Showing papers by "University of Tübingen published in 2011"
••
Memorial Sloan Kettering Cancer Center1, University of Kiel2, Institut Gustave Roussy3, Netherlands Cancer Institute4, The Royal Marsden NHS Foundation Trust5, University of Zurich6, University of Tübingen7, University of Manchester8, University of Paris9, University of Duisburg-Essen10, University of California, Los Angeles11, Vanderbilt University12, University of Pittsburgh13, University of Nantes14, Plexxikon15, Hoffmann-La Roche16, Genentech17, Harvard University18, Peter MacCallum Cancer Centre19
TL;DR: Vemurafenib produced improved rates of overall and progression-free survival in patients with previously untreated melanoma with the BRAF V600E mutation in a phase 3 randomized clinical trial.
Abstract: At 6 months, overall survival was 84% (95% confidence interval [CI], 78 to 89) in the vemurafenib group and 64% (95% CI, 56 to 73) in the dacarbazine group. In the interim analysis for overall survival and final analysis for progression-free survival, vemurafenib was associated with a relative reduction of 63% in the risk of death and of 74% in the risk of either death or disease progression, as compared with dacarbazine (P<0.001 for both comparisons). After review of the interim analysis by an independent data and safety monitoring board, crossover from dacarbazine to vemurafenib was recommended. Response rates were 48% for vemurafenib and 5% for dacarbazine. Common adverse events associated with vemurafenib were arthralgia, rash, fatigue, alopecia, keratoacanthoma or squamous-cell carcinoma, photosensitivity, nausea, and diarrhea; 38% of patients required dose modification because of toxic effects. Conclusions Vemurafenib produced improved rates of overall and progression-free survival in patients with previously untreated melanoma with the BRAF V600E mutation. (Funded by Hoffmann–La Roche; BRIM-3 ClinicalTrials.gov number, NCT01006980.)
6,773 citations
••
Institut Gustave Roussy1, University of South Florida2, University of Tübingen3, University of Paris4, Université catholique de Louvain5, Aix-Marseille University6, National Health Service7, University of Kiel8, McGill University9, University of Barcelona10, MedImmune11, Bristol-Myers Squibb12, Memorial Sloan Kettering Cancer Center13
TL;DR: Ipilimumab (at a dose of 10 mg per kilogram) in combination with dacarbazine, as compared with dACarbazine plus placebo, improved overall survival in patients with previously untreated metastatic melanoma.
Abstract: A B S T R AC T Background Ipilimumab monotherapy (at a dose of 3 mg per kilogram of body weight), as compared with glycoprotein 100, improved overall survival in a phase 3 study involving patients with previously treated metastatic melanoma. We conducted a phase 3 study of ipilimumab (10 mg per kilogram) plus dacarbazine in patients with previously untreated metastatic melanoma. Methods We randomly assigned 502 patients with previously untreated metastatic melanoma, in a 1:1 ratio, to ipilimumab (10 mg per kilogram) plus dacarbazine (850 mg per square meter of body-surface area) or dacarbazine (850 mg per square meter) plus placebo, given at weeks 1, 4, 7, and 10, followed by dacarbazine alone every 3 weeks through week 22. Patients with stable disease or an objective response and no doselimiting toxic effects received ipilimumab or placebo every 12 weeks thereafter as maintenance therapy. The primary end point was overall survival. Results Overall survival was significantly longer in the group receiving ipilimumab plus dacarbazine than in the group receiving dacarbazine plus placebo (11.2 months vs. 9.1 months, with higher survival rates in the ipilimumab–dacarbazine group at 1 year (47.3% vs. 36.3%), 2 years (28.5% vs. 17.9%), and 3 years (20.8% vs. 12.2%) (hazard ratio for death, 0.72; P<0.001). Grade 3 or 4 adverse events occurred in 56.3% of patients treated with ipilimumab plus dacarbazine, as compared with 27.5% treated with dacarbazine and placebo (P<0.001). No drug-related deaths or gastrointestinal perforations occurred in the ipilimumab–dacarbazine group. Conclusions Ipilimumab (at a dose of 10 mg per kilogram) in combination with dacarbazine, as compared with dacarbazine plus placebo, improved overall survival in patients with previously untreated metastatic melanoma. The types of adverse events were consistent with those seen in prior studies of ipilimumab; however, the rates of elevated liver-function values were higher and the rates of gastrointestinal events were lower than expected on the basis of prior studies. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00324155.)
