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  • 1
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    Genomic modelling of the ESR1 Y537S mutation for evaluating function and new therapeutic approaches for metastatic breast cancer (2017)
    Nature Publishing Group (NPG)
    In: Oncogene
    Details
    Publikationsdatum: 2017-04-21
    Beschreibung: Genomic modelling of the ESR1 Y537S mutation for evaluating function and new therapeutic approaches for metastatic breast cancer Oncogene 36, 2286 (20 April 2017). doi:10.1038/onc.2016.382 Authors: A Harrod, J Fulton, V T M Nguyen, M Periyasamy, L Ramos-Garcia, C-F Lai, G Metodieva, A de Giorgio, R L Williams, D B Santos, P J Gomez, M-L Lin, M V Metodiev, J Stebbing, L Castellano, L Magnani, R C Coombes, L Buluwela & S Ali
    Print ISSN: 0950-9232
    Thema: Medizin
    Publiziert von Nature Publishing Group (NPG)
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 2
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    A functional synonymous mutation in melanoma [Genetics] (2013)
    National Academy of Sciences
    Details
    Publikationsdatum: 2013-08-14
    Beschreibung: Synonymous mutations, which do not alter the protein sequence, have been shown to affect protein function [Sauna ZE, Kimchi-Sarfaty C (2011) Nat Rev Genet 12(10):683–691]. However, synonymous mutations are rarely investigated in the cancer genomics field. We used whole-genome and -exome sequencing to identify somatic mutations in 29 melanoma samples....
    Print ISSN: 0027-8424
    Digitale ISSN: 1091-6490
    Thema: Biologie , Medizin , Allgemeine Naturwissenschaft
    Publiziert von National Academy of Sciences
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 3
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    TOPS: Trial Of Prevention Strategies for low back pain in patients recently recovered from low back pain--study rationale and protocol (2016)
    BMJ Publishing
    In: BMJ Open
    Details
    Publikationsdatum: 2016-05-25
    Beschreibung: Introduction Low back pain (LBP) is the health condition that carries the greatest disability burden worldwide; however, there is only modest support for interventions to prevent LBP. The aim of this trial is to establish the effectiveness and cost-effectiveness of group-based exercise and educational classes compared with a minimal intervention control in preventing recurrence of LBP in people who have recently recovered from an episode of LBP. Methods and analysis TOPS will be a pragmatic comparative effectiveness randomised clinical trial with a parallel economic evaluation combining three separate cohorts (TOPS Workers, TOPS Primary Care, TOPS Defence) with the same methodology. 1482 participants who have recently recovered from LBP will be randomised to either a comprehensive exercise and education programme or a minimal intervention control. Participants will be followed up for a minimum of 1 year. The primary outcome will be days till recurrence of LBP. Effectiveness will be assessed using survival analysis. Cost-effectiveness will be assessed from the societal perspective. Ethics and dissemination This trial has been approved by the University of Sydney Human Research Ethics Committee (HREC) (ref: 2015/728) and prospectively registered with the Australian and New Zealand Clinical Trials Registry (ref: 12615000939594). We will also obtain ethics approval from the Australian Defence Force HREC. The results of this study will be submitted for publication in a prominent journal and widely publicised in the general media. Trial registration number Australian and New Zealand Clinical Trial Registry (ANZCTR) 12615000939594.
