the range of 5–215 μmol·L−1 and 5–370 μmol·L−1 with corresponding detection limits of 3.5 μmol·L−1 and 1.46 μmol·L−1 (S/N = 3) respectively. Moreover, the modified electrode exhibited good sensitivity, stability and reproducibility for the determination of CT and HQ, indicating the promising applications of the modified electrode in real sample analysis.
doi:10.3390/s141222274
PMCID: PMC4299013  PMID: 25429411
copper(II) Schiff base complex; single-walled carbon nanotubes; modified electrode; catechol; hydroquinone; electrochemical detection
5.  The China PEACE (Patient-centered Evaluative Assessment of Cardiac Events) Retrospective Study of Acute Myocardial Infarction: Study Design China PEACE-Retrospective AMI Study Design 
Background
Cardiovascular diseases are rising as a cause of death and disability in China. To improve outcomes for patients with these conditions, the Chinese government, academic researchers, clinicians, and more than 200 hospitals have created China Patient-centered Evaluative Assessment of Cardiac Events (China-PEACE), a national network for research and performance improvement. The first study from China PEACE, the Retrospective Study of Acute Myocardial Infarction (China PEACE-Retrospective AMI Study), is designed to promote improvements in AMI quality of care by generating knowledge about the characteristics, treatments, and outcomes of patients hospitalized with acute myocardial infarction (AMI) across a representative sample of Chinese hospitals over the last decade.
Methods and Results
The China PEACE-Retrospective AMI Study will examine more than 18,000 patient records from 162 hospitals identified using a 2-stage cluster sampling design within economic-geographic regions. Records were chosen from 2001, 2006, and 2011 to identify temporal trends. Data quality will be monitored by a central coordinating center and will, in particular, address case ascertainment, data abstraction, and data management. Analyses will examine patient characteristics, diagnostic testing patterns, in-hospital treatments, in-hospital outcomes, and variation in results by time and site of care. In addition to publications, data will be shared with participating hospitals and the Chinese government to develop strategies to promote quality improvement.
Conclusions
The China PEACE-Retrospective AMI Study is the first to leverage the China PEACE platform to better understand AMI across representative sites of care and over the last decade in China. The China PEACE collaboration between government, academicians, clinicians and hospitals is poised to translate research about trends and patterns of AMI practices and outcomes into improved care for patients.
doi:10.1161/CIRCOUTCOMES.113.000441
PMCID: PMC4054693  PMID: 24221838
myocardial infarction; epidemiology; morbidity; mortality
6.  Relationship between post-operative cognitive dysfunction and regional cerebral oxygen saturation and β-amyloid protein*  
Objective: To investigate the relationship between post-operative cognitive dysfunction (POCD) and regional cerebral oxygen saturation (rSO2) and β-amyloid protein (Aβ) in patients undergoing laparoscopic pancreaticoduodenectomy. Methods: Fifty patients undergoing elective laparoscopic pancreaticoduodenectomy received five groups of neuropsychological tests 1 d pre-operatively and 7 d post-operatively, with continuous monitoring of rSO2 intra-operatively. Before anesthesia induction (t 0), at the beginning of laparoscopy (t 1), and at the time of pneumoperitoneum 120 min (t 2), pneumoperitoneum 240 min (t 3), pneumoperitoneum 480 min (t 4), the end of pneumoperitoneum (t 5), and 24 h after surgery, jugular venous blood was drawn respectively for the measurement of Aβ by enzyme-linked immunosorbent assay (ELISA). Results: Twenty-one cases of the fifty patients suffered from POCD after operation. We found that the maximum percentage drop in rSO2 (rSO2, %max) was significantly higher in the POCD group than in the non-POCD group. The rSO2, %max value of over 10.2% might be a potential predictor of neurocognitive injury for those patients. In the POCD group, the plasma Aβ levels after 24 h were significantly higher than those of pre-operative values (P<0.01). After 24 h, levels of plasma Aβ in the POCD group were significantly higher than those in the non-POCD group (P<0.01). Conclusions: The development of POCD in patients undergoing laparoscopic pancreaticoduodenectomy is associated with alterations of rSO2 and Aβ. Monitoring of rSO2 might be useful in the prediction of POCD, and Aβ might be used as a sensitive biochemical marker to predict the occurrence of POCD.
doi:10.1631/jzus.B1400130
PMCID: PMC4201315  PMID: 25294376
Laparoscopic pancreaticoduodenectomy; Regional cerebral oxygen saturation; β-Amyloid protein; Post-operative cognitive dysfunction
7.  ANKRD7 and CYTL1 are novel risk genes for alcohol drinking behavior 
Chinese medical journal  2012;125(6):1127-1134.