4,069 citations
••
TL;DR: This work presents the first comprehensive pipeline capable of identifying biosynthetic loci covering the whole range of known secondary metabolite compound classes, and integrates or cross-links all previously available secondary-metabolite specific gene analysis methods in one interactive view.
Abstract: Bacterial and fungal secondary metabolism is a rich source of novel bioactive compounds with potential pharmaceutical applications as antibiotics, anti-tumor drugs or cholesterol-lowering drugs To find new drug candidates, microbiologists are increasingly relying on sequencing genomes of a wide variety of microbes However, rapidly and reliably pinpointing all the potential gene clusters for secondary metabolites in dozens of newly sequenced genomes has been extremely challenging, due to their biochemical heterogeneity, the presence of unknown enzymes and the dispersed nature of the necessary specialized bioinformatics tools and resources Here, we present antiSMASH (antibiotics & Secondary Metabolite Analysis Shell), the first comprehensive pipeline capable of identifying biosynthetic loci covering the whole range of known secondary metabolite compound classes (polyketides, non-ribosomal peptides, terpenes, aminoglycosides, aminocoumarins, indolocarbazoles, lantibiotics, bacteriocins, nucleosides, beta-lactams, butyrolactones, siderophores, melanins and others) It aligns the identified regions at the gene cluster level to their nearest relatives from a database containing all other known gene clusters, and integrates or cross-links all previously available secondary-metabolite specific gene analysis methods in one interactive view antiSMASH is available at http://antismashsecondarymetabolitesorg
1,496 citations
••
TL;DR: The new program, MEGAN4, provides an integrated approach to the taxonomic and functional analysis of metagenomic, metatranscriptome, metaproteomic, and rRNA data, and illustrates how such analyses can be performed.
Abstract: A major challenge in the analysis of environmental sequences is data integration. The question is how to analyze different types of data in a unified approach, addressing both the taxonomic and functional aspects. To facilitate such analyses, we have substantially extended MEGAN, a widely used taxonomic analysis program. The new program, MEGAN4, provides an integrated approach to the taxonomic and functional analysis of metagenomic, metatranscriptomic, metaproteomic, and rRNA data. While taxonomic analysis is performed based on the NCBI taxonomy, functional analysis is performed using the SEED classification of subsystems and functional roles or the KEGG classification of pathways and enzymes. A number of examples illustrate how such analyses can be performed, and show that one can also import and compare classification results obtained using others' tools. MEGAN4 is freely available for academic purposes, and installers for all three major operating systems can be downloaded from www-ab.informatik.uni-tuebingen.de/software/megan.
1,322 citations
••
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.
1,312 citations
•
TL;DR: The epidemiological distinction between the generic term "physical activity" and the specific category of "exercise", which implies activity for a specific purpose such as improvement of physical condition or competition is recognised.
Abstract: An ever-growing volume of peer-reviewed publications speaks to the recent and rapid growth in both scope and understanding of exercise immunology. Indeed, more than 95% of all peer-reviewed publications in exercise immunology (currently >2, 200 publications using search terms "exercise" and "immune") have been published since the formation of the International Society of Exercise and Immunology (ISEI) in 1989 (ISI Web of Knowledge). We recognise the epidemiological distinction between the generic term "physical activity" and the specific category of "exercise", which implies activity for a specific purpose such as improvement of physical condition or competition. Extreme physical activity of any type may have implications for the immune system. However, because of its emotive component, exercise is likely to have a larger effect, and to date the great majority of our knowledge on this subject comes from exercise studies.
1,260 citations
••
TL;DR: In this paper, a review of recent achievements on various aspects of black hole perturbations are discussed such as decoupling of variables in the perturbation equations, quasinormal modes (with special emphasis on various numerical and analytical methods of calculations), late-time tails, gravitational stability, anti-de Sitter/conformal field theory interpretation, and holographic superconductors.
Abstract: Perturbations of black holes, initially considered in the context of possible observations of astrophysical effects, have been studied for the past 10 years in string theory, brane-world models, and quantum gravity. Through the famous gauge/gravity duality, proper oscillations of perturbed black holes, called quasinormal modes, allow for the description of the hydrodynamic regime in the dual finite temperature field theory at strong coupling, which can be used to predict the behavior of quark-gluon plasmas in the nonperturbative regime. On the other hand, the brane-world scenarios assume the existence of extra dimensions in nature, so that multidimensional black holes can be formed in a laboratory experiment. All this stimulated active research in the field of perturbations of higher-dimensional black holes and branes during recent years. In this review recent achievements on various aspects of black hole perturbations are discussed such as decoupling of variables in the perturbation equations, quasinormal modes (with special emphasis on various numerical and analytical methods of calculations), late-time tails, gravitational stability, anti--de Sitter/conformal field theory interpretation of quasinormal modes, and holographic superconductors. We also touch on state-of-the-art observational possibilities for detecting quasinormal modes of black holes.
