Showing papers by "University of Chicago published in 2010"
TL;DR: An object detection system based on mixtures of multiscale deformable part models that is able to represent highly variable object classes and achieves state-of-the-art results in the PASCAL object detection challenges is described.
Abstract: We describe an object detection system based on mixtures of multiscale deformable part models. Our system is able to represent highly variable object classes and achieves state-of-the-art results in the PASCAL object detection challenges. While deformable part models have become quite popular, their value had not been demonstrated on difficult benchmarks such as the PASCAL data sets. Our system relies on new methods for discriminative training with partially labeled data. We combine a margin-sensitive approach for data-mining hard negative examples with a formalism we call latent SVM. A latent SVM is a reformulation of MI--SVM in terms of latent variables. A latent SVM is semiconvex, and the training problem becomes convex once latent information is specified for the positive examples. This leads to an iterative training algorithm that alternates between fixing latent values for positive examples and optimizing the latent SVM objective function.
10,501 citations
TL;DR: It is demonstrated in macrophages and B cells that collaborative interactions of the common factor PU.1 with small sets of macrophage- or B cell lineage-determining transcription factors establish cell-specific binding sites that are associated with the majority of promoter-distal H3K4me1-marked genomic regions.
9,620 citations
TL;DR: Nanocrystals (NCs) discussed in this Review are tiny crystals of metals, semiconductors, and magnetic material consisting of hundreds to a few thousand atoms each that are among the hottest research topics of the last decades.
Abstract: Nanocrystals (NCs) discussed in this Review are tiny crystals of metals, semiconductors, and magnetic material consisting of hundreds to a few thousand atoms each. Their size ranges from 2-3 to about 20 nm. What is special about this size regime that placed NCs among the hottest research topics of the last decades? The quantum mechanical coupling * To whom correspondence should be addressed. E-mail: dvtalapin@uchicago.edu. † The University of Chicago. ‡ Argonne National Lab. Chem. Rev. 2010, 110, 389–458 389
3,720 citations
TL;DR: The past success in organic light-emitting diodes provides scientists with confidence that organic photovoltaic devices will be a vital alternate to the inorganic counterpart, and the easiness of the fabrication holds the promise of very low-cost manufacturing process.
Abstract: Sun is the largest carbon-neutral energy source that has not been fully utilized. Although there are solar cell devices based on inorganic semiconductor to efficiently harvest solar energy, the cost of these conventional devices is too high to be economically viable. This is the major motivation for the development of organic photovoltaic (OPV) materials and devices, which are envisioned to exhibit advantages such as low cost, flexibility, and abundant availability. [1] The past success in organic light-emitting diodes provides scientists with confidence that organic photovoltaic devices will be a vital alternate to the inorganic counterpart. At the heart of the OPV technology advantage is the easiness of the fabrication, which holds the promise of very low-cost manufacturing process. A simple, yet successful technique is the solution-processed bulk heterojunction (BHJ) solar cell composed of electron-donating semiconducting polymers and electron-withdrawing fullerides as active layers. [2] The composite active layer can be prepared as a large area in a single step by using techniques such as spin-coating, inkjet-printing, spraycoating, gravure-coating, roller-casting etc. [3] In the last fifteen years, a significant progress has been made on the improvement of the power-conversion efficiency (PCE) of polymer BHJ solar cells, and the achieved efficiencies have evolved from less than 1% in the poly(phenylene vinylene) (PPV) system in 1995, [2] to 4‐5% in the poly(3-hexylthiphene) (P3HT) system in 2005, [4] to around 6%, as reported recently. [5] However, the efficiency of polymer solar cells is still significantly lower than their inorganic counterparts, such as silicon, CdTe and CIGS, which prevents practical applications in large scale.
3,602 citations
University of Ulm1, University of Rome Tor Vergata2, Fred Hutchinson Cancer Research Center3, University of Münster4, University of Wales5, University of Chicago6, Nagoya University7, Leipzig University8, VU University Medical Center9, Northwestern University10, Erasmus University Medical Center11, Ohio State University12
TL;DR: An international expert panel is provided to provide updated evidence- and expert opinion-based recommendations for the diagnosis and management of AML, that contain both minimal requirements for general practice as well as standards for clinical trials.
3,000 citations
TL;DR: In this article, a biennial review summarizes much of particle physics using data from previous editions, plus 2158 new measurements from 551 papers, they list, evaluate and average measured properties of gauge bosons, leptons, quarks, mesons, and baryons.
Abstract: This biennial Review summarizes much of particle physics. Using data from previous editions, plus 2158 new measurements from 551 papers, we list, evaluate, and average measured properties of gauge bosons, leptons, quarks, mesons, and baryons. We also summarize searches for hypothetical particles such as Higgs bosons, heavy neutrinos, and supersymmetric particles. All the particle properties and search limits are listed in Summary Tables. We also give numerous tables, figures, formulae, and reviews of topics such as the Standard Model, particle detectors, probability, and statistics. Among the 108 reviews are many that are new or heavily revised including those on neutrino mass, mixing, and oscillations, QCD, top quark, CKM quark-mixing matrix, V-ud & V-us, V-cb & V-ub, fragmentation functions, particle detectors for accelerator and non-accelerator physics, magnetic monopoles, cosmological parameters, and big bang cosmology.
