Showing papers by "Osaka University published in 2020"
TL;DR: Global health has steadily improved over the past 30 years as measured by age-standardised DALY rates, and there has been a marked shift towards a greater proportion of burden due to YLDs from non-communicable diseases and injuries.
5,802 citations
Book•
23 Feb 2020
TL;DR: The ATLAS detector as installed in its experimental cavern at point 1 at CERN is described in this paper, where a brief overview of the expected performance of the detector when the Large Hadron Collider begins operation is also presented.
Abstract: The ATLAS detector as installed in its experimental cavern at point 1 at CERN is described in this paper. A brief overview of the expected performance of the detector when the Large Hadron Collider begins operation is also presented.
3,111 citations
Christopher J L Murray1, Christopher J L Murray2, Christopher J L Murray3, Aleksandr Y. Aravkin2 +2269 more•Institutions (286)
TL;DR: The largest declines in risk exposure from 2010 to 2019 were among a set of risks that are strongly linked to social and economic development, including household air pollution; unsafe water, sanitation, and handwashing; and child growth failure.
3,059 citations
National Yang-Ming University1, The Chinese University of Hong Kong2, Mahidol University3, University of Tokyo4, Seoul National University Bundang Hospital5, Peking Union Medical College Hospital6, Kyung Hee University7, Nagoya University8, Seoul National University9, Taipei Veterans General Hospital10, Ajou University11, Tan Tock Seng Hospital12, Osaka University13, University of Tsukuba14, Chinese Ministry of Health15
TL;DR: The Asian Working Group for Sarcopenia 2019 introduces "possible sarcopenia," defined by either low muscle strength or low physical performance only, specifically for use in primary health care or community-based health promotion, to enable earlier lifestyle interventions.
2,287 citations
TL;DR: The flagship paper of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium describes the generation of the integrative analyses of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types, the structures for international data sharing and standardized analyses, and the main scientific findings from across the consortium studies.
Abstract: Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale1,2,3. Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4–5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter4; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation5,6; analyses timings and patterns of tumour evolution7; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity8,9; and evaluates a range of more-specialized features of cancer genomes8,10,11,12,13,14,15,16,17,18.
1,600 citations
Duke University1, University of British Columbia2, Albert Einstein College of Medicine3, University of Parma4, University of Wisconsin-Madison5, Lenox Hill Hospital6, Columbia University7, New Generation University College8, Medical College of Wisconsin9, Stanford University10, University of Missouri11, National Institutes of Health12, University of California, Los Angeles13, Université Paris-Saclay14, University Hospital Heidelberg15, Sichuan University16, Cleveland Clinic17, Radboud University Nijmegen18, university of lille19, Catholic University of the Sacred Heart20, Osaka University21
TL;DR: A multidisciplinary panel comprised principally of radiologists and pulmonologists from 10 countries with experience managing COVID-19 patients across a spectrum of healthcare environments evaluated the utility of imaging within three scenarios representing varying risk factors, community conditions, and resource constraints, resulting in five main and three additional recommendations intended to guide medical practitioners in the use of CXR and CT in the management of COIDs.
1,232 citations
TL;DR: An overview of the field of Variational Quantum Algorithms is presented and strategies to overcome their challenges as well as the exciting prospects for using them as a means to obtain quantum advantage are discussed.
Abstract: Applications such as simulating complicated quantum systems or solving large-scale linear algebra problems are very challenging for classical computers due to the extremely high computational cost. Quantum computers promise a solution, although fault-tolerant quantum computers will likely not be available in the near future. Current quantum devices have serious constraints, including limited numbers of qubits and noise processes that limit circuit depth. Variational Quantum Algorithms (VQAs), which use a classical optimizer to train a parametrized quantum circuit, have emerged as a leading strategy to address these constraints. VQAs have now been proposed for essentially all applications that researchers have envisioned for quantum computers, and they appear to the best hope for obtaining quantum advantage. Nevertheless, challenges remain including the trainability, accuracy, and efficiency of VQAs. Here we overview the field of VQAs, discuss strategies to overcome their challenges, and highlight the exciting prospects for using them to obtain quantum advantage.