Background
Alcohol dependence (AD) is a complex disorder characterized by impaired control over drinking. It is determined by both genetic and environmental factors. The recent approach of genome-wide association study (GWAS) is a powerful tool for identifying complex disease-associated susceptibility alleles, however, a few GWASs have been conducted for AD, and their results are largely inconsistent. The present study aimed to screen the loci associated with alcohol-related phenotypes using GWAS technology.
Methods
A genome-wide association study with the behavior of regular alcohol drinking and alcohol consumption was performed to identify susceptibility genes associated with AD, using the Affymetrix 500K SNP array in an initial sample consisting of 904 unrelated Caucasian subjects. Then, the initial results in GWAS were replicated in three independent samples: 1972 Caucasians in 593 nuclear families, 761 unrelated Caucasian subjects, and 2955 unrelated Chinese Hans.
Results
Several genes were associated with the alcohol-related phenotypes at the genome-wide significance level, with the ankyrin repeat domain 7 gene (ANKRD7) showing the strongest statistical evidence for regular alcohol drinking and suggestive statistical evidence for alcohol consumption. In addition, certain haplotypes within the ANKRD7 and cytokine-like1 (CYTL1) genes were significantly associated with regular drinking behavior, such as one ANKRD7 block composed of the SNPs rs6466686-rs4295599-rs12531086 (P = 6.51×10–8). The association of alcohol consumption was successfully replicated with rs4295599 in ANKRD7 gene in independent Caucasian nuclear families and independent unrelated Chinese Hans, and with rs16836497 in CYTL1 gene in independent unrelated Caucasians. Meta-analyses based on both the GWAS and replication samples further supported the observed significant associations between the ANKRD7 or CYTL1 gene and alcohol consumption.
Conclusion
The evidence suggests that ANKRD7 and CYTL1 genes may play an important role in the variance in AD risk.
PMCID: PMC4174677  PMID: 22613542
alcohol dependence; ANKRD7; CYTL1; genome-wide association study
8.  Stigmasterol isolated from marine microalgae Navicula incerta induces apoptosis in human hepatoma HepG2 cells 
BMB Reports  2014;47(8):433-438.
Plant sterols have shown potent anti-proliferative effects and apoptosis induction against breast and prostate cancers. However, the effect of sterols against hepatic cancer has not been investigated. In the present study, we assessed whether the stigmasterol isolated from Navicula incerta possesses apoptosis inductive effect in hepatocarcimona (HepG2) cells. According to the results, Stigmasterol has up-regulated the expression of pro-apoptotic gene expressions (Bax, p53) while down-regulating the anti-apoptotic genes (Bcl-2). Probably via mitochondrial apoptosis signaling pathway. With the induction of apoptosis caspase-8, 9 were activated. The DNA damage and increase in apoptotic cell numbers were observed through Hoechst staining, annexin V staining and cell cycle analysis. According to these results, we can suggest that the stigmasterol shows potent apoptosis inductive effects and has the potential to be tested as an anti-cancer therapeutic against liver cancer. [BMB Reports 2014; 47(8): 433-438]
doi:10.5483/BMBRep.2014.47.8.153
PMCID: PMC4206714  PMID: 24286323
Apoptosis; Bcl-2 family; Caspase8; 9; Marine microalgae; Navicula incerta; Stigmasterol
9.  SmartMal: A Service-Oriented Behavioral Malware Detection Framework for Mobile Devices 
The Scientific World Journal  2014;2014:101986.
This paper presents SmartMal—a novel service-oriented behavioral malware detection framework for vehicular and mobile devices. The highlight of SmartMal is to introduce service-oriented architecture (SOA) concepts and behavior analysis into the malware detection paradigms. The proposed framework relies on client-server architecture, the client continuously extracts various features and transfers them to the server, and the server's main task is to detect anomalies using state-of-art detection algorithms. Multiple distributed servers simultaneously analyze the feature vector using various detectors and information fusion is used to concatenate the results of detectors. We also propose a cycle-based statistical approach for mobile device anomaly detection. We accomplish this by analyzing the users' regular usage patterns. Empirical results suggest that the proposed framework and novel anomaly detection algorithm are highly effective in detecting malware on Android devices.
doi:10.1155/2014/101986
PMCID: PMC4138728  PMID: 25165729
10.  p300-Dependent Acetylation of Activating Transcription Factor 5 Enhances C/EBPβ Transactivation of C/EBPα during 3T3-L1 Differentiation 
Molecular and Cellular Biology  2014;34(3):315-324.
