Showing papers by "Ohio State University published in 2012"
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Daniel C. Koboldt1, Robert S. Fulton1, Michael D. McLellan1, Heather Schmidt1 +352 more•Institutions (35)
TL;DR: The ability to integrate information across platforms provided key insights into previously defined gene expression subtypes and demonstrated the existence of four main breast cancer classes when combining data from five platforms, each of which shows significant molecular heterogeneity.
Abstract: We analysed primary breast cancers by genomic DNA copy number arrays, DNA methylation, exome sequencing, messenger RNA arrays, microRNA sequencing and reverse-phase protein arrays. Our ability to integrate information across platforms provided key insights into previously defined gene expression subtypes and demonstrated the existence of four main breast cancer classes when combining data from five platforms, each of which shows significant molecular heterogeneity. Somatic mutations in only three genes (TP53, PIK3CA and GATA3) occurred at >10% incidence across all breast cancers; however, there were numerous subtype-associated and novel gene mutations including the enrichment of specific mutations in GATA3, PIK3CA and MAP3K1 with the luminal A subtype. We identified two novel protein-expression-defined subgroups, possibly produced by stromal/microenvironmental elements, and integrated analyses identified specific signalling pathways dominant in each molecular subtype including a HER2/phosphorylated HER2/EGFR/phosphorylated EGFR signature within the HER2-enriched expression subtype. Comparison of basal-like breast tumours with high-grade serous ovarian tumours showed many molecular commonalities, indicating a related aetiology and similar therapeutic opportunities. The biological finding of the four main breast cancer subtypes caused by different subsets of genetic and epigenetic abnormalities raises the hypothesis that much of the clinically observable plasticity and heterogeneity occurs within, and not across, these major biological subtypes of breast cancer.
9,355 citations
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TL;DR: In this article, a search for the Standard Model Higgs boson in proton-proton collisions with the ATLAS detector at the LHC is presented, which has a significance of 5.9 standard deviations, corresponding to a background fluctuation probability of 1.7×10−9.
9,282 citations
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TL;DR: In this paper, results from searches for the standard model Higgs boson in proton-proton collisions at 7 and 8 TeV in the CMS experiment at the LHC, using data samples corresponding to integrated luminosities of up to 5.8 standard deviations.
8,857 citations
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TL;DR: Integrative analyses suggest new markers for aggressive colorectal carcinoma and an important role for MYC-directed transcriptional activation and repression.
Abstract: To characterize somatic alterations in colorectal carcinoma, we conducted a genome-scale analysis of 276 samples, analysing exome sequence, DNA copy number, promoter methylation and messenger RNA and microRNA expression. A subset of these samples (97) underwent low-depth-of-coverage whole-genome sequencing. In total, 16% of colorectal carcinomas were found to be hypermutated: three-quarters of these had the expected high microsatellite instability, usually with hypermethylation and MLH1 silencing, and one-quarter had somatic mismatch-repair gene and polymerase e (POLE) mutations. Excluding the hypermutated cancers, colon and rectum cancers were found to have considerably similar patterns of genomic alteration. Twenty-four genes were significantly mutated, and in addition to the expected APC, TP53, SMAD4, PIK3CA and KRAS mutations, we found frequent mutations in ARID1A, SOX9 and FAM123B. Recurrent copy-number alterations include potentially drug-targetable amplifications of ERBB2 and newly discovered amplification of IGF2. Recurrent chromosomal translocations include the fusion of NAV2 and WNT pathway member TCF7L1. Integrative analyses suggest new markers for aggressive colorectal carcinoma and an important role for MYC-directed transcriptional activation and repression.