842 citations
Queen's University1, University of Texas Southwestern Medical Center2, Osaka University3, Ben-Gurion University of the Negev4, VU University Amsterdam5, University of Milan6, University of São Paulo7, Laval University8, Harvard University9, University of Surrey10, University of Padua11, University of New South Wales12, University of Colorado Denver13
TL;DR: The evidence is summarized that waist circumference and BMI together can provide improved assessments of cardiometabolic risk compared with either measurement alone, and it is recommended that health professionals are trained to properly perform this simple measurement in clinical practice.
Abstract: Despite decades of unequivocal evidence that waist circumference provides both independent and additive information to BMI for predicting morbidity and risk of death, this measurement is not routinely obtained in clinical practice. This Consensus Statement proposes that measurements of waist circumference afford practitioners with an important opportunity to improve the management and health of patients. We argue that BMI alone is not sufficient to properly assess or manage the cardiometabolic risk associated with increased adiposity in adults and provide a thorough review of the evidence that will empower health practitioners and professional societies to routinely include waist circumference in the evaluation and management of patients with overweight or obesity. We recommend that decreases in waist circumference are a critically important treatment target for reducing adverse health risks for both men and women. Moreover, we describe evidence that clinically relevant reductions in waist circumference can be achieved by routine, moderate-intensity exercise and/or dietary interventions. We identify gaps in the knowledge, including the refinement of waist circumference threshold values for a given BMI category, to optimize obesity risk stratification across age, sex and ethnicity. We recommend that health professionals are trained to properly perform this simple measurement and consider it as an important 'vital sign' in clinical practice.
619 citations
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Kyoto University1, Brookhaven National Laboratory2, KEK3, Université Paris-Saclay4, University of Connecticut5, University of Bern6, University of Regensburg7, University of Southern Denmark8, University of Rome Tor Vergata9, University of Wuppertal10, Forschungszentrum Jülich11, Osaka University12, San Francisco State University13, Indiana University14, Los Alamos National Laboratory15, Graduate University for Advanced Studies16, American Physical Society17, Autonomous University of Madrid18, University of Edinburgh19, University of Southampton20, National Chiao Tung University21, Chung Yuan Christian University22, Columbia University23, University of North Carolina at Chapel Hill24, Trinity College, Dublin25, University of Washington26, Fermilab27, Humboldt University of Berlin28, University of Mainz29
TL;DR: In this article, a review of lattice results related to pion, kaon, D-meson, neutral kaon mixing, B-meon, and nucleon physics with the aim of making them easily accessible to the nuclear and particle physics communities is presented.
Abstract: We review lattice results related to pion, kaon, D-meson, B-meson, and nucleon physics with the aim of making them easily accessible to the nuclear and particle physics communities. More specifically, we report on the determination of the light-quark masses, the form factor $f_+(0)$ arising in the semileptonic $K \rightarrow \pi $ transition at zero momentum transfer, as well as the decay constant ratio $f_K/f_\pi $ and its consequences for the CKM matrix elements $V_{us}$ and $V_{ud}$. Furthermore, we describe the results obtained on the lattice for some of the low-energy constants of $SU(2)_L\times SU(2)_R$ and $SU(3)_L\times SU(3)_R$ Chiral Perturbation Theory. We review the determination of the $B_K$ parameter of neutral kaon mixing as well as the additional four B parameters that arise in theories of physics beyond the Standard Model. For the heavy-quark sector, we provide results for $m_c$ and $m_b$ as well as those for D- and B-meson decay constants, form factors, and mixing parameters. These are the heavy-quark quantities most relevant for the determination of CKM matrix elements and the global CKM unitarity-triangle fit. We review the status of lattice determinations of the strong coupling constant $\alpha _s$. Finally, in this review we have added a new section reviewing results for nucleon matrix elements of the axial, scalar and tensor bilinears, both isovector and flavor diagonal.
