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Find video protocols related to scientific articles indexed in Pubmed.
[Role of SPHK1 Regulates Multi-drug Resistance of Small Cell Lung Cancer?and Its Clinical Significance].
Zhongguo Fei Ai Za Zhi
PUBLISHED: 11-19-2014
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Lung cancer is the leading cause of cancer-related deaths worldwide. Approximately 15% of all histological types consist of small cell lung cancer (SCLC). Chemotherapy is one of the major treatment method. Though the current first-line standard chemotherapy regimen for SCLC is active in most SCLC cases, however the disease recurs shortly after the first successful treatment with multi-drug resistance (MDR) phenotype. Our previously study showed that SPHK1 was associated with MDR in SCLC. The aim of this study is to investigate the role of sphingosine kinase 1 (SPHK1) showed in small cell lung multi-drug resistance.
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Germline mutation in BRCA1 or BRCA2 and ten-year survival for women diagnosed with epithelial ovarian cancer.
Clin. Cancer Res.
PUBLISHED: 11-16-2014
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Purpose:To analyse the effect of germline mutations in BRCA1 and BRCA2 on mortality in ovarian cancer patients up to ten years after diagnosis. Experimental Design:We used unpublished survival time data for 2,242 patients from two case-control studies and extended survival-time data for 4,314 patients from previously reported studies. All participants had been screened for deleterious germline mutations in BRCA1 and BRCA2. Survival time was analysed for the combined data using Cox proportional hazard models with BRCA1 and BRCA2 as time-varying covariates. Competing risks were analysed using Fine and Gray model. Results: The combined 10-year overall survival was 30% (95% CI, 28%-31%) for non-carriers, 25% (95% CI, 22%-28%) for BRCA1 carriers, and 35% (95% CI, 30%-41%) for BRCA2 carriers. The hazard ratio for BRCA1 was 0.53 at time zero and increased over time becoming greater than one at 4.8 years. For BRCA2, the hazard ratio was 0.42 at time zero and increased over time (predicted to become greater than one at 10.5 years). The results were similar when restricted to 3,202 patients with high-grade serous tumors, and to ovarian cancer specific mortality. Conclusions: BRCA1/2 mutations are associated with better short-term survival, but this advantage decreases over time and, in BRCA1 carriers is eventually reversed. This may have important implications for therapy of both primary and relapsed disease and for analysis of long-term survival in clinical trials of new agents, particularly those that are effective in BRCA1/2 mutation carriers.
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MicroRNA-26b Functions as a Pro-Apoptotic Factor in Porcine Follicular Granulosa Cells by Targeting Sma-and Mad-Related Protein 4.
Biol. Reprod.
PUBLISHED: 11-15-2014
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Sma-and Mad-related protein 4 (SMAD4) is the central mediator of the transforming growth factor beta signaling pathway and is closely related to mammalian reproductive ability and the development of ovarian follicles. However, little is currently known about the role of SMAD4 in mammalian follicular granulosa cell (GC) apoptosis or its regulation by miRNAs. Here, we found that the porcine SMAD4 protein was expressed at high levels in GCs and oocytes from primary, preantral, and antral follicles, and only slightly expressed in theca cells; its expression level was down-regulated in apoptotic ovarian GCs, suggesting that SMAD4 may be involved in ovary development and selection. Overexpression and knockdown of SMAD4 increased the proliferation and apoptosis of cultured porcine GCs, respectively. In addition, the use of microRNA mimics and luciferase reporter assays revealed that microRNA-26b (miR-26b) functions as a pro-apoptotic factor in porcine follicular GCs by targeting the 3'-UTR of the SMAD4 gene. Overexpression of miR-26b in follicular GCs suppressed SMAD4 mRNA and protein levels, resulting in down-regulation of the anti-apoptotic BCL-2 gene and the promotion of GC apoptosis. Furthermore, transforming growth factor beta 1 (TGF-beta1) down-regulates miR-26b expression in porcine GCs. Taken together, these data suggest that SMAD4 plays a critical role in porcine follicular GC apoptosis and follicular atresia, and that miR-26b may have a pro-apoptotic role in GCs by regulating the expression of SMAD4 in the transforming growth factor beta signaling pathway.
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Fe-promoted radical cyanomethylation/arylation of arylacrylamides to access oxindoles via cleavage of the sp(3) C-H of acetonitrile and the sp(2) C-H of the phenyl group.
Org. Biomol. Chem.
PUBLISHED: 11-13-2014
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Radical cyanomethylation/arylation of arylacrylamides to access oxindoles with acetonitrile as the radical precursor is described. This reaction involves dual C-H bond functionalization, including the sp(3) C-H of acetonitrile and the sp(2) C-H of the phenyl group. A variety of functional groups, such as methoxy, ethyloxy carbonyl, chloro, bromo, iodo, nitro, trifluoromethoxy and trifluoromethyl groups, are well tolerated.
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Computational studies on the binding mechanism between triazolone inhibitors and Chk1 by molecular docking and molecular dynamics.
Mol Biosyst
PUBLISHED: 11-06-2014
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Chk1, a serine/threonine protein kinase that participates in transducing DNA damage signals, is an attractive target due to its involvement in tumor initiation and progression. As a novel Chk1 inhibitor, the triazolone's bioactivity mechanism is not clear. In this study, we carried out an integrated computational study that combines molecular docking, molecular dynamics (MD) simulations, and binding free energy calculations to identify the key factors necessary for the bioactivities. With the aim of discerning the structural features that affect the inhibitory activity of triazolones, , a Chk1 inhibitor that reached the clinical stage, was also used as a reference for simulations. A comparative analysis of the triazolone inhibitors at the molecular level offers valuable insight into the structural and energetic properties. A general feature is that all the studied inhibitors bind in the pocket characterized by residues Leu14, Val22, Ala35, Glu84, Tyr85, Cys86, and Leu136 of Chk1. Moreover, introducing hydrophobic groups into triazolone inhibitors is favorable for binding to Chk1, which is corroborated by residue Leu136 with a relatively large difference in the contribution between and five triazolones to the total binding free energies. A hydrogen bond between the polar hydrogen atoms at R1 and Cys86 can facilitate proper placement of the inhibitor in the binding pocket of Chk1 that favors binding. However, the introduction of hydrophilic groups into the R2 position diminishes binding affinity. The information provided by this research is of benefit for further rational design of novel promising inhibitors of Chk1.
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Short-Chain Fatty Acids Enhance Adipocyte Differentiation in the Stromal Vascular Fraction of Porcine Adipose Tissue.
J. Nutr.
PUBLISHED: 10-15-2014
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Short-chain fatty acids (SCFAs), including acetate, propionate, and butyrate, are the main products of microbial fermentation in the gut and might mediate some of the effects of gut microbiota and nutrition on development, metabolism, and pathogenesis of obesity and other diseases.
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Transmission of H7N9 influenza virus in mice by different infective routes.
Virol. J.
PUBLISHED: 10-03-2014
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On 19 February 2013, the first patient infected with a novel influenza A H7N9 virus from an avian source showed symptoms of sickness. More than 349 laboratory-confirmed cases and 109 deaths have been reported in mainland China since then. Laboratory-confirmed, human-to-human H7N9 virus transmission has not been documented between individuals having close contact; however, this transmission route could not be excluded for three families. To control the spread of the avian influenza H7N9 virus, we must better understand its pathogenesis, transmissibility, and transmission routes in mammals. Studies have shown that this particular virus is transmitted by aerosols among ferrets.
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Raman scattering and plasmonic photocatalysis of single particles of NaYF4:Yb,Er@Ag under near-infrared laser excitation.
Analyst
PUBLISHED: 10-01-2014
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This study has investigated the plasmonic photocatalytic ability of silver nanoparticles (Ag NPs) and the significantly improved Raman achieved by decorating them on a single NaYF4:Yb,Er upconversion (UC) microcrystal under near-infrared excitation. This points to new applications for UC-noble metal composites and promises a novel method for constructing SERS-active nanostructures.
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Iridium-catalyzed phosphoramidation of arene C-H bonds with phosphoryl azide.
J. Org. Chem.
PUBLISHED: 09-23-2014
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An iridium-catalyzed phosphoramidation of arene C-H bonds with phosphoryl azide as the amino source is described. The direct C-H phosphoramidation of arenes bearing pyridinyl, pyrazoyl, and quinolinyl as the directing group has good functional group tolerance and occurs smoothly under mild conditions, providing N-aryl phosphoramidates in good yields.
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The clinical research of the endoscopic sequential treatment for patients with intermediate-advanced esophageal cancer: a randomized clinical trial.
Med. Oncol.
PUBLISHED: 09-21-2014
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We tried to find an ideal therapeutic regimen for patients with advanced esophageal cancer. Totally 240 patients with advanced esophageal cancer were randomly divided into experimental group (endoscopic sequential treatment, 126 cases) and control group (traditional treatment, 114 cases) with a 2-year follow-up period. The experimental group was randomly divided into three subgroups: group A: local chemotherapeutic drug injection with ordinary metal stent implantation; group B: local chemotherapeutic drug injection with iodine-125 particle implantation; and group C: radiofrequency (RF) therapy with ordinary metal stent group. The control group was also randomly divided into three subgroups: group D: local chemotherapeutic drug injection group; group E: RF therapy group; and group F: common metal stent implantation group. The survival rate, survival quality, adverse reactions, and complications were compared among these groups. A significant improvement of curative effect was found in the experimental group. Group A and B had higher survival rate and survival quality, and lower esophagotracheal fistula incidence and metastasis rate, compared with group C. There was no significant difference in survival rate between group A and group B, while the quality of life was higher in group B than in group A. While patients in group B had lower esophagotracheal fistula incidence and metastasis rate comparing with group A. Local chemotherapeutic drug injection combined with iodine-125 particle stent might be an effective sequential treatment to improve the life quality of advanced esophageal cancer patients.
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EZH2 is essential for development of mouse preimplantation embryos.
Reprod. Fertil. Dev.
PUBLISHED: 07-30-2014
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Enhancer of zeste homologue 2 (Ezh2) is essential for the development of the early mouse preimplantation embryo. Loss of Ezh2 results in embryonic lethality in mice. Ezh2-deficient embryos display impaired outgrowth potential, defective establishment of Ezh2-null embryonic stem (ES) cells and adherence and differentiation of the trophoblast layer into giant cells. We investigated if Ezh2 controls the fate of embryos at an earlier stage by treating with cycloheximide (CHX) or microinjecting short interfering RNA (siRNA) to restrict embryonic Ezh2 expression during preimplantation. CHX inhibited de novo EZH2 protein synthesis in zygotes, suggesting that EZH2 requires de novo synthesis during post-fertilisation stages. We found that loss of Ezh2 at the pronuclear stage caused severe growth retardation and reduced blastocyst formation. Expression of the pluripotency-associated markers Oct4, Sox2 and Nanog were significantly decreased in embryos that had been injected with Ezh2 siRNA. In addition, Ezh2 loss induced upregulated expression of genes related to the differentiation of germ layers, including Gata6, Hoxb1 and Hand1. Finally, apoptosis was increased in the blastocyst embryos with Ezh2 knockdown. Modification of histone H3-Lysine 27 de-methylation and tri-methylation (H3K27me2/3) was strongly reduced in Ezh2 siRNA embryos. We conclude that Ezh2 is essential for early preimplantation embryo development through the regulation of epigenetic modification and apoptosis.
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Circulating Epstein-Barr virus microRNAs miR-BART7 and miR-BART13 as biomarkers for nasopharyngeal carcinoma diagnosis and treatment.
Int. J. Cancer
PUBLISHED: 07-09-2014
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More than 75% of nasopharyngeal carcinoma (NPC) patients have already developed local or regional spread at diagnosis, which hampers effective treatment and results in a poor prognosis. It is essential to characterize more sensitive and specific biomarkers for screening of high risk individuals and assessment of NPC treatment effectiveness. NPC is an Epstein-Barr virus (EBV) associated tumor in which only a few viral proteins but more than 20 BamHI A rightward transcripts (BART) microRNAs are detected, at abundant levels. We hypothesized that these BART microRNAs may be novel biomarkers for NPC. Systematic analysis of EBV BART microRNA expression profiles in EBV latently infected Mutu I and Mutu III cell lines, EBV-harboring NPC and noncancerous NP cells found that miR-BART3, miR-BART7 and miR-BART13 microRNAs are highly expressed and regularly secreted into the extracellular environment of NPC cells. These BART microRNAs were evaluated for used as potential NPC biomarkers. Analysis of plasma specimens obtained from NPC patients (n?=?89), and healthy (n?=?28) and non-NPC tumor patient controls (n?=?18) found levels of both miR-BART7 and miR-BART13, but not miR-BART3, to be distinctly presence among NPC patients, with elevated levels being particularly apparent among patients with advanced disease. Receiver operating characteristic curve analysis combining miR-BART7 and miR-BART13 levels produces a 90% predictive value for the presence of NPC. Analysis of 41 NPC patients before and after radiotherapy showed that miR-BART7 and miR-BART13, but not miR-BART3, were diminished after treatment. These results indicate that EBV microRNAs, miR-BART7 and miR-BART13, may constitute useful new serological biomarkers for diagnosis of NPC and prediction of treatment efficacy.