2,788 citations
TL;DR: Feshbach resonances are the essential tool to control the interaction between atoms in ultracold quantum gases and have found numerous experimental applications, opening up the way to important breakthroughs as mentioned in this paper.
Abstract: Feshbach resonances are the essential tool to control the interaction between atoms in ultracold quantum gases. They have found numerous experimental applications, opening up the way to important breakthroughs. This review broadly covers the phenomenon of Feshbach resonances in ultracold gases and their main applications. This includes the theoretical background and models for the description of Feshbach resonances, the experimental methods to find and characterize the resonances, a discussion of the main properties of resonances in various atomic species and mixed atomic species systems, and an overview of key experiments with atomic Bose-Einstein condensates, degenerate Fermi gases, and ultracold molecules.
2,642 citations
TL;DR: This review summarizes the most up‐to‐date findings on how autophagy is executed and regulated at the molecular level and how its disruption can lead to disease.
Abstract: Autophagy is a self-degradative process that is important for balancing sources of energy at critical times in development and in response to nutrient stress. Autophagy also plays a housekeeping role in removing misfolded or aggregated proteins, clearing damaged organelles, such as mitochondria, endoplasmic reticulum and peroxisomes, as well as eliminating intracellular pathogens. Thus, autophagy is generally thought of as a survival mechanism, although its deregulation has been linked to non-apoptotic cell death. Autophagy can be either non-selective or selective in the removal of specific organelles, ribosomes and protein aggregates, although the mechanisms regulating aspects of selective autophagy are not fully worked out. In addition to elimination of intracellular aggregates and damaged organelles, autophagy promotes cellular senescence and cell surface antigen presentation, protects against genome instability and prevents necrosis, giving it a key role in preventing diseases such as cancer, neurodegeneration, cardiomyopathy, diabetes, liver disease, autoimmune diseases and infections. This review summarizes the most up-to-date findings on how autophagy is executed and regulated at the molecular level and how its disruption can lead to disease.
2,594 citations
University of Kiel1, Cedars-Sinai Medical Center2, Wellcome Trust Sanger Institute3, University of Pennsylvania4, QIMR Berghofer Medical Research Institute5, Peninsula College of Medicine and Dentistry6, University of Edinburgh7, University of Cambridge8, University of Otago9, University of Washington10, University of Groningen11, University of Liège12, Harvard University13, Casa Sollievo della Sofferenza14, King's College London15, University of Chicago16, Yale University17, Johns Hopkins University18, Ludwig Maximilian University of Munich19, Charité20, McGill University21, Lille University of Science and Technology22, Cincinnati Children's Hospital Medical Center23, Ghent University24, Torbay Hospital25, Mater Health Services26, Université libre de Bruxelles27, RWTH Aachen University28, University of Utah29, Örebro University30, Leiden University31, University of Paris32, Technion – Israel Institute of Technology33, University of Western Australia34, Tel Aviv University35, University of Dundee36, University of Manchester37, University of Pittsburgh38, Royal Hospital for Sick Children39, Katholieke Universiteit Leuven40, Guy's and St Thomas' NHS Foundation Trust41, University of Bern42, University of Toronto43, University of Amsterdam44, Karolinska Institutet45, University of Zurich46, Université de Montréal47, Emory University48, Newcastle University49
TL;DR: A meta-analysis of six Crohn's disease genome-wide association studies and a series of in silico analyses highlighted particular genes within these loci implicated functionally interesting candidate genes including SMAD3, ERAP2, IL10, IL2RA, TYK2, FUT2, DNMT3A, DENND1B, BACH2 and TAGAP.
Abstract: We undertook a meta-analysis of six Crohn's disease genome-wide association studies (GWAS) comprising 6,333 affected individuals (cases) and 15,056 controls and followed up the top association signals in 15,694 cases, 14,026 controls and 414 parent-offspring trios. We identified 30 new susceptibility loci meeting genome-wide significance (P < 5 × 10⁻⁸). A series of in silico analyses highlighted particular genes within these loci and, together with manual curation, implicated functionally interesting candidate genes including SMAD3, ERAP2, IL10, IL2RA, TYK2, FUT2, DNMT3A, DENND1B, BACH2 and TAGAP. Combined with previously confirmed loci, these results identify 71 distinct loci with genome-wide significant evidence for association with Crohn's disease.
2,482 citations
TL;DR: The features and consequences of loneliness are reviewed within a comprehensive theoretical framework that informs interventions to reduce loneliness and features of a loneliness regulatory loop are employed to explain cognitive, behavioral, and physiological consequences.
