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1.  Lunasin Inhibits Cell Proliferation via Apoptosis and Reduces the Production of Proinflammatory Cytokines in Cultured Rheumatoid Arthritis Synovial Fibroblasts 
BioMed Research International  2015;2015:346839.
Lunasin, a peptide with 43 amino acid residues and initially isolated and identified in soybean cotyledon, has gained extensive attention due to its anti-inflammatory and anticancer properties. However, its treatment efficacy on rheumatoid arthritis (RA) and corresponding mechanisms have not been reported. Herein, the synovial fibroblasts harvested and isolated from patients with RA were treated with lunasin at various concentrations to examine the proliferation, apoptosis status, and corresponding cell cycle of cultured RA synovial fibroblasts. Meanwhile, the underlying mechanisms of lunasin for RA treatment are explored through Western blot, real-time PCR, ELISA, and luciferase reporter assays. Lunasin significantly inhibited the proliferation and induced the apoptosis of cultured RA synovial fibroblasts. In addition, lunasin reduced the production of interleukin-6 (IL-6), IL-8, and matrix metalloproteinase-3 (MMP-3) and suppressed the activation of NF-κB in cultured RA synovial fibroblasts but did not reveal obvious modulation on the secretion and gene expression of MMP-1. Therefore, lunasin will have promising potential as a novel nutritional supplement or drug candidate for RA due to its potency of suppressing synovial cell proliferation and decreasing the production of proinflammatory cytokines and MMPs in synovial cells.
doi:10.1155/2015/346839
PMCID: PMC4322854
2.  Glycyrrhetinic acid induces G1-phase cell cycle arrest in human non-small cell lung cancer cells through endoplasmic reticulum stress pathway 
International Journal of Oncology  2015;46(3):981-988.
Glycyrrhetinic acid (GA) is a natural compound extracted from liquorice, which is often used in traditional Chinese medicine. The purpose of the present study was to investigate the antitumor effect of GA in human non-small cell lung cancer (NSCLC), and its underlying mechanisms in vitro. We have shown that GA suppressed the proliferation of A549 and NCI-H460 cells. Flow cytometric analysis showed that GA arrested cell cycle in G0/G1 phase without inducing apoptosis. Western blot analysis indicated that GA mediated G1-phase cell cycle arrest by upregulation of cyclin-dependent kinase inhibitors (CKIs) (p18, p16, p27 and p21) and inhibition of cyclins (cyclin-D1, -D3 and -E) and cyclin-dependent kinases (CDKs) (CDK4, 6 and 2). GA also maintained pRb phosphorylation status, and inhibited E2F transcription factor 1 (E2F-1) in both cell lines. GA upregulated the unfolded proteins, Bip, PERK and ERP72. Accumulation of unfolded proteins in the endoplasmic reticulum (ER) triggered the unfolded protein response (UPR), which could be the mechanism by which GA inhibited cell proliferation in NSCLC cells. GA then coordinated the induction of ER chaperones, which decreased protein synthesis and induced cell cycle arrest in the G1 phase. This study provides experimental evidence to support the development of GA as a chemotherapeutic agent for NSCLC.
doi:10.3892/ijo.2015.2819
PMCID: PMC4324580  PMID: 25573651
glycyrrhetinic acid; cell cycle arrest; ER stress; NSCLC
3.  Increased C-C Chemokine Receptor 2 Gene Expression in Monocytes of Severe Obstructive Sleep Apnea Patients and under Intermittent Hypoxia 
PLoS ONE  2014;9(11):e113304.
Background
Obstructive sleep apnea (OSA) is known to be a risk factor of coronary artery disease. The chemotaxis and adhesion of monocytes to the endothelium in the early atherosclerosis is important. This study aimed to investigate the effect of intermittent hypoxia, the hallmark of OSA, on the chemotaxis and adhesion of monocytes.
Methods
Peripheral blood was sampled from 54 adults enrolled for suspected OSA. RNA was prepared from the isolated monocytes for the analysis of C-C chemokine receptor 2 (CCR2). The effect of intermittent hypoxia on the regulation and function of CCR2 was investigated on THP-1 monocytic cells and monocytes. The mRNA and protein expression levels were investigated by RT/real-time PCR and western blot analysis, respectively. Transwell filter migration assay and cell adhesion assay were performed to study the chemotaxis and adhesion of monocytes.
Results
Monocytic CCR2 gene expression was found to be increased in severe OSA patients and higher levels were detected after sleep. Intermittent hypoxia increased the CCR2 expression in THP-1 monocytic cells even in the presence of TNF-α and CRP. Intermittent hypoxia also promoted the MCP-1-mediated chemotaxis and adhesion of monocytes to endothelial cells. Furthermore, inhibitor for p42/44 MAPK or p38 MAPK suppressed the activation of monocytic CCR2 expression by intermittent hypoxia.
Conclusions
This is the first study to demonstrate the increase of CCR2 gene expression in monocytes of severe OSA patients. Monocytic CCR2 gene expression can be induced under intermittent hypoxia which contributes to the chemotaxis and adhesion of monocytes.
doi:10.1371/journal.pone.0113304
PMCID: PMC4239065  PMID: 25411969
4.  Cone beam computed tomographic analyses of alveolar bone anatomy at the maxillary anterior region in Chinese adults 
Journal of Biomedical Research  2013;28(6):498-505.