6,883 citations
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Tohoku University1, University of Zurich2, Lawrence Berkeley National Laboratory3, Stanford University4, College of William & Mary5, University of Genoa6, University of Urbino7, CERN8, Budker Institute of Nuclear Physics9, University of California, Irvine10, Cornell University11, Argonne National Laboratory12, ETH Zurich13, Tata Institute of Fundamental Research14, Hillsdale College15, Spanish National Research Council16, Ohio State University17, University of Notre Dame18, Kent State University19, University of California, San Diego20, University of California, Berkeley21, University of Minnesota22, University of Alabama23, University of Helsinki24, Los Alamos National Laboratory25, California Institute of Technology26, George Washington University27, Syracuse University28, Lawrence Livermore National Laboratory29, Oklahoma State University–Stillwater30, University of Washington31, Max Planck Society32, Boston University33, University of California, Los Angeles34, Royal Holloway, University of London35, Université Paris-Saclay36, Fermilab37, University of Pennsylvania38, University of Illinois at Urbana–Champaign39, University of Bristol40, University of Tokyo41, University of Delaware42, Carnegie Mellon University43, University of California, Santa Cruz44, Karlsruhe Institute of Technology45, Heidelberg University46, Florida State University47, Carleton University48, University of Mainz49, University of Edinburgh50, Brookhaven National Laboratory51, Durham University52, University of Lausanne53, Massachusetts Institute of Technology54, University of Southampton55, Nagoya University56, University of Oxford57, Northwestern University58, University of British Columbia59, Columbia University60, Lund University61, University of Sheffield62, University of California, Santa Barbara63, Iowa State University64, University of Alberta65, University of Cambridge66
TL;DR: The Particle Data Group's biennial review as mentioned in this paper summarizes much of particle physics, using data from previous editions, plus 2658 new measurements from 644 papers, and lists, evaluates, 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 2658 new measurements from 644 papers, we list, evaluate, and average measured properties of gauge bosons, leptons, quarks, mesons, and baryons. We 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 112 reviews are many that are new or heavily revised including those on Heavy-Quark and Soft-Collinear Effective Theory, Neutrino Cross Section Measurements, Monte Carlo Event Generators, Lattice QCD, Heavy Quarkonium Spectroscopy, Top Quark, Dark Matter, V-cb & V-ub, Quantum Chromodynamics, High-Energy Collider Parameters, Astrophysical Constants, Cosmological Parameters, and Dark Matter. A booklet is available containing the Summary Tables and abbreviated versions of some of the other sections of this full Review. All tables, listings, and reviews (and errata) are also available on the Particle Data Group website: http://pdg.lbl.gov.
4,465 citations
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Daniel J. Klionsky1, Fábio Camargo Abdalla2, Hagai Abeliovich3, Robert T. Abraham4 +1284 more•Institutions (463)
TL;DR: These guidelines are presented for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes.
Abstract: In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
4,316 citations
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McMaster University1, American University of Beirut2, University of Alcalá3, University of Geneva4, Leiden University Medical Center5, Virginia Commonwealth University6, University of California, San Diego7, Ohio State University8, University of Utah9, UCLA Medical Center10, Ottawa Hospital Research Institute11, Uniformed Services University of the Health Sciences12
TL;DR: Recommendations on 12 topics that were in the 9th edition of these guidelines are updated, and 3 new topics are addressed.
3,934 citations
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TL;DR: A meta-analysis of recent neuroimaging studies on the relationship between heart rate variability and regional cerebral blood flow identified a number of regions, including the amygdala and ventromedial prefrontal cortex, in which significant associations across studies were found.
2,174 citations
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University of Washington1, Paris Diderot University2, Lawrence Berkeley National Laboratory3, New York University4, University of Utah5, Apache Corporation6, Autonomous University of Madrid7, University of Barcelona8, Yale University9, Harvard University10, Aix-Marseille University11, Princeton University12, Carnegie Mellon University13, Ohio State University14, University of Portsmouth15, University of California, Irvine16, University College London17, University of Valencia18, Max Planck Society19, Leibniz Institute for Astrophysics Potsdam20, Institut d'Astrophysique de Paris21, Spanish National Research Council22, Columbia University23, University of California, Berkeley24, Drexel University25, Korea Institute for Advanced Study26, Institute for the Physics and Mathematics of the Universe27, Abastumani Astrophysical Observatory28, Pennsylvania State University29, University of California, San Diego30, University of Wisconsin-Madison31, Open University32, Case Western Reserve University33
TL;DR: In this paper, the authors present a measurement of the cosmic distance scale from detections of the baryon acoustic oscillations in the clustering of galaxies from the Baryon Oscillation Spectroscopic Survey (BOSS), which is part of the Sloan Digital Sky Survey III (SDSS-III).
Abstract: We present a one per cent measurement of the cosmic distance scale from the detections of the baryon acoustic oscillations in the clustering of galaxies from the Baryon Oscillation Spectroscopic Survey (BOSS), which is part of the Sloan Digital Sky Survey III (SDSS-III). Our results come from the Data Release 11 (DR11) sample, containing nearly one million galaxies and covering approximately $8\,500$ square degrees and the redshift range $0.2
2,040 citations
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TL;DR: This paper found that the most intensive glacier shrinkage is in the Himalayan region, whereas glacial retreat in the Pamir Plateau region is less apparent, due to changes in atmospheric circulations and precipitation patterns.