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High-sensitivity temperature sensor based on a droplet-like fiber circle.
Appl Opt
PUBLISHED: 07-01-2014
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A low-cost yet high-sensitivity temperature fiber sensor is proposed and demonstrated in this paper. A single-mode fiber with coating is simply bent in a droplet-like circle with a radius of several millimeters. The strong bending induces mode interferences between the silica core mode and the excited modes propagating in the polymer coating. Many resonant dips were observed in the transmission spectra and are found to shift to a shorter wavelength with the increase of environmental temperature. Our linear fitting result of the experimental data shows that the proposed sensor presents high temperature sensitivity up to -3.102??nm/°C, which is even comparable with sensors based on selective liquid-filled photonic crystal fibers. Such high temperature sensitivity results from the large thermo-optical coefficient difference between the silica core and the polymer coating. The influence of a circle radius to the sensitivities is also discussed.
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Metabolic control of oocyte development: linking maternal nutrition and reproductive outcomes.
Cell. Mol. Life Sci.
PUBLISHED: 06-22-2014
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Obesity, diabetes, and related metabolic disorders are major health issues worldwide. As the epidemic of metabolic disorders continues, the associated medical co-morbidities, including the detrimental impact on reproduction, increase as well. Emerging evidence suggests that the effects of maternal nutrition on reproductive outcomes are likely to be mediated, at least in part, by oocyte metabolism. Well-balanced and timed energy metabolism is critical for optimal development of oocytes. To date, much of our understanding of oocyte metabolism comes from the effects of extrinsic nutrients on oocyte maturation. In contrast, intrinsic regulation of oocyte development by metabolic enzymes, intracellular mediators, and transport systems is less characterized. Specifically, decreased acid transport proteins levels, increased glucose/lipid content and elevated reactive oxygen species in oocytes have been implicated in meiotic defects, organelle dysfunction and epigenetic alteration. Therefore, metabolic disturbances in oocytes may contribute to the diminished reproductive potential experienced by women with metabolic disorders. In-depth research is needed to further explore the underlying mechanisms. This review also discusses several approaches for metabolic analysis. Metabolomic profiling of oocytes, the surrounding granulosa cells, and follicular fluid will uncover the metabolic networks regulating oocyte development, potentially leading to the identification of oocyte quality markers and prevention of reproductive disease and poor outcomes in offspring.
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Study on the agonists for the human Toll-like receptor-8 by molecular modeling.
Mol Biosyst
PUBLISHED: 06-12-2014
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Toll-like receptor-8 agonists could be promising candidates for vaccine adjuvants, especially for neonatal vaccines. In this study, we established reliable models and explored valuable information which could explain the known experimental facts at the molecular level. Firstly, we divided the whole dataset into four splits and obtained many dependable models based on the simplified molecular input line entry system (SMILES). Secondly, the whole dataset was divided into three splits and other reliable comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) models were established. Thirdly, we validated the prediction ability of these models using various validation methods for the test set. Lastly, for a better understanding of the binding modes between agonists and Toll-like receptor-8, molecular docking was applied to reveal the structural factors that impact the activity of agonists towards Toll-like receptor-8. Furthermore, molecular dynamics simulation was employed to further validate the docking results. The results obtained from molecular modeling support each other, which not only provides models to predict the activities of agonists but also leads to a better understanding of the essential features that should be considered when designing novel agonists with desired activities.
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MicroRNA-21 Attenuates Renal Ischemia Reperfusion Injury via Targeting Caspase Signaling in Mice.
Am. J. Nephrol.
PUBLISHED: 05-28-2014
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MicroRNAs (miR) have come into focus as powerful regulators of gene expression and potential diagnostic tools during renal ischemia reperfusion injury (IRI). The aim of this study was to investigate the molecular regulation and function of miR-21, and to analyze the relationship between caspases and miR-21 expression levels in an experimental model of renal IRI.
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Radical arylalkoxycarbonylation of 2-isocyanobiphenyl with carbazates: dual C-C bond formation toward phenanthridine-6-carboxylates.
J. Org. Chem.
PUBLISHED: 05-13-2014
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A sequential oxidative radical alkoxycarbonylation and aromatization of 2-isocyanobiphenyl with carbazates was developed to furnish phenanthridine-6-carboxylates. Various functional groups such as methoxy, chloro, fluoro, trifluoromethoxy, and trifluoromethyl groups were tolerated well under the reaction conditions. The sequential radical addition-cyclization strategy represents a practical route to access phenanthridine-6-carboxylates.
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An important amino acid in nucleoprotein contributes to influenza A virus replication by interacting with polymerase PB2.
Virology
PUBLISHED: 04-16-2014
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The nucleoprotein (NP) of influenza A virus plays a critical role in the formation of viral ribonucleoprotein (vRNP) complex. However, it remains unclear which key residues in NP are associated with the assembly of vRNP and contribute to virus replication. Here, a highly conserved aspartic acid at residue 88 (D88) of NP was identified by molecular docking of NP with the Fv region of a broad-spectrum anti-NP mAb 19C10 and further demonstrated to be an important residue contributes to the RNP activity, virus growth in MDCK cells and replication in lungs of infected mice by comparing recombinant wild-type A/WSN/1933 virus to the mutant virus that contains an alanine instead of aspartic acid at NP residue 88. D88 was also predicted to interact with PB2 by molecular docking and further verified by immunoprecipitation. These findings provide new information for understanding the interaction between NP and other polymerase subunits in virus replication.
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Variation in NF-?B signaling pathways and survival in invasive epithelial ovarian cancer.
Matthew S Block, Bridget Charbonneau, Robert A Vierkant, Zachary Fogarty, William R Bamlet, Paul D P Pharoah, , Mary Anne Rossing, Daniel Cramer, Celeste Leigh Pearce, Joellen Schildkraut, Usha Menon, Susanne K Kjaer, Douglas A Levine, Jacek Gronwald, Hoda Anton Culver, Alice S Whittemore, Beth Y Karlan, Diether Lambrechts, Nicolas Wentzensen, Jolanta Kupryjanczyk, Jenny Chang-Claude, Elisa V Bandera, Estrid Hogdall, Florian Heitz, Stanley B Kaye, Peter A Fasching, Ian Campbell, Marc T Goodman, Tanja Pejovic, Yukie T Bean, Laura E Hays, Galina Lurie, Diana Eccles, Alexander Hein, Matthias W Beckmann, Arif B Ekici, James Paul, Robert Brown, James M Flanagan, Philipp Harter, Andreas du Bois, Ira Schwaab, Claus K Hogdall, Lene Lundvall, Sara H Olson, Irene Orlow, Lisa E Paddock, Anja Rudolph, Ursula Eilber, Agnieszka Dansonka-Mieszkowska, Iwona K Rzepecka, Izabela Ziolkowska-Seta, Louise A Brinton, Hannah Yang, Montserrat Garcia-Closas, Evelyn Despierre, Sandrina Lambrechts, Ignace Vergote, Christine S Walsh, Jenny Lester, Weiva Sieh, Valerie McGuire, Joseph H Rothstein, Argyrios Ziogas, Jan Lubiński, Cezary Cybulski, Janusz Menkiszak, Allan Jensen, Simon A Gayther, Susan J Ramus, Aleksandra Gentry-Maharaj, Andrew Berchuck, Anna H Wu, Malcolm C Pike, David Van Den Berg, Kathryn L Terry, Allison F Vitonis, Starr M Ramirez, David N Rider, Keith L Knutson, Thomas A Sellers, Catherine M Phelan, Jennifer A Doherty, Sharon E Johnatty, Anna deFazio, Honglin Song, Jonathan Tyrer, Kimberly R Kalli, Brooke L Fridley, Julie M Cunningham, Ellen L Goode.
Cancer Epidemiol. Biomarkers Prev.
PUBLISHED: 04-16-2014
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Survival in epithelial ovarian cancer (EOC) is influenced by the host immune response, yet the key genetic determinants of inflammation and immunity that affect prognosis are not known. The nuclear factor-?B (NF-?B) transcription factor family plays an important role in many immune and inflammatory responses, including the response to cancer. We studied common inherited variation in 210 genes in the NF-?B family in 10,084 patients with invasive EOC (5,248 high-grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous) from the Ovarian Cancer Association Consortium. Associations between genotype and overall survival were assessed using Cox regression for all patients and by major histology, adjusting for known prognostic factors and correcting for multiple testing (threshold for statistical significance, P < 2.5 × 10(-5)). Results were statistically significant when assessed for patients of a single histology. Key associations were with caspase recruitment domain family, member 11 (CARD11) rs41324349 in patients with mucinous EOC [HR, 1.82; 95% confidence interval (CI), 1.41-2.35; P = 4.13 × 10(-6)] and tumor necrosis factor receptor superfamily, member 13B (TNFRSF13B) rs7501462 in patients with endometrioid EOC (HR, 0.68; 95% CI, 0.56-0.82; P = 2.33 × 10(-5)). Other associations of note included TNF receptor-associated factor 2 (TRAF2) rs17250239 in patients with high-grade serous EOC (HR, 0.84; 95% CI, 0.77-0.92; P = 6.49 × 10(-5)) and phospholipase C, gamma 1 (PLCG1) rs11696662 in patients with clear cell EOC (HR, 0.43; 95% CI, 0.26-0.73; P = 4.56 × 10(-4)). These associations highlight the potential importance of genes associated with host inflammation and immunity in modulating clinical outcomes in distinct EOC histologies.
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The contribution of deleterious germline mutations in BRCA1, BRCA2 and the mismatch repair genes to ovarian cancer in the population.
Hum. Mol. Genet.
PUBLISHED: 04-12-2014
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The aim of this study was to estimate the contribution of deleterious mutations in BRCA1, BRCA2, MLH1, MSH2, MSH6 and PMS2 to invasive epithelial ovarian cancer (EOC) in the population. The coding sequence and splice site boundaries of all six genes were amplified in germline DNA from 2240 invasive EOC cases and 1535 controls. Barcoded fragment libraries were sequenced using the Illumina GAII or HiSeq and sequence data for each subject de-multiplexed prior to interpretation. GATK and Annovar were used for variant detection and annotation. After quality control 2222 cases (99.2%) and 1528 controls (99.5%) were included in the final analysis. We identified 193 EOC cases (8.7%) carrying a deleterious mutation in at least one gene compared with 10 controls (0.65%). Mutations were most frequent in BRCA1 and BRCA2, with 84 EOC cases (3.8%) carrying a BRCA1 mutation and 94 EOC cases (4.2%) carrying a BRCA2 mutation. The combined BRCA1 and BRCA2 mutation prevalence was 11% in high-grade serous disease. Seventeen EOC cases carried a mutation in a mismatch repair gene, including 10 MSH6 mutation carriers (0.45%) and 4 MSH2 mutation carriers (0.18%). At least 1 in 10 women with high-grade serous EOC has a BRCA1 or BRCA2 mutation. The development of next generation sequencing technologies enables rapid mutation screening for multiple susceptibility genes at once, suggesting that routine clinical testing of all incidence cases should be considered.
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Three-dimensional and time-ordered surface-enhanced Raman scattering hotspot matrix.