To provide an anatomical basis for clinical implant esthetics, we evaluated the morphology of the nasopalatine canal (NPC) and analyzed labial and interproximal bone anatomy at the maxillary anterior region. We sought to investigate the effect of maxillary protrusion and tooth labiolingual inclination on labial bone anatomy in Chinese adults. Three dimensional (3D) images were reconstructed using cone-beam computed tomography (CBCT) images from 80 Chinese subjects and by SimPlant 11.04. The dimensions of the NPC, the thickness and profile of the labial bone, the width and height of the interproximal bone, angle sella-nasion-subspinale (SNA) and angle upper central incisor-nasion,subspinale (U1-NA) were measured. The incisive foramen of the NPC was markedly wider than its nasal foramen. The dimension of its labial bone wall demonstrated an increasing width from the crestal to apical measurements. The labial bone at the maxillary anterior region was rather thin, especially at 3 mm below the cemento-enamel junction (CEJ) and the mid-root level; the profile of the labial bone was more curved at the central incisor, and the interproximal bone became wider and shorter posteriorly. There were significant relationships between maxillary protrusion and labial bone profile, tooth labiolingual inclination and labial bone thickness (P < 0.02). To achieve optimal esthetic outcome of implant, bone augmentation is necessary at the maxillary anterior region. For immediate or early placement at the maxillary anterior region, the implant should be located palatally to reduce labial bone resorption and marginal recession; its apex should be angulated palatally to avoid labial perforation at the apical region. To protect the NPC, implants at the central incisor region should be placed away from NPC.
doi:10.7555/JBR.27.20130002
PMCID: PMC4250963  PMID: 25469120
cone beam computed tomography (CBCT); nasopalatine canal (NPC); alveolar bone; maxillary anterior region; implant esthetics
5.  Development of a Finite Element Head Model for the Study of Impact Head Injury 
BioMed Research International  2014;2014:408278.
This study is aimed at developing a high quality, validated finite element (FE) human head model for traumatic brain injuries (TBI) prediction and prevention during vehicle collisions. The geometry of the FE model was based on computed tomography (CT) and magnetic resonance imaging (MRI) scans of a volunteer close to the anthropometry of a 50th percentile male. The material and structural properties were selected based on a synthesis of current knowledge of the constitutive models for each tissue. The cerebrospinal fluid (CSF) was simulated explicitly as a hydrostatic fluid by using a surface-based fluid modeling method. The model was validated in the loading condition observed in frontal impact vehicle collision. These validations include the intracranial pressure (ICP), brain motion, impact force and intracranial acceleration response, maximum von Mises stress in the brain, and maximum principal stress in the skull. Overall results obtained in the validation indicated improved biofidelity relative to previous FE models, and the change in the maximum von Mises in the brain is mainly caused by the improvement of the CSF simulation. The model may be used for improving the current injury criteria of the brain and anthropometric test devices.
doi:10.1155/2014/408278
PMCID: PMC4227498  PMID: 25405201
6.  Adenosine promotes vascular barrier function in hyperoxic lung injury 
Physiological Reports  2014;2(9):e12155.
Abstract
Hyperoxic lung injury is characterized by cellular damage from high oxygen concentrations that lead to an inflammatory response in the lung with cellular infiltration and pulmonary edema. Adenosine is a signaling molecule that is generated extracellularly by CD73 in response to injury. Extracellular adenosine signals through cell surface receptors and has been found to be elevated and plays a protective role in acute injury situations. In particular, ADORA2B activation is protective in acute lung injury. However, little is known about the role of adenosine signaling in hyperoxic lung injury. We hypothesized that hyperoxia‐induced lung injury leads to CD73‐mediated increases in extracellular adenosine, which is protective through ADORA2B signaling pathways. To test this hypothesis, we exposed C57BL6, CD73−/−, and Adora2B−/− mice to 95% oxygen or room air and examined markers of pulmonary inflammation, edema, and monitored lung histology. Hyperoxic exposure caused pulmonary inflammation and edema in association with elevations in lung adenosine levels. Loss of CD73‐mediated extracellular adenosine production exacerbated pulmonary edema without affecting inflammatory cell counts. Furthermore, loss of the ADORA2B had similar results with worsening of pulmonary edema following hyperoxia exposure without affecting inflammatory cell infiltration. This loss of barrier function correlated with a decrease in occludin in pulmonary vasculature in CD73−/− and Adora2B−/− mice following hyperoxia exposure. These results demonstrate that exposure to a hyperoxic environment causes lung injury associated with an increase in adenosine concentration, and elevated adenosine levels protect vascular barrier function in hyperoxic lung injury through the ADORA2B‐dependent regulation of occludin.
e12155
Hyperoxic lung injury is characterized by cellular damage from high oxygen concentrations that lead to an inflammatory response in the lung with cellular infiltration and pulmonary edema, and extracellular adenosine has been found to be elevated and plays a protective role in acute injury situations; however, little is known about the role of adenosine signaling in hyperoxic lung injury. We hypothesized that hyperoxia‐induced lung injury leads to CD73‐mediated increases in extracellular adenosine, which is protective through ADORA2B signaling pathways. Our results demonstrate that exposure to a hyperoxic environment causes lung injury associated with an increase in adenosine concentration, and elevated adenosine levels protect vascular barrier function in hyperoxic lung injury through the ADORA2B‐dependent regulation of occludin.