    Schlagwort(e): Open access, Public health, Sports and exercise medicine
    Digitale ISSN: 2044-6055
    Thema: Medizin
    Publiziert von BMJ Publishing
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  • 4
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    Paternal occupation and birth defects: findings from the National Birth Defects Prevention Study (2012)
    BMJ Publishing Group
    Details
    Publikationsdatum: 2012-07-14
    Beschreibung: Objectives Several epidemiological studies have suggested that certain paternal occupations may be associated with an increased prevalence of birth defects in offspring. Using data from the National Birth Defects Prevention Study, the authors investigated the association between paternal occupation and birth defects in a case–control study of cases comprising over 60 different types of birth defects (n=9998) and non-malformed controls (n=4066) with dates of delivery between 1997 and 2004. Methods Using paternal occupational histories reported by mothers via telephone interview, jobs were systematically classified into 63 groups based on shared exposure profiles within occupation and industry. Data were analysed using Bayesian logistic regression with a hierarchical prior for dependent shrinkage to stabilise estimation with sparse data. Results Several occupations were associated with an increased prevalence of various birth defect categories, including mathematical, physical and computer scientists; artists; photographers and photo processors; food service workers; landscapers and groundskeepers; hairdressers and cosmetologists; office and administrative support workers; sawmill workers; petroleum and gas workers; chemical workers; printers; material moving equipment operators; and motor vehicle operators. Conclusions Findings from this study might be used to identify specific occupations worthy of further investigation and to generate hypotheses about chemical or physical exposures common to such occupations.
    Schlagwort(e): Press releases
    Print ISSN: 1351-0711
    Digitale ISSN: 1470-7926
    Thema: Medizin
    Publiziert von BMJ Publishing Group
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 5
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    Prolonged Antigen Presentation following an Acute Virus Infection Requires Direct and Then Cross-Presentation [INFECTIOUS DISEASE AND HOST RESPONSE] (2014)
    The American Association of Immunologists (AAI)
    Details
    Publikationsdatum: 2014-10-04
    Beschreibung: Antiviral CD8 + T cell recognition of MHC class I–peptide complexes on the surface of professional APCs is a requisite step in an effective immune response following many potentially lethal infections. Although MHC class I–peptide production is thought to be closely linked to the continued presence of virus, several studies have shown that the persistence of Ag presentation occurs for an extended period of time following the clearance of RNA viruses. However, the mechanism responsible for Ag presentation persistence following viral clearance was unknown until now. In this study, we used a recombinant DNA virus expressing different forms of a model Ag to study the mechanism of prolonged Ag presentation in mice. We determined that the persistence of Ag presentation consists of three distinct mechanistic phases, as follows: ongoing viral replication, persistence of virally infected cells, and cross-presentation of Ag. These data will allow manipulation of the form of Ag contained within viral vectors to produce the most effective and protective CD8 + T cell response to be generated following vaccination.
    Print ISSN: 0022-1767
    Digitale ISSN: 1550-6606
    Thema: Medizin
    Publiziert von The American Association of Immunologists (AAI)
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 6
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    HSP90 empowers evolution of hormone resistance [Medical Sciences] (2014)
    National Academy of Sciences
    Details
    Publikationsdatum: 2014-12-24
    Beschreibung: The efficacy of hormonal therapies for advanced estrogen receptor-positive breast cancers is limited by the nearly inevitable development of acquired resistance. Efforts to block the emergence of resistance have met with limited success, largely because the mechanisms underlying it are so varied and complex. Here, we investigate a new strategy...
    Print ISSN: 0027-8424
    Digitale ISSN: 1091-6490
    Thema: Biologie , Medizin , Allgemeine Naturwissenschaft
    Publiziert von National Academy of Sciences
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 7
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    The Drug-Drug Effects of Rhein on the Pharmacokinetics and Pharmacodynamics of Clozapine in Rat Brain Extracellular Fluid by In Vivo Microdialysis [Metabolism, Transport, and Pharmacogenomics] (2015)
    The American Society for Pharmacology and Experimental Therapeutics
    Details
    Publikationsdatum: 2015-09-10
    Beschreibung: Clozapine, an atypical antipsychotic agent, is highly effective in treatment-resistant schizophrenia; however, its major side effect is constipation. Instead of laxatives, rhein is a pharmacologically active component found in Rheum palmatum L., a medicinal herbal remedy for constipation. The purpose of this study is to determine whether rhein impacts the pharmacokinetics (PK) and pharmacodynamics (PD) of clozapine in brain when used to relieve clozapine-induced constipation. Here, we have investigated not only the PK of clozapine in blood but also the effects of rhein on the PK of clozapine in blood and in brain extracellular fluid together with the PD effects on neurotransmitters in extracellular fluid. The concentrations of clozapine and norclozapine in biologic samples were measured by ultra-performance liquid chromatography–tandem mass spectrometry. The drug-drug effects of rhein on extracellular neurotransmitter efflux in the rat medial prefrontal cortex (mPFC) produced by clozapine were assayed by high-performance liquid chromatography–electrochemical detection. The results demonstrate that the clozapine PK was nonlinear. Pretreatment with rhein for 7 days increased the total blood concentration of clozapine, but significantly reduced the unbound clozapine concentrations in the mPFC by approximately 3-fold. Furthermore, 7 days of rhein pretreatment thoroughly abolished the efflux of dopamine and its metabolite (3,4-dihydroxyphenylacetic acid) and altered the profile of homovanillic acid, another metabolite of dopamine, in the mPFC. In conclusion, rhein was found to substantially decrease clozapine and norclozapine concentrations in the mPFC dialysate, and this is accompanied by lower concentrations in the neurotransmitters in the same biophase. These findings suggest that a detailed clinical study for drug-drug interactions is recommended.