Adipogenesis is a multistep process by which 3T3-L1 preadipocytes differentiate into mature adipocytes through mitotic clonal expansion (MCE) and terminal differentiation. The CCAAT/enhancer-binding protein β (C/EBPβ) is an important transcription factor that takes part in both of these processes. C/EBPβ not only transactivates C/EBPα and the peroxisome proliferator-activated receptor γ (PPARγ), which cause 3T3-L1 preadipocytes to enter terminal adipocyte differentiation, but also is required to activate cell cycle genes necessary for MCE. The identification of potential cofactors of C/EBPβ will help to explain how C/EBPβ undertakes these specialized roles during the different stages of adipogenesis. In this study, we found that activating transcription factor 5 (ATF5) can bind to the promoter of C/EBPα via its direct interaction with C/EBPβ (which is mediated via the p300-dependent acetylation of ATF5), leading to enhanced C/EBPβ transactivation of C/EBPα. We also show that p300 is important for the interaction of ATF5 with C/EBPβ as well as for the binding activity of this complex on the C/EBPα promoter. Consistent with these findings, overexpression of ATF5 and an acetylated ATF5 mimic both promoted 3T3-L1 adipocyte differentiation, whereas short interfering RNA-mediated ATF5 downregulation inhibited this process. Furthermore, we show that the elevated expression of ATF5 is correlated with an obese phenotype in both mice and humans. In summary, we have identified ATF5 as a new cofactor of C/EBPβ and examined how C/EBPβ and ATF5 (acetylated by a p300-dependent mechanism) regulate the transcription of C/EBPα.
doi:10.1128/MCB.00956-13
PMCID: PMC3911509  PMID: 24216764
11.  Neuroprotective Effects of Sulforaphane on Cholinergic Neurons in Mice with Alzheimer’s Disease-Like Lesions 
Alzheimer’s disease (AD) is a common neurodegenerative disease in elderly individuals, and effective therapies are unavailable. This study was designed to investigate the neuroprotective effects of sulforaphane (an activator of NF-E2-related factor 2) on mice with AD-like lesions induced by combined administration of aluminum and d-galactose. Step-down-type passive avoidance tests showed sulforaphane ameliorated cognitive impairment in AD-like mice. Immunohistochemistry results indicated sulforaphane attenuated cholinergic neuron loss in the medial septal and hippocampal CA1 regions in AD-like mice. However, spectrophotometry revealed no significant difference in acetylcholine level or the activity of choline acetyltransferase or acetylcholinesterase in the cerebral cortex among groups of control and AD-like mice with and without sulforaphane treatment. Sulforaphane significantly increased the numbers of 5-bromo-2'-deoxyuridine-positive neurons in the subventricular and subgranular zones in AD-like mice which were significantly augmented compared with controls. Atomic absorption spectrometry revealed significantly lower aluminum levels in the brains of sulforaphane-treated AD-like mice than in those that did not receive sulforaphane treatment. In conclusion, sulforaphane ameliorates neurobehavioral deficits by reducing cholinergic neuron loss in the brains of AD-like mice, and the mechanism may be associated with neurogenesis and aluminum load reduction. These findings suggest that phytochemical sulforaphane has potential application in AD therapeutics.
doi:10.3390/ijms150814396
PMCID: PMC4159858  PMID: 25196440
Alzheimer’s disease; sulforaphane; neurobehavior; cholinergic neuron
12.  Preparation of Triple-Negative Breast Cancer Vaccine through Electrofusion with Day-3 Dendritic Cells 
PLoS ONE  2014;9(7):e102197.