doi:10.14814/phy2.12155
PMCID: PMC4270235  PMID: 25263205
Adenosine; hyperoxic lung injury; vascular barrier function
7.  Blockade of IL-6 Trans Signaling Attenuates Pulmonary Fibrosis 
Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease with progressive fibrosis and death within 2–3 y of diagnosis. IPF incidence and prevalence rates are increasing annually with few effective treatments available. Inhibition of IL-6 results in the attenuation of pulmonary fibrosis in mice. It is unclear whether this is due to blockade of classical signaling, mediated by membrane-bound IL-6Rα, or trans signaling, mediated by soluble IL-6Rα (sIL-6Rα). Our study assessed the role of sIL-6Rα in IPF. We demonstrated elevations of sIL-6Rα in IPF patients and in mice during the onset and progression of fibrosis. We demonstrated that protease-mediated cleavage from lung macrophages was important in production of sIL-6Rα. In vivo neutralization of sIL-6Rα attenuated pulmonary fibrosis in mice as seen by reductions in myofibroblasts, fibronectin, and collagen in the lung. In vitro activation of IL-6 trans signaling enhanced fibroblast proliferation and extracellular matrix protein production, effects relevant in the progression of pulmonary fibrosis. Taken together, these findings demonstrate that the production of sIL-6Rα from macrophages in the diseased lung contributes to IL-6 trans signaling that in turn influences events crucial in pulmonary fibrosis.
doi:10.4049/jimmunol.1302470
PMCID: PMC4169999  PMID: 25172494
8.  Dose of Incorporated Immunodominant Antigen in Recombinant BCG Impacts Modestly on Th1 Immune Response and Protective Efficiency against Mycobacterium tuberculosis in Mice 
Journal of Immunology Research  2014;2014:196124.
One approach for improving BCG efficacy is to utilize BCG as vehicle to develop recombinant BCG (rBCG) strains overexpressing Mycobacterium tuberculosis (M. tb) antigens. Also expression level of a candidate antigen should impact the final T cell responses conferred by rBCG. In this study, based on our previously constructed differential expression system, we developed two rBCG strains overexpressing M. tb chimeric antigen Ag856A2 (coding a recombinant ag85a with 2 copies of esat-6 inserted at Acc I site of ag85a) at differential levels under the control of the subtly modified furA promoters. These two rBCG strains were used to vaccinate C57BL/6 mice and exploit dose of incorporated antigen in rBCG to optimize immune response and protective efficiency against M. tb challenge in mouse model. The results showed that rBCG strains overexpressing Ag856A2 at differential levels induced different antigen-specific IFN-γ production and comparable number of M. tb-specific CD4 T cells expressing IL-2. M. tb challenge experiment showed that rBCG strains afforded enhanced but comparable immune protection characterized by reduced bacillary load, lung pathology, and inflammation. These results suggested that the dose of antigens incorporated in rBCG can impact T cell immune responses but imposed no significantly differential protective efficacies.
doi:10.1155/2014/196124
PMCID: PMC4134796  PMID: 25152895
9.  Identifying and Quantifying Heterogeneity in High Content Analysis: Application of Heterogeneity Indices to Drug Discovery 
PLoS ONE  2014;9(7):e102678.
One of the greatest challenges in biomedical research, drug discovery and diagnostics is understanding how seemingly identical cells can respond differently to perturbagens including drugs for disease treatment. Although heterogeneity has become an accepted characteristic of a population of cells, in drug discovery it is not routinely evaluated or reported. The standard practice for cell-based, high content assays has been to assume a normal distribution and to report a well-to-well average value with a standard deviation. To address this important issue we sought to define a method that could be readily implemented to identify, quantify and characterize heterogeneity in cellular and small organism assays to guide decisions during drug discovery and experimental cell/tissue profiling. Our study revealed that heterogeneity can be effectively identified and quantified with three indices that indicate diversity, non-normality and percent outliers. The indices were evaluated using the induction and inhibition of STAT3 activation in five cell lines where the systems response including sample preparation and instrument performance were well characterized and controlled. These heterogeneity indices provide a standardized method that can easily be integrated into small and large scale screening or profiling projects to guide interpretation of the biology, as well as the development of therapeutics and diagnostics. Understanding the heterogeneity in the response to perturbagens will become a critical factor in designing strategies for the development of therapeutics including targeted polypharmacology.
doi:10.1371/journal.pone.0102678
PMCID: PMC4103836  PMID: 25036749
10.  Enrichment of MTHFR 677 T in a Chinese long-lived cohort and its association with lipid modulation 
Background
Variants in the Methylenetetrahydrofolate reductase (MTHFR) gene may result in a lowered catalytic activity and associate with subsequent elevated serum homocysteine (Hcy) concentration, abnormal DNA synthesis and methylation, cardiovascular risk, and unhealthy aging. Several investigations on the relationship of MTHFR C677T polymorphism with serum lipid profile and longevity have been conducted in some populations, but the findings remain mixed. Herein, we sought to look at the association between MTHFR C677T and lipid profile in a longevous cohort in Bama, a well-known home of longevity in China.
Methods
Genotyping of MTHFR C677T was undertaken in 516 long-lived inhabitants (aged 90 and older, long-lived group, LG) and 493 healthy controls (aged 60–75, non-long-lived group, non-LG) recruited from Bama area. Correlation between MTHFR genotypes and lipids was then evaluated.
Results
T allele and TT genotype were significantly more prevalent in LG (P = 0.001 and 0.002, respectively), especially in females, than in non-LG. No difference in the tested lipid measures among MTHFR C677T genotypes was observed in LG, non-LG and total population (P > 0.05 for all). However, female but not male T carriers exhibited higher TC and LDL-C levels than did T noncarriers in the total population and in LG after stratification by sex (P < 0.05 for each). These differences did not however remain through further subdivision by hyperlipidemia and normolipidemia.