    Print ISSN: 0022-3565
    Digitale ISSN: 1521-0103
    Thema: Medizin
    Publiziert von The American Society for Pharmacology and Experimental Therapeutics
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 8
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    Regulation of CTP Synthase Filament Formation During DNA Endoreplication in Drosophila [Developmental and Behavioral Genetics] (2015)
    Genetics Society of America (GSA)
    In: Genetics
    Details
    Publikationsdatum: 2015-12-08
    Beschreibung: CTP synthase (CTPsyn) plays an essential role in DNA, RNA, and lipid synthesis. Recent studies in bacteria, yeast, and Drosophila all reveal a polymeric CTPsyn structure, which dynamically regulates its enzymatic activity. However, the molecular mechanism underlying the formation of CTPsyn polymers is not completely understood. In this study, we found that reversible ubiquitination regulates the dynamic assembly of the filamentous structures of Drosophila CTPsyn. We further determined that the proto-oncogene Cbl, an E3 ubiquitin ligase, controls CTPsyn filament formation in endocycles. While the E3 ligase activity of Cbl is required for CTPsyn filament formation, Cbl does not affect the protein levels of CTPsyn. It remains unclear whether the regulation of CTPsyn filaments by Cbl is through direct ubiquitination of CTPsyn. In the absence of Cbl or with knockdown of CTPsyn, the progression of the endocycle-associated S phase was impaired. Furthermore, overexpression of wild-type, but not enzymatically inactive CTPsyn, rescued the endocycle defect in Cbl mutant cells. Together, these results suggest that Cbl influences the nucleotide pool balance and controls CTPsyn filament formation in endocycles. This study links Cbl-mediated ubiquitination to the polymerization of a metabolic enzyme and reveals a role for Cbl in endocycles during Drosophila development.
    Print ISSN: 0016-6731
    Thema: Biologie
    Publiziert von Genetics Society of America (GSA)
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  • 9
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    Hepatic Fibrosis Is Universal Following Fontan Operation, and Severity is Associated With Time From Surgery: A Liver Biopsy and Hemodynamic Study [Congenital Heart Disease] (2017)
    American Heart Association (AHA)
    Details
    Publikationsdatum: 2017-06-01
    Beschreibung: BackgroundCongestive hepatopathy is a recognized complication of Fontan physiology. Data regarding the incidence of hepatopathy and risk factors are lacking.Methods and ResultsLiver biopsies and cardiac catherizations were performed as part of an evaluation offered to all patients ≥10 years after Fontan. Quantitative determination of hepatic fibrosis was performed using Sirius red staining with automated calculation of collagen deposition per slide (%CD). Biopsies from included subjects were compared to stained specimens from controls without known fibrotic liver disease. Patient characteristics, echocardiographic findings, and hemodynamic measures were evaluated as potential risk factors. The cohort consisted of 67 patients (31 female) at mean age of 17.3±4.5 years and mean time from Fontan of 14.9±4.5 years. Right ventricular morphology was present in 37 subjects. Median %CD by Sirius red staining was 21.6% (range 8.7% to 49.4%) compared to 2.6% (range 2.2% to 3.0%) in controls. There was a significant correlation between time from Fontan and degree of Sirius red staining (r=0.33, P
    Schlagwort(e): Fibrosis, Congenital Heart Disease, Heart Failure
    Digitale ISSN: 2047-9980
    Thema: Medizin