1,070 citations
••
Marcos Daniel Actis1, G. Agnetta2, Felix Aharonian3, A. G. Akhperjanian +682 more•Institutions (109)
TL;DR: The ground-based gamma-ray astronomy has had a major breakthrough with the impressive results obtained using systems of imaging atmospheric Cherenkov telescopes as mentioned in this paper, which is an international initiative to build the next generation instrument, with a factor of 5-10 improvement in sensitivity in the 100 GeV-10 TeV range and the extension to energies well below 100GeV and above 100 TeV.
Abstract: Ground-based gamma-ray astronomy has had a major breakthrough with the impressive results obtained using systems of imaging atmospheric Cherenkov telescopes. Ground-based gamma-ray astronomy has a huge potential in astrophysics, particle physics and cosmology. CTA is an international initiative to build the next generation instrument, with a factor of 5-10 improvement in sensitivity in the 100 GeV-10 TeV range and the extension to energies well below 100 GeV and above 100 TeV. CTA will consist of two arrays (one in the north, one in the south) for full sky coverage and will be operated as open observatory. The design of CTA is based on currently available technology. This document reports on the status and presents the major design concepts of CTA.
1,006 citations
••
21 Oct 2011TL;DR: In this article, the authors discuss an emerging field of study: adversarial machine learning (AML), the study of effective machine learning techniques against an adversarial opponent, and give a taxonomy for classifying attacks against online machine learning algorithms.
Abstract: In this paper (expanded from an invited talk at AISEC 2010), we discuss an emerging field of study: adversarial machine learning---the study of effective machine learning techniques against an adversarial opponent. In this paper, we: give a taxonomy for classifying attacks against online machine learning algorithms; discuss application-specific factors that limit an adversary's capabilities; introduce two models for modeling an adversary's capabilities; explore the limits of an adversary's knowledge about the algorithm, feature space, training, and input data; explore vulnerabilities in machine learning algorithms; discuss countermeasures against attacks; introduce the evasion challenge; and discuss privacy-preserving learning techniques.
947 citations
••
TL;DR: These data provide an insight into the genetics of Parkinson's disease and the molecular cause of the disease and could provide future targets for therapies.
895 citations
••
TL;DR: It is argued that plant resistance is determined by immune receptors that recognize appropriate ligands to activate defense, the amplitude of which is likely determined by the level required for effective immunity.
Abstract: Typically, pathogen-associated molecular patterns (PAMPs) are considered to be conserved throughout classes of microbes and to contribute to general microbial fitness, whereas effectors are species, race, or strain specific and contribute to pathogen virulence. Both types of molecule can trigger plant immunity, designated PAMP-triggered and effector-triggered immunity (PTI and ETI, respectively). However, not all microbial defense activators conform to the common distinction between PAMPs and effectors. For example, some effectors display wide distribution, while some PAMPs are rather narrowly conserved or contribute to pathogen virulence. As effectors may elicit defense responses and PAMPs may be required for virulence, single components cannot exclusively be referred to by one of the two terms. Therefore, we put forward that the distinction between PAMPs and effectors, between PAMP receptors and resistance proteins, and, therefore, also between PTI and ETI, cannot strictly be maintained. Rather, as illustrated by examples provided here, there is a continuum between PTI and ETI. We argue that plant resistance is determined by immune receptors that recognize appropriate ligands to activate defense, the amplitude of which is likely determined by the level required for effective immunity.
••
TL;DR: In a mouse model of a lethal congenital lung disease caused by a lack of surfactant protein B (SP-B), twice weekly local application of an aerosol of modified SP-B mRNA to the lung restored 71% of the wild-type SP- B expression, and treated mice survived until the predetermined end of the study after 28 days.
Abstract: Current viral vectors for gene therapy are associated with serious safety concerns, including leukemogenesis, and nonviral vectors are limited by low gene transfer efficiency. Here we investigate the therapeutic utility of chemically modified mRNA as an alternative to DNA-based gene therapy. A combination of nucleotide modifications abrogates mRNA interaction with Toll-like receptor (TLR)3, TLR7, TLR8 and retinoid-inducible gene I (RIG-I), resulting in low immunogenicity and higher stability in mice. A single intramuscular injection of modified murine erythropoietin mRNA raises the average hematocrit in mice from 51.5% to 64.2% after 28 days. In a mouse model of a lethal congenital lung disease caused by a lack of surfactant protein B (SP-B), twice weekly local application of an aerosol of modified SP-B mRNA to the lung restored 71% of the wild-type SP-B expression, and treated mice survived until the predetermined end of the study after 28 days.