Abstract: As a social species, humans rely on a safe, secure social surround to survive and thrive. Perceptions of social isolation, or loneliness, increase vigilance for threat and heighten feelings of vulnerability while also raising the desire to reconnect. Implicit hypervigilance for social threat alters psychological processes that influence physiological functioning, diminish sleep quality, and increase morbidity and mortality. The purpose of this paper is to review the features and consequences of loneliness within a comprehensive theoretical framework that informs interventions to reduce loneliness. We review physical and mental health consequences of loneliness, mechanisms for its effects, and effectiveness of extant interventions. Features of a loneliness regulatory loop are employed to explain cognitive, behavioral, and physiological consequences of loneliness and to discuss interventions to reduce loneliness. Loneliness is not simply being alone. Interventions to reduce loneliness and its health consequences may need to take into account its attentional, confirmatory, and memorial biases as well as its social and behavioral effects.
2,467 citations
TL;DR: Mutational and epigenetic profiling of a large acute myeloid leukemia (AML) patient cohort revealed that IDH1/2-mutant AMLs display global DNA hypermethylation and a specificHypermethylation signature, suggesting a shared proleukemogenic effect.
Boston Children's Hospital1, Emory University2, University of Washington3, GeneDx4, National Institutes of Health5, University of Utah6, Wellcome Trust Sanger Institute7, Salisbury University8, University of California, San Francisco9, Uppsala University10, University of British Columbia11, Johns Hopkins University School of Medicine12, Drexel University13, University of Groningen14, University of Pennsylvania15, University of California, Santa Cruz16, Brigham and Women's Hospital17, The Centre for Applied Genomics18, Research Triangle Park19, Mayo Clinic20, Katholieke Universiteit Leuven21, University of Chicago22, American College of Medical Genetics23
TL;DR: Chromosomal microarray (CMA) is increasingly utilized for genetic testing of individuals with unexplained developmental delay/intellectual disability (DD/ID), autism spectrum disorders (ASD), or multiple congenital anomalies (MCA).
Abstract: Chromosomal microarray (CMA) is increasingly utilized for genetic testing of individuals with unexplained developmental delay/intellectual disability (DD/ID), autism spectrum disorders (ASD), or multiple congenital anomalies (MCA). Performing CMA and G-banded karyotyping on every patient substantially increases the total cost of genetic testing. The International Standard Cytogenomic Array (ISCA) Consortium held two international workshops and conducted a literature review of 33 studies, including 21,698 patients tested by CMA. We provide an evidence-based summary of clinical cytogenetic testing comparing CMA to G-banded karyotyping with respect to technical advantages and limitations, diagnostic yield for various types of chromosomal aberrations, and issues that affect test interpretation. CMA offers a much higher diagnostic yield (15%–20%) for genetic testing of individuals with unexplained DD/ID, ASD, or MCA than a G-banded karyotype (~3%, excluding Down syndrome and other recognizable chromosomal syndromes), primarily because of its higher sensitivity for submicroscopic deletions and duplications. Truly balanced rearrangements and low-level mosaicism are generally not detectable by arrays, but these are relatively infrequent causes of abnormal phenotypes in this population (<1%). Available evidence strongly supports the use of CMA in place of G-banded karyotyping as the first-tier cytogenetic diagnostic test for patients with DD/ID, ASD, or MCA. G-banded karyotype analysis should be reserved for patients with obvious chromosomal syndromes (e.g., Down syndrome), a family history of chromosomal rearrangement, or a history of multiple miscarriages.
TL;DR: In this article, the role of social learning in the diffusion of a new agri cultural technology in Ghana is investigated, using unique data on farmers' communication patterns to define each individual's information neighborhood, finding evidence that farmers adjust their inputs to align with those of their information neighbors who were surpris ingly successful in previous periods.
Abstract: This paper investigates the role of social learning in the diffusion of a new agri cultural technology in Ghana. We use unique data on farmers' communication patterns to define each individual's information neighborhood. Conditional on many potentially confounding variables, we find evidence that farmers adjust their inputs to align with those of their information neighbors who were surpris ingly successful in previous periods. The relationship of these input adjustments to experience further indicates the presence of social learning. In addition, applying the same method to input choices for another crop, of known technol ogy, correctly indicates an absence of social learning effects. (JEL D83, 013, 033, Q16)
Hennepin County Medical Center1, Heidelberg University2, Westmead Hospital3, Children's Hospital at Westmead4, Lund University5, University of Minnesota6, Boston Children's Hospital7, University of Chicago8, Dalhousie University9, Paris Descartes University10, University of Washington11, Panamerican University12, University of California, San Francisco13, National Kidney Foundation14, Tufts Medical Center15
TL;DR: The guideline makes recommendations for immunosuppression and graft monitoring, as well as prevention and treatment of infection, cardiovascular disease, malignancy, and other complications that are common in kidney transplant recipients, including hematological and bone disorders.
