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1.  Stenotrophomonas maltophilia bloodstream infection in patients with hematologic malignancies: a retrospective study and in vitro activities of antimicrobial combinations 
Stenotrophomonas maltophilia causes serious infections in immunocompromised hosts. Here, we analyzed the clinical characteristics of S. maltophilia bloodstream infection (BSI) in patients with hematologic malignancies and evaluated in vitro synergistic effects of antimicrobial combinations.
We retrospectively reviewed all consecutive episodes of S. maltophilia BSIs in adult hematologic patients from June 2009 to May 2014, with in vitro susceptibility and synergy tests using high-throughput bioluminescence assay performed for available clinical isolates.
Among 11,004 admissions during 5-year period, 31 cases were identified as S. maltophilia BSIs. The incidence rate of S. maltophilia BSI was 0.134 cases/1,000 patient-days. Overall and attributable mortality of S. maltophilia BSI was 64.5% and 38.7%, respectively. Severe neutropenia (adjusted hazard ratio [HR] 5.24, p =0.013), shock at the onset of BSI (adjusted HR 6.05, p <0.001), and pneumonia (adjusted HR 3.15, p =0.017) were independent risk factors for mortality. In vitro susceptibilities to ceftazidime, levofloxacin, ticarcillin-clavulanic acid (TIM) and trimethoprim-sulfamethoxazole (SXT) were 11.1%, 44.0%, 40.7%, and 88.9%, respectively. MIC50/MIC90 for moxifloxacin and tigecycline were 1/4 mg/L and 4/8 mg/L. The 50% and 90% fractional inhibitory concentrations (FIC50/FIC90) of clinical isolates against a combination of SXT and TIM were 0.500/0.750. For SXT plus levofloxacin or moxifloxacin, FIC50/FIC90 were 0.625/1.000 and 0.625/0.625, respectively.
S. maltophilia BSIs show high mortality, which is related to severe neutropenia, shock, and S. maltophilia pneumonia. Based upon drug susceptibility testing, the primary treatment of choice for S. maltophilia BSIs should be SXT in hematologic patients, rather than quinolones, with combination therapies including SXT serving as a feasible treatment option.
PMCID: PMC4336707
Bacteremia; Drug combinations; Hematologic diseases; Mortality; Stenotrophomonas maltophilia
2.  The Association between NQO1 Pro187Ser Polymorphism and Bladder Cancer Susceptibility: A Meta-Analysis of 15 Studies 
PLoS ONE  2015;10(1):e0116500.
NAD(P)H:quinone oxidoreductase 1 (NQO1), an obligate two-electron reductase, plays an important role in reducing reactive quinones to less reactive and less toxic hydroquinones. Genetic variations in NQO1 gene that impede its enzyme function may be considered as putative risk factor for cancer. Numerous studies have been performed to investigate the association between NQO1 Pro187Ser polymorphism and bladder cancer risk; nevertheless, the results remain controversial.
We indentified eligible publications from PubMed, Embase and CBM databases. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were used to access the strength of the associations. False-positive report probability (FPRP) analysis was also performed for all statistically significant findings.
We collected a total of 15 studies including 4298 cases and 4275 controls in the final meta-analysis. Overall, the NQO1 187Ser carriers were associated with an increased bladder cancer risk (homozygous: OR = 1.43, 95% CI = 1.08-1.90; recessive: OR = 1.33, 95% CI = 1.03-1.72; dominant: OR = 1.19, 95% CI = 1.04-1.37, and allele comparing: OR = 1.18, 95% CI = 1.06-1.33). Stratification analyses showed a statistically significant association among Asians (homozygous: OR = 1.82, 95% CI = 1.39-2.38; recessive: OR = 1.52, 95% CI = 1.20-1.93, dominant: OR = 1.40, 95% CI = 1.05-1.88, and allele comparing: OR = 1.35, 95% CI = 1.15-1.58), never smokers (homozygous: OR = 2.30, 95% CI = 1.14-4.65; heterozygous: OR = 2.26, 95% CI = 1.43-3.56; dominant model: OR = 1.59, 95% CI = 1.14-2.21, and allele comparing: OR = 1.72, 95% CI = 1.27-2.33), hospital-based studies (homozygous: OR = 1.46, 95% CI = 1.09-1.94; recessive: OR = 1.32, 95% CI = 1.02-1.69; dominant: OR = 1.28, 95% CI = 1.05-1.56, and allele comparing: OR = 1.24, 95% CI = 1.07-1.43), studies with genotyping performed by PCR-RFLP under all genetic models, and studies with minor allele frequency >0.30 (homozygous: OR = 1.69, 95% CI = 1.25-2.27; recessive: OR = 1.46, 95% CI = 1.10-1.95, and allele comparing: OR = 1.25, 95% CI = 1.04-1.51), respectively.
Despite some limitations, our meta-analysis provides sufficient evidence that NQO1 Pro187Ser polymorphism may contribute to bladder cancer risk. These findings need further validation in well-designed prospective studies with larger sample size and different ethnicities, especially for Asians.
PMCID: PMC4300190  PMID: 25602258
3.  African Green Monkeys Recapitulate the Clinical Experience with Replication of Live Attenuated Pandemic Influenza Virus Vaccine Candidates 
Journal of Virology  2014;88(14):8139-8152.
Live attenuated cold-adapted (ca) H5N1, H7N3, H6N1, and H9N2 influenza vaccine viruses replicated in the respiratory tract of mice and ferrets, and 2 doses of vaccines were immunogenic and protected these animals from challenge infection with homologous and heterologous wild-type (wt) viruses of the corresponding subtypes. However, when these vaccine candidates were evaluated in phase I clinical trials, there were inconsistencies between the observations in animal models and in humans. The vaccine viruses did not replicate well and immune responses were variable in humans, even though the study subjects were seronegative with respect to the vaccine viruses before vaccination. Therefore, we sought a model that would better reflect the findings in humans and evaluated African green monkeys (AGMs) as a nonhuman primate model. The distribution of sialic acid (SA) receptors in the respiratory tract of AGMs was similar to that in humans. We evaluated the replication of wt and ca viruses of avian influenza (AI) virus subtypes H5N1, H6N1, H7N3, and H9N2 in the respiratory tract of AGMs. All of the wt viruses replicated efficiently, while replication of the ca vaccine viruses was restricted to the upper respiratory tract. Interestingly, the patterns and sites of virus replication differed among the different subtypes. We also evaluated the immunogenicity and protective efficacy of H5N1, H6N1, H7N3, and H9N2 ca vaccines. Protection from wt virus challenge correlated well with the level of serum neutralizing antibodies. Immune responses were slightly better when vaccine was delivered by both intranasal and intratracheal delivery than when it was delivered intranasally by sprayer. We conclude that live attenuated pandemic influenza virus vaccines replicate similarly in AGMs and human subjects and that AGMs may be a useful model to evaluate the replication of ca vaccine candidates.
IMPORTANCE Ferrets and mice are commonly used for preclinical evaluation of influenza vaccines. However, we observed significant inconsistencies between observations in humans and in these animal models. We used African green monkeys (AGMs) as a nonhuman primate (NHP) model for a comprehensive and comparative evaluation of pairs of wild-type and pandemic live attenuated influenza virus vaccines (pLAIV) representing four subtypes of avian influenza viruses and found that pLAIVs replicate similarly in AGMs and humans and that AGMs can be useful for evaluation of the protective efficacy of pLAIV.
PMCID: PMC4097805  PMID: 24807726
4.  Examining deterrence of adult sex crimes: A semi-parametric intervention time series approach 
Motivated by recent developments on dimension reduction (DR) techniques for time series data, the association of a general deterrent effect towards South Carolina (SC)’s registration and notification (SORN) policy for preventing sex crimes was examined. Using adult sex crime arrestee data from 1990 to 2005, the the idea of Central Mean Subspace (CMS) is extended to intervention time series analysis (CMS-ITS) to model the sequential intervention effects of 1995 (the year SC’s SORN policy was initially implemented) and 1999 (the year the policy was revised to include online notification) on the time series spectrum. The CMS-ITS model estimation was achieved via kernel smoothing techniques, and compared to interrupted auto-regressive integrated time series (ARIMA) models. Simulation studies and application to the real data underscores our model’s ability towards achieving parsimony, and to detect intervention effects not earlier determined via traditional ARIMA models. From a public health perspective, findings from this study draw attention to the potential general deterrent effects of SC’s SORN policy. These findings are considered in light of the overall body of research on sex crime arrestee registration and notification policies, which remain controversial.
PMCID: PMC4002981  PMID: 24795489
Central mean subspace; Nadaraya-Watson kernel smoother; Nonlinear time series; Sex crime arrestee
5.  Mild Clinical Features and Histopathologically Atypical Cores in Two Korean Families with Central Core Disease Harboring RYR1 Mutations at the C-Terminal Region 
Central core disease (CCD) is a congenital myopathy characterized by distinctive cores in muscle fibers. Mutations in the gene encoding ryanodine receptor 1 (RYR1) have been identified in most CCD patients.
Case Report
Two unrelated patients presented with slowly progressive or nonprogressive proximal muscle weakness since childhood. Their family history revealed some members with the same clinical problem. Histological analysis of muscle biopsy samples revealed numerous peripheral cores in the muscle fibers. RYR1 sequence analysis disclosed a novel mutation in exon 101 (c.14590T>C) and confirmed a previously reported mutation in exon 102 (c.14678G>A).
We report herein two families with CCD in whom missense mutations at the C-terminal of RYR1 were identified. Although it has been accepted that such mutations are usually associated with a severe clinical phenotype and clearly demarcated central cores, our patients exhibited a mild clinical phenotype without facial muscle involvement and skeletal deformities, and atypical cores in their muscle biopsy specimens.
PMCID: PMC4302187  PMID: 25628744
central core disease; ryanodine receptor 1; RYR1; core myopathy
6.  H5N1 vaccines in humans 
Virus research  2013;178(1):10.1016/j.virusres.2013.05.006.
The spread of highly pathogenic avian H5N1 influenza viruses since 1997 and their virulence for poultry and humans has raised concerns about their potential to cause an influenza pandemic. Vaccines offer the most viable means to combat a pandemic threat. However, it will be a challenge to produce, distribute and implement a new vaccine if a pandemic spreads rapidly. Therefore, efforts are being undertaken to develop pandemic vaccines that use less antigen and induce cross-protective and long-lasting responses, that can be administered as soon as a pandemic is declared or possibly even before, in order to prime the population and allow for a rapid and protective antibody response. In the last few years, several vaccine manufacturers have developed candidate pandemic and pre-pandemic vaccines, based on reverse genetics and have improved the immunogenicity by formulating these vaccines with different adjuvants. Some of the important and consistent observations from clinical studies with H5N1 vaccines are as follows: two doses of inactivated vaccine are generally necessary to elicit the level of immunity required to meet licensure criteria, less antigen can be used if an oil-in-water adjuvant is included, in general antibody titers decline rapidly but can be boosted with additional doses of vaccine and if high titers of antibody are elicited, cross-reactivity against other clades is observed. Prime-boost strategies elicit a more robust immune response. In this review, we discuss data from clinical trials with a variety of H5N1 influenza vaccines. We also describe studies conducted in animal models to explore the possibility of reassortment between pandemic live attenuated vaccine candidates and seasonal influenza viruses, since this is an important consideration for the use of live vaccines in a pandemic setting.
PMCID: PMC3795810  PMID: 23726847
H5N1; vaccine strategies; pandemic; adjuvants; clinical trials
7.  Development of a High-Yield Live Attenuated H7N9 Influenza Virus Vaccine That Provides Protection against Homologous and Heterologous H7 Wild-Type Viruses in Ferrets 
Journal of Virology  2014;88(12):7016-7023.
Live attenuated H7N9 influenza vaccine viruses that possess the hemagglutinin (HA) and neuraminidase (NA) gene segments from the newly emerged wild-type (wt) A/Anhui/1/2013 (H7N9) and six internal protein gene segments from the cold-adapted influenza virus A/Ann Arbor/6/60 (AA ca) were generated by reverse genetics. The reassortant virus containing the original wt A/Anhui/1/2013 HA and NA sequences replicated poorly in eggs. Multiple variants with amino acid substitutions in the HA head domain that improved viral growth were identified by viral passage in eggs and MDCK cells. The selected vaccine virus containing two amino acid changes (N133D/G198E) in the HA improved viral titer by more than 10-fold (reached a titer of 108.6 fluorescent focus units/ml) without affecting viral antigenicity. Introduction of these amino acid changes into an H7N9 PR8 reassortant virus also significantly improved viral titers and HA protein yield in eggs. The H7N9 ca vaccine virus was immunogenic in ferrets. A single dose of vaccine conferred complete protection of ferrets from homologous wt A/Anhui/1/2013 (H7N9) and nearly complete protection from heterologous wt A/Netherlands/219/2003 (H7N7) challenge infection. Therefore, this H7N9 live attenuated influenza vaccine (LAIV) candidate has been selected for vaccine manufacture and clinical evaluation to protect humans from wt H7N9 virus infection.
IMPORTANCE In response to the recent avian H7N9 influenza virus infection in humans, we developed a live attenuated H7N9 influenza vaccine (LAIV) with two amino acid substitutions in the viral HA protein that improved vaccine yield by 10-fold in chicken embryonated eggs, the substrate for vaccine manufacture. The two amino acids also improved the antigen yield for inactivated H7N9 vaccines, demonstrating that this finding could great facilitate the efficiency of H7N9 vaccine manufacture. The candidate H7N9 LAIV was immunogenic and protected ferrets against homologous and heterologous wild-type H7 virus challenge, making it suitable for use in protecting humans from H7 infection.
PMCID: PMC4054345  PMID: 24719414
8.  A Broadly Neutralizing Human Monoclonal Antibody Directed against a Novel Conserved Epitope on the Influenza Virus H3 Hemagglutinin Globular Head 
Journal of Virology  2014;88(12):6743-6750.
Most neutralizing antibodies elicited during influenza virus infection or vaccination target immunodominant, variable epitopes on the globular head region of hemagglutinin (HA), which leads to narrow strain protection. In this report, we describe the properties of a unique anti-HA monoclonal antibody (MAb), D1-8, that was derived from human B cells and exhibits potent, broad neutralizing activity across antigenically diverse influenza H3 subtype viruses. Based on selection of escape variants, we show that D1-8 targets a novel epitope on the globular head region of the influenza virus HA protein. The HA residues implicated in D1-8 binding are highly conserved among H3N2 viruses and are located proximal to antigenic site D. We demonstrate that the potent in vitro antiviral activity of D1-8 translates into protective activity in mouse models of influenza virus infection. Furthermore, D1-8 exhibits superior therapeutic survival benefit in influenza virus-infected mice compared to the neuraminidase inhibitor oseltamivir when treatment is started late in infection. The present study suggests the potential application of this monoclonal antibody for the therapeutic treatment of H3N2 influenza virus infection.
IMPORTANCE Recently, a few globular head-targeting MAbs have been discovered that exhibit activity against different subtypes of influenza subtypes, such as H1; however, none of the previously described MAbs showed broadly neutralizing activity against diverse H3 viruses. In this report, we describe a human MAb, D1-8, that exhibits potent, broadly neutralizing activity against antigenically diverse H3 subtype viruses. The genotypic analysis of escape mutants revealed a unique putative epitope region in the globular head of H3 HA that is comprised of highly conserved residues and is distinct from the receptor binding site. Furthermore, we demonstrate that D1-8 exhibits superior therapeutic efficacy in influenza virus-infected mice compared to the neuraminidase inhibitor oseltamivir when treatment is started late in infection. In addition to describing a novel anti-globular head of H3 HA MAb with potent broadly neutralizing activity, our report suggests the potential of D1-8 for therapeutic treatment of seasonal influenza virus H3 infection.
PMCID: PMC4054378  PMID: 24696468
9.  Effects of Atrial Fibrillation on the Outcome of the Rehabilitation in Patients With Cerebral Infarction 
Annals of Rehabilitation Medicine  2014;38(6):766-774.
To evaluate the influence of atrial fibrillation (Af) on the clinical characteristics and rehabilitation outcomes of patients with cerebral infarction.
We evaluated 87 of 101 consecutive patients with cerebral infarction admitted to the department of physical medicine and rehabilitation during their rehabilitation period. The patients were divided into two groups, Af and non-Af groups. We estimated characteristics of patient demographic features, disease duration, length of hospital stay, other comorbidities and risk factors for stroke, and functional status at admission and at discharge and compared those in patients with and without Af. Functional Independence Measure (FIM), the Modified Barthel Index (MBI), and the PULSES profile (PULSES) were used to evaluate functional status.
The number in the Af group was 20 (22.9%) and that of the non-Af group was 67 (77.1%). Demographic features, other comorbidities, motor function, cognitive function, neurological scales, and brain lesions did not differ significantly between the groups. The incidence of coronary artery disease and valvular heart disease were significantly correlated with the incidence of Af in multivariate analysis. Based on FIM, MBI, and PULSES scores, functional improvement in the Af group after rehabilitation was significantly less than that of the non-Af group.
Af was shown to be associated with a markedly negative result in rehabilitation in patients with cerebral infarction. Thus, early recognition and proper treatment of Af may help patients achieve more effective rehabilitation.
PMCID: PMC4280372  PMID: 25566475
Atrial fibrillation; Cerebral infarction; Rehabilitation outcomes
10.  Cooperativity and Equilibrium with FOXA1 Define the Androgen Receptor Transcriptional Program 
Nature communications  2014;5:3972.
The pioneering factor FOXA1 opens chromatin to facilitate androgen receptor (AR) binding to prostate-specific genes. How FOXA1 controls the AR cistrome, however, is incompletely understood. Here we show that AR directly binds chromatin through the androgen-response elements (AREs). FOXA1 is not required for AR-chromatin interaction, but instrumental in recruiting AR to low-affinity half-AREs by opening local chromatin around adjacent FKHD sites. Too much FOXA1 creates excessive open chromatin regions, which serve as reservoirs that retain AR via abundant half-AREs, thereby reducing its availability for specific sites. FOXA1 down-regulation, by contrast, relinquishes AR to permissively bind AREs across the genome, resulting in substantial AR binding events and AR-target gene expression even in the absence of androgen. Taken together, our data illustrate the mechanistic details by which cooperativity and equilibrium with FOXA1 define AR cistrome and reveal a previously unknown function of FOXA1 in inhibiting AR signaling and castration-resistant prostate cancer growth.
PMCID: PMC4088269  PMID: 24875621
11.  Identification of Key Licorice Constituents Which Interact with Cytochrome P450: Evaluation by LC/MS/MS Cocktail Assay and Metabolic Profiling 
The AAPS Journal  2013;16(1):101-113.
Licorice has been shown to affect the activities of several cytochrome P450 enzymes. This study aims to identify the key constituents in licorice which may affect these activities. Bioactivity assay was combined with metabolic profiling to identify these compounds in several complex licorice extracts. Firstly, the inhibition potencies of 40 pure licorice compounds were tested using an liquid chromatography/tandem mass spectrometry cocktail method. Significant inhibitors of human P450 isozymes 1A2, 2C9, 2C19, 2D6, and 3A4 were then selected for examination of their structural features by molecular docking to determine their molecular interaction with several P450 isozymes. Based on the present in vitro inhibition findings, along with our previous in vivo metabolic studies and the prevalence of individual compounds in licorice extract, we identified several licorice constituents, viz., liquiritigenin, isoliquiritigenin, together with seven isoprenylated flavonoids and arylcoumarins, which could be key components responsible for the herb–drug interaction between cytochrome P450 and licorice. In addition, hydrophilic flavonoid glycosides and saponins may be converted into these P450 inhibitors in vivo. These studies represent a comprehensive examination of the potential effects of licorice components on the metabolic activities of P450 enzymes.
Electronic supplementary material
The online version of this article (doi:10.1208/s12248-013-9544-9) contains supplementary material, which is available to authorized users.
PMCID: PMC3889530  PMID: 24254844
CYP450; herb–drug interaction; isoliquiritigenin; licorice; liquiritigenin
12.  Quantitative Proteomic Analysis of Serum from Pregnant Women Carrying a Fetus with Conotruncal Heart Defect Using Isobaric Tags for Relative and Absolute Quantitation (iTRAQ) Labeling 
PLoS ONE  2014;9(11):e111645.
To identify differentially expressed proteins from serum of pregnant women carrying a conotruncal heart defects (CTD) fetus, using proteomic analysis.
The study was conducted using a nested case-control design. The 5473 maternal serum samples were collected at 14–18 weeks of gestation. The serum from 9 pregnant women carrying a CTD fetus, 10 with another CHD (ACHD) fetus, and 11 with a normal fetus were selected from the above samples, and analyzed by using isobaric tags for relative and absolute quantitation (iTRAQ) coupled with two-dimensional liquid chromatography-tandem mass spectrometry(2D LC-MS/MS). The differentially expressed proteins identified by iTRAQ were further validated with Western blot.
A total of 105 unique proteins present in the three groups were identified, and relative expression data were obtained for 92 of them with high confidence by employing the iTRAQ-based experiments. The downregulation of gelsolin in maternal serum of fetus with CTD was further verified by Western blot.
The identification of differentially expressed protein gelsolin in the serum of the pregnant women carrying a CTD fetus by using proteomic technology may be able to serve as a foundation to further explore the biomarker for detection of CTD fetus from the maternal serum.
PMCID: PMC4230941  PMID: 25393621
13.  miR-24 limits aortic vascular inflammation and murine abdominal aneurysm development 
Nature Communications  2014;5:5214.
Identification and treatment of abdominal aortic aneurysm (AAA) remain among the most prominent challenges in vascular medicine. MicroRNAs (miRNAs) are crucial regulators of cardiovascular pathology and represent intriguing targets to limit AAA expansion. Here we show, by using two established murine models of AAA disease along with human aortic tissue and plasma analysis, that miR-24 is a key regulator of vascular inflammation and AAA pathology. In vivo and in vitro studies reveal chitinase 3-like 1 (Chi3l1) to be a major target and effector under the control of miR-24, regulating cytokine synthesis in macrophages as well as their survival, promoting aortic smooth muscle cell migration and cytokine production, and stimulating adhesion molecule expression in vascular endothelial cells. We further show that modulation of miR-24 alters AAA progression in animal models, and that miR-24 and CHI3L1 represent novel plasma biomarkers of AAA disease progression in humans.
Abdominal aortic aneurysm (AAA) is a potentially fatal and often asymptomatic disease whose causes remain unclear. Here the authors show that a microRNA, miR-24, and its target, the glycoprotein chitinase 3-like 1, represent key regulators of AAA development.
PMCID: PMC4217126  PMID: 25358394
14.  MBP-Positive and CD11c-Positive Cells Are Associated with Different Phenotypes of Korean Patients with Non-Asthmatic Chronic Rhinosinusitis 
PLoS ONE  2014;9(10):e111352.
Asthmatic nasal polyps primarily exhibit eosinophilic infiltration. However, the identities of the immune cells that infiltrate non-asthmatic nasal polyps remain unclear. Thus, we thought to investigate the distribution of innate immune cells and its clinical relevance in non-asthmatic chronic rhinosinusitis (CRS) in Korea.
Tissues from uncinate process (UP) were obtained from controls (n = 18) and CRS without nasal polyps (CRSsNP, n = 45). Nasal polyps (NP) and UP were obtained from CRS with nasal polyps (CRSwNP, n = 56). The innate immune cells was evaluated by immunohistochemistry such as, eosinophil major basic protein (MBP), tryptase, CD68, CD163, CD11c, 2D7, human neutrophil elastase (HNE) and its distribution was analyzed according to clinical parameters.
In comparisons between UP from each group, CRSwNP had a higher number of MPB+, CD68+, and CD11c+ cells relative to CRSsNP. Comparisons between UP and NP from CRSwNP indicated that NP have a higher infiltrate of MBP+, CD163+, CD11c+, 2D7+ and HNE+ cells, whereas fewer CD68+ cells were found in NP. In addition, MBP+ and CD11c+ cells were increased from UP of CRSsNP, to UP of CRSwNP, and to NP of CRSwNP. Moreover, in UP from CRSwNP, the number of MBP+ and CD11c+ cells positively correlated with CT scores. In the analysis of CRSwNP phenotype, allergic eosinophilic polyps had a higher number of MBP+, tryptase+, CD11c+, 2D7+ cells than others, whereas allergic non-eosinophilic polyps showed mainly infiltration of HNE+ and 2D7+ cells.
The infiltration of MBP+ and CD11c+ innate immune cells show a significant association with phenotype and disease extent of CRS and allergic status also may influences cellular phenotype in non-asthmatic CRSwNP in Korea.
PMCID: PMC4216068  PMID: 25361058
15.  Association of BRCA2 N372H polymorphism with cancer susceptibility: A comprehensive review and meta-analysis 
Scientific Reports  2014;4:6791.
BRCA2 gene plays an important role in homologous recombination. Polymorphic variants in this gene has been suggested to confer cancer susceptibility. Numerous studies have investigated association between BRCA2 N372H polymorphism and risk of several cancers, especially breast cancer. However, the results were inconsistent. We performed a comprehensive meta-analysis to provide a more precise assessment of the association between N372H and cancer risk, following the latest meta-analysis guidelines (PRISMA). Forty six studies involving 36299 cases and 48483 controls were included in our meta-analysis. The crude ORs and the 95% CIs were used to evaluate the strength of the association. The results indicated that the BRCA2 N372H variant was significantly associated with an increased risk of overall cancer (dominant model: OR = 1.07, 95% CI = 1.01–1.13; recessive model: OR = 1.12, 95% CI = 1.02–1.23). Moreover, stratified analyses by the cancer type and source of control observed significantly increased risk associated with BRCA2 N372H in subgroups with ovarian cancer, non-Hodgkin lymphoma and population-based controls, but not breast cancer or hospital-based controls. We also found such association among Africans. Overall, the meta-analysis suggested that BRCA2 N372H may be a cancer susceptibility polymorphism. Well-designed and large-scale studies are needed to substantiate the association between BRCA2 N372H polymorphism and cancer risk.
PMCID: PMC4210867  PMID: 25348552
16.  ERG is a critical regulator of Wnt/LEF1 signaling in prostate cancer 
Cancer research  2013;73(19):6068-6079.
Chromosomal translocations juxtaposing the androgen-responsive TMPRSS2 promoter with the ETS-family transcription factor ERG result in aberrant ERG up-regulation in approximately 50% of prostate cancers. Studies to date have demonstrated important roles of ERG in inducing oncogenic properties of prostate cancer. Its molecular mechanisms of action, however, are yet to be fully understood. Here we report that ERG activates Wnt/LEF1 signaling cascade through multiple mechanisms. ERG bound to the promoters of various Wntgenes to directly increase ligand expression. Consequently, ERG overexpression increased active β-catenin level in the cells and enhancedTCF/LEF1 luciferase reporter activity, which could be partially blocked by WNT-3A inhibitor IWP-2. Most importantly, our data defined LEF1 as a direct target of ERG and that LEF1 inhibitionfully abolished ERG-induced Wnt signaling and target gene expression. Further, functional assays demonstrated that Wnt/LEF1 activation phenocopiedthat of ERG in inducing cell growth, epithelial-to-mesenchymal transition, and cellinvasion, while blockade of Wnt signaling attenuated these effects. Concordantly, LEF1 expression is significantly up-regulated in ERG-high human prostate cancers. Overall, this study provides an important mechanism of activation of Wnt signaling in prostate cancer and nominates LEF1 as a critical mediator of ERG-induced tumorigenesis. Wnt/LEF1 pathway might provide novel targets for therapeutic management of patients with fusion-positive prostate cancer.
PMCID: PMC3790861  PMID: 23913826
18.  Age-related differences in factors associated with the underuse of recommended medications in acute coronary syndrome patients at least one year after hospital discharge 
Few studies have evaluated age-related predictors associated with the underuse of medications in patients with coronary heart disease (CHD). The objective of this study was to identify age-related differences in the factors associated with the underuse of recommended medications in patients diagnosed with acute coronary syndrome (ACS).
From August 2009 to April 2011, we recruited 469 consecutive ACS patients from a cardiac center at a university hospital. We divided the patients into older (65 years of age and older, n = 202) and younger groups (younger than 65 years of age, n = 267). Data on socio-demographic characteristics, depressive symptoms, and medication use were obtained from a telephone survey administered 18 to 24 months after hospital discharge. Additionally, we asked the patients to provide reasons for not taking their medications.
A significantly increased underuse of medication was noted in older patients compared with younger patients, including aspirin (24.8% vs. 37.1%, p = 0.005), beta-blockers (20.3% vs. 34.8%, p = 0.001), ACE inhibitor/angiotensin receptor blockers (27.2% vs. 36.7%, p = 0.030), and statins (21.8% vs. 29.6%, p = 0.005). Among older patients, the factors associated with the underuse of medications included low education level (odds ratio [OR], 3.93), greater number of comorbidities (OR, 1.64), and total number of discharge medications (OR, 1.31). The reasons provided by older patients for not taking medication included the fact that the medication was considered to be non-essential and the large number of medications. Among younger patients, low income (OR, 3.97) and depression (OR, 2.62) were predictors for underuse of medication, and the reasons provided for not taking medications included high costs and the fear of adverse effects.
At least one year after ACS hospital discharge, the underuse of recommended medications is related to low education level, comorbidities, and the total number of discharge medications in elderly patients, whereas underuse in younger patients is associated with low income and depression. The disparities related to these different predictors may have implications for age-related interventions targeting secondary preventions in CHD patients to improve their use of medication.
PMCID: PMC4181620  PMID: 25252927
Medications; Secondary prevention; Age factors; Aged; Coronary heart disease
19.  Androgen receptor genomic regulation 
The transcriptional activity of the androgen receptor (AR) is not only critical for the normal development and function of the prostate but also pivotal to the onset and progression of prostate cancer (PCa). The studies of AR transcriptional regulation were previously limited to a handful of AR-target genes. Owing to the development of various high-throughput genomic technologies, significant advances have been made in recent years. Here we discuss the discoveries of genome-wide androgen-regulated genes in PCa cell lines, animal models and tissues using expression microarray and sequencing, the mapping of genomic landscapes of AR using Combining Chromatin Immunoprecipitation (ChIP)-on-chip and ChIP-seq assays, the interplay of transcriptional cofactors in defining AR binding profiles, and the genomic regulation and AR reprogramming in advanced PCa.
PMCID: PMC4165347  PMID: 25237629
Androgen receptor (AR); prostate cancer (PCa); AR transcriptional regulation; AR-target genes; Combining Chromatin Immunoprecipitation (ChIP)-on-chip; ChIP-seq assays
20.  Evaluation of Three Live Attenuated H2 Pandemic Influenza Vaccine Candidates in Mice and Ferrets 
Journal of Virology  2014;88(5):2867-2876.
H2 influenza viruses have not circulated in humans since 1968, and therefore a significant portion of the population would be susceptible to infection should H2 influenza viruses reemerge. H2 influenza viruses continue to circulate in avian reservoirs worldwide, and these reservoirs are a potential source from which these viruses could emerge. Three reassortant cold-adapted (ca) H2 pandemic influenza vaccine candidates with hemagglutinin (HA) and neuraminidase (NA) genes derived from the wild-type A/Japan/305/1957 (H2N2) (Jap/57), A/mallard/6750/1978 (H2N2) (mal/78), or A/swine/MO/4296424/2006 (H2N3) (sw/06) viruses and the internal protein gene segments from the A/Ann Arbor/6/60 ca virus were generated by plasmid-based reverse genetics (Jap/57 ca, mal/78 ca, and sw/06 ca, respectively). The vaccine candidates exhibited the in vitro phenotypes of temperature sensitivity and cold adaptation and were restricted in replication in the respiratory tract of ferrets. In mice and ferrets, the vaccines elicited neutralizing antibodies and conferred protection against homologous wild-type virus challenge. Of the three candidates, the sw/06 ca vaccine elicited cross-reactive antibodies and provided significant protection against the greatest number of heterologous viruses. These observations suggest that the sw/06 ca vaccine should be further evaluated in a clinical trial as an H2 pandemic influenza vaccine candidate.
IMPORTANCE Influenza pandemics arise when novel influenza viruses are introduced into a population with little prior immunity to the new virus and often result in higher rates of illness and death than annual seasonal influenza epidemics. An influenza H2 subtype virus caused a pandemic in 1957, and H2 viruses circulated in humans till 1968. H2 influenza viruses continue to circulate in birds, and the development of an H2 influenza vaccine candidate is therefore considered a priority in preparing for future pandemics. However, we cannot predict whether a human H2 virus will reemerge or a novel avian H2 virus will emerge. We identified three viruses as suitable candidates for further evaluation as vaccines to protect against H2 influenza viruses and evaluated the immune responses and protection that these three vaccines provided in mice and ferrets.
PMCID: PMC3958078  PMID: 24371061
21.  Effects of total body irradiation-based conditioning on allogeneic stem cell transplantation for pediatric acute leukemia: a single-institution study 
Radiation Oncology Journal  2014;32(3):198-207.
To evaluate the effects of total body irradiation (TBI), as a conditioning regimen prior to allogeneic stem cell transplantation (allo-SCT), in pediatric acute leukemia patients.
Materials and Methods
From January 2001 to December 2011, 28 patients, aged less than 18 years, were treated with TBI-based conditioning for allo-SCT in our institution. Of the 28 patients, 21 patients were diagnosed with acute lymphoblastic leukemia (ALL, 75%) and 7 were diagnosed with acute myeloid leukemia (AML, 25%). TBI was completed 4 days or 1 day before stem cell infusion. Patients underwent radiation therapy with bilateral parallel opposing fields and 6-MV X-rays. The Kaplan-Meier method was used to calculate survival outcomes.
The 2-year event-free survival and overall survival rates were 66% and 56%, respectively (71.4% and 60.0% in AML patients vs. 64.3% and 52.4% in ALL patients, respectively). Treatment related mortality rate were 25%. Acute and chronic graft-versus-host disease was a major complication; other complications included endocrine dysfunction and pulmonary complications. Common complications from TBI were nausea (89%) and cataracts (7.1%).
The efficacy and toxicity data in this study of TBI-based conditioning to pediatric acute leukemia patients were comparable with previous studies. However, clinicians need to focus on the acute and chronic complications related to allo-SCT.
PMCID: PMC4194303  PMID: 25324992
Total body irradiation; Acute lymphoid leukemia; Acute myeloid leukemia; Child; Stem cell transplantation
22.  A dosimetric comparison of volumetric modulated arc therapy (VMAT) and non-coplanar intensity modulated radiotherapy (IMRT) for nasal cavity and paranasal sinus cancer 
To compare dosimetric parameters of volumetric modulated arc therapy (VMAT) and non-coplanar intensity modulated radiotherapy (IMRT) for nasal cavity and paranasal sinus cancer with regard to the coverage of planning target volume (PTV) and the sparing of organs at risk (OAR).
Ten patients with nasal cavity or paranasal sinus cancer were re-planned by VMAT (two-arc) plan and non-coplanar IMRT (7-, 11-, and 15-beam) plans. Planning objectives were to deliver 60 Gy in 30 fractions to 95% of PTV, with maximum doses (Dmax) of <50 Gy to the optic nerves, optic chiasm, and brainstem, <40 Gy to the eyes and <10 Gy to the lenses. The target mean dose (Dmean) to the parotid glands was <25 Gy, and no constraints were applied to the lacrimal glands. Planning was optimized to minimized doses to OAR without compromising coverage of the PTV. VMAT and three non-coplanar IMRT (7-, 11-, and 15-beam) plans were compared using the heterogeneity and conformity indices (HI and CI) of the PTV, Dmax and Dmean of the OAR, treatment delivery time, and monitor units (MUs).
The HI and CI of VMAT plan were superior to those of the 7-, 11-, and 15-beam non-coplanar IMRT. VMAT and non-coplanar IMRT (7-, 11-, and 15-beam) showed equivalent sparing effects for the optic nerves, optic chiasm, brainstem, and parotid glands. For the eyes and lenses, VMAT achieved equivalent or better sparing effects when compared with the non-coplanar IMRT plans. VMAT showed lower MUs and reduced treatment delivery time when compared with non-coplanar IMRT.
In 10 patients with nasal cavity or paranasal sinus cancer, a VMAT plan provided better homogeneity and conformity for PTV than non-coplanar IMRT plans, with a shorter treatment delivery time, while achieving equal or better OAR-sparing effects and using fewer MUs.
PMCID: PMC4261880  PMID: 25175383
Paranasal sinus cancer; Nasal cavity cancer; Volumetric modulated arc therapy; Non-coplanar intensity modulated radiotherapy; Planning target volume; Organs at risk
23.  Isolation and Characterization of Two Novel Plasmids from Pathogenic Leptospira interrogans Serogroup Canicola Serovar Canicola Strain Gui44 
Previous genomic analysis of pathogenic Leptospira has identified two circular chromosomes but no plasmid. This study aims to investigate potential extrachromosomal elements of L.interrogans serovar Canicola strain Gui44.
Two novel plasmids, pGui1 and pGui2, were isolated from the pathogenic strain Gui44, using a modified alkaline lysis method. Southern blotting was performed to determine the presence and size of them. Then, 454 and Hiseq sequencing were applied to obtain and analyze the complete sequences of the two plasmids. Furthermore, real-time quantitative PCR and next-generation sequencing were used to compare relative copy numbers of the two plasmids with that of the chromosomes. Finally, after serial passages in vitro for more than 2 years, the strain Gui44 was subsequently re-sequenced to estimate stability of the two plasmids.
Principal Findings
The larger plasmid, pGui1, 74,981 base pairs (bp) in length with GC content of 34.63%, possesses 62 open reading frames (ORFs). The smaller plasmid, pGui2, is 66,851 bp in length with GC content of 33.33%, and contains 63 ORFs. The replication initiation proteins encoded by pGui1 and pGui2 demonstrate significant sequence similarity with LA1839 (86% and 88%), a well-known replication protein in another pathogenic L.interrogans serovar Lai strain Lai, suggesting the ability for autonomous plasmid replication. Quantitative PCR and next-generation sequencing confirms a single copy of both plasmids and their stable presence in the strain Gui44 with in vitro serial passages after more than 2 years. Interestingly, the two plasmids both contain a significant number of novel genes (35 in pGui1 and 52 in pGui2).
This report confirms the presence of two separate circular plasmids in serovar Canicola strain Gui44 and provides a new understanding of genomic organization, adaptation, evolution and pathogenesis of Leptospira, which will aid in the development of in vivo genetic manipulation systems in pathogenic Leptospira species.
Author Summary
Leptospira species are the causative agent of leptospirosis, one of the most common animal to human transmitted diseases. Previous genomic analysis of L.interrogans serovar Lai and Copenhageni has identified the presence of large (4.33 mega base) and small (350 kilo base) circular chromosomes without evidence of any plasmids. Detailed understanding of Leptospira and its pathogenicity was delayed by the lack of available genetic tools. In this study we confirm the existence of two novel plasmids in L.interrogans serovar Canicola strain Gui44, an epidemic strain in China. Some novel genes identified in the two plasmids may play important roles in the characterization of the strain. The two plasmids will provide useful information in understanding the diversity of Leptospira genome and markedly improve our understanding of the evolution and pathogenesis of L.interrogans. In particular, it will contribute to the development of genetic manipulation systems in pathogenic Leptospira species.
PMCID: PMC4140679  PMID: 25144555
24.  Retrieval Intention Modulates the Effects of Directed Forgetting Instructions on Recollection 
PLoS ONE  2014;9(8):e104701.
The neurocognitive basis of memory retrieval is often examined by investigating brain potential old/new effects, which are differences in brain activity between successfully remembered repeated stimuli and correctly rejected new stimuli in a recognition test. In this study, we combined analyses of old/new effects for words with an item-method directed-forgetting manipulation in order to isolate differences between the retrieval processes elicited by words that participants were initially instructed to commit to memory and those that participants were initially instructed to forget. We compared old/new effects elicited by to-be-forgotten (TBF) words with those elicited by to-be-remembered (TBR) words in both an explicit-memory test (a recognition test) and an implicit-memory test (a lexical-decision test). Behavioral results showed clear directed forgetting effects in the recognition test, but not in the lexical decision test. Mirroring the behavioral findings, analyses of brain potentials showed evidence of directed forgetting only in the recognition test. In this test, potentials from 450–650 ms (P600 old/new effects) were more positive for TBR relative to TBF words. By contrast, P600 effects evident during the lexical-decision test did not differ in magnitude between TBR and TBF items. When taken in the context of prior studies that have linked similar parietal old/new effects to the recollection of episodic information, these data suggest that directed-forgetting effects manifest primarily in greater episodic retrieval by TBR than TBF items, and that retrieval intention may be important for these directed-forgetting effects to occur.
PMCID: PMC4139323  PMID: 25140658
25.  The Mechanism of Enterohepatic Circulation in the Formation of Gallstone Disease 
The Journal of Membrane Biology  2014;247(11):1067-1082.
Bile acids entering into enterohepatic circulating are primary acids synthesized from cholesterol in hepatocyte. They are secreted actively across canalicular membrane and carried in bile to gallbladder, where they are concentrated during digestion. About 95 % BAs are actively taken up from the lumen of terminal ileum efficiently, leaving only approximately 5 % (or approximately 0.5 g/d) in colon, and a fraction of bile acids are passively reabsorbed after a series of modifications in the human large intestine including deconjugation and oxidation of hydroxy groups. Bile salts hydrolysis and hydroxy group dehydrogenation reactions are performed by a broad spectrum of intestinal anaerobic bacteria. Next, hepatocyte reabsorbs bile acids from sinusoidal blood, which are carried to liver through portal vein via a series of transporters. Bile acids (BAs) transporters are critical for maintenance of the enterohepatic BAs circulation, where BAs exert their multiple physiological functions including stimulation of bile flow, intestinal absorption of lipophilic nutrients, solubilization, and excretion of cholesterol. Tight regulation of BA transporters via nuclear receptors (NRs) is necessary to maintain proper BA homeostasis. In conclusion, disturbances of enterohepatic circulation may account for pathogenesis of gallstones diseases, including BAs transporters and their regulatory NRs and the metabolism of intestinal bacterias, etc.
PMCID: PMC4207937  PMID: 25107305
Bile acids metabolism; Enterohepatic circulation; Transporters; Nuclear receptor; Gallstone formation

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