Showing papers by "Cardiff University published in 2011"
Université Paris-Saclay1, Cross Cancer Institute2, University of British Columbia3, Nevada Cancer Institute4, Université de Montréal5, Cardiff University6, University of Colorado Denver7, Baylor University Medical Center8, University of Calgary9, Sarah Cannon Research Institute10, University of California, San Francisco11, Memorial Sloan Kettering Cancer Center12
TL;DR: The inhibition of androgen biosynthesis by abiraterone acetate prolonged overall survival among patients with metastatic castration-resistant prostate cancer who previously received chemotherapy.
Abstract: BACKGROUND Biosynthesis of extragonadal androgen may contribute to the progression of castration-resistant prostate cancer. We evaluated whether abiraterone acetate, an inhibitor of androgen biosynthesis, prolongs overall survival among patients with metastatic castration-resistant prostate cancer who have received chemotherapy. METHODS We randomly assigned, in a 2:1 ratio, 1195 patients who had previously received docetaxel to receive 5 mg of prednisone twice daily with either 1000 mg of abiraterone acetate (797 patients) or placebo (398 patients). The primary end point was overall survival. The secondary end points included time to prostate-specific antigen (PSA) progression (elevation in the PSA level according to prespecified criteria), progression-free survival according to radiologic findings based on prespecified criteria, and the PSA response rate. RESULTS After a median follow-up of 12.8 months, overall survival was longer in the abiraterone acetate–prednisone group than in the placebo–prednisone group (14.8 months vs. 10.9 months; hazard ratio, 0.65; 95% confidence interval, 0.54 to 0.77; P<0.001). Data were unblinded at the interim analysis, since these results exceeded the preplanned criteria for study termination. All secondary end points, including time to PSA progression (10.2 vs. 6.6 months; P<0.001), progression-free survival (5.6 months vs. 3.6 months; P<0.001), and PSA response rate (29% vs. 6%, P<0.001), favored the treatment group. Mineralocorticoid-related adverse events, including fluid retention, hypertension, and hypokalemia, were more frequently reported in the abiraterone acetate–prednisone group than in the placebo–prednisone group. CONCLUSIONS The inhibition of androgen biosynthesis by abiraterone acetate prolonged overall survival among patients with metastatic castration-resistant prostate cancer who previously received chemotherapy. (Funded by Cougar Biotechnology; COU-AA-301 ClinicalTrials.gov number, NCT00638690.)
3,875 citations
National Institutes of Health1, Cardiff University2, VU University Amsterdam3, Erasmus University Rotterdam4, University of Manchester5, University College London6, University of Helsinki7, University of Oulu8, Georgetown University9, Johns Hopkins University10, Illumina11, University Hospital of Wales12, University of Eastern Finland13, University of Miami14, University of Turin15, University of Cagliari16, The Catholic University of America17, Microsoft18, University of Toronto19, University of Würzburg20, University of Washington21, Aneurin Bevan University Health Board22
TL;DR: The chromosome 9p21 amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) locus contains one of the last major unidentified autosomal-dominant genes underlying these common neurodegenerative diseases, and a large hexanucleotide repeat expansion in the first intron of C9ORF72 is shown.
3,784 citations
Brigham and Women's Hospital1, Boston University2, University of California, Los Angeles3, Boston Children's Hospital4, University of Alabama at Birmingham5, Stanford University6, Northwestern University7, Aalborg University8, Cardiff University9, University of Pennsylvania10, Erasmus University Rotterdam11, Medical University of South Carolina12
TL;DR: The revised guidelines for the management of thyroid disease in pregnancy include recommendations regarding the interpretation of thyroid function tests in pregnancy, iodine nutrition, thyroid autoantibodies and pregnancy complications, thyroid considerations in infertile women, hypothyroidism in pregnancy and thyrotoxicosis in pregnancy.
Abstract: Background: Thyroid disease in pregnancy is a common clinical problem. Since the guidelines for the management of these disorders by the American Thyroid Association (ATA) were first published in 2...
2,409 citations
TL;DR: Meta-analyses of all data provided compelling evidence that ABCA7 and the MS4A gene cluster are new Alzheimer's disease susceptibility loci and independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance.
