Showing papers by "University of Pennsylvania published in 2019"
Northern Arizona University1, National Institutes of Health2, University of Minnesota3, University of California, Davis4, Woods Hole Oceanographic Institution5, Massachusetts Institute of Technology6, University of Copenhagen7, University of Trento8, Chinese Academy of Sciences9, University of California, San Francisco10, University of Pennsylvania11, Pacific Northwest National Laboratory12, North Carolina State University13, University of California, San Diego14, Institute for Systems Biology15, Dalhousie University16, University of British Columbia17, Statens Serum Institut18, Anschutz Medical Campus19, University of Washington20, Michigan State University21, Stanford University22, Broad Institute23, Harvard University24, Australian National University25, University of Düsseldorf26, University of New South Wales27, Sookmyung Women's University28, San Diego State University29, Howard Hughes Medical Institute30, Cornell University31, Max Planck Society32, Colorado State University33, Google34, Syracuse University35, Webster University36, United States Department of Agriculture37, University of Arkansas for Medical Sciences38, Colorado School of Mines39, University of Southern Mississippi40, National Oceanic and Atmospheric Administration41, University of California, Merced42, Wageningen University and Research Centre43, University of Arizona44, Environment Agency45, University of Florida46, Merck & Co.47
TL;DR: QIIME 2 development was primarily funded by NSF Awards 1565100 to J.G.C. and R.K.P. and partial support was also provided by the following: grants NIH U54CA143925 and U54MD012388.
Abstract: QIIME 2 development was primarily funded by NSF Awards 1565100 to J.G.C. and 1565057 to R.K. Partial support was also provided by the following: grants NIH U54CA143925 (J.G.C. and T.P.) and U54MD012388 (J.G.C. and T.P.); grants from the Alfred P. Sloan Foundation (J.G.C. and R.K.); ERCSTG project MetaPG (N.S.); the Strategic Priority Research Program of the Chinese Academy of Sciences QYZDB-SSW-SMC021 (Y.B.); the Australian National Health and Medical Research Council APP1085372 (G.A.H., J.G.C., Von Bing Yap and R.K.); the Natural Sciences and Engineering Research Council (NSERC) to D.L.G.; and the State of Arizona Technology and Research Initiative Fund (TRIF), administered by the Arizona Board of Regents, through Northern Arizona University. All NCI coauthors were supported by the Intramural Research Program of the National Cancer Institute. S.M.G. and C. Diener were supported by the Washington Research Foundation Distinguished Investigator Award.
8,821 citations
TL;DR: In this article, the authors introduce physics-informed neural networks, which are trained to solve supervised learning tasks while respecting any given laws of physics described by general nonlinear partial differential equations.
5,448 citations
Scott & White Hospital1, Columbia University2, Georgetown University3, Rutgers University4, Cleveland Clinic5, Laval University6, University of British Columbia7, New York University8, University of Washington9, Emory University10, Lankenau Institute for Medical Research11, University of Pennsylvania12, Morristown Medical Center13, University of London14
TL;DR: Among patients with severe aortic stenosis who were at low surgical risk, the rate of the composite of death, stroke, or rehospitalization at 1 year was significantly lower with TAVR than with surgery.
Abstract: Background Among patients with aortic stenosis who are at intermediate or high risk for death with surgery, major outcomes are similar with transcatheter aortic-valve replacement (TAVR) an...
2,917 citations
University of Pennsylvania1, University of Chicago2, University of Melbourne3, Emory University4, University of Cologne5, University of Kansas6, Medical University of Vienna7, Ohio State University8, University of California, San Francisco9, University of Texas MD Anderson Cancer Center10, Université de Montréal11, University of Minnesota12, McMaster University13, Royal Prince Alfred Hospital14, Karolinska Institutet15, University of Würzburg16, University of Michigan17, University of Oslo18, Novartis19, University of Lyon20
TL;DR: The chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel targets and eliminates CD19-expressing B cells and showed efficacy against B-cell lymphomas in a single-center, phase 2a study.