University of Portsmouth1, University of Barcelona2, Princeton University3, Spanish National Research Council4, University of Arizona5, Johns Hopkins University6, University of Chicago7, Fermilab8, University of Tokyo9, University of Washington10, University of Sussex11, University of Michigan12, University of Edinburgh13, Los Alamos National Laboratory14, Lawrence Berkeley National Laboratory15, Pennsylvania State University16, Massachusetts Institute of Technology17, Drexel University18, Ohio State University19, Case Western Reserve University20
TL;DR: In this article, an almost independent constraint on the ratio of distances D-V(0.275) = 0.1390 +/- 0.0037 (2.7 per cent accuracy), where r(s) is the comoving sound horizon at the baryon-drag epoch, DV(z) equivalent to [(1 + z)D(A)(2)cz/H(z)](1/3), D-A(z), is the angular diameter distance and H(z).
Abstract: The spectroscopic Sloan Digital Sky Survey (SDSS) Data Release 7 (DR7) galaxy sample represents the final set of galaxies observed using the original SDSS target selection criteria. We analyse the clustering of galaxies within this sample, including both the luminous red galaxy and main samples, and also include the 2-degree Field Galaxy Redshift Survey data. In total, this sample comprises 893 319 galaxies over 9100 deg(2). Baryon acoustic oscillations (BAO) are observed in power spectra measured for different slices in redshift; this allows us to constrain the distance-redshift relation at multiple epochs. We achieve a distance measure at redshift z = 0.275, of r(s)(z(d))/D-V(0.275) = 0.1390 +/- 0.0037 (2.7 per cent accuracy), where r(s)(z(d)) is the comoving sound horizon at the baryon-drag epoch, D-V(z) equivalent to [(1 + z)(2)D(A)(2)cz/H(z)](1/3), D-A(z) is the angular diameter distance and H(z) is the Hubble parameter. We find an almost independent constraint on the ratio of distances D-V(0.35)/D-V(0.2) = 1.736 +/- 0.065, which is consistent at the 1.1 sigma level with the best-fitting Lambda cold dark matter model obtained when combining our z = 0.275 distance constraint with the Wilkinson Microwave Anisotropy Probe 5-year (WMAP5) data. The offset is similar to that found in previous analyses of the SDSS DR5 sample, but the discrepancy is now of lower significance, a change caused by a revised error analysis and a change in the methodology adopted, as well as the addition of more data. Using WMAP5 constraints on Omega(b)h(2) and Omega(c) h(2), and combining our BAO distance measurements with those from the Union supernova sample, places a tight constraint on Omega(m) = 0.286 +/- 0.018 and H-0 = 68.2 +/- 2.2 km s(-1) Mpc(-1) that is robust to allowing Omega(k) not equal 0 and omega not equal -1. This result is independent of the behaviour of dark energy at redshifts greater than those probed by the BAO and supernova measurements. Combining these data sets with the full WMAP5 likelihood constraints provides tight constraints on both Omega(k) = -0.006 +/- 0.008 and omega = -0.97 +/- 0.10 for a constant dark energy equation of state.
TL;DR: This review details the epidemiology of CA-MRSA strains and the clinical spectrum of infectious syndromes associated with them that ranges from a commensal state to severe, overwhelming infection and addresses the therapy of these infections and strategies for their prevention.
Abstract: Summary: Staphylococcus aureus is an important cause of skin and soft-tissue infections (SSTIs), endovascular infections, pneumonia, septic arthritis, endocarditis, osteomyelitis, foreign-body infections, and sepsis. Methicillin-resistant S. aureus (MRSA) isolates were once confined largely to hospitals, other health care environments, and patients frequenting these facilities. Since the mid-1990s, however, there has been an explosion in the number of MRSA infections reported in populations lacking risk factors for exposure to the health care system. This increase in the incidence of MRSA infection has been associated with the recognition of new MRSA clones known as community-associated MRSA (CA-MRSA). CA-MRSA strains differ from the older, health care-associated MRSA strains; they infect a different group of patients, they cause different clinical syndromes, they differ in antimicrobial susceptibility patterns, they spread rapidly among healthy people in the community, and they frequently cause infections in health care environments as well. This review details what is known about the epidemiology of CA-MRSA strains and the clinical spectrum of infectious syndromes associated with them that ranges from a commensal state to severe, overwhelming infection. It also addresses the therapy of these infections and strategies for their prevention.
TL;DR: It is shown that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait, and indicates that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.
Abstract: Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.
TL;DR: The role that geometric shape cues can play in orchestrating the mechanochemical signals and paracrine/autocrine factors that can direct MSCs to appropriate fates is pointed to.
