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1.  GP73-regulated oncolytic adenoviruses possess potent killing effect on human liver cancer stem-like cells 
Oncotarget  2016;7(20):29346-29358.
Cancer stem cells (CSCs), also known as tumor-initiating cells, are highly metastatic, chemo-resistant and tumorigenic, and are critical for cancer development, maintenance and recurrence. Oncolytic adenovirus could targetedly kill CSCs and has been acted as a promising anticancer agent. Currently, a novel GP73-regulated oncolytic adenovirus GD55 was constructed to specifically treat liver cancer and exhibited obvious cytotoxicity effect. However, there remains to be confirmed that whether GD55 could effectively eliminate liver CSCs. We first utilized the suspension culture to enrich the liver CSCs-like cells, which acquires the properties of liver CSCs in self-renewal, differentiation, quiescence, chemo-resistance and tumorigenicity. The results indicated that GD55 elicited more significant cytotoxicity and stronger oncolytic effect in liver CSC-like cells compared to common oncolytic virus ZD55. Additionally, GD55 possessed the greater efficacy in suppressing the growth of implanted tumors derived from liver CSC-like cells than ZD55. Furthermore, GD55 induced remarkable apoptosis of liver CSC-like cells in vitro and in vivo, and inhibited the propogation of cells and angiogenesis in xenograft tumor tissues. Thus, GD55 may virtually represent an attractive therapeutic agent for targeting liver CSCs to achieve better clinical outcomes for HCC patients.
PMCID: PMC5045400  PMID: 27121064
GP73; oncolytic adenovirus; liver cancer stem-like cells
2.  Application of the analytic hierarchy approach to the risk assessment of Zika virus disease transmission in Guangdong Province, China 
An international spread of Zika virus (ZIKV) infection has attracted global attention in 2015. The infection also affected Guangdong province, which is located in southern China. Multiple factors, including frequent communication with South America and Southeast Asia, suitable climate (sub-tropical) for the habitat of Aedes species, may increase the risk of ZIKV disease transmission in this region.
An analytic hierarchy process (AHP) method was used to develop a semi-quantitative ZIKV risk assessment model. After selecting indicators, we invited experts in related professions to identify the index weight and based on that a hierarchical structure was generated. Then a series of pairwise comparisons were used to determine the relative importance of the criteria. Finally, the optimal model was established to estimate the spatial and seasonal transmission risk of ZIKV.
A total of 15 factors that potentially influenced the risk of ZIKV transmission were identified. The factor that received the largest weight was epidemic of ZIKV in Guangdong province (combined weight [CW] =0.37), followed by the mosquito density (CW = 0.18) and the epidemic of DENV in Guangdong province (CW = 0.14). The distribution of 123 districts/counties’ RIs of ZIKV in Guangdong through different seasons were presented, respectively.
Higher risk was observed within Pearl River Delta including Guangzhou, Shenzhen and Jiangmen, and the risk is greater in summer and autumn compared to spring and winter.
PMCID: PMC5234119  PMID: 28086897
Zika virus; Risk assessment; Transmission; China
3.  Design optimization of stent and its dilatation balloon using kriging surrogate model 
Although stents have great success of treating cardiovascular disease, it actually undermined by the in-stent restenosis and their long-term fatigue failure. The geometry of stent affects its service performance and ultimately affects its fatigue life. Besides, improper length of balloon leads to transient mechanical injury to the vessel wall and in-stent restenosis. Conventional optimization method of stent and its dilatation balloon by comparing several designs and choosing the best one as the optimal design cannot find the global optimal design in the design space. In this study, an adaptive optimization method based on Kriging surrogate model was proposed to optimize the structure of stent and the length of stent dilatation balloon so as to prolong stent service life and improve the performance of stent.
A finite element simulation based optimization method combing with Kriging surrogate model is proposed to optimize geometries of stent and length of stent dilatation balloon step by step. Kriging surrogate model coupled with design of experiment method is employed to construct the approximate functional relationship between optimization objectives and design variables. Modified rectangular grid is used to select initial training samples in the design space. Expected improvement function is used to balance the local and global searches to find the global optimal result. Finite element method is adopted to simulate the free expansion of balloon-expandable stent and the expansion of stent in stenotic artery. The well-known Goodman diagram was used for the fatigue life prediction of stent, while dogboning effect was used for stent expansion performance measurement. As the real design cases, diamond-shaped stent and sv-shaped stent were studied to demonstrate how the proposed method can be harnessed to design and refine stent fatigue life and expansion performance computationally.
The fatigue life and expansion performance of both the diamond-shaped stent and sv-shaped stent are designed and refined, respectively. (a) diamond-shaped stent: The shortest distance from the data points to the failure line in the Goodman diagram was increased by 22.39%, which indicated a safer service performance of the optimal stent. The dogboning effect was almost completely eliminated, which implies more uniform expansion of stent along its length. Simultaneously, radial elastic recoil (RR) at the proximal and distal ends was reduced by 40.98 and 35% respectively and foreshortening (FS) was also decreased by 1.75%. (b) sv-shaped stent: The shortest distance from the data point to the failure line in the Goodman diagram was increased by 15.91%. The dogboning effect was also completely eliminated, RR at the proximal and distal ends was reduced by 82.70 and 97.13%, respectively, and the FS was decreased by 16.81%. Numerical results showed that the fatigue life of both stents was refined and the comprehensive expansion performance of them was improved.