Abstract: Background Patients with diffuse large B-cell lymphoma that is refractory to primary and second-line therapies or that has relapsed after stem-cell transplantation have a poor prognosis. The chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel targets and eliminates CD19-expressing B cells and showed efficacy against B-cell lymphomas in a single-center, phase 2a study. Methods We conducted an international, phase 2, pivotal study of centrally manufactured tisagenlecleucel involving adult patients with relapsed or refractory diffuse large B-cell lymphoma who were ineligible for or had disease progression after autologous hematopoietic stem-cell transplantation. The primary end point was the best overall response rate (i.e., the percentage of patients who had a complete or partial response), as judged by an independent review committee. Results A total of 93 patients received an infusion and were included in the evaluation of efficacy. The median time from infusion to data cutoff was 14 ...
2,086 citations
TL;DR: It is shown that U1 AMO also modulates cancer cells’ phenotype, dose-dependently increasing migration and invasion in vitro by up to 500%, whereas U1 over-expression has the opposite effect.
Abstract: Stimulated cells and cancer cells have widespread shortening of mRNA 3’-utranslated regions (3’UTRs) and switches to shorter mRNA isoforms due to usage of more proximal polyadenylation signals (PASs) in the last exon and in introns. U1 snRNA (U1), vertebrates’ most abundant non-coding (spliceosomal) small nuclear RNA, silences proximal PASs and its inhibition with antisense morpholino oligonucleotides (U1 AMO) triggers widespread mRNA shortening. Here we show that U1 AMO also modulates cancer cells’ phenotype, dose-dependently increasing migration and invasion in vitro by up to 500%, whereas U1 over-expression has the opposite effect. In addition to 3’UTR length, numerous transcriptome changes that could contribute to this phenotype are observed, including alternative splicing, and mRNA expression levels of proto-oncogenes and tumor suppressors. These findings reveal an unexpected link between U1 regulation and oncogenic and activated cell states, and suggest U1 as a potential target for their modulation.
1,660 citations
Aarhus University1, Lundbeck2, Broad Institute3, Harvard University4, Cardiff University5, Karolinska Institutet6, Statens Serum Institut7, QIMR Berghofer Medical Research Institute8, deCODE genetics9, University of Iceland10, Mental Health Services11, Charité12, University of California, Los Angeles13, Semel Institute for Neuroscience and Human Behavior14, University of Queensland15, Oslo University Hospital16, King's College London17, University of Toronto18, VU University Amsterdam19, Radboud University Nijmegen20, Veterans Health Administration21, Yale University22, Children's Hospital of Philadelphia23, University of Bergen24, Haukeland University Hospital25, University of Pennsylvania26, I.M. Sechenov First Moscow State Medical University27, University of Würzburg28, Maastricht University29, Goethe University Frankfurt30, Universidade Federal do Rio Grande do Sul31, Icahn School of Medicine at Mount Sinai32, University of North Carolina at Chapel Hill33, Emory University34, University of Copenhagen35, Aarhus University Hospital36, State University of New York Upstate Medical University37
TL;DR: A genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls identifies variants surpassing genome- wide significance in 12 independent loci and implicates neurodevelopmental pathways and conserved regions of the genome as being involved in underlying ADHD biology.
Abstract: Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, finding important new information about the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes and around brain-expressed regulatory marks. Analyses of three replication studies: a cohort of individuals diagnosed with ADHD, a self-reported ADHD sample and a meta-analysis of quantitative measures of ADHD symptoms in the population, support these findings while highlighting study-specific differences on genetic overlap with educational attainment. Strong concordance with GWAS of quantitative population measures of ADHD symptoms supports that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits.
1,436 citations
University of Virginia1, Memorial Sloan Kettering Cancer Center2, Washington University in St. Louis3, Fred Hutchinson Cancer Research Center4, National Institutes of Health5, Harvard University6, Novartis7, Seattle Children's8, University of Pennsylvania9, University College London10, Center for International Blood and Marrow Transplant Research11, University of Miami12, University of Texas MD Anderson Cancer Center13
TL;DR: The goal is to provide a uniform consensus grading system for CRS and neurotoxicity associated with immune effector cell therapies, for use across clinical trials and in the postapproval clinical setting.
1,403 citations
19 May 2019
TL;DR: Spectre as mentioned in this paper is a side channel attack that can leak the victim's confidential information via side channel to the adversary. And it can read arbitrary memory from a victim's process.
