Showing papers by "University of Chicago published in 2017"
••
TL;DR: The association of GRB 170817A, detected by Fermi-GBM 1.7 s after the coalescence, corroborates the hypothesis of a neutron star merger and provides the first direct evidence of a link between these mergers and short γ-ray bursts.
Abstract: On August 17, 2017 at 12∶41:04 UTC the Advanced LIGO and Advanced Virgo gravitational-wave detectors made their first observation of a binary neutron star inspiral. The signal, GW170817, was detected with a combined signal-to-noise ratio of 32.4 and a false-alarm-rate estimate of less than one per 8.0×10^{4} years. We infer the component masses of the binary to be between 0.86 and 2.26 M_{⊙}, in agreement with masses of known neutron stars. Restricting the component spins to the range inferred in binary neutron stars, we find the component masses to be in the range 1.17-1.60 M_{⊙}, with the total mass of the system 2.74_{-0.01}^{+0.04}M_{⊙}. The source was localized within a sky region of 28 deg^{2} (90% probability) and had a luminosity distance of 40_{-14}^{+8} Mpc, the closest and most precisely localized gravitational-wave signal yet. The association with the γ-ray burst GRB 170817A, detected by Fermi-GBM 1.7 s after the coalescence, corroborates the hypothesis of a neutron star merger and provides the first direct evidence of a link between these mergers and short γ-ray bursts. Subsequent identification of transient counterparts across the electromagnetic spectrum in the same location further supports the interpretation of this event as a neutron star merger. This unprecedented joint gravitational and electromagnetic observation provides insight into astrophysics, dense matter, gravitation, and cosmology.
7,327 citations
••
University of Ulm1, Fred Hutchinson Cancer Research Center2, King's College London3, University of Rome Tor Vergata4, University of Münster5, Brigham and Women's Hospital6, University of Chicago7, Memorial Sloan Kettering Cancer Center8, Leipzig University9, VU University Amsterdam10, University of Valencia11, National Taiwan University12, Alfred Hospital13, Monash University14, Erasmus University Medical Center15, Ohio State University16
TL;DR: An international panel to provide updated evidence- and expert opinion-based recommendations for diagnosis and management of acute myeloid leukemia in adults includes a revised version of the ELN genetic categories, a proposal for a response category based on MRD status, and criteria for progressive disease.
4,066 citations
••
TL;DR: In this paper, the authors used the observed time delay of $(+1.74\pm 0.05)\,{\rm{s}}$ between GRB 170817A and GW170817 to constrain the difference between the speed of gravity and speed of light to be between $-3
Abstract: On 2017 August 17, the gravitational-wave event GW170817 was observed by the Advanced LIGO and Virgo detectors, and the gamma-ray burst (GRB) GRB 170817A was observed independently by the Fermi Gamma-ray Burst Monitor, and the Anti-Coincidence Shield for the Spectrometer for the International Gamma-Ray Astrophysics Laboratory. The probability of the near-simultaneous temporal and spatial observation of GRB 170817A and GW170817 occurring by chance is $5.0\times {10}^{-8}$. We therefore confirm binary neutron star mergers as a progenitor of short GRBs. The association of GW170817 and GRB 170817A provides new insight into fundamental physics and the origin of short GRBs. We use the observed time delay of $(+1.74\pm 0.05)\,{\rm{s}}$ between GRB 170817A and GW170817 to: (i) constrain the difference between the speed of gravity and the speed of light to be between $-3\times {10}^{-15}$ and $+7\times {10}^{-16}$ times the speed of light, (ii) place new bounds on the violation of Lorentz invariance, (iii) present a new test of the equivalence principle by constraining the Shapiro delay between gravitational and electromagnetic radiation. We also use the time delay to constrain the size and bulk Lorentz factor of the region emitting the gamma-rays. GRB 170817A is the closest short GRB with a known distance, but is between 2 and 6 orders of magnitude less energetic than other bursts with measured redshift. A new generation of gamma-ray detectors, and subthreshold searches in existing detectors, will be essential to detect similar short bursts at greater distances. Finally, we predict a joint detection rate for the Fermi Gamma-ray Burst Monitor and the Advanced LIGO and Virgo detectors of 0.1–1.4 per year during the 2018–2019 observing run and 0.3–1.7 per year at design sensitivity.