This article presents an adaptive optimization method based on the Kriging surrogate model to optimize the structure of stents and the length of their dilatation balloon to prolong stents fatigue life and decreases the dogboning effect of stents during expansion process. Numerical results show that the adaptive optimization method based on Kriging surrogate model can effectively optimize the design of stents and the dilatation balloon. Further investigations containing more design goals and more effective multidisciplinary design optimization method are warranted.
PMCID: PMC5234108  PMID: 28086895
Stent; Fatigue life; Dogboning effect; Finite element method; Kriging surrogate model; Design optimization
4.  A Model for the Stop Planning and Timetables of Customized Buses 
PLoS ONE  2017;12(1):e0168762.
Customized buses (CBs) are a new mode of public transportation and an important part of diversified public transportation, providing advanced, attractive and user-led service. The operational activity of a CB is planned by aggregating space–time demand and similar passenger travel demands. Based on an analysis of domestic and international research and the current development of CBs in China and considering passenger travel data, this paper studies the problems associated with the operation of CBs, such as stop selection, line planning and timetables, and establishes a model for the stop planning and timetables of CBs. The improved immune genetic algorithm (IIGA) is used to solve the model with regard to the following: 1) multiple population design and transport operator design, 2) memory library design, 3) mutation probability design and crossover probability design, and 4) the fitness calculation of the gene segment. Finally, a real-world example in Beijing is calculated, and the model and solution results are verified and analyzed. The results illustrate that the IIGA solves the model and is superior to the basic genetic algorithm in terms of the number of passengers, travel time, average passenger travel time, average passenger arrival time ahead of schedule and total line revenue. This study covers the key issues involving operational systems of CBs, combines theoretical research and empirical analysis, and provides a theoretical foundation for the planning and operation of CBs.
PMCID: PMC5216015  PMID: 28056041
5.  The clinical impact of recent advances in LC-MS for cancer biomarker discovery and verification 
Expert review of proteomics  2015;13(1):99-114.
Mass spectrometry (MS) -based proteomics has become an indispensable tool with broad applications in systems biology and biomedical research. With recent advances in liquid chromatography (LC) and MS instrumentation, LC–MS is making increasingly significant contributions to clinical applications, especially in the area of cancer biomarker discovery and verification. To overcome challenges associated with analyses of clinical samples (for example, a wide dynamic range of protein concentrations in bodily fluids and the need to perform high throughput and accurate quantification of candidate biomarker proteins), significant efforts have been devoted to improve the overall performance of LC–MS-based clinical proteomics platforms. Reviewed here are the recent advances in LC–MS and its applications in cancer biomarker discovery and quantification, along with the potentials, limitations and future perspectives.
PMCID: PMC4822694  PMID: 26581546
LC–MS; cancer biomarker; proteomics; targeted quantification; selected reaction monitoring; multiple reaction monitoring; isobaric labelling; label-free; PRISM
7.  Rational Design of Dual Agonist-Antibody Fusions as Long-acting Therapeutic Hormones 
ACS chemical biology  2016;11(11):2991-2995.
Recent studies have suggested that modulation of two or more signaling pathways can achieve substantial weight loss and glycemic stability. We have developed an approach to the generation of bi-functional antibody agonists that activate leptin receptor and GLP-1 receptor. Leptin was fused into the complementarity determining region 3 loop of the light chain alone, or in combination with exendin-4 (EX4) fused at the N-terminus of the heavy chain of Herceptin. The antibody fusions exhibit similar or increased in vitro activities on their cognate receptors, but 50~100 folder longer circulating half-lives in rodents compared to the corresponding native peptides/proteins. The efficacy of the leptin/EX4 dual antibody fusion on weight loss, especially fat mass loss, was enhanced in ob/ob mice and DIO mice compared to the antibody fusion of either EX4 or leptin alone. This work demonstrates the versatility of this combinatorial fusion strategy for generating dual antibody agonists with long half-lives.
PMCID: PMC5148668  PMID: 27704775
8.  The impact of cold spells on mortality and effect modification by cold spell characteristics 
Scientific Reports  2016;6:38380.