••
Selidji T Agnandji1, Bertrand Lell1, Bertrand Lell2, Solange Soulanoudjingar2 +147 more•Institutions (10)
TL;DR: The RTS,S/AS01 vaccine provided protection against both clinical and severe malaria in African children, and serious adverse events occurred with a similar frequency in the two study groups.
Abstract: BACKGROUND
An ongoing phase 3 study of the efficacy, safety, and immunogenicity of candidate malaria vaccine RTS,S/AS01 is being conducted in seven African countries.
METHODS
From March 2009 through January 2011, we enrolled 15,460 children in two age categories--6 to 12 weeks of age and 5 to 17 months of age--for vaccination with either RTS,S/AS01 or a non-malaria comparator vaccine. The primary end point of the analysis was vaccine efficacy against clinical malaria during the 12 months after vaccination in the first 6000 children 5 to 17 months of age at enrollment who received all three doses of vaccine according to protocol. After 250 children had an episode of severe malaria, we evaluated vaccine efficacy against severe malaria in both age categories.
RESULTS
In the 14 months after the first dose of vaccine, the incidence of first episodes of clinical malaria in the first 6000 children in the older age category was 0.32 episodes per person-year in the RTS,S/AS01 group and 0.55 episodes per person-year in the control group, for an efficacy of 50.4% (95% confidence interval [CI], 45.8 to 54.6) in the intention-to-treat population and 55.8% (97.5% CI, 50.6 to 60.4) in the per-protocol population. Vaccine efficacy against severe malaria was 45.1% (95% CI, 23.8 to 60.5) in the intention-to-treat population and 47.3% (95% CI, 22.4 to 64.2) in the per-protocol population. Vaccine efficacy against severe malaria in the combined age categories was 34.8% (95% CI, 16.2 to 49.2) in the per-protocol population during an average follow-up of 11 months. Serious adverse events occurred with a similar frequency in the two study groups. Among children in the older age category, the rate of generalized convulsive seizures after RTS,S/AS01 vaccination was 1.04 per 1000 doses (95% CI, 0.62 to 1.64).
CONCLUSIONS
The RTS,S/AS01 vaccine provided protection against both clinical and severe malaria in African children. (Funded by GlaxoSmithKline Biologicals and the PATH Malaria Vaccine Initiative; RTS,S ClinicalTrials.gov number, NCT00866619 .).
••
TL;DR: These results demonstrate for the first time that subretinal micro-electrode arrays with 1500 photodiodes can create detailed meaningful visual perception in previously blind individuals.
Abstract: A light-sensitive, externally powered microchip was surgically implanted subretinally near the macular region of volunteers blind from hereditary retinal dystrophy. The implant contains an array of 1500 active microphotodiodes (‘chip’), each with its own amplifier and local stimulation electrode. At the implant's tip, another array of 16 wire-connected electrodes allows light-independent direct stimulation and testing of the neuron–electrode interface. Visual scenes are projected naturally through the eye's lens onto the chip under the transparent retina. The chip generates a corresponding pattern of 38 × 40 pixels, each releasing light-intensity-dependent electric stimulation pulses. Subsequently, three previously blind persons could locate bright objects on a dark table, two of whom could discern grating patterns. One of these patients was able to correctly describe and name objects like a fork or knife on a table, geometric patterns, different kinds of fruit and discern shades of grey with only 15 per cent contrast. Without a training period, the regained visual functions enabled him to localize and approach persons in a room freely and to read large letters as complete words after several years of blindness. These results demonstrate for the first time that subretinal micro-electrode arrays with 1500 photodiodes can create detailed meaningful visual perception in previously blind individuals.