Dendritic cells (DCs) are professional antigen-presenting cells (APCs) in human immune system. DC-based tumor vaccine has met with some success in specific malignancies, inclusive of breast cancer. In this study, we electrofused MDA-MB-231 breast cancer cell line with day-3 DCs derived from peripheral blood monocytes, and explored the biological characteristics of fusion vaccine and its anti-tumor effects in vitro. Day-3 mature DCs were generated from day-2 immature DCs by adding cocktails composed of TNF-α, IL-1β, IL-6 and PEG2. Day-3 mature DCs were identified and electofused with breast cancer cells to generate fusion vaccine. Phenotype of fusion cells were identified by fluorescence microscope and flow cytometer. The fusion vaccine was evaluated for T cell proliferation, secretion of IL-12 and IFN-γ, and induction of tumor-specific CTL response. Despite differences in morphology, day-3 and day-7 DC expressed similar surface markers. The secretion of IL-12 and IFN-γ in fusion vaccine group was much higher than that in the control group. Compared with control group, DC-tumor fusion vaccine could better stimulate the proliferation of allogeneic T lymphocytes and kill more breast cancer cells (MDA-MB-231) in vitro. Day-3 DCs had the same function as the day-7 DCs, but with a shorter culture period. Our findings suggested that day-3 DCs fused with whole apoptotic breast cancer cells could elicit effective specific antitumor T cell responses in vitro and may be developed into a prospective candidate for adoptivet immunotherapy.
doi:10.1371/journal.pone.0102197
PMCID: PMC4103844  PMID: 25036145
13.  Comparative Analyses of Physiological Responses of Cynodon dactylon Accessions from Southwest China to Sulfur Dioxide Toxicity 
The Scientific World Journal  2014;2014:916595.
Sulfur dioxide (SO2), a major air pollutant in developing countries, is highly toxic to plants. To achieve better air quality and landscape, planting appropriate grass species in severe SO2 polluted areas is very critical. Cynodon dactylon, a widely used warm season turfgrass species, has good SO2-tolerant ability. In this study, we selected 9 out of 38 C. dactylon accessions from Southwest China as representatives of high, intermediate SO2-tolerant and SO2-sensitive accessions to comparatively analyze their physiological differences in leaves under SO2 untreated and treated conditions. Our results revealed that SO2-tolerant C. dactylon accessions showed higher soluble sugar, proline, and chlorophyll a contents under both SO2 treated and untreated conditions; higher chlorophyll b and carotenoid under SO2 treated condition; lower reactive oxygen species (ROS) level, oxidative damages, and superoxide dismutase (SOD) activities under SO2 treated condition; and higher peroxidase (POD) activities under SO2 untreated condition. Further results indicated that SO2-tolerant C. dactylon accessions had higher sulfur contents under both SO2 treated and untreated conditions, consistent with higher SO activities under both SO2 treated and untreated conditions, and higher SiR activities under SO2 treated condition. Taken together, our results indicated that SO2 tolerance of C. dactylon might be largely related to soluble sugar, proline and chlorophyll a contents, and SO enzyme activity.
doi:10.1155/2014/916595
PMCID: PMC4109121  PMID: 25097893
14.  Clinical Characteristics and Outcomes of Patients with Primary Lung Adenocarcinoma Harboring ALK Rearrangements Detected by FISH, IHC, and RT-PCR 
PLoS ONE  2014;9(7):e101551.
EML4-ALK is a new driver gene of non-small cell lung cancer and a target of crizotinib. The objectives of this study were to determine the frequency of ALK rearrangements in a large cohort of patients with primary lung adenocarcinoma and to analyze the association of ALK rearrangements with clinicopathological characteristics and clinical outcomes. The roles of fluorescence in situ hybridization (FISH), Ventana immunohistochemistry (IHC), and reverse transcriptase polymerase chain reaction (RT-PCR) in the detection of ALK rearrangements were evaluated. The ALK rearrangement was detected in 430 specimens from individual patients with primary lung adenocarcinoma using FISH and Ventana IHC based on tissue microarrays. The EGFR status was detected in all of the specimens through DNA sequencing. An RT-PCR was performed on 200 of the specimens and confirmed by sequencing. Of the 430 patients, 46 (10.7%) harbored ALK rearrangements. The ALK rearrangements were associated with a younger age and the EGFR wild type in comparison with ALK-negative patients. The sensitivity and specificity of the Ventana IHC were 100% and 98.2%, respectively, and the concordance rate between the FISH and the Ventana IHC was 98.4%. The sensitivity and specificity of RT-PCR were 95.5% and 87.0%, respectively, and the concordance rate between the FISH and the RT-PCR was 89.0%. The Cox analysis indicated that an early stage and EGFR-activating mutations were independently associated with a longer OS. This study demonstrated that ALK rearrangements are associated with a younger age and the EGFR wild type rather than with other clinicopathological factors. Although the FISH and Ventana IHC have better concordance, and RT-PCR is a more sensitive method and can identify different variants or partners, the IHC and RT-PCR need to be further evaluated in clinical trials to identify their roles in guiding patients’ targeted therapy using crizotinib.