    Publiziert von American Heart Association (AHA)
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 10
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    Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma (2011)
    Nature Publishing Group (NPG)
    Details
    Publikationsdatum: 2011-01-21
    Beschreibung: The genetics of renal cancer is dominated by inactivation of the VHL tumour suppressor gene in clear cell carcinoma (ccRCC), the commonest histological subtype. A recent large-scale screen of approximately 3,500 genes by PCR-based exon re-sequencing identified several new cancer genes in ccRCC including UTX (also known as KDM6A), JARID1C (also known as KDM5C) and SETD2 (ref. 2). These genes encode enzymes that demethylate (UTX, JARID1C) or methylate (SETD2) key lysine residues of histone H3. Modification of the methylation state of these lysine residues of histone H3 regulates chromatin structure and is implicated in transcriptional control. However, together these mutations are present in fewer than 15% of ccRCC, suggesting the existence of additional, currently unidentified cancer genes. Here, we have sequenced the protein coding exome in a series of primary ccRCC and report the identification of the SWI/SNF chromatin remodelling complex gene PBRM1 (ref. 4) as a second major ccRCC cancer gene, with truncating mutations in 41% (92/227) of cases. These data further elucidate the somatic genetic architecture of ccRCC and emphasize the marked contribution of aberrant chromatin biology.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3030920/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3030920/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Varela, Ignacio -- Tarpey, Patrick -- Raine, Keiran -- Huang, Dachuan -- Ong, Choon Kiat -- Stephens, Philip -- Davies, Helen -- Jones, David -- Lin, Meng-Lay -- Teague, Jon -- Bignell, Graham -- Butler, Adam -- Cho, Juok -- Dalgliesh, Gillian L -- Galappaththige, Danushka -- Greenman, Chris -- Hardy, Claire -- Jia, Mingming -- Latimer, Calli -- Lau, King Wai -- Marshall, John -- McLaren, Stuart -- Menzies, Andrew -- Mudie, Laura -- Stebbings, Lucy -- Largaespada, David A -- Wessels, L F A -- Richard, Stephane -- Kahnoski, Richard J -- Anema, John -- Tuveson, David A -- Perez-Mancera, Pedro A -- Mustonen, Ville -- Fischer, Andrej -- Adams, David J -- Rust, Alistair -- Chan-on, Waraporn -- Subimerb, Chutima -- Dykema, Karl -- Furge, Kyle -- Campbell, Peter J -- Teh, Bin Tean -- Stratton, Michael R -- Futreal, P Andrew -- 077012/Wellcome Trust/United Kingdom -- 077012/Z/05/Z/Wellcome Trust/United Kingdom -- 088340/Wellcome Trust/United Kingdom -- 093867/Wellcome Trust/United Kingdom -- R01 CA113636/CA/NCI NIH HHS/ -- R01 CA134759/CA/NCI NIH HHS/ -- Cancer Research UK/United Kingdom -- England -- Nature. 2011 Jan 27;469(7331):539-42. doi: 10.1038/nature09639. Epub 2011 Jan 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21248752" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Animals ; Carcinoma, Renal Cell/*genetics ; Cell Line, Tumor ; Disease Models, Animal ; Gene Expression Regulation ; Gene Knockdown Techniques ; Humans ; Kidney Neoplasms/*genetics ; Mice ; Mutation/*genetics ; Nuclear Proteins/*genetics/*metabolism ; Pancreatic Neoplasms/genetics ; Transcription Factors/*genetics/*metabolism
    Print ISSN: 0028-0836
    Digitale ISSN: 1476-4687
    Thema: Biologie , Chemie und Pharmazie , Medizin , Allgemeine Naturwissenschaft , Physik
    Publiziert von Nature Publishing Group (NPG)
    Standort Signatur Einschränkungen Verfügbarkeit
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