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1.  Superconductivity in Weyl semimetal candidate MoTe2 
Nature Communications  2016;7:11038.
Transition metal dichalcogenides have attracted research interest over the last few decades due to their interesting structural chemistry, unusual electronic properties, rich intercalation chemistry and wide spectrum of potential applications. Despite the fact that the majority of related research focuses on semiconducting transition-metal dichalcogenides (for example, MoS2), recently discovered unexpected properties of WTe2 are provoking strong interest in semimetallic transition metal dichalcogenides featuring large magnetoresistance, pressure-driven superconductivity and Weyl semimetal states. We investigate the sister compound of WTe2, MoTe2, predicted to be a Weyl semimetal and a quantum spin Hall insulator in bulk and monolayer form, respectively. We find that bulk MoTe2 exhibits superconductivity with a transition temperature of 0.10 K. Application of external pressure dramatically enhances the transition temperature up to maximum value of 8.2 K at 11.7 GPa. The observed dome-shaped superconductivity phase diagram provides insights into the interplay between superconductivity and topological physics.
Materials which simultaneously exhibit superconductivity and topologically non-trivial electronic band structure possess potential applications in quantum computing but have yet to be found. Here, the authors find superconductivity in MoTe2, a material predicted to be topologically non-trivial.
doi:10.1038/ncomms11038
PMCID: PMC4793082  PMID: 26972450
2.  The effect of cholesteryl ester transfer protein on pancreatic beta cell dysfunction in mice 
Background
Cholesterol accumulation causes pancreatic beta cell lipotoxicity and dysfunction. Cholesteryl ester transfer protein (CETP) plays an important role in blood lipid homeostasis. However, its role in tissue lipid metabolism remains unclear. We hypothesized that plasma CETP impact cholesterol homeostasis in the beta cells, thus damaging their functions.
Methods
The adipose tissue-specific CETP expression transgenic (aP2-CETPTg) mice, characterized by high CETP levels in the circulation, were used in this study. Pancreatic islet cholesterol and beta cell function were assessed in mice. We further measured mRNA levels of the genes involved in beta cell proliferation and differentiation, inflammation and cholesterol metabolism. TUNEL assay was applied to investigate beta cell apoptosis in islets.
Results
The aP2-CETPTg mice exhibited glucose intolerance, lower plasma insulin concentrations but increased insulin sensitivity compared with wild type mice. In addition, glucose-stimulated insulin secretion from isolated pancreatic islets significantly decreased, and free cholesterol significantly increased. Moreover, the number and size of islets from aP2-CETPTg mice were significantly decreased. Genes involved in beta cell proliferation, such as Pdx1 and BETA2, were down-regulated; genes involved in inflammation and ER stress, such as IL-1β, CHOP, and Xbp1 were up-regulated, in line with an increase of beta cell apoptosis.
Conclusions
Plasma CETP causes free cholesterol accumulation in islets which could contribute to beta cell dysfunction. Thus, CETP inhibition could be a novel protective strategy for dyslipidemia related to diabetes and obese.
doi:10.1186/s12986-016-0082-1
PMCID: PMC4788865  PMID: 26973702
Cholesterol ester transfer protein; Free cholesterol; Beta cell function; Glucose metabolism
3.  The efficacy of iodine-125 permanent brachytherapy versus intensity-modulated radiation for inoperable salivary gland malignancies: study protocol of a randomised controlled trial 
BMC Cancer  2016;16:193.
Background
Radiation therapy is the method of choice for subjects with inoperable salivary gland malignancies. I-125 brachytherapy, delivering a high radiation dose to a tumor but sparing surrounding normal tissues, is supposed to be ideal modality for the treatment of salivary gland malignancies. We designed a randomised controlled clinical trial to compare the efficacy of I-125 permanent brachytherapy (PBT) versus intensity-modulated radiation therapy (IMRT) for inoperable salivary gland malignancies.
Methods/Design
In this study, inclusion criteria are subjects with inoperable salivary gland malignancies, aged 18–80 years, have provided informed consent, with at least one measurable tumor focus, be able to survive ≥3 months, Karnofsky performance status ≥60, have adequate hematopoietic function of bone marrow, have normal liver and kidney function, and are willing to prevent pregnancy.
Exclusion criteria include a history of radiation or chemotherapy, a history of other malignant tumors in the past 5 years, receiving other effective treatments, participating in other clinical trials, with circulatory metastasis, cognitive impairment, severe cardiovascular and cerebrovascular diseases, acute infection, uncontrolled systemic disease, history of interstitial lungdisease, and being pregnant or breast feeding.
The study will be conducted as a clinical, prospective, randomised controlled trial with balanced randomisation (1:1). The planned sample size is 90 subjects. Subjects with inoperable salivary gland malignancies are randomised to receive either I-125 PBT or IMRT, with stratification by tumor size and neck lymph node metastasis. Participants in both groups will be followed up at 2, 4, 6, 9, 12, 15, 18, 21 and 24 months after randomization. The primary outcome is local control rate of the primary site (based on imaging findings and clinical examination, RECIST criteria) in 1 year. Secondary outcomes are progression-free survival, overall survival, quality of life (QOL) measured with the European Organization for Research and Treatment of Cancer QOL Questionnaire (EORTC QLQ-C30 and QLQ-H&N35) of Chinese version, and safety of treatment. Chi-squared test is used to compare the local control rates in both groups. The survival curves are estimated by the Kaplan-Meier method, and log-rank test is used to test the significant difference.
Discussion
Only few observational studies have investigated the effect of I-125 PBT on inoperable salivary gland malignancies. To our knowledge, this is the first randomised controlled trial to investigate the efficacy of I-125 PBT for subjects with inoperable salivary gland malignancies, and will add to the knowledge base for the treatment of these subjects.
Trial registration
The study is registered to Clinical Trials.gov (NCT02048254) on Jan 29, 2014.
doi:10.1186/s12885-016-2248-7
PMCID: PMC4782516  PMID: 26951097
I-125 permanent brachytherapy; Intensity-modulated radiation therapy; Inoperable salivary gland malignancy; Local control rate; Quality of life
4.  Effects of copper oxide nanoparticles on developing zebrafish embryos and larvae 
Copper oxide nanoparticles (CuO NPs) are used for a variety of purposes in a wide range of commercially available products. Some CuO NPs probably end up in the aquatic systems, thus raising concerns about aqueous exposure toxicity, and the impact of CuO NPs on liver development and neuronal differentiation remains unclear. In this study, particles were characterized using Fourier transform infrared spectra, scanning electron microscopy, and transmission electron microscopy. Zebrafish embryos were continuously exposed to CuO NPs from 4 hours postfertilization at concentrations of 50, 25, 12.5, 6.25, or 1 mg/L. The expression of gstp1 and cyp1a was examined by quantitative reverse transcription polymerase chain reaction. The expression of tumor necrosis factor alpha and superoxide dismutase 1 was examined by quantitative reverse transcription polymerase chain reaction and Western blotting. Liver development and retinal neurodifferentiation were analyzed by whole-mount in situ hybridization, hematoxylin–eosin staining, and immunohistochemistry, and a behavioral test was performed to track the movement of larvae. We show that exposure of CuO NPs at low doses has little effect on embryonic development. However, exposure to CuO NPs at concentrations of 12.5 mg/L or higher leads to abnormal phenotypes and induces an inflammatory response in a dose-dependent pattern. Moreover, exposure to CuO NPs at high doses results in an underdeveloped liver and a delay in retinal neurodifferentiation accompanied by reduced locomotor ability. Our data demonstrate that short-term exposure to CuO NPs at high doses shows hepatotoxicity and neurotoxicity in zebrafish embryos and larvae.
doi:10.2147/IJN.S100350
PMCID: PMC4788362  PMID: 27022258
copper oxide nanoparticles; biotoxicity; liver; neuronal differentiation; zebrafish; oxidative stress; behavior
5.  X chromosome-wide analysis identifies DNA methylation sites influenced by cigarette smoking 
Clinical Epigenetics  2016;8:20.
Background
Tobacco smoking is a major cause of chronic disease worldwide. Smoking may induce cellular and molecular changes including epigenetic modification, with both short-term and long-term modification patterns that may contribute to phenotypic expression of diseases. Recent epigenome-wide association studies (EWAS) have identified dozens of smoking-related DNA methylation (DNAm) sites. However, the X chromosomal DNAm sites have been largely overlooked due to a lack of an analytical framework for dealing with the sex-dimorphic distribution. To identify novel smoking-related DNAm sites on the X chromosome, we examined the modality of each X chromosomal DNAm site and conducted a sex-specific association study of cigarette smoking.
Results
We used a discovery sample of 139 middle-age twins, and three replication samples of 78 twins, 464 and 333 unrelated individuals including 47, 17, 22, and 89 current smokers, respectively. After correction for multiple testing, the top smoking-related DNAm sites in BCOR and TSC22D3 were significantly hypermethylated and hypomethylated, respectively, among current smokers. These smoking-associated sites were replicated with meta-analysis p-values of 9.17 × 10−12 and 1.61 × 10−9. For both sites, the smoking effects on methylation levels were larger in males than that in females.
Conclusions
Our findings highlight the importance of investigating X chromosome methylation patterns and their associations with environmental exposures and disease phenotypes and demonstrate a robust statistical methodology for such study. Existing EWAS of human diseases should incorporate the X chromosomal sites to complete a comprehensive epigenome-wide scan.
Electronic supplementary material
The online version of this article (doi:10.1186/s13148-016-0189-2) contains supplementary material, which is available to authorized users.
doi:10.1186/s13148-016-0189-2
PMCID: PMC4765206  PMID: 26913089
X chromosome; Epigenome; Epigenetics; DNA methylation; Methylome; Smoking; Epigenome-wide association study; Twin; Heritability
6.  Multifocal electroretinogram in non-pathological myopic subjects: correlation with optical coherence tomography 
AIM
To investigate the changes of retinal function in non-pathological myopic subjects using multifocal electroretinography (mfERG) and to correlate the data with the central macular thickness obtained using optical coherence tomography (OCT).
METHODS
One hundred and thirteen subjects (113 eyes) with age range from 18 to 35y were enrolled in the study. The subjects were divided into four groups according to spherical equivalent (SE) and axial length (AL): emmetropia group (EG, n=31; SE: +0.75 to -0.50 D; AL: 22 to 24 mm), low and medium myopia group (LMMG, n=26; SE: >-0.50 to -6.00 D; AL: >24 to 26 mm), high myopia group (HMG, n=34; SE: >-6.00 to -10.00 D; AL: >26 to 28 mm) and super high myopia group (SHMG, n=22; SE: >-10.00 D; AL:>28 mm). The P1 amplitude density, P1 amplitude, and P1 implicit time of the first-order kernel mfERG responses were obtained and grouped into five rings. The central subfield macular thickness (CST) was obtained using macular cube 512×218 scan of Cirrus HD-OCT.
RESULTS
With the increasing of eccentricity, the first positive peak (P1) amplitude density (P=0.0000, 0.0001, 0.0021 in ring 1-3 respectively) and P1 amplitude (all P=0.0000 in ring 1-5) of each group decreased. With the increasing of myopia, P1 implicit time gradually extended (all P=0.0000 in ring 1-3). The average CST in four diagnostic groups was 241.56±12.72 µm, 244.56±12.19 µm, 254.33±11.61 µm, 261.75±11.83 µm respectively. With the increasing of myopia, CST increased (P<0.001). There was negative relationship between CST and P1 amplitude, P1 amplitude density (r=-0.402, P<0.001; r=-0.261, P=0.003). There was positive relationship between CST and P1 implicit time (r=0.34, P<0.001).
CONCLUSION
With the increasing of myopia, P1 amplitude density and P1 amplitude of the first-order reaction gradually reduced. This showed potential decline in retinal function in myopia. To some extent it may reflect the functional disorder or depression of the visual cells. The exact mechanism needs further study.
doi:10.18240/ijo.2016.02.21
PMCID: PMC4761745  PMID: 26949653
multifocal electroretinogram; optical coherence tomography; myopia
7.  De Novo Transcriptome Assembly and Characterization for the Widespread and Stress-Tolerant Conifer Platycladus orientalis 
PLoS ONE  2016;11(2):e0148985.
Platycladus orientalis, of the family Cupressaceae, is a widespread conifer throughout China and is extensively used for ecological reforestation, horticulture, and in medicine. Transcriptome assemblies are required for this ecologically important conifer for understanding genes underpinning adaptation and complex traits for breeding programs. To enrich the species’ genomic resources, a de novo transcriptome sequencing was performed using Illumina paired-end sequencing. In total, 104,073,506 high quality sequence reads (approximately 10.3 Gbp) were obtained, which were assembled into 228,948 transcripts and 148,867 unigenes that were longer than 200 nt. Quality assessment using CEGMA showed that the transcriptomes obtained were mostly complete for highly conserved core eukaryotic genes. Based on similarity searches with known proteins, 62,938 (42.28% of all unigenes), 42,158 (28.32%), and 23,179 (15.57%) had homologs in the Nr, GO, and KOG databases, 25,625 (17.21%) unigenes were mapped to 322 pathways by BLASTX comparison against the KEGG database and 1,941 unigenes involved in environmental signaling and stress response were identified. We also identified 43 putative terpene synthase (TPS) functional genes loci and compared them with TPSs from other species. Additionally, 5,296 simple sequence repeats (SSRs) were identified in 4,715 unigenes, which were assigned to 142 motif types. This is the first report of a complete transcriptome analysis of P. orientalis. These resources provide a foundation for further studies of adaptation mechanisms and molecular-based breeding programs.
doi:10.1371/journal.pone.0148985
PMCID: PMC4755536  PMID: 26881995
8.  Comparison of Subconjunctival Mitomycin C and 5-Fluorouracil Injection for Needle Revision of Early Failed Trabeculectomy Blebs 
Journal of Ophthalmology  2016;2016:3762674.
Background. To compare the efficacy of needle revision with 5-fluorouracil (5-FU) and mitomycin C (MMC) on dysfunctional filtration blebs shortly after trabeculectomy. Methods. It is a prospective randomized study comparing needle revision augmented with MMC or 5-FU for failed trabeculectomy blebs. Results. To date 71 patients (75 eyes) have been enrolled, 40 eyes in the MMC group and 35 in the 5-FU group. 68 patients (72 eyes) have completed 12-month follow-up, 38 eyes in the MMC group and 34 in the 5-FU group. The mean IOP before and that after needle revision in the MMC group were 26.5 ± 4.3 mmHg and 11.3 ± 3.4 mmHg, respectively (P < 0.05), and in the 5-FU group were 27.1 ± 3.8 mmHg and 10.9 ± 3.4 mmHg, respectively (P < 0.05). At 12-month follow-up, complete success rates were 57.5% for MMC group and 34.3% for 5-FU group (P = 0.042; log-rank test) and 75% and 60% (P = 0.145; log-rank test), respectively, for the qualified success. Complication rates between the two groups were not statistically different (P > 0.05). Conclusions. Needle revision and subconjunctival MMC injection were more effective than needling and subconjunctival 5-FU injection for early dysfunctional filtration blebs after trabeculectomies.
doi:10.1155/2016/3762674
PMCID: PMC4771896  PMID: 26989499
9.  STIM1 Overexpression Promotes Colorectal Cancer Progression, Cell Motility and COX-2 Expression 
Oncogene  2014;34(33):4358-4367.
Tumor metastasis is the major cause of death among cancer patients, with more than 90% of cancer-related death attributable to the spreading of metastatic cells to secondary organs. Store-operated Ca2+ entry (SOCE) is the predominant Ca2+ entry mechanism in most cancer cells, and STIM1 is the endoplasmic reticulum (ER) Ca2+ sensor for store-operated channels (SOC). Here we reported that the STIM1 was overexpressed in colorectal cancer (CRC) patients. STIM1 overexpression in CRC was significantly associated with tumor size, depth of invasion, lymphnode metastasis status and serum levels of carcinoembryonic antigen. Furthermore, ectopic expression of STIM1 promoted CRC cell motility, while depletion of STIM1 with shRNA inhibited CRC cell migration. Our data further suggested that STIM1 promoted CRC cell migration through increasing the expression of cyclooxygenase-2 (COX-2) and production of prostaglandin E2 (PGE2). Importantly, ectopically expressed COX-2 or exogenous PGE2 were able to rescue migration defect in STIM1 knockdown CRC cells, and inhibition of COX-2 with ibuprofen and indomethacin abrogated STIM1-mediated CRC cell motility. In short, our data provided clinicopathological significance for STIM1 and store-operated Ca2+ entry in CRC progression, and implicated a role for COX-2 in STIM1-mediated CRC metastasis. Our studies also suggested a new approach to inhibit STIM1-mediated metastasis with COX-2 inhibitors.
doi:10.1038/onc.2014.366
PMCID: PMC4426254  PMID: 25381814
stromal interaction molecular 1 gene; store-operated calcium channel; colon cancer; metastasis; invasion; COX-2; colorectal cancer; cell migration
10.  A Retrospective Cohort Study of Lesion Distribution of HIV-1 Infection Patients With Cryptococcal Meningoencephalitis on MRI 
Medicine  2016;95(6):e2654.
Abstract
The objective of this paper is to correlate the MRI distribution of cryptococcal meningoencephalitis in HIV-1 infection patients with CD4 T cell count and immune reconstitution effect.
A large retrospective cohort study of HIV patients from multi-HIV centers in China was studied to demonstrate the MRI distribution of cryptococcal meningoencephalitis and its correlation with the different immune status.
The consecutive clinical and neuroimaging data of 55 HIV-1-infected patients with cryptococcal meningoencephalitis collected at multi-HIV centers in China during the years of 2011 to 2014 was retrospectively analyzed. The enrolled patients were divided into 2 groups based on the distribution of lesions. One group of patients had their lesions at the central brain (group 1, n = 34) and the other group of patients had their lesions at the superficial brain (group 2, n = 21). We explored their MRI characterization of brain. In addition, we also compared their CD4 T cell counts and immune reconstitution effects between the 2 groups based on the imaging findings.
No statistical difference was found in terms of age and gender between the 2 groups. The medians of CD4 T cell counts were 11.67 cells/mm3 (3.00–52.00 cells/mm3) in group 1 and 42.00 cells/mm3 (10.00–252.00 cells/mm3) in group 2. Statistical difference of CD4 T cell count was found between the 2 groups (P = 0.023). Thirteen patients in group 1 (13/34) and 12 patients in group 2 (12/21) received highly active antiretroviral treatment (HAART). Patients of group 2 received HAART therapy more frequently than patients of group 1 (P = 0.021).
Central and superficial brain lesions detected by MR imaging in HIV-1-infected patients with cryptococcal meningoencephalitis are in correlation with the host immunity and HAART therapy.
doi:10.1097/MD.0000000000002654
PMCID: PMC4753886  PMID: 26871791
11.  Evaluation of the utricular and saccular function using oVEMPs and cVEMPs in BPPV patients 
Background
It is well-known that ocular vestibular evoked myogenic potentials (oVEMPs) predominantly reflect utricular function whilst cervical vestibular evoked myogenic potentials (cVEMPs) reflect saccular function. To date, there are no published reports on the systemic evaluation of utricular and saccular function in benign paroxysmal positional vertigo (BPPV), nor are there any reports on the differences in VEMPs between patients with recurrent and non-recurrent BPPV. The aim of this study was to evaluate the difference in cervical and ocular (c/o)VEMPs between patients with BPPV and normal controls, as well as between patients with recurrent and non-recurrent BPPV.
Methods
Thirty patients with posterior canal BPPV and 30 healthy subjects (as normal controls) were prospectively enrolled. cVEMP and oVEMP testing using 500 Hz tone-burst stimuli were performed on all. VEMP tests were repeated 3 times on each subject to ensure reliability and reproducibility of responses. VEMPs were defined as present or absent. Abnormal VEMP was defined by lack of VEMP response.
Results
In the control group, abnormal cVEMPs responses were detected in 6.67 % and abnormal oVEMPs responses were detected in 3.34 %. In BPPV patients (10 with recurrent BPPV, 20 with non-recurrent BPPV), abnormal cVEMPs responses were detected in 30 % and abnormal oVEMPs responses were detected in 56.7 %. More patients with BPPV showed abnormal responses in c/oVEMPs as compared to the control group (p < 0.05). oVEMPs was more often abnormal as compared to cVEMPs in BPPV patients (p < 0.05). There was no statistical difference between abnormal cVEMP responses in non-recurrent BPPV patients (25 %) and recurrent BPPV patients (40 %) (p > 0.05). Differences in abnormal oVEMP responses (non-recurrent BPPV, 40 %; recurrent BPPV, 90 %) were significant (p < 0.05).
Conclusion
An increased occurrence of abnormal c/oVEMP recordings appeared in BPPV patients, possibly as a result of degeneration of the otolith macula. oVEMPs were more often abnormal in BPPV patients as compared to cVEMPs, suggesting that utricular dysfunction may be more common than saccular dysfunction. Furthermore, oVEMP abnormalities in the recurrent BPPV group were significantly higher than those in the non-recurrent BPPV group. Assessment of c/oVEMPs in BPPV patients may therefore be of prognostic value in predicting likelihood of BPPV recurrence.
doi:10.1186/s40463-016-0125-7
PMCID: PMC4746908  PMID: 26857819
Cervical/ocular vestibular evoked myogenic potentials (c/oVEMPs); Benign paroxysmal positional vertigo (BPPV); Utricular; Saccular
12.  Site disparities in apoptotic variants as predictors of risk for second primary malignancy in patients with squamous cell carcinoma of the head and neck 
BMC Cancer  2016;16:70.
Background
FAS/FASL promoter variants are considered in altering transcriptional activity of those genes and consequently alter regulation of cell death. However, no studies have investigated whether tumor sites contribute to the association between FAS/FASL polymorphisms and risk for second primary malignancy (SPM).
Method
In this study, FAS670 A > G, FAS1377 G > A, FASL124 A > G, and FASL844C > T polymorphisms were genotyped in 752 OPC and 777 non-OPC patients. Both univariate and multivariable cox proportional hazard models were used to assess the associations.
Results
The univariate and multivariable analyses showed that patients with index OPC and FASL844 CT/TT genotype had significantly increased risk of SPM (cHR, 2.5; 95 % CI, 1.1–5.8, P = 0.043 and aHR, 2.7; 95 % CI, 1.2–6.0, P = 0.032) compared with those with FASL844 CC genotype as the reference group, while index non-OPC patients with FAS670 AG/GG and FasL844 CT/TT genotypes had significantly increased risk of SPM (cHR, 2.2 and 1.8; 95 % CI, 1.2–5.7 and 1.1–3.2; and P = 0.04 and 0.041, respectively and aHR, 2.4 and 1.7; 95 % CI, 1.1–5.1 and 1.0-3.0; and P = 0.043 and 0.049, respectively) compared with their corresponding AA and CC genotypes . Moreover, patients carrying more FAS/FASL variants significantly increased risk of SPM among index non-OPC patients. The stratified analysis showed that smoking status differently modified the associations between FAS/FASL polymorphisms and risk of SPM among index non-OPC from OPC patients.
Conclusion
These results suggested that FAS/FASL polymorphisms might significantly modify SPM risk among patients with SCCHN in a tumor site-specific manner.
doi:10.1186/s12885-016-2110-y
PMCID: PMC4746789  PMID: 26858129
FAS/FASLG; Squamous cell carcinoma of head and neck; Second primary malignancy; Susceptibility; Polymorphism; Oropharyngeal cancer; Nonoropharyngeal cancer
13.  MiR-278-3p regulates pyrethroid resistance in Culex pipiens pallens 
Parasitology research  2014;114(2):699-706.
MicroRNAs (miRNAs) regulate gene expression and biological processes including embryonic development, innate immunity and infection in many species. Emerging evidence indicates that miRNAs are involved in drug resistance. However, little is known about the relationship between the miRNAs and insecticide resistance in mosquitos. Here, we reported that conserved miR-278-3p and its target gene are critical for pyrethroid resistance in Culex pipiens pallens. We found that CYP6AG11 is the target of miR-278-3p, through bioinformatic analysis and experimental verification. The expression level of miR-278-3p was lower, whereas the level of CYP6AG11 was higher in deltamethrin-resistant strain, which were detected using qRT-PCR. We also found that CYP6AG11 was regulated by miR-278-3p via a specific target site with the 3′UTR by luciferase reporter assay. In addition, overexpression of CYP6AG11 in the mosquito C6/36 cells showed better prolification than the cells with empty vector when treated by deltamethrin at different concentrations. Moreover, the overexpression of miR-278-3p through microinjection led to a significant reduction in the survival rate, and the level of CYP6AG11 was simultaneously reduced. These results indicated that miR-278-3p could regulate the pyrethroid resistance through CYP6AG11.
doi:10.1007/s00436-014-4236-7
PMCID: PMC4304972  PMID: 25420996
Culex pipiens pallens; microRNA; CYP6AG11; pyrethroid resistance
14.  Topoisomerase IIα in Chromosome Instability and Personalized Cancer Therapy 
Oncogene  2014;34(31):4019-4031.
Genome instability is a hallmark of cancer cells. Chromosome instability (CIN), which is often mutually exclusive from hypermutation genotypes, represents a distinct subtype of genome instability. Hypermutations in cancer cells are due to defects in DNA repair genes, but the cause of CIN is still elusive. However, because of the extensive chromosomal abnormalities associated with CIN, its cause is likely a defect in a network of genes that regulate mitotic checkpoints and chromosomal organization and segregation. Emerging evidence has shown that the chromosomal decatenation checkpoint, which is critical for chromatin untangling and packing during genetic material duplication, is defective in cancer cells with CIN. The decatenation checkpoint is known to be regulated by a family of enzymes called topoisomerases. Among them, the gene encoding topoisomerase IIα (TOP2A) is commonly altered at both gene copy number and gene expression level in cancer cells. Thus, abnormal alterations of TOP2A, its interacting proteins, and its modifications may play a critical role in CIN in human cancers. Clinically, a large arsenal of topoisomerase inhibitors have been used to suppress DNA replication in cancer. However, they often lead to the secondary development of leukemia because of their effect on the chromosomal decatenation checkpoint. Therefore, topoisomerase drugs must be used judiciously and administered on an individual basis. In this review, we highlight the biological function of TOP2A in chromosome segregation and the mechanisms that regulate this enzyme's expression and activity. We also review the roles of TOP2A and related proteins in human cancers, and raise a perspective for how to target TOP2A in personalized cancer therapy.
doi:10.1038/onc.2014.332
PMCID: PMC4404185  PMID: 25328138
Chromosome instability; DNA topoisomerase IIalpha; cancer genome; cancer progression; personalized cancer therapy
15.  Grape seed proanthocyanidin extract protects the retina against early diabetic injury by activating the Nrf2 pathway 
The present study aimed to investigate whether grape seed proanthocyanidin extract (GSPE) has a protective effect on diabetic retinal function. A total of 30 Wistar rats were randomly divided into three equal groups, including the control, diabetic and GSPE-treated diabetic groups. Retinal tissue was harvested and subsequently stained with hematoxylin and eosin. Superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and methane dicarboxylic aldehyde (MDA) levels were evaluated using respective assay kits; whereas nuclear erythroid 2-related factor 2 (Nrf2) and heme oxygenase (HO)-1 expression levels were assessed by immunohistochemical and western blot analysis. Cell apoptosis in the retina was determined using the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling method. The results showed that the structure of the retina was damaged in diabetic rats, as compared with the control rats. Notably, the structure of the retina improved in the GSPE-treated diabetic group, as compared with the diabetic group. SOD and GSH-Px activities were significantly increased in the retina of rats in the GSPE-treated diabetic group, as compared with the diabetic group (P=0.011 and P=0.001, respectively). Furthermore, a significant reduction in MDA was detected (P=0.013) and the expression levels of Nrf2 and HO-1 in the bladders of rats in the GSPE-treated diabetic group were significantly increased, as compared with the diabetic group (P=0.038 and P=0.043, respectively). Apoptosis of retinal cells was significantly increased in the diabetic group, as compared with the control group (P<0.001); a significant reduction was also detected in the GSPE-treated diabetic group, as compared with the diabetic group (P=0.014). These results demonstrate that GSPE administration may protect the retina against hyperglycemic damage, possibly by ameliorating oxidative stress-mediated injury via the activation of the Nrf2 pathway.
doi:10.3892/etm.2016.3033
PMCID: PMC4812468  PMID: 27073432
diabetic retinopathy; grape seed proanthocyanidin extracts; nuclear erythroid 2-related factor 2; oxidative stress; apoptosis
17.  Ultraviolet light-emitting diode irradiation-induced cell death in HL-60 human leukemia cells in vitro 
Molecular Medicine Reports  2016;13(3):2506-2510.
Ultraviolet (UV) radiation is considered to be a potent cell-damaging agent in various cell lineages; however, the effect of UV light-emitting diode (LED) irradiation on human cells remains unclear. The aim of the present study was to examine the effect of UV LED irradiation emitting at 280 nm on cultured HL-60 human leukemia cells, and to explore the underlying mechanisms. HL-60 cells were irradiated with UV LED (8, 15, 30 and 60 J/m2) and incubated for 2 h after irradiation. The rates of cell proliferation and apoptosis, the cell cycle profiles and the mRNA expression of B-cell lymphoma 2 (Bcl-2) were detected using cell counting kit-8, multicaspase assays, propidium iodide staining and reverse transcription-quantitative polymerase chain reaction, respectively. The results showed that UV LED irradiation (8–60 J/m2) inhibited the proliferation of HL-60 cells in a dose-dependent manner. UV LED at 8–30 J/m2 induced dose-dependent apoptosis and G0/G1 cell cycle arrest, and inhibited the expression of Bcl-2 mRNA, while UV LED at 60 J/m2 induced necrosis. In conclusion, 280 nm UV LED irradiation inhibits proliferation and induces apoptosis and necrosis in cultured HL-60 cells. In addition, the cell cycle arrest at the G0/G1 phase and the downregulation of Bcl-2 mRNA expression were shown to be involved in UV LED-induced apoptosis.
doi:10.3892/mmr.2016.4812
PMCID: PMC4768973  PMID: 26820261
ultraviolet radiation; light-emitting diode; HL-60 cells; apoptosis; necrosis
18.  cis p-tau: early driver of brain injury and tauopathy blocked by antibody 
Nature  2015;523(7561):431-436.
Traumatic brain injury (TBI), characterized by acute neurological dysfunction, is one of the best known environmental risk factors for chronic traumatic encephalopathy (CTE) and Alzheimer's disease (AD), whose defining pathologic features include tauopathy made of phosphorylated tau (p-tau). However, tauopathy has not been detected in early stages after TBI and how TBI leads to tauopathy is unknown. Here we find robust cis p-tau pathology after sport- and military-related TBI in humans and mice. Acutely after TBI in mice and stress in vitro, neurons prominently produce cis p-tau, which disrupts axonal microtubule network and mitochondrial transport, spreads to other neurons, and leads to apoptosis. This process, termed “cistauosis”, appears long before other tauopathy. Treating TBI mice with cis antibody blocks cistauosis, prevents tauopathy development and spread, and restores many TBI-related structural and functional sequelae. Thus, cis p-tau is a major early driver after TBI and leads to tauopathy in CTE and AD, and cis antibody may be further developed to detect and treat TBI, and prevent progressive neurodegeneration after injury.
doi:10.1038/nature14658
PMCID: PMC4718588  PMID: 26176913
19.  Epigenomic Indicators of Age in African Americans 
Age is a well-established risk factor for chronic diseases. However, the cellular and molecular changes associated with aging processes that are related to chronic disease initiation and progression are not well-understood. Thus, there is an increased need to identify new markers of cellular and molecular changes that occur during aging processes. In this study, we use genome-wide DNA methylation from 26,428 CpG sites in 13,877 genes to investigate the relationship between age and epigenetic variation in the peripheral blood cells of 972 African American adults from the Genetic Epidemiology Network of Arteriopathy (GENOA) study (mean age=66.3 years, range=39–95). Age was significantly associated with 7,601 (28.8%) CpG sites after Bonferroni correction for α=0.05 (p<1.89×10−6). Due to the extraordinarily strong associations between age and many of the CpG sites (>7,000 sites with p-values ranging from 10−6 to 10−43), we investigated how well the DNA methylation markers predict age. We found that 2,095 (7.9%) CpG sites were significant predictors of age after Bonferroni correction. The top five principal components of the 2,095 age-associated CpG sites accounted for 69.3% of the variability in these CpG sites, and they explained 26.8% of the variation in age. The associations between methylation markers and adult age are so ubiquitous and strong that we hypothesize that DNA methylation patterns may be an important measure of cellular aging processes. Given the highly correlated nature of the age-associated epigenome (as evidenced by the principal components analysis), whole pathways may be regulated as a consequence of aging.
doi:10.4172/2161-1041.1000137
PMCID: PMC4721639  PMID: 26807331
Epigenetics; Epigenomics; Methylation; Age; Aging; African Americans
20.  Myeloid cell-derived reactive oxygen species externally regulate the proliferation of myeloid progenitors in emergency granulopoiesis 
Immunity  2015;42(1):159-171.
Summary
The cellular mechanisms controlling infection-induced emergency granulopoiesis are poorly defined. Here we found that reactive oxygen species (ROS) concentrations in the bone marrow (BM) were elevated during acute infection in a phagocytic NADPH oxidase-dependent manner in myeloid cells. Gr1+ myeloid cells were uniformly distributed in the BM, and all c-Kit+ progenitor cells were adjacent to Gr1+ myeloid cells. Inflammation-induced ROS production in the BM played a critical role in myeloid progenitor expansion during emergency granulopoiesis. ROS elicited oxidation and deactivation of phosphatase and tensin homolog (PTEN), resulting in up-regulation of PtdIns(3,4,5)P3 signaling in BM myeloid progenitors. We further revealed that BM myeloid cell-produced ROS stimulated proliferation of myeloid progenitors via a paracrine mechanism. Taken together, our results establish that phagocytic NADPH oxidase-mediated ROS production by BM myeloid cells plays a critical role in mediating emergency granulopoiesis during acute infection.
doi:10.1016/j.immuni.2014.12.017
PMCID: PMC4303526  PMID: 25579427
Infection and inflammation; emergency granulopoiesis; neutrophils; myeloid cells; reactive oxygen species; NADPH oxidase; PTEN; PtdIns(3,4,5)P3
21.  Effect of Graph Scale on Risky Choice: Evidence from Preference and Process in Decision-Making 
PLoS ONE  2016;11(1):e0146914.
We investigate the effect of graph scale on risky choices. By (de)compressing the scale, we manipulate the relative physical distance between options on a given attribute in a coordinate graphical context. In Experiment 1, the risky choice changes as a function of the scale in the graph. In Experiment 2, we show that the type of graph scale also affects decision times. In Experiment 3, we examine the graph scale effect by using real money among students who have taken statistics courses. Consequently, the scale effects still appear even when we control the variations in calculation ability and increase the gravity with which participants view the consequence of their decisions. This finding is inconsistent with descriptive invariance of preference. The theoretical implications and practical applications of the findings are discussed.
doi:10.1371/journal.pone.0146914
PMCID: PMC4714888  PMID: 26771530
22.  Celastrol Ameliorates Ulcerative Colitis-Related Colorectal Cancer in Mice via Suppressing Inflammatory Responses and Epithelial-Mesenchymal Transition 
Celastrol, also named as tripterine, is a pharmacologically active ingredient extracted from the root of traditional Chinese herb Tripterygium wilfordii Hook F with potent anti-inflammatory and anti-tumor activities. In the present study, we investigated the effects of celastrol on ulcerative colitis-related colorectal cancer (UC-CRC) as well as CRC in vivo and in vitro and explored its underlying mechanisms. UC-CRC model was induced in C57BL/6 mice by administration of azoxymethane (AOM) and dextran sodium sulfate (DSS). Colonic tumor xenograft models were developed in BALB/c-nu mice by subcutaneous injection with HCT116 and HT-29 cells. Intragastric administration of celastrol (2 mg/kg/d) for 14 weeks significantly increased the survival ratio and reduced the multiplicity of colonic neoplasms compared with AOM/DSS model mice. Mechanically, celastrol treatment significantly prevented AOM/DSS-induced up-regulation of expression levels of oncologic markers including mutated p53 and phospho-p53, β-catenin and proliferating cell nuclear antigen (PCNA). In addition, treatment with celastrol inhibited inflammatory responses, as indicated by the decrease of serum tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-6, down-regulation of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), and inactivation of nuclear factor κB (NF-κB). Moreover, celastrol obviously suppressed epithelial-mesenchymal transition (EMT) through up-regulating E-cadherin and down-regulating N-cadherin, Vimentin and Snail. Additionally, we also demonstrated that celastrol inhibited human CRC cell proliferation and attenuated colonic xenograft tumor growth via reversing EMT. Taken together, celastrol could effectively ameliorate UC-CRC by suppressing inflammatory responses and EMT, suggesting a potential drug candidate for UC-CRC therapy.
doi:10.3389/fphar.2015.00320
PMCID: PMC4711309  PMID: 26793111
celastrol; ulcerative colitis; colorectal cancer; inflammation; epithelial-mesenchymal transition; oncologic proteins
23.  A Genome-wide study of blood pressure in African Americans accounting for gene-smoking interaction 
Scientific Reports  2016;6:18812.
Cigarette smoking has been shown to be a health hazard. In addition to being considered a negative lifestyle behavior, studies have shown that cigarette smoking has been linked to genetic underpinnings of hypertension. Because African Americans have the highest incidence and prevalence of hypertension, we examined the joint effect of genetics and cigarette smoking on health among this understudied population. The sample included African Americans from the genome wide association studies of HyperGEN (N = 1083, discovery sample) and GENOA (N = 1427, replication sample), both part of the FBPP. Results suggested that 2 SNPs located on chromosomes 14 (NEDD8; rs11158609; raw p = 9.80 × 10−9, genomic control-adjusted p = 2.09 × 10−7) and 17 (TTYH2; rs8078051; raw p = 6.28 × 10−8, genomic control-adjusted p = 9.65 × 10−7) were associated with SBP including the genetic interaction with cigarette smoking. These two SNPs were not associated with SBP in a main genetic effect only model. This study advances knowledge in the area of main and joint effects of genetics and cigarette smoking on hypertension among African Americans and offers a model to the reader for assessing these risks. More research is required to determine how these genes play a role in expression of hypertension.
doi:10.1038/srep18812
PMCID: PMC4707536  PMID: 26752167
24.  Targeting adeno-associated virus and adenoviral gene therapy for hepatocellular carcinoma 
World Journal of Gastroenterology  2016;22(1):326-337.
Human hepatocellular carcinoma (HCC) heavily endangers human heath worldwide. HCC is one of most frequent cancers in China because patients with liver disease, such as chronic hepatitis, have the highest cancer susceptibility. Traditional therapeutic approaches have limited efficacy in advanced liver cancer, and novel strategies are urgently needed to improve the limited treatment options for HCC. This review summarizes the basic knowledge, current advances, and future challenges and prospects of adeno-associated virus (AAV) and adenoviruses as vectors for gene therapy of HCC. This paper also reviews the clinical trials of gene therapy using adenovirus vectors, immunotherapy, toxicity and immunological barriers for AAV and adenoviruses, and proposes several alternative strategies to overcome the therapeutic barriers to using AAV and adenoviruses as vectors.
doi:10.3748/wjg.v22.i1.326
PMCID: PMC4698495  PMID: 26755879
Hepatocellular carcinoma; Adeno-associated virus; Adenovirus; Virus vectors
25.  MiR-506 inhibits multiple targets in the epithelial-to-mesenchymal transition network and is associated with good prognosis in epithelial ovarian cancer 
The Journal of pathology  2014;235(1):25-36.
Extensive investigations have shown that miRNAs are important regulators of epithelial-to-mesenchymal transition (EMT), mainly targeting the transcriptional repressors of E-cadherin (Ecad). Less is known about the post-transcriptional regulation of vimentin or N-cadherin (N-cad) in EMT. Our previous study identified miR-506 as a key EMT inhibitor through directly targeting the E-cad transcriptional repressor, SNAI2. In this study, we provide evidence that miR-506 simultaneously suppresses vimentin and N-cad. The knockdown of vimentin using siRNA reversed EMT, suppressed cell migration and invasion, and increased E-cad expression on cell membrane in epithelial ovarian cancer (EOC) cells. In a set of tissue microarrays that included 204 EOCs of all major subtypes (e.g., serous, endometrioid, clear cell, and mucinous), miR-506 was positively correlated with E-cad and negatively correlated with vimentin and N-cad in all subtypes of EOC. A high level of miR-506 was positively associated with early FIGO stage and longer survival in EOC. Introduction of miR-506, mediated by nanoparticle delivery, in EOC orthotopic mouse models resulted in decreased vimentin, N-cad, and SNAI2 expression and increased E-cad expression; it also suppressed the dissemination of EOC cells. Thus, miR-506 represents a new class of miRNA that regulates both E-cad and vimentin/N-cad in the suppression of EMT and metastasis.
doi:10.1002/path.4443
PMCID: PMC4268369  PMID: 25230372
miR-506; epithelial-to-mesenchymal transition; vimentin; N-cadherin; epithelial ovarian cancer; nanoparticle

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