In China, the health impact of cold weather has received little attention, which limits our understanding of the health impacts of climate change. We collected daily mortality and meteorological data in 66 communities across China from 2006 to 2011. Within each community, we estimated the effect of cold spell exposure on mortality using a Distributed Lag Nonlinear Model (DLNM). We also examined the modification effect of cold spell characteristics (intensity, duration, and timing) and individual-specific factors (causes of death, age, gender and education). Meta-analysis method was finally used to estimate the overall effects. The overall cumulative excess risk (CER) of non-accidental mortality during cold spell days was 28.2% (95% CI: 21.4%, 35.3%) compared with non-cold spell days. There was a significant increase in mortality when the cold spell duration and intensity increased or occurred earlier in the season. Cold spell effects and effect modification by cold spell characteristics were more pronounced in south China. The elderly, people with low education level and those with respiratory diseases were generally more vulnerable to cold spells. Cold spells statistically significantly increase mortality risk in China, with greater effects in southern China. This effect is modified by cold spell characteristics and individual-level factors.
PMCID: PMC5138587  PMID: 27922084
9.  An optimized informatics pipeline for mass spectrometry-based peptidomics 
The comprehensive MS analysis of the peptidome, the intracellular and intercellular products of protein degradation, has the potential to provide novel insights on endogenous proteolytic processing and their utility in disease diagnosis and prognosis. Along with the advances in MS instrumentation and related platforms, a plethora of proteomics data analysis tools have been applied for direct use in peptidomics; however an evaluation of the currently available informatics pipelines for peptidomics data analysis has yet to be reported. In this study, we begin by evaluating the results of several popular MS/MS database search engines including MS-GF+, SEQUEST and MS-Align+ for peptidomics data analysis, followed by identification and label-free quantification using the well-established accurate mass and time (AMT) tag and newly developed informed quantification (IQ) approaches, both based on direct LC-MS analysis. Our results demonstrate that MS-GF+ out-performed both SEQUEST and MS-Align+ in identifying peptidome peptides. Using a database established from MS-GF+ peptide identifications, both the AMT tag and IQ approaches provided significantly deeper peptidome coverage and less missing data for each individual data set than the MS/MS methods, while achieving robust label-free quantification. Besides having an excellent correlation with the AMT tag quantification results, IQ also provided slightly higher peptidome coverage. Taken together, we propose an optimized informatics pipeline combining MS-GF+ for initial database searching with IQ (or AMT tag) approaches for identification and label-free quantification for high-throughput, comprehensive and quantitative peptidomics analysis.
PMCID: PMC4655184  PMID: 26015166
peptidomics; identification; quantification; MS-GF+; accurate mass and time tag; informed quantitation
10.  Evaluation of a Brief Intervention to Reduce the Negative Consequences of Drug Misuse among Adult Emergency Department Patients* 
Drug and alcohol dependence  2015;157:44-53.
Determine if a brief intervention (BI) reduces the negative consequences of drug use/misuse among adult emergency department (ED) patients, and identify patients more likely to benefit from the BI.
This randomized, controlled trial enrolled 1,026 18–64 year-old ED patients whose drug misuse indicated a needed for a BI. Differences in total Inventory of Drug Use Consequences (InDUC) scores between the treatment (BI) and control arms (no BI) were assessed every 90 days over a one-year period. Regression models were constructed to identify demographic and clinical factors associated with greater reductions in total InDUC scores.
Although total InDUC scores decreased for both the treatment and control arms, there were no differences in scores between the treatment and the control arms at baseline at each follow-up. In the regression analyses, participants who were not using drugs or received drug treatment in the past 90 days generally had lower InDUC scores at each follow-up.
Although negative consequences decreased in both study arms over time, receiving a BI did not lead to a greater reduction in the negative consequences of drug misuse than not receiving a BI. Of importance in the design of future ED drug misuse interventions, participants who were successful in stopping their drug misuse or receiving drug treatment did show fewer negative consequences of drug use/misuse.
PMCID: PMC4663151  PMID: 26482090
adult; emergency medical services/methods; emergency service; motivational interviewing; substance-related disorders/therapy; treatment outcome
11.  Chromatin landscapes and genetic risk in systemic lupus 
Systemic lupus erythematosus (SLE) is a multi-system, complex disease in which the environment interacts with inherited genes to produce broad phenotypes with inter-individual variability. Of 46 single nucleotide polymorphisms (SNPs) shown to confer genetic risk for SLE in recent genome-wide association studies, 30 lie within noncoding regions of the human genome. We therefore sought to identify and describe the functional elements (aside from genes) located within these regions of interest.
We used chromatin immunoprecipitation followed by sequencing to identify epigenetic marks associated with enhancer function in adult neutrophils to determine whether enhancer-associated histone marks were enriched within the linkage disequilibrium (LD) blocks encompassing the 46 SNPs of interest. We also interrogated available data in Roadmap Epigenomics for CD4+ T cells and CD19+ B cells to identify these same elements in lymphoid cells.
All three cell types demonstrated enrichment of enhancer-associated histone marks compared with genomic background within LD blocks encoded by SLE-associated SNPs. In addition, within the promoter regions of these LD blocks, all three cell types demonstrated enrichment for transcription factor binding sites above genomic background. In CD19+ B cells, all but one of the LD blocks of interest were also enriched for enhancer-associated histone marks.