Abstract: We sought to identify new susceptibility loci for Alzheimer's disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer's Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P ≤ 1 × 10−5. We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (stage 3). Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 × 10−17; including ADGC data, meta P = 5.0 × 10−21) and the MS4A gene cluster (rs610932, meta P = 1.8 × 10−14; including ADGC data, meta P = 1.2 × 10−16) are new Alzheimer's disease susceptibility loci. We also found independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance: CD2AP (GERAD+, P = 8.0 × 10−4; including ADGC data, meta P = 8.6 × 10−9), CD33 (GERAD+, P = 2.2 × 10−4; including ADGC data, meta P = 1.6 × 10−9) and EPHA1 (GERAD+, P = 3.4 × 10−4; including ADGC data, meta P = 6.0 × 10−10).
1,771 citations
Heribert Schunkert1, Inke R. König1, Sekar Kathiresan2, Muredach P. Reilly3 +163 more•Institutions (59)
TL;DR: This paper performed a meta-analysis of 14 genome-wide association studies of coronary artery disease (CAD) comprising 22,233 individuals with CAD (cases) and 64,762 controls of European descent followed by genotyping of top association signals in 56,682 additional individuals.
Abstract: We performed a meta-analysis of 14 genome-wide association studies of coronary artery disease (CAD) comprising 22,233 individuals with CAD (cases) and 64,762 controls of European descent followed by genotyping of top association signals in 56,682 additional individuals. This analysis identified 13 loci newly associated with CAD at P < 5 - 10'8 and confirmed the association of 10 of 12 previously reported CAD loci. The 13 new loci showed risk allele frequencies ranging from 0.13 to 0.91 and were associated with a 6% to 17% increase in the risk of CAD per allele. Notably, only three of the new loci showed significant association with traditional CAD risk factors and the majority lie in gene regions not previously implicated in the pathogenesis of CAD. Finally, five of the new CAD risk loci appear to have pleiotropic effects, showing strong association with various other human diseases or traits.
1,705 citations
Stephan Ripke1, Alan R. Sanders2, Kenneth S. Kendler3, Douglas F. Levinson4 +207 more•Institutions (71)
TL;DR: The authors examined the role of common genetic variation in schizophrenia in a genome-wide association study of substantial size: a stage 1 discovery sample of 21,856 individuals of European ancestry and a stage 2 replication sample of 29,839 independent subjects.
Abstract: We examined the role of common genetic variation in schizophrenia in a genome-wide association study of substantial size: a stage 1 discovery sample of 21,856 individuals of European ancestry and a stage 2 replication sample of 29,839 independent subjects. The combined stage 1 and 2 analysis yielded genome-wide significant associations with schizophrenia for seven loci, five of which are new (1p21.3, 2q32.3, 8p23.2, 8q21.3 and 10q24.32-q24.33) and two of which have been previously implicated (6p21.32-p22.1 and 18q21.2). The strongest new finding (P = 1.6 x 10(-11)) was with rs1625579 within an intron of a putative primary transcript for MIR137 (microRNA 137), a known regulator of neuronal development. Four other schizophrenia loci achieving genome-wide significance contain predicted targets of MIR137, suggesting MIR137-mediated dysregulation as a previously unknown etiologic mechanism in schizophrenia. In a joint analysis with a bipolar disorder sample (16,374 affected individuals and 14,044 controls), three loci reached genome-wide significance: CACNA1C (rs4765905, P = 7.0 x 10(-9)), ANK3 (rs10994359, P = 2.5 x 10(-8)) and the ITIH3-ITIH4 region (rs2239547, P = 7.8 x 10(-9)).
1,671 citations
TL;DR: A long-lived human memory T cell population that has an enhanced capacity for self-renewal and a multipotent ability to derive central memory, effector memory and effector T cells is described.
Abstract: Immunological memory is thought to depend on a stem cell–like, self-renewing population of lymphocytes capable of differentiating into effector cells in response to antigen re-exposure. Here we describe a long-lived human memory T cell population that has an enhanced capacity for self-renewal and a multipotent ability to derive central memory, effector memory and effector T cells. These cells, specific to multiple viral and self-tumor antigens, were found within a CD45RO−, CCR7+, CD45RA+, CD62L+, CD27+, CD28+ and IL-7Rα+ T cell compartment characteristic of naive T cells. However, they expressed large amounts of CD95, IL-2Rβ, CXCR3, and LFA-1, and showed numerous functional attributes distinctive of memory cells. Compared with known memory populations, these lymphocytes had increased proliferative capacity and more efficiently reconstituted immunodeficient hosts, and they mediated superior antitumor responses in a humanized mouse model. The identification of a human stem cell–like memory T cell population is of direct relevance to the design of vaccines and T cell therapies.