Conclusion
The higher prevalence of MTHFR 677 T genotypes and its modest unfavorable impact on lipids in Bama long-lived individuals may imply an existence of other protective genotypes which require further determination.
doi:10.1186/1476-511X-13-104
PMCID: PMC4092207  PMID: 24968810
11.  Comparative Effects of Snoring Sound between Two Minimally Invasive Surgeries in the Treatment of Snoring: A Randomized Controlled Trial 
PLoS ONE  2014;9(5):e97186.
Background
Minimally invasive surgeries of the soft palate have emerged as a less-invasive treatment for habitual snoring. To date, there is only limited information available comparing the effects of snoring sound between different minimally invasive surgeries in the treatment of habitual snoring.
Objective
To compare the efficacy of palatal implant and radiofrequency surgery, in the reduction of snoring through subjective evaluation of snoring and objective snoring sound analysis.
Patients and Method
Thirty patients with habitual snoring due to palatal obstruction (apnea-hypopnea index ≤15, body max index ≤30) were prospectively enrolled and randomized to undergo a single session of palatal implant or temperature-controlled radiofrequency surgery of the soft palate under local anesthesia. Snoring was primarily evaluated by the patient with a 10 cm visual analogue scale (VAS) at baseline and at a 3-month follow-up visit and the change in VAS was the primary outcome. Moreover, life qualities, measured by snore outcomes survey, and full-night snoring sounds, analyzed by a sound analytic program (Snore Map), were also investigated at the same time.
Results
Twenty-eight patients completed the study; 14 received palatal implant surgery and 14 underwent radiofrequency surgery. The VAS and snore outcomes survey scores were significantly improved in both groups. However, the good response (postoperative VAS ≤3 or postoperative VAS ≤5 plus snore outcomes survey score ≥60) rate of the palatal implant group was significantly higher than that of the radiofrequency group (79% vs. 29%, P = 0.021). The maximal loudness of low-frequency (40–300 Hz) snores was reduced significantly in the palatal implant group. In addition, the snoring index was significantly reduced in the radiofrequency group.
Conclusions
Both palatal implants and a single-stage radiofrequency surgery improve subjective snoring outcomes, but palatal implants have a greater effect on most measures of subjective and objective snoring. Multi-stage radiofrequency surgery was not tested.
Trial Registration
ClinicalTrials.gov NCT01955083
doi:10.1371/journal.pone.0097186
PMCID: PMC4016275  PMID: 24816691
12.  Emergency Department Crowding and the Use of Nontraditional Beds 
Background and Objectives
In an effort to compensate for crowding, many emergency departments (EDs) evaluate and treat patients in nontraditional settings such as gurneys in hallways and conference rooms. The impact of this practice on ED evaluation time is unknown.
Research Design and Subjects
An historical cohort of adult ED visits to an academic hospital between 8/1/2009 and 8/1/2010 was used to evaluate the relationship between ED bed assignment (traditional, hallway, or conference room bed) and mean ED evaluation time, defined as the time spent in an ED bed before admission or discharge. Chief complaints were categorized into the five most frequent categories: abdominal/genitourinary, joint/muscle, general (fever, malaise), head/neck, and other. Multiple linear regression and marginal prediction were used to calculate mean ED evaluation times for each bed type, overall and by chief complaint category.
Results
During the study period, 15,073 patient visits met inclusion criteria. After adjustment for patient and ED factors, assignments to hallway and conference room beds were associated with increases in mean ED evaluation time of 13.3 minutes (95% confidence interval 13.2, 13.3) and 10.9 minutes (95% CI 10.8, 10.9), respectively, compared to the traditional bed ED evaluation time. This varied by chief complaint category.
Conclusions
Use of nontraditional beds is associated with increases in mean ED evaluation time; however, these increases are small and may be further minimized by restricting use of nontraditional beds to patients with specific chief complaints. Nontraditional beds may have a role in improving ED throughput during times of crowding.
doi:10.1016/j.ajem.2011.12.007
PMCID: PMC3888805  PMID: 22386355
emergency department; throughput; hallway bed; conference room bed
13.  Asthmatic Airway Neutrophilia after Allergen Challenge Is Associated with the Glutathione S-Transferase M1 Genotype 
Rationale: Asthma is a heterogeneous lung disorder characterized by airway inflammation and airway dysfunction, manifesting as hyperresponsiveness and obstruction. Glutathione S-transferase M1 (GSTM1) is a multifunctional phase II enzyme and regulator of stress-activated cellular signaling relevant to asthma pathobiology. A common homozygous deletion polymorphism of the GSTM1 gene eliminates enzyme activity.
Objectives: To determine the effect of GSTM1 on airway inflammation and reactivity in adults with established atopic asthma in vivo.
Methods: Nineteen GSTM1 wild-type and eighteen GSTM1-null individuals with mild atopic asthma underwent methacholine and inhaled allergen challenges, and endobronchial allergen provocations through a bronchoscope.