Abstract: Modern processors use branch prediction and speculative execution to maximize performance. For example, if the destination of a branch depends on a memory value that is in the process of being read, CPUs will try to guess the destination and attempt to execute ahead. When the memory value finally arrives, the CPU either discards or commits the speculative computation. Speculative logic is unfaithful in how it executes, can access the victim's memory and registers, and can perform operations with measurable side effects. Spectre attacks involve inducing a victim to speculatively perform operations that would not occur during correct program execution and which leak the victim's confidential information via a side channel to the adversary. This paper describes practical attacks that combine methodology from side channel attacks, fault attacks, and return-oriented programming that can read arbitrary memory from the victim's process. More broadly, the paper shows that speculative execution implementations violate the security assumptions underpinning numerous software security mechanisms, including operating system process separation, containerization, just-in-time (JIT) compilation, and countermeasures to cache timing and side-channel attacks. These attacks represent a serious threat to actual systems since vulnerable speculative execution capabilities are found in microprocessors from Intel, AMD, and ARM that are used in billions of devices. While makeshift processor-specific countermeasures are possible in some cases, sound solutions will require fixes to processor designs as well as updates to instruction set architectures (ISAs) to give hardware architects and software developers a common understanding as to what computation state CPU implementations are (and are not) permitted to leak.
1,317 citations
TL;DR: How recent developments in drug delivery could enable new cancer immunotherapies and improve on existing ones are discussed, and the current delivery obstacles are examined.
Abstract: Immunotherapy has become a powerful clinical strategy for treating cancer. The number of immunotherapy drug approvals has been increasing, with numerous treatments in clinical and preclinical development. However, a key challenge in the broad implementation of immunotherapies for cancer remains the controlled modulation of the immune system, as these therapeutics have serious adverse effects including autoimmunity and nonspecific inflammation. Understanding how to increase the response rates to various classes of immunotherapy is key to improving efficacy and controlling these adverse effects. Advanced biomaterials and drug delivery systems, such as nanoparticles and the use of T cells to deliver therapies, could effectively harness immunotherapies and improve their potency while reducing toxic side effects. Here, we discuss these research advances, as well as the opportunities and challenges for integrating delivery technologies into cancer immunotherapy, and we critically analyse the outlook for these emerging areas.
1,295 citations
Broad Institute1, University of Chicago2, University of Geneva3, University of Dundee4, Columbia University5, Princeton University6, Max Planck Society7, Johns Hopkins University8, Stanford University9, Vanderbilt University10, University of Cambridge11, Vanderbilt University Medical Center12, Massachusetts Eye and Ear Infirmary13, Harvard University14, Scripps Health15, Polytechnic University of Catalonia16, University of Pennsylvania17
TL;DR: Analysis of the v8 data provides insights into the tissue-specificity of genetic effects, and shows that cell type composition is a key factor in understanding gene regulatory mechanisms in human tissues.
Abstract: The Genotype-Tissue Expression (GTEx) project was established to characterize genetic effects on the transcriptome across human tissues, and to link these regulatory mechanisms to trait and disease associations. Here, we present analyses of the v8 data, based on 17,382 RNA-sequencing samples from 54 tissues of 948 post-mortem donors. We comprehensively characterize genetic associations for gene expression and splicing in cis and trans, showing that regulatory associations are found for almost all genes, and describe the underlying molecular mechanisms and their contribution to allelic heterogeneity and pleiotropy of complex traits. Leveraging the large diversity of tissues, we provide insights into the tissue-specificity of genetic effects, and show that cell type composition is a key factor in understanding gene regulatory mechanisms in human tissues.
1,243 citations
Hospital Universitario La Paz1, Memorial Sloan Kettering Cancer Center2, Gynecologic Oncology Group3, Medical University of South Carolina4, Rigshospitalet5, McGill University Health Centre6, Ohio State University7, Thomas Jefferson University8, Medical College of Wisconsin9, Technion – Israel Institute of Technology10, GlaxoSmithKline11, University of Arizona12, University of Girona13, University of Pennsylvania14, Vita-Salute San Raffaele University15
TL;DR: Among patients with newly diagnosed advanced ovarian cancer who had a response to platinum-based chemotherapy, those who received niraparib had significantly longer progression-free survival thanThose who received placebo, regardless of the presence or absence of homologous-recombination deficiency.