J. Am. Chem. Soc.
PUBLISHED: 03-28-2014
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The "fixed" or "flexible" design of plasmonic hotspots is a frontier area of research in the field of surface-enhanced Raman scattering (SERS). Most reported SERS hotspots have been shown to exist in zero-dimensional point-like, one-dimensional linear, or two-dimensional planar geometries. Here, we demonstrate a novel three-dimensional (3D) hotspot matrix that can hold hotspots between every two adjacent particles in 3D space, simply achieved by evaporating a droplet of citrate-Ag sols on a fluorosilylated silicon wafer. In situ synchrotron-radiation small-angle X-ray scattering (SR-SAXS), combined with dark-field microscopy and in situ micro-UV, was employed to explore the evolution of the 3D geometry and plasmonic properties of Ag nanoparticles in a single droplet. In such a droplet, there is a distinct 3D geometry with minimal polydispersity of particle size and maximal uniformity of interparticle distance, significantly different from the dry state. According to theoretical simulations, the liquid adhesive force promotes a closely packed assembly of particles, and the interparticle distance is not fixed but can be balanced in a small range by the interplay of the van der Waals attraction and electrostatic repulsion experienced by a particle. The "trapping well" for immobilizing particles in 3D space can result in a large number of hotspots in a 3D geometry. Both theoretical and experimental results demonstrate that the 3D hotspots are predictable and time-ordered in the absence of any sample manipulation. Use of the matrix not only produces giant Raman enhancement at least 2 orders of magnitude larger than that of dried substrates, but also provides the structural basis for trapping molecules. Even a single molecule of resonant dye can generate a large SERS signal. With a portable Raman spectrometer, the detection capability is also greatly improved for various analytes with different natures, including pesticides and drugs. This 3D hotspot matrix overcomes the long-standing limitations of SERS for the ultrasensitive characterization of various substrates and analytes and promises to transform SERS into a practical analytical technique.
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3D-QSAR modeling and molecular docking study on Mer kinase inhibitors of pyridine-substituted pyrimidines.
Mol. Divers.
PUBLISHED: 03-21-2014
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Mer kinase is a novel therapeutic target for many cancers, and overexpression of Mer receptor tyrosine kinase has been observed in several kinds of tumors. To deeply understand the structure-activity correlation of a series of pyridine/pyrimidine analogs as potent Mer inhibitors, a combined molecular docking and three-dimensional quantitative structure-activity relationship modeling was carried out. A comparative molecular similarity indices analysis model was developed based on the maximum common substructure alignment. The optimum model exhibited statistically significant results: the cross-validated correlation coefficient [Formula: see text] was 0.599, and non-cross-validated [Formula: see text] value was 0.984. Furthermore, the results of internal validation such as bootstrapping, Y-randomization as well as external validation (the external predictive correlation coefficient [Formula: see text] confirmed the rationality and good predictive ability of the model. Using the crystal structure of Mer kinase, the selected pyridine/pyrimidine compounds were docked into the enzyme active site. Some key amino acid residues were determined, and hydrogen bonding and hydrophobic interactions between Mer kinase and inhibitors were identified. The satisfactory results from this study may aid in the research and development of novel potent Mer kinase inhibitors.
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Disruption of the myostatin gene in porcine primary fibroblasts and embryos using zinc-finger nucleases.
Mol. Cells
PUBLISHED: 03-19-2014
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Myostatin represses muscle growth by negatively regulating the number and size of muscle fibers. Myostatin lossof- function can result in the double-muscling phenotype and increased muscle mass. Thus, knockout of myostatin gene could improve the quality of meat from mammals. In the present study, zinc finger nucleases, a useful tool for generating gene knockout animals, were designed to target exon 1 of the myostatin gene. The designed ZFNs were introduced into porcine primary fibroblasts and early implantation embryos via electroporation and microinjection, respectively. Mutations around the ZFNs target site were detected in both primary fibroblasts and blastocysts. The proportion of mutant fibroblast cells and blastocyst was 4.81% and 5.31%, respectively. Thus, ZFNs can be used to knockout myostatin in porcine primary fibroblasts and early implantation embryos.
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NF90 exerts antiviral activity through regulation of PKR phosphorylation and stress granules in infected cells.
J. Immunol.
PUBLISHED: 03-12-2014
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NF90 was shown to exhibit broad antiviral activity against several viruses, but detailed mechanisms remain unclear. In this study, we examined the molecular basis for the inhibitory effect of NF90 on virus replication mediated through protein kinase (PKR)-associated translational regulation. We first verified the interaction between NF90 and PKR in mammalian cells and showed that NF90 interacts with PKR through its C-terminal and that the interaction is independent of NF90 RNA-binding properties. We further showed that knockdown of NF90 resulted in significantly lower levels of PKR phosphorylation in response to dsRNA induction and influenza virus infection. We also showed that high concentrations of NF90 exhibit negative regulatory effects on PKR phosphorylation, presumably through competition for dsRNA via the C-terminal RNA-binding domain. PKR activation is essential for the formation of stress granules in response to dsRNA induction. Our results showed that NF90 is a component of stress granules. In NF90-knockdown cells, dsRNA treatment induced significantly lower levels of stress granules than in control cells. Further evidence for an NF90-PKR antiviral pathway was obtained using an NS1 mutated influenza A virus specifically attenuated in its ability to inhibit PKR activation. This mutant virus replicated indistinguishably from wild-type virus in NF90-knockdown cells, but not in scrambled control cells or Vero cells, indicating that NF90's antiviral function occurs through interaction with PKR. Taken together, these results reveal a yet-to-be defined host antiviral mechanism in which NF90 upregulation of PKR phosphorylation restricts virus infection.
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Unravelling the relationship between Raman enhancement and photocatalytic activity on single anisotropic Au microplates.
Chemistry
PUBLISHED: 02-28-2014
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Anisotropic noble-metal structures are attracting increasing attention because of interesting size- and shape-dependent properties and have emerging applications in the fields of optics and catalysis. However, it remains a significant challenge to overcome chemical contributions and acquire molecular insight into the relationship between Raman enhancement and photocatalytic activity. This study gives visualized experimental evidence of the anisotropic spatial distribution of Raman signals and photocatalytic activity at the level of single nanometer-thin Au microtriangles and microhexagons. Theoretical simulations indicate an anisotropic spatial distribution and sharpness-dependent strength of the electric-field enhancement. Analysis by using statistical surface-enhanced Raman scattering (SERS) supports this view, that is, Raman enhancement is on the order of corner>edge>face for a single microplate, but SERS measurements at different depths of focus also imply a concentration-dependent feature of SERS signals, especially at the corners and edges. Similarly, the SERS signals of product molecules in plasmonic photocatalysis also exhibit asymmetrical strengths at different corners of the same microplate. However, by examining the variations in the relative intensities of the SERS peaks, the difference in the photocatalytic activities at the corners, edges, and faces has been successfully calculated and is highly consistent with electric-field simulations, thus indicating that an increased number of molecules adsorbed at specific sites does not necessarily lead to a higher conversion ratio in noble-metal photocatalysis. Our strategy weakens the assumed impact of plasmonic local heating and, to a certain extent, excludes the influence of concentration effects and chemical contributions in noble-metal photocatalysis, thus clearly profiling plasmon-related characteristics. This study also promises a new research direction to understand the enhancement mechanism of SERS-active structures.
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Unique reassortant of influenza A(H7N9) virus associated with severe disease emerging in Hong Kong.
J. Infect.
PUBLISHED: 02-19-2014
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Human infections caused by avian influenza virus A(H7N9) re-emerged in late 2013. We reported the first Hong Kong patient without risk factors for severe A(H7N9) disease.
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Dynamic behavior of lymphocyte subgroups correlates with clinical outcomes in human H7N9 infection.
J. Infect.
PUBLISHED: 02-17-2014
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To investigate peripheral blood lymphocyte subgroups response to the H7N9 virus and identify potential correlations between the anti-viral response and clinical outcomes in infected patients.
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Targeted Activation of Human V?9V?2-T Cells Controls Epstein-Barr Virus-Induced B Cell Lymphoproliferative Disease.
Cancer Cell
PUBLISHED: 02-14-2014
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Epstein-Barr virus-induced lymphoproliferative disease (EBV-LPD) after transplantation remains a serious and life-threatening complication. Herein we showed that the aminobisphosphonate pamidronate-expanded human V?9V?2-T cells efficiently killed EBV-transformed autologous lymphoblastoid B cell lines (EBV-LCL) through ?/?-TCR and NKG2D receptor triggering and Fas and TRAIL engagement. By inoculation of EBV-LCL in Rag2(-/-)?c(-/-) mice and humanized mice, we established lethal EBV-LPD with characteristics close to those of the human disease. Adoptive transfer of pamidronate-expanded V?9V?2-T cells alone effectively prevented EBV-LPD in Rag2(-/-)?c(-/-) mice and induced EBV-LPD regression in EBV(+) tumor-bearing Rag2(-/-)?c(-/-) mice. Pamidronate treatment inhibited EBV-LPD development in humanized mice through selective activation and expansion of V?9V?2-T cells. This study provides proof-of-principle for a therapeutic approach using pamidronate to control EBV-LPD through V?9V?2-T cell targeting.
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TRIB3 alters endoplasmic reticulum stress-induced ?-cell apoptosis via the NF-?B pathway.
Metab. Clin. Exp.
PUBLISHED: 02-06-2014
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To examine the effect of TRIB3 on endoplasmic reticulum stress induced ?-cell apoptosis and to investigate the mechanism with a specific emphasis on the role of NF-?B pathway.
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Consortium analysis of gene and gene-folate interactions in purine and pyrimidine metabolism pathways with ovarian carcinoma risk.
Linda E Kelemen, Kathryn L Terry, Marc T Goodman, Penelope M Webb, Elisa V Bandera, Valerie McGuire, Mary Anne Rossing, Qinggang Wang, Ed Dicks, Jonathan P Tyrer, Honglin Song, Jolanta Kupryjanczyk, Agnieszka Dansonka-Mieszkowska, Joanna Plisiecka-Halasa, Agnieszka Timorek, Usha Menon, Aleksandra Gentry-Maharaj, Simon A Gayther, Susan J Ramus, Steven A Narod, Harvey A Risch, John R McLaughlin, Nadeem Siddiqui, Rosalind Glasspool, James Paul, Karen Carty, Jacek Gronwald, Jan Lubiński, Anna Jakubowska, Cezary Cybulski, Lambertus A Kiemeney, Leon F A G Massuger, Anne M Van Altena, Katja K H Aben, Sara H Olson, Irene Orlow, Daniel W Cramer, Douglas A Levine, Maria Bisogna, Graham G Giles, Melissa C Southey, Fiona Bruinsma, Susanne K Kjaer, Estrid Høgdall, Allan Jensen, Claus K Høgdall, Lene Lundvall, Svend-Aage Engelholm, Florian Heitz, Andreas du Bois, Philipp Harter, Ira Schwaab, Ralf Bützow, Heli Nevanlinna, Liisa M Pelttari, Arto Leminen, Pamela J Thompson, Galina Lurie, Lynne R Wilkens, Diether Lambrechts, Els Van Nieuwenhuysen, Sandrina Lambrechts, Ignace Vergote, Jonathan Beesley, , Peter A Fasching, Matthias W Beckmann, Alexander Hein, Arif B Ekici, Jennifer A Doherty, Anna H Wu, Celeste L Pearce, Malcolm C Pike, Daniel Stram, Jenny Chang-Claude, Anja Rudolph, Thilo Dörk, Matthias Dürst, Peter Hillemanns, Ingo B Runnebaum, Natalia Bogdanova, Natalia Antonenkova, Kunle Odunsi, Robert P Edwards, Joseph L Kelley, Francesmary Modugno, Roberta B Ness, Beth Y Karlan, Christine Walsh, Jenny Lester, Sandra Orsulic, Brooke L Fridley, Robert A Vierkant, Julie M Cunningham, Xifeng Wu, Karen Lu, Dong Liang, Michelle A T Hildebrandt, Rachel Palmieri Weber, Edwin S Iversen, Shelley S Tworoger, Elizabeth M Poole, Helga B Salvesen, Camilla Krakstad, Line Bjorge, Ingvild L Tangen, Tanja Pejovic, Yukie Bean, Melissa Kellar, Nicolas Wentzensen, Louise A Brinton, Jolanta Lissowska, Montserrat Garcia-Closas, Ian G Campbell, Diana Eccles, Alice S Whittemore, Weiva Sieh, Joseph H Rothstein, Hoda Anton-Culver, Argyrios Ziogas, Catherine M Phelan, Kirsten B Moysich, Ellen L Goode, Joellen M Schildkraut, Andrew Berchuck, Paul D P Pharoah, Thomas A Sellers, Angela Brooks-Wilson, Linda S Cook, Nhu D Le.
Mol Nutr Food Res
PUBLISHED: 02-01-2014
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We reevaluated previously reported associations between variants in pathways of one-carbon (1-C) (folate) transfer genes and ovarian carcinoma (OC) risk, and in related pathways of purine and pyrimidine metabolism, and assessed interactions with folate intake.
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Large-scale evaluation of common variation in regulatory T cell-related genes and ovarian cancer outcome.