Measurements and Main Results: The influx of inflammatory cells, panels of cytokines and chemokines linked to asthmatic inflammation, F2-isoprostanes (markers of oxidative stress), and IgE were measured in bronchoalveolar lavage fluid at baseline and 24 hours after allergen instillation. Individuals with asthma with the GSTM1 wild-type genotype had greater baseline and allergen-provoked airway neutrophilia and concentrations of myeloperoxidase than GSTM1-null patients. In contrast, the eosinophilic inflammation was unaffected by GSTM1. The allergen-stimulated generation of acute-stress and proneutrophilic mediators, tumor necrosis factor-α, CXCL-8, IL-1β, and IL-6, was also greater in the GSTM1 wild-type patients. Moreover, post-allergen airway concentrations of IgE and neutrophil-generated mediators, matrix metalloproteinase-9, B-cell activating factor, transforming growth factor-β1, and elastase were higher in GSTM1 wild-type individuals with asthma. Total airway IgE correlated with B-cell activating factor concentrations. In contrast, levels of F2-isoprostane were comparable in both groups. Finally, GSTM1 wild-type individuals with asthma required lower threshold concentrations of allergen to produce bronchoconstriction.
Conclusions: The functional GSTM1 genotype promotes neutrophilic airway inflammation in humans with atopic asthma in vivo.
doi:10.1164/rccm.201204-0786OC
PMCID: PMC3570644  PMID: 23204253
atopic asthma; GSTM1 polymorphism; inflammatory asthma phenotypes; neutrophilic airway inflammation
14.  Research on the relationship between fibrinogen level and subtypes of the TOAST criteria in the acute ischemic stroke 
BMC Neurology  2013;13:207.
Background
Cerebral infarction caused by different reasons seems differ in fibrinogen levels, so the current work intends to explore the relationship between the fibrinogen level and subtypes of the TOAST criteria in the acute stage of ischemic stroke.
Methods
A total of 577 case research objects were treated acute ischemic stroke patients in our hospital from December 2008 to December 2010, and blood samples within 72 hours of the onset were processed with the fibrinogen (PT-der) measurement. Classification of selected patients according to the TOAST Criteria was conducted to study the distribution of fibrinogen levels in the stroke subtypes.
Results
The distribution of fibrinogen levels in the subtypes was observed to be statistically insignificant.
Conclusions
In the acute stage of ischemic stroke, fibrinogen level was not related to the subtypes of the TOAST criteria.
doi:10.1186/1471-2377-13-207
PMCID: PMC3878231  PMID: 24354692
Fibrinogen; Ischemic stroke; Subtypes of stroke; TOAST Criteria; Correlation
15.  High-Frequency Stimulation of Nucleus Accumbens Changes in Dopaminergic Reward Circuit 
PLoS ONE  2013;8(11):e79318.
Deep brain stimulation (DBS) of the nucleus accumbens (NAc) is a potential remedial therapy for drug craving and relapse, but the mechanism is poorly understood. We investigated changes in neurotransmitter levels during high frequency stimulation (HFS) of the unilateral NAc on morphine-induced rats. Sixty adult Wistar rats were randomized into five groups: the control group (administration of saline), the morphine-only group (systematic administration of morphine without electrode implantation), the morphine-sham-stimulation group (systematic administration of morphine with electrode implantation but not given stimulation), the morphine-stimulation group (systematic administration of morphine with electrode implantation and stimulation) and the saline-stimulation group (administration of saline with electrode implantation and stimulation). The stimulation electrode was stereotaxically implanted into the core of unilateral NAc and microdialysis probes were unilaterally lowered into the ipsilateral ventral tegmental area (VTA), NAc, and ventral pallidum (VP). Samples from microdialysis probes in the ipsilateral VTA, NAc, and VP were analyzed for glutamate (Glu) and γ-aminobutyric acid (GABA) by high-performance liquid chromatography (HPLC). The levels of Glu were increased in the ipsilateral NAc and VP of morphine-only group versus control group, whereas Glu levels were not significantly changed in the ipsilateral VTA. Furthermore, the levels of GABA decreased significantly in the ipsilateral NAc, VP, and VTA of morphine-only group when compared with control group. The profiles of increased Glu and reduced GABA in morphine-induced rats suggest that the presence of increased excitatory neurotransmission in these brain regions. The concentrations of the Glu significantly decreased while the levels of GABA increased in ipsilateral VTA, NAc, and VP in the morphine-stimulation group compared with the morphine-only group. No significant changes were seen in the morphine-sham stimulation group compared with the morphine-only group. These findings indicated that unilateral NAc stimulation inhibits the morphine-induced rats associated hyperactivation of excitatory neurotransmission in the mesocorticolimbic reward circuit.
doi:10.1371/journal.pone.0079318
PMCID: PMC3828386  PMID: 24244479
16.  Human cancer cell line microRNAs associated with in vitro sensitivity to paclitaxel 
Oncology Reports  2013;31(1):376-383.