••
Purdue University1, Kanazawa University2, Graduate University for Advanced Studies3, National Institutes of Natural Sciences, Japan4, Monash University5, University of California, Davis6, Pennsylvania State University7, University at Buffalo8, New York Botanical Garden9, University of Regina10, University of Arizona11, University of Georgia12, University of Potsdam13, Salk Institute for Biological Studies14, Charles University in Prague15, College of William & Mary16, University of California, San Diego17, École normale supérieure de Lyon18, Carnegie Institution for Science19, Hokkaido University20, University of Jena21, Martin Luther University of Halle-Wittenberg22, University of Copenhagen23, University of Tokyo24, Nagoya University25, Free University of Berlin26, University of Tsukuba27, University of Rostock28, University of Tübingen29, Nara Institute of Science and Technology30, Mayo Clinic31, University of California, Berkeley32, Rutgers University33, National Institute of Genetics34, Max Planck Society35, University of Tennessee Health Science Center36, University of Washington37, Dalhousie University38, University of Oxford39, University of Freiburg40, University of Los Andes41, University of Rhode Island42, Joint BioEnergy Institute43, Ruhr University Bochum44, Texas A&M University45, Osaka University46, Cornell University47, Cold Spring Harbor Laboratory48, University of Burgundy49, Utah State University50, United States Department of Energy51
TL;DR: The genome sequence of the lycophyte Selaginella moellendorffii (Selaginella), the first nonseed vascular plant genome reported, is reported, finding that the transition from a gametophytes- to a sporophyte-dominated life cycle required far fewer new genes than the Transition from a non Seed vascular to a flowering plant.
Abstract: Vascular plants appeared ~410 million years ago, then diverged into several lineages of which only two survive: the euphyllophytes (ferns and seed plants) and the lycophytes. We report here the genome sequence of the lycophyte Selaginella moellendorffii (Selaginella), the first nonseed vascular plant genome reported. By comparing gene content in evolutionarily diverse taxa, we found that the transition from a gametophyte- to a sporophyte-dominated life cycle required far fewer new genes than the transition from a nonseed vascular to a flowering plant, whereas secondary metabolic genes expanded extensively and in parallel in the lycophyte and angiosperm lineages. Selaginella differs in posttranscriptional gene regulation, including small RNA regulation of repetitive elements, an absence of the trans-acting small interfering RNA pathway, and extensive RNA editing of organellar genes.
••
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 that SHARPIN functions as a novel component of the linear ubiquitin chain assembly complex (LUBAC) and that the absence of SHARPin causes dysregulation of NF-κB and apoptotic signalling pathways, explaining the severe phenotypes displayed by chronic proliferative dermatitis (cpdm) in SHARPIn-deficient mice.
Abstract: SHARPIN is a ubiquitin-binding and ubiquitin-like-domain-containing protein which, when mutated in mice, results in immune system disorders and multi-organ inflammation. Here we report that SHARPIN functions as a novel component of the linear ubiquitin chain assembly complex (LUBAC) and that the absence of SHARPIN causes dysregulation of NF-κB and apoptotic signalling pathways, explaining the severe phenotypes displayed by chronic proliferative dermatitis (cpdm) in SHARPIN-deficient mice. Upon binding to the LUBAC subunit HOIP (also known as RNF31), SHARPIN stimulates the formation of linear ubiquitin chains in vitro and in vivo. Coexpression of SHARPIN and HOIP promotes linear ubiquitination of NEMO (also known as IKBKG), an adaptor of the IκB kinases (IKKs) and subsequent activation of NF-κB signalling, whereas SHARPIN deficiency in mice causes an impaired activation of the IKK complex and NF-κB in B cells, macrophages and mouse embryonic fibroblasts (MEFs). This effect is further enhanced upon concurrent downregulation of HOIL-1L (also known as RBCK1), another HOIP-binding component of LUBAC. In addition, SHARPIN deficiency leads to rapid cell death upon tumour-necrosis factor α (TNF-α) stimulation via FADD- and caspase-8-dependent pathways. SHARPIN thus activates NF-κB and inhibits apoptosis via distinct pathways in vivo.
••
TL;DR: Current data demonstrate that neoadjuvant chemotherapy in conjunction with radical cystectomy (RC) is recommended in certain constellations of MiM-BC, and a new drug for second-line chemotherapy (vinflunine) in metastatic disease has been approved and is recommended.
••
Vanderbilt University1, University of Tübingen2, University of Southern California3, Lund University4, Thermo Fisher Scientific5, Agilent Technologies6, University of Giessen7, Leibniz Association8, University of Pennsylvania9, European Bioinformatics Institute10, Stowers Institute for Medical Research11, Swiss Institute of Bioinformatics12, Institute for Systems Biology13
TL;DR: The resulting standard data format, mzML, is a well tested open-source format formass spectrometer output files that can be readily utilized by the community and easily adapted for incremental advances in mass spectrometry technology.
••
TL;DR: It is shown that reproductive factors and BMI are most clearly associated with hormone receptor-positive tumors and suggest that triple-negative or CBP tumors may have distinct etiology.