Abstract: Significant efforts have been directed to understanding the factors that influence the lineage commitment of stem cells. This paper demonstrates that cell shape, independent of soluble factors, has a strong influence on the differentiation of human mesenchymal stem cells (MSCs) from bone marrow. When exposed to competing soluble differentiation signals, cells cultured in rectangles with increasing aspect ratio and in shapes with pentagonal symmetry but with different subcellular curvature—and with each occupying the same area—display different adipogenesis and osteogenesis profiles. The results reveal that geometric features that increase actomyosin contractility promote osteogenesis and are consistent with in vivo characteristics of the microenvironment of the differentiated cells. Cytoskeletal-disrupting pharmacological agents modulate shape-based trends in lineage commitment verifying the critical role of focal adhesion and myosin-generated contractility during differentiation. Microarray analysis and pathway inhibition studies suggest that contractile cells promote osteogenesis by enhancing c-Jun N-terminal kinase (JNK) and extracellular related kinase (ERK1/2) activation in conjunction with elevated wingless-type (Wnt) signaling. Taken together, this work points to the role that geometric shape cues can play in orchestrating the mechanochemical signals and paracrine/autocrine factors that can direct MSCs to appropriate fates.
TL;DR: A brief introduction to ABMS is provided, the main concepts and foundations are illustrated, some recent applications across a variety of disciplines are discussed, and methods and toolkits for developing agent models are identified.
Abstract: Agent-based modelling and simulation (ABMS) is a relatively new approach to modelling systems composed of autonomous, interacting agents. Agent-based modelling is a way to model the dynamics of complex systems and complex adaptive systems. Such systems often self-organize themselves and create emergent order. Agent-based models also include models of behaviour (human or otherwise) and are used to observe the collective effects of agent behaviours and interactions. The development of agent modelling tools, the availability of micro-data, and advances in computation have made possible a growing number of agent-based applications across a variety of domains and disciplines. This article provides a brief introduction to ABMS, illustrates the main concepts and foundations, discusses some recent applications across a variety of disciplines, and identifies methods and toolkits for developing agent models.
TL;DR: The details of several different statistical methods for imputing genotypes are described, the factors that influence imputation performance are illustrated and discussed, and methods that can be used to assess imputations performance and test association at imputed SNPs are reviewed.
Abstract: In the past few years genome-wide association (GWA) studies have uncovered a large number of convincingly replicated associations for many complex human diseases. Genotype imputation has been used widely in the analysis of GWA studies to boost power, fine-map associations and facilitate the combination of results across studies using meta-analysis. This Review describes the details of several different statistical methods for imputing genotypes, illustrates and discusses the factors that influence imputation performance, and reviews methods that can be used to assess imputation performance and test association at imputed SNPs.
University of Virginia1, University of Chicago2, University of Texas MD Anderson Cancer Center3, Thomas Jefferson University4, Wake Forest University5, University of Colorado Denver6, Stanford University7, Memorial Sloan Kettering Cancer Center8, Orlando Regional Medical Center9, University of Texas Southwestern Medical Center10, University of Toronto11, University of Rochester12, University of Utah13, Johns Hopkins University14, University of Wisconsin-Madison15, Vrije Universiteit Brussel16, Fox Chase Cancer Center17, Duke University18
TL;DR: The task group report includes a review of the literature to identify reported clinical findings and expected outcomes for this treatment modality.
Abstract: Task Group 101 of the AAPM has prepared this report for medical physicists, clinicians, and therapists in order to outline the best practice guidelines for the external-beam radiation therapy technique referred to as stereotactic body radiation therapy (SBRT). The task group report includes a review of the literature to identify reported clinical findings and expected outcomes for this treatment modality. Information is provided for establishing a SBRT program, including protocols, equipment, resources, and QA procedures. Additionally, suggestions for developing consistent documentation for prescribing, reporting, and recording SBRT treatment delivery is provided.
TL;DR: Recent progress in the understanding of ThT-fibril interactions at an atomic resolution is reviewed to offer guidance for designing the next generation of amyloid assembly diagnostics, inhibitors, and therapeutics.
TL;DR: This study demonstrates the feasibility of GWA studies in A. thaliana and suggests that the approach will be appropriate for many other organisms, particularly when inbred lines are available.
Abstract: Although pioneered by human geneticists as a potential solution to the challenging problem of finding the genetic basis of common human diseases, genome-wide association (GWA) studies have, owing to advances in genotyping and sequencing technology, become an obvious general approach for studying the genetics of natural variation and traits of agricultural importance. They are particularly useful when inbred lines are available, because once these lines have been genotyped they can be phenotyped multiple times, making it possible (as well as extremely cost effective) to study many different traits in many different environments, while replicating the phenotypic measurements to reduce environmental noise. Here we demonstrate the power of this approach by carrying out a GWA study of 107 phenotypes in Arabidopsis thaliana, a widely distributed, predominantly self-fertilizing model plant known to harbour considerable genetic variation for many adaptively important traits. Our results are dramatically different from those of human GWA studies, in that we identify many common alleles of major effect, but they are also, in many cases, harder to interpret because confounding by complex genetics and population structure make it difficult to distinguish true associations from false. However, a-priori candidates are significantly over-represented among these associations as well, making many of them excellent candidates for follow-up experiments. Our study demonstrates the feasibility of GWA studies in A. thaliana and suggests that the approach will be appropriate for many other organisms.