Paclitaxel is a mainstay of treatment for many solid tumors, and frequently, clinical outcome is influenced by paclitaxel sensitivity. Despite this, our understanding of the molecular basis of paclitaxel response is incomplete. Recently, it has been shown that microRNAs (miRNAs) influence messenger RNA (mRNA) transcriptional control and can contribute to human carcinogenesis. In the present study, our objective was to identify miRNAs associated with cancer cell line response to paclitaxel and to evaluate these miRNAs as therapeutic targets to increase paclitaxel sensitivity. We measured the expression of 335 unique miRNAs in 40 human cancer cell lines selected from the NCI panel. We then integrated miRNA expression data with publicly available paclitaxel-sensitivity (GI50) data for each of the 40 cell lines to identify miRNAs associated with paclitaxel sensitivity. Ovarian cancer cell lines with differential miRNA expression and paclitaxel sensitivity were transiently transfected with miRNA precursors and inhibitors, and the effects on in vitro cell paclitaxel sensitivity were evaluated. Pearson’s correlation identified 2 miRNAs (miR-367 and miR-30a-5p) associated with the NCI40 cell line in vitro paclitaxel response (P<0.0003). Ovarian cancer cells were selected based on the association between paclitaxel sensitivity and miR-367/miR-30a-5p expression. Overexpression of miR-367 in the paclitaxel-sensitive cells [PA1; IC50, 1.69 nM, high miR-367 (2.997), low miR-30a-5p (−0.323)] further increased paclitaxel sensitivity, whereas miR-367 depletion decreased paclitaxel sensitivity. In contrast, overexpression and depletion of miR-30a-5p in the paclitaxel-resistant cells [OVCAR4; IC50, 17.8 nM, low miR-367 (−0.640), high miR-30a-5p (3.270)] decreased and increased paclitaxel sensitivity, respectively. We identified and successfully targeted miRNAs associated with human cancer cell line response to paclitaxel. Our strategy of integrating in vitro miRNA expression and drug sensitivity data may not only aid in the characterization of determinants of drug response but also in the identification of novel therapeutic targets to increase activity of existing therapeutics.
doi:10.3892/or.2013.2847
PMCID: PMC3981115  PMID: 24220856
cancer; chemosensitivity; microRNA; NCI60
17.  A Macaque Model of Mesial Temporal Lobe Epilepsy Induced by Unilateral Intrahippocampal Injection of Kainic Acid 
PLoS ONE  2013;8(8):e72336.
Objective
In order to better investigate the cause/effect relationships of human mesial temporal lobe epilepsy (mTLE), we hereby describe a new non-human primate model of mTLE.
Methods
Ten macaques were studied and divided into 2 groups: saline control group (n = 4) and kainic acid (KA) injection group (n = 6). All macaques were implanted bilaterally with subdural electrodes over temporal cortex and depth electrodes in CA3 hippocampal region. KA was stereotaxically injected into the right hippocampus of macaques. All animals were monitored by video and electrocorticography (ECoG) to assess status epilepticus (SE) and subsequent spontaneous recurrent seizures (SRS). Additionally, in order to evaluate brain injury produced by SE or SRS, we used both neuroimaging, including magnetic resonance image (MRI) & magnetic resonance spectroscopy (MRS), and histological pathology, including Nissl stainning and glial fibrillary acid protein (GFAP) immunostaining.
Results
The typical seizures were observed in the KA-injected animal model. Hippocampal sclerosis could be found by MRI & MRS. Hematoxylin and eosin (H&E) staining and GFAP immunostaining showed neuronal loss, proliferation of glial cells, formation of glial scars, and hippocampal atrophy. Electron microscopic analysis of hippocampal tissues revealed neuronal pyknosis, partial ribosome depolymerization, an abnormal reduction in rough endoplasmic reticulum size, expansion of Golgi vesicles and swollen star-shaped cells. Furthermore, we reported that KA was able to induce SE followed by SRS after a variable period of time. Similar to human mTLE, brain damage is confined to the hippocampus. Accordingly, hippocampal volume is in positive correlations with the neuronal cells count in the CA3, especially the ratio of neuron/glial cell.
Conclusions
The results suggest that a model of mTLE can be developed in macaques by intra-hippocampal injection of KA. Brain damage is confined to the hippocampus which is similar to the human mTLE. The hippocampal volume correlates with the extension of the hippocampal damage.
doi:10.1371/journal.pone.0072336
PMCID: PMC3753347  PMID: 23991095
18.  Diseases in Patients Coming to a Sleep Center with Symptoms Related to Restless Legs Syndrome 
PLoS ONE  2013;8(8):e71499.
Study Objective
To explore the profile of patients who visit a sleep center with symptoms that fulfill the four essential criteria for restless legs syndrome (RLS).
Design
A prospective study.
Setting
Outpatients from one sleep disorders clinic in Taiwan.
Participants
1,200 consecutive patients visit sleep disorders clinic with any sleep complaints.
Interventions
After completing a history and physical examination, all participants answered the RLS questionnaire. Subjects who fulfilled the four essential criteria for RLS were referred to a special clinic. A work-up including blood tests, polysomnography, and specialized neurological tests etc. was performed to make the final diagnosis.
Measurements and Results
A total of 1,185 participants were enrolled, and, of these, 131(11.1%) fulfilled the four essential criteria for RLS, and 121 completed the supplemental work-up. Their mean age was 47.6±13.3 and 52.9% were male. Insomnia and snoring were the most common chief complaints. Obstructive sleep apnea syndrome and other diseases were found in 103 patients. Only 18 (14.9%) patients had no comorbid condition and were diagnosed with primary RLS.
Conclusions
Symptoms of RLS are common in patients with sleep complaints. Even in a sleep clinic, using a questionnaire approach for identification of RLS has a low positive predictive value. Clinicians should pay attention to the limitations of the 4-item questionnaire in diagnosis of RLS and also the importance of a careful differential diagnosis to identify possible secondary causes of RLS.
doi:10.1371/journal.pone.0071499
PMCID: PMC3747238  PMID: 23977057
19.  Noninvasive Prenatal Detection for Pathogenic CNVs: The Application in α-Thalassemia 
PLoS ONE  2013;8(6):e67464.
Background
The discovery of cell free fetal DNA (cff-DNA) in maternal plasma has brought new insight for noninvasive prenatal diagnosis. Combining with the rapidly developed massively parallel sequencing technology, noninvasive prenatal detection of chromosome aneuploidy and single base variation has been successfully validated. However, few studies discussed the possibility of noninvasive pathogenic CNVs detection.