2,633 citations
••
Icahn School of Medicine at Mount Sinai1, Pure Earth2, World Bank3, University of Arizona4, McGill University5, Indian Ministry of Environment and Forests6, Qatar Airways7, Ludwig Maximilian University of Munich8, University of Health Sciences Antigua9, Johns Hopkins University10, Boston College11, Chulabhorn Research Institute12, University of Maryland, College Park13, University of Ghana14, Centro Nacional de Investigaciones Cardiovasculares15, University of Chicago16, University of London17, University of Oxford18, Indian Institute of Technology Delhi19, Simon Fraser University20, Consortium of Universities for Global Health21, University of Ottawa22, Columbia University23, Stockholm Resilience Centre24, Massachusetts Institute of Technology25, University of Queensland26, University of California, Berkeley27, New York University28, National Institutes of Health29, Public Health Research Institute30, United Nations Industrial Development Organization31, Renmin University of China32
TL;DR: This book is dedicated to the memory of those who have served in the armed forces and their families during the conflicts of the twentieth century.
2,628 citations
••
TL;DR: The magnitude of modifications to the gravitational-wave dispersion relation is constrain, the graviton mass is bound to m_{g}≤7.7×10^{-23} eV/c^{2} and null tests of general relativity are performed, finding that GW170104 is consistent with general relativity.
Abstract: We describe the observation of GW170104, a gravitational-wave signal produced by the coalescence of a pair of stellar-mass black holes. The signal was measured on January 4, 2017 at 10∶11:58.6 UTC by the twin advanced detectors of the Laser Interferometer Gravitational-Wave Observatory during their second observing run, with a network signal-to-noise ratio of 13 and a false alarm rate less than 1 in 70 000 years. The inferred component black hole masses are 31.2^(8.4) _(−6.0)M_⊙ and 19.4^(5.3)_( −5.9)M_⊙ (at the 90% credible level). The black hole spins are best constrained through measurement of the effective inspiral spin parameter, a mass-weighted combination of the spin components perpendicular to the orbital plane, χ_(eff) = −0.12^(0.21)_( −0.30). This result implies that spin configurations with both component spins positively aligned with the orbital angular momentum are disfavored. The source luminosity distance is 880^(450)_(−390) Mpc corresponding to a redshift of z = 0.18^(0.08)_( −0.07) . We constrain the magnitude of modifications to the gravitational-wave dispersion relation and perform null tests of general relativity. Assuming that gravitons are dispersed in vacuum like massive particles, we bound the graviton mass to m_g ≤ 7.7 × 10^(−23) eV/c^2. In all cases, we find that GW170104 is consistent with general relativity.
2,569 citations
••
TL;DR: The T cell–inflamed GEP contained IFN-&ggr;–responsive genes related to antigen presentation, chemokine expression, cytotoxic activity, and adaptive immune resistance, and these features were necessary, but not always sufficient, for clinical benefit.
Abstract: Programmed death-1-directed (PD-1-directed) immune checkpoint blockade results in durable antitumor activity in many advanced malignancies. Recent studies suggest that IFN-γ is a critical driver of programmed death ligand-1 (PD-L1) expression in cancer and host cells, and baseline intratumoral T cell infiltration may improve response likelihood to anti-PD-1 therapies, including pembrolizumab. However, whether quantifying T cell-inflamed microenvironment is a useful pan-tumor determinant of PD-1-directed therapy response has not been rigorously evaluated. Here, we analyzed gene expression profiles (GEPs) using RNA from baseline tumor samples of pembrolizumab-treated patients. We identified immune-related signatures correlating with clinical benefit using a learn-and-confirm paradigm based on data from different clinical studies of pembrolizumab, starting with a small pilot of 19 melanoma patients and eventually defining a pan-tumor T cell-inflamed GEP in 220 patients with 9 cancers. Predictive value was independently confirmed and compared with that of PD-L1 immunohistochemistry in 96 patients with head and neck squamous cell carcinoma. The T cell-inflamed GEP contained IFN-γ-responsive genes related to antigen presentation, chemokine expression, cytotoxic activity, and adaptive immune resistance, and these features were necessary, but not always sufficient, for clinical benefit. The T cell-inflamed GEP has been developed into a clinical-grade assay that is currently being evaluated in ongoing pembrolizumab trials.
2,142 citations
••
Houston Methodist Hospital1, Duke University2, Northwestern University3, Mayo Clinic4, University of California, San Francisco5, Baylor University Medical Center6, Columbia University Medical Center7, Hospital of the University of Pennsylvania8, Harvard University9, University of Chicago10, Brigham and Women's Hospital11, University Health Network12, MedStar Health13
TL;DR: William A. Zoghbi, MD, FASE (Chair), David Adams, RCS, RDCS, Fase, Robert O. Bonow,MD, Maurice Enriquez-Sarano, MDs, Elyse Foster, Md, Fases, Paul A. Grayburn, MD-FASE, Rebecca T. Hahn,MD-MMSc, Yuchi Han, PhD, MMSc,* Judy Hung, MD.