607 citations
TL;DR: This review broadly discusses various C-H bond functionalization reactions for the formation of C-C bonds with the aid of bidentate directing groups.
Abstract: During the past decades, synthetic organic chemistry discovered that directing group assisted C–H activation is a key tool for the expedient and siteselective construction of C–C bonds. Among the v...
573 citations
TL;DR: It is important to develop new strategies to address loneliness and social isolation among older adults for the post-pandemic era and to maintain social connections with each other, especially with older persons.
Abstract: Loneliness and social isolation are associated with adverse physical and psychological consequences which are particularly prevalent in older persons. During this unprecedented time of the COVID-19 pandemic, we must follow social distancing guidelines to protect ourselves and to reduce the spread of coronavirus. At the same time, it is crucial to maintain social connections with each other, especially with older persons, to help cope and reduce the negative consequences of loneliness and social isolation. It is important to develop new strategies (e.g. virtual health care and new government policy) to address loneliness and social isolation among older adults for the post-pandemic era.
Katrina L. Grasby1, Neda Jahanshad2, Jodie N. Painter1, Lucía Colodro-Conde3 +356 more•Institutions (115)
TL;DR: Results support the radial unit hypothesis that different developmental mechanisms promote surface area expansion and increases in thickness and find evidence that brain structure is a key phenotype along the causal pathway that leads from genetic variation to differences in general cognitive function.
Abstract: The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder.
TL;DR: This review discusses the current understanding of T Reg immunobiology in normal and disease states, with the perspective on the realization of Treg-targeting therapies in the clinic.
Abstract: Naturally occurring CD4+ regulatory T cells (Tregs), which specifically express the transcription factor FoxP3 in the nucleus and CD25 and CTLA-4 on the cell surface, are a functionally distinct T cell subpopulation actively engaged in the maintenance of immunological self-tolerance and homeostasis. Recent studies have facilitated our understanding of the cellular and molecular basis of their generation, function, phenotypic and functional stability, and adaptability. It is under investigation in humans how functional or numerical Treg anomalies, whether genetically determined or environmentally induced, contribute to immunological diseases such as autoimmune diseases. Also being addressed is how Tregs can be targeted to control physiological and pathological immune responses, for example, by depleting them to enhance tumor immunity or by expanding them to treat immunological diseases. This review discusses our current understanding of Treg immunobiology in normal and disease states, with a perspective on the realization of Treg-targeting therapies in the clinic.
TL;DR: In this article, the authors demonstrate robust terahertz topological valley transport through several sharp bends on the all-silicon chip and achieve real-time transmission of uncompressed 4K high-definition video.
Abstract: The realization of integrated, low-cost and efficient solutions for high-speed, on-chip communication requires terahertz-frequency waveguides and has great potential for information and communication technologies, including sixth-generation (6G) wireless communication, terahertz integrated circuits, and interconnects for intrachip and interchip communication. However, conventional approaches to terahertz waveguiding suffer from sensitivity to defects and sharp bends. Here, building on the topological phase of light, we experimentally demonstrate robust terahertz topological valley transport through several sharp bends on the all-silicon chip. The valley kink states are excellent information carriers owing to their robustness, single-mode propagation and linear dispersion. By leveraging such states, we demonstrate error-free communication through a highly twisted domain wall at an unprecedented data transfer rate (exceeding ten gigabits per second) that enables real-time transmission of uncompressed 4K high-definition video (that is, with a horizontal display resolution of approximately 4,000 pixels). Terahertz communication with topological devices opens a route towards terabit-per-second datalinks that could enable artificial intelligence and cloud-based technologies, including autonomous driving, healthcare, precision manufacturing and holographic communication. Robust terahertz wave transport is demonstrated on a silicon chip using the valley Hall topological phase. Error-free communication is achieved at a data rate of 11 Gbit s−1, enabling real-time transmission of uncompressed 4K high-definition video.