Methodology/Principal Findings
A novel algorithm for noninvasive prenatal detection of fetal pathogenic CNVs was firstly tested in 5 pairs of parents with heterozygote α-thalassemia of Southeast Asian (SEA) deletion using target region capture sequencing for maternal plasma. Capture probes were designed for α-globin (HBA) and β-globin (HBB) gene, as well as 4,525 SNPs selected from 22 automatic chromosomes. Mixed adaptors with 384 different barcodes were employed to construct maternal plasma DNA library for massively parallel sequencing. The signal of fetal CNVs was calculated using the relative copy ratio (RCR) of maternal plasma combined with the analysis of R-score and L-score by comparing with normal control. With mean of 101.93× maternal plasma sequencing depth for the target region, the RCR value combined with further R-score and L-score analysis showed a possible homozygous deletion in the HBA gene region for one fetus, heterozygous deletion for two fetus and normal for the other two fetus, which was consistent with that of invasive prenatal diagnosis.
Conclusions/Significance
Our study showed the feasibility to detect pathogenic CNVs using target region capture sequencing, which might greatly extend the scope of noninvasive prenatal diagnosis.
doi:10.1371/journal.pone.0067464
PMCID: PMC3696090  PMID: 23840709
20.  The utility of surgical lung biopsy in cancer patients with acute respiratory distress syndrome 
Background
This retrospective study evaluated the utility and safety of surgical lung biopsy (SLB) in cancer patients with acute respiratory distress syndrome (ARDS).
Methods
All cases of critically ill patients with cancer and diagnosed with ARDS who underwent SLB in a tertiary care hospital from January 2002 to July 2009 were reviewed. Clinical data including patient baseline characteristics, surgical complications, pathological findings, treatment alterations, and survival outcomes were retrospectively collected and analyzed.
Results
A total of 16 critically ill patients with cancer diagnosed with ARDS who underwent SLB were enrolled. The meantime from ARDS onset to SLB was 3.0 ± 1.5 days. All SLB specimens offered a pathological diagnosis, and specific diagnoses were made in 9 of 16 patients. Biopsy findings resulted in a change in therapy in 11 of 16 patients. Overall, the SLB surgical complication rate was 19% (3/16). SLB did not directly cause the observed operative mortality. The ICU mortality rate was 38% (6/16). Patients who switched therapies after SLB had a trend toward decreased mortality than patients without a change in therapy (27% versus 60%; P = 0.299).
Conclusions
In selected critically ill cancer patients with ARDS, SLB had a high diagnostic yield rate and an acceptable surgical complication rate.
doi:10.1186/1749-8090-8-128
PMCID: PMC3716885  PMID: 23680446
Surgical lung biopsy; Cancer; Acute respiratory distress syndrome; Outcomes
21.  Single-atom Catalysis Using Pt/Graphene Achieved through Atomic Layer Deposition 
Scientific Reports  2013;3:1775.
Platinum-nanoparticle-based catalysts are widely used in many important chemical processes and automobile industries. Downsizing catalyst nanoparticles to single atoms is highly desirable to maximize their use efficiency, however, very challenging. Here we report a practical synthesis for isolated single Pt atoms anchored to graphene nanosheet using the atomic layer deposition (ALD) technique. ALD offers the capability of precise control of catalyst size span from single atom, subnanometer cluster to nanoparticle. The single-atom catalysts exhibit significantly improved catalytic activity (up to 10 times) over that of the state-of-the-art commercial Pt/C catalyst. X-ray absorption fine structure (XAFS) analyses reveal that the low-coordination and partially unoccupied densities of states of 5d orbital of Pt atoms are responsible for the excellent performance. This work is anticipated to form the basis for the exploration of a next generation of highly efficient single-atom catalysts for various applications.
doi:10.1038/srep01775
PMCID: PMC3642722
22.  High expression of a disintegrin and metalloproteinase-9 predicts a shortened survival time in completely resected stage I non-small cell lung cancer 
Oncology Letters  2013;5(5):1461-1466.
The aim of this study was to investigate the abnormal expression of a disintegrin and metalloproteinase-9 (ADAM9) in human resected non-small cell lung cancer (NSCLC) tissue, in order to evaluate the significance of ADAM9 expression in surgically resected NSCLC. Sixty-four cases of completely resected stage I NSCLC with mediastinal N2 lymph node dissection were immunohistochemically analyzed for ADAM9 protein expression. Survival, univariate and multivariate analyses were conducted to assess the significance of ADAM9 expression and its correlation with other clinicopathological characteristics. ADAM9 was observed to be significantly more highly expressed in NSCLC tissue compared with normal control lung tissue (P=0.001). The 5-year survival rate for patients with NSCLC tissues highly expressing ADAM9 was significantly lower when compared with NSCLC tissues of patients exhibiting low expression of ADAM9 (56.9 vs. 88.9%, P= 0.012). Multivariate analysis identified that high expression of ADAM9 is an independent factor of shortened survival time in resected stage I NSCLC (HR, 3.385; 95% CI, 1.224–9.360; P=0.019). These results clearly demonstrate that ADAM9 is highly expressed in NSCLC and highly expressed ADAM9 correlates with shortened survival time, suggesting that ADAM9 is a novel biomarker for predicting prognosis in resected stage I NSCLC. ADAM9 may also become a useful predictive biomarker for the selection of adjuvant chemotherapy treatment of NSCLC.