Abstract: Glacial melting in the Tibetan Plateau affects the water resources of millions of people. This study finds that—partly owing to changes in atmospheric circulations and precipitation patterns—the most intensive glacier shrinkage is in the Himalayan region, whereas glacial retreat in the Pamir Plateau region is less apparent.
1,738 citations
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Christopher P. Ahn1, Rachael Alexandroff2, Carlos Allende Prieto3, Scott F. Anderson4 +256 more•Institutions (65)
TL;DR: In this paper, the authors presented the first spectroscopic data from the Baryon Oscillation Spectroscopic Survey (BOSS) for the Sloan Digital Sky Survey III (SDSS-III) dataset.
Abstract: The Sloan Digital Sky Survey III (SDSS-III) presents the first spectroscopic data from the Baryon Oscillation Spectroscopic Survey (BOSS). This ninth data release (DR9) of the SDSS project includes 535,995 new galaxy spectra (median z ~ 0.52), 102,100 new quasar spectra (median z ~ 2.32), and 90,897 new stellar spectra, along with the data presented in previous data releases. These spectra were obtained with the new BOSS spectrograph and were taken between 2009 December and 2011 July. In addition, the stellar parameters pipeline, which determines radial velocities, surface temperatures, surface gravities, and metallicities of stars, has been updated and refined with improvements in temperature estimates for stars with T eff -0.5. DR9 includes new stellar parameters for all stars presented in DR8, including stars from SDSS-I and II, as well as those observed as part of the SEGUE-2. The astrometry error introduced in the DR8 imaging catalogs has been corrected in the DR9 data products. The next data release for SDSS-III will be in Summer 2013, which will present the first data from the APOGEE along with another year of data from BOSS, followed by the final SDSS-III data release in 2014 December.
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TL;DR: Current knowledge about the involvement of microRNAs in cancer, and their potential as diagnostic, prognostic and therapeutic tools are reviewed.
Abstract: Early studies have shown how aberrantly expressed microRNAs are a hallmark of several diseases like cancer. MicroRNA expression profiling was shown to be associated with tumour development, progression and response to therapy, suggesting their possible use as diagnostic, prognostic and predictive biomarkers. Moreover, based on the increasing number of studies demonstrating that microRNAs can function as potential oncogenes or oncosuppressor genes, with the goal to improve disease response and increase cure rates, miRNA-based anticancer therapies have recently been exploited, either alone or in combination with current targeted therapies. The advantage of using microRNA approaches is based on its ability to concurrently target multiple effectors of pathways involved in cell differentiation, proliferation and survival. Here, we review our current knowledge about the involvement of microRNAs in cancer, and their potential as diagnostic, prognostic and therapeutic tools.
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TL;DR: The second Fermi-LAT catalog (2FGL) as mentioned in this paper includes source location regions, defined in terms of elliptical fits to the 95% confidence regions and spectral fits in terms either power-law, exponentially cutoff power law, or log-normal forms.
Abstract: We present the second catalog of high-energy γ-ray sources detected by the Large Area Telescope (LAT), the primary science instrument on the Fermi Gamma-ray Space Telescope (Fermi), derived from data taken during the first 24 months of the science phase of the mission, which began on 2008 August 4. Source detection is based on the average flux over the 24 month period. The second Fermi-LAT catalog (2FGL) includes source location regions, defined in terms of elliptical fits to the 95% confidence regions and spectral fits in terms of power-law, exponentially cutoff power-law, or log-normal forms. Also included are flux measurements in five energy bands and light curves on monthly intervals for each source. Twelve sources in the catalog are modeled as spatially extended. We provide a detailed comparison of the results from this catalog with those from the first Fermi-LAT catalog (1FGL). Although the diffuse Galactic and isotropic models used in the 2FGL analysis are improved compared to the 1FGL catalog, we attach caution flags to 162 of the sources to indicate possible confusion with residual imperfections in the diffuse model. The 2FGL catalog contains 1873 sources detected and characterized in the 100 MeV to 100 GeV range of which we consider 127 as being firmly identified and 1171 as being reliably associated with counterparts of known or likely γ-ray-producing source classes.
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TL;DR: This paper found that those with the highest degrees of science literacy and technical reasoning capacity were not the most concerned about climate change, rather, they were the ones among whom cultural polarization was greatest, suggesting that public divisions over climate change stem not from the public's incomprehension of science but from a distinctive conflict of interest.