Abstract: BACKGROUND: Previous studies have suggested that breast cancer risk factors are associated with estrogen receptor (ER) and progesterone receptor (PR) expression status of the tumors. METHODS: We pooled tumor marker and epidemiological risk factor data from 35,568 invasive breast cancer case patients from 34 studies participating in the Breast Cancer Association Consortium. Logistic regression models were used in case-case analyses to estimate associations between epidemiological risk factors and tumor subtypes, and case-control analyses to estimate associations between epidemiological risk factors and the risk of developing specific tumor subtypes in 12 population-based studies. All statistical tests were two-sided. RESULTS: In case-case analyses, of the epidemiological risk factors examined, early age at menarche (≤12 years) was less frequent in case patients with PR(-) than PR(+) tumors (P = .001). Nulliparity (P = 3 × 10(-6)) and increasing age at first birth (P = 2 × 10(-9)) were less frequent in ER(-) than in ER(+) tumors. Obesity (body mass index [BMI] ≥ 30 kg/m(2)) in younger women (≤50 years) was more frequent in ER(-)/PR(-) than in ER(+)/PR(+) tumors (P = 1 × 10(-7)), whereas obesity in older women (>50 years) was less frequent in PR(-) than in PR(+) tumors (P = 6 × 10(-4)). The triple-negative (ER(-)/PR(-)/HER2(-)) or core basal phenotype (CBP; triple-negative and cytokeratins [CK]5/6(+) and/or epidermal growth factor receptor [EGFR](+)) accounted for much of the heterogeneity in parity-related variables and BMI in younger women. Case-control analyses showed that nulliparity, increasing age at first birth, and obesity in younger women showed the expected associations with the risk of ER(+) or PR(+) tumors but not triple-negative (nulliparity vs parity, odds ratio [OR] = 0.94, 95% confidence interval [CI] = 0.75 to 1.19, P = .61; 5-year increase in age at first full-term birth, OR = 0.95, 95% CI = 0.86 to 1.05, P = .34; obesity in younger women, OR = 1.36, 95% CI = 0.95 to 1.94, P = .09) or CBP tumors. CONCLUSIONS: This study shows that reproductive factors and BMI are most clearly associated with hormone receptor-positive tumors and suggest that triple-negative or CBP tumors may have distinct etiology.
••
National Institutes of Natural Sciences, Japan1, National Institute of Information and Communications Technology2, Raman Research Institute3, Waseda University4, Osaka Institute of Technology5, Kyoto University6, Osaka City University7, Japan Aerospace Exploration Agency8, University of Electro-Communications9, Kindai University10, National Institute of Advanced Industrial Science and Technology11, Tokyo Institute of Technology12, Goddard Space Flight Center13, University of Tokyo14, Hiroshima University15, Ochanomizu University16, Liverpool John Moores University17, Nagoya University18, Nihon University19, Rikkyo University20, Tokyo Keizai University21, Yamanashi Eiwa College22, Rochester Institute of Technology23, Stanford University24, California Institute of Technology25, Hirosaki University26, Niigata University27, Tokai University28, Tohoku University29, Osaka University30, National Defense Academy of Japan31, University of Tübingen32, Hosei University33, University of Wisconsin–Milwaukee34, Tokyo University of Science35, University of Birmingham36
••
TL;DR: A reconstructed ancient genome of Yersinia pestis is reported at 30-fold average coverage from Black Death victims securely dated to episodes of pestilence-associated mortality in London, England, 1348–1350, suggesting that contemporary Y. pestis epidemics have their origins in the medieval era.
Abstract: Technological advances in DNA recovery and sequencing have drastically expanded the scope of genetic analyses of ancient specimens to the extent that full genomic investigations are now feasible and are quickly becoming standard. This trend has important implications for infectious disease research because genomic data from ancient microbes may help to elucidate mechanisms of pathogen evolution and adaptation for emerging and re-emerging infections. Here we report a reconstructed ancient genome of Yersinia pestis at 30-fold average coverage from Black Death victims securely dated to episodes of pestilence-associated mortality in London, England, 1348-1350. Genetic architecture and phylogenetic analysis indicate that the ancient organism is ancestral to most extant strains and sits very close to the ancestral node of all Y. pestis commonly associated with human infection. Temporal estimates suggest that the Black Death of 1347-1351 was the main historical event responsible for the introduction and widespread dissemination of the ancestor to all currently circulating Y. pestis strains pathogenic to humans, and further indicates that contemporary Y. pestis epidemics have their origins in the medieval era. Comparisons against modern genomes reveal no unique derived positions in the medieval organism, indicating that the perceived increased virulence of the disease during the Black Death may not have been due to bacterial phenotype. These findings support the notion that factors other than microbial genetics, such as environment, vector dynamics and host susceptibility, should be at the forefront of epidemiological discussions regarding emerging Y. pestis infections.