Abstract: Background Niraparib, an inhibitor of poly(adenosine diphosphate [ADP]–ribose) polymerase (PARP), has been associated with significantly increased progression-free survival among patients ...
TL;DR: Genome-wide analysis identifies 30 loci associated with bipolar disorder, allowing for comparisons of shared genes and pathways with other psychiatric disorders, including schizophrenia and depression.
Abstract: Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P < 1 × 10-4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (P < 5 × 10-8) in the discovery GWAS were not genome-wide significant in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis, 30 loci were genome-wide significant, including 20 newly identified loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene sets, including regulation of insulin secretion and endocannabinoid signaling. Bipolar I disorder is strongly genetically correlated with schizophrenia, driven by psychosis, whereas bipolar II disorder is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential biological mechanisms for bipolar disorder.
TL;DR: Data from the T1D Exchange registry demonstrate that only a minority of adults and youth with type 1 diabetes in the United States achieve ADA goals for HbA1c, and racial differences were evident in use of pumps and CGM and Hb a1c levels.
Abstract: Objective To provide a snapshot of the profile of adults and youth with type 1 diabetes (T1D) in the United States and assessment of longitudinal changes in T1D management and clinical outcomes in the T1D Exchange registry. Research design and methods Data on diabetes management and outcomes from 22,697 registry participants (age 1-93 years) were collected between 2016 and 2018 and compared with data collected in 2010-2012 for 25,529 registry participants. Results Mean HbA1c in 2016-2018 increased from 65 mmol/mol at the age of 5 years to 78 mmol/mol between ages 15 and 18, with a decrease to 64 mmol/mol by age 28 and 58-63 mmol/mol beyond age 30. The American Diabetes Association (ADA) HbA1c goal of 10-fold in children Conclusions Data from the T1D Exchange registry demonstrate that only a minority of adults and youth with T1D in the United States achieve ADA goals for HbA1c.
TL;DR: The Simons Observatory (SO) is a new cosmic microwave background experiment being built on Cerro Toco in Chile, due to begin observations in the early 2020s as mentioned in this paper.
Abstract: The Simons Observatory (SO) is a new cosmic microwave background experiment being built on Cerro Toco in Chile, due to begin observations in the early 2020s. We describe the scientific goals of the experiment, motivate the design, and forecast its performance. SO will measure the temperature and polarization anisotropy of the cosmic microwave background in six frequency bands centered at: 27, 39, 93, 145, 225 and 280 GHz. The initial configuration of SO will have three small-aperture 0.5-m telescopes and one large-aperture 6-m telescope, with a total of 60,000 cryogenic bolometers. Our key science goals are to characterize the primordial perturbations, measure the number of relativistic species and the mass of neutrinos, test for deviations from a cosmological constant, improve our understanding of galaxy evolution, and constrain the duration of reionization. The small aperture telescopes will target the largest angular scales observable from Chile, mapping ≈ 10% of the sky to a white noise level of 2 μK-arcmin in combined 93 and 145 GHz bands, to measure the primordial tensor-to-scalar ratio, r, at a target level of σ(r)=0.003. The large aperture telescope will map ≈ 40% of the sky at arcminute angular resolution to an expected white noise level of 6 μK-arcmin in combined 93 and 145 GHz bands, overlapping with the majority of the Large Synoptic Survey Telescope sky region and partially with the Dark Energy Spectroscopic Instrument. With up to an order of magnitude lower polarization noise than maps from the Planck satellite, the high-resolution sky maps will constrain cosmological parameters derived from the damping tail, gravitational lensing of the microwave background, the primordial bispectrum, and the thermal and kinematic Sunyaev-Zel'dovich effects, and will aid in delensing the large-angle polarization signal to measure the tensor-to-scalar ratio. The survey will also provide a legacy catalog of 16,000 galaxy clusters and more than 20,000 extragalactic sources.
TL;DR: The expansive and growing field of MSC research is teaching us basic human cell biology as well as how to use this type of cell for cellular therapy in a variety of clinical settings, and while much promise is evident, careful new work is still needed.