Abstract: Seeming public apathy over climate change is often attributed to a deficit in comprehension. The public knows too little science, it is claimed, to understand the evidence or avoid being misled. Widespread limits on technical reasoning aggravate the problem by forcing citizens to use unreliable cognitive heuristics to assess risk. An empirical study found no support for this position. Members of the public with the highest degrees of science literacy and technical reasoning capacity were not the most concerned about climate change. Rather, they were the ones among whom cultural polarization was greatest. This result suggests that public divisions over climate change stem not from the public’s incomprehension of science but from a distinctive conflict of interest: between the personal interest individuals have in forming beliefs in line with those held by others with whom they share close ties and the collective one they all share in making use of the best available science to promote common welfare.
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TL;DR: The authors found that individuals with the highest degrees of science literacy and technical reasoning capacity are not the most concerned about climate change and are the most culturally polarized, while those with the lowest degrees are concerned.
Abstract: Public apathy over climate change is often attributed to a deficit in comprehension and to limits on technical reasoning. However, evidence suggests that individuals with the highest degrees of science literacy and technical reasoning capacity are not the most concerned about climate change and are the most culturally polarized.
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TL;DR: It is shown that tumor-secreted miR-21 andmiR-29a also can function by another mechanism, by binding as ligands to receptors of the Toll-like receptor (TLR) family, murine TLR7 and human TLR8, in immune cells, triggering a TLR-mediated prometastatic inflammatory response that ultimately may lead to tumor growth and metastasis.
Abstract: MicroRNAs (miRNAs) are small noncoding RNAs, 19–24 nucleotides in length, that regulate gene expression and are expressed aberrantly in most types of cancer. MiRNAs also have been detected in the blood of cancer patients and can serve as circulating biomarkers. It has been shown that secreted miRNAs within exosomes can be transferred from cell to cell and can regulate gene expression in the receiving cells by canonical binding to their target messenger RNAs. Here we show that tumor-secreted miR-21 and miR-29a also can function by another mechanism, by binding as ligands to receptors of the Toll-like receptor (TLR) family, murine TLR7 and human TLR8, in immune cells, triggering a TLR-mediated prometastatic inflammatory response that ultimately may lead to tumor growth and metastasis. Thus, by acting as paracrine agonists of TLRs, secreted miRNAs are key regulators of the tumor microenvironment. This mechanism of action of miRNAs is implicated in tumor–immune system communication and is important in tumor growth and spread, thus representing a possible target for cancer treatment.
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TL;DR: In this paper, the authors proposed a new factor model that consists of the market factor, a size factor, an investment factor, and a return-on-equity factor.
Abstract: Motivated from investment-based asset pricing, we propose a new factor model that consists of the market factor, a size factor, an investment factor, and a return-on-equity factor The new model [i] outperforms the Carhart (1997) four-factor model in pricing portfolios formed on earnings surprise, idiosyncratic volatility, financial distress, equity issues, as well as on investment and return-on-equity; [ii] performs similarly as the Carhart model in pricing portfolios on momentum as well as on size and book-to-market; but [iii] underperforms in pricing the total accrual deciles Our model's performance, combined with its clear economic intuition, suggests that it can serve as a new workhorse model for academic research and investment management practice
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University of Leeds1, Jet Propulsion Laboratory2, University of Colorado Boulder3, Technical University of Denmark4, Durham University5, University of Texas at Austin6, Ohio State University7, University College London8, Technische Universität München9, Lamont–Doherty Earth Observatory10, Johns Hopkins University Applied Physics Laboratory11, University of Tasmania12, Newcastle University13, Utrecht University14, University of Kansas15, Swansea University16, Goddard Space Flight Center17, University of Ottawa18, University of California, Irvine19, University of Bristol20, British Antarctic Survey21, University of Innsbruck22, Delft University of Technology23
TL;DR: There is good agreement between different satellite methods—especially in Greenland and West Antarctica—and that combining satellite data sets leads to greater certainty, and the mass balance of Earth’s polar ice sheets is estimated by combining the results of existing independent techniques.