Much of the genetic risk for SLE lies within or near genomic regions of disease-relevant cells that are enriched for epigenetic marks associated with enhancer function. Elucidating the specific roles of these noncoding elements within these cell-type-specific genomes will be crucial to our understanding of SLE pathogenesis.
Electronic supplementary material
The online version of this article (doi:10.1186/s13075-016-1169-9) contains supplementary material, which is available to authorized users.
PMCID: PMC5134118  PMID: 27906046
Systemic lupus erythematosus; Genetics; Enhancers; Neutrophils; Lymphocytes
12.  Role of CTGF in sensitivity to hyperthermia in ovarian and uterine cancers 
Cell reports  2016;17(6):1621-1631.
Even though hyperthermia is a promising treatment for cancer, the relationship between specific temperatures and clinical benefits of and predictors of sensitivity of cancer to hyperthermia are poorly understood. Ovarian and uterine tumors have diverse hyperthermia sensitivities. Integrative analyses of the specific gene signatures in and the differences in response to hyperthermia between hyperthermia-sensitive and -resistant cancer cells identified CTGF as a key regulator of sensitivity. CTGF silencing sensitized resistant cells to hyperthermia. CTGF siRNA treatment also sensitized resistant cancers to localized hyperthermia induced by copper sulfide nanoparticles and near-infrared laser in orthotopic ovarian cancer models. CTGF silencing aggravated energy stress induced by hyperthermia and enhanced apoptosis of hyperthermia resistant cancers.
PMCID: PMC5123842  PMID: 27806300
Hyperthermia; ovarian cancer; CTGF; DOPC-liposome; thermosensitivity; copper sulfide nanoparticle
13.  An Epitope-Specific Respiratory Syncytial Virus Vaccine based on an Antibody Scaffold 
Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infections in children. We have generated an epitope-specific RSV vaccine by grafting a neutralizing epitope (F-epitope) in its native conformation into an immunoglobulin scaffold. The resulting antibody fusion exhibited strong binding affinity to Motavizumab, an RSV neutralizing antibody, and effectively induced potent neutralizing antibodies in mice. This work illustrates the potential of the immunoglobulin molecule as a scaffold to present conformationally constrained B-cell epitopes.
PMCID: PMC4715490  PMID: 26434555
antibodies; RSV vaccine; conformation; polypeptide; protein engineering
14.  Immunomodulatory effects of OX40Ig gene-modified adipose tissue-derived mesenchymal stem cells on rat kidney transplantation 
Recent studies have suggested that adipose tissue-derived mesenchymal stem cell (ADSC) therapy and OX40 costimulation blockade are two immunomodulatory strategies used to suppress the immune response to alloantigens. However, relatively little has been reported regarding the immunomodulatory potential of the abilityof these two strategies to synergize. Thus, in the present study, we aimed to investigate OX40-Ig fusion protein (OX40Ig) expression in ADSCs and to validate their more potent immunosuppressive activity in preventing renal allograft rejection. For this purpose, ADSCs from Lewis rats were transfected with the recombinant plasmid, pcDNA3.1(−)OX40Ig, by nucleofection. The ADSCs transduced with the plasmid (termed ADSCsOX40Ig) or untransduced ADSCs (termed ADSCsnative) were added to allostimulated mixed lymphocyte reaction (MLR) in vitro. In vivo, ADSCsOX40Ig, ADSCsnative, or PBS were administered to an allogeneic renal transplantation model, and the therapeutic effects, as well as the underlying mechanisms were examined. The results revealed that both the ADSCsnative and ADSCsOX40Ig significantly suppressed T cell proliferation and increased the percentage of CD4+CD25+ regulatory T cells in allogeneic MLR assays, with the ADSCsOX40Ig being more effective. Furthermore, the results from our in vivo experiments revealed that compared with the ADSCsnative or PBS group, the administration of autologous ADSCsOX40Ig markedly prolonged the mean survival time of renal grafts, reduced allograft rejection, and significantly downregulated the mRNA expression of intragraft interferon-γ (IFN-γ), and upregulated the mRNA expression of interleukin (IL)-10, transforming growth factor-β (TGF-β) and forkhead box protein 3 (Foxp3). The findings of our study indicate that the use of ADSCsOX40Ig is a promising strategy for preventing renal allograft rejection. This strategy provides the synergistic benefits of ADSC immune modulation and OX40-OX40L pathway blockade, and may therefore have therapeutic potential in clinical renal transplantation.
PMCID: PMC5179179  PMID: 27878248
adipose tissue-derived mesenchymal stem cells; OX40; fusion protein; rat renal transplantation; acute rejections
15.  Tanshinone IIA combined with adriamycin inhibited malignant biological behaviors of NSCLC A549 cell line in a synergistic way 
BMC Cancer  2016;16:899.
The study was designed to develop a platform to verify whether the extract of herbs combined with chemotherapy drugs play a synergistic role in anti-tumor effects, and to provide experimental evidence and theoretical reference for finding new effective sensitizers.