Keio University1, Osaka University2, Graduate University for Advanced Studies3, Mie University4, Chinese Academy of Sciences5, Yale University6, University of Florida7, Academy of Sciences of the Czech Republic8, University of California, Davis9, Chiba University10, National Institute of Genetics11, Yokohama City University12
TL;DR: A comprehensive lipidome atlas with retention time, collision cross-section and tandem mass spectrometry information is presented and mass spectral fragmentations of lipids across 117 lipid subclasses are presented in a lipidomeAtlas.
Abstract: We present Mass Spectrometry-Data Independent Analysis software version 4 (MS-DIAL 4), a comprehensive lipidome atlas with retention time, collision cross-section and tandem mass spectrometry information. We formulated mass spectral fragmentations of lipids across 117 lipid subclasses and included ion mobility tandem mass spectrometry. Using human, murine, algal and plant biological samples, we annotated and semiquantified 8,051 lipids using MS-DIAL 4 with a 1–2% estimated false discovery rate. MS-DIAL 4 helps standardize lipidomics data and discover lipid pathways. Mass spectral fragmentations of lipids across 117 lipid subclasses are presented in a lipidome atlas.
Newcastle University1, Mayo Clinic2, University of Strasbourg3, Nagoya University4, University of Cambridge5, McGill University6, King's College London7, University of Exeter8, University of Chieti-Pescara9, University of Miami10, University of California, San Diego11, Northwestern University12, Harvard University13, Columbia University14, Osaka University15, Cleveland Clinic16, University of Sydney17, Sunnybrook Health Sciences Centre18, University of Washington19, University College London20, University of Toronto21
TL;DR: This work proposes operationalized diagnostic criteria for probable and possible mild cognitive impairment with Lewy bodies, which are intended for use in research settings pending validation for Use in clinical practice and are compatible with current criteria for other prodromal neurodegenerative disorders including Alzheimer and Parkinson disease.
Abstract: The prodromal phase of dementia with Lewy bodies (DLB) includes (1) mild cognitive impairment (MCI), (2) delirium-onset, and (3) psychiatric-onset presentations. The purpose of our review is to determine whether there is sufficient information yet available to justify development of diagnostic criteria for each of these. Our goal is to achieve evidence-based recommendations for the recognition of DLB at a predementia, symptomatic stage. We propose operationalized diagnostic criteria for probable and possible mild cognitive impairment with Lewy bodies, which are intended for use in research settings pending validation for use in clinical practice. They are compatible with current criteria for other prodromal neurodegenerative disorders including Alzheimer and Parkinson disease. Although there is still insufficient evidence to propose formal criteria for delirium-onset and psychiatric-onset presentations of DLB, we feel that it is important to characterize them, raising the index of diagnostic suspicion and prioritizing them for further investigation.
TL;DR: The importance of θ disorder as an unconventional type of disorder enabling the use of twist-angle gradients for bandstructure engineering, for realization of correlated phenomena and for gate-tunable built-in planar electric fields for device applications is established.
Abstract: The recently discovered flat electronic bands and strongly correlated and superconducting phases in magic-angle twisted bilayer graphene (MATBG)1,2 crucially depend on the interlayer twist angle, θ. Although control of the global θ with a precision of about 0.1 degrees has been demonstrated1-7, little information is available on the distribution of the local twist angles. Here we use a nanoscale on-tip scanning superconducting quantum interference device (SQUID-on-tip)8 to obtain tomographic images of the Landau levels in the quantum Hall state9 and to map the local θ variations in hexagonal boron nitride (hBN)-encapsulated MATBG devices with relative precision better than 0.002 degrees and a spatial resolution of a few moire periods. We find a correlation between the degree of θ disorder and the quality of the MATBG transport characteristics and show that even state-of-the-art devices-which exhibit correlated states, Landau fans and superconductivity-display considerable local variation in θ of up to 0.1 degrees, exhibiting substantial gradients and networks of jumps, and may contain areas with no local MATBG behaviour. We observe that the correlated states in MATBG are particularly fragile with respect to the twist-angle disorder. We also show that the gradients of θ generate large gate-tunable in-plane electric fields, unscreened even in the metallic regions, which profoundly alter the quantum Hall state by forming edge channels in the bulk of the sample and may affect the phase diagram of the correlated and superconducting states. We thus establish the importance of θ disorder as an unconventional type of disorder enabling the use of twist-angle gradients for bandstructure engineering, for realization of correlated phenomena and for gate-tunable built-in planar electric fields for device applications.