doi:10.1371/journal.pone.0101551
PMCID: PMC4081522  PMID: 24992725
15.  Treatment protocols for growth hormone-secreting pituitary adenomas combined with craniofacial fibrous dysplasia: A case report of atypical McCune-Albright syndrome 
McCune-Albright syndrome (MAS) is a rare, post-zygotic (non-germline) disorder, characterized by hypersecretory endocrinopathies, fibrous dysplasia of the bone and café-au-lait macules. The most common endocrine dysfunction is gonadal hyperfunction; thus, hypersecretion of growth hormones (GHs) as a manifestation of endocrine hyperfunction in MAS is rarely reported. MAS affects both genders, although the majority of cases have been reported in young females. Atypical presentations of MAS, with only one or two of the classic symptoms, have been previously described, but remain particularly challenging due to the lack of a diagnostic phenotype. In patients with atypical MAS, analysis of mutations in the gene of the α-subunit of the stimulatory G-protein is limited; thus, diagnosis is based on clinical judgment. In the present study, a male with polyostotic fibrous dysplasia and GH-secreting pituitary adenomas, diagnosed with atypical MAS, was reported. The pituitary adenoma was effectively treated with radiotherapy and the patient underwent surgery for the polyostotic fibrous dysplasia, with marked improvements observed in appearance.
doi:10.3892/etm.2014.1792
PMCID: PMC4113538  PMID: 25120617
McCune-Albright syndrome; fibrous dysplasia; growth hormone-secreting pituitary adenoma
16.  Taurine improves the spatial learning and memory ability impaired by sub-chronic manganese exposure 
Background
Excessive manganese exposure induced cognitive deficit. Several lines of evidence have demonstrated that taurine improves cognitive impairment induced by numerous neurotoxins. However, the role of taurine on manganese-induced damages in learning and memory is still elusive. This goal of this study was to investigate the beneficial effect of taurine on learning and memory capacity impairment by manganese exposure in an animal model.
Results
The escape latency in the Morris Water Maze test was significantly longer in the rats injected with manganese than that in the rats received both taurine and manganese. Similarly, the probe trial showed that the annulus crossings were significantly greater in the taurine plus manganese treated rats than those in the manganese-treated rats. However, the blood level of manganese was not altered by the taurine treatment. Interestingly, the exposure of manganese led to a significant increase in the acetylcholinesterase activity and an evidently decrease in the choline acetyltransferase activity, which were partially restored by the addition of taurine. Additionally, we identified 9 differentially expressed proteins between the rat hippocampus treated by manganese and the control or the manganese plus taurine in the proteomic analysis using the 2-dimensional gel electrophoresis followed by the tandem mass spectrometry (MS/MS). Most of these proteins play a role in energy metabolism, oxidative stress, inflammation, and neuron synapse.
Conclusions
In summary, taurine restores the activity of AChE and ChAT, which are critical for the regulation of acetylcholine. We have identified seven differentially expressed proteins specifically induced by manganese and two proteins induced by taurine from the rat hippocampus. Our results support that taurine improves the impaired learning and memory ability caused by excessive exposure of manganese.
doi:10.1186/1423-0127-21-51
PMCID: PMC4045917  PMID: 24885898
17.  Oncolytic therapy of a recombinant Newcastle disease virus D90 strain for lung cancer 
Virology Journal  2014;11:84.
Background
Lung cancer is one of the leading causes of deaths from cancer worldwide. Tumor virotherapy using naturally oncolytic Newcastle disease virus (NDV) has been shown to be safe and effective in preclinical studies and clinical trials. Previously, we have reported the NDV D90 strain that was isolated from natural source has an antiproliferative effect in human lung cancer cell line A549.
Methods and results
In this study, we constructed a reverse genetics system based on the oncolytic NDV D90 strain and generated a recombinant NDV carrying a gene encoding enhanced green fluorescent protein (rNDV-GFP). The rescued virus rNDV-D90 and rNDV-GFP showed the similar characteristics of replication and apoptotic ability in lung cancer A549 cells, which suggested that the recombinant viruses sustained the property of tumor-selective replication and induced apoptosis of tumor cells. The athymic mice bearing implanted lung cancer were treated with the parental D90 virus, the rescued rNDV-D90 and rNDV-GFP via intratumoral injections, respectively. The results showed that the recombinant viruses as well as the parental D90 virus significantly suppressed the loss of body weight and tumor growth.