Abstract: The terms MSC and MSCs have become the preferred acronym to describe a cell and a cell population of multipotential stem/progenitor cells commonly referred to as mesenchymal stem cells, multipotential stromal cells, mesenchymal stromal cells, and mesenchymal progenitor cells. The MSCs can differentiate to important lineages under defined conditions in vitro and in limited situations after implantation in vivo. MSCs were isolated and described about 30 years ago and now there are over 55,000 publications on MSCs readily available. Here, we have focused on human MSCs whenever possible. The MSCs have broad anti-inflammatory and immune-modulatory properties. At present, these provide the greatest focus of human MSCs in clinical testing; however, the properties of cultured MSCs in vitro suggest they can have broader applications. The medical utility of MSCs continues to be investigated in over 950 clinical trials. There has been much progress in understanding MSCs over the years, and there is a strong foundation for future scientific research and clinical applications, but also some important questions remain to be answered. Developing further methods to understand and unlock MSC potential through intracellular and intercellular signaling, biomedical engineering, delivery methods and patient selection should all provide substantial advancements in the coming years and greater clinical opportunities. The expansive and growing field of MSC research is teaching us basic human cell biology as well as how to use this type of cell for cellular therapy in a variety of clinical settings, and while much promise is evident, careful new work is still needed.
TL;DR: Current understanding of Tex cell biology is reviewed, including the developmental paths, transcriptional and epigenetic features, and cell intrinsic and extrinsic factors contributing to exhaustion and how this knowledge may inform therapeutic targeting of Tex cells in chronic infections, autoimmunity, and cancer.
Abstract: Exhausted CD8 T (Tex) cells are a distinct cell lineage that arise during chronic infections and cancers in animal models and humans. Tex cells are characterized by progressive loss of effector fun...
TL;DR: The Large Synoptic Survey Telescope (LSST) as discussed by the authors is a large, wide-field ground-based system designed to obtain repeated images covering the sky visible from Cerro Pachon in northern Chile.
Abstract: We describe here the most ambitious survey currently planned in the optical, the Large Synoptic Survey Telescope (LSST). The LSST design is driven by four main science themes: probing dark energy and dark matter, taking an inventory of the solar system, exploring the transient optical sky, and mapping the Milky Way. LSST will be a large, wide-field ground-based system designed to obtain repeated images covering the sky visible from Cerro Pachon in northern Chile. The telescope will have an 8.4 m (6.5 m effective) primary mirror, a 9.6 deg2 field of view, a 3.2-gigapixel camera, and six filters (ugrizy) covering the wavelength range 320–1050 nm. The project is in the construction phase and will begin regular survey operations by 2022. About 90% of the observing time will be devoted to a deep-wide-fast survey mode that will uniformly observe a 18,000 deg2 region about 800 times (summed over all six bands) during the anticipated 10 yr of operations and will yield a co-added map to r ~ 27.5. These data will result in databases including about 32 trillion observations of 20 billion galaxies and a similar number of stars, and they will serve the majority of the primary science programs. The remaining 10% of the observing time will be allocated to special projects such as Very Deep and Very Fast time domain surveys, whose details are currently under discussion. We illustrate how the LSST science drivers led to these choices of system parameters, and we describe the expected data products and their characteristics.
TL;DR: While previously polarization was primarily seen only in issue-based terms, a new type of division has emerged in the mass public in recent years: Ordinary Americans increasingly dislike and distru...
Abstract: While previously polarization was primarily seen only in issue-based terms, a new type of division has emerged in the mass public in recent years: Ordinary Americans increasingly dislike and distru...
University of Vermont1, Karolinska University Hospital2, Universidade Federal de Minas Gerais3, Universidade Católica de Pelotas4, University of Tokyo5, Fujita Health University6, Central University of Venezuela7, University of Trieste8, University of Cape Town9, Monash University10, Ohio State University11, University of Alberta12, Hospital General de México13, University of Waterloo14, American Society for Parenteral and Enteral Nutrition15, Brigham and Women's Hospital16, Saint Louis University Hospital17, Sapienza University of Rome18, La Trobe University19, Khon Kaen University20, HAN University of Applied Sciences21, Rabin Medical Center22, University of Illinois at Chicago23, Pontifical Catholic University of Chile24, University of São Paulo25, Peking Union Medical College Hospital26, University of Pennsylvania27, Free University of Brussels28
TL;DR: A consensus scheme for diagnosing malnutrition in adults in clinical settings on a global scale is proposed and it is recommended that the etiologic criteria be used to guide intervention and anticipated outcomes.