TL;DR: To assess current trajectories towards the GPW13 UHC billion target—1 billion more people benefiting from UHC by 2023—the authors estimated additional population equivalents with UHC effective coverage from 2018 to 2023, and quantified frontiers of U HC effective coverage performance on the basis of pooled health spending per capita.
TL;DR: The authors recount the earliest stages of translational research into IL-6 biology and the subsequent development of therapeutic IL- 6 pathway inhibitors for the treatment of autoimmune rheumatic diseases and potentially numerous other indications.
Abstract: In 1973, IL-6 was identified as a soluble factor that is secreted by T cells and is important for antibody production by B cells. Since its discovery more than 40 years ago, the IL-6 pathway has emerged as a pivotal pathway involved in immune regulation in health and dysregulation in many diseases. Targeting of the IL-6 pathway has led to innovative therapeutic approaches for various rheumatic diseases, such as rheumatoid arthritis, juvenile idiopathic arthritis, adult-onset Still's disease, giant cell arteritis and Takayasu arteritis, as well as other conditions such as Castleman disease and cytokine release syndrome. Targeting this pathway has also identified avenues for potential expansion into several other indications, such as uveitis, neuromyelitis optica and, most recently, COVID-19 pneumonia. To mark the tenth anniversary of anti-IL-6 receptor therapy worldwide, we discuss the history of research into IL-6 biology and the development of therapies that target IL-6 signalling, including the successes and challenges and with an emphasis on rheumatic diseases.
National Institute for Health Research1, Harvard University2, Montreal Heart Institute3, University of North Carolina at Chapel Hill4, Wellcome Trust Sanger Institute5, VA Boston Healthcare System6, Osaka University7, Icahn School of Medicine at Mount Sinai8, University of Wisconsin–Milwaukee9, Kyushu University10, University of Washington11, University of Bristol12, University of Copenhagen13, Erasmus University Medical Center14, National Institutes of Health15, Veterans Health Administration16, Kaiser Permanente17, International Agency for Research on Cancer18, Wake Forest University19, Imperial College London20, Broad Institute21, Greifswald University Hospital22, University of Pennsylvania23, British Heart Foundation24, Fred Hutchinson Cancer Research Center25, Chinese National Human Genome Center26, Technische Universität München27, University of Tampere28, University of Tokyo29, University of Ioannina30, University of Colorado Denver31, Duke University32, University of Virginia33, University of Minnesota34, Turku University Hospital35, Los Angeles Biomedical Research Institute36, Stanford University37, Mashhad University of Medical Sciences38, NHS Blood and Transplant39, Brigham and Women's Hospital40, University of Oxford41, University of Liège42, European Bioinformatics Institute43, John Radcliffe Hospital44
TL;DR: The results show the power of large-scale blood cell trait GWAS to interrogate clinically meaningful variants across a wide allelic spectrum of human variation.
TL;DR: Findings for the secondary endpoint of FVC% predicted indicate that tocilizumab might preserve lung function in people with early SSc-ILD and elevated acute-phase reactants.
Brigham and Women's Hospital1, Memorial Sloan Kettering Cancer Center2, Cleveland Clinic3, Netherlands Cancer Institute4, University of Texas MD Anderson Cancer Center5, Beatson West of Scotland Cancer Centre6, BC Cancer Agency7, Aix-Marseille University8, Osaka University9, University of Ulsan10, Macquarie University11, Medical University of Vienna12, Georgetown University Medical Center13, City of Hope National Medical Center14, Pfizer15, Institut Gustave Roussy16
TL;DR: Among patients with previously untreated aRCC, treatment with avelumab plus axit inib continued to result in a statistically significant improvement in PFS vs sunitinib; OS data were still immature.