TL;DR: Nilotinib at a dose of either 300 mg or 400 mg twice daily was superior to imatinib in patients with newly diagnosed chronic-phase Philadelphia chromosome-positive CML, and no patient with progression to the accelerated phase or blast crisis had a major molecular response.
Abstract: Background Nilotinib has been shown to be a more potent inhibitor of BCR-ABL than imatinib. We evaluated the efficacy and safety of nilotinib, as compared with imatinib, in patients with newly diagnosed Philadelphia chromosome–positive chronic myeloid leukemia (CML) in the chronic phase. Methods In this phase 3, randomized, open-label, multicenter study, we assigned 846 patients with chronic-phase Philadelphia chromosome–positive CML in a 1:1:1 ratio to receive nilotinib (at a dose of either 300 mg or 400 mg twice daily) or imatinib (at a dose of 400 mg once daily). The primary end point was the rate of major molecular response at 12 months. Results At 12 months, the rates of major molecular response for nilotinib (44% for the 300-mg dose and 43% for the 400-mg dose) were nearly twice that for imatinib (22%) (P<0.001 for both comparisons). The rates of complete cytogenetic response by 12 months were significantly higher for nilotinib (80% for the 300-mg dose and 78% for the 400-mg dose) than for imatinib (65%) (P<0.001 for both comparisons). Patients receiving either the 300-mg dose or the 400-mg dose of nilotinib twice daily had a significant improvement in the time to progression to the accelerated phase or blast crisis, as compared with those receiving imatinib (P = 0.01 and P = 0.004, respectively). No patient with progression to the accelerated phase or blast crisis had a major molecular response. Gastrointestinal and fluid-retention events were more frequent among patients receiving imatinib, whereas dermatologic events and headache were more frequent in those receiving nilotinib. Discontinuations due to aminotransferase and bilirubin elevations were low in all three study groups. Conclusions Nilotinib at a dose of either 300 mg or 400 mg twice daily was superior to imatinib in patients with newly diagnosed chronic-phase Philadelphia chromosome–positive CML. (ClinicalTrials.gov number, NCT00471497.)
University of Ottawa1, University of Cincinnati2, COMSATS Institute of Information Technology3, University of Chicago4, Brown University5, Thomas Jefferson University6, University of Pennsylvania7, Howard University8, Harvard University9, Oregon State University10, Exponent11, Massachusetts Institute of Technology12, Technical University of Denmark13, Pfizer14, Natural Resources Defense Council15, The Humane Society of the United States16, Johns Hopkins University17, California Department of Fish and Wildlife18
TL;DR: Implementation of a new toxicity testing paradigm firmly based on human biology by transitioning from current expensive and lengthy in vivo testing with qualitative endpoints to in vitro toxicity pathway assays on human cells or cell lines using robotic high-throughput screening with mechanistic quantitative parameters.
Abstract: With the release of the landmark report Toxicity Testing in the 21st Century: A Vision and a Strategy, the U.S. National Academy of Sciences, in 2007, precipitated a major change in the way toxicity testing is conducted. It envisions increased efficiency in toxicity testing and decreased animal usage by transitioning from current expensive and lengthy in vivo testing with qualitative endpoints to in vitro toxicity pathway assays on human cells or cell lines using robotic high-throughput screening with mechanistic quantitative parameters. Risk assessment in the exposed human population would focus on avoiding significant perturbations in these toxicity pathways. Computational systems biology models would be implemented to determine the dose-response models of perturbations of pathway function. Extrapolation of in vitro results to in vivo human blood and tissue concentrations would be based on pharmacokinetic models for the given exposure condition. This practice would enhance human relevance of test results, and would cover several test agents, compared to traditional toxicological testing strategies. As all the tools that are necessary to implement the vision are currently available or in an advanced stage of development, the key prerequisites to achieving this paradigm shift are a commitment to change in the scientific community, which could be facilitated by a broad discussion of the vision, and obtaining necessary resources to enhance current knowledge of pathway perturbations and pathway assays in humans and to implement computational systems biology models. Implementation of these strategies would result in a new toxicity testing paradigm firmly based on human biology.
TL;DR: This work identified key predictors of survival based on the patient's most recent evaluation and formulated a contemporary prognostic equation that may allow the individualization and optimization of therapeutic strategies.