1,526 citations
TL;DR: A rapid and reliable PCR-based technique was developed for detection of genes encoding carbapenemases belonging to different classes using optimized conditions, with PCR giving distinct amplicon sizes corresponding to the different genes for each mixture.
1,438 citations
TL;DR: It is shown that a novel small molecule inhibitor of the BET family, GSK1210151A (I-BET151), has profound efficacy against human and murine MLL-fusion leukaemic cell lines, through the induction of early cell cycle arrest and apoptosis, establishing the displacement of BET proteins from chromatin as a promising epigenetic therapy for these aggressive leukaemias.
Abstract: Recurrent chromosomal translocations involving the mixed lineage leukaemia (MLL) gene initiate aggressive forms of leukaemia, which are often refractory to conventional therapies1. Many MLL-fusion partners are members of the super elongation complex (SEC), a critical regulator of transcriptional elongation, suggesting that aberrant control of this process has an important role in leukaemia induction2, 3. Here we use a global proteomic strategy to demonstrate that MLL fusions, as part of SEC2, 3 and the polymerase-associated factor complex (PAFc)4, 5, are associated with the BET family of acetyl-lysine recognizing, chromatin ‘adaptor’ proteins. These data provided the basis for therapeutic intervention in MLL-fusion leukaemia, via the displacement of the BET family of proteins from chromatin. We show that a novel small molecule inhibitor of the BET family, GSK1210151A (I-BET151), has profound efficacy against human and murine MLL-fusion leukaemic cell lines, through the induction of early cell cycle arrest and apoptosis. I-BET151 treatment in two human leukaemia cell lines with different MLL fusions alters the expression of a common set of genes whose function may account for these phenotypic changes. The mode of action of I-BET151 is, at least in part, due to the inhibition of transcription at key genes (BCL2, C-MYC and CDK6) through the displacement of BRD3/4, PAFc and SEC components from chromatin. In vivo studies indicate that I-BET151 has significant therapeutic value, providing survival benefit in two distinct mouse models of murine MLL–AF9 and human MLL–AF4 leukaemia. Finally, the efficacy of I-BET151 against human leukaemia stem cells is demonstrated, providing further evidence of its potent therapeutic potential. These findings establish the displacement of BET proteins from chromatin as a promising epigenetic therapy for these aggressive leukaemias.
1,388 citations
TL;DR: It is concluded that the fecal microbiota of the elderly shows temporal stability over limited time in the majority of subjects but is characterized by unusual phylum proportions and extreme variability.
Abstract: Alterations in the human intestinal microbiota are linked to conditions including inflammatory bowel disease, irritable bowel syndrome, and obesity. The microbiota also undergoes substantial changes at the extremes of life, in infants and older people, the ramifications of which are still being explored. We applied pyrosequencing of over 40,000 16S rRNA gene V4 region amplicons per subject to characterize the fecal microbiota in 161 subjects aged 65 y and older and 9 younger control subjects. The microbiota of each individual subject constituted a unique profile that was separable from all others. In 68% of the individuals, the microbiota was dominated by phylum Bacteroides, with an average proportion of 57% across all 161 baseline samples. Phylum Firmicutes had an average proportion of 40%. The proportions of some phyla and genera associated with disease or health also varied dramatically, including Proteobacteria, Actinobacteria, and Faecalibacteria. The core microbiota of elderly subjects was distinct from that previously established for younger adults, with a greater proportion of Bacteroides spp. and distinct abundance patterns of Clostridium groups. Analyses of 26 fecal microbiota datasets from 3-month follow-up samples indicated that in 85% of the subjects, the microbiota composition was more like the corresponding time-0 sample than any other dataset. We conclude that the fecal microbiota of the elderly shows temporal stability over limited time in the majority of subjects but is characterized by unusual phylum proportions and extreme variability.
1,387 citations
TL;DR: A summary of the 2010 version of the EAU guidelines on the treatment of advanced, relapsing, and castration-resistant prostate cancer (CRPC) summarise the most recent findings and put them into clinical practice.
TL;DR: An analysis of all 11,974 bipolar disorder cases and 51,792 controls confirmed genome-wide significant evidence of association for CACNA1C and identified a new intronic variant in ODZ4, and a pathway comprised of subunits of calcium channels enriched in bipolar disorder association intervals was identified.