TL;DR: In this article, a search for the electroweak production of charginos and sleptons decaying into final states with two electrons or muons is presented, based on 139.fb$^{-1}$ of proton-proton collisions recorded by the ATLAS detector at the Large Hadron Collider at
Abstract: A search for the electroweak production of charginos and sleptons decaying into final states with two electrons or muons is presented. The analysis is based on 139 fb$^{-1}$ of proton–proton collisions recorded by the ATLAS detector at the Large Hadron Collider at $\sqrt{s}=13$ $\text {TeV}$. Three R-parity-conserving scenarios where the lightest neutralino is the lightest supersymmetric particle are considered: the production of chargino pairs with decays via either W bosons or sleptons, and the direct production of slepton pairs. The analysis is optimised for the first of these scenarios, but the results are also interpreted in the others. No significant deviations from the Standard Model expectations are observed and limits at 95% confidence level are set on the masses of relevant supersymmetric particles in each of the scenarios. For a massless lightest neutralino, masses up to 420 $\text {Ge}\text {V}$ are excluded for the production of the lightest-chargino pairs assuming W-boson-mediated decays and up to 1 $\text {TeV}$ for slepton-mediated decays, whereas for slepton-pair production masses up to 700 $\text {Ge}\text {V}$ are excluded assuming three generations of mass-degenerate sleptons.
Broad Institute1, Harvard University2, Kyushu University3, Chiba University4, University of Tokyo5, Osaka University6, University of North Carolina at Chapel Hill7, Japanese Foundation for Cancer Research8, Tokyo Medical and Dental University9, Tohoku University10, National Cancer Research Institute11, Fujita Health University12, Hiroshima University13, Shiga University of Medical Science14, University of Tokushima15, Kyoto University16, Iwate Medical University17, Nagoya University18, Nippon Medical School19, Nihon University20, Juntendo University21, University of Hyogo22, Saga University23, University of Manchester24
TL;DR: A large-scale genome-wide association study in a Japanese population provides insights into the etiology of complex diseases and highlights the importance of performing GWAS in non-European populations.
Abstract: The overwhelming majority of participants in current genetic studies are of European ancestry. To elucidate disease biology in the East Asian population, we conducted a genome-wide association study (GWAS) with 212,453 Japanese individuals across 42 diseases. We detected 320 independent signals in 276 loci for 27 diseases, with 25 novel loci (P < 9.58 × 10-9). East Asian-specific missense variants were identified as candidate causal variants for three novel loci, and we successfully replicated two of them by analyzing independent Japanese cohorts; p.R220W of ATG16L2 (associated with coronary artery disease) and p.V326A of POT1 (associated with lung cancer). We further investigated enrichment of heritability within 2,868 annotations of genome-wide transcription factor occupancy, and identified 378 significant enrichments across nine diseases (false discovery rate < 0.05) (for example, NKX3-1 for prostate cancer). This large-scale GWAS in a Japanese population provides insights into the etiology of complex diseases and highlights the importance of performing GWAS in non-European populations.
Memorial Sloan Kettering Cancer Center1, Pfizer2, St Bartholomew's Hospital3, Institut Gustave Roussy4, Netherlands Cancer Institute5, The Royal Marsden NHS Foundation Trust6, Osaka University7, City of Hope National Medical Center8, University of Texas MD Anderson Cancer Center9, University of Ulsan10, Ipsen11, Brigham and Women's Hospital12
TL;DR: Important biological features associated with differential PFS between the treatment arms are identified, including new immunomodulatory and angiogenesis gene expression signatures (GESs), previously undescribed mutational profiles and their corresponding GESs, and several HLA types.