Bridget Charbonneau, Kirsten B Moysich, Kimberly R Kalli, Ann L Oberg, Robert A Vierkant, Zachary C Fogarty, Matthew S Block, Matthew J Maurer, Krista M Goergen, Brooke L Fridley, Julie M Cunningham, David N Rider, Claudia Preston, Lynn C Hartmann, Kate Lawrenson, Chen Wang, Jonathan Tyrer, Honglin Song, Anna deFazio, Sharon E Johnatty, Jennifer A Doherty, Catherine M Phelan, Thomas A Sellers, Starr M Ramirez, Allison F Vitonis, Kathryn L Terry, David Van Den Berg, Malcolm C Pike, Anna H Wu, Andrew Berchuck, Aleksandra Gentry-Maharaj, Susan J Ramus, Brenda Diergaarde, Howard Shen, Allan Jensen, Janusz Menkiszak, Cezary Cybulski, Jan Lubiłski, Argyrios Ziogas, Joseph H Rothstein, Valerie McGuire, Weiva Sieh, Jenny Lester, Christine Walsh, Ignace Vergote, Sandrina Lambrechts, Evelyn Despierre, Montserrat Garcia-Closas, Hannah Yang, Louise A Brinton, Beata Spiewankiewicz, Iwona K Rzepecka, Agnieszka Dansonka-Mieszkowska, Petra Seibold, Anja Rudolph, Lisa E Paddock, Irene Orlow, Lene Lundvall, Sara H Olson, Claus K Hogdall, Ira Schwaab, Andreas du Bois, Philipp Harter, James M Flanagan, Robert Brown, James Paul, Arif B Ekici, Matthias W Beckmann, Alexander Hein, Diana Eccles, Galina Lurie, Laura E Hays, Yukie T Bean, Tanja Pejovic, Marc T Goodman, Ian Campbell, Peter A Fasching, Gottfried Konecny, Stanley B Kaye, Florian Heitz, Estrid Hogdall, Elisa V Bandera, Jenny Chang-Claude, Jolanta Kupryjanczyk, Nicolas Wentzensen, Diether Lambrechts, Beth Y Karlan, Alice S Whittemore, Hoda Anton Culver, Jacek Gronwald, Douglas A Levine, Susanne K Kjaer, Usha Menon, Joellen M Schildkraut, Celeste Leigh Pearce, Daniel W Cramer, Mary Anne Rossing, Georgia Chenevix-Trench, , Paul D P Pharoah, Simon A Gayther, Roberta B Ness, Kunle Odunsi, Lara E Sucheston, Keith L Knutson, Ellen L Goode.
Cancer Immunol Res
PUBLISHED: 01-27-2014
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The presence of regulatory T cells (Treg) in solid tumors is known to play a role in patient survival in ovarian cancer and other malignancies. We assessed inherited genetic variations via 749 tag single-nucleotide polymorphisms (SNP) in 25 Treg-associated genes (CD28, CTLA4, FOXP3, IDO1, IL10, IL10RA, IL15, 1L17RA, IL23A, IL23R, IL2RA, IL6, IL6R, IL8, LGALS1, LGALS9, MAP3K8, STAT5A, STAT5B, TGFB1, TGFB2, TGFB3, TGFBR1, TGRBR2, and TGFBR3) in relation to ovarian cancer survival. We analyzed genotype and overall survival in 10,084 women with invasive epithelial ovarian cancer, including 5,248 high-grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous carcinoma cases of European descent across 28 studies from the Ovarian Cancer Association Consortium (OCAC). The strongest associations were found for endometrioid carcinoma and IL2RA SNPs rs11256497 [HR, 1.42; 95% confidence interval (CI), 1.22-1.64; P = 5.7 × 10(-6)], rs791587 (HR, 1.36; 95% CI, 1.17-1.57; P = 6.2 × 10(-5)), rs2476491 (HR, = 1.40; 95% CI, 1.19-1.64; P = 5.6 × 10(-5)), and rs10795763 (HR, 1.35; 95% CI, 1.17-1.57; P = 7.9 × 10(-5)), and for clear cell carcinoma and CTLA4 SNP rs231775 (HR, 0.67; 95% CI, 0.54-0.82; P = 9.3 × 10(-5)) after adjustment for age, study site, population stratification, stage, grade, and oral contraceptive use. The rs231775 allele associated with improved survival in our study also results in an amino acid change in CTLA4 and previously has been reported to be associated with autoimmune conditions. Thus, we found evidence that SNPs in genes related to Tregs seem to play a role in ovarian cancer survival, particularly in patients with clear cell and endometrioid epithelial ovarian cancer.
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Rapid adaptation of avian H7N9 virus in pigs.
Virology
PUBLISHED: 01-20-2014
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How the H7N9 avian influenza virus gained the distinct ability to infect humans is unclear. Pigs are an important host in influenza virus ecology because they are susceptible to infection with both avian and human influenza viruses and are often involved in interspecies transmission. Here, we passaged one avian isolate and one human isolate in pigs to examine the mammalian host adaptation of the H7N9 virus. The avian virus replicated to a high titer after one passage, whereas the human isolate replicated poorly after three passages in pig lungs. Sequence analysis found nine substitutions in the HA, NA, M and NS segments of the avian isolate, which enhanced the binding affinity for human-type receptors. These results indicate that avian H7N9 influenza viruses can be easily adapted to pigs and that pigs may act as an important intermediate host for the reassortment and transmission of such novel viruses.
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Six1: A critical transcription factor in tumorigenesis.
Int. J. Cancer
PUBLISHED: 01-15-2014
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In the past two decades, many studies have shown that sine oculis homeobox 1 (Six1) is a powerful regulator of organogenesis and disease, with important roles in tumorigenesis; therefore, it is important to review the biology of Six1 gene comprehensively. This review describes the function of Six1 in normal organ development, summarizes its role in several diseases, including cancer. The review will extend our understanding about the functional roles of Six1 and suggests opportunities to target Six1 for diagnostic, prognostic, and therapeutic purposes.
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Distribution and content of lipid droplets and mitochondria in pig parthenogenetically activated embryos after delipation.
Theriogenology
PUBLISHED: 01-14-2014
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The present study examines the effect of delipation on developmental competence and the distribution pattern of lipid droplets (LDs) and mitochondria in parthenogenetically activated (PA) pig embryos. Mature oocytes were delipated by centrifugation after partial digestion of the zonae pellucidae, subjected to parthenogenetic activation after total removal of zonae pellucidae by pronase, and then cultured in vitro up to the blastocyst stage. The contents and distributions of LDs and mitochondria in the oocytes and/or embryos were observed by staining with Oil Red O and MitoTracker Red CMXRos, respectively. The LD and mitochondrial contents were significantly reduced by the delipation process, and only smaller LDs remained in the delipated oocytes and/or embryos. Their content remained constant from the metaphase II oocyte to the blastocyst stage, but they became gradually smaller as the oocytes and/or embryos developed. The distribution pattern of the LDs in the delipated embryos changed over time and in a manner different to that seen in the controls. In the early developmental stages (1- to 4-cell stages), they were distributed peripherally and formed a ring around the nucleus. However, by the blastocyst stage, a homogeneous distribution of LDs was observed in both the inner cell mass and trophectoderm. The distribution pattern of mitochondria also changed with the development of the delipated PA embryos and again, in ways different to those seen in the controls. In the early 1- to 4-cell stages, a peripheral distribution of mitochondrial foci was observed in each blastomere. However, in blastocysts, the mitochondria were homogeneously distributed throughout the inner cell mass and trophectoderm. Although the cleavage rate at the 2- and 4-cell stages of the PA embryos was not affected by delipation (95.83 ± 2.25% vs. 97.44 ± 0.67%; 79.17 ± 4.47% vs. 84.62 ± 1.19%), it was reduced significantly in the blastocyst compared with the controls (21.67 ± 3.78% vs. 49.36 ± 1.77%). The distribution pattern of the LDs in oocytes and/or embryos at different developmental stages, and that of the mitochondria in metaphase II oocytes, was affected by delipation. The developmental competence of porcine PA embryos would appear to be affected by delipation.
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Polystyrene/Ag nanoparticles as dynamic surface-enhanced Raman spectroscopy substrates for sensitive detection of organophosphorus pesticides.
Talanta
PUBLISHED: 01-13-2014
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We report the use of Polystyrene/Ag (PS/Ag) nanoparticles as dynamic surface-enhanced Raman spectroscopy (dynamic-SERS) substrates for sensitive detection of low levels of organophosphorus pesticides. The PS particles clearly observed using Raman microscopy provide the masterplate for in situ growth of Ag NPs, leading to multiple active sites for SERS measurements. Besides obtaining the fingerprints of target molecules and recording time-resolved Raman spectra, this dynamic-SERS method can be used as an ultra-sensitive analytical technique which can enhance 1-2 orders of magnitude the signals of analytes in comparison to that of the traditional methods. On the other hand, importantly, it shows much better correlations between concentration and intensity than does the conventional SERS technique so that it can build the foundation for quantitative analysis of analytes. The as-prepared individual PS/Ag nanoparticle has been demonstrated for the sensitive detection of organophosphorus paraoxon and sumithion. SERS spectra are acquired at different concentrations of each pesticide and linear calibration curves are obtained by monitoring the strongest intensity value of bands arising from stronger stretching mode as a function of analyte concentration. The limits of detection and limits of quantitation are reported for two pesticides. The limit of detection for paraoxon is 96 nM (0.026 ppm) and for sumithion is 34 nM (0.011 ppm). The limits of quantitation are 152 nM (0.042 ppm) and 57 nM (0.016 ppm) for paraoxon and sumithion, respectively. It can be seen that these two organophosphorus pesticides can be detected in the low nM range based on this dynamic-SERS analytical method. Also, in the real sample experiments of paraoxon and sumithion, the results confirm that this dynamic-SERS technique would have potential applicability for quantitative analysis with slight interference.
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Growth Hormone-Regulated mRNAs and miRNAs in Chicken Hepatocytes.
PLoS ONE
PUBLISHED: 01-01-2014
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Growth hormone (GH) is a key regulatory factor in animal growth, development and metabolism. Based on the expression level of the GH receptor, the chicken liver is a major target organ of GH, but the biological effects of GH on the chicken liver are not fully understood. In this work we identified mRNAs and miRNAs that are regulated by GH in primary hepatocytes from female chickens through RNA-seq, and analyzed the functional relevance of these mRNAs and miRNAs through GO enrichment analysis and miRNA target prediction. A total of 164 mRNAs were found to be differentially expressed between GH-treated and control chicken hepatocytes, of which 112 were up-regulated and 52 were down-regulated by GH. A total of 225 chicken miRNAs were identified by the RNA-Seq analysis. Among these miRNAs 16 were up-regulated and 1 miRNA was down-regulated by GH. The GH-regulated mRNAs were mainly involved in growth and metabolism. Most of the GH-upregulated or GH-downregulated miRNAs were predicted to target the GH-downregulated or GH-upregulated mRNAs, respectively, involved in lipid metabolism. This study reveals that GH regulates the expression of many mRNAs involved in metabolism in female chicken hepatocytes, which suggests that GH plays an important role in regulating liver metabolism in female chickens. The results of this study also support the hypothesis that GH regulates lipid metabolism in chicken liver in part by regulating the expression of miRNAs that target the mRNAs involved in lipid metabolism.
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Avian influenza A H7N9 virus induces severe pneumonia in mice without prior adaptation and responds to a combination of zanamivir and COX-2 inhibitor.
PLoS ONE
PUBLISHED: 01-01-2014
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Human infection caused by the avian influenza A H7N9 virus has a case-fatality rate of over 30%. Systematic study of the pathogenesis of avian H7N9 isolate and effective therapeutic strategies are needed.
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The role of Six1 in the genesis of muscle cell and skeletal muscle development.
Int. J. Biol. Sci.
PUBLISHED: 01-01-2014
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The sine oculis homeobox 1 (Six1) gene encodes an evolutionarily conserved transcription factor. In the past two decades, much research has indicated that Six1 is a powerful regulator participating in skeletal muscle development. In this review, we summarized the discovery and structural characteristics of Six1 gene, and discussed the functional roles and molecular mechanisms of Six1 in myogenesis and in the formation of skeletal muscle fibers. Finally, we proposed areas of future interest for understanding Six1 gene function.
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TRB3 is involved in free fatty acid-induced INS-1-derived cell apoptosis via the protein kinase C ? pathway.