Inhibition of tanshinone IIA and adriamycin on the proliferation of A549, PC9 and HLF cells were assessed by CCK8 assays. The combination index (CI) was calculated with the Chou-Talalay method, based on the median-effect principle. Migration and invasion ability of A549 cells were determined by wound healing assay and transwell assay. Flow cytometry was used to detect the cell apoptosis and the distribution of cell cycles. TUNEL staining was used to detect the apoptotic cells. Immunofluorescence staining was used to detect the expression of Cleaved Caspase-3. Western blotting was used to detect the proteins expression of relative apoptotic signal pathways. CDOCKER module in DS 2.5 was used to detect the binding modes of the drugs and the proteins.
Both tanshinone IIA and adriamycin could inhibit the growth of A549, PC9, and HLF cells in a dose- and time-dependent manner, while the proliferative inhibition effect of tanshinone IIA on cells was much weaker than that of adriamycin. Different from the cancer cells, HLF cells displayed a stronger sensitivity to adriamycin, and a weaker sensitivity to tanshinone IIA. When tanshinone IIA combined with adriamycin at a ratio of 20:1, they exhibited a synergistic anti-proliferation effect on A549 and PC9 cells, but not in HLF cells. Tanshinone IIA combined with adriamycin could synergistically inhibit migration, induce apoptosis and arrest cell cycle at the S and G2 phases in A549 cells. Both groups of the single drug treatment and the drug combination up-regulated the expressions of Cleaved Caspase-3 and Bax, but down-regulated the expressions of VEGF, VEGFR2, p-PI3K, p-Akt, Bcl-2, and Caspase-3 protein. Compared with the single drug treatment groups, the drug combination groups were more statistically significant. The molecular docking algorithms indicated that tanshinone IIA could be docked into the active sites of all the tested proteins with H-bond and aromatic interactions, compared with that of adriamycin.
Tanshinone IIA can be developed as a novel agent in the postoperative adjuvant therapy combined with other anti-tumor agents, and improve the sensibility of chemotherapeutics for non-small cell lung cancer with fewer side effects. In addition, this experiment can not only provide a reference for the development of more effective anti-tumor medicine ingredients, but also build a platform for evaluating the anti-tumor effects of Chinese herbal medicines in combination with chemotherapy drugs.
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-016-2921-x) contains supplementary material, which is available to authorized users.
PMCID: PMC5116215  PMID: 27863471
NSCLC; Tanshinone IIA; Adriamycin; Synergistic effect; A549; VEGF/PI3K/Akt signal pathway
16.  The effect of the disulfideisomerase domain containing protein in the defense against polyhexamethylene biguanide of highly tolerant Acanthamoeba at the trophozoite stage 
Acanthamoeba castellanii is a free-living protozoan pathogen capable of causing a blinding keratitis and fatal granulomatous encephalitis. Current treatment generally involves an hourly application of polyhexamethylene biguanide (PHMB) over a period of several days but this is not entirely effective against all strains/isolates. The tolerance mechanisms of PHMB in Acanthamoeba cells remain unclear. In this study, we found that the mRNA expression level of disulfideisomerase domain containing protein (PDI) increased rapidly in surviving cells of the highly PHMB-tolerant Acanthamoeba castellanii strain, NCKH_D, during PHMB treatment, but not in the ATCC standard strain. After PDI-specific silencing, NCKH_D was found to be more vulnerable to PHMB treatment. The results described above show that PDI is an important gene for PHMB tolerance ability in a highly PHMB-tolerant strain of Acanthamoeba and provide a new insight for more efficient medicine development for Acanthamoeba keratitis.
Graphical abstract
Image 1
PMCID: PMC5124359  PMID: 27888770
Acanthamoeba keratitis; Polyhexamethylene biguanide; Disulfideisomerase domain containing protein
17.  Comparison of acute phase reaction and postoperative stress in pigs undergoing video-assisted thoracoscopic versus thoracotomy pneumonectomy 
Video-assisted thoracoscopic surgery (VATS) has been used for many thoracic diseases as an alternate approach to thoracotomy. The aim of this study was to compare the surgical outcome of pneumonectomy using VATS with that using thoracotomy pneumonectomy in pigs. Fourteen pigs were equally divided into two groups; one group underwent VATS and the other group underwent transthoracic pneumonectomy. We monitored pre-, intra-, and post-operative physiologic parameters, along with blood cell count, serum C-reactive protein (CRP), serum amyloid A (SAA), interleukin-6 (IL-6) and cortisol. The differences between the two approaches were analyzed.
Mean surgical time in the VATS group (160.6 ± 16.2 min) was significantly longer than that in the thoracotomy group (123.7 ± 13.2 min). In both groups, CRP and IL-6 concentrations were significantly increased at postoperative 4 h, and then gradually decreased to preoperative levels. CRP and IL-6 at postoperative day 1 were significant lower in the VATS group compared with the thoracotomy group. SAA was significantly increased at postoperative days 1 and 3 in both groups compared with preoperative levels. Cortisol was significantly increased immediately after surgery in both groups compared with preoperative levels, and was significantly higher in the thoracotomy group than the VATS group at postoperative 4 h and 1 day.