Abstract: We combined an ensemble of satellite altimetry, interferometry, and gravimetry data sets using common geographical regions, time intervals, and models of surface mass balance and glacial isostatic adjustment to estimate the mass balance of Earth’s polar ice sheets. We find that there is good agreement between different satellite methods—especially in Greenland and West Antarctica—and that combining satellite data sets leads to greater certainty. Between 1992 and 2011, the ice sheets of Greenland, East Antarctica, West Antarctica, and the Antarctic Peninsula changed in mass by –142 ± 49, +14 ± 43, –65 ± 26, and –20 ± 14 gigatonnes year−1, respectively. Since 1992, the polar ice sheets have contributed, on average, 0.59 ± 0.20 millimeter year−1 to the rate of global sea-level rise.
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La Trobe University1, Harvard University2, German Cancer Research Center3, Yale University4, Morehouse School of Medicine5, Autonomous University of Barcelona6, University of Massachusetts Medical School7, Semmelweis University8, Cardiff University9, Ikerbasque10, Karolinska Institutet11, Pohang University of Science and Technology12, Allahabad University13, Ghent University14, University of Melbourne15, London Metropolitan University16, Erasmus University Rotterdam17, University of Mainz18, National University of Singapore19, University of Oslo20, University of Gothenburg21, University of Valencia22, Umeå University23, University of Freiburg24, University of Amsterdam25, Utrecht University26, Johns Hopkins University27, Mayo Clinic28, Ohio State University29, University of Cambridge30, University of Zurich31, Curie Institute32, Michigan State University33, Autonomous University of Madrid34, University of Helsinki35, Aalborg University36, University of Louisville37, Carlos III Health Institute38, Centre national de la recherche scientifique39, Heidelberg University40
TL;DR: Vesiclepedia is a community-annotated compendium of molecular data on extracellular vesicles that aims to provide a single authoritative source for information on vesicle structure and function.
Abstract: Extracellular vesicles (EVs) are membraneous vesicles released by a variety of cells into their microenvironment. Recent studies have elucidated the role of EVs in intercellular communication, pathogenesis, drug, vaccine and gene-vector delivery, and as possible reservoirs of biomarkers. These findings have generated immense interest, along with an exponential increase in molecular data pertaining to EVs. Here, we describe Vesiclepedia, a manually curated compendium of molecular data (lipid, RNA, and protein) identified in different classes of EVs from more than 300 independent studies published over the past several years. Even though databases are indispensable resources for the scientific community, recent studies have shown that more than 50% of the databases are not regularly updated. In addition, more than 20% of the database links are inactive. To prevent such database and link decay, we have initiated a continuous community annotation project with the active involvement of EV researchers. The EV research community can set a gold standard in data sharing with Vesiclepedia, which could evolve as a primary resource for the field.
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University Health Network1, University Hospitals of Leicester NHS Trust2, Imperial College London3, Nanjing University4, Mayo Clinic5, Austral University of Chile6, RWTH Aachen University7, University of North Carolina at Chapel Hill8, University of Michigan9, Complutense University of Madrid10, University of California, Los Angeles11, Columbia University12, University of Sydney13, Ohio State University14, Post Graduate Institute of Medical Education and Research15, Université de Montréal16, The Chinese University of Hong Kong17, Radboud University Nijmegen18
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TL;DR: With recently developed pharmacological agents, it is now possible to restore metabolic equilibrium and envisage novel therapeutic interventions on the basis of the kynurenine pathway.
Abstract: The essential amino acid tryptophan is not only a precursor of serotonin but is also degraded to several other neuroactive compounds, including kynurenic acid, 3-hydroxykynurenine and quinolinic acid. The synthesis of these metabolites is regulated by an enzymatic cascade, known as the kynurenine pathway, that is tightly controlled by the immune system. Dysregulation of this pathway, resulting in hyper-or hypofunction of active metabolites, is associated with neurodegenerative and other neurological disorders, as well as with psychiatric diseases such as depression and schizophrenia. With recently developed pharmacological agents, it is now possible to restore metabolic equilibrium and envisage novel therapeutic interventions.
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Karol Estrada1, Unnur Styrkarsdottir, Evangelos Evangelou2, Yi-Hsiang Hsu3 +187 more•Institutions (69)
TL;DR: Light is shed on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility and within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways.
Abstract: Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10(-4), Bonferroni corrected), of which six reached P < 5 × 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.
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TL;DR: Although rituximab therapy led to more responders and greater reductions in anti-dsDNA and C3/C4 levels, it did not improve clinical outcomes after 1 year of treatment.
Abstract: Objective
To evaluate the efficacy and safety of rituximab in a randomized, double-blind, placebo-controlled phase III trial in patients with lupus nephritis treated concomitantly with mycophenolate mofetil (MMF) and corticosteroids.