Abstract: We report on molecular analyses of baseline tumor samples from the phase 3 JAVELIN Renal 101 trial (n = 886;
NCT02684006
), which demonstrated significantly prolonged progression-free survival (PFS) with first-line avelumab + axitinib versus sunitinib in advanced renal cell carcinoma (aRCC). We found that neither expression of the commonly assessed biomarker programmed cell death ligand 1 (PD-L1) nor tumor mutational burden differentiated PFS in either study arm. Similarly, the presence of FcɣR single nucleotide polymorphisms was unimpactful. We identified important biological features associated with differential PFS between the treatment arms, including new immunomodulatory and angiogenesis gene expression signatures (GESs), previously undescribed mutational profiles and their corresponding GESs, and several HLA types. These findings provide insight into the determinants of response to combined PD-1/PD-L1 and angiogenic pathway inhibition and may aid in the development of strategies for improved patient care in aRCC. Biomarker analysis of the phase 3 JAVELIN Renal 101 trial uncovers molecular determinants of therapy-specific outcomes, which may inform personalized treatment strategies for patients with advanced renal cell carcinoma.
University of North Carolina at Chapel Hill1, Montreal Heart Institute2, Osaka University3, VA Boston Healthcare System4, Icahn School of Medicine at Mount Sinai5, Queen Mary University of London6, University of Cambridge7, National Institute for Health Research8, Wellcome Trust Sanger Institute9, Harvard University10, Vanderbilt University11, University of Wisconsin–Milwaukee12, Université de Montréal13, University of Southern California14, Kyushu University15, University of Washington16, University of Bristol17, University of Copenhagen18, Erasmus University Medical Center19, National Institutes of Health20, Brigham and Women's Hospital21, Kaiser Permanente22, University of Mississippi Medical Center23, International Agency for Research on Cancer24, Wake Forest University25, Imperial College London26, Broad Institute27, University of Pennsylvania28, Greifswald University Hospital29, Fred Hutchinson Cancer Research Center30, Chinese National Human Genome Center31, Technische Universität München32, University of Tampere33, University of Tokyo34, University of Ioannina35, University of Colorado Denver36, Duke University37, University of Virginia38, NHS Blood and Transplant39, University of Minnesota40, Turku University Hospital41, Los Angeles Biomedical Research Institute42, Stanford University43, King's College London44, Mashhad University of Medical Sciences45, Veterans Health Administration46
TL;DR: The clinical significance and predictive value of trans-ethnic variants in multiple populations are explored, genetic architecture and the effect of natural selection on these blood phenotypes between populations are compared and the value of a more global representation of populations in genetic studies is highlighted.
University of Massachusetts Amherst1, University of North Carolina at Chapel Hill2, University of Oxford3, The Chinese University of Hong Kong4, Kyoto University5, Seoul National University Hospital6, Vanderbilt University Medical Center7, National University of Singapore8, Academia Sinica9, Nagoya University10, University of California, Los Angeles11, Los Angeles Biomedical Research Institute12, Hallym University13, University of Texas Health Science Center at Houston14, University of Michigan15, Wake Forest University16, Genentech17, Imperial College London18, London North West Healthcare NHS Trust19, University of Liverpool20, University of Manchester21, Kyushu University22, Peking Union Medical College23, National Taiwan University24, University of Minnesota25, Chinese National Human Genome Center26, Tri-Service General Hospital27, National Defense Medical Center28, National Yang-Ming University29, Taipei Veterans General Hospital30, Jichi Medical University31, Heidelberg University32, University of Tokyo33, Osaka University34, Agency for Science, Technology and Research35, University of the Ryukyus36, Ehime University37, Yonsei University38, Samsung Medical Center39, University of San Carlos40, Peking University41, Macau University of Science and Technology42, China Medical University (Taiwan)43, Shanghai Jiao Tong University44, Kurume University45, University of Pittsburgh46, Capital Medical University47, New Generation University College48, Seoul National University49
TL;DR: A meta-analysis of genome-wide association study data from 77,418 individuals of East Asian ancestry with type 2 diabetes identifies novel variants associated with increased risk of type 2abetes in both East Asian and European populations.