doi:10.3892/ol.2013.1209
PMCID: PMC3678878  PMID: 23761811
ADAM9; lung neoplasm; immunohistochemistry; prognosis; lobectomy
23.  Gender and age affect the levels of exhaled nitric oxide in healthy children 
Asthma is a chronic inflammatory disorder of the lung and diagnosis is difficult in children. The measurement of fractional exhaled nitric oxide (FeNO) may be useful in the diagnosis and monitoring of treatments. A number of factors affect FeNO levels and their influence varies across countries and regions. This study included 300 healthy students, aged from 6 to 14 years, who participated voluntarily. A comprehensive medical survey was used and measurements of FeNO levels and spirometric parameters were recorded in Shenyang, China. We observed that the median FeNO was 11 ppb (range, 8–16 ppb) in children from the northern areas of China. For males, the median level was 13 ppb (range, 9–18 ppb) and the median level was 10 ppb (range, 8–14 ppb) for females. There was a significant difference between males and females (P= 0.007) and age was correlated with FeNO (R2= 0.6554), while weight, height, body mass index (BMI), forced vital capacity (FVC), forced expiratory volume (FEV1), FEV1/FVC and peak expiratory flow (PEF) had no correlation with FeNO. In conclusion, the median FeNO is 11 ppb (range, 8–16 ppb) in male and female healthy children from northern areas of China and is affected by gender and age.
doi:10.3892/etm.2013.922
PMCID: PMC3628114  PMID: 23596487
exhaled nitric oxide; healthy children; gender; age
24.  Energy Types of Snoring Sounds in Patients with Obstructive Sleep Apnea Syndrome: A Preliminary Observation 
PLoS ONE  2012;7(12):e53481.
Background
Annoying snore is the principle symptom and problem in obstructive sleep apnea syndrome (OSAS). However, investigation has been hampered by the complex snoring sound analyses.
Objective
This study was aimed to investigate the energy types of the full-night snoring sounds in patients with OSAS.
Patients and Method
Twenty male OSAS patients underwent snoring sound recording throughout 6 hours of in-lab overnight polysomnogragphy. Snoring sounds were processed and analyzed by a new sound analytic program, named as Snore Map®. We transformed the 6-hour snoring sound power spectra into the energy spectrum and classified it as snore map type 1 (monosyllabic low-frequency snore), type 2 (duplex low-&mid-frequency snore), type 3 (duplex low- & high-frequency snore), and type 4 (triplex low-, mid-, & high-frequency snore). The interrator and test-retest reliabilities of snore map typing were assessed. The snore map types and their associations among demographic data, subjective snoring questionnaires, and polysomnographic parameters were explored.
Results
The interrator reliability of snore map typing were almost perfect (κ = 0.87) and the test-retest reliability was high (r = 0.71). The snore map type was proportional to the body mass index (r = 0.63, P = 0.003) and neck circumference (r = 0.52, P = 0.018). Snore map types were unrelated to subjective snoring questionnaire scores (All P>0.05). After adjustment for body mass index and neck circumference, snore map type 3–4 was significantly associated with severity of OSAS (r = 0.52, P = 0.026).
Conclusions
Snore map typing of a full-night energy spectrum is feasible and reliable. The presence of a higher snore map type is a warning sign of severe OSAS and indicated priority OSAS management. Future studies are warranted to evaluate whether snore map type can be used to discriminate OSAS from primary snoring and whether it is affected by OSAS management.
doi:10.1371/journal.pone.0053481
PMCID: PMC3534069  PMID: 23300931
25.  GSTP1 negatively regulates Stat3 activation in epidermal growth factor signaling 
Oncology Letters  2012;5(3):1053-1057.
Glutathione S-transferases (GSTs) are the enzymes that defend cells against the damage mediated by oxidant and electrophilic carcinogens. GSTπ (GSTP1) is a member of the GST family and the hypermethylation GSTP1 CpG island DNA is detected in human hepatocellular carcinoma (HCC) tissues, which contributes to the negative expression of GSTP1 mRNA and protein. GSTP1 expression is considered to be an early event in HCC. Stat3, a member of the signal transduction and activator of transcription (Stat) family, is important for promoting the proliferation, survival and other biological processes of cells triggered by cytokines and growth factors. Activated Stat3 may participate in oncogenesis. Previous studies have demonstrated that overexpression of phosphorylated Stat3 is important in the proliferation of HCC cells, suggesting that disturbance of the Stat3 pathway may be an early event. We hypothesize that the suppression of GSTP1 expression in HCC cells increases Stat3 activation. In order to test this hypothesis, HepG2 cells were genetically modified to transiently express high levels of GSTP1. The transient expression of GSTP1 specifically downregulated epidermal growth factor (EGF)-mediated tyrosine phosphorylation of Stat3, and subsequently suppressed the transcriptional activity of Stat3. By contrast, GSTP1 RNAi was able to lead to an increase in the phosphorylation of Stat3. In addition, overexpression of GSTP1 was capable of reducing the survival of HepG2 cells and inducing cell cycle arrest. This inhibition was mediated by a direct interaction between GSTP1 and Stat3. Overall, our results suggest that GSTP1 is important in the regulation of the transcriptional activity of Stat3, and that it is also a regulator of the cell cycle via EGF signaling.
doi:10.3892/ol.2012.1098
PMCID: PMC3576364  PMID: 23426146
glutathione S-transferase π; Stat3; phosphorylation; cell cycle

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