Methods
Patients (n = 144) with class III or class IV lupus nephritis were randomized 1:1 to receive rituximab (1,000 mg) or placebo on days 1, 15, 168, and 182. The primary end point was renal response status at week 52.
Results
Rituximab depleted peripheral CD19+ B cells in 71 of 72 patients. The overall (complete and partial) renal response rates were 45.8% among the 72 patients receiving placebo and 56.9% among the 72 patients receiving rituximab (P = 0.18); partial responses accounted for most of the difference. The primary end point (superior response rate with rituximab) was not achieved. Eight placebo-treated patients and no rituximab-treated patients required cyclophosphamide rescue therapy through week 52. Statistically significant improvements in serum complement C3, C4, and anti–double-stranded DNA (anti-dsDNA) levels were observed among patients treated with rituximab. In both treatment groups, a reduction in anti-dsDNA levels greater than the median reduction was associated with reduced proteinuria. The rates of serious adverse events, including infections, were similar in both groups. Neutropenia, leukopenia, and hypotension occurred more frequently in the rituximab group.
Conclusion
Although rituximab therapy led to more responders and greater reductions in anti-dsDNA and C3/C4 levels, it did not improve clinical outcomes after 1 year of treatment. The combination of rituximab with MMF and corticosteroids did not result in any new or unexpected safety signals.
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University of California, San Diego1, Hong Kong University of Science and Technology2, Rockefeller University3, National Institutes of Health4, Keio University5, University of Vienna6, Tufts University7, University of Michigan8, Boston Children's Hospital9, Ohio State University10, University of Texas Southwestern Medical Center11, La Jolla Institute for Allergy and Immunology12
TL;DR: It is proposed that barrier deterioration induced by colorectal-cancer-initiating genetic lesions results in adenoma invasion by microbial products that trigger tumour-elicited inflammation, which in turn drives tumour growth.
Abstract: Approximately 2% of colorectal cancer is linked to pre-existing inflammation known as colitis-associated cancer, but most develops in patients without underlying inflammatory bowel disease. Colorectal cancer often follows a genetic pathway whereby loss of the adenomatous polyposis coli (APC) tumour suppressor and activation of β-catenin are followed by mutations in K-Ras, PIK3CA and TP53, as the tumour emerges and progresses. Curiously, however, 'inflammatory signature' genes characteristic of colitis-associated cancer are also upregulated in colorectal cancer. Further, like most solid tumours, colorectal cancer exhibits immune/inflammatory infiltrates, referred to as 'tumour-elicited inflammation'. Although infiltrating CD4(+) T(H)1 cells and CD8(+) cytotoxic T cells constitute a positive prognostic sign in colorectal cancer, myeloid cells and T-helper interleukin (IL)-17-producing (T(H)17) cells promote tumorigenesis, and a 'T(H)17 expression signature' in stage I/II colorectal cancer is associated with a drastic decrease in disease-free survival. Despite its pathogenic importance, the mechanisms responsible for the appearance of tumour-elicited inflammation are poorly understood. Many epithelial cancers develop proximally to microbial communities, which are physically separated from immune cells by an epithelial barrier. We investigated mechanisms responsible for tumour-elicited inflammation in a mouse model of colorectal tumorigenesis, which, like human colorectal cancer, exhibits upregulation of IL-23 and IL-17. Here we show that IL-23 signalling promotes tumour growth and progression, and development of a tumoural IL-17 response. IL-23 is mainly produced by tumour-associated myeloid cells that are likely to be activated by microbial products, which penetrate the tumours but not adjacent tissue. Both early and late colorectal neoplasms exhibit defective expression of several barrier proteins. We propose that barrier deterioration induced by colorectal-cancer-initiating genetic lesions results in adenoma invasion by microbial products that trigger tumour-elicited inflammation, which in turn drives tumour growth.
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TL;DR: Consideration of a more conservative approach for most patients with thyroid nodules that are cytologically indeterminate on fine-needle aspiration and benign according to gene-expression classifier results are suggested.