Abstract: Background— Factors that determine survival in pulmonary arterial hypertension (PAH) drive clinical management. A quantitative survival prediction tool has not been established for research or clinical use. Methods and Results— Data from 2716 patients with PAH enrolled consecutively in the US Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) were analyzed to assess predictors of 1-year survival. We identified independent prognosticators of survival and derived a multivariable, weighted risk formula for clinical use. One-year survival from the date of enrollment was 91.0% (95% confidence interval [CI], 89.9 to 92.1). In a multivariable analysis with Cox proportional hazards, variables independently associated with increased mortality included pulmonary vascular resistance >32 Wood units (hazard ratio [HR], 4.1; 95% CI, 2.0 to 8.3), PAH associated with portal hypertension (HR, 3.6; 95% CI, 2.4 to 5.4), modified New York Heart Association/World Health Organization functional class IV (HR, 3.1; 95% CI, 2.2 to 4.4), men >60 years of age (HR, 2.2; 95% CI, 1.6 to 3.0), and family history of PAH (HR, 2.2; 95% CI, 1.2 to 4.0). Renal insufficiency, PAH associated with connective tissue disease, functional class III, mean right atrial pressure, resting systolic blood pressure and heart rate, 6-minute walk distance, brain natriuretic peptide, percent predicted carbon monoxide diffusing capacity, and pericardial effusion on echocardiogram all predicted mortality. Based on these multivariable analyses, a prognostic equation was derived and validated by bootstrapping technique. Conclusions— We identified key predictors of survival based on the patient’s most recent evaluation and formulated a contemporary prognostic equation. Use of this tool may allow the individualization and optimization of therapeutic strategies. Serial follow-up and reassessment are warranted. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00370214.
National Heart Foundation of Australia1, University of Toronto2, Cleveland Clinic3, University of Chicago4, University of Alberta5, Inova Fairfax Hospital6, Ochsner Health System7, University of Alabama at Birmingham8, Newcastle upon Tyne Hospitals NHS Foundation Trust9, Ludwig Maximilian University of Munich10, Saint Barnabas Medical Center11, Duke University12, Primary Children's Hospital13, University of Pittsburgh14, University of Utah15, University of Maryland, Baltimore16, University of Vienna17, Stanford University18, University College London19, Washington University in St. Louis20, Loma Linda University21, University of A Coruña22, The Texas Heart Institute23, Katholieke Universiteit Leuven24, Northwestern University25, University of Wisconsin-Madison26, Yeshiva University27, Cincinnati Children's Hospital Medical Center28, University of Colorado Denver29, Drexel University30, University of Pennsylvania31, Mayo Clinic32, St Vincent Hospital33, Papworth Hospital34, Emory University35, Johns Hopkins University36
TL;DR: Institutional Affiliations Chair Costanzo MR: Midwest Heart Foundation, Lombard Illinois, USA Task Force 1 Dipchand A: Hospital for Sick Children, Toronto Ontario, Canada; Starling R: Cleveland Clinic Foundation, Cleveland, Ohio, USA; Starlings R: University of Chicago, Chicago, Illinois,USA; Chan M: university of Alberta, Edmonton, Alberta, Canada ; Desai S: Inova Fairfax Hospital, Fairfax, Virginia, USA.
Abstract: Institutional Affiliations Chair Costanzo MR: Midwest Heart Foundation, Lombard Illinois, USA Task Force 1 Dipchand A: Hospital for Sick Children, Toronto Ontario, Canada; Starling R: Cleveland Clinic Foundation, Cleveland, Ohio, USA; Anderson A: University of Chicago, Chicago, Illinois, USA; Chan M: University of Alberta, Edmonton, Alberta, Canada; Desai S: Inova Fairfax Hospital, Fairfax, Virginia, USA; Fedson S: University of Chicago, Chicago, Illinois, USA; Fisher P: Ochsner Clinic, New Orleans, Louisiana, USA; Gonzales-Stawinski G: Cleveland Clinic Foundation, Cleveland, Ohio, USA; Martinelli L: Ospedale Niguarda, Milano, Italy; McGiffin D: University of Alabama, Birmingham, Alabama, USA; Parisi F: Ospedale Pediatrico Bambino Gesu, Rome, Italy; Smith J: Freeman Hospital, Newcastle upon Tyne, UK Task Force 2 Taylor D: Cleveland Clinic Foundation, Cleveland, Ohio, USA; Meiser B: University of Munich/Grosshaden, Munich, Germany; Baran D: Newark Beth Israel Medical Center, Newark, New Jersey, USA; Carboni M: Duke University Medical Center, Durham, North Carolina, USA; Dengler T: University of Hidelberg, Heidelberg, Germany; Feldman D: Minneapolis Heart Institute, Minneapolis, Minnesota, USA; Frigerio M: Ospedale Niguarda, Milano, Italy; Kfoury A: Intermountain Medical Center, Murray, Utah, USA; Kim D: University of Alberta, Edmonton, Alberta, Canada; Kobashigawa J: Cedar-Sinai Heart Institute, Los Angeles, California, USA; Shullo M: University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Stehlik J: University of Utah, Salt Lake City, Utah, USA; Teuteberg J: University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Uber P: University of Maryland, Baltimore, Maryland, USA; Zuckermann A: University of Vienna, Vienna, Austria. Task Force 3 Hunt S: Stanford University, Palo Alto, California, USA; Burch M: Great Ormond Street Hospital, London, UK; Bhat G: Advocate Christ Medical Center, Oak Lawn, Illinois, USA; Canter C: St. Louis Children