There was no difference between the two groups in physiologic parameters and blood cell count. However, the results indicate that VATS resulted in a smaller incision, less acute-phase reaction, less stress and less pain compared with thoracotomy pneumonectomy.
PMCID: PMC5101706  PMID: 27829432
VATS; Pneumonectomy; Acute-phase reaction; Body stress; Postoperative pain
18.  Five endometrial cancer risk loci identified through genome-wide association analysis 
Cheng, Timothy HT | Thompson, Deborah J | O’Mara, Tracy A | Painter, Jodie N | Glubb, Dylan M | Flach, Susanne | Lewis, Annabelle | French, Juliet D | Freeman-Mills, Luke | Church, David | Gorman, Maggie | Martin, Lynn | Hodgson, Shirley | Webb, Penelope M | Attia, John | Holliday, Elizabeth G | McEvoy, Mark | Scott, Rodney J | Henders, Anjali K | Martin, Nicholas G | Montgomery, Grant W | Nyholt, Dale R | Ahmed, Shahana | Healey, Catherine S | Shah, Mitul | Dennis, Joe | Fasching, Peter A | Beckmann, Matthias W | Hein, Alexander | Ekici, Arif B | Hall, Per | Czene, Kamila | Darabi, Hatef | Li, Jingmei | Dörk, Thilo | Dürst, Matthias | Hillemanns, Peter | Runnebaum, Ingo | Amant, Frederic | Schrauwen, Stefanie | Zhao, Hui | Lambrechts, Diether | Depreeuw, Jeroen | Dowdy, Sean C | Goode, Ellen L | Fridley, Brooke L | Winham, Stacey J | Njølstad, Tormund S | Salvesen, Helga B | Trovik, Jone | Werner, Henrica MJ | Ashton, Katie | Otton, Geoffrey | Proietto, Tony | Liu, Tao | Mints, Miriam | Tham, Emma | Consortium, CHIBCHA | Jun Li, Mulin | Yip, Shun H | Wang, Junwen | Bolla, Manjeet K | Michailidou, Kyriaki | Wang, Qin | Tyrer, Jonathan P | Dunlop, Malcolm | Houlston, Richard | Palles, Claire | Hopper, John L | Peto, Julian | Swerdlow, Anthony J | Burwinkel, Barbara | Brenner, Hermann | Meindl, Alfons | Brauch, Hiltrud | Lindblom, Annika | Chang-Claude, Jenny | Couch, Fergus J | Giles, Graham G | Kristensen, Vessela N | Cox, Angela | Cunningham, Julie M | Pharoah, Paul D P | Dunning, Alison M | Edwards, Stacey L | Easton, Douglas F | Tomlinson, Ian | Spurdle, Amanda B
Nature genetics  2016;48(6):667-674.
We conducted a meta-analysis of three endometrial cancer GWAS and two replication phases totaling 7,737 endometrial cancer cases and 37,144 controls of European ancestry. Genome-wide imputation and meta-analysis identified five novel risk loci of genome-wide significance at likely regulatory regions on chromosomes 13q22.1 (rs11841589, near KLF5), 6q22.31 (rs13328298, in LOC643623 and near HEY2 and NCOA7), 8q24.21 (rs4733613, telomeric to MYC), 15q15.1 (rs937213, in EIF2AK4, near BMF) and 14q32.33 (rs2498796, in AKT1 near SIVA1). A second independent 8q24.21 signal (rs17232730) was found. Functional studies of the 13q22.1 locus showed that rs9600103 (pairwise r2=0.98 with rs11841589) is located in a region of active chromatin that interacts with the KLF5 promoter region. The rs9600103-T endometrial cancer protective allele suppressed gene expression in vitro suggesting that regulation of KLF5 expression, a gene linked to uterine development, is implicated in tumorigenesis. These findings provide enhanced insight into the genetic and biological basis of endometrial cancer.
PMCID: PMC4907351  PMID: 27135401
19.  Factors Influencing Uptake of Rapid HIV and Hepatitis C Screening Among Drug Misusing Adult Emergency Department Patients: Implications for Future HIV/HCV Screening Interventions 
AIDS and behavior  2015;19(11):2025-2035.
In this randomized, controlled trial among 957 English- or Spanish-speaking drug misusing adult emergency department (ED) patients, we determined if a tailored brief intervention (BI) increased uptake of rapid HIV/ HCV screening, and identified factors associated with greater screening uptake. Rapid HIV/HCV screening uptake was greater in the control than the BI arm (45 vs. 38 %; p < 0.04). Screening uptake depended on elapsed study time and which research staff member offered testing. In the control arm, uptake was lowest for those spending <30 or ≥90 min in the study. In the BI arm, screening uptake generally increased over time. Tailored BI content specifically addressing participant HIV/HCV knowledge, HIV/HCV risk behaviors, or need for HIV/ HCV screening was not associated with greater screening uptake. These study findings suggested factors that should be considered when designing future ED-based screening initiatives, such as elapsed study time, who offers testing, and the content of interventions.