••
TL;DR: The theory that many chronic neurodegenerative diseases can originate and progress via the seeded corruption of misfolded proteins has the potential to unify experimental and translational approaches to these increasingly prevalent disorders.
Abstract: The misfolding and aggregation of specific proteins is a seminal occurrence in a remarkable variety of neurodegenerative disorders. In Alzheimer’s disease (the most prevalent cerebral proteopathy), the two principal aggregating proteins are β-amyloid (Aβ) and tau. The abnormal assemblies formed by conformational variants of these proteins range in size from small oligomers to the characteristic lesions that are visible by optical microscopy, such as senile plaques and neurofibrillary tangles. Pathologic similarities with prion disease suggest that the formation and spread of these proteinaceous lesions might involve a common molecular mechanism – corruptive protein templating. Experimentally, cerebral β-amyloidosis can be exogenously induced by exposure to dilute brain extracts containing aggregated Aβ seeds. The amyloid-inducing agent probably is Aβ itself, in a conformation generated most effectively in the living brain. Once initiated, Aβ lesions proliferate within and among brain regions. The induction process is governed by the structural and biochemical nature of the Aβ seed, as well as the attributes of the host, reminiscent of pathogenically variant prion strains. The concept of prion-like induction and spreading of pathogenic proteins recently has been expanded to include aggregates of tau, α-synuclein, huntingtin, superoxide dismutase-1, and TDP-43, which characterize such human neurodegenerative disorders as frontotemporal lobar degeneration, Parkinson’s/Lewy body disease, Huntington’s disease, and amyotrophic lateral sclerosis. Our recent finding that the most effective Aβ seeds are small and soluble intensifies the search in bodily fluids for misfolded protein seeds that are upstream in the proteopathic cascade, and thus could serve as predictive diagnostics and the targets of early, mechanism-based interventions. Establishing the clinical implications of corruptive protein templating will require further mechanistic and epidemiologic investigations. However, the theory that many chronic neurodegenerative diseases can originate and progress via the seeded corruption of misfolded proteins has the potential to unify experimental and translational approaches to these increasingly prevalent disorders.
••
K. Aamodt1, A. Abrahantes Quintana, Dagmar Adamová2, Andrew Marshall Adare3 +938 more•Institutions (80)
TL;DR: In this paper, the centrality dependence of the chargedparticle multiplicity density at midrapidity in Pb-Pb collisions at root s(NN) = 2: 76 TeV is presented.
Abstract: The centrality dependence of the charged-particle multiplicity density at midrapidity in Pb-Pb collisions at root s(NN) = 2: 76 TeV is presented. The charged-particle density normalized per participating nucleon pair increases by about a factor of 2 from peripheral (70%-80%) to central (0%-5%) collisions. The centrality dependence is found to be similar to that observed at lower collision energies. The data are compared with models based on different mechanisms for particle production in nuclear collisions.
••
TL;DR: An improved predictor is presented, based on previous work (NRPSpredictor), that predicts A-domain specificity using Support Vector Machines on four hierarchical levels, ranging from gross physicochemical properties of an A- domain’s substrates down to single amino acid substrates.
Abstract: The products of many bacterial non-ribosomal peptide synthetases (NRPS) are highly important secondary metabolites, including vancomycin and other antibiotics. The ability to predict substrate specificity of newly detected NRPS Adenylation (A-) domains by genome sequencing efforts is of great importance to identify and annotate new gene clusters that produce secondary metabolites. Prediction of A-domain specificity based on the sequence alone can be achieved through sequence signatures or, more accurately, through machine learning methods. We present an improved predictor, based on previous work (NRPSpredictor), that predicts A-domain specificity using Support Vector Machines on four hierarchical levels, ranging from gross physicochemical properties of an A-domain's substrates down to single amino acid substrates. The three more general levels are predicted with an F-measure better than 0.89 and the most detailed level with an average F-measure of 0.80. We also modeled the applicability domain of our predictor to estimate for new A-domains whether they lie in the applicability domain. Finally, since there are also NRPS that play an important role in natural products chemistry of fungi, such as peptaibols and cephalosporins, we added a predictor for fungal A-domains, which predicts gross physicochemical properties with an F-measure of 0.84. The service is available at http://nrps.informatik.uni-tuebingen.de/.
••
TL;DR: Strong perceptual correlates support their functional relevance: the strength of synchronization within these networks predicted the subjects' perception of an ambiguous audiovisual stimulus as well as the integration of auditory and visual information.