Abstract: Summary Rationale This initiative is focused on building a global consensus around core diagnostic criteria for malnutrition in adults in clinical settings Methods In January 2016, the Global Leadership Initiative on Malnutrition (GLIM) was convened by several of the major global clinical nutrition societies GLIM appointed a core leadership committee and a supporting working group with representatives bringing additional global diversity and expertise Empirical consensus was reached through a series of face-to-face meetings, telephone conferences, and e-mail communications Results A two-step approach for the malnutrition diagnosis was selected, ie, first screening to identify “at risk” status by the use of any validated screening tool, and second, assessment for diagnosis and grading the severity of malnutrition The malnutrition criteria for consideration were retrieved from existing approaches for screening and assessment Potential criteria were subjected to a ballot among the GLIM core and supporting working group members The top five ranked criteria included three phenotypic criteria (non-volitional weight loss, low body mass index, and reduced muscle mass) and two etiologic criteria (reduced food intake or assimilation, and inflammation or disease burden) To diagnose malnutrition at least one phenotypic criterion and one etiologic criterion should be present Phenotypic metrics for grading severity as Stage 1 (moderate) and Stage 2 (severe) malnutrition are proposed It is recommended that the etiologic criteria be used to guide intervention and anticipated outcomes The recommended approach supports classification of malnutrition into four etiology-related diagnosis categories Conclusion A consensus scheme for diagnosing malnutrition in adults in clinical settings on a global scale is proposed Next steps are to secure further collaboration and endorsements from leading nutrition professional societies, to identify overlaps with syndromes like cachexia and sarcopenia, and to promote dissemination, validation studies, and feedback The diagnostic construct should be re-considered every 3–5 years
Uppsala University1, Karolinska University Hospital2, University of Vermont3, Universidade Federal de Minas Gerais4, Universidade Católica de Pelotas5, University of Tokyo6, Fujita Health University7, Central University of Venezuela8, University of Trieste9, University of Cape Town10, University of Warwick11, Monash University12, Ohio State University13, University of Alberta14, Hospital General de México15, University of Waterloo16, American Society for Parenteral and Enteral Nutrition17, Brigham and Women's Hospital18, Saint Louis University Hospital19, Sapienza University of Rome20, Khon Kaen University21, HAN University of Applied Sciences22, VU University Amsterdam23, Rabin Medical Center24, Tel Aviv University25, University of Illinois at Chicago26, Pontifical Catholic University of Chile27, University of São Paulo28, Peking Union Medical College Hospital29, Free University of Brussels30, University of Pennsylvania31
TL;DR: This initiative is focused on building a global consensus around core diagnostic criteria for malnutrition in adults in clinical settings.
Abstract: Rationale
This initiative is focused on building a global consensus around core diagnostic criteria for malnutrition in adults in clinical settings.
TL;DR: The transcription factor TOX is a central regulator of the transcriptional and epigenetic development of exhausted T cells in mice, and robust expression of TOX results in commitment to Tex cells by translating persistent stimulation into a distinct Tex cell transcriptionaland epigenetic developmental program.
Abstract: Exhausted CD8+ T (Tex) cells in chronic infections and cancer have limited effector function, high co-expression of inhibitory receptors and extensive transcriptional changes compared with effector (Teff) or memory (Tmem) CD8+ T cells. Tex cells are important clinical targets of checkpoint blockade and other immunotherapies. Epigenetically, Tex cells are a distinct immune subset, with a unique chromatin landscape compared with Teff and Tmem cells. However, the mechanisms that govern the transcriptional and epigenetic development of Tex cells remain unknown. Here we identify the HMG-box transcription factor TOX as a central regulator of Tex cells in mice. TOX is largely dispensable for the formation of Teff and Tmem cells, but it is critical for exhaustion: in the absence of TOX, Tex cells do not form. TOX is induced by calcineurin and NFAT2, and operates in a feed-forward loop in which it becomes calcineurin-independent and sustained in Tex cells. Robust expression of TOX therefore results in commitment to Tex cells by translating persistent stimulation into a distinct Tex cell transcriptional and epigenetic developmental program.