PMCID: PMC4600425  PMID: 26036465
HIV; Hepatitis C; Emergency medicine; Mass screening; Intervention studies; Drug abuse
20.  Synthesis and evaluation of 8,4′-dideshydroxy-leinamycin revealing new insights into the structure-activity relationship of the anticancer natural product leinamycin 
Leinamycin (LNM, 1) is a novel antitumor antibiotic produced by Streptomyces atroolivaceus S-140 and features an unusual 1,3-dioxo-1,2-dithiolane moiety that is spiro-fused to a thiazole-containing 18-membered lactam ring. The 1,3-dioxo-1,2-dithiolane moiety of LNM is essential for its antitumor activity via an episulfonium ion-mediated DNA alkylation upon reductive activation in the presence of cellular thiols. We recently isolated leinamycin E1 (LNM E1, 2) from an engineered strain S. atroolivaceus SB3033, which lacks the 1,3-dioxo-1,2-dithiolane moiety. Here we report the chemical synthesis of 8,4′-dideshydroxy-LNM (5) from 2 and determination of the cytotoxicity of 5 against selected cancer cell lines in comparison with 1; 5 exhibits comparable activity as 1 with the EC50 values between 8.21 and 275 nM. This work reveals new insight into the structure-activity relationship of LNM and highlights the synergy between metabolic pathway engineering and medicinal chemistry for natural product drug discovery.
PMCID: PMC4607584  PMID: 26071634
antitumor antibiotic; DNA alkylation; leinamycin; metabolic pathway engineering; structure-activity relationship
21.  Cistrome Data Browser: a data portal for ChIP-Seq and chromatin accessibility data in human and mouse 
Nucleic Acids Research  2016;45(Database issue):D658-D662.
Chromatin immunoprecipitation, DNase I hypersensitivity and transposase-accessibility assays combined with high-throughput sequencing enable the genome-wide study of chromatin dynamics, transcription factor binding and gene regulation. Although rapidly accumulating publicly available ChIP-seq, DNase-seq and ATAC-seq data are a valuable resource for the systematic investigation of gene regulation processes, a lack of standardized curation, quality control and analysis procedures have hindered extensive reuse of these data. To overcome this challenge, we built the Cistrome database, a collection of ChIP-seq and chromatin accessibility data (DNase-seq and ATAC-seq) published before January 1, 2016, including 13 366 human and 9953 mouse samples. All the data have been carefully curated and processed with a streamlined analysis pipeline and evaluated with comprehensive quality control metrics. We have also created a user-friendly web server for data query, exploration and visualization. The resulting Cistrome DB (Cistrome Data Browser), available online at, is expected to become a valuable resource for transcriptional and epigenetic regulation studies.
PMCID: PMC5210658  PMID: 27789702
22.  1,2Aspirin-exacerbated respiratory disease involves a cysteinyl leukotriene-driven IL-33-mediated mast cell activation pathway 
Aspirin exacerbated respiratory disease (AERD), a severe eosinophilic inflammatory disorder of the airways, involves overproduction of cysteinyl leukotrienes (cysLTs), activation of airway mast cells (MCs), and bronchoconstriction in response to nonselective cyclooxygenase inhibitors that deplete homeostatic prostaglandin (PG)E2. The mechanistic basis for MC activation in this disorder is unknown. We now demonstrate that patients with AERD have markedly increased epithelial expression of the alarmin-like cytokine IL-33 in nasal polyps, as compared to polyps from aspirin tolerant (AT) controls. The murine model of AERD, generated by dust mite priming of mice lacking microsomal PGE2 synthase (ptges−/− mice), shows a similar upregulation of IL-33 protein in the airway epithelium, along with marked eosinophilic bronchovascular inflammation. Deletion of LTC4 synthase (LTC4S), the terminal enzyme needed to generate cysLTs, eliminates the increased IL-33 content of the ptges−/− lungs and sharply reduces pulmonary eosinophilia and basal secretion of MC products. Challenges of dust mite-primed ptges−/− mice with lysine aspirin (Lys-ASA) induce IL-33-dependent MC activation and bronchoconstriction. Thus, IL-33 is a component of a cysLT-driven innate type 2 immune response that drives pathogenic MC activation and contributes substantially to AERD pathogenesis.
PMCID: PMC4592820  PMID: 26342029
23.  Efficiency of International Classification of Diseases, Ninth Revision, Billing Code Searches to Identify Emergency Department Visits for Blood or Body Fluid Exposures through a Statewide Multicenter Database 
Blood and body fluid exposures are frequently evaluated in emergency departments (EDs). However, efficient and effective methods for estimating their incidence are not yet established.
Evaluate the efficiency and accuracy of estimating statewide ED visits for blood or body fluid exposures using International Classification of Diseases, Ninth Revision (ICD-9), code searches.
Secondary analysis of a database of ED visits for blood or body fluid exposure.
EDs of 11 civilian hospitals throughout Rhode Island from January 1, 1995, through June 30, 2001.
Patients presenting to the ED for possible blood or body fluid exposure were included, as determined by prespecified ICD-9 codes.
Positive predictive values (PPVs) were estimated to determine the ability of 10 ICD-9 codes to distinguish ED visits for blood or body fluid exposure from ED visits that were not for blood or body fluid exposure. Recursive partitioning was used to identify an optimal subset of ICD-9 codes for this purpose. Random-effects logistic regression modeling was used to examine variations in ICD-9 coding practices and styles across hospitals. Cluster analysis was used to assess whether the choice of ICD-9 codes was similar across hospitals.
The PPV for the original 10 ICD-9 codes was 74.4% (95% confidence interval [CI], 73.2%–75.7%), whereas the recursive partitioning analysis identified a subset of 5 ICD-9 codes with a PPV of 89.9% (95% CI, 88.9%–90.8%) and a misclassification rate of 10.1%. The ability, efficiency, and use of the ICD-9 codes to distinguish types of ED visits varied across hospitals.
Although an accurate subset of ICD-9 codes could be identified, variations across hospitals related to hospital coding style, efficiency, and accuracy greatly affected estimates of the number of ED visits for blood or body fluid exposure.
PMCID: PMC5065064  PMID: 22561713
24.  Capsaicin mediates caspases activation and induces apoptosis through P38 and JNK MAPK pathways in human renal carcinoma 
BMC Cancer  2016;16:790.
Renal cell carcinoma (RCC) is one of the tumors most refractory to chemotherapy to date. Therefore, novel therapeutic agents are urgently needed for this disease. Capsaicin (CPS), a natural active ingredient of green and red peppers, and a ligand of transient receptor potential vanilloid type 1 (TRPV1), has been showed potential in suppression of tumorigenesis of several cancers. Nonetheless, the anti-cancer activity of CPS has never been studied in human RCC.
CCK8 analysis, LDH release activity and ROS generation analysis, flow cytometry analysis, and nuclear staining test were performed to test the influence of CPS in cultured cells in vitro, meanwhile western blot was done to uncover the precise molecular mechanisms. 786-O renal cancer xenografts were builded to investigate the antitumor activity of CPS in vivo.
We found treatment of CPS reduced proliferation of renal carcinoma cells, which could be attenuated by TRPV1 representative antagonist capsazepine (CPZ). CPS induced obvious apoptosis in renal carcinoma cells. These events were associated with substantial up-regulation of pro-apoptotic genes including c-myc, FADD, Bax and cleaved-caspase-3, -8, and -9, while down-regulation of anti-apoptotic gene Bcl2. Besides, CPS-treatment activated P38 and JNK MAPK pathways, yet P38 and JNK inhibitors afforded protection against CPS-induced apoptosis by abolishing activation of caspase-3, -8, and -9. Furthermore, CPS significantly slowed the growth of 786-O renal cancer xenografts in vivo.
Such results reveal that CPS is an efficient and potential drug for management of human RCC.
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-016-2831-y) contains supplementary material, which is available to authorized users.
PMCID: PMC5059898  PMID: 27729033
Capsaicin; Renal cell carcinoma; TRPV1; Caspases; Apoptosis; MAPK
25.  RNA binding protein Nova1 promotes tumor growth in vivo and its potential mechanism as an oncogene may due to its interaction with GABAA Receptor-γ2 
The mechanism of Nova1’s role in hepatocellular carcinoma has not been delineated. Also its interaction with GABAA receptor γ2 in HCC is unveiled. This study is aimed to make it clear the distribution, prognostic value of GABAARγ2 in human hepatocellular carcinoma. And its role in HCC tumorigenesis under the regulation of its alternative splicing factor Nova1.
Immunohistochemistry staining was used to investigate the distribution and clinical significance of GABAARγ2 protein expression in hepatocellular carcinoma. In vivo tumorigenticity test was conducted in nude mice by regulation the expression of Nova1. Later, western blot and co-immunoprecipitation were carried out to verify the interaction between Nova1 and GABAARγ2 in HCC tissue.
Immunohistochemical staining showed GABAARγ2 expression in HCC. Survival analysis showed intratumoral GABAARγ2 was an independent prognostic factor for overall survival (OS) and disease free survival (DFS). Up-regulation of Nova1 expression promotes subcutaneous HCC growth in nude mice and western blot showed the ectopic expression of Nova-1 restro-regulates the expression of GABAARγ2 and GABA. Protein level interaction of GABAARγ2 and Nova-1 was evidenced by co-immunoprecipitation.
Nova1 interacts with GABAARγ2 not only in CNS but also in HCC. Nova1’s potential mechanism as an oncogene may due to its interaction with GABAA Rγ2. A better understanding of the mechanism of Nova1 for HCC progression provides a novel target for an optimal immunotherapy against this fatal malignancy.
PMCID: PMC5062898  PMID: 27733149
Nova1; GABAA Receptor-γ2; Oncogene; RNA binding protein

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