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1.  Decision-Making for Risky Gains and Losses among College Students with Internet Gaming Disorder 
PLoS ONE  2015;10(1):e0116471.
Individuals with Internet gaming disorder (IGD) tend to exhibit disadvantageous risky decision-making not only in their real life but also in laboratory tasks. Decision-making is a complex multifaceted function and different cognitive processes are involved in decision-making for gains and losses. However, the relationship between impaired decision-making and gain versus loss processing in the context of IGD is poorly understood. The main aim of the present study was to separately evaluate decision-making for risky gains and losses among college students with IGD using the Cups task. Additionally, we further examined the effects of outcome magnitude and probability level on decision-making related to risky gains and losses respectively. Sixty college students with IGD and 42 matched healthy controls (HCs) participated. Results indicated that IGD subjects exhibited generally greater risk taking tendencies than HCs. In comparison to HCs, IGD subjects made more disadvantageous risky choices in the loss domain (but not in the gain domain). Follow-up analyses indicated that the impairment was associated to insensitivity to changes in outcome magnitude and probability level for risky losses among IGD subjects. In addition, higher Internet addiction severity scores were associated with percentage of disadvantageous risky options in the loss domain. These findings emphasize the effect of insensitivity to losses on disadvantageous decisions under risk in the context of IGD, which has implications for future intervention studies.
doi:10.1371/journal.pone.0116471
PMCID: PMC4304794  PMID: 25615595
2.  Statins and Finasteride Use Differentially Modify the Impact of Metformin on Prostate Cancer Incidence in Men with Type 2 Diabetes 
Background
Metformin has shown promise for cancer prevention. Prior studies suggested that metformin might interact potential prostate cancer (PCa) prevention agents: finasteride and statins. This study assessed if concurrent use of statins or finasteride modified the long-term impact of metformin on PCa risk in men with type 2 diabetes (T2DM).
Materials and Methods
The study cohort consisted of 71,999 men with T2DM seen in the Veteran Administration Health Care System, without prior cancer or liver diseases, nor prescription of thiazolidinediones or insulin between FY2003-FY2013. Cox proportional hazard analyses (adjusting for covariates and propensity scores of metformin use) were conducted to compare the hazard ratio (HR) of PCa associated with metformin use between statins or finasteride users and none users.
Results
Mean follow-up was 6.4±2.8 years; 5.2% (N= 3,756) of the cohort subsequently received a PCa diagnosis. Both statins and finasteride significantly modified the impact of metformin on PCa incidence (p-value<0.001): HR’s of PCa associated with metformin use were 0.89 (p-value=0.02) among non-statin/non-finasteride users, 0.73 (p-value<0.001) among statin users, and 1.42 (p-value<0.001) among finasteride users.
Conclusion
Metformin was associated with reduced PCa risk in men with T2DM. This impact was enhanced by statins but reversed by finasteride. Metformin, statins, and finasteride are potential PCa prevention agents. The interaction of these drugs on PCa risk needs further confirmation in other cohorts. Our finding of differential impacts of metformin, statins, and finasteride (alone or in combination) on PCa risk is informative for treatment management in men at risk for PCa and T2DM.
PMCID: PMC4300536  PMID: 25621309
Prostate cancer; Metformin; Statins; Finasteride; Type 2 diabetes
3.  Complete Genome Sequence of Human Enterovirus Strain 71 (EV71/Taipei/3118/2011), Isolated from a Patient in Taiwan 
Genome Announcements  2015;3(1):e01375-14.
This full-length genome sequence of human enterovirus strain 71 (EV71/Taipei/3118/2011) was isolated from a clinical patient in Taiwan in 2011. According to the phylogenetic analysis, the complete genome sequence in this study is part of the subgenotype C4.
doi:10.1128/genomeA.01375-14
PMCID: PMC4290987  PMID: 25573934
4.  Association between HIF-1α C1772T/G1790A polymorphisms and cancer susceptibility: an updated systematic review and meta-analysis based on 40 case-control studies 
BMC Cancer  2014;14(1):950.
Background
HIF-1 (hypoxia-inducible factor 1) is a transcriptional activator that functions as a critical regulator of oxygen homeostasis. Recently, a large number of epidemiological studies have investigated the relationship between HIF-1α C1772T/G1790A polymorphisms and cancer susceptibility. However, the results remain inconclusive. Therefore, we performed a meta-analysis on all of the available case-control studies to systematically summarize the possible association.
Methods
A literature search was performed using PubMed and the Web of Science database to obtain relevant published studies. Pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) for the relationship between HIF-1α C1772T/G1790A polymorphisms and cancer susceptibility were calculated using fixed- and random-effects models when appropriate. Heterogeneity tests, sensitivity analyses and publication bias assessments were also performed in our meta-analysis.
Results
A total of 40 studies met the inclusion criteria were included in the meta-analysis: 40 studies comprised of 10869 cases and 14289 controls for the HIF-1α C1772T polymorphism and 30 studies comprised of 7117 cases and 10442 controls for the HIF-1α G1790A polymorphism. The results demonstrated that there were significant association between the HIF-1α C1772T polymorphism and cancer susceptibility under four genetic models (TT vs. CC: OR = 1.63, 95% CI = 1.02-2.60; CT + TT vs. CC: OR = 1.15, 95% CI = 1.01-1.34; TT vs. CT + CC: OR = 2.11, 95% CI = 1.32-3.77; T vs. C: OR = 1.21, 95% CI = 1.04-1.41). Similarly, the statistically significant association between the HIF-1α G1790A polymorphism and cancer susceptibility was found to be consistently strong in all of the genetic models. Moreover, increased cancer risk was observed when the data were stratified by cancer type, ethnicity and the source of controls.
Conclusions
This meta-analysis demonstrates that both the C1772T and G1790A polymorphisms in the HIF-1α gene likely contribute to increased cancer susceptibility, especially in the Asian population and in breast cancer, lung cancer, pancreatic cancer and oral cancer. However, further research is necessary to evaluate the relationship between these polymorphisms and cancer risk.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2407-14-950) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2407-14-950
PMCID: PMC4301938  PMID: 25496056
HIF-1 gene; Polymorphism; Cancer; Susceptibility; Meta-analysis
5.  Frailty Attenuates the Impact of Metformin on Reducing Mortality in Older Adults with Type 2 Diabetes 
Objective
To determine whether the protective effect of metformin against death is modified by frailty status in older adults with type 2 diabetes.
Research Design and Methods
We conducted a cohort study during October 1, 1999–September 30, 2006 among veterans aged 65–89 years old with type 2 diabetes but without history of liver, renal diseases, or cancers, who had sulfonylureas or metformin as the sole antidiabetic drug for ≥180 days. The Cox proportional hazard model was used to compare hazard rates of all-cause mortality between the metformin and sulfonylurea users adjusting for the propensity score of metformin use and covariates: age, race/ethnicity, diabetes duration, Charlson comorbidity score, statin use, smoking status, BMI, LDL, and HbA1c.
Results
In this cohort of 2,415 veterans, 307 (12.7%) were metformin users, 2,108 (87.3%) were sulfonylurea users, the mean age was 73.7±5.2 years, the mean study period was 5.6±2.3 years, the mean HbA1c at baseline was 6.7±1.0%, 23% had diabetes for ≥10 years, and 43.6% (N=1,048) died during the study period. For patients with and without frailty, the adjusted hazard ratio (HR) of death for metformin vs. sulfonylurea use were 0.92 (95% CI=0.90–1.31, p-value=0.19) and 0.69 (95% CI = 0.60–0.79, p-value<0.001), respectively. Logistic regression analyses showed that metformin (vs. sulfonylurea) was significantly associated with a decreased odds of frailty (OR: 0.66, 95% CI: 0.61–0.71, p-value <.0001)
Conclusion
Our study suggests that metformin could potentially promote longevity via preventing frailty in older adults with type 2 diabetes.
PMCID: PMC4264048  PMID: 25506599
Metformin; Frailty; Mortality; Type 2 diabetes
6.  Pharmacodynamic and Therapeutic Investigation of Focused Ultrasound-Induced Blood-Brain Barrier Opening for Enhanced Temozolomide Delivery in Glioma Treatment 
PLoS ONE  2014;9(12):e114311.
Focused ultrasound (FUS) exposure with the presence of microbubbles has been shown to transiently open the blood-brain barrier (BBB), and thus has potential to enhance the delivery of various kinds of therapeutic agents into brain tumors. The purpose of this study was to assess the preclinical therapeutic efficacy of FUS-BBB opening for enhanced temozolomide (TMZ) delivery in glioma treatment. FUS exposure with microbubbles was delivered to open the BBB of nude mice that were either normal or implanted with U87 human glioma cells. Different TMZ dose regimens were tested, ranging from 2.5 to 25 mg/kg. Plasma and brain samples were obtained at different time-points ranging from 0.5 to 4 hours, and the TMZ concentration within samples was quantitated via a developed LC-MS/MS procedure. Tumor progression was followed with T2-MRI, and animal survival and brain tissue histology were conducted. Results demonstrated that FUS-BBB opening caused the local TMZ accumulation in the brain to increase from 6.98 to 19 ng/mg. TMZ degradation time in the tumor core was found to increase from 1.02 to 1.56 hours. Improved tumor progression and animal survival were found at different TMZ doses (up to 15% and 30%, respectively). In conclusion, this study provides preclinical evidence that FUS-BBB opening increases the local concentration of TMZ to improve the control of tumor progression and animal survival, suggesting the potential for clinical application to improve current brain tumor treatment.
doi:10.1371/journal.pone.0114311
PMCID: PMC4260869  PMID: 25490097
7.  Gadoxetic Acid-Enhanced MRI and Sonoelastography: Non-Invasive Assessments of Chemoprevention of Liver Fibrosis in Thioacetamide-Induced Rats with Sho-Saiko-To 
PLoS ONE  2014;9(12):e114756.
Background
This study aimed to compare the performance of gadoxetic acid -enhanced magnetic resonance imaging (MRI) and sonoelastography in evaluating chemopreventive effects of Sho-Saiko-To (SST) in thioacetamide (TAA)-induced early liver fibrosis in rats.
Materials and Methods
Ten of Sprague-Dawley rats receiving TAA (200 mg/kg of body weight) intraperitoneal injection were divided into three groups: Group 1 (TAA only, n = 3), Group 2 (TAA +0.25 g/kg SST, n = 4) and Group 3 (TAA+1 g/kg SST, n = 3). Core needle liver biopsy at week 2 and liver specimens after sacrifice at week 6 confirmed liver fibrosis using histological examinations, including Sirius red staining, Ishak and Metavir scoring systems. Gadoxetic acid-enhanced MRI and shear-wave sonoelastography were employed to evaluate liver fibrosis. The expression of hepatic transporter organic anion transporter 1 (Oatp1), multidrug-resistant protein 2 (Mrp2) and alpha-smooth muscle actin (α-Sma) were also analyzed in each group by immunohistochemistry (IHC) and Western blot.
Results
According to histological grading by Sirius red staining, Ishak scores of liver fibrosis in Groups 1, 2 and 3 were 3, 2 and 1, respectively. As shown in gadoxetic acid-enhanced MRI, the ratio of relative enhancement was significantly lower in Group 1 (1.87±0.21) than in Group 2 of low-dose (2.82±0.25) and Group 3 of high-dose (2.72±0.12) SST treatment at 10 minutes after gadoxetic acid intravenous injection (p<0.05). Sonoelastography showed that the mean difference before and after experiments in Groups 1, 2 and 3 were 4.66±0.1, 4.4±0.57 and 3±0.4 KPa (p<0.1), respectively. Chemopreventive effects of SST reduced the Mrp2 protein level (p<0.01) but not Oatp1 and α-Sma levels.
Conclusion
Sonoelastography and gadoxetic acid-enhanced MRI could monitor the treatment effect of SST in an animal model of early hepatic fibrosis.
doi:10.1371/journal.pone.0114756
PMCID: PMC4260946  PMID: 25490034
8.  Cost and effectiveness of video-assisted thoracoscopic surgery for clinical stage I non-small cell lung cancer: a population-based analysis 
Journal of Thoracic Disease  2014;6(12):1690-1696.
Background
Video-assisted thoracoscopic surgery (VATS) is a minimally invasive alternative to conventional surgery (CS). We aimed to estimate the short-term cost-effectiveness of VATS vs. CS for clinical stage I non-small cell lung cancer (NSCLC-c-stage-I) patients from the payer’s perspective (National Health Insurance).
Methods
We identified NSCLC-c-stage-I patients diagnosed and received surgery within 2007-2009 through a comprehensive population-based database containing cancer and death registries, and reimbursement data. The duration of interest was 1 year. We included potential confounding covariables through literature searching and our own experience, and used a propensity score to construct a 1:1 population for adjustment.
Results
Our study population constituted 966 patients. The mean hospital stay [days, standard deviation (SD)] were 14.4 [7] and 16.1 (7.7) for VATS and CS respectively (P=0.002). The mean cost (2013 USD) and survival (year) was $22,316 vs. $21,976 and 0.98 vs. 0.974 for VATS vs. CS. The probability for VATS to be cost-effective (i.e., positive net benefit) was 0.49 & 0.56 at willingness-to-pay (WTP) 50,000 & 100,000 USD/life-year, respectively.
Conclusions
We provide the first empirical evidence that when compared to CS, VATS was potentially cost-effective in the short term (1 year) within the common WTP levels in Taiwan.
doi:10.3978/j.issn.2072-1439.2014.10.27
PMCID: PMC4283335  PMID: 25589961
Cost-effectiveness analysis; video-assisted thoracoscopic surgery (VATS); clinical stage I non-small cell lung cancer (NSCLC-c-stage-I)
9.  Temporal trends in new exposure to antiepileptic drug monotherapy and suicide-related behavior 
Neurology  2013;81(22):1900-1906.
Objective:
Because some recent studies suggest increased risk for suicide-related behavior (SRB; ideation, attempts) among those receiving antiepileptic drugs (AEDs), we examined the temporal relationship between new AED exposure and SRB in a cohort of older veterans.
Methods:
We used national Veterans Health Administration databases to identify veterans aged ≥65 years who received a new AED prescription in 2004–2006. All instances of SRB were identified using ICD-9-CM codes 1 year before and after the AED exposure (index) date. We also identified comorbid conditions and medication associated with SRB in prior research. We used generalized estimating equations with a logit link to examine the association between new AED exposure and SRB during 30-day intervals during the year before and after the index date, controlling for potential confounders.
Results:
In this cohort of 90,263 older veterans, the likelihood of SRB the month prior to AED exposure was significantly higher than in other time periods even after adjusting for potential confounders. Although there were 87 SRB events (74 individuals) the year before and 106 SRB events (92 individuals) after, approximately 22% (n = 16) of those also had SRB before the index date. Moreover, the rate of SRB after AED start was gradually reduced over time.
Conclusions:
The temporal pattern of AED exposure and SRB suggests that, in clinical practice, the peak in SRB is prior to exposure. While speculative, the rate of gradual reduction in SRB thereafter suggests that symptoms may prompt AED prescription.
doi:10.1212/01.wnl.0000436614.51081.2e
PMCID: PMC3843385  PMID: 24174583
10.  A Kullback-Leibler Divergence for Bayesian Model Diagnostics 
Open journal of statistics  2011;1(3):172-184.
This paper considers a Kullback-Leibler distance (KLD) which is asymptotically equivalent to the KLD by Goutis and Robert [1] when the reference model (in comparison to a competing fitted model) is correctly specified and that certain regularity conditions hold true (ref. Akaike [2]). We derive the asymptotic property of this Goutis-Robert-Akaike KLD under certain regularity conditions. We also examine the impact of this asymptotic property when the regularity conditions are partially satisfied. Furthermore, the connection between the Goutis-Robert-Akaike KLD and a weighted posterior predictive p-value (WPPP) is established. Finally, both the Goutis-Robert-Akaike KLD and WPPP are applied to compare models using various simulated examples as well as two cohort studies of diabetes.
doi:10.4236/ojs.2011.13021
PMCID: PMC4235748  PMID: 25414801
Kullback-Leibler Distance; Model Diagnostic; Weighted Posterior Predictive p-Value
11.  Change-point diagnostics in competing risks models: Two posterior predictive p-value approaches 
Test (Madrid, Spain)  2007;16(1):145-171.
This paper presents a Bayesian diagnostic procedure for examining change-point assumption in the competing risks model framework. It considers the family of distributions arising from the cause-specific model as reported by Chiang (Introduction to stochastic processes in biostatistics. Wiley, New York, 1968) upon which change-points are added to accommodate possible distributional heterogeneity. Model departure, due to misspecification of change-points associated with either the overall survival distribution or cause-specific probabilities, is quantified in terms of a sequence of cumulative-sum statistics between each pair of adjacent change-points assumed. When assessing the asymptotic behavior of each sequence of cumulative-sum statistics using its posterior predictive p-values, see Rubin (Ann Stat 12:1151–1172, 1984) and partial posterior predictive p-values as reported by Bayarri and Berger (J Am Stat Assoc 95:1127–1142, 2000), we show that both types of p-values attain their greatest departure from 0.5 at the change-point that is missed in the assumed model, from which a diagnostic procedure is formalized. Statistical power of these two types of p-values is discussed.
doi:10.1007/s11749-006-0006-x
PMCID: PMC4226243  PMID: 25392679
Change-point; Competing risks; Posterior predictive p-values
12.  Chylothorax following endovascular aortic repair with subclavian revascularization – a case report 
Background
Thoracic endovascular aortic repair (TEVAR) is becoming increasingly popular due to reduced perioperative morbidity and mortality compared with open surgical repair. However, complications can occur when the left subclavian artery is involved. When performing TEVAR with left carotid-subclavian artery bypass the stent graft will extend to the left common carotid artery. We herein present the case of a patient with a type B aortic dissection with an acute intramural hematoma. Chylothorax was noted after TEVAR with left carotid-subclavian artery bypass.
Case report
A 66-year-old female with descending aortic dissection that was treated conservatively developed the sudden onset of back pain. Aortic computed tomography (CT) showed a type B intramural aortic dissection. TEVAR with left carotid-subclavian artery bypass was performed. Left chylothorax was noted after surgery with drainage of up to 1000 mL per day. Conservative management was ineffective. Thoracoscopic ligation of the thoracic duct was performed with resolution of the chyle leakage.
Conclusion
Chylothorax can occur after TEVAR with carotid-subclavian artery bypass and likely results from thoracic duct injury. When conservative treatments fail, ligation of the thoracic duct cephalad to aortic hiatus can resolve the chyle leakage.
doi:10.1186/s13019-014-0165-x
PMCID: PMC4234843  PMID: 25361705
13.  Evaluation of Doxorubicin-loaded 3-Helix Micelles as Nanocarriers 
Biomacromolecules  2013;14(10):3697-3705.
Designing stable drug nanocarriers, 10-30 nm in size, would have significant impact on their transport in circulation, tumor penetration and therapeutic efficacy. In the present study, biological properties of 3-helix micelles loaded with 8 wt% doxorubicin (DOX), ~15 nm in size, were characterized to validate their potential as a nanocarrier platform. DOX-loaded micelles exhibited high stability in terms of size and drug retention in concentrated protein environments similar to conditions after intravenous injections. DOX-loaded micelles were cytotoxic to PPC-1 and 4T1 cancer cells at levels comparable to free DOX. 3-helix micelles can be disassembled by proteolytic degradation of peptide shell to enable drug release and clearance to minimize long-term accumulation. Local administration to normal rat striatum by convection enhanced delivery (CED) showed greater extent of drug distribution and reduced toxicity relative to free drug. Intravenous administration of DOX-loaded 3-helix micelles demonstrated improved tumor half-life and reduced toxicity to healthy tissues in comparison to free DOX. In vivo delivery of DOX-loaded 3-helix micelles through two different routes clearly indicates the potential of 3-helix micelles as safe and effective nanocarriers for cancer therapeutics.
doi:10.1021/bm4010518
PMCID: PMC3923314  PMID: 24050265
Dox-loaded 3-helix micelles; Biological Stability; Cytotoxicity; Biodistribution; Off-Target Accumulation
14.  Microfluidic, marker-free isolation of circulating tumor cells from blood samples 
Nature protocols  2014;9(3):694-710.
The ability to isolate and analyze rare circulating tumor cells (CTCs) has the potential to further our understanding of cancer metastasis and enhance the care of cancer patients. In this protocol, we describe the procedure for isolating rare CTCs from blood samples by using tumor antigen–independent microfluidic CTC-iChip technology. The CTC-iChip uses deterministic lateral displacement, inertial focusing and magnetophoresis to sort up to 107 cells/s. By using two-stage magnetophoresis and depletion antibodies against leukocytes, we achieve 3.8-log depletion of white blood cells and a 97% yield of rare cells with a sample processing rate of 8 ml of whole blood/h. The CTC-iChip is compatible with standard cytopathological and RNA-based characterization methods. This protocol describes device production, assembly, blood sample preparation, system setup and the CTC isolation process. Sorting 8 ml of blood sample requires 2 h including setup time, and chip production requires 2–5 d.
doi:10.1038/nprot.2014.044
PMCID: PMC4179254  PMID: 24577360
15.  Transglutaminase 2 Expression Is Increased as a Function of Malignancy Grade and Negatively Regulates Cell Growth in Meningioma 
PLoS ONE  2014;9(9):e108228.
Most meningiomas are benign, but some clinical-aggressive tumors exhibit brain invasion and cannot be resected without significant complications. To identify molecular markers for these clinically-aggressive meningiomas, we performed microarray analyses on 24 primary cultures from 21 meningiomas and 3 arachnoid membranes. Using this approach, increased transglutaminase 2 (TGM2) expression was observed, which was subsequently validated in an independent set of 82 meningiomas by immunohistochemistry. Importantly, the TGM2 expression level was associated with increasing WHO malignancy grade as well as meningioma recurrence. Inhibition of TGM2 function by siRNA or cystamine induced meningioma cell death, which was associated with reduced AKT phosphorylation and caspase-3 activation. Collectively, these findings suggest that TGM2 expression increases as a function of malignancy grade and tumor recurrence and that inhibition of TGM2 reduces meningioma cell growth.
doi:10.1371/journal.pone.0108228
PMCID: PMC4172767  PMID: 25247996
16.  Causal Inference in Longitudinal Comparative Effectiveness Studies With Repeated Measures of A Continuous Intermediate Variable 
Statistics in medicine  2014;33(20):3509-3527.
We propose a principal stratification approach to assess causal effects in non-randomized longitudinal comparative effectiveness studies with a binary endpoint outcome and repeated measures of a continuous intermediate variable. Our method is an extension of the principal stratification approach by Lin et al. [10,11], originally proposed for a longitudinal randomized study to assess the treatment effect of a continuous outcome adjusting for the heterogeneity of a repeatedly measured binary intermediate variable. Our motivation for this work comes from a comparison of the effect of two glucose-lowering medications on a clinical cohort of patients with type 2 diabetes. Here we consider a causal inference problem assessing how well the two medications work relative to one another on two binary endpoint outcomes: cardiovascular disease related hospitalization and all-cause mortality. Clinically, these glucose-lowering medications can have differential effects on the intermediate outcome, glucose level over time. Ultimately we want to compare medication effects on the endpoint outcomes among individuals in the same glucose trajectory stratum while accounting for the heterogeneity in baseline covariates (i.e., to obtain “principal effects” on the endpoint outcomes). The proposed method involves a 3-step model estimation procedure. Step 1 identifies principal strata associated with the intermediate variable using hybrid growth mixture modeling analyses [13]. Step 2 obtains the stratum membership using the pseudoclass technique [17,18], and derives propensity scores for treatment assignment. Step 3 obtains the stratum-specific treatment effect on the endpoint outcome weighted by inverse propensity probabilities derived from Step 2.
doi:10.1002/sim.6120
PMCID: PMC4122661  PMID: 24577715
Causal inference; Comparative effectiveness studies; Growth mixture model; Principal stratification; Propensity score
17.  Gene expression analysis of human induced pluripotent stem cell-derived neurons carrying copy number variants of chromosome 15q11-q13.1 
Molecular Autism  2014;5:44.
Background
Duplications of the chromosome 15q11-q13.1 region are associated with an estimated 1 to 3% of all autism cases, making this copy number variation (CNV) one of the most frequent chromosome abnormalities associated with autism spectrum disorder (ASD). Several genes located within the 15q11-q13.1 duplication region including ubiquitin protein ligase E3A (UBE3A), the gene disrupted in Angelman syndrome (AS), are involved in neural function and may play important roles in the neurobehavioral phenotypes associated with chromosome 15q11-q13.1 duplication (Dup15q) syndrome.
Methods
We have generated induced pluripotent stem cell (iPSC) lines from five different individuals containing CNVs of 15q11-q13.1. The iPSC lines were differentiated into mature, functional neurons. Gene expression across the 15q11-q13.1 locus was compared among the five iPSC lines and corresponding iPSC-derived neurons using quantitative reverse transcription PCR (qRT-PCR). Genome-wide gene expression was compared between neurons derived from three iPSC lines using mRNA-Seq.
Results
Analysis of 15q11-q13.1 gene expression in neurons derived from Dup15q iPSCs reveals that gene copy number does not consistently predict expression levels in cells with interstitial duplications of 15q11-q13.1. mRNA-Seq experiments show that there is substantial overlap in the genes differentially expressed between 15q11-q13.1 deletion and duplication neurons, Finally, we demonstrate that UBE3A transcripts can be pharmacologically rescued to normal levels in iPSC-derived neurons with a 15q11-q13.1 duplication.
Conclusions
Chromatin structure may influence gene expression across the 15q11-q13.1 region in neurons. Genome-wide analyses suggest that common neuronal pathways may be disrupted in both the Angelman and Dup15q syndromes. These data demonstrate that our disease-specific stem cell models provide a new tool to decipher the underlying cellular and genetic disease mechanisms of ASD and may also offer a pathway to novel therapeutic intervention in Dup15q syndrome.
doi:10.1186/2040-2392-5-44
PMCID: PMC4332023
UBE3A; autism; induced pluripotent stem cells; 15q duplication; Angelman syndrome
18.  Reduced BMPR2 expression induces GM-CSF translation and macrophage recruitment in humans and mice to exacerbate pulmonary hypertension 
Reduced expression of bone morphogenetic protein receptor 2 subverts a stress granule response, heightens GM-CSF mRNA translation, and increases inflammatory cell recruitment to exacerbate pulmonary arterial hypertension.
Idiopathic pulmonary arterial hypertension (PAH [IPAH]) is an insidious and potentially fatal disease linked to a mutation or reduced expression of bone morphogenetic protein receptor 2 (BMPR2). Because intravascular inflammatory cells are recruited in IPAH pathogenesis, we hypothesized that reduced BMPR2 enhances production of the potent chemokine granulocyte macrophage colony-stimulating factor (GM-CSF) in response to an inflammatory perturbation. When human pulmonary artery (PA) endothelial cells deficient in BMPR2 were stimulated with tumor necrosis factor (TNF), a twofold increase in GM-CSF was observed and related to enhanced messenger RNA (mRNA) translation. The mechanism was associated with disruption of stress granule formation. Specifically, loss of BMPR2 induced prolonged phospho-p38 mitogen-activated protein kinase (MAPK) in response to TNF, and this increased GADD34–PP1 phosphatase activity, dephosphorylating eukaryotic translation initiation factor (eIF2α), and derepressing GM-CSF mRNA translation. Lungs from IPAH patients versus unused donor controls revealed heightened PA expression of GM-CSF co-distributing with increased TNF and expanded populations of hematopoietic and endothelial GM-CSF receptor α (GM-CSFRα)–positive cells. Moreover, a 3-wk infusion of GM-CSF in mice increased hypoxia-induced PAH, in association with increased perivascular macrophages and muscularized distal arteries, whereas blockade of GM-CSF repressed these features. Thus, reduced BMPR2 can subvert a stress granule response, heighten GM-CSF mRNA translation, increase inflammatory cell recruitment, and exacerbate PAH.
doi:10.1084/jem.20111741
PMCID: PMC3920564  PMID: 24446489
19.  Porcine Coronin 1A Contributes to Nuclear Factor-Kappa B (NF-κB) Inactivation during Haemophilus parasuis Infection 
PLoS ONE  2014;9(8):e103904.
Haemophilus parasuis (H.parasuis) is the etiological agent of porcine polyserositis and arthritis (Glässer's disease) characterized by fibrinous polyserositis, meningitis and polyarthritis, causing severe economic losses to the swine industry. Currently, the molecular basis of this infection is largely unkonwn. Coronin 1A (Coro1A) plays important roles in host against bacterial infection, yet little is known about porcine Coro1A. In this study, we investigated the molecular characterization of porcine Coro1A, revealing that porcine Coro1A was widely expressed in different tissues. Coro1A could be induced by lipopolysaccharide (LPS), polyinosinic acid-polycytidylic acid [poly (I:C)] and H.parasuis in porcine kidney-15 (PK-15) cells. Functional analyses revealed that porcine Coro1A suppressed the NF-κB activation during H.parasuis infection by inhibiting the degradation of IκBα and nuclear translocation of p65. Overexpression of porcine Coro1A inhibited the transcription of NF-κB-mediated downstream genes [Interleukin-6 (IL-6), Interleukin-8 (IL-8) and COX-2] through down-regulation of NF-κB. The results indicated that porcine Coro1A is an important immunity related gene that helps to inhibit NF-kB activation during H. parasuis infection.
doi:10.1371/journal.pone.0103904
PMCID: PMC4122374  PMID: 25093672
20.  Association Between the XRCC6 Promoter rs2267437 Polymorphism and Cancer Risk: Evidence Based on the Current Literature 
Background: Increasing evidence suggests that the DNA repair gene XRCC6 (Ku70) may be critically involved in the aetiology of the human carcinogenesis. Many studies have investigated the association between the rs2267437 polymorphism and cancer susceptibility. However, the results of these studies have been controversial. This meta-analysis was conducted to quantitatively summarize the evidence for a relationship between the rs2267437 polymorphism and cancer risk. Methods: Electronic databases, including PUBMED and EMBASE, were searched for publications that met the inclusion criteria. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the strength of the association between the XRCC6 promoter rs2267437 polymorphism and cancer risk in a fixed-effects model (the Mantel-Haenszel method) or a random-effects model (the DerSimonian and Laird method), as appropriate. Results: A total of 13 case–control studies, involving 3675 cases and 4247 controls, investigating the XRCC6 rs2267437 polymorphism and cancer susceptibility were identified for the meta-analysis. The pooled analysis showed that there is a significant relationship between the XRCC6 rs2267437 polymorphism and cancer susceptibility (GG vs. CC: OR=1.28, 95% CI=1.03–1.60). Subgroup analyses based on the cancer type, ethnicity, and source of the controls were also performed, and these results indicated that the XRCC6 promoter rs2267437 polymorphism was associated with cancer risk in breast cancer studies (GG vs. CC: OR=1.79, 95% CI=1.25–2.56; GG vs. CG+CC: OR=1.40, 95% CI=1.01–1.95), in Asian populations (GG vs. CC: OR=1.33, 95% CI=1.01–1.74) and in population-based studies (GG vs. CC: OR=1.57, 95% CI=1.12–2.22; CG vs. CC: OR=1.35, 95% CI=1.11–1.64; GG+CG vs. CC: OR=1.37, 95% CI=1.14–1.65). Conclusion: This meta-analysis suggests that the XRCC6 rs2267437 polymorphism may affect breast cancer susceptibility and increase the risk of cancer in Asian populations and in the general population. It is critical that further large-scale and well-designed studies be conducted to confirm the association between the rs2267437 genotype and cancer risk.
doi:10.1089/gtmb.2013.0083
PMCID: PMC3732414  PMID: 23745766
21.  The Correlation of the Presence and Expression Levels of cry Genes with the Insecticidal Activities against Plutella xylostella for Bacillus thuringiensis Strains 
Toxins  2014;6(8):2453-2470.
The use of Bacillus thuringiensis (Bt) strains with high insecticidal activity is essential for the preparation of bioinsecticide. In this study, for 60 Bt strains isolated in Taiwan, their genotypes and the correlation of some cry genes as well as the expression levels of cry1 genes, with their insecticidal activities against Plutella xylostella, were investigated. Pulsed field gel electrophoresis (PFGE) and random amplified polymorphic DNA (RAPD) results revealed that the genotypes of these Bt strains are highly diversified. Also, a considerable number of the Bt strains isolated in Taiwan were found to have high insecticidal activities. Since strains that showed individual combined patterns of PFGE and RAPD exhibited distinct insecticidal activities against P. xylostella, thus, these genotypes may be useful for the identification of the new Bt strains and those which have been used in bioinsecticides. In addition, although the presence of cry2Aa1 may have a greater effect on the insecticidal activity of Bt strains in bioassay than other cry genes, only high expression level of cry1 genes plays a key role to determine the insecticidal activity of Bt strains. In conclusion, both RAPD and PFGE are effective in the differentiation of Bt strains. The presence of cry2Aa1 and, especially, the expression level of cry1 genes are useful for the prediction of the insecticidal activities of Bt strains against P. xylostella.
doi:10.3390/toxins6082453
PMCID: PMC4147593  PMID: 25153253
Bacillus thuringiensis; insecticidal activity; PFGE; RAPD; cry genes
22.  Induction of Apurinic Endonuclease 1 Overexpression by Endoplasmic Reticulum Stress in Hepatoma Cells 
Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide with poor prognosis due to resistance to conventional chemotherapy and limited efficacy of radiotherapy. Previous studies have noted the induction of endoplasmic reticulum stress or apurinic endonuclease 1 (APE1) expression in many tumors. Therefore, the aim of this study was to investigate the relationship between endoplasmic reticulum (ER stress) and APE1 in hepatocellular carcinoma. Here we investigate the expression of APE1 during ER stress in HepG2 and Huh-7 cell lines. Tunicamycin or brefeldin A, two ER stress inducers, increased APE1 and GRP78, an ER stress marker, expression in HepG2 and Huh-7 cells. Induction of APE1 expression was observed through transcription level in response to ER stress. APE1 nuclear localization during ER stress was determined using immunofluorescence assays in HepG2 cells. Furthermore, expression of Hepatitis B virus pre-S2∆ large mutant surface protein (pre-S2∆), an ER stress-induced protein, also increased GRP78 and APE1 expression in the normal hepatocyte NeHepLxHT cell line. Similarly, tumor samples showed higher expression of APE1 in ER stress-correlated liver cancer tissue in vivo. Our results demonstrate that ER stress and HBV pre-S2∆ increased APE1 expression, which may play an important role in resistance to chemotherapeutic agents or tumor development. Therefore, these data provide an important chemotherapeutic strategy in ER stress and HBV pre-S2∆-associated tumors.
doi:10.3390/ijms150712442
PMCID: PMC4139852  PMID: 25026174
hepatocellular carcinoma; Huh-7; HepG2; NeHepLxHT; hepatitis B virus; hepatitis B virus pre-S2∆ large mutant surface protein; endoplasmic reticulum stress; apurinic endonuclease 1; GRP78
23.  Association of interferon regulatory factor 4 gene polymorphisms rs12203592 and rs872071 with skin cancer and haematological malignancies susceptibility: a meta-analysis of 19 case–control studies 
BMC Cancer  2014;14:410.
Background
Research has indicated that the rs12203592 and rs872071 interferon regulatory factor 4 (IRF4) gene polymorphisms correlate with the risk of cancer, especially skin cancer and haematological malignancies, but the results remain controversial. To understand better the effects of these two polymorphisms on skin cancer and haematological malignancies susceptibility, a cumulative meta-analysis was performed.
Methods
We conducted a search using the PubMed and Web of Science databases for relevant case-control studies published before April 2014. Summary odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated using fixed- or random-effects models where appropriate. Heterogeneity test, publication bias test, and sensitivity analysis were also performed.
Results
In total, 11 articles comprised of 19 case–control studies were identified; five focused on the rs12203592 polymorphism with 7,992 cases and 8,849 controls, and six were on the rs872071 polymorphism with 3108 cases and 8300 controls. As for rs12203592, a significant correlation with overall skin cancer and haematological malignancies risk was found with the homozygote comparison model (OR = 1.566, 95% CI 1.087-2.256) and recessive model (OR = 1.526, 95% CI 1.107-2.104). For rs872071, a significantly elevated haematological malignancies risk was observed in all genetic models (homozygote comparison: OR = 1.805, 95% CI 1.402-2.323; heterozygote comparison: OR = 1.427, 95% CI 1.203-1.692; dominant: OR = 1.556, 95% CI 1.281-1.891; recessive: OR = 1.432, 95% CI 1.293-1.587; additive: OR = 1.349, 95% CI 1.201-1.515). Similarly, increased skin cancer and haematological malignancies risk was also identified after stratification of the SNP data by cancer type, ethnicity and source of controls for both polymorphisms.
Conclusions
Our meta-analysis indicated that the rs12203592 and rs872071 IRF4 gene polymorphisms are associated with individual susceptibility to skin cancer and haematological malignancies. Moreover, the effect of the rs12203592 polymorphism on skin cancer risk was particularly prominent among Caucasians. Further functional research should be performed to validate the association.
doi:10.1186/1471-2407-14-410
PMCID: PMC4059085  PMID: 24906573
Meta-analysis; IRF4; Interferon regulatory factor 4; Polymorphisms; rs12203592; rs872071; Cancer risk
24.  Combination of Gefitinib and DNA Methylation Inhibitor Decitabine Exerts Synergistic Anti-Cancer Activity in Colon Cancer Cells 
PLoS ONE  2014;9(5):e97719.
Despite recent advances in the treatment of human colon cancer, the chemotherapy efficacy against colon cancer is still unsatisfactory. In the present study, effects of concomitant inhibition of the epidermal growth factor receptor (EGFR) and DNA methyltransferase were examined in human colon cancer cells. We demonstrated that decitabine (a DNA methyltransferase inhibitor) synergized with gefitinib (an EGFR inhibitor) to reduce cell viability and colony formation in SW1116 and LOVO cells. However, the combination of the two compounds displayed minimal toxicity to NCM460 cells, a normal human colon mucosal epithelial cell line. The combination was also more effective at inhibiting the AKT/mTOR/S6 kinase pathway. In addition, the combination of decitabine with gefitinib markedly inhibited colon cancer cell migration. Furthermore, gefitinib synergistically enhanced decitabine-induced cytotoxicity was primarily due to apoptosis as shown by Annexin V labeling that was attenuated by z-VAD-fmk, a pan caspase inhibitor. Concomitantly, cell apoptosis resulting from the co-treatment of gefitinib and decitabine was accompanied by induction of BAX, cleaved caspase 3 and cleaved PARP, along with reduction of Bcl-2 compared to treatment with either drug alone. Interestingly, combined treatment with these two drugs increased the expression of XIAP-associated factor 1 (XAF1) which play an important role in cell apoptosis. Moreover, small interfering RNA (siRNA) depletion of XAF1 significantly attenuated colon cancer cells apoptosis induced by the combination of the two drugs. Our findings suggested that gefitinib in combination with decitabine exerted enhanced cell apoptosis in colon cancer cells were involved in mitochondrial-mediated pathway and induction of XAF1 expression. In conclusion, based on the observations from our study, we suggested that the combined administration of these two drugs might be considered as a novel therapeutic regimen for treating colon cancer.
doi:10.1371/journal.pone.0097719
PMCID: PMC4038521  PMID: 24874286
25.  Considering Angle Selection When Using Ultrasound Electrode Displacement Elastography to Evaluate Radiofrequency Ablation of Tissues 
BioMed Research International  2014;2014:764320.
Percutaneous radiofrequency ablation (RFA) is a minimally invasive treatment to thermally destroy tumors. Ultrasound-based electrode-displacement elastography is an emerging technique for evaluating the region of RFA-induced lesions. The angle between the imaging probe and the RFA electrode can influence electrode-displacement elastography when visualizing the ablation zone. We explored the angle effect on electrode-displacement elastography to measure the ablation zone. Phantoms embedded with meatballs were fabricated and then ablated using an RFA system to simulate RFA-induced lesions. For each phantom, a commercial ultrasound scanner with a 7.5 MHz linear probe was used to acquire raw image data at different angles, ranging from 30° to 90° at increments of 10°, to construct electrode-displacement images and facilitate comparisons with tissue section images. The results revealed that the ablation regions detected using electrode-displacement elastography were highly correlated with those from tissue section images when the angle was between 30° and 60°. However, the boundaries of lesions were difficult to distinguish, when the angle was larger than 60°. The experimental findings suggest that angle selection should be considered to achieve reliable electrode-displacement elastography to describe ablation zones.
doi:10.1155/2014/764320
PMCID: PMC4058241  PMID: 24971347

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