University of Kentucky1, Mayo Clinic2, University of Pennsylvania3, Rush University Medical Center4, Illinois Institute of Technology5, Uppsala University6, Newcastle University7, University of Cambridge8, University of Southern California9, University of Minnesota10, University of Sydney11, University of California, Irvine12, University of Washington13, Medical University of Vienna14, Emory University15, Stanford University16, University of California, San Diego17, University of California, San Francisco18, Harvard University19, University of Texas Southwestern Medical Center20
TL;DR: A recently recognized brain disorder that mimics the clinical features of Alzheimer’s disease: Limbic-predominant Age-related TDP-43 Encephalopathy (LATE).
Abstract: We describe a recently recognized disease entity, limbic-predominant age-related TDP-43 encephalopathy (LATE). LATE neuropathological change (LATE-NC) is defined by a stereotypical TDP-43 proteinopathy in older adults, with or without coexisting hippocampal sclerosis pathology. LATE-NC is a common TDP-43 proteinopathy, associated with an amnestic dementia syndrome that mimicked Alzheimer's-type dementia in retrospective autopsy studies. LATE is distinguished from frontotemporal lobar degeneration with TDP-43 pathology based on its epidemiology (LATE generally affects older subjects), and relatively restricted neuroanatomical distribution of TDP-43 proteinopathy. In community-based autopsy cohorts, ∼25% of brains had sufficient burden of LATE-NC to be associated with discernible cognitive impairment. Many subjects with LATE-NC have comorbid brain pathologies, often including amyloid-β plaques and tauopathy. Given that the 'oldest-old' are at greatest risk for LATE-NC, and subjects of advanced age constitute a rapidly growing demographic group in many countries, LATE has an expanding but under-recognized impact on public health. For these reasons, a working group was convened to develop diagnostic criteria for LATE, aiming both to stimulate research and to promote awareness of this pathway to dementia. We report consensus-based recommendations including guidelines for diagnosis and staging of LATE-NC. For routine autopsy workup of LATE-NC, an anatomically-based preliminary staging scheme is proposed with TDP-43 immunohistochemistry on tissue from three brain areas, reflecting a hierarchical pattern of brain involvement: amygdala, hippocampus, and middle frontal gyrus. LATE-NC appears to affect the medial temporal lobe structures preferentially, but other areas also are impacted. Neuroimaging studies demonstrated that subjects with LATE-NC also had atrophy in the medial temporal lobes, frontal cortex, and other brain regions. Genetic studies have thus far indicated five genes with risk alleles for LATE-NC: GRN, TMEM106B, ABCC9, KCNMB2, and APOE. The discovery of these genetic risk variants indicate that LATE shares pathogenetic mechanisms with both frontotemporal lobar degeneration and Alzheimer's disease, but also suggests disease-specific underlying mechanisms. Large gaps remain in our understanding of LATE. For advances in prevention, diagnosis, and treatment, there is an urgent need for research focused on LATE, including in vitro and animal models. An obstacle to clinical progress is lack of diagnostic tools, such as biofluid or neuroimaging biomarkers, for ante-mortem detection of LATE. Development of a disease biomarker would augment observational studies seeking to further define the risk factors, natural history, and clinical features of LATE, as well as eventual subject recruitment for targeted therapies in clinical trials.
TL;DR: This commentary justifies the need to study more diverse populations using both empirical examples and theoretical reasoning for risk prediction of diseases across global populations.
Wake Forest University1, University of Mississippi Medical Center2, University of Pennsylvania3, University of Utah4, University of Alabama at Birmingham5, Veterans Health Administration6, National Institutes of Health7, University of Tennessee Health Science Center8, Stanford University9, Case Western Reserve University10, Tufts Medical Center11, Tulane University12
TL;DR: Among ambulatory adults with hypertension, treating to a systolic blood pressure goal of less than 120 mm Hg compared with a goal of more than 140mm Hg did not result in a significant reduction in the risk of probable dementia.
Abstract: Importance There are currently no proven treatments to reduce the risk of mild cognitive impairment and dementia. Objective To evaