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1.  Centrifugation-assisted Assembly of Colloidal Silica into Crack-Free and Transferrable Films with Tunable Crystalline Structures 
Scientific Reports  2015;5:12100.
Self-assembly of colloidal particles into colloidal films has many actual and potential applications. While various strategies have been developed to direct the assembly of colloidal particles, fabrication of crack-free and transferrable colloidal film with controllable crystal structures still remains a major challenge. Here we show a centrifugation-assisted assembly of colloidal silica spheres into free-standing colloidal film by using the liquid/liquid interfaces of three immiscible phases. Through independent control of centrifugal force and interparticle electrostatic repulsion, polycrystalline, single-crystalline and quasi-amorphous structures can be readily obtained. More importantly, by dehydration of silica particles during centrifugation, the spontaneous formation of capillary water bridges between particles enables the binding and pre-shrinkage of the assembled array at the fluid interface. Thus the assembled colloidal films are not only crack-free, but also robust and flexible enough to be easily transferred on various planar and curved substrates.
PMCID: PMC4498329  PMID: 26159121
2.  Discrimination of Transgenic Rice containing the Cry1Ab Protein using Terahertz Spectroscopy and Chemometrics 
Scientific Reports  2015;5:11115.
Spectroscopic techniques combined with chemometrics methods have proven to be effective tools for the discrimination of objects with similar properties. In this work, terahertz time-domain spectroscopy (THz-TDS) combined with discriminate analysis (DA) and principal component analysis (PCA) with derivative pretreatments was performed to differentiate transgenic rice (Hua Hui 1, containing the Cry1Ab protein) from its parent (Ming Hui 63). Both rice samples and the Cry1Ab protein were ground and pressed into pellets for terahertz (THz) measurements. The resulting time-domain spectra were transformed into frequency-domain spectra, and then, the transmittances of the rice and Cry1Ab protein were calculated. By applying the first derivative of the THz spectra in conjunction with the DA model, the discrimination of transgenic from non-transgenic rice was possible with accuracies up to 89.4% and 85.0% for the calibration set and validation set, respectively. The results indicated that THz spectroscopic techniques and chemometrics methods could be new feasible ways to differentiate transgenic rice.
PMCID: PMC4495602  PMID: 26154950
3.  Association between EHBP1 rs721048(A>G) polymorphism and prostate cancer susceptibility: a meta-analysis of 17 studies involving 150,678 subjects 
OncoTargets and therapy  2015;8:1671-1680.
EHBP1 rs721048(A) was first identified as a prostate cancer (PCa) risk in Caucasians by genome-wide association study, but subsequent replication studies involving Caucasian and other ethnicities did not produce consistent results. The aim of this study was to obtain a more definite association between rs721048(A) and PCa risk.
We comprehensively searched several databases updated to September 2014, including PubMed, Web of Science, EBSCO, and Google Scholar. Two authors independently screened and reviewed the eligibility of each study. The quality of the included studies was assessed by the Newcastle–Ottawa scale. The association of rs721048(A) and PCa risk was assessed by pooling odds ratios (ORs) with 95% confidence intervals (CIs).
A total of 17 studies, including 48,135 cases and 102,543 controls, published between 2008 and 2014 were included in the meta-analysis. Overall, the pooled analysis demonstrated that rs721048(A) was significantly associated with the risk of PCa under the allele model (OR=1.14, 95% CI=1.11–1.17, P=0.000). Subgroup analysis based on ethnicity revealed a significant association between rs721048(A) and PCa in Caucasian (OR=1.14, 95% CI=1.11–1.16, P=0.000), African descent (OR=1.11, 95% CI=1.01–1.23, P=0.025), and Asian (OR=1.35, 95% CI=1.12–1.64, P=0.002).
Our results provided strong evidence that rs721048(A) could be a risk factor for PCa.
PMCID: PMC4500625  PMID: 26185455
EHBP1; rs721048; meta-analysis; prostate cancer
4.  Autophagy promotes resistance to photodynamic therapy-induced apoptosis selectively in colorectal cancer stem-like cells 
Autophagy  2014;10(7):1179-1192.
Recent studies have indicated that cancer stem-like cells (CSCs) exhibit a high resistance to current therapeutic strategies, including photodynamic therapy (PDT), leading to the recurrence and progression of colorectal cancer (CRC). In cancer, autophagy acts as both a tumor suppressor and a tumor promoter. However, the role of autophagy in the resistance of CSCs to PDT has not been reported. In this study, CSCs were isolated from colorectal cancer cells using PROM1/CD133 (prominin 1) expression, which is a surface marker commonly found on stem cells of various tissues. We demonstrated that PpIX-mediated PDT induced the formation of autophagosomes in PROM1/CD133+ cells, accompanied by the upregulation of autophagy-related proteins ATG3, ATG5, ATG7, and ATG12. The inhibition of PDT-induced autophagy by pharmacological inhibitors and silencing of the ATG5 gene substantially triggered apoptosis of PROM1/CD133+ cells and decreased the ability of colonosphere formation in vitro and tumorigenicity in vivo. In conclusion, our results revealed a protective role played by autophagy against PDT in CSCs and indicated that targeting autophagy could be used to elevate the PDT sensitivity of CSCs. These findings would aid in the development of novel therapeutic approaches for CSC treatment.
PMCID: PMC4203546  PMID: 24905352
apoptosis; autophagy; autophagy-related proteins; cancer stem-like cells; colonosphere; colorectal cancer; photodynamic therapy; prominin 1 (PROM1)/CD133; tumorigenicity
5.  Multiparametric MRI correlates of sensorimotor function in the spinal cord in multiple sclerosis 
Spinal cord (SC) pathology is a major contributor to clinical disability in multiple sclerosis (MS). Conventional magnetic resonance imaging (MRI), specifically SC-MRI lesion load measures that include lesion count and volume, demonstrate only a modest relationship with the clinical status of MS patients. Although SC cross-sectional area (CSA) correlates better with clinical dysfunction than MRI lesion count, SC atrophy likely signifies irreversible tissue loss. Using quantitative MRI indices sensitive to early and late microstructural changes in the spinal cord, we searched for the presence of better correlations between MRI measures and clinical status in MS.
We investigated whether diffusion-tensor imaging indices and the magnetization-transfer ratio (MTR) were better associated with the clinical status of MS patients than conventional SC-MRI measures.
A total of 129 MS patients underwent 3-tesla cervical SC-MRI and quantitative sensorimotor function testing, using the Vibratron-II and dynamometer. Regions-of-interest circumscribed the SC on axial slices between C3-C4. We calculated SC-CSA, fractional anisotropy (FA), mean diffusivity (MD), perpendicular diffusivity (λ⊥), parallel diffusivity (λ‖) and MTR. We used multivariable linear regression to determine if there were any associations between MRI indices and clinical measures of dysfunction.
All MRI indices were significantly different in subjects with MS versus healthy controls, and between the progressive versus relapsing MS subtypes, with the exception of λ‖. In multivariable regression models that were adjusted for age, sex, brain parenchymal fraction, and SC-CSA, the MRI indices independently explained variability in hip flexion strength (p-values: MD, λ⊥, λ‖ < 0.001; FA = 0.07), vibration sensation threshold (p-values: FA = 0.04; MTR = 0.05; λ⊥ = 0.06), and Expanded Disability Status Scale scores (p-values: FA = 0.003; MD = 0.03; λ⊥ = 0.005; MTR = 0.02).
In a large, heterogeneous MS sample, quantitative SC-MRI indices demonstrated independent associations with system-specific and global clinical dysfunction. Our findings suggest that the indices studied may provide important information about microstructural SC changes and the substrates of limb disability in MS. The identified structure-function relationships underpin the potential utility of these measures in assessments of therapeutic efficacy.
PMCID: PMC4482216  PMID: 22891033
MRI; multiple sclerosis; spinal cord; cross-sectional area; diffusion-tensor imaging; magnetization-transfer ratio; fractional anisotropy; diffusivity; clinical dysfunction
6.  Tumor Necrosis Factor (TNF) –308G>A, Nitric Oxide Synthase 3 (NOS3) +894G>T Polymorphisms and Migraine Risk: A Meta-Analysis 
PLoS ONE  2015;10(6):e0129372.
Background and Objective
Conflicting data have been reported on the association between tumor necrosis factor (TNF) –308G>A and nitric oxide synthase 3 (NOS3) +894G>T polymorphisms and migraine. We performed a meta-analysis of case-control studies to evaluate whether the TNF –308G>A and NOS3 +894G>T polymorphisms confer genetic susceptibility to migraine.
We performed an updated meta-analysis for TNF –308G>A and a meta-analysis for NOS3 +894G>T based on studies published up to July 2014. We calculated study specific odds ratios (OR) and 95% confidence intervals (95% CI) assuming allele contrast, dominant model, recessive model, and co-dominant model as pooled effect estimates.
Eleven studies in 6682 migraineurs and 22591 controls for TNF –308G>A and six studies in 1055 migraineurs and 877 controls for NOS3 +894G>T were included in the analysis. Neither indicated overall associations between gene polymorphisms and migraine risk. Subgroup analyses suggested that the “A” allele of the TNF –308G>A variant increases the risk of migraine among non-Caucasians (dominant model: pooled OR = 1.82; 95% CI 1.15 – 2.87). The risk of migraine with aura (MA) was increased among both Caucasians and non-Caucasians. Subgroup analyses suggested that the “T” allele of the NOS3 +894G>T variant increases the risk of migraine among non-Caucasians (co-dominant model: pooled OR = 2.10; 95% CI 1.14 – 3.88).
Our findings appear to support the hypothesis that the TNF –308G>A polymorphism may act as a genetic susceptibility factor for migraine among non-Caucasians and that the NOS3 +894G>T polymorphism may modulate the risk of migraine among non-Caucasians.
PMCID: PMC4476787  PMID: 26098763
7.  Retrograde regulation of STIM1-Orai1 interaction and store-operated Ca2+ entry by calsequestrin 
Scientific Reports  2015;5:11349.
Interaction between the endoplasmic reticulum (ER)-located stromal interaction molecue1 (STIM1) and the plasma membrane-located Ca2+ channel subunit, Orai1, underlies store-operated Ca2+ entry (SOCE). Calsequestrin1 (CSQ1), a sarcoplasmic reticulum Ca2+ buffering protein, inhibits SOCE, but the mechanism of action is unknown. We identified an interaction between CSQ1 and STIM1 in HEK293 cells. An increase in monomeric CSQ1 induced by depleted Ca2+ stores, or trifluoperazine (TFP), a blocker of CSQ folding and aggregation, enhanced the CSQ1-STIM1 interaction. In cells with Ca2+ stores depleted, TFP further increased CSQ1 monomerization and CSQ1-STIM1 interaction, but reduced the association of STIM1 with Orai1 and SOCE. Over-expression of CSQ1 or a C-terminal (amino acid 388–396) deletion mutant significantly promoted the association of CSQ1 with STIM1, but suppressed both STIM1-Orai1 interaction and SOCE, while over-expression of the C-terminal (amino acid 362–396) deletion mutant had no effect. The physical interaction between low polymeric forms of CSQ1 and STIM1 likely acts by interfering with STIM1 oligimerization and inhibits STIM1-Orai1 interaction, providing a brake to SOCE under physiological conditions. This novel regulatory mechanism for SOCE may also contribute to the pathological Ca2+ overload in calsequestrin deficient diseases, such as malignant hyperthermia and ventricular tachycardia.
PMCID: PMC4471903  PMID: 26087026
8.  Prmt5 is required for germ cell survival during spermatogenesis in mice 
Scientific Reports  2015;5:11031.
During germ cell development, epigenetic modifications undergo extensive remodeling. Abnormal epigenetic modifications usually result in germ cell loss and reproductive defect. Prmt5 (Protein arginine methyltransferase 5) encodes a protein arginine methyltransferase which has been demonstrated to play important roles in germ cell development during embryonic stages. In the present study, we found that Prmt5 was also abundantly expressed in male germ cells after birth. Inactivation of this gene by crossing with Stra8-Cre transgenic mice resulted in germ cell loss during spermatogenesis. Further study revealed that the germ cell development was grossly normal before P10. However, most of the germ cells in Prmt5Δ/f; Stra8-Cre mice were blocked at meiotic stage. The expression of meiosis associated genes was reduced in Prmt5Δ/f; Stra8-Cre testes compared to control testes at P10. γH2AX was detected in sex body of control germ cells at P12, whereas multiple foci were observed in Prmt5-deficient germ cells. Further study revealed that H4R3me2s was virtually absent in germ cells after Prmt5 inactivation. The results of this study indicate that Prmt5 also plays important roles in germ cell development during spermatogenesis.
PMCID: PMC4466585  PMID: 26072710
9.  Esomeprazole regimens for reflux symptoms in Chinese patients with chronic gastritis 
AIM: To compare symptom control with esomeprazole regimens for non-erosive reflux disease and chronic gastritis in patients with a negative endoscopy.
METHODS: This randomized, open-label study was designed in line with clinical practice in China. Patients with typical reflux symptoms for ≥ 3 mo and a negative endoscopy who had a Gastroesophageal Reflux Disease Questionnaire score ≥ 8 were randomized to initial treatment with esomeprazole 20 mg once daily either for 8 wk or for 2 wk. Patients with symptom relief could enter another 24 wk of maintenance/on-demand treatment, where further courses of esomeprazole 20 mg once daily were given if symptoms recurred. The primary endpoint was the symptom control rate at week 24 of the maintenance/on-demand treatment period. Secondary endpoints were symptom relief rate, success rate (defined as patients who had symptom relief after initial treatment and after 24 wk of maintenance treatment), time-to-first-relapse and satisfaction rate.
RESULTS: Based on the data collected in the modified intention-to-treat population (MITT; patients in the ITT population with symptom relief after initial esomeprazole treatment, n = 262), the symptom control rate showed a small but statistically significant difference in favor of the 8-wk regimen (94.9% vs 87.3%, P = 0.0473). Among the secondary endpoints, based on the data collected in the ITT population (n = 305), the 8-wk group presented marginally better results in symptom relief after initial esomeprazole treatment (88.3% vs 83.4%, P = 0.2513) and success rate over the whole study (83.8% vs 72.8%, P = 0.0258). The 8-wk regimen was found to provide a 46% reduction in risk of relapse vs the 2-wk regimen (HR = 0.543; 95%CI: 0.388-0.761). In addition, fewer unscheduled visits and higher patient satisfaction supported the therapeutic benefits of the 8-wk regimen over the 2-wk regimen. Safety was comparable between the two groups, with both regimens being well tolerated.
CONCLUSION: Chinese patients diagnosed with chronic gastritis achieved marginally better control of reflux symptoms with an 8-wk vs a 2-wk esomeprazole regimen, with a similar safety profile.
PMCID: PMC4462738  PMID: 26078574
Esomeprazole; Non-erosive reflux disease regimen; Chronic gastritis regimen; Symptom control rate
10.  Shifts in the Antibiotic Susceptibility, Serogroups, and Clonal Complexes of Neisseria meningitidis in Shanghai, China: A Time Trend Analysis of the Pre-Quinolone and Quinolone Eras 
PLoS Medicine  2015;12(6):e1001838.
Fluoroquinolones have been used broadly since the end of the 1980s and have been recommended for Neisseria meningitidis prophylaxis since 2005 in China. The aim of this study was to determine whether and how N. meningitidis antimicrobial susceptibility, serogroup prevalence, and clonal complex (CC) prevalence shifted in association with the introduction and expanding use of quinolones in Shanghai, a region with a traditionally high incidence of invasive disease due to N. meningitidis.
Methods and Findings
A total of 374 N. meningitidis isolates collected by the Shanghai Municipal Center for Disease Control and Prevention between 1965 and 2013 were studied. Shifts in the serogroups and CCs were observed, from predominantly serogroup A CC5 (84%) in 1965–1973 to serogroup A CC1 (58%) in 1974–1985, then to serogroup C or B CC4821 (62%) in 2005–2013. The rates of ciprofloxacin nonsusceptibility in N. meningitidis disease isolates increased from 0% in 1965–1985 to 84% (31/37) in 2005–2013 (p < 0.001). Among the ciprofloxacin-nonsusceptible isolates, 87% (27/31) were assigned to either CC4821 (n = 20) or CC5 (n = 7). The two predominant ciprofloxacin-resistant clones were designated ChinaCC4821-R1-C/B and ChinaCC5-R14-A. The ChinaCC4821-R1-C/B clone acquired ciprofloxacin resistance by a point mutation, and was present in 52% (16/31) of the ciprofloxacin-nonsusceptible disease isolates. The ChinaCC5-R14-A clone acquired ciprofloxacin resistance by horizontal gene transfer, and was found in 23% (7/31) of the ciprofloxacin-nonsusceptible disease isolates. The ciprofloxacin nonsusceptibility rate was 47% (7/15) among isolates from asymptomatic carriers, and nonsusceptibility was associated with diverse multi-locus sequence typing profiles and pulsed-field gel electrophoresis patterns. As detected after 2005, ciprofloxacin-nonsusceptible strains were shared between some of the patients and their close contacts. A limitation of this study is that isolates from 1986–2004 were not available and that only a small sample of convenience isolates from 1965–1985 were available.
The increasing prevalence of ciprofloxacin resistance since 2005 in Shanghai was associated with the spread of hypervirulent lineages CC4821 and CC5. Two resistant meningococcal clones ChinaCC4821-R1-C/B and ChinaCC5-R14-A have emerged in Shanghai during the quinolone era. Ciprofloxacin should be utilized with caution for the chemoprophylaxis of N. meningitidis in China.
Minggui Wang and colleagues assess the genetic origin and changing prevalence of N. meningitidis resistance to ciprofloxacin.
Editors' Summary
Meningitis is a viral, bacterial, or fungal infection of the meninges, the thin membrane that covers the brain and the spinal cord. Neisseria meningitidis is the most common cause of bacterial meningitis in children and is a leading cause of meningitis in adults. N. meningitidis lives harmlessly in the mucous membranes of the nose and throat of 10%–20% of human beings. These symptom-free (asymptomatic) carriers are crucial to the transmission of N. meningitidis, which spreads from person to person through droplets of respiratory or throat secretions produced by infected individuals. Although N. meningitidis usually causes no harm, it occasionally overwhelms its host’s immune system and spreads through the bloodstream and into the brain. The characteristic symptoms of meningococcal meningitis—a rash, fever, stiff neck, sensitivity to light, confusion, headaches, and vomiting—then develop rapidly. Even with early treatment with intravenous antibiotics, about 10% of the 1.2 million people affected by meningococcal meningitis every year die, usually within 24–48 hours of symptom development.
Why Was This Study Done?
Meningococcal meningitis can be prevented by vaccination against N. meningitidis. In addition, experts recommend that the family and close contacts of anyone with meningococcal meningitis be treated immediately with antibiotics to stop the disease spreading (N. meningitidis prophylaxis). The quinolone antibiotic ciprofloxacin is sometimes recommended for N. meningitidis prophylaxis, but quinolones have been used to treat many bacterial infections since the late 1980s and ciprofloxacin-resistant strains of N. meningitidis have recently emerged in some countries. Thus, policymakers in countries where ciprofloxacin may be used for meningococcal prophylaxis (for example, China, which has recommended several antibiotics, including ciprofloxacin, for meningococcal prophylaxis since 2005) need to know whether and how the susceptibility of N. meningitidis to ciprofloxacin is changing in their country. In this time trend analysis, the researchers investigate how the ciprofloxacin susceptibility, serogroup prevalence, and clonal complex prevalence of N. meningitidis have shifted in association with increasing use of quinolones in Shanghai (China), a region where many cases of meningococcal disease occur. A serogroup is a group of bacteria that carries a common antigen (a molecule recognized by the immune system); the prevalence of a serogroup is the proportion of the infected population that carries that serogroup. Only some N. meningitidis serogroups cause meningococcal disease. A clonal complex is a group of genetically related bacteria that may share genes that confer resistance to antibiotics. A strain of N. meningitidis is classified by both its serogoup and its clonal complex; the changing composition of prevalent strains can inform projections for disease spread and plans for disease management, including recommendations for prophylaxis.
What Did the Researchers Do and Find?
The researchers analyzed the characteristics of 374 N. meningitidis isolates collected in Shanghai between 1965 and 2013 from patients with meningococcal disease, their close contacts, and asymptomatic N. meningitidis carriers identified in throat swab surveys. N. meningitidis serogroups and clonal complexes (CCs) shifted from predominantly serogroup A CC5 among isolates collected in 1965–1973, to serogroup A CC1 in 1974–1985, and to serogroup C or B CC4821 in 2005–2013. Notably, the rate of nonsusceptibility to ciprofloxacin in isolates from people with meningococcal meningitis increased from 0% in 1965–1985 to 84% in 2005–2013, and 87% (27/31) of the ciprofloxacin-nonsusceptible disease isolates belonged to either CC4821 or CC5. The researchers identified the two predominant ciprofloxacin-resistant strains (designated ChinaCC4821-R1-C/B and ChinaCC5-R14-A) and showed that a different genetic alteration was responsible for the acquisition of antibiotic resistance in the two strains. Finally, the researchers report that, after 2005, the rate of ciprofloxacin nonsusceptibility among N. meningitidis isolates from asymptomatic carriers was 47%, and that some of the individuals with meningococcal meningitis shared nonsusceptible strains with their close contacts.
What Do These Findings Mean?
These findings suggest that the increased prevalence of ciprofloxacin resistance seen in Shanghai since 2005 is associated with the spread of two hypervirulent clonal complexes of N. meningitidis (CC4821 and CC5) among individuals with meningococcal disease and within the healthy population. The findings also identify two resistant meningococcal strains (ChinaCC4821-R1-C/B and ChinaCC5-R14-A) that have emerged in Shanghai since the use of quinolones to treat bacterial infections became widespread. Because this time trend analysis is based on a limited number of meningococcal isolates and because the researchers analyzed very few isolates collected between 1965 and 1985 and none collected between 1986 and 2004, this study cannot pinpoint exactly when, where, or how ciprofloxacin-resistant N. meningitidis emerged in Shanghai. Nevertheless, these findings suggest that the use of fluoroquinolones for N. meningitidis prophylaxis should be discouraged in China. Instead, the researchers suggest, physicians should turn to one of the other antibiotics recommended in China’s 2005 national scheme (for example, rifampicin) for the prevention and control of meningococcal meningitis.
Additional Information
These websites can be accessed when viewing the PDF on a device, or via the online version of this article at The US Centers for Disease Control and Prevention provide information about meningococcal diseaseThe World Health Organization has a fact sheet about meningococcal meningitisThe UK National Health Service Choices website provides information about meningitis, including some personal storiesThe non-profit Meningitis Foundation of America also provides information about meningitis and stories from survivors of meningitisMedlinePlus has links to further resources about meningitis and about meningococcal infections; the MedlinePlus Encyclopedia also provides information about meningococcal meningitis (in English and Spanish)
PMCID: PMC4461234  PMID: 26057853
11.  An ELISA Method to Compute Endpoint Titers to Epstein-Barr Virus and Cytomegalovirus: Application to Population-Based Studies 
Indirect fluorescence analysis (IFA), the gold standard for determining herpesvirus antibody titers, is labor-intensive and poorly suited for large population-based studies. The enzyme-linked immunosorbent assay (ELISA) is used widely for measuring antiviral antibodies but also suffers drawbacks such as reduced specificity and the qualitative nature of the results due to limited interpretation of the optical density (OD) units. This paper describes a method to titer herpesvirus antibodies using microplates coated with virally-infected cells in which a standard curve, derived from IFA-scored samples, allowed OD units to be converted into titers. A LOOKUP function was created in order to report the data as traditional IFA-based (i.e., 2-fold) titers. The modified ELISA correlated significantly with IFA and was subsequently used to compute endpoint antibody titers to Epstein-Barr virus (EBV)-virus capsid antigen (VCA) and cytomegalovirus (CMV) in blood samples taken from 398 pregnant Hispanic women. Four women were EBV negative (1%), while 58 women were CMV negative (14.6%). EBV VCA antibody titers were significantly higher than CMV antibody titers (p <0.001). This method allows titering of herpesvirus antibodies by ELISA suitable for large population-based studies. In addition, the LOOKUP table enables conversion from OD-derived titers into 2-fold titers for comparison of results with other studies.
PMCID: PMC4098116  PMID: 24859346
herpesvirus; EBV; CMV; ELISA; antibody titer; IFA
12.  Limb Ischemic Preconditioning Protects Endothelium from Oxidative Stress by Enhancing Nrf2 Translocation and Upregulating Expression of Antioxidases 
PLoS ONE  2015;10(6):e0128455.
Remote ischemic preconditioning is often performed by limb ischemic preconditioning (LIPC), which has been demonstrated to be beneficial to various cells, including endothelial cells. The mechanisms underlying the protection have not been well clarified. The present study was designed to observe the effects of sera derived from rats after LIPC on human umbilical vein endothelial cells (HUVECs) injured by hydrogen peroxide (H2O2) -induced oxidative stress and explore the involvement of redox state in the protection. Incubation with 1 mM H2O2 for 2 h induced a significant reduction in HUVECs’ viability with increased production of malondialdehyde (MDA) and reactive oxygen species (ROS). Preincubation with early preconditioning serum (EPS) or delayed preconditioning serum (DPS) derived from rats subjected to LIPC alleviated these changes. Both EPS and DPS increased the nuclear translocation of transcription factor nuclear factor E2-related factor 2 (Nrf2) and the expression of antioxidases. The protective effects of EPS and DPS were blocked neither by MEK/ERK inhibitors U0126 nor by PI3K/Akt inhibitors LY294002. In conclusion, the present study provides the evidence that LIPC protects the HUVECs from H2O2-induced injury by, at least partially, enhancement of Nrf2 translocation and upregulation of antioxidases via signaling pathways independent of MEK/ERK and PI3K/Akt.
PMCID: PMC4451753  PMID: 26029932
13.  Transcriptome-Wide Identification of miRNA Targets under Nitrogen Deficiency in Populus tomentosa Using Degradome Sequencing 
miRNAs are endogenous non-coding small RNAs with important regulatory roles in stress responses. Nitrogen (N) is an indispensable macronutrient required for plant growth and development. Previous studies have identified a variety of known and novel miRNAs responsive to low N stress in plants, including Populus. However, miRNAs involved in the cleavage of target genes and the corresponding regulatory networks in response to N stress in Populus remain largely unknown. Consequently, degradome sequencing was employed for global detection and validation of N-responsive miRNAs and their targets. A total of 60 unique miRNAs (39 conserved, 13 non-conserved, and eight novel) were experimentally identified to target 64 mRNA transcripts and 21 precursors. Among them, we further verified the cleavage of 11 N-responsive miRNAs identified previously and provided empirical evidence for the cleavage mode of these miRNAs on their target mRNAs. Furthermore, five miRNA stars (miRNA*s) were shown to have cleavage function. The specificity and diversity of cleavage sites on the targets and miRNA precursors in P. tomentosa were further detected. Identification and annotation of miRNA-mediated cleavage of target genes in Populus can increase our understanding of miRNA-mediated molecular mechanisms of woody plants adapted to low N environments.
PMCID: PMC4490532  PMID: 26096002
degradome; miRNA; miRNA*; precursor; targets; Populus tomentosa
14.  Identifying CDKN3 Gene Expression as a Prognostic Biomarker in Lung Adenocarcinoma via Meta-analysis 
Cancer Informatics  2015;14(Suppl 2):183-191.
Lung cancer is among the major causes of cancer deaths, and the survival rate of lung cancer patients is extremely low. Recent studies have demonstrated that the gene CDKN3 is related to neoplasia, but in the literature severe controversy exists over whether it is involved in cancer progression or, conversely, tumor inhibition. In this study, we investigated the expression of CDKN3 and its association with prognosis in lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC) using datasets in Lung Cancer Explorer (LCE; We found that CDKN3 was up-regulated in ADC and SCC compared to normal tissues. We also found that CDKN3 was expressed at a higher level in SCC than in ADC, which was further validated through meta-analysis (coefficient = 2.09, 95% CI = 1.50–2.67, P < 0.0001). In addition, based on meta-analysis for the prognostic value of CDKN3, we found that higher CDKN3 expression was associated with poorer survival outcomes in ADC (HR = 1.65, 95% CI = 1.39–1.96, P < 0.0001), but not in SCC (HR = 1.10, 95% CI = 0.84–1.44, P = 0.494). Our findings indicate that CDKN3 may be a prognostic marker in ADC, though the detailed mechanism is yet to be revealed.
PMCID: PMC4444140  PMID: 26052221
lung adenocarcinoma; lung squamous cell carcinoma; CDKN3; prognostic marker; meta-analysis
15.  Genome Sequence of Penicillium capsulatum Strain ATCC 48735, a Rare Penicillium Species Used in Paper Manufactories but That Recently Caused Invasive Infection 
Genome Announcements  2015;3(3):e00307-15.
The genus Penicillium phylogenetically belongs to Trichocomaceae, with approximately 300 reported species. The majority of these species are saprobic and commonly occur in soil. This paper reports the genome sequence of Penicillium capsulatum strain ATCC 48735, a rare Penicillium species used in paper manufactories and that was recently reported as a human-invasive opportunist.
PMCID: PMC4440943  PMID: 25999563
16.  Plasma complement factor H is associated with disease activity of patients with ANCA-associated vasculitis 
Increasing evidences have demonstrated that activation of alternative complement pathway plays an important role in the pathogenesis of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). The current study aimed to investigate the association of complement factor H (CFH), a key regulator of the alternative complement pathway, with the disease activity of AAV.
Plasma CFH levels were measured in 82 patients with myeloperoxidase (MPO)-AAV in active stage. Of the 82 patients, plasma CFH levels of 27 patients were longitudinally measured. Serum anti-CFH autoantibodies were screened in AAV patients. Circulating complement activation profiles including C4d, Bb, C3a, C5a and soluble C5b-9 of AAV patients in active stage were further detected. Associations between plasma CFH levels and clinicopathological parameters as well as the prognosis were analyzed.
Plasma CFH levels were significantly lower in active AAV patients compared with AAV patients in remission and normal controls. Correlation analysis showed that plasma CFH levels inversely correlated with initial serum creatinine, Birmingham Vasculitis Activity Score (BVAS), proportion of total crescents and cellular crescents in renal specimens, and circulating levels of C3a, C5a and Sc5b-9, meanwhile positively correlated with estimated glomerular filtration rate (eGFR), hemoglobin levels and circulating levels of C3. Moreover, multivariate survival analysis revealed that plasma CFH levels were independently associated with composite outcome of death or end stage renal disease (ESRD) in AAV patients, after adjusting for age, gender, hemoglobin level and urinary protein (P = 0.03, HR 0.85, 95 % CI 0.73–0.98) or adjusting for age, gender, total crescents (%) and urinary protein (P = 0.03, HR 0.85, 95 % CI 0.73–0.98), while not as an independent predictor after adjusting for age, gender, serum creatinine and urinary protein (P = 0.57, HR 0.96, 95 % CI 0.83–1.11).
In conclusion, plasma CFH levels are associated with disease activity, and, to some extent, associated with composite outcomes of patients with MPO-ANCA-associated vasculitis.
PMCID: PMC4489360  PMID: 25994214
17.  Effects of Gray-Scale Ultrasonography Immediate Post-Contrast on Characterization of Focal Liver Lesions 
BioMed Research International  2015;2015:193178.
This study compared the imaging features of conventional gray scale ultrasound (US) before and after contrast-enhanced ultrasound (CEUS) for focal liver lesions and 22 evaluated the role of US post-CEUS in characterizing liver lesions. 126 patients with 158 focal liver lesions underwent CEUS and US post-CEUS examination and entered this study. There were 74 hepatocellular carcinomas (HCC), 43 hepatic metastases, and 41 hemangiomas. Imaging features of US pre-CEUS and US post-CEUS were analyzed offsite by two blinded experienced radiologists to evaluate size, boundary, echogenicity, internal texture, posterior acoustic enhancement, spatial resolution, and contrast resolution. In the end with pathological and clinical evidence, the diagnostic accuracy rate of US pre-CEUS was 53.8% (85/158 lesions), lower than that of CEUS (88.0%, 139/158 lesions); with the complementation of US post-CEUS the rate rose to 93.0% (147/158 lesions). US post-CEUS could improve the visibility of typical structures of focal liver lesions and might provide important complementary information for CEUS diagnosis. It also increases the visibility of small liver lesions compared with US pre-CEUS and helps to guide local interventional procedure.
PMCID: PMC4450236  PMID: 26090387
18.  Guilt by rewiring: gene prioritization through network rewiring in Genome Wide Association Studies 
Human Molecular Genetics  2013;23(10):2780-2790.
Although Genome Wide Association Studies (GWAS) have identified many susceptibility loci for common diseases, they only explain a small portion of heritability. It is challenging to identify the remaining disease loci because their association signals are likely weak and difficult to identify among millions of candidates. One potentially useful direction to increase statistical power is to incorporate functional genomics information, especially gene expression networks, to prioritize GWAS signals. Most current methods utilizing network information to prioritize disease genes are based on the ‘guilt by association’ principle, in which networks are treated as static, and disease-associated genes are assumed to locate closer with each other than random pairs in the network. In contrast, we propose a novel ‘guilt by rewiring’ principle. Studying the dynamics of gene networks between controls and patients, this principle assumes that disease genes more likely undergo rewiring in patients, whereas most of the network remains unaffected in disease condition. To demonstrate this principle, we consider the changes of co-expression networks in Crohn's disease patients and controls, and how network dynamics reveals information on disease associations. Our results demonstrate that network rewiring is abundant in the immune system, and disease-associated genes are more likely to be rewired in patients. To integrate this network rewiring feature and GWAS signals, we propose to use the Markov random field framework to integrate network information to prioritize genes. Applications in Crohn's disease and Parkinson's disease show that this framework leads to more replicable results, and implicates potentially disease-associated pathways.
PMCID: PMC3990172  PMID: 24381306
19.  Klotho: a novel and early biomarker of acute kidney injury after cardiac valve replacement surgery in adults 
Klotho is a potential biomarker and therapeutic target in a model of acute kidney injury (AKI) induced in rats by ischemia-reperfusion injury. However, the sensitivity and specificity of serum Klotho for early detecting clinical AKI are unknown. This prospective study evaluated the significance of serum Klotho for early detection of postoperative AKI among adult patients undergoing cardiac valve replacement surgery. Moreover, we also compared the utilities of serum Klotho, serum creatinine and cystatin C in early detection of AKI. There was no marked difference between AKI and non-AKI groups in preoperative serum Klotho levels. Immediately after the operation, serum Klotho decreased significantly in patients with AKl. In spite of the poor specificity, its diagnostic sensitivity was excellent. On postoperative 1 d, with the rapid recovery toward the preoperative level, the ability of serum Klotho for early detecting AKI declined. Changes in serum Klotho levels at every time point among patients without AKI did not reveal any statistical significance. We showed that AKI is a state of transient Klotho deficiency in patients undergoing cardiac valve replacement surgery. Serum Klotho levels were drastically decreased beginning at 0h with ideal ROC-AUC, sensitivity but poor specificity, which didn’t exceed 4 h after operation, suggesting that serum Klotho could serve as a potential biomarker for CSA-AKI, especially during the short period after cardiac surgery. A larger multicentre cohort study of population in different ages undergoing on-pump cardiac surgery is required to identify the optimal timing of serum Klotho measurement and the optimal cut-off points for clinical use to further refine the optimal timing for early detection of AKI.
PMCID: PMC4509220  PMID: 26221275
Cardiac surgery; acute kidney injury; serum Klotho; cystatin C; serum creatinine
20.  Inflammation scores predict survival for hepatitis B virus-related hepatocellular carcinoma patients after transarterial chemoembolization 
AIM: To compare the prognostic ability of inflammation scores for patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) undergoing transarterial chemoembolization (TACE).
METHODS: Data of 224 consecutive patients who underwent TACE for unresectable HBV-related HCC from September 2009 to November 2011 were retrieved from a prospective database. The association of inflammation scores with clinicopathologic variables and overall survival (OS) were analyzed, and receiver operating characteristic curves were generated, and the area under the curve (AUC) was calculated to evaluate the discriminatory ability of each inflammation score and staging system, including tumor-node-metastasis, Barcelona Clinic Liver Cancer, and Cancer of the Liver Italian Program (CLIP) scores.
RESULTS: The median follow-up period was 390 d, the one-, two-, and three-year OS were 38.4%, 18.3%, and 11.1%, respectively, and the median OS was 390 d. The Glasgow Prognostic Score (GPS), modifed GPS, neutrophil-lymphocyte ratio, and Prognostic Index were associated with OS. The GPS consistently had a higher AUC value at 6 mo (0.702), 12 mo (0.676), and 24 mo (0.687) in comparison with other inflammation scores. CLIP consistently had a higher AUC value at 6 mo (0.656), 12 mo (0.711), and 24 mo (0.721) in comparison with tumor-node-metastasis and Barcelona Clinic Liver Cancer staging systems. Multivariate analysis revealed that alanine aminotransferase, GPS, and CLIP were independent prognostic factors for OS. The combination of GPS and CLIP (AUC = 0.777) was superior to CLIP or GPS alone in prognostic ability for OS.
CONCLUSION: The prognostic ability of GPS is superior to other inflammation scores for HCC patients undergoing TACE. Combining GPS and CLIP improved the prognostic power for OS.
PMCID: PMC4427682  PMID: 25987783
Hepatocellular carcinoma; Inflammation-based prognostic score; Prognostic index; Staging system; Transarterial chemoembolization
21.  Increased risk of second primary malignancies following uterine cancer: a population-based study in Taiwan over a 30-year period 
BMC Cancer  2015;15:393.
Previous studies assessing second primary malignancies (SPMs) after uterine cancer have been conducted in Western populations with conflicting results. This study aimed to define the incidence and risk of SPMs in Taiwanese patients with an initial diagnosis of uterine cancer.
Using population-based data from the Taiwan Cancer Registry for the period 1979–2008, we quantified standardized incidence ratios (SIRs) among 11,571 women with an initial diagnosis of uterine cancer.
Among the 11,571 women, 555 (4.80 %) developed at least one SPM during 69,987 person-years of follow-up. There was a 71 % increased risk of SPM following uterine cancer (SIR = 1.71, 95 % CI, 1.57–1.86), with higher risks in the vagina/vulva (SIR = 9.06), small intestine (SIR = 8.45), ovary (SIR = 4.15), urinary bladder (SIR = 2.31), kidney (SIR = 2.24), colorectum (SIR = 2.24), lung (SIR = 1.96), and breast (SIR = 1.43). The risk of SPM was found to be the highest within the first 5 years after diagnosis of uterine cancer, with surveillance bias possibly contributing to the extremely high risk observed in the first follow-up year. The overall risk and pattern of SPM development observed in this study differed from those previously reported in Western populations, possibly because of the methodology and shorter follow-up period employed in this study. The cumulative incidence of SPMs was significantly higher in older patients (≥50 years) than in younger patients (P < 0.001).
To our knowledge, this is the first study in an Asian population to report 71 % increased risk in SPMs in women previously diagnosed with uterine cancer. A younger age at diagnosis of uterine cancer conferred an increased risk of second malignancies, and SPMs worsened survivorship in patients who survived uterine cancer.
PMCID: PMC4469104  PMID: 25957789
Uterine cancer; Second primary malignancy; Standardized incidence ratios
22.  Combined inhibition of EGFR and c-ABL suppresses the growth of triple-negative breast cancer growth through inhibition of HOTAIR 
Oncotarget  2015;6(13):11150-11161.
Triple-negative breast cancer (TNBC) does not express conventional therapeutic targets and is the only type of malignant breast cancer for which no designated FDA-approved targeted therapy is available. Although overexpression of epidermal growth factor receptor (EGFR) is frequently found in TNBC, the therapeutic effect of EGFR inhibitors in TNBC has been underwhelming. Here we show that co-treatment with clinically validated inhibitors of c-ABL (imatinib) and EGFR (lapatinib) results in synergistic growth inhibition in TNBC cells. The dual treatment leads to synergistic repression of the long non-coding RNA (lncRNA) HOTAIR (HOX Antisense Intergenic RNA). HOTAIR has been known to induce tumor growth and metastasis in breast cancer. Depleting HOTAIR alone phenocopies the dual treatment in growth suppression. We show that expression of HOTAIR is regulated by β-catenin through a LEF1/TCF4-binding site. The dual treatment blocks nuclear expression of β-catenin and prevents its recruitment to the HOTAIR promoter. Consistently, forced expression of β-catenin rescued HOTAIR expression and cell viability in the presence of both drugs. Upregulation of HOTAIR is associated with TNBC in cell lines and a cohort of primary tumors. This study elucidates a previously unidentified mechanism in TNBC linking signaling with lncRNA regulation which may be exploited for therapeutic gain.
PMCID: PMC4484446  PMID: 25883211
EGFR; c-ABL; lncRNA; b-catenin; breast cancer
23.  Digoxin Suppresses Tumor Malignancy through Inhibiting Multiple Src-Related Signaling Pathways in Non-Small Cell Lung Cancer 
PLoS ONE  2015;10(5):e0123305.
Non-small cell lung cancer is the predominant type of lung cancer, resulting in high mortality worldwide. Digoxin, a cardiac glycoside, has recently been suggested to be a novel chemotherapeutic agent. Src is an oncogene that plays an important role in cancer progression and is therefore a potential target for cancer therapy. Here, we investigated whether digoxin could suppress lung cancer progression through the inhibition of Src activity. The effects of digoxin on lung cancer cell functions were investigated using colony formation, migration and invasion assays. Western blotting and qPCR assays were used to analyze the mRNA and protein expression levels of Src and its downstream proteins, and a cell viability assay was used to measure cellular cytotoxicity effects. The results of the cell function assays revealed that digoxin inhibited the proliferation, invasion, migration, and colony formation of A549 lung cancer cells. Similar effects of digoxin were also observed in other lung cancer cell lines. Furthermore, we found that digoxin significantly suppressed Src activity and its protein expression in a dose- and time-dependent manner as well as reduced EGFR and STAT3 activity. Our data suggest that digoxin is a potential anticancer agent that may suppress lung cancer progression through inhibiting Src and the activity of related proteins.
PMCID: PMC4425490  PMID: 25955608
24.  Interventions for migraine prophylaxis: protocol of an umbrella systematic review and network meta-analysis 
BMJ Open  2015;5(5):e007594.
Multiple interventions are effective for migraine prophylaxis. However, the comparative effectiveness of these interventions is still not clear. Therefore, the aim of this study is to summarise the direct and indirect evidence for pharmacological and non-pharmacological interventions to prevent migraine attack.
Methods and analysis
We will perform an umbrella systematic review to identify eligible randomised controlled trials (RCTs) for the recommended interventions for migraine prophylaxis according to the guidelines. A comprehensive literature search will be conducted in MEDLINE, EMBASE and the Cochrane library for systematic reviews, which will be screened for RCTs. We will describe the general information of the RCTs for participants, interventions, outcome measurements, comparisons and the primary findings. Additionally, a network meta-analysis will be conducted to determine the comparative effectiveness of the treatments with a random-effects model. The absolute and relative effectiveness of the treatments will be provided. The heterogeneity and inconsistency between trials will be assessed by the I2 statistical test and Cochrane's Q test. Risk of bias will be assessed and the overall strength of the evidence will be summarised.
The result of this network meta-analysis will provide direct and indirect evidence of treatments for migraine prophylaxis, and it may provide a ranking of the treatments for patients and clinicians to help them select the best option.
Trial registration number
PROSPERO CRD42015015297.
PMCID: PMC4431061  PMID: 25948410
25.  Accessing to arteriovenous blood flow dynamics response using combined laser speckle contrast imaging and skin optical clearing 
Biomedical Optics Express  2015;6(6):1977-1989.
Laser speckle contrast imaging (LSCI) shows a great potential for monitoring blood flow, but the spatial resolution suffers from the scattering of tissue. Here, we demonstrate the capability of a combination method of LSCI and skin optical clearing to describe in detail the dynamic response of cutaneous vasculature to vasoactive noradrenaline injection. Moreover, the superior resolution, contrast and sensitivity make it possible to rebuild arteries-veins separation and quantitatively assess the blood flow dynamical changes in terms of flow velocity and vascular diameter at single artery or vein level.
PMCID: PMC4473738  PMID: 26114023
(120.6150) Speckle imaging; (290.0290) Scattering; (170.1470) Blood or tissue constituent monitoring; (150.1135) Algorithms

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