Abstract: William A. Zoghbi, MD, FASE (Chair), David Adams, RCS, RDCS, FASE, Robert O. Bonow, MD, Maurice Enriquez-Sarano, MD, Elyse Foster, MD, FASE, Paul A. Grayburn, MD, FASE, Rebecca T. Hahn, MD, FASE, Yuchi Han, MD, MMSc,* Judy Hung, MD, FASE, Roberto M. Lang, MD, FASE, Stephen H. Little, MD, FASE, Dipan J. Shah, MD, MMSc,* Stanton Shernan, MD, FASE, Paaladinesh Thavendiranathan, MD, MSc, FASE,* James D. Thomas, MD, FASE, and Neil J. Weissman, MD, FASE, Houston and Dallas, Texas; Durham, North Carolina; Chicago, Illinois; Rochester, Minnesota; San Francisco, California; New York, New York; Philadelphia, Pennsylvania; Boston, Massachusetts; Toronto, Ontario, Canada; and Washington, DC
2,030 citations
••
TL;DR: For the first time, the nature of gravitational-wave polarizations from the antenna response of the LIGO-Virgo network is tested, thus enabling a new class of phenomenological tests of gravity.
Abstract: On August 14, 2017 at 10∶30:43 UTC, the Advanced Virgo detector and the two Advanced LIGO detectors coherently observed a transient gravitational-wave signal produced by the coalescence of two stellar mass black holes, with a false-alarm rate of ≲1 in 27 000 years. The signal was observed with a three-detector network matched-filter signal-to-noise ratio of 18. The inferred masses of the initial black holes are 30.5-3.0+5.7M⊙ and 25.3-4.2+2.8M⊙ (at the 90% credible level). The luminosity distance of the source is 540-210+130 Mpc, corresponding to a redshift of z=0.11-0.04+0.03. A network of three detectors improves the sky localization of the source, reducing the area of the 90% credible region from 1160 deg2 using only the two LIGO detectors to 60 deg2 using all three detectors. For the first time, we can test the nature of gravitational-wave polarizations from the antenna response of the LIGO-Virgo network, thus enabling a new class of phenomenological tests of gravity.
1,979 citations
••
TL;DR: Roles for mRNA modification in nearly every aspect of the mRNA life cycle, as well as in various cellular, developmental, and disease processes are revealed.
1,855 citations
••
University of California, San Diego1, University of Southern Mississippi2, Atlantic Oceanographic and Meteorological Laboratory3, University of California, San Francisco4, Indiana University5, IBM6, Broad Institute7, Massachusetts Institute of Technology8, Harvard University9, Northern Arizona University10, Pacific Northwest National Laboratory11, Argonne National Laboratory12, University of Illinois at Chicago13, University of Colorado Boulder14, Cooperative Institute for Research in Environmental Sciences15, University of Southern California16, University of Chicago17, Michigan State University18
TL;DR: A meta-analysis of microbial community samples collected by hundreds of researchers for the Earth Microbiome Project is presented, creating both a reference database giving global context to DNA sequence data and a framework for incorporating data from future studies, fostering increasingly complete characterization of Earth’s microbial diversity.
Abstract: Our growing awareness of the microbial world’s importance and diversity contrasts starkly with our limited understanding of its fundamental structure. Despite recent advances in DNA sequencing, a lack of standardized protocols and common analytical frameworks impedes comparisons among studies, hindering the development of global inferences about microbial life on Earth. Here we present a meta-analysis of microbial community samples collected by hundreds of researchers for the Earth Microbiome Project. Coordinated protocols and new analytical methods, particularly the use of exact sequences instead of clustered operational taxonomic units, enable bacterial and archaeal ribosomal RNA gene sequences to be followed across multiple studies and allow us to explore patterns of diversity at an unprecedented scale. The result is both a reference database giving global context to DNA sequence data and a framework for incorporating data from future studies, fostering increasingly complete characterization of Earth’s microbial diversity.
1,676 citations
••
Harvard University1, Mayo Clinic2, Duke University3, Ohio State University4, Hannover Medical School5, Monash University6, Autonomous University of Barcelona7, Radboud University Nijmegen8, Fred Hutchinson Cancer Research Center9, Stanford University10, Memorial Sloan Kettering Cancer Center11, University of Chicago12, University Health Network13, Leipzig University14, University of Ulm15, Goethe University Frankfurt16, Dresden University of Technology17, University of Rome Tor Vergata18
TL;DR: The addition of the multitargeted kinase inhibitor midostaurin to standard chemotherapy significantly prolonged overall and event‐free survival among patients with AML and a FLT3 mutation.