••
TL;DR: In this paper, a review summarizes the advances in in vivo and in vitro applications of tissue-engineered skin and highlights novel efforts in the design of complex disease-in-a-dish models for studies ranging from disease etiology to drug development.
••
TL;DR: Evidence is provided suggesting, for the first time, the involvement of RNF213 in genetic susceptibility to moyamoya disease, and a founder haplotype transmitted in 42 families is revealed.
Abstract: Background
Moyamoya disease is an idiopathic vascular disorder of intracranial arteries Its susceptibility locus has been mapped to 17q253 in Japanese families, but the susceptibility gene is unknown
Methodology/Principal Findings
Genome-wide linkage analysis in eight three-generation families with moyamoya disease revealed linkage to 17q253 (P<10-4) Fine mapping demonstrated a 15-Mb disease locus bounded by D17S1806 and rs2280147 We conducted exome analysis of the eight index cases in these families, with results filtered through Ng criteria There was a variant of pN321S in PCMTD1 and pR4810K in RNF213 in the 15-Mb locus of the eight index cases The pN321S variant in PCMTD1 could not be confirmed by the Sanger method Sequencing RNF213 in 42 index cases confirmed pR4810K and revealed it to be the only unregistered variant Genotyping 39 SNPs around RNF213 revealed a founder haplotype transmitted in 42 families Sequencing the 260-kb region covering the founder haplotype in one index case did not show any coding variants except pR4810K A case-control study demonstrated strong association of pR4810K with moyamoya disease in East Asian populations (251 cases and 707 controls) with an odds ratio of 1118 (P = 10−119) Sequencing of RNF213 in East Asian cases revealed additional novel variants: pD4863N, pE4950D, pA5021V, pD5160E, and pE5176G Among Caucasian cases, variants pN3962D, pD4013N, pR4062Q and pP4608S were identified RNF213 encodes a 591-kDa cytosolic protein that possesses two functional domains: a Walker motif and a RING finger domain These exhibit ATPase and ubiquitin ligase activities Although the mutant alleles (pR4810K or pD4013N in the RING domain) did not affect transcription levels or ubiquitination activity, knockdown of RNF213 in zebrafish caused irregular wall formation in trunk arteries and abnormal sprouting vessels
Conclusions/Significance
We provide evidence suggesting, for the first time, the involvement of RNF213 in genetic susceptibility to moyamoya disease
••
11 Jul 2011
TL;DR: The first measurement of the triangular v3, quadrangular v4, and pentagonal v5 charged particle flow in Pb-Pb collisions is reported, and a double peaked structure in the two-particle azimuthal correlations is observed, which can be naturally explained from the measured anisotropic flow Fourier coefficients.
Abstract: We report on the first measurement of the triangular nu(3), quadrangular nu(4), and pentagonal nu(5) charged particle flow in Pb-Pb collisions at root s(NN) = 2.76 TeV measured with the ALICE detector at the CERN Large Hadron Collider. We show that the triangular flow can be described in terms of the initial spatial anisotropy and its fluctuations, which provides strong constraints on its origin. In the most central events, where the elliptic flow nu(2) and nu(3) have similar magnitude, a double peaked structure in the two-particle azimuthal correlations is observed, which is often interpreted as a Mach cone response to fast partons. We show that this structure can be naturally explained from the measured anisotropic flow Fourier coefficients.
••
TL;DR: Advances in the understanding of the mechanism of chemotherapy resistance offer the hope for improved results with chemotherapy, and the triumvirate of more effective chemotherapy, immunotherapy, and targeted therapy are likely to be combined with one another for significant advances in melanoma over the coming few years.
Abstract: The incidence of melanoma is increasing worldwide, and the prognosis for patients with high-risk or advanced metastatic melanoma remains poor despite advances in the field. Standard treatment for patients with thick (≥2.0 mm) primary melanoma with or without regional metastases to lymph nodes is surgery followed by adjuvant therapy or clinical trial enrollment. Adjuvant therapy with interferon-α and cancer vaccines is discussed in detail. Patients who progress to stage IV metastatic melanoma have a median survival of ≤1 year. Standard treatment with chemotherapy yields low response rates, of which few are durable. Cytokine therapy with IL-2 achieves durable benefits in a greater fraction, but it is accompanied by severe toxicities that require the patient to be hospitalized for support during treatment. A systematic literature review of treatments for advanced, metastatic disease was conducted to present the success of current treatments and the promise of those still in clinical development that may yield incremental improvements in the treatment of advanced, metastatic melanoma.