Abstract: Meta-analyses of genome-wide association studies (GWAS) have identified more than 240 loci that are associated with type 2 diabetes (T2D)1,2; however, most of these loci have been identified in analyses of individuals with European ancestry. Here, to examine T2D risk in East Asian individuals, we carried out a meta-analysis of GWAS data from 77,418 individuals with T2D and 356,122 healthy control individuals. In the main analysis, we identified 301 distinct association signals at 183 loci, and across T2D association models with and without consideration of body mass index and sex, we identified 61 loci that are newly implicated in predisposition to T2D. Common variants associated with T2D in both East Asian and European populations exhibited strongly correlated effect sizes. Previously undescribed associations include signals in or near GDAP1, PTF1A, SIX3, ALDH2, a microRNA cluster, and genes that affect the differentiation of muscle and adipose cells3. At another locus, expression quantitative trait loci at two overlapping T2D signals affect two genes-NKX6-3 and ANK1-in different tissues4-6. Association studies in diverse populations identify additional loci and elucidate disease-associated genes, biology, and pathways.
TL;DR: A magnetically controllable superconducting diode in an artificial superlattice [Nb/V/Ta]n without a centre of inversion is demonstrated, enabling directional charge transport without energy loss and paving the way for the construction of non-dissipative electronic circuits.
Abstract: Nonlinear optical and electrical effects associated with a lack of spatial inversion symmetry allow direction-selective propagation and transport of quantum particles, such as photons1 and electrons2-9. The most common example of such nonreciprocal phenomena is a semiconductor diode with a p-n junction, with a low resistance in one direction and a high resistance in the other. Although the diode effect forms the basis of numerous electronic components, such as rectifiers, alternating-direct-current converters and photodetectors, it introduces an inevitable energy loss due to the finite resistance. Therefore, a worthwhile goal is to realize a superconducting diode that has zero resistance in only one direction. Here we demonstrate a magnetically controllable superconducting diode in an artificial superlattice [Nb/V/Ta]n without a centre of inversion. The nonreciprocal resistance versus current curve at the superconducting-to-normal transition was clearly observed by a direct-current measurement, and the difference of the critical current is considered to be related to the magnetochiral anisotropy caused by breaking of the spatial-inversion and time-reversal symmetries10-13. Owing to the nonreciprocal critical current, the [Nb/V/Ta]n superlattice exhibits zero resistance in only one direction. This superconducting diode effect enables phase-coherent and direction-selective charge transport, paving the way for the construction of non-dissipative electronic circuits.
TL;DR: An understanding of the intimate interactions between the intestinal microbiota, epithelial cells, and immune cells that are crucial for the maintenance of intestinal homeostasis might promote advances in diagnostic and therapeutic approaches for various diseases.
Abstract: The gastrointestinal tract harbors numerous commensal bacteria, referred to as the microbiota, that benefit host health by digesting dietary components and eliminating pathogens. The intestinal microbiota maintains epithelial barrier integrity and shapes the mucosal immune system, balancing host defense and oral tolerance with microbial metabolites, components, and attachment to host cells. To avoid aberrant immune responses, epithelial cells segregate the intestinal microbiota from immune cells by constructing chemical and physical barriers, leading to the establishment of host-commensal mutualism. Furthermore, intestinal immune cells participate in the maintenance of a healthy microbiota community and reinforce epithelial barrier functions. Perturbations of the microbiota composition are commonly observed in patients with autoimmune diseases and chronic inflammatory disorders. An understanding of the intimate interactions between the intestinal microbiota, epithelial cells, and immune cells that are crucial for the maintenance of intestinal homeostasis might promote advances in diagnostic and therapeutic approaches for various diseases.
TL;DR: It is found that secondary responses are characterized by a clonality bottleneck that restricts the engagement of the large diversity of MBC clones generated by priming, and understanding how to counter this bottleneck may improve the ability to elicit antibodies to non-immunodominant epitopes by vaccination.