Conclusions
The study provides a new platform to develop effective therapeutic agents for tumor treatment. The availability of the reverse genetics system for NDV D90 strain will make it possible to develop novel recombinant oncolytic viruses based on the NDV D90 strain for improving the efficacy of tumor treatment.
doi:10.1186/1743-422X-11-84
PMCID: PMC4032357  PMID: 24885546
Newcastle disease virus; Lung cancer; Oncolytic therapy; Recombinant virus; Nude mice
18.  Cancer Stem-like Cell Properties are Regulated by EGFR/AKT/β-catenin Signaling and Preferentially Inhibited by Gefitinib in Nasopharyngeal Carcinoma 
The FEBS journal  2013;280(9):10.1111/febs.12226.
We report that the EGFR pathway plays a critical role in regulating cancer stem-like cells (CSCs) in nasopharyngeal carcinoma (NPC), one of the most common malignant tumors in Southeast Asia. Effects of EGFR on maintaining CSCs are mainly mediated by AKT signaling, and β-catenin is responsible for governing CSC properties in response to EGFR/AKT activation. Significantly, CSCs are enriched by cisplatin and decreased by gefitinib in NPC xenograft models. Upon reimplantation in secondary mice, tumor cells derived from cisplatin-treated mice grew rapidly, whereas regrowth of tumor cells from gefitinib-treated mice was severely diminished. We further demonstrate that expression of EGFR correlates with expression of β-catenin and Nanog in primary tumor specimens from NPC patients. These findings provide mechanistic and preclinical evidence supporting the use of gefitinib alone or in combination with a chemotherapeutic agent in first-line therapy for patients with NPC. In addition, our results suggest that targeting β-catenin represents a rational clinical modality for patients whose tumors harbor activated EGFR or AKT.
doi:10.1111/febs.12226
PMCID: PMC3831031  PMID: 23461856
Nasopharyngeal carcinoma; Cancer stem-like cells; EGFR; β-catenin; Gefitinib
19.  Protein Inhibitor of Activated STAT 1 (PIAS1) Is Identified as the SUMO E3 Ligase of CCAAT/Enhancer-Binding Protein β (C/EBPβ) during Adipogenesis 
Molecular and Cellular Biology  2013;33(22):4606-4617.
It is well recognized that PIAS1, a SUMO (small ubiquitin-like modifier) E3 ligase, modulates such cellular processes as cell proliferation, DNA damage responses, and inflammation responses. Recent studies have shown that PIAS1 also plays a part in cell differentiation. However, the role of PIAS1 in adipocyte differentiation remains unknown. CCAAT/enhancer-binding protein β (C/EBPβ), a major regulator of adipogenesis, is a target of SUMOylation, but the E3 ligase responsible for the SUMOylation of C/EBPβ has not been identified. The present study showed that PIAS1 functions as a SUMO E3 ligase of C/EBPβ to regulate adipogenesis. PIAS1 expression was significantly and transiently induced on day 4 of 3T3-L1 adipocyte differentiation, when C/EBPβ began to decline. PIAS1 was found to interact with C/EBPβ through the SAP (scaffold attachment factor A/B/acinus/PIAS) domain and SUMOylate it, leading to increased ubiquitination and degradation of C/EBPβ. C/EBPβ became more stable when PIAS1 was silenced by RNA interference (RNAi). Moreover, adipogenesis was inhibited by overexpression of wild-type PIAS1 and promoted by knockdown of PIAS1. The mutational study indicated that the catalytic activity of SUMO E3 ligase was required for PIAS1 to restrain adipogenesis. Importantly, the inhibitory effect of PIAS1 overexpression on adipogenesis was rescued by overexpressed C/EBPβ. Thus, PIAS1 could play a dynamic role in adipogenesis by promoting the SUMOylation of C/EBPβ.