Abstract: We conducted a combined genome-wide association study (GWAS) of 7,481 individuals with bipolar disorder (cases) and 9,250 controls as part of the Psychiatric GWAS Consortium. Our replication study tested 34 SNPs in 4,496 independent cases with bipolar disorder and 42,422 independent controls and found that 18 of 34 SNPs had P < 0.05, with 31 of 34 SNPs having signals with the same direction of effect (P = 3.8 × 10−7). An analysis of all 11,974 bipolar disorder cases and 51,792 controls confirmed genome-wide significant evidence of association for CACNA1C and identified a new intronic variant in ODZ4. We identified a pathway comprised of subunits of calcium channels enriched in bipolar disorder association intervals. Finally, a combined GWAS analysis of schizophrenia and bipolar disorder yielded strong association evidence for SNPs in CACNA1C and in the region of NEK4-ITIH1-ITIH3-ITIH4. Our replication results imply that increasing sample sizes in bipolar disorder will confirm many additional loci.
TL;DR: Current evidence is insufficient to warrant widespread population-based screening by prostate-specific antigen (PSA) for PCa, and these EAU guidelines on PCa summarise the most recent findings and put them into clinical practice.
TL;DR: The presence of NDM-1 β-lactamase-producing bacteria in environmental samples in New Delhi has important implications for people living in the city who are reliant on public water and sanitation facilities.
Abstract: Summary Background Not all patients infected with NDM-1-positive bacteria have a history of hospital admission in India, and extended-spectrum β-lactamases are known to be circulating in the Indian community. We therefore measured the prevalence of the NDM-1 gene in drinking water and seepage samples in New Delhi. Methods Swabs absorbing about 100 μL of seepage water (ie, water pools in streets or rivulets) and 15 mL samples of public tap water were collected from sites within a 12 km radius of central New Delhi, with each site photographed and documented. Samples were transported to the UK and tested for the presence of the NDM-1 gene, bla NDM-1 , by PCR and DNA probing. As a control group, 100 μL sewage effluent samples were taken from the Cardiff Wastewater Treatment Works, Tremorfa, Wales. Bacteria from all samples were recovered and examined for bla NDM-1 by PCR and sequencing. We identified NDM-1-positive isolates, undertook susceptibility testing, and, where appropriate, typed the isolates. We undertook Inc typing on bla NDM-1 -positive plasmids. Transconjugants were created to assess plasmid transfer frequency and its relation to temperature. Findings From Sept 26 to Oct 10, 2010, 171 seepage samples and 50 tap water samples from New Delhi and 70 sewage effluent samples from Cardiff Wastewater Treatment Works were collected. We detected bla NDM-1 in two of 50 drinking-water samples and 51 of 171 seepage samples from New Delhi; the gene was not found in any sample from Cardiff. Bacteria with bla NDM-1 were grown from 12 of 171 seepage samples and two of 50 water samples, and included 11 species in which NDM-1 has not previously been reported, including Shigella boydii and Vibrio cholerae . Carriage by enterobacteria, aeromonads, and V cholera was stable, generally transmissible, and associated with resistance patterns typical for NDM-1; carriage by non-fermenters was unstable in many cases and not associated with typical resistance. 20 strains of bacteria were found in the samples, 12 of which carried bla NDM-1 on plasmids, which ranged in size from 140 to 400 kb. Isolates of Aeromonas caviae and V cholerae carried bla NDM-1 on chromosomes. Conjugative transfer was more common at 30°C than at 25°C or 37°C. Interpretation The presence of NDM-1 β-lactamase-producing bacteria in environmental samples in New Delhi has important implications for people living in the city who are reliant on public water and sanitation facilities. International surveillance of resistance, incorporating environmental sampling as well as examination of clinical isolates, needs to be established as a priority. Funding European Union.
University of London1, International Agency for Research on Cancer2, Canadian Partnership Against Cancer3, Cancer Council Victoria4, Alberta Health Services5, BC Cancer Agency6, Cancer Care Ontario7, National Board of Health8, Karolinska University Hospital9, Karolinska Institutet10, Uppsala University Hospital11, Cardiff University12
TL;DR: In this paper, the first study in a programme to investigate international survival disparities, with the aim of informing health policy to raise standards and reduce inequalities in survival, was presented, where data from population-based cancer registries in 12 jurisdictions in six countries were provided for 2·4 million adults diagnosed with primary colorectal, lung, breast, ovarian, or ovarian cancer during 1995-2007, with follow-up to Dec 31, 2007.
University of St Andrews1, European Southern Observatory2, University of Edinburgh3, Liverpool John Moores University4, University of Nottingham5, Australian Astronomical Observatory6, University of Sussex7, Max Planck Society8, University of Sydney9, Monash University, Clayton campus10, École Polytechnique Fédérale de Lausanne11, Cardiff University12, University of Queensland13, Swinburne University of Technology14, University of Portsmouth15, University of Bristol16, University of Central Lancashire17, University of Melbourne18, Durham University19, University of Hertfordshire20, Carnegie Institution for Science21, University of Western Australia22, Queen Mary University of London23, Imperial College London24
TL;DR: The Galaxy and Mass Assembly (GAMA) survey has been operating since 2008 February on the 3.9m Anglo-Australian Telescope using the AAOmega fibre-fed spectrograph facility to acquire spectra with a resolution of R ≈ 1300 for 120 862 Sloan Digital Sky Survey selected galaxies.
Abstract: The Galaxy and Mass Assembly (GAMA) survey has been operating since 2008 February on the 3.9-m Anglo-Australian Telescope using the AAOmega fibre-fed spectrograph facility to acquire spectra with a resolution of R ≈ 1300 for 120 862 Sloan Digital Sky Survey selected galaxies. The target catalogue constitutes three contiguous equatorial regions centred at 9h (G09), 12h (G12) and 14.5h (G15) each of 12 × 4 deg2 to limiting fluxes of rpet < 19.4, rpet < 19.8 and rpet <19.4 mag, respectively (and additional limits at other wavelengths). Spectra and reliable redshifts have been acquired for over 98 per cent of the galaxies within these limits. Here we present the survey footprint, progression, data reduction, redshifting, re-redshifting, an assessment of data quality after 3 yr, additional image analysis products (including ugrizYJHK photometry, S´ersic profiles and photometric redshifts), observing mask and construction of our core survey catalogue (GamaCore). From this we create three science-ready catalogues: GamaCoreDR1 for public release, which includes data acquired during year 1 of operations within specified magnitude limits (2008 February to April); GamaCoreMainSurvey containing all data above our survey limits for use by the GAMA Team and collaborators; and GamaCore-AtlasSV containing year 1, 2 and 3 data matched to Herschel-ATLAS science demonstration data. These catalogues along with the associated spectra, stamps and profiles can be accessed via the GAMA website: http://www.gama-survey.org/
Indiana University1, Pasteur Institute2, Washington University in St. Louis3, University of British Columbia4, Cubist Pharmaceuticals5, University of Turku6, Lahey Hospital & Medical Center7, Harvard University8, University of Medicine and Dentistry of New Jersey9, The Evergreen State College10, Wayne State University11, Tufts University12, Northeastern University13, University of California, Los Angeles14, University of Notre Dame15, University of Birmingham16, MedImmune17, Rockefeller University18, Université catholique de Louvain19, Cardiff University20, Cold Spring Harbor Laboratory21, Robert Koch Institute22, McMaster University23, University of Oklahoma24
TL;DR: To explore how the problem of antibiotic resistance might best be addressed, a group of 30 scientists from academia and industry gathered at the Banbury Conference Centre in Cold Spring Harbor, New York, USA, from 16 to 18 May 2011.
Abstract: The development and spread of antibiotic resistance in bacteria is a universal threat to both humans and animals that is generally not preventable but can nevertheless be controlled, and it must be tackled in the most effective ways possible. To explore how the problem of antibiotic resistance might best be addressed, a group of 30 scientists from academia and industry gathered at the Banbury Conference Centre in Cold Spring Harbor, New York, USA, from 16 to 18 May 2011. From these discussions there emerged a priority list of steps that need to be taken to resolve this global crisis.
TL;DR: This trial has not confirmed a benefit of addition of cetuximab to oxaliplatin-based chemotherapy in first-line treatment of patients with advanced colorectal cancer, with no evidence of benefit in progression-free or overall survival in KRAS wild-type patients or even in patients selected by additional mutational analysis of their tumours.
TL;DR: In this article, a regional innovation policy model based on the idea of constructing regional advantage is presented, which brings together concepts like related variety, knowledge bases and policy platforms, and the implications of this are traced for evolving platform policies that facilitate economic development within and between regions in action lines appropriate to incorporate the basic principles behind related variety and differentiated knowledge bases.
Abstract: This paper presents a regional innovation policy model based on the idea of constructing regional advantage. This policy model brings together concepts like related variety, knowledge bases and policy platforms. Related variety attaches importance to knowledge spillovers across complementary sectors. The paper categorizes knowledge into ‘analytical’ (science based), ‘synthetic’ (engineering based) and ‘symbolic’ (arts based) in nature, with different requirements of ‘virtual’ and real proximity mixes. The implications of this are traced for evolving ‘platform policies’ that facilitate economic development within and between regions in action lines appropriate to incorporate the basic principles behind related variety and differentiated knowledge bases.
TL;DR: For example, this article found that those who report experience of flooding express more concern over climate change, see it as less uncertain and feel more confident that their actions will have an effect on climate change.
Abstract: One of the reasons that people may not take action to mitigate climate change is that they lack first-hand experience of its potential consequences. From this perspective, individuals who have direct experience of phenomena that may be linked to climate change would be more likely to be concerned by the issue and thus more inclined to undertake sustainable behaviours. So far, the evidence available to test this hypothesis is limited, and in part contradictory1, 2, 3, 4. Here we use national survey data collected from 1,822 individuals across the UK in 2010, to examine the links between direct flooding experience, perceptions of climate change and preparedness to reduce energy use. We show that those who report experience of flooding express more concern over climate change, see it as less uncertain and feel more confident that their actions will have an effect on climate change. Importantly, these perceptual differences also translate into a greater willingness to save energy to mitigate climate change. Highlighting links between local weather events and climate change is therefore likely to be a useful strategy for increasing concern and action.
TL;DR: In this paper, the authors demonstrate the squeezed-light enhancement of GEO600, which will be the GW observatory operated by the LIGO Scientific Collaboration in its search for GWs for the next 3-4 years.
Abstract: Around the globe several observatories are seeking the first direct detection of gravitational waves (GWs). These waves are predicted by Einstein’s general theory of relativity1 and are generated, for example, by black-hole binary systems2. Present GW detectors are Michelson-type kilometre-scale laser interferometers measuring the distance changes between mirrors suspended in vacuum. The sensitivity of these detectors at frequencies above several hundred hertz is limited by the vacuum (zero-point) fluctuations of the electromagnetic field. A quantum technology—the injection of squeezed light3—offers a solution to this problem. Here we demonstrate the squeezed-light enhancement of GEO 600, which will be the GW observatory operated by the LIGO Scientific Collaboration in its search for GWs for the next 3–4 years. GEO 600 now operates with its best ever sensitivity, which proves the usefulness of quantum entanglement and the qualification of squeezed light as a key technology for future GW astronomy4.
Medical Research Council1, University of Oxford2, National Institute for Health Research3, Structural Genomics Consortium4, University of Bristol5, University of Bath6, University of Queensland7, National Institutes of Health8, Cedars-Sinai Medical Center9, University of Toronto10, University of Alberta11, Memorial University of Newfoundland12, University of Leeds13, Norfolk and Norwich University Hospital14, Repatriation General Hospital15, University of Porto16, Sapienza University of Rome17, QIMR Berghofer Medical Research Institute18, Second Military Medical University19, Telethon Institute for Child Health Research20, Wellcome Trust Sanger Institute21, University of London22, Trinity College, Dublin23, Cardiff University24, Wellcome Trust25, Wellcome Trust Centre for Human Genetics26, St George's, University of London27, King's College London28, Churchill Hospital29, University of Leicester30, University of Cambridge31, Moorfields Eye Hospital32, University College London33, University of Texas Health Science Center at Houston34, Princess Alexandra Hospital35
TL;DR: In this paper, the identification of three variants in the RUNX3, LTBR-TNFRSF1A and IL12B regions convincingly associated with ankylosing spondylitis (P < 5 x 10(-8) in the combined discovery and replication datasets) and a further four loci at PTGER4, TBKBP1, ANTXR2 and CARD9 that show strong association across all their datasets (p < 5x 10(-6) overall, with support in each of the three datasets studied).
Abstract: Ankylosing spondylitis is a common form of inflammatory arthritis predominantly affecting the spine and pelvis that occurs in approximately 5 out of 1,000 adults of European descent. Here we report the identification of three variants in the RUNX3, LTBR-TNFRSF1A and IL12B regions convincingly associated with ankylosing spondylitis (P < 5 x 10(-8) in the combined discovery and replication datasets) and a further four loci at PTGER4, TBKBP1, ANTXR2 and CARD9 that show strong association across all our datasets (P < 5 x 10(-6) overall, with support in each of the three datasets studied). We also show that polymorphisms of ERAP1, which encodes an endoplasmic reticulum aminopeptidase involved in peptide trimming before HLA class I presentation, only affect ankylosing spondylitis risk in HLA-B27-positive individuals. These findings provide strong evidence that HLA-B27 operates in ankylosing spondylitis through a mechanism involving aberrant processing of antigenic peptides.
TL;DR: In this paper, the results of the Herschel Gould Belt survey toward the IC 5146 molecular cloud were analyzed and a preliminary analysis of the filamentary structure in this region was presented.
Abstract: We provide a first look at the results of the Herschel Gould Belt survey toward the IC 5146 molecular cloud and present a preliminary analysis of the filamentary structure in this region. The column density map, derived from our 70–500 μm Herschel data, reveals a complex network of filaments and confirms that these filaments are the main birth sites of prestellar cores. We analyze the column density profiles of 27 filaments and show that the underlying radial density profiles fall off as r-1.5 to r-2.5 at large radii. Our main result is that the filaments seem to be characterized by a narrow distribution of widths with a median value of 0.10 ± 0.03 pc, which is in stark contrast to a much broader distribution of central Jeans lengths. This characteristic width of ~0.1 pc corresponds to within a factor of ~2 to the sonic scale below which interstellar turbulence becomes subsonic in diffuse gas, which supports the argument that the filaments may form as a result of the dissipation of large-scale turbulence.
TL;DR: In this article, an amended low-latitude (tropical and subtropical) Cenozoic planktonic foraminiferal zonation is presented, based on the first appearance dates of Globigerinatheka kugleri and Hantkenina singanoae.
TL;DR: The authors used two representative postal surveys of the UK public to measure scepticism and uncertainty about climate change; determine how scepticism varies according to individual characteristics, knowledge, and values; and examine how climate change has changed over time.
Abstract: While scientific consensus and political and media messages appear to be increasingly certain, public attitudes and action towards the issue do not appear to be following suit. Popular and academic debate often assumes this is due to ignorance or misunderstanding on the part of the public, but some studies have suggested political beliefs and values may play a more important role in determining belief versus scepticism about climate change. The current research used two representative postal surveys of the UK public to: measure scepticism and uncertainty about climate change; determine how scepticism varies according to individual characteristics, knowledge and values; and examine how scepticism has changed over time. Findings show denial of climate change is less common than the perception that the issue has been exaggerated. Scepticism was found to be strongly determined by individuals’ environmental and political values (and indirectly by age, gender, location and lifestyle) rather than by education or knowledge. Between 2003 and 2008, public uncertainty about climate change has remained remarkably constant, although belief that claims about the issue are exaggerated has doubled over that period. These results are interpreted with reference to psychological concepts of motivated reasoning, confirmation bias and ‘finite pool of worry’. Implications for communication and policy are discussed.
TL;DR: There remains a substantial proportion of patients older than 60 years who do not receive intensive chemotherapy, but there is considerable interest in developing new treatments for this patient group, including novel nucleoside analogs and several other agents.
Abstract: The choice of treatment approach and outcome in acute myeloid leukemia (AML) depends on the age of the patient. In younger patients, arbitrarily defined as being younger than 60 years, 70% to 80% enter complete disease remission with several anthracycline-based chemotherapy combinations. Consolidation with high-dose cytarabine or stem-cell transplantation in high-risk patients will restrict overall relapse to approximately 50%. A number of demographic features can predict the outcome of treatment including cytogenetics and an increasing list of molecular features (ie, FLT3, NPM1, MLL, WT1, CEBPalpha, EVI1). These are increasingly being used to direct postinduction therapy, but they are also molecular targets for a new generation of small molecule inhibitors that are in early development; however, randomized data have yet to emerge. In older patients who comprise the majority, which will increase with demographic change, the initial clinical decision to be made is whether the patient should receive an intensive or nonintensive approach. If the same anthracycline/cytarabine-based approach is deployed, the remission rate will be around 50%, but the risk of subsequent relapse is approximately 85% at 3 years. This difference from younger patients is explained partly by the ability of patients to tolerate effective therapy, and also the aggregation of several poor risk factors compared with the young. There remains a substantial proportion of patients older than 60 years who do not receive intensive chemotherapy. Their survival is approximately 4 months, but there is considerable interest in developing new treatments for this patient group, including novel nucleoside analogs and several other agents.