Hospital, St. Louis, Missouri, USA; Chinnock R: Loma Linda University Children's Hospital, Loma Linda, California, USA; Crespo-Leiro M: Hospital Universitario A Coruna, La Coruna, Spain; Delgado R: Texas Heart Institute, Houston, Texas, USA; Dobbels F: Katholieke Universiteit Leuven, Leuven, Belgium; Grady K: Northwestern University, Chicago, Illlinois, USA; Kao W: University of Wisconsin, Madison Wisconsin, USA; Lamour J: Montefiore Medical Center, New York, New York, USA; Parry G: Freeman Hospital, Newcastle upon Tyne, UK; Patel J: Cedar-Sinai Heart Institute, Los Angeles, California, USA; Pini D: Istituto Clinico Humanitas, Rozzano, Italy; Pinney S: Mount Sinai Medical Center, New York, New York, USA; Towbin J: Cincinnati Children's Hospital, Cincinnati, Ohio, USA; Wolfel G: University of Colorado, Denver, Colorado, USA Independent Reviewers Delgado D: University of Toronto, Toronto, Ontario, Canada; Eisen H: Drexler University College of Medicine, Philadelphia, Pennsylvania, USA; Goldberg L: University of Pennsylvania, Philadelphia, Pennsylvania, USA; Hosenpud J: Mayo Clinic, Jacksonville, Florida, USA; Johnson M: University of Wisconsin, Madison, Wisconsin, USA; Keogh A: St Vincent Hospital, Sidney, New South Wales, Australia; Lewis C: Papworth Hospital Cambridge, UK; O'Connell J: St. Joseph Hospital, Atlanta, Georgia, USA; Rogers J: Duke University Medical Center, Durham, North Carolina, USA; Ross H: University of Toronto, Toronto, Ontario, Canada; Russell S: Johns Hopkins Hospital, Baltimore, Maryland, USA; Vanhaecke J: University Hospital Gasthuisberg, Leuven, Belgium.
TL;DR: The initial steps of metastasis are regulated by a controlled interaction of adhesion receptors and proteases, and late metastasis is characterized by the oncogene-driven fast growth of tumor nodules on mesothelium covered surfaces, causing ascites, bowel obstruction, and tumor cachexia.
Abstract: The biology of ovarian carcinoma differs from that of hematogenously metastasizing tumors because ovarian cancer cells primarily disseminate within the peritoneal cavity and are only superficially invasive. However, since the rapidly proliferating tumors compress visceral organs and are only temporarily chemosensitive, ovarian carcinoma is a deadly disease, with a cure rate of only 30%. There are a number of genetic and epigenetic changes that lead to ovarian carcinoma cell transformation. Ovarian carcinoma could originate from any of three potential sites: the surfaces of the ovary, the fallopian tube, or the mesothelium-lined peritoneal cavity. Ovarian cacinoma tumorigenesis then either progresses along a stepwise mutation process from a slow growing borderline tumor to a well-differentiated carcinoma (type I) or involves a genetically unstable high-grade serous carcinoma that metastasizes rapidly (type II). During initial tumorigenesis, ovarian carcinoma cells undergo an epithelial-to-mesenchymal transition, which involves a change in cadherin and integrin expression and up-regulation of proteolytic pathways. Carried by the peritoneal fluid, cancer cell spheroids overcome anoikis and attach preferentially on the abdominal peritoneum or omentum, where the cancer cells revert to their epithelial phenotype. The initial steps of metastasis are regulated by a controlled interaction of adhesion receptors and proteases, and late metastasis is characterized by the oncogene-driven fast growth of tumor nodules on mesothelium covered surfaces, causing ascites, bowel obstruction, and tumor cachexia.
TL;DR: It is demonstrated that eQTLs near genes generally act by a mechanism involving allele-specific expression, and that variation that influences the inclusion of an exon is enriched within and near the consensus splice sites.
Abstract: Understanding the genetic mechanisms underlying natural variation in gene expression is a central goal of both medical and evolutionary genetics, and studies of expression quantitative trait loci (eQTLs) have become an important tool for achieving this goal. Although all eQTL studies so far have assayed messenger RNA levels using expression microarrays, recent advances in RNA sequencing enable the analysis of transcript variation at unprecedented resolution. We sequenced RNA from 69 lymphoblastoid cell lines derived from unrelated Nigerian individuals that have been extensively genotyped by the International HapMap Project. By pooling data from all individuals, we generated a map of the transcriptional landscape of these cells, identifying extensive use of unannotated untranslated regions and more than 100 new putative protein-coding exons. Using the genotypes from the HapMap project, we identified more than a thousand genes at which genetic variation influences overall expression levels or splicing. We demonstrate that eQTLs near genes generally act by a mechanism involving allele-specific expression, and that variation that influences the inclusion of an exon is enriched within and near the consensus splice sites. Our results illustrate the power of high-throughput sequencing for the joint analysis of variation in transcription, splicing and allele-specific expression across individuals.
TL;DR: The ASRA consensus statements represent the collective experience of recognized experts in the field of neuraxial anesthesia and anticoagulation and are based on case reports, clinical series, pharmacology, hematology, and risk factors for surgical bleeding.