Abstract: BackgroundPatients with acute myeloid leukemia (AML) and a FLT3 mutation have poor outcomes. We conducted a phase 3 trial to determine whether the addition of midostaurin — an oral multitargeted kinase inhibitor that is active in patients with a FLT3 mutation — to standard chemotherapy would prolong overall survival in this population. MethodsWe screened 3277 patients, 18 to 59 years of age, who had newly diagnosed AML for FLT3 mutations. Patients were randomly assigned to receive standard chemotherapy (induction therapy with daunorubicin and cytarabine and consolidation therapy with high-dose cytarabine) plus either midostaurin or placebo; those who were in remission after consolidation therapy entered a maintenance phase in which they received either midostaurin or placebo. Randomization was stratified according to subtype of FLT3 mutation: point mutation in the tyrosine kinase domain (TKD) or internal tandem duplication (ITD) mutation with either a high ratio (>0.7) or a low ratio (0.05 to 0.7) of muta...
••
Peking University1, Nanjing Agricultural University2, Stanford University3, Chinese Academy of Sciences4, University of Sassari5, Commissariat à l'énergie atomique et aux énergies alternatives6, Institut national de la recherche agronomique7, University of Chicago8, University of Bonn9, University of Antwerp10, International Rice Research Institute11, Potsdam Institute for Climate Impact Research12, Goddard Institute for Space Studies13, University of Florida14
TL;DR: Investigating the impacts of temperature on yields of the four crops by compiling extensive published results from four analytical methods consistently showed negative temperature impacts on crop yield at the global scale, generally underpinned by similar impacts at country and site scales.
Abstract: Wheat, rice, maize, and soybean provide two-thirds of human caloric intake. Assessing the impact of global temperature increase on production of these crops is therefore critical to maintaining global food supply, but different studies have yielded different results. Here, we investigated the impacts of temperature on yields of the four crops by compiling extensive published results from four analytical methods: global grid-based and local point-based models, statistical regressions, and field-warming experiments. Results from the different methods consistently showed negative temperature impacts on crop yield at the global scale, generally underpinned by similar impacts at country and site scales. Without CO2 fertilization, effective adaptation, and genetic improvement, each degree-Celsius increase in global mean temperature would, on average, reduce global yields of wheat by 6.0%, rice by 3.2%, maize by 7.4%, and soybean by 3.1%. Results are highly heterogeneous across crops and geographical areas, with some positive impact estimates. Multimethod analyses improved the confidence in assessments of future climate impacts on global major crops and suggest crop- and region-specific adaptation strategies to ensure food security for an increasing world population.
••
University of Chicago1, New York University2, Sungkyunkwan University3, Stanford University4, University of British Columbia5, Cleveland Clinic6, Kobe University7, Icahn School of Medicine at Mount Sinai8, Radboud University Nijmegen9, Duke University10, Memorial Sloan Kettering Cancer Center11, University of Antwerp12, Harvard University13
TL;DR: These guidelines represent the consensus of the Fleischner Society, and as such, they incorporate the opinions of a multidisciplinary international group of thoracic radiologists, pulmonologists, surgeons, pathologists, and other specialists.
Abstract: The Fleischner Society Guidelines for management of solid nodules were published in 2005, and separate guidelines for subsolid nodules were issued in 2013. Since then, new information has become available; therefore, the guidelines have been revised to reflect current thinking on nodule management. The revised guidelines incorporate several substantive changes that reflect current thinking on the management of small nodules. The minimum threshold size for routine follow-up has been increased, and recommended follow-up intervals are now given as a range rather than as a precise time period to give radiologists, clinicians, and patients greater discretion to accommodate individual risk factors and preferences. The guidelines for solid and subsolid nodules have been combined in one simplified table, and specific recommendations have been included for multiple nodules. These guidelines represent the consensus of the Fleischner Society, and as such, they incorporate the opinions of a multidisciplinary international group of thoracic radiologists, pulmonologists, surgeons, pathologists, and other specialists. Changes from the previous guidelines issued by the Fleischner Society are based on new data and accumulated experience. © RSNA, 2017 Online supplemental material is available for this article. An earlier incorrect version of this article appeared online. This article was corrected on March 13, 2017.
••
Roswell Park Cancer Institute1, University of Texas MD Anderson Cancer Center2, Merck & Co.3, Johns Hopkins University4, Bristol-Myers Squibb5, Memorial Sloan Kettering Cancer Center6, Brigham and Women's Hospital7, Washington University in St. Louis8, Indiana University – Purdue University Indianapolis9, Harvard University10, University of Chicago11, Oncology Nursing Society12
TL;DR: A multidisciplinary Toxicity Management Working Group met for a full-day workshop to develop recommendations to standardize management of immune-related adverse events, and presents their consensus recommendations on managing toxicities associated with immune checkpoint inhibitor therapy.
Abstract: Cancer immunotherapy has transformed the treatment of cancer. However, increasing use of immune-based therapies, including the widely used class of agents known as immune checkpoint inhibitors, has exposed a discrete group of immune-related adverse events (irAEs). Many of these are driven by the same immunologic mechanisms responsible for the drugs' therapeutic effects, namely blockade of inhibitory mechanisms that suppress the immune system and protect body tissues from an unconstrained acute or chronic immune response. Skin, gut, endocrine, lung and musculoskeletal irAEs are relatively common, whereas cardiovascular, hematologic, renal, neurologic and ophthalmologic irAEs occur much less frequently. The majority of irAEs are mild to moderate in severity; however, serious and occasionally life-threatening irAEs are reported in the literature, and treatment-related deaths occur in up to 2% of patients, varying by ICI. Immunotherapy-related irAEs typically have a delayed onset and prolonged duration compared to adverse events from chemotherapy, and effective management depends on early recognition and prompt intervention with immune suppression and/or immunomodulatory strategies. There is an urgent need for multidisciplinary guidance reflecting broad-based perspectives on how to recognize, report and manage organ-specific toxicities until evidence-based data are available to inform clinical decision-making. The Society for Immunotherapy of Cancer (SITC) established a multidisciplinary Toxicity Management Working Group, which met for a full-day workshop to develop recommendations to standardize management of irAEs. Here we present their consensus recommendations on managing toxicities associated with immune checkpoint inhibitor therapy.
••
TL;DR: Comprehensive genomic profiling data in this study provide insight into nivolumab's mechanism of action and reveal expansion of T cell clones in the setting of neoantigen loss.
••
TL;DR: In this article, a GW signal from the merger of two stellar-mass black holes was observed by the two Advanced Laser Interferometer Gravitational-Wave Observatory detectors with a network signal-to-noise ratio of 13.5%.
Abstract: On 2017 June 8 at 02:01:16.49 UTC, a gravitational-wave (GW) signal from the merger of two stellar-mass black holes was observed by the two Advanced Laser Interferometer Gravitational-Wave Observatory detectors with a network signal-to-noise ratio of 13. This system is the lightest black hole binary so far observed, with component masses of ${12}_{-2}^{+7}\,{M}_{\odot }$ and ${7}_{-2}^{+2}\,{M}_{\odot }$ (90% credible intervals). These lie in the range of measured black hole masses in low-mass X-ray binaries, thus allowing us to compare black holes detected through GWs with electromagnetic observations. The source's luminosity distance is ${340}_{-140}^{+140}\,\mathrm{Mpc}$, corresponding to redshift ${0.07}_{-0.03}^{+0.03}$. We verify that the signal waveform is consistent with the predictions of general relativity.
••
TL;DR: In this article, the authors show that the impact of regularization bias and overfitting on estimation of the parameter of interest θ0 can be removed by using two simple, yet critical, ingredients: (1) using Neyman-orthogonal moments/scores that have reduced sensitivity with respect to nuisance parameters, and (2) making use of cross-fitting, which provides an efficient form of data-splitting.
Abstract: Summary
We revisit the classic semi-parametric problem of inference on a low-dimensional parameter θ0 in the presence of high-dimensional nuisance parameters η0. We depart from the classical setting by allowing for η0 to be so high-dimensional that the traditional assumptions (e.g. Donsker properties) that limit complexity of the parameter space for this object break down. To estimate η0, we consider the use of statistical or machine learning (ML) methods, which are particularly well suited to estimation in modern, very high-dimensional cases. ML methods perform well by employing regularization to reduce variance and trading off regularization bias with overfitting in practice. However, both regularization bias and overfitting in estimating η0 cause a heavy bias in estimators of θ0 that are obtained by naively plugging ML estimators of η0 into estimating equations for θ0. This bias results in the naive estimator failing to be N−1/2 consistent, where N is the sample size. We show that the impact of regularization bias and overfitting on estimation of the parameter of interest θ0 can be removed by using two simple, yet critical, ingredients: (1) using Neyman-orthogonal moments/scores that have reduced sensitivity with respect to nuisance parameters to estimate θ0; (2) making use of cross-fitting, which provides an efficient form of data-splitting. We call the resulting set of methods double or debiased ML (DML). We verify that DML delivers point estimators that concentrate in an N−1/2-neighbourhood of the true parameter values and are approximately unbiased and normally distributed, which allows construction of valid confidence statements. The generic statistical theory of DML is elementary and simultaneously relies on only weak theoretical requirements, which will admit the use of a broad array of modern ML methods for estimating the nuisance parameters, such as random forests, lasso, ridge, deep neural nets, boosted trees, and various hybrids and ensembles of these methods. We illustrate the general theory by applying it to provide theoretical properties of the following: DML applied to learn the main regression parameter in a partially linear regression model; DML applied to learn the coefficient on an endogenous variable in a partially linear instrumental variables model; DML applied to learn the average treatment effect and the average treatment effect on the treated under unconfoundedness; DML applied to learn the local average treatment effect in an instrumental variables setting. In addition to these theoretical applications, we also illustrate the use of DML in three empirical examples.
••
TL;DR: The Pathosystems Resource Integration Center (PATRIC) is the bacterial Bioinformatics Resource Center, which provides services for RNA-Seq, variation, model reconstruction and differential expression analysis, all delivered through an updated private workspace.
Abstract: The Pathosystems Resource Integration Center (PATRIC) is the bacterial Bioinformatics Resource Center (https://www.patricbrc.org). Recent changes to PATRIC include a redesign of the web interface and some new services that provide users with a platform that takes them from raw reads to an integrated analysis experience. The redesigned interface allows researchers direct access to tools and data, and the emphasis has changed to user-created genome-groups, with detailed summaries and views of the data that researchers have selected. Perhaps the biggest change has been the enhanced capability for researchers to analyze their private data and compare it to the available public data. Researchers can assemble their raw sequence reads and annotate the contigs using RASTtk. PATRIC also provides services for RNA-Seq, variation, model reconstruction and differential expression analysis, all delivered through an updated private workspace. Private data can be compared by 'virtual integration' to any of PATRIC's public data. The number of genomes available for comparison in PATRIC has expanded to over 80 000, with a special emphasis on genomes with antimicrobial resistance data. PATRIC uses this data to improve both subsystem annotation and k-mer classification, and tags new genomes as having signatures that indicate susceptibility or resistance to specific antibiotics.
••
TL;DR: All three YTHDF proteins may act in an integrated and cooperative manner to impact fundamental biological processes related to m6A RNA methylation in the cytoplasm.
Abstract: N6-methyladenosine (m6A) is the most abundant internal modification in eukaryotic messenger RNAs (mRNAs), and plays important roles in cell differentiation and tissue development. It regulates multiple steps throughout the RNA life cycle including RNA processing, translation, and decay, via the recognition by selective binding proteins. In the cytoplasm, m6A binding protein YTHDF1 facilitates translation of m6A-modified mRNAs, and YTHDF2 accelerates the decay of m6A-modified transcripts. The biological function of YTHDF3, another cytoplasmic m6A binder of the YTH (YT521-B homology) domain family, remains unknown. Here, we report that YTHDF3 promotes protein synthesis in synergy with YTHDF1, and affects methylated mRNA decay mediated through YTHDF2. Cells deficient in all three YTHDF proteins experience the most dramatic accumulation of m6A-modified transcripts. These results indicate that together with YTHDF1 and YTHDF2, YTHDF3 plays critical roles to accelerate metabolism of m6A-modified mRNAs in the cytoplasm. All three YTHDF proteins may act in an integrated and cooperative manner to impact fundamental biological processes related to m6A RNA methylation.
••
TL;DR: It is shown that the co-receptor CD28 is strongly preferred over the TCR as a target for dephosphorylation by PD-1–recruited Shp2 phosphatase, suggesting that costimulatory pathways play key roles in regulating effector T cell function and responses to anti-PD-L1/PD-1 therapy.
Abstract: Programmed cell death–1 (PD-1) is a coinhibitory receptor that suppresses T cell activation and is an important cancer immunotherapy target. Upon activation by its ligand PD-L1, PD-1 is thought to suppress signaling through the T cell receptor (TCR). By titrating PD-1 signaling in a biochemical reconstitution system, we demonstrate that the co-receptor CD28 is strongly preferred over the TCR as a target for dephosphorylation by PD-1–recruited Shp2 phosphatase. We also show that CD28, but not the TCR, is preferentially dephosphorylated in response to PD-1 activation by PD-L1 in an intact cell system. These results reveal that PD-1 suppresses T cell function primarily by inactivating CD28 signaling, suggesting that costimulatory pathways play key roles in regulating effector T cell function and responses to anti–PD-L1/PD-1 therapy.
••
Columbia University1, University of Amsterdam2, University of Mainz3, University of Coimbra4, New York University Abu Dhabi5, University of Zurich6, Stockholm University7, Rensselaer Polytechnic Institute8, Max Planck Society9, Weizmann Institute of Science10, University of Freiburg11, Purdue University12, University of Nantes13, University of Bologna14, University of California, San Diego15, University of Münster16, University of Chicago17, Rice University18, Pierre-and-Marie-Curie University19, University of California, Los Angeles20
TL;DR: The first dark matter search results from XENON1T, a ∼2000-kg-target-mass dual-phase (liquid-gas) xenon time projection chamber in operation at the Laboratori Nazionali del Gran Sasso in Italy, are reported and a profile likelihood analysis shows that the data are consistent with the background-only hypothesis.
Abstract: We report the first dark matter search results from XENON1T, a ∼2000-kg-target-mass dual-phase (liquid-gas) xenon time projection chamber in operation at the Laboratori Nazionali del Gran Sasso in Italy and the first ton-scale detector of this kind The blinded search used 342 live days of data acquired between November 2016 and January 2017 Inside the (1042±12)-kg fiducial mass and in the [5,40] keVnr energy range of interest for weakly interacting massive particle (WIMP) dark matter searches, the electronic recoil background was (193±025)×10-4 events/(kg×day×keVee), the lowest ever achieved in such a dark matter detector A profile likelihood analysis shows that the data are consistent with the background-only hypothesis We derive the most stringent exclusion limits on the spin-independent WIMP-nucleon interaction cross section for WIMP masses above 10 GeV/c2, with a minimum of 77×10-47 cm2 for 35-GeV/c2 WIMPs at 90% CL
••
University of California, Los Angeles1, Roswell Park Cancer Institute2, Huntsman Cancer Institute3, University Hospital of Lausanne4, Fox Chase Cancer Center5, Heidelberg University6, University of Pittsburgh7, University of Chicago8, Amgen9, Merck & Co.10, Harvard University11, University of Sydney12
TL;DR: The findings suggest that oncolytic virotherapy may improve the efficacy of anti-PD-1 therapy by changing the tumor microenvironment.
••
Kyriaki Michailidou1, Kyriaki Michailidou2, Sara Lindström3, Sara Lindström4 +393 more•Institutions (127)
TL;DR: A genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry finds that heritability of Breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2–5-fold enriched relative to the genome- wide average.
Abstract: Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P < 5 × 10-8. The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention.
••
TL;DR: This work uncovers a critical function for ALKBH5 and provides insight into critical roles of m6A methylation in glioblastoma and a long non-coding RNA antisense to FOXM1 (FOXM1-AS) promotes the interaction of AL KBH5 withFOXM1 nascent transcripts.
••
TL;DR: It is shown that FTO, as an m6A demethylase, plays a critical oncogenic role in acute myeloid leukemia (AML) and provides profound insights into leukemogenesis and drug response.
••
TL;DR: In this article, the design principles leading to these properties are identified and discussed, in particular, linear and mechanism-based metamaterials (such as origami-based and kirigami based metammaterials), harnessing instabilities and frustration, and topological and nonlinear metam materials.
Abstract: Mechanical metamaterials exhibit properties and functionalities that cannot be realized in conventional materials. Originally, the field focused on achieving unusual (zero or negative) values for familiar mechanical parameters, such as density, Poisson's ratio or compressibility, but more recently, new classes of metamaterials — including shape-morphing, topological and nonlinear metamaterials — have emerged. These materials exhibit exotic functionalities, such as pattern and shape transformations in response to mechanical forces, unidirectional guiding of motion and waves, and reprogrammable stiffness or dissipation. In this Review, we identify the design principles leading to these properties and discuss, in particular, linear and mechanism-based metamaterials (such as origami-based and kirigami-based metamaterials), metamaterials harnessing instabilities and frustration, and topological metamaterials. We conclude by outlining future challenges for the design, creation and conceptualization of advanced mechanical metamaterials.
••
04 Aug 2017TL;DR: This work reformulate algorithmic fairness as constrained optimization: the objective is to maximize public safety while satisfying formal fairness constraints designed to reduce racial disparities, and also to human decision makers carrying out structured decision rules.
Abstract: Algorithms are now regularly used to decide whether defendants awaiting trial are too dangerous to be released back into the community. In some cases, black defendants are substantially more likely than white defendants to be incorrectly classified as high risk. To mitigate such disparities, several techniques have recently been proposed to achieve algorithmic fairness. Here we reformulate algorithmic fairness as constrained optimization: the objective is to maximize public safety while satisfying formal fairness constraints designed to reduce racial disparities. We show that for several past definitions of fairness, the optimal algorithms that result require detaining defendants above race-specific risk thresholds. We further show that the optimal unconstrained algorithm requires applying a single, uniform threshold to all defendants. The unconstrained algorithm thus maximizes public safety while also satisfying one important understanding of equality: that all individuals are held to the same standard, irrespective of race. Because the optimal constrained and unconstrained algorithms generally differ, there is tension between improving public safety and satisfying prevailing notions of algorithmic fairness. By examining data from Broward County, Florida, we show that this trade-off can be large in practice. We focus on algorithms for pretrial release decisions, but the principles we discuss apply to other domains, and also to human decision makers carrying out structured decision rules.
••
TL;DR: First-line pembrolizumab has antitumour activity and acceptable tolerability in cisplatin-ineligible patients with urothelial cancer, most of whom were elderly, had poor prognostic factors, or had serious comorbidities.
Abstract: Summary Background More than half of all patients with advanced urothelial cancer cannot receive standard, first-line cisplatin-based chemotherapy because of renal dysfunction, poor performance status, or other comorbidities. We assessed the activity and safety of first-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer. Methods In this multicentre, single-arm, phase 2 study (KEYNOTE-052), cisplatin-ineligible patients with advanced urothelial cancer who had not been previously treated with systemic chemotherapy were recruited from 91 academic medical centres in 20 countries. Enrolled patients received intravenous pembrolizumab 200 mg every 3 weeks. The primary endpoint was objective response (the proportion of patients who achieved complete or partial response) in all patients and by PD-L1 expression status according to the Response Evaluation Criteria in Solid Tumors, version 1.1, as assessed by independent central review. PD-L1 expression was assessed in tumour and inflammatory cells from tumour biopsies provided at study entry. Activity and safety were analysed in all patients who received at least one dose of pembrolizumab (all-patients-treated population). This study is registered with ClinicalTrials.gov, number NCT02335424, and follow-up is ongoing. Findings Between Feb 24, 2015, and Aug 8, 2016, 374 patients were enrolled and 370 patients received at least one dose of pembrolizumab. 89 (24%, 95% CI 20–29) of 370 patients had a centrally assessed objective response, and as of Sept 1, 2016 (data cutoff), 74 (83%) of 89 responses were ongoing. Median follow-up was 5 months (IQR 3·0–8·6). A PD-L1-expression cutoff of 10% was associated with a higher frequency of response to pembrolizumab; 42 (38%, 95% CI 29–48) of 110 patients with a combined positive score of 10% or more had a centrally assessed objective response. The most common grade 3 or 4 treatment-related adverse events were fatigue (eight [2%] of 370 patients), alkaline phosphatase increase (five [1%]), colitis, and muscle weakness (both four [1%]). 36 (10%) of 370 patients had a serious treatment-related adverse event. 17 (5%) of 370 patients died from non-treatment-related adverse events associated with death, and one patient died from treatment-related adverse events (myositis in addition to grade 3 thyroiditis, grade 3 hepatitis, grade 3 pneumonia, and grade 4 myocarditis). Interpretation First-line pembrolizumab has antitumour activity and acceptable tolerability in cisplatin-ineligible patients with urothelial cancer, most of whom were elderly, had poor prognostic factors, or had serious comorbidities. In view of this result, pembrolizumab has become a new treatment option for patients who are cisplatin-ineligible or not suitable candidates for chemotherapy. Pembrolizumab in the first-line setting is being further assessed in the phase 3 KEYNOTE-361 trial (ClinicalTrials.gov, NCT02335424). Funding Merck & Co.
••
University of California, San Diego1, Johns Hopkins University2, University of Washington3, University of California, San Francisco4, University of Pennsylvania5, Duke University6, University of Toronto7, University of Chicago8, New York University9, University of Maryland, Baltimore10, University of Paris11, University of Jena12, Victoria University of Wellington13, Primary Children's Hospital14, Brigham Young University15, McGill University16, Kaiser Permanente17, University of Pittsburgh18, Brown University19
TL;DR: An international multidisciplinary team of 29 members with expertise in guideline development, evidence analysis, and family-centered care is assembled to revise the 2007 Clinical Practice Guidelines for support of the family in the patient-centered ICU.
Abstract: Objective:To provide clinicians with evidence-based strategies to optimize the support of the family of critically ill patients in the ICU.Methods:We used the Council of Medical Specialty Societies principles for the development of clinical guidelines as the framework for guideline development. We a
••
TL;DR: The data indicate that lack of CD103+ DCs within the tumor microenvironment dominantly resists the effector phase of an anti-tumor T cell response, contributing to immune escape.