University of Glasgow1, University of Salerno2, Max Planck Society3, University of Southampton4, University of Paris-Sud5, University of Nice Sophia Antipolis6, Washington State University7, Istituto Nazionale di Fisica Nucleare8, University of Warsaw9, University of Naples Federico II10, University of Birmingham11, Cardiff University12, University of Rome Tor Vergata13, Moscow State University14, California Institute of Technology15, VU University Amsterdam16, fondazione bruno kessler17, Leibniz University of Hanover18, University of Cambridge19, University of Tübingen20, University of Urbino21, University of Jena22, University of the Balearic Islands23, Northwestern University24, University of Minnesota25, University of Savoy26, Pennsylvania State University27, University of Pisa28, Roma Tre University29, Sapienza University of Rome30, University of Mississippi31
TL;DR: In this article, a special focus is set on evaluating the frequency band below 10 Hz where a complex mixture of seismic, gravity gradient, suspension thermal and radiation pressure noise dominates, including the most relevant fundamental noise contributions.
Abstract: Advanced gravitational wave detectors, currently under construction, are expected to directly observe gravitational wave signals of astrophysical origin. The Einstein Telescope (ET), a third-generation gravitational wave detector, has been proposed in order to fully open up the emerging field of gravitational wave astronomy. In this paper we describe sensitivity models for ET and investigate potential limits imposed by fundamental noise sources. A special focus is set on evaluating the frequency band below 10 Hz where a complex mixture of seismic, gravity gradient, suspension thermal and radiation pressure noise dominates. We develop the most accurate sensitivity model, referred to as ET-D, for a third-generation detector so far, including the most relevant fundamental noise contributions.
TL;DR: It is reported here that supported gold-palladium nanoparticles on carbon or TiO2 are active for the oxidation of the primary carbon-hydrogen bonds in toluene and related molecules, giving high selectivities to benzyl benzoate under mild solvent-free conditions.
Abstract: Selective oxidation of primary carbon-hydrogen bonds with oxygen is of crucial importance for the sustainable exploitation of available feedstocks. To date, heterogeneous catalysts have either shown low activity and/or selectivity or have required activated oxygen donors. We report here that supported gold-palladium (Au-Pd) nanoparticles on carbon or TiO2 are active for the oxidation of the primary carbon-hydrogen bonds in toluene and related molecules, giving high selectivities to benzyl benzoate under mild solvent-free conditions. Differences between the catalytic activity of the Au-Pd nanoparticles on carbon and TiO2 supports are rationalized in terms of the particle/support wetting behavior and the availability of exposed corner/edge sites.
TL;DR: It is explored how gp130 signaling controls disease progression and why IL-6 has a special role among these cytokines as an inflammatory regulator in autoimmunity, inflammation, and cancer.
Abstract: The successful treatment of certain autoimmune conditions with the humanized anti–IL-6 receptor (IL-6R) antibody tocilizumab has emphasized the clinical importance of cytokines that signal through the β-receptor subunit glycoprotein 130 (gp130). In this Review, we explore how gp130 signaling controls disease progression and examine why IL-6 has a special role among these cytokines as an inflammatory regulator. Attention will be given to the role of the soluble IL-6R, and we will provide a perspective into the clinical blockade of IL-6 activity in autoimmunity, inflammation, and cancer.
University of Chicago1, Cardiff University2, University of California, Berkeley3, General Dynamics4, National Institute of Standards and Technology5, McGill University6, University of Colorado Boulder7, Marshall Space Flight Center8, Case Western Reserve University9, University of Illinois at Urbana–Champaign10, Lawrence Berkeley National Laboratory11, Harvard University12, National Center for Supercomputing Applications13
TL;DR: The South Pole Telescope (SPT) as mentioned in this paper is a 10m diameter, wide-field, offset Gregorian telescope with a 966-pixel, multicolor, millimeter-wave, bolometer camera.
Abstract: .The South Pole Telescope (SPT) is a 10 m diameter, wide-field, offset Gregorian telescope with a 966 pixel, multicolor, millimeter-wave, bolometer camera. It is located at the Amundsen-Scott South Pole station in Antarctica. The design of the SPT emphasizes careful control of spillover and scattering, to minimize noise and false signals due to ground pickup. The key initial project is a large-area survey at wavelengths of 3, 2, and 1.3 mm, to detect clusters of galaxies via the Sunyaev-Zel’dovich effect and to measure the small-scale angular power spectrum of the cosmic microwave background (CMB). The data will be used to characterize the primordial matter power spectrum and to place constraints on the equation of state of dark energy. A second-generation camera will measure the polarization of the CMB, potentially leading to constraints on the neutrino mass and the energy scale of inflation.