Abstract: BACKGROUND Approximately 15 to 30% of thyroid nodules evaluated by means of fine-needle aspiration are not clearly benign or malignant. Patients with cytologically indeterminate nodules are often referred for diagnostic surgery, though most of these nodules prove to be benign. A novel diagnostic test that measures the expression of 167 genes has shown promise in improving preoperative risk assessment. METHODS We performed a 19-month, prospective, multicenter validation study involving 49 clinical sites, 3789 patients, and 4812 fine-needle aspirates from thyroid nodules 1 cm or larger that required evaluation. We obtained 577 cytologically indeterminate aspirates, 413 of which had corresponding histopathological specimens from excised lesions. Results of a central, blinded histopathological review served as the reference standard. After inclusion criteria were met, a gene-expression classifier was used to test 265 indeterminate nodules in this analysis, and its performance was assessed. RESULTS Of the 265 indeterminate nodules, 85 were malignant. The gene-expression classifier correctly identified 78 of the 85 nodules as suspicious (92% sensitivity; 95% confidence interval [CI], 84 to 97), with a specificity of 52% (95% CI, 44 to 59). The negative predictive values for “atypia (or follicular lesion) of undetermined clinical significance,” “follicular neoplasm or lesion suspicious for follicular neoplasm,” or “suspicious cytologic findings” were 95%, 94%, and 85%, respectively. Analysis of 7 aspirates with false negative results revealed that 6 had a paucity of thyroid follicular cells, suggesting insufficient sampling of the nodule. CONCLUSIONS These data suggest consideration of a more conservative approach for most patients with thyroid nodules that are cytologically indeterminate on fine-needle aspiration and benign according to gene-expression classifier results. (Funded by Veracyte.)
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Roswell Park Cancer Institute1, Duke University2, Ohio State University3, Wake Forest University4, Memorial Sloan Kettering Cancer Center5, Harvard University6, University of Pennsylvania7, University of Minnesota8, Washington University in St. Louis9, University of Florida10, University of Wisconsin-Madison11, University of Chicago12, State University of New York Upstate Medical University13, Icahn School of Medicine at Mount Sinai14, Oregon Health & Science University15, University of North Carolina at Chapel Hill16, University of California, San Francisco17, University of Texas MD Anderson Cancer Center18, Medical College of Wisconsin19
TL;DR: Lenalidomide maintenance therapy, initiated at day 100 after hematopoietic stem-cell transplantation, was associated with more toxicity and second cancers but a significantly longer time to disease progression and significantly improved overall survival among patients with myeloma.
Abstract: Background Data are lacking on whether lenalidomide maintenance therapy prolongs the time to disease progression after autologous hematopoietic stem-cell transplantation in patients with multiple myeloma. Methods Between April 2005 and July 2009, we randomly assigned 460 patients who were younger than 71 years of age and had stable disease or a marginal, partial, or complete response 100 days after undergoing stem-cell transplantation to lenalidomide or placebo, which was administered until disease progression. The starting dose of lenalidomide was 10 mg per day (range, 5 to 15). Results The study-drug assignments were unblinded in 2009, when a planned interim analysis showed a significantly longer time to disease progression in the lenalidomide group. At unblinding, 20% of patients who received lenalidomide and 44% of patients who received placebo had progressive disease or had died (P<0.001); of the remaining 128 patients who received placebo and who did not have progressive disease, 86 crossed over to ...
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TL;DR: A framework for pragmatic analysis is proposed which treats discourse as a game, with context as a scoreboard organized around the questions under discussion by the interlocutors, and it is argued that the prosodic focus of an utterance canonically serves to reflect the question under discussion, placing additional constraints on felicity in context.
Abstract: A framework for pragmatic analysis is proposed which treats discourse as a game, with context as a scoreboard organized around the questions under discussion by the interlocutors. The framework is intended to be coordinated with a dynamic compositional semantics. Accordingly, the context of utterance is modeled as a tuple of different types of information, and the questions therein — modeled, as is usual in formal semantics, as alternative sets of propositions — constrain the felicitous flow of discourse. A requirement of Relevance is satisfied by an utterance (whether an assertion, a question or a suggestion) iff it addresses the question under discussion. Finally, it is argued that the prosodic focus of an utterance canonically serves to reflect the question under discussion (at least in English), placing additional constraints on felicity in context.
http://dx.doi.org/10.3765/sp.5.6
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William F. Laurance1, William F. Laurance2, D. Carolina Useche1, Julio Rendeiro1 +213 more•Institutions (101)
TL;DR: These findings suggest that tropical protected areas are often intimately linked ecologically to their surrounding habitats, and that a failure to stem broad-scale loss and degradation of such habitats could sharply increase the likelihood of serious biodiversity declines.
Abstract: The rapid disruption of tropical forests probably imperils global biodiversity more than any other contemporary phenomenon(1-3). With deforestation advancing quickly, protected areas are increasingly becoming final refuges for threatened species and natural ecosystem processes. However, many protected areas in the tropics are themselves vulnerable to human encroachment and other environmental stresses(4-9). As pressures mount, it is vital to know whether existing reserves can sustain their biodiversity. A critical constraint in addressing this question has been that data describing a broad array of biodiversity groups have been unavailable for a sufficiently large and representative sample of reserves. Here we present a uniquely comprehensive data set on changes over the past 20 to 30 years in 31 functional groups of species and 21 potential drivers of environmental change, for 60 protected areas stratified across the world's major tropical regions. Our analysis reveals great variation in reserve 'health': about half of all reserves have been effective or performed passably, but the rest are experiencing an erosion of biodiversity that is often alarmingly widespread taxonomically and functionally. Habitat disruption, hunting and forest-product exploitation were the strongest predictors of declining reserve health. Crucially, environmental changes immediately outside reserves seemed nearly as important as those inside in determining their ecological fate, with changes inside reserves strongly mirroring those occurring around them. These findings suggest that tropical protected areas are often intimately linked ecologically to their surrounding habitats, and that a failure to stem broad-scale loss and degradation of such habitats could sharply increase the likelihood of serious biodiversity declines.
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TL;DR: Among men and women aged 14 to 69 years in the United States, the overall prevalence of Oral HPV infection was 6.9%, and the prevalence was higher among men than among women, and associations with age, sex, number of sexual partners, and current number of cigarettes smoked per day were independently associated with oral HPV infection in multivariable models.
Abstract: 69 years was 6.9% (95% CI, 5.7%-8.3%) and of HPV type 16 was 1.0% (95% CI, 0.7%-1.3%). Oral HPV infection followed a bimodal pattern with respect to age, with peak prevalence among individuals aged 30 to 34 years (7.3%; 95% CI, 4.6%11.4%) and 60 to 64 years (11.4%; 95% CI, 8.5%-15.1%). Men had a significantly higher prevalence than women for any oral HPV infection (10.1% [95% CI, 8.3%12.3%] vs 3.6% [95% CI, 2.6%-5.0%], P.001; unadjusted prevalence ratio [PR], 2.80 [95% CI, 2.02-3.88]). Infection was less common among those without vs those with a history of any type of sexual contact (0.9% [95% CI, 0.4%-1.8%] vs 7.5% [95% CI, 6.1%-9.1%], P.001; PR, 8.69 [95% CI, 3.91-19.31]) and increased with number of sexual partners (P.001 for trend) and cigarettes smoked per day (P.001 for trend). Associations with age, sex, number of sexual partners, and current number of cigarettes smoked per day were independently associated with oral HPV infection in multivariable models.
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King Juan Carlos University1, University of Vermont2, Pablo de Olavide University3, Technical University of Madrid4, Northern Arizona University5, University of La Serena6, Instituto Potosino de Investigación Científica y Tecnológica7, Universidad Simón Rodríguez8, Ben-Gurion University of the Negev9, State University of Feira de Santana10, Universidad Técnica Particular de Loja11, University of Sfax12, University of New South Wales13, Central University of Venezuela14, National University of San Juan15, University of the Bío Bío16, Virginia Tech College of Natural Resources and Environment17, Ohio State University18, National Agrarian University19, National University of La Pampa20, University of New England (Australia)21, Office of Environment and Heritage22, Spanish National Research Council23, Northeast Normal University24, Agricultural Research Organization, Volcani Center25
TL;DR: A global empirical study relating plant species richness and abiotic factors to multifunctionality in drylands, which collectively cover 41% of Earth’s land surface and support over 38% of the human population, suggests that the preservation of plant biodiversity is crucial to buffer negative effects of climate change and desertification in dryland.
Abstract: Experiments suggest that biodiversity enhances the ability of ecosystems to maintain multiple functions, such as carbon storage, productivity, and the buildup of nutrient pools (multifunctionality). However, the relationship between biodiversity and multifunctionality has never been assessed globally in natural ecosystems. We report here on a global empirical study relating plant species richness and abiotic factors to multifunctionality in drylands, which collectively cover 41% of Earth’s land surface and support over 38% of the human population. Multifunctionality was positively and significantly related to species richness. The best-fitting models accounted for over 55% of the variation in multifunctionality and always included species richness as a predictor variable. Our results suggest that the preservation of plant biodiversity is crucial to buffer negative effects of climate change and desertification in drylands.