doi:10.1128/MCB.00723-13
PMCID: PMC3838193  PMID: 24061474
20.  Huperzine A Ameliorates Cognitive Deficits in Streptozotocin-Induced Diabetic Rats 
The present study was designed to probe the effects of Huperzine A (HupA) on diabetes-associated cognitive decline (DACD) using a streptozotocin (STZ)-injected rat model. Diabetic rats were treated with HupA (0.05 and 0.1 mg/kg) for seven weeks. Memory functions were evaluated by the water maze test. Nissl staining was selected for detecting neuronal loss. Protein and mRNA levels of brain-derived neurotrophic factor (BDNF) were analyzed by ELISA and real-time PCR, respectively. The activities of choline acetylase (ChAT), Acetylcholinesterase (AChE), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), NF-κB p65 unit, TNF-α, IL-1β, IL-6 and caspase-3 were measured using corresponding kits. After seven weeks, diabetic rats exhibited remarkable reductions in: body weight, percentage of time spent in target quadrant, number of times crossing the platform, ChAT and BDNF levels, SOD, GSH-Px and CAT accompanied with increases in neuronal damage, plasma glucose levels, escape latency, mean path length, AChE, MDA level as well as CAT, NF-κB p65 unit, TNF-α, IL-1β, IL-6 and caspase-3 in cerebral cortex and hippocampus. Supplementation with HupA significantly and dose-dependently reversed the corresponding values in diabetes. It is concluded that HupA ameliorates DACD via modulating BDNF, oxidative stress, inflammation and apoptosis.
doi:10.3390/ijms15057667
PMCID: PMC4057698  PMID: 24857910
huperzine A; diabetes-associated cognitive decline; brain-derived neurotrophic factor; oxidative stress; inflammation; apoptosis
21.  Novel Calibration Algorithm for a Three-Axis Strapdown Magnetometer 
Sensors (Basel, Switzerland)  2014;14(5):8485-8504.
A complete error calibration model with 12 independent parameters is established by analyzing the three-axis magnetometer error mechanism. The said model conforms to an ellipsoid restriction, the parameters of the ellipsoid equation are estimated, and the ellipsoid coefficient matrix is derived. However, the calibration matrix cannot be determined completely, as there are fewer ellipsoid parameters than calibration model parameters. Mathematically, the calibration matrix derived from the ellipsoid coefficient matrix by a different matrix decomposition method is not unique, and there exists an unknown rotation matrix R between them. This paper puts forward a constant intersection angle method (angles between the geomagnetic field and gravitational field are fixed) to estimate R. The Tikhonov method is adopted to solve the problem that rounding errors or other errors may seriously affect the calculation results of R when the condition number of the matrix is very large. The geomagnetic field vector and heading error are further corrected by R. The constant intersection angle method is convenient and practical, as it is free from any additional calibration procedure or coordinate transformation. In addition, the simulation experiment indicates that the heading error declines from ±1° calibrated by classical ellipsoid fitting to ±0.2° calibrated by a constant intersection angle method, and the signal-to-noise ratio is 50 dB. The actual experiment exhibits that the heading error is further corrected from ±0.8° calibrated by the classical ellipsoid fitting to ±0.3° calibrated by a constant intersection angle method.
doi:10.3390/s140508485
PMCID: PMC4063011  PMID: 24831110
constant intersection angle assumption; ellipsoid fitting; restricted least squares solution; rotation matrix
22.  Proteomics Based Identification of Cell Migration Related Proteins in HBV Expressing HepG2 Cells 
PLoS ONE  2014;9(4):e95621.
Proteomics study was performed to investigate the specific protein expression profiles of HepG2 cells transfected with mutant HBV compared with wildtype HBV genome, aiming to identify the specific functions of SH3 binding domain (proline rich region) located in HBx. In addition to the cell movement and kinetics changes due to the expression of HBV genome we have observed previously, here we further targeted to explore the specific changes of cellular proteins and potential intracellular protein interactions, which might provide more information of the potential cellular mechanism of the differentiated cell movements. Specific changes of a number of proteins were shown in global protein profiling in HepG2 cells expressing wildtype HBV, including cell migration related proteins, and interestingly the changes were found recovered by SH3 binding domain mutated HBV. The distinctive expressions of proteins were validated by Western blot analysis.
doi:10.1371/journal.pone.0095621
PMCID: PMC3999089  PMID: 24763314
23.  Understanding the polypharmacological anticancer effects of Xiao Chai Hu Tang via a computational pharmacological model 
Xiao Chai Hu Tang (XCHT), a traditional herbal formula, is widely administered as a cancer treatment. However, the underlying molecular mechanisms of its anticancer effects are not fully understood. In the present study, a computational pharmacological model that combined chemical space mapping, molecular docking and network analysis was employed to predict which chemical compounds in XCHT are potential inhibitors of cancer-associated targets, and to establish a compound-target (C-T) network and compound-compound (C-C) association network. The identified compounds from XCHT demonstrated diversity in chemical space. Furthermore, they occupied regions of chemical space that were the same, or close to, those occupied by drug or drug-like compounds that are associated with cancer, according to the Therapeutic Targets Database. The analysis of the molecular docking and the C-T network demonstrated that the potential inhibitors possessed the properties of promiscuous drugs and combination therapies. The C-C network was classified into four clusters and the different clusters contained various multi-compound combinations that acted on different targets. The study indicated that XCHT has a polypharmacological role in treating cancer and the potential inhibitory components of XCHT require further investigation as potential therapeutic strategies for cancer patients.
doi:10.3892/etm.2014.1660
PMCID: PMC4043560  PMID: 24926384
Xiao Chai Hu Tang; polypharmacology; cancer; computational pharmacology
24.  Protocol for the China PEACE (Patient-centered Evaluative Assessment of Cardiac Events) retrospective study of coronary catheterisation and percutaneous coronary intervention 
BMJ Open  2014;4(3):e004595.
Introduction
During the past decade, the volume of percutaneous coronary intervention (PCI) in China has risen by more than 20-fold. Yet little is known about patterns of care and outcomes across hospitals, regions and time during this period of rising cardiovascular disease and dynamic change in the Chinese healthcare system.
Methods and analysis
Using the China PEACE (Patient-centered Evaluative Assessment of Cardiac Events) research network, the Retrospective Study of Coronary Catheterisation and Percutaneous Coronary Intervention (China PEACE-Retrospective CathPCI Study) will examine a nationally representative sample of 11 900 patients who underwent coronary catheterisation or PCI at 55 Chinese hospitals during 2001, 2006 and 2011. We selected patients and study sites using a two-stage cluster sampling design with simple random sampling stratified within economical-geographical strata. A central coordinating centre will monitor data quality at the stages of case ascertainment, medical record abstraction and data management. We will examine patient characteristics, diagnostic testing patterns, procedural treatments and in-hospital outcomes, including death, complications of treatment and costs of hospitalisation. We will additionally characterise variation in treatments and outcomes by patient characteristics, hospital, region and study year.
Ethics and dissemination
The China PEACE collaboration is designed to translate research into improved care for patients. The study protocol was approved by the central ethics committee at the China National Center for Cardiovascular Diseases (NCCD) and collaborating hospitals. Findings will be shared with participating hospitals, policymakers and the academic community to promote quality monitoring, quality improvement and the efficient allocation and use of coronary catheterisation and PCI in China.
Registration details
http://www.clinicaltrials.gov (NCT01624896).
doi:10.1136/bmjopen-2013-004595
PMCID: PMC3948460  PMID: 24607563
Catheterization; Angiography; Angioplasty; China
25.  The Pro-Apoptotic Role of the Regulatory Feedback Loop between miR-124 and PKM1/HNF4α in Colorectal Cancer Cells 
Accumulating evidence indicates that miRNA regulatory circuits play important roles in tumorigenesis. We previously reported that miR-124 is correlated with prognosis of colorectal cancer due to PKM-dependent regulation of glycolysis. However, the mechanism by which miR-124 regulates apoptosis in colorectal cancer remains largely elusive. Here, we show that miR-124 induced significant apoptosis in a panel of colorectal cancer cell lines. The mitochondrial apoptosis pathway was activated by miR-124. Furthermore, the pro-apoptotic role of miR-124 was dependent on the status of PKM1/2 level. PKM1 was required for miR-124-induced apoptosis. Via direct protein-protein interaction, PKM1 promoted HNF4α binding to the promoter region of miR-124 and transcribing miR-124. Moreover, HNF4α or PKM1 had a more dramatic effect on colorectal cancer cell apoptosis in the presence of miR-124. However, inhibition of miR-124 blocked cell apoptosis induced by HNF4α or PKM1. These data indicate that miR-124 not only alters the expression of genes involved in glucose metabolism but also stimulates cancer cell apoptosis. In addition, the positive feedback loop between miR-124 and PKM1/HNF4α plays an important role in colorectal cancer cell apoptosis; it suggests that disrupting this regulatory circuit might be a potential therapeutic tool for colorectal cancer treatment.
doi:10.3390/ijms15034318
PMCID: PMC3975400  PMID: 24619225
PKM; HNF4α; miR-124; colorectal cancer

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