PLoS ONE
PUBLISHED: 01-01-2014
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Chronic exposure to free fatty acids (FFAs) may induce ? cell apoptosis in type 2 diabetes. However, the precise mechanism by which FFAs trigger ? cell apoptosis is still unclear. Tribbles homolog 3 (TRB3) is a pseudokinase inhibiting Akt, a key mediator of insulin signaling, and contributes to insulin resistance in insulin target tissues. This paper outlined the role of TRB3 in FFAs-induced INS-1 ? cell apoptosis. TRB3 was promptly induced in INS-1 cells after stimulation by FFAs, and this was accompanied by enhanced INS-1 cell apoptosis. The overexpression of TRB3 led to exacerbated apoptosis triggered by FFAs in INS-1-derived cell line and the subrenal capsular transplantation animal model. In contrast, cell apoptosis induced by FFAs was attenuated when TRB3 was knocked down. Moreover, we observed that activation and nuclear accumulation of protein kinase C (PKC) ? was enhanced by upregulation of TRB3. Preventing PKC? nuclear translocation and PKC? selective antagonist both significantly lessened the pro-apoptotic effect. These findings suggest that TRB3 was involved in lipoapoptosis of INS-1 ? cell, and thus could be an attractive pharmacological target in the prevention and treatment of T2DM.
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Stac3 inhibits myoblast differentiation into myotubes.
PLoS ONE
PUBLISHED: 01-01-2014
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The functionally undefined Stac3 gene, predicted to encode a SH3 domain- and C1 domain-containing protein, was recently found to be specifically expressed in skeletal muscle and essential to normal skeletal muscle development and contraction. In this study we determined the potential role of Stac3 in myoblast proliferation and differentiation, two important steps of muscle development. Neither siRNA-mediated Stac3 knockdown nor plasmid-mediated Stac3 overexpression affected the proliferation of C2C12 myoblasts. Stac3 knockdown promoted the differentiation of C2C12 myoblasts into myotubes as evidenced by increased fusion index, increased number of nuclei per myotube, and increased mRNA and protein expression of myogenic markers including myogenin and myosin heavy chain. In contrast, Stac3 overexpression inhibited the differentiation of C2C12 myoblasts into myotubes as evidenced by decreased fusion index, decreased number of nuclei per myotube, and decreased mRNA and protein expression of myogenic markers. Compared to wild-type myoblasts, myoblasts from Stac3 knockout mouse embryos showed accelerated differentiation into myotubes in culture as evidenced by increased fusion index, increased number of nuclei per myotube, and increased mRNA expression of myogenic markers. Collectively, these data suggest an inhibitory role of endogenous Stac3 in myoblast differentiation. Myogenesis is a tightly controlled program; myofibers formed from prematurely differentiated myoblasts are dysfunctional. Thus, Stac3 may play a role in preventing precocious myoblast differentiation during skeletal muscle development.
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Expression of miR-33 from an SREBF2 intron targets the FTO gene in the chicken.
PLoS ONE
PUBLISHED: 01-01-2014
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The sterol regulatory element binding transcription factor 2 (SREBF2) gene encodes a transcription factor that activates the expression of many genes involved in the synthesis and uptake of cholesterol, fatty acids, triglycerides, and phospholipids. Through bioinformatics, we found that intron 16 of the chicken SREBF2 gene might encode the chicken miR-33. Using quantitative RT-PCR, we detected the expression of miR-33 in a variety of chicken tissues including skeletal muscle, adipose tissue, and liver. Three hundred and seventy eight genes were predicted to be potential targets of miR-33 in chickens via miRNA target prediction programs "miRanda" and "TargetScan". Among these targets, the gene FTO (fat mass and obesity associated) encodes a Fe(II)- and 2-oxoglutarate-dependent nucleic acid demethylase that regulates lipid metabolism, and the possibility that its expression is negatively regulated by miR-33 in the chicken liver was therefore further studied. Co-transfection and dual-luciferase reporter assays showed that the expression of luciferase reporter gene linked to the 3'-untranslated region (3'UTR) of the chicken FTO mRNA was down-regulated by overexpression of the chicken miR-33 in the C2C12 cells (P<0.05). Furthermore, this down-regulation was completely abolished when the predicted miR-33 target site in the FTO 3'UTR was mutated. In contrast, the expression of FTO mRNA in the primary chicken hepatocytes was up-regulated after transfection with the miR-33 inhibitor LNA-anti-miR-33. Using quantitative RT-PCR, we also found that the expression of miR-33 was increased in the chicken liver from day 0 to day 49 of age, whereas that of the FTO mRNA was decreased during the same age period. These data together suggest that miR-33 might play an important role in lipid metabolism in the chicken liver by negatively regulating the expression of the FTO gene.
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Ovarian cancer familial relative risks by tumour subtypes and by known ovarian cancer genetic susceptibility variants.
J. Med. Genet.
PUBLISHED: 11-25-2013
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Family history is one of the most important risk factors for epithelial ovarian cancer (EOC). Little is known, however, on how EOC familial relative risks (FRRs) vary by factors such as tumour subtype or the combined effects of common EOC susceptibility alleles. In addition, no data currently exist on the FRRs associated with EOC after exclusion of BRCA1 or BRCA2 mutation carriers.
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Risk of Ovarian Cancer and the NF-?B Pathway: Genetic association with IL1A and TNFSF10.
Bridget Charbonneau, Matthew S Block, William R Bamlet, Robert A Vierkant, Kimberly R Kalli, Zachary Fogarty, David N Rider, Thomas A Sellers, Shelley S Tworoger, Elizabeth Poole, Harvey A Risch, Helga B Salvesen, Lambertus A Kiemeney, Laura Baglietto, Graham G Giles, Gianluca Severi, Britton Trabert, Nicolas Wentzensen, Georgia Chenevix-Trench, , Alice S Whittemore, Weiva Sieh, Jenny Chang-Claude, Elisa V Bandera, Irene Orlow, Kathryn Terry, Marc T Goodman, Pamela J Thompson, Linda S Cook, Mary Anne Rossing, Roberta B Ness, Steven A Narod, Jolanta Kupryjanczyk, Karen Lu, Ralf Bützow, Thilo Dörk, Tanja Pejovic, Ian Campbell, Nhu D Le, Clareann H Bunker, Natalia Bogdanova, Ingo B Runnebaum, Diana Eccles, James Paul, Anna H Wu, Simon A Gayther, Estrid Hogdall, Florian Heitz, Stanley B Kaye, Beth Y Karlan, Hoda Anton-Culver, Jacek Gronwald, Claus K Hogdall, Diether Lambrechts, Peter A Fasching, Usha Menon, Joellen Schildkraut, Celeste Leigh Pearce, Douglas A Levine, Susanne Krüger Kjaer, Daniel Cramer, James M Flanagan, Catherine M Phelan, Robert Brown, Leon F A G Massuger, Honglin Song, Jennifer A Doherty, Camilla Krakstad, Dong Liang, Kunle Odunsi, Andrew Berchuck, Allan Jensen, Jan Lubiński, Heli Nevanlinna, Yukie T Bean, Galina Lurie, Argyrios Ziogas, Christine Walsh, Evelyn Despierre, Louise Brinton, Alexander Hein, Anja Rudolph, Agnieszka Dansonka-Mieszkowska, Sara H Olson, Philipp Harter, Jonathan Tyrer, Allison F Vitonis, Angela Brooks-Wilson, Katja K Aben, Malcolm C Pike, Susan J Ramus, Elisabeth Wik, Cezary Cybulski, Jie Lin, Lara Sucheston, Robert Edwards, Valerie McGuire, Jenny Lester, Andreas du Bois, Lene Lundvall, Shan Wang-Gohrke, Lukasz M Szafron, Sandrina Lambrechts, Hannah Yang, Matthias W Beckmann, Liisa M Pelttari, Anne M Van Altena, David Van Den Berg, Mari K Halle, Aleksandra Gentry-Maharaj, Ira Schwaab, Urmila Chandran, Janusz Menkiszak, Arif B Ekici, Lynne R Wilkens, Arto Leminen, Francesmary Modugno, Grace Friel, Joseph H Rothstein, Ignace Vergote, Montserrat Garcia-Closas, Michelle A T Hildebrandt, Piotr Sobiczewski, Linda E Kelemen, Paul D P Pharoah, Kirsten Moysich, Keith L Knutson, Julie M Cunningham, Brooke L Fridley, Ellen L Goode.
Cancer Res.
PUBLISHED: 11-22-2013
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A missense single nucleotide polymorphism in the immune modulatory gene IL1A has been associated with ovarian cancer risk (rs17561), but the functional implications of this polymorphism are undefined. IL-1? is regulated by and activated by NF-?B, a transcription factor family that induces transcription of IL1A along with other pro-inflammatory genes and is an important modifier in carcinogenesis. We therefore tagged SNPs in over 200 genes in the NF-?B pathway for a total of 2,282 SNPs (including rs17561) for genotype analysis of 15,604 cases of ovarian cancer in patients of European descent, including 6,179 of high grade serous (HGS), 2,100 endometrioid, 1,591 mucinous, 1,034 clear cell and 1,016 low grade serous (LGS), including 23,235 control cases spanning 40 studies in the Ovarian Cancer Association Consortium (OCAC). In this large population, we confirmed the association between rs17561 and clear cell ovarian cancer (OR=0.84, 95% CI: 0.76-0.93; p=0.00075), which remained intact even after excluding participants in the prior study (OR=0.85, 95% CI: 0.75-0.95; p=0.006). Considering a multiple-testing-corrected significance threshold of p< 2.5x10-5, only one other variant, the TNFSF10 SNP rs6785617, was associated significantly with a risk of ovarian cancer (low malignant potential (LMP) tumors OR=0.85, 95% CI: 0.79-0.91; p=0.00002). Our results extend the evidence that borderline tumors may have a distinct genetic etiology. Further investigation of how these SNPs might modify ovarian cancer associations with other inflammation related risk factors is warranted.
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An Animal Model of MERS Produced by Infection of Rhesus Macaques With MERS Coronavirus.
J. Infect. Dis.
PUBLISHED: 11-11-2013
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In 2012, a novel coronavirus (CoV) associated with severe respiratory disease, Middle East respiratory syndrome (MERS-CoV; previously known as human coronavirus-Erasmus Medical Center or hCoV-EMC), emerged in the Arabian Peninsula. To date, 114 human cases of MERS-CoV have been reported, with 54 fatalities. Animal models for MERS-CoV infection of humans are needed to elucidate MERS pathogenesis and to develop vaccines and antivirals. In this study, we developed rhesus macaques as a model for MERS-CoV using intratracheal inoculation. The infected monkeys showed clinical signs of disease, virus replication, histological lesions, and neutralizing antibody production, indicating that this monkey model is suitable for studies of MERS-CoV infection.
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Antigenicity and transmissibility of a novel clade 2.3.2.1 avian influenza H5N1 virus.
J. Gen. Virol.
PUBLISHED: 09-28-2013
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A genetic variant of the H5N1 influenza virus, termed subclade 2.3.2.1, was first identified in Bulgaria in 2010 and has subsequently been found in Vietnam and Laos. Several cases of human infections with this virus have been identified. Thus, it is important to understand the antigenic properties and transmissibility of this variant. Our results showed that, although it is phylogenetically closely related to other previously characterized clade 2.3 viruses, this novel 2.3.2.1 variant exhibited distinct antigenic properties and showed little cross-reactivity to sera raised against other H5N1 viruses. Like other H5N1 viruses, this variant bound preferentially to avian-type receptors, but contained substitutions at positions 190 and 158 of the haemagglutinin (HA) protein that have been postulated to facilitate HA binding to human-type receptors and to enhance viral transmissibility among mammals, respectively. However, this virus did not appear to have acquired the capacity for airborne transmission between ferrets. These findings highlight the challenges in selecting vaccine candidates for H5N1 influenza because these viruses continue to evolve rapidly in the field. It is important to note that some variants have obtained mutations that may gain transmissibility between model animals, and close surveillance of H5N1 viruses in poultry is warranted.
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Delayed induction of proinflammatory cytokines and suppression of innate antiviral response by the novel Middle East respiratory syndrome coronavirus: implications for pathogenesis and treatment.
J. Gen. Virol.
PUBLISHED: 09-28-2013
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The high mortality associated with the novel Middle East respiratory syndrome coronavirus (MERS-CoV) has raised questions about the possible role of a cytokine storm in its pathogenesis. Although recent studies showed that MERS-CoV infection is associated with an attenuated IFN response, no induction of inflammatory cytokines was demonstrated during the early phase of infection. To study both early and late cytokine responses associated with MERS-CoV infection, we measured the mRNA levels of eight cytokine genes [TNF-?, IL-1?, IL-6, IL-8, IFN-?, monocyte chemotactic protein-1, transforming growth factor-? and IFN-?-induced protein (IP)-10] in cell lysates of polarized airway epithelial Calu-3 cells infected with MERS-CoV or severe acute respiratory syndrome (SARS)-CoV up to 30 h post-infection. Among the eight cytokine genes, IL-1?, IL-6 and IL-8 induced by MERS-CoV were markedly higher than those induced by SARS-CoV at 30 h, whilst TNF-?, IFN-? and IP-10 induced by SARS-CoV were markedly higher than those induced by MERS-CoV at 24 and 30 h in infected Calu-3 cells. The activation of IL-8 and attenuated IFN-? response by MERS-CoV were also confirmed by protein measurements in the culture supernatant when compared with SARS-CoV and Sendai virus. To further confirm the attenuated antiviral response, cytokine response was compared with human HCoV-229E in embryonal lung fibroblast HFL cells, which also revealed higher IFN-? and IP-10 levels induced by HCoV-229E than MERS-CoV at 24 and 30 h. Whilst our data supported recent findings that MERS-CoV elicits attenuated innate immunity, this represents the first report to demonstrate delayed proinflammatory cytokine induction by MERS-CoV. Our results provide insights into the pathogenesis and treatment of MERS-CoV infections.
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Broad-spectrum antivirals for the emerging Middle East respiratory syndrome coronavirus.
J. Infect.
PUBLISHED: 09-24-2013
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Middle East respiratory syndrome coronavirus (MERS-CoV) has emerged to cause fatal infections in patients in the Middle East and traveler-associated secondary cases in Europe and Africa. Person-to-person transmission is evident in outbreaks involving household and hospital contacts. Effective antivirals are urgently needed.
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Perturbation of biogenesis and targeting of Epstein-Barr virus-encoded miR-BART3 microRNA by adenosine-to-inosine editing.
J. Gen. Virol.
PUBLISHED: 09-17-2013
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Epstein-Barr virus (EBV) encodes at least 44 mature microRNAs (miRNAs), some of which are abundantly expressed in nasopharyngeal carcinoma cells. EBV-encoded miR-BART6 miRNA is known to undergo adenosine-to-inosine (A-to-I) RNA editing, which impacts on processing and function. Whether additional EBV miRNAs might be A-to-I edited remains to be determined. In this study, we have reported on A-to-I editing of EBV miR-BART3. The A-to-I editing enzyme was expressed abundantly in EBV-infected epithelial carcinoma cells. pri-miR-BART3 was found to be edited at four sites in these cells and in nasopharyngeal carcinoma samples. Whereas editing of the second site located within the seed region prevented the targeting of DICE1 mRNA, editing of the third site effectively crippled the biogenesis of mature miR-BART3. Thus, A-to-I editing perturbs biogenesis and targeting of miR-BART3 and may contribute to its differential expression and function in EBV-infected epithelial cells.
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Mouse oocyte meiosis is disturbed by knockdown of Suv4-20h.
Reprod. Fertil. Dev.
PUBLISHED: 09-17-2013
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Suv4-20h was initially characterised as a histone methyltransferase (HMTase) that catalyses lysine 20 of histone H4 dimethylation (H4K20me2) and trimethylation (H4K20me3). In the present study, using RNA interference (RNAi), we found that Suv4-20h activity is required for the fidelity of chromosome distribution during meiosis in the mammalian oocyte. Knockdown of Suv4-20h resulted in attenuation of H4K20me3 and the accumulation of H4K20me1. After Suv4-20h knockdown, oocytes exhibited an increasing percentage of aberrant chromosome alignment in MI, together with a decreasing percentage of polar body I extrusion. We conclude that Suv4-20h may be required for normal chromosome behaviour and that it is crucial for proper meiotic progression in mammalian oocytes.
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Novel Avian-Origin Human Influenza A(H7N9) Can Be Transmitted Between Ferrets via Respiratory Droplets.
J. Infect. Dis.
PUBLISHED: 08-29-2013
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The outbreak of human infections caused by novel avian-origin influenza A(H7N9) in China since March 2013 underscores the need to better understand the pathogenicity and transmissibility of these viruses in mammals. In a ferret model, the pathogenicity of influenza A(H7N9) was found to be less than that of an influenza A(H5N1) strain but comparable to that of 2009 pandemic influenza A(H1N1), based on the clinical signs, mortality, virus dissemination, and results of histopathologic analyses. Influenza A(H7N9) could replicate in the upper and lower respiratory tract, the heart, the liver, and the olfactory bulb. It is worth noting that influenza A(H7N9) exhibited a low level of transmission between ferrets via respiratory droplets. There were 4 mutations in the virus isolated from the contact ferret: D678Y in the gene encoding PB2, R157K in the gene encoding hemagglutinin (H3 numbering), I109T in the gene encoding nucleoprotein, and T10I in the gene encoding neuraminidase. These data emphasized that avian-origin influenza A(H7N9) can be transmitted between mammals, highlighting its potential for human-to-human transmissibility.
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The emergence of influenza A H7N9 in human beings 16 years after influenza A H5N1: a tale of two cities.
Lancet Infect Dis
PUBLISHED: 08-24-2013
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Infection with either influenza A H5N1 virus in 1997 or avian influenza A H7N9 virus in 2013 caused severe pneumonia that did not respond to typical or atypical antimicrobial treatment, and resulted in high mortality. Both viruses are reassortants with internal genes derived from avian influenza A H9N2 viruses that circulate in Asian poultry. Both viruses have genetic markers of mammalian adaptation in their haemagglutinin and polymerase PB2 subunits, which enhanced binding to human-type receptors and improved replication in mammals, respectively. Hong Kong (affected by H5N1 in 1997) and Shanghai (affected by H7N9 in 2013) are two rapidly flourishing cosmopolitan megacities that were increasing in human population and poultry consumption before the outbreaks. Both cities are located along the avian migratory route at the Pearl River delta and Yangtze River delta. Whether the widespread use of the H5N1 vaccine in east Asia-with suboptimum biosecurity measures in live poultry markets and farms-predisposed to the emergence of H7N9 or other virus subtypes needs further investigation. Why H7N9 seems to be more readily transmitted from poultry to people than H5N1 is still unclear.
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Avian-Origin Influenza A(H7N9) Infection in Influenza A(H7N9)-Affected Areas of China: A Serological Study.
J. Infect. Dis.
PUBLISHED: 08-09-2013
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Serological surveillance conducted in areas of an outbreak of influenza A(H7N9) infection in China found no seropositivity for antibodies specific for avian-origin influenza A(H7N9) among 1129 individuals of the general population, whereas >6% of 396 poultry workers were positive (on the basis of a hemagglutination inhibition titer of ? 80) for this subtype, confirming that infected poultry is the principal source of human infections and that subclinical infections are possible. Fourteen days after symptom onset, elevated levels of antibodies to A(H7N9) were found in 65.8% of patients (25/38) who survived but in only 28.6% of those (2/7) who died, suggesting that the presence of antibodies may improve clinical outcome in infected patients.
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Assembly of polymer-gold nanostructures with high reproducibility into a monolayer film SERS substrate with 5 nm gaps for pesticide trace detection.
Analyst
PUBLISHED: 08-06-2013
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A very simple and versatile polymer assembly approach was developed. We use methoxy-mercapto-poly(ethylene glycol) (mPEG-SH) to conjugate multiple Au shapes to form dense Au monolayer films (MLFs) with 5 nm gaps and generate gigantic enhancement. The results of the discrete dipole approximation (DDA) method to calculate the local electric field distribution of the nanoparticle dimer are in agreement with the experimental data of sensitivity of multiple Au MLFs. 3D Raman spectra, relative standard deviation (RSD) calculation and Raman mapping were used to study the high-reproducibility of the assembled substrate, which is sufficient for trace pesticide residue detection.
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The siRNA cocktail targeting VEGF and HER2 inhibition on the proliferation and induced apoptosis of gastric cancer cell.
Mol. Cell. Biochem.
PUBLISHED: 07-18-2013
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The aim of this study was to investigate the inhibitory effect of a siRNA cocktail targeting Vascular endothelial growth factor (VEGF) and Human epidermal growth factor receptor 2 (HER2) on cell proliferation, induced apoptosis and the expression of VEGF and HER2 in human gastric carcinoma cell. The silencing rate of pre-designed siRNAs that targeted VEGF and HER2 was detected by Real-time Quantitative PCR (RT-QPCR) analysis. Furthermore, the best silencing siRNA that targeted VEGF and HER2 was prepared as a cocktail to co-knockdown VEGF and HER2 expression at both mRNA and protein levels which were detected by RT-QPCR and Western blot analysis. Cell proliferation inhibition rates were determined by CCK8 assay. The effect of siRNA cocktail on cell apoptosis was determined by flow cytometry. The migration inhibition of siRNA cocktail was analyzed by wound-healing assay. The ability of VEGF to induce endothelial cells to proliferate was examined in HUVECs by the method of tube formation assay. The pre-designed siRNAs could inhibit VEGF and HER2 mRNA level. siRNA cocktail, and co-downregulation of VEGF and HER2 result in significant inhibition of gastric cancer growth and migration in vitro. The inhibition of VEGF and HER2 expressions can induce apoptosis of SGC-7901 cells.
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Genome-wide association study of subtype-specific epithelial ovarian cancer risk alleles using pooled DNA.
Madalene A Earp, Linda E Kelemen, Anthony M Magliocco, Kenneth D Swenerton, Georgia Chenevix-Trench, , Yi Lu, Alexander Hein, Arif B Ekici, Matthias W Beckmann, Peter A Fasching, Diether Lambrechts, Evelyn Despierre, Ignace Vergote, Sandrina Lambrechts, Jennifer A Doherty, Mary Anne Rossing, Jenny Chang-Claude, Anja Rudolph, Grace Friel, Kirsten B Moysich, Kunle Odunsi, Lara Sucheston-Campbell, Galina Lurie, Marc T Goodman, Michael E Carney, Pamela J Thompson, Ingo B Runnebaum, Matthias Dürst, Peter Hillemanns, Thilo Dörk, Natalia Antonenkova, Natalia Bogdanova, Arto Leminen, Heli Nevanlinna, Liisa M Pelttari, Ralf Bützow, Clareann H Bunker, Francesmary Modugno, Robert P Edwards, Roberta B Ness, Andreas du Bois, Florian Heitz, Ira Schwaab, Philipp Harter, Beth Y Karlan, Christine Walsh, Jenny Lester, Allan Jensen, Susanne K Kjær, Claus K Høgdall, Estrid Høgdall, Lene Lundvall, Thomas A Sellers, Brooke L Fridley, Ellen L Goode, Julie M Cunningham, Robert A Vierkant, Graham G Giles, Laura Baglietto, Gianluca Severi, Melissa C Southey, Dong Liang, Xifeng Wu, Karen Lu, Michelle A T Hildebrandt, Douglas A Levine, Maria Bisogna, Joellen M Schildkraut, Edwin S Iversen, Rachel Palmieri Weber, Andrew Berchuck, Daniel W Cramer, Kathryn L Terry, Elizabeth M Poole, Shelley S Tworoger, Elisa V Bandera, Urmila Chandran, Irene Orlow, Sara H Olson, Elisabeth Wik, Helga B Salvesen, Line Bjorge, Mari K Halle, Anne M Van Altena, Katja K H Aben, Lambertus A Kiemeney, Leon F A G Massuger, Tanja Pejovic, Yukie T Bean, Cezary Cybulski, Jacek Gronwald, Jan Lubiński, Nicolas Wentzensen, Louise A Brinton, Jolanta Lissowska, Montserrat Garcia-Closas, Ed Dicks, Joe Dennis, Douglas F Easton, Honglin Song, Jonathan P Tyrer, Paul D P Pharoah, Diana Eccles, Ian G Campbell, Alice S Whittemore, Valerie McGuire, Weiva Sieh, Joseph H Rothstein, James M Flanagan, James Paul, Robert Brown, Catherine M Phelan, Harvey A Risch, John R McLaughlin, Steven A Narod, Argyrios Ziogas, Hoda Anton-Culver, Aleksandra Gentry-Maharaj, Usha Menon, Simon A Gayther, Susan J Ramus, Anna H Wu, Celeste L Pearce, Malcolm C Pike, Agnieszka Dansonka-Mieszkowska, Iwona K Rzepecka, Lukasz M Szafron, Jolanta Kupryjanczyk, Linda S Cook, Nhu D Le, Angela Brooks-Wilson.
Hum. Genet.
PUBLISHED: 07-17-2013
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Epithelial ovarian cancer (EOC) is a heterogeneous cancer with both genetic and environmental risk factors. Variants influencing the risk of developing the less-common EOC subtypes have not been fully investigated. We performed a genome-wide association study (GWAS) of EOC according to subtype by pooling genomic DNA from 545 cases and 398 controls of European descent, and testing for allelic associations. We evaluated for replication 188 variants from the GWAS [56 variants for mucinous, 55 for endometrioid and clear cell, 53 for low-malignant potential (LMP) serous, and 24 for invasive serous EOC], selected using pre-defined criteria. Genotypes from 13,188 cases and 23,164 controls of European descent were used to perform unconditional logistic regression under the log-additive genetic model; odds ratios (OR) and 95 % confidence intervals are reported. Nine variants tagging six loci were associated with subtype-specific EOC risk at P < 0.05, and had an OR that agreed in direction of effect with the GWAS results. Several of these variants are in or near genes with a biological rationale for conferring EOC risk, including ZFP36L1 and RAD51B for mucinous EOC (rs17106154, OR = 1.17, P = 0.029, n = 1,483 cases), GRB10 for endometrioid and clear cell EOC (rs2190503, P = 0.014, n = 2,903 cases), and C22orf26/BPIL2 for LMP serous EOC (rs9609538, OR = 0.86, P = 0.0043, n = 892 cases). In analyses that included the 75 GWAS samples, the association between rs9609538 (OR = 0.84, P = 0.0007) and LMP serous EOC risk remained statistically significant at P < 0.0012 adjusted for multiple testing. Replication in additional samples will be important to verify these results for the less-common EOC subtypes.
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Genetic characterization of Betacoronavirus lineage C viruses in bats reveals marked sequence divergence in the spike protein of pipistrellus bat coronavirus HKU5 in Japanese pipistrelle: implications for the origin of the novel Middle East respiratory sy
J. Virol.
PUBLISHED: 05-29-2013
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While the novel Middle East respiratory syndrome coronavirus (MERS-CoV) is closely related to Tylonycteris bat CoV HKU4 (Ty-BatCoV HKU4) and Pipistrellus bat CoV HKU5 (Pi-BatCoV HKU5) in bats from Hong Kong, and other potential lineage C betacoronaviruses in bats from Africa, Europe, and America, its animal origin remains obscure. To better understand the role of bats in its origin, we examined the molecular epidemiology and evolution of lineage C betacoronaviruses among bats. Ty-BatCoV HKU4 and Pi-BatCoV HKU5 were detected in 29% and 25% of alimentary samples from lesser bamboo bat (Tylonycteris pachypus) and Japanese pipistrelle (Pipistrellus abramus), respectively. Sequencing of their RNA polymerase (RdRp), spike (S), and nucleocapsid (N) genes revealed that MERS-CoV is more closely related to Pi-BatCoV HKU5 in RdRp (92.1% to 92.3% amino acid [aa] identity) but is more closely related to Ty-BatCoV HKU4 in S (66.8% to 67.4% aa identity) and N (71.9% to 72.3% aa identity). Although both viruses were under purifying selection, the S of Pi-BatCoV HKU5 displayed marked sequence polymorphisms and more positively selected sites than that of Ty-BatCoV HKU4, suggesting that Pi-BatCoV HKU5 may generate variants to occupy new ecological niches along with its host in diverse habitats. Molecular clock analysis showed that they diverged from a common ancestor with MERS-CoV at least several centuries ago. Although MERS-CoV may have diverged from potential lineage C betacoronaviruses in European bats more recently, these bat viruses were unlikely to be the direct ancestor of MERS-CoV. Intensive surveillance for lineage C betaCoVs in Pipistrellus and related bats with diverse habitats and other animals in the Middle East may fill the evolutionary gap.
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The time-resolved D-SERS vibrational spectra of pesticide thiram.
Talanta
PUBLISHED: 05-27-2013
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Time-resolved dynamic-SERS (D-SERS) can observe the process of chemical reaction between target and substrate and changes of adsorptive forms for analytes. In this paper, the vibrational spectra of pesticide thiram adsorbed on Au nanoparticles and intensity alternation of SERS spectra depended on different laser powers have been systematically investigated using the method of D-SERS. The Raman intensities of b2 and a1 modes of thiram related to the standard band appear different regulars with the extending time. Meanwhile, due to SERS vibrational spectra of pesticide thiram at different concentrations exhibit different SERS signals, the results of time-resolve D-SERS demonstrate the breakdown of band and different adsorptive forms of molecule on Au substrate. The continuous time-resolved the spectroscopic method offers the fingerprints of target molecules and provides great practical potentials for the continuous assessment and identification of pesticide or other probe molecules.
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Core promoter analysis of porcine Six1 gene and its regulation of the promoter activity by CpG methylation.
Gene
PUBLISHED: 04-13-2013
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Six1, an evolutionary conserved transcription factor, has been shown to play an important role in organogenesis and diseases. However, no reports were shown to investigate its transcriptional regulatory mechanisms. In the present study, we first identified porcine Six1 gene core promoter region (+170/-360) using luciferase reporter assay system and found that promoter activities were significantly higher in the mouse myoblast C2C12 cells than that in the mouse fibroblast C3H10T1/2 cells, implying that Six1 promoter could possess muscle-specific characteristics. Moreover, our results showed that promoter activities of Six1 were decreased as induction of differentiation of C2C12 cells, which was accompanied by the down-regulation of mRNA expression of Six1 gene. In addition, we found that the DNA methylation of Six1 promoters in vitro obviously influences the promoter activities and the DNA methylation level of Six1 promoter core region was negatively correlated to Six1 gene expression in vivo. Taken together, we preliminarily clarified transcriptional regulatory mechanisms of Six1 gene, which should be useful for investigating its subtle transcriptional regulatory mechanisms in the future. On the other hand, based on Six1 involved in tumorigenesis, our data also provide a genetic foundation to control the generation of diseases via pursuing Six1 as therapeutic target gene.
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Analysis of over 10,000 Cases finds no association between previously reported candidate polymorphisms and ovarian cancer outcome.
Kristin L White, Robert A Vierkant, Zachary C Fogarty, Bridget Charbonneau, Matthew S Block, Paul D P Pharoah, Georgia Chenevix-Trench, , Mary Anne Rossing, Daniel W Cramer, Celeste Leigh Pearce, Joellen M Schildkraut, Usha Menon, Susanne Krüger Kjaer, Douglas A Levine, Jacek Gronwald, Hoda Anton Culver, Alice S Whittemore, Beth Y Karlan, Diether Lambrechts, Nicolas Wentzensen, Jolanta Kupryjanczyk, Jenny Chang-Claude, Elisa V Bandera, Estrid Hogdall, Florian Heitz, Stanley B Kaye, Peter A Fasching, Ian Campbell, Marc T Goodman, Tanja Pejovic, Yukie Bean, Galina Lurie, Diana Eccles, Alexander Hein, Matthias W Beckmann, Arif B Ekici, James Paul, Robert Brown, James M Flanagan, Philipp Harter, Andreas du Bois, Ira Schwaab, Claus K Hogdall, Lene Lundvall, Sara H Olson, Irene Orlow, Lisa E Paddock, Anja Rudolph, Ursula Eilber, Agnieszka Dansonka-Mieszkowska, Iwona K Rzepecka, Izabela Ziolkowska-Seta, Louise Brinton, Hannah Yang, Montserrat Garcia-Closas, Evelyn Despierre, Sandrina Lambrechts, Ignace Vergote, Christine Walsh, Jenny Lester, Weiva Sieh, Valerie McGuire, Joseph H Rothstein, Argyrios Ziogas, Jan Lubiński, Cezary Cybulski, Janusz Menkiszak, Allan Jensen, Simon A Gayther, Susan J Ramus, Aleksandra Gentry-Maharaj, Andrew Berchuck, Anna H Wu, Malcolm C Pike, David Van Denberg, Kathryn L Terry, Allison F Vitonis, Jennifer A Doherty, Sharon E Johnatty, Anna deFazio, Honglin Song, Jonathan Tyrer, Thomas A Sellers, Catherine M Phelan, Kimberly R Kalli, Julie M Cunningham, Brooke L Fridley, Ellen L Goode.
Cancer Epidemiol. Biomarkers Prev.
PUBLISHED: 03-19-2013
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Ovarian cancer is a leading cause of cancer-related death among women. In an effort to understand contributors to disease outcome, we evaluated single-nucleotide polymorphisms (SNP) previously associated with ovarian cancer recurrence or survival, specifically in angiogenesis, inflammation, mitosis, and drug disposition genes.
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Preliminary evaluation of an MRI-based technique for displaying and quantifying bony deformities in cam-type femoroacetabular impingement.
Int J Comput Assist Radiol Surg
PUBLISHED: 03-18-2013
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PURPOSE : Characterizing aspheric deformities of the femoral head-neck junction in cam-type femoroacetabular impingement (FAI) requires representing the location, size, or extent of the bony lesion. The objectives of this work are to (1) assess the feasibility of creating 3D models of cam deformities from MRI sets, (2) present a standardized 2D visualization of the lesion, and (3) present and evaluate the potential utility of summary metrics in distinguishing between FAI patients and control subjects.
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Cetylpyridinium chloride activated trinitrotoluene explosive lights up robust and ultrahigh surface-enhanced resonance Raman scattering in a silver sol.
Chemistry
PUBLISHED: 03-02-2013
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Surface-enhanced resonance Raman scattering (SERRS) is not realized for most molecules of interest. Here, we developed a new SERRS platform for the fast and sensitive detection of 2,4,6-trinitrotoluene (TNT), a molecule with low Raman cross section. A cationic surfactant, cetylpyridinium chloride (CPC) was modified on the surface of silver sols (CP-capped Ag). CPC not only acts as the surface-seeking species to trap sulfite-sulfonated TNT, but also undergoes complexation with it, resulting in the presence of two charge-transfer bands at 467 and 530 nm, respectively. This chromophore absorbs the visible light that matches with the incident laser and plasmon resonance of Ag sols by the use of a 532.06 nm laser, and offered large resonance Raman enhancement. This SERRS platform evidenced a fast and accurate detection of TNT with a detection limit of 5×10(-11) M under a low laser power (200 ?W) and a short integration time (3 s). The CP-capped Ag also provides remarkable sensitivity and reliable repeatability. This study provides a facile and reliable method for TNT detection and a viable idea for the SERS detection of various non-resonant molecules.
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Signaling pathways mediating the effects of insulin-like growth factor-I in bovine muscle satellite cells.
Mol. Cell. Endocrinol.
PUBLISHED: 02-28-2013
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The objective of this study was to identify the signaling pathways mediating the effects of IGF-I on muscle cell proliferation, protein synthesis, and protein degradation in a physiologically more relevant muscle cell model. We isolated muscle satellite cells from adult cattle and expanded them as myoblasts or induced them to form myotubes in culture. We determined the effects of IGF-I on proliferation of myoblasts and protein synthesis and degradation in myotubes in the presence or absence of specific signaling inhibitors. Our data suggest that both the MEK/ERK and PI3K/AKT pathways mediate the stimulatory effect of IGF-I on myoblast proliferation and that the PI3K/AKT pathway mediates this effect through cyclin D2. Our data also suggest that both the MEK/ERK and PI3K/AKT pathways mediate the stimulatory effect of IGF-I on protein synthesis through p70S6K and that the PI3K/AKT pathway mediates the inhibitory effect of IGF-I on protein degradation through FoxO3a.
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Epigenetic analysis leads to identification of HNF1B as a subtype-specific susceptibility gene for ovarian cancer.
Hui Shen, Brooke L Fridley, Honglin Song, Kate Lawrenson, Julie M Cunningham, Susan J Ramus, Mine S Cicek, Jonathan Tyrer, Douglas Stram, Melissa C Larson, Martin Köbel, , Argyrios Ziogas, Wei Zheng, Hannah P Yang, Anna H Wu, Eva L Wozniak, Yin Ling Woo, Boris Winterhoff, Elisabeth Wik, Alice S Whittemore, Nicolas Wentzensen, Rachel Palmieri Weber, Allison F Vitonis, Daniel Vincent, Robert A Vierkant, Ignace Vergote, David Van Den Berg, Anne M Van Altena, Shelley S Tworoger, Pamela J Thompson, Daniel C Tessier, Kathryn L Terry, Soo-Hwang Teo, Claire Templeman, Daniel O Stram, Melissa C Southey, Weiva Sieh, Nadeem Siddiqui, Yurii B Shvetsov, Xiao-Ou Shu, Viji Shridhar, Shan Wang-Gohrke, Gianluca Severi, Ira Schwaab, Helga B Salvesen, Iwona K Rzepecka, Ingo B Runnebaum, Mary Anne Rossing, Lorna Rodriguez-Rodriguez, Harvey A Risch, Stefan P Renner, Elizabeth M Poole, Malcolm C Pike, Catherine M Phelan, Liisa M Pelttari, Tanja Pejovic, James Paul, Irene Orlow, Siti Zawiah Omar, Sara H Olson, Kunle Odunsi, Stefan Nickels, Heli Nevanlinna, Roberta B Ness, Steven A Narod, Toru Nakanishi, Kirsten B Moysich, Alvaro N A Monteiro, Joanna Moes-Sosnowska, Francesmary Modugno, Usha Menon, John R McLaughlin, Valerie McGuire, Keitaro Matsuo, Noor Azmi Mat Adenan, Leon F A G Massuger, Galina Lurie, Lene Lundvall, Jan Lubiński, Jolanta Lissowska, Douglas A Levine, Arto Leminen, Alice W Lee, Nhu D Le, Sandrina Lambrechts, Diether Lambrechts, Jolanta Kupryjanczyk, Camilla Krakstad, Gottfried E Konecny, Susanne Krüger Kjaer, Lambertus A Kiemeney, Linda E Kelemen, Gary L Keeney, Beth Y Karlan, Rod Karevan, Kimberly R Kalli, Hiroaki Kajiyama, Bu-Tian Ji, Allan Jensen, Anna Jakubowska, Edwin Iversen, Satoyo Hosono, Claus K Høgdall, Estrid Høgdall, Maureen Hoatlin, Peter Hillemanns, Florian Heitz, Rebecca Hein, Philipp Harter, Mari K Halle, Per Hall, Jacek Gronwald, Martin Gore, Marc T Goodman, Graham G Giles, Aleksandra Gentry-Maharaj, Montserrat Garcia-Closas, James M Flanagan, Peter A Fasching, Arif B Ekici, Robert Edwards, Diana Eccles, Douglas F Easton, Matthias Dürst, Andreas du Bois, Thilo Dörk, Jennifer A Doherty, Evelyn Despierre, Agnieszka Dansonka-Mieszkowska, Cezary Cybulski, Daniel W Cramer, Linda S Cook, Xiaoqing Chen, Bridget Charbonneau, Jenny Chang-Claude, Ian Campbell, Ralf Bützow, Clareann H Bunker, Doerthe Brueggmann, Robert Brown, Angela Brooks-Wilson, Louise A Brinton, Natalia Bogdanova, Matthew S Block, Elizabeth Benjamin, Jonathan Beesley, Matthias W Beckmann, Elisa V Bandera, Laura Baglietto, Francois Bacot, Sebastian M Armasu, Natalia Antonenkova, Hoda Anton-Culver, Katja K Aben, Dong Liang, Xifeng Wu, Karen Lu, Michelle A T Hildebrandt, Joellen M Schildkraut, Thomas A Sellers, David Huntsman, Andrew Berchuck, Georgia Chenevix-Trench, Simon A Gayther, Paul D P Pharoah, Peter W Laird, Ellen L Goode, Celeste Leigh Pearce.
Nat Commun
PUBLISHED: 02-21-2013
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HNF1B is overexpressed in clear cell epithelial ovarian cancer, and we observed epigenetic silencing in serous epithelial ovarian cancer, leading us to hypothesize that variation in this gene differentially associates with epithelial ovarian cancer risk according to histological subtype. Here we comprehensively map variation in HNF1B with respect to epithelial ovarian cancer risk and analyse DNA methylation and expression profiles across histological subtypes. Different single-nucleotide polymorphisms associate with invasive serous (rs7405776 odds ratio (OR)=1.13, P=3.1 × 10(-10)) and clear cell (rs11651755 OR=0.77, P=1.6 × 10(-8)) epithelial ovarian cancer. Risk alleles for the serous subtype associate with higher HNF1B-promoter methylation in these tumours. Unmethylated, expressed HNF1B, primarily present in clear cell tumours, coincides with a CpG island methylator phenotype affecting numerous other promoters throughout the genome. Different variants in HNF1B associate with risk of serous and clear cell epithelial ovarian cancer; DNA methylation and expression patterns are also notably distinct between these subtypes. These findings underscore distinct mechanisms driving different epithelial ovarian cancer histological subtypes.
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Identification and molecular characterization of a new ovarian cancer susceptibility locus at 17q21.31.
Jennifer Permuth-Wey, Kate Lawrenson, Howard C Shen, Aneliya Velkova, Jonathan P Tyrer, Zhihua Chen, Hui-Yi Lin, Y Ann Chen, Ya-Yu Tsai, Xiaotao Qu, Susan J Ramus, Rod Karevan, Janet Lee, Nathan Lee, Melissa C Larson, Katja K Aben, Hoda Anton-Culver, Natalia Antonenkova, Antonis C Antoniou, Sebastian M Armasu, , Francois Bacot, Laura Baglietto, Elisa V Bandera, Jill Barnholtz-Sloan, Matthias W Beckmann, Michael J Birrer, Greg Bloom, Natalia Bogdanova, Louise A Brinton, Angela Brooks-Wilson, Robert Brown, Ralf Bützow, Qiuyin Cai, Ian Campbell, Jenny Chang-Claude, Stephen Chanock, Georgia Chenevix-Trench, Jin Q Cheng, Mine S Cicek, Gerhard A Coetzee, Linda S Cook, Fergus J Couch, Daniel W Cramer, Julie M Cunningham, Agnieszka Dansonka-Mieszkowska, Evelyn Despierre, Jennifer A Doherty, Thilo Dörk, Andreas du Bois, Matthias Dürst, Douglas F Easton, Diana Eccles, Robert Edwards, Arif B Ekici, Peter A Fasching, David A Fenstermacher, James M Flanagan, Montserrat Garcia-Closas, Aleksandra Gentry-Maharaj, Graham G Giles, Rosalind M Glasspool, Jesus Gonzalez-Bosquet, Marc T Goodman, Martin Gore, Bohdan Górski, Jacek Gronwald, Per Hall, Mari K Halle, Philipp Harter, Florian Heitz, Peter Hillemanns, Maureen Hoatlin, Claus K Høgdall, Estrid Høgdall, Satoyo Hosono, Anna Jakubowska, Allan Jensen, Heather Jim, Kimberly R Kalli, Beth Y Karlan, Stanley B Kaye, Linda E Kelemen, Lambertus A Kiemeney, Fumitaka Kikkawa, Gottfried E Konecny, Camilla Krakstad, Susanne Krüger Kjaer, Jolanta Kupryjanczyk, Diether Lambrechts, Sandrina Lambrechts, Johnathan M Lancaster, Nhu D Le, Arto Leminen, Douglas A Levine, Dong Liang, Boon Kiong Lim, Jie Lin, Jolanta Lissowska, Karen H Lu, Jan Lubiński, Galina Lurie, Leon F A G Massuger, Keitaro Matsuo, Valerie McGuire, John R McLaughlin, Usha Menon, Francesmary Modugno, Kirsten B Moysich, Toru Nakanishi, Steven A Narod, Lotte Nedergaard, Roberta B Ness, Heli Nevanlinna, Stefan Nickels, Houtan Noushmehr, Kunle Odunsi, Sara H Olson, Irene Orlow, James Paul, Celeste L Pearce, Tanja Pejovic, Liisa M Pelttari, Malcolm C Pike, Elizabeth M Poole, Paola Raska, Stefan P Renner, Harvey A Risch, Lorna Rodriguez-Rodriguez, Mary Anne Rossing, Anja Rudolph, Ingo B Runnebaum, Iwona K Rzepecka, Helga B Salvesen, Ira Schwaab, Gianluca Severi, Viji Shridhar, Xiao-Ou Shu, Yurii B Shvetsov, Weiva Sieh, Honglin Song, Melissa C Southey, Beata Spiewankiewicz, Daniel Stram, Rebecca Sutphen, Soo-Hwang Teo, Kathryn L Terry, Daniel C Tessier, Pamela J Thompson, Shelley S Tworoger, Anne M Van Altena, Ignace Vergote, Robert A Vierkant, Daniel Vincent, Allison F Vitonis, Shan Wang-Gohrke, Rachel Palmieri Weber, Nicolas Wentzensen, Alice S Whittemore, Elisabeth Wik, Lynne R Wilkens, Boris Winterhoff, Yin Ling Woo, Anna H Wu, Yong-Bing Xiang, Hannah P Yang, Wei Zheng, Argyrios Ziogas, Famida Zulkifli, Catherine M Phelan, Edwin Iversen, Joellen M Schildkraut, Andrew Berchuck, Brooke L Fridley, Ellen L Goode, Paul D P Pharoah, Alvaro N A Monteiro, Thomas A Sellers, Simon A Gayther.
Nat Commun
PUBLISHED: 02-18-2013
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Epithelial ovarian cancer (EOC) has a heritable component that remains to be fully characterized. Most identified common susceptibility variants lie in non-protein-coding sequences. We hypothesized that variants in the 3 untranslated region at putative microRNA (miRNA)-binding sites represent functional targets that influence EOC susceptibility. Here, we evaluate the association between 767 miRNA-related single-nucleotide polymorphisms (miRSNPs) and EOC risk in 18,174 EOC cases and 26,134 controls from 43 studies genotyped through the Collaborative Oncological Gene-environment Study. We identify several miRSNPs associated with invasive serous EOC risk (odds ratio=1.12, P=10(-8)) mapping to an inversion polymorphism at 17q21.31. Additional genotyping of non-miRSNPs at 17q21.31 reveals stronger signals outside the inversion (P=10(-10)). Variation at 17q21.31 is associated with neurological diseases, and our collaboration is the first to report an association with EOC susceptibility. An integrated molecular analysis in this region provides evidence for ARHGAP27 and PLEKHM1 as candidate EOC susceptibility genes.
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Pioglitazone protects against renal ischemia-reperfusion injury by enhancing antioxidant capacity.
J. Surg. Res.
PUBLISHED: 02-16-2013
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In our previous study, we showed that pioglitazone exerts protective effects on renal ischemia-reperfusion injury (IRI) in mice by abrogating renal cell apoptosis. Oxidative stress due to excessive production of reactive oxygen species and subsequent lipid peroxidation plays a critical role in renal IRI. The purpose of the current study is to demonstrate the effect of pioglitazone on renal IRI by modulation of oxidative stress.
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Cigarette smoking and risk of ovarian cancer: a pooled analysis of 21 case-control studies.
Cancer Causes Control
PUBLISHED: 02-11-2013
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The majority of previous studies have observed an increased risk of mucinous ovarian tumors associated with cigarette smoking, but the association with other histological types is unclear. In a large pooled analysis, we examined the risk of epithelial ovarian cancer associated with multiple measures of cigarette smoking with a focus on characterizing risks according to tumor behavior and histology.
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Fenofibrate increases serum vaspin by upregulating its expression in adipose tissue.
Endocrine
PUBLISHED: 02-05-2013
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Fenofibrate is a peroxisome proliferator-activated receptor-? that has been clinically used to treat dyslipidemia and insulin resistance. To better understand the molecular mechanisms underlying fenofibrate action, we investigated whether fenofibrate affects serum levels of vaspin, an adipocytokine that has recently been shown to link obesity and insulin resistance. Fenofibrate treatment significantly increased serum vaspin levels of dyslipidemic patients, which correlated with reduced body weight and increased insulin sensitivity. To elucidate the biochemical mechanisms of fenofibrate action, we investigated the effect of fenofibrate on vaspin mRNA and protein expressions in obese rats. Fenofibrate greatly increased vaspin mRNA and protein levels in visceral adipose tissue consisting of retroperitoneal, mesenteric, and periepididymal adipose tissue but not in the subcutaneous adipose tissue, which correlated with increased serum vaspin levels and increased insulin sensitivity in obese rats. Consistent with a direct effect on vaspin expression, fenofibrate treatment significantly increased the mRNA and protein expression levels of vaspin in 3T3-L1 adipocytes. Together, our results demonstrate for the first time that fenofibrate upregulates vaspin expression in dyslipidemic human subjects and suggest that upregulation of vaspin expression in adipocytes may provide a mechanism by which fenofibrate improves insulin sensitivity in dyslipidemic patients.
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SERS and OWGS detection of dynamic trapping molecular TNT based on a functional self-assembly Au monolayer film.
Analyst
PUBLISHED: 02-04-2013
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A gold monolayer film and cysteine layer-by-layer self-assemble onto modified glasses, and through the use of optical waveguide spectroscopy (OWGS) and a dynamic SERS technique for the first time to study the dynamic generation process of the Meisenheimer complex between TNT and cysteine. This strategy can detect TNT down to 1 nM with high sensitivity and selectivity.
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What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

How does it work?

We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

Video X seems to be unrelated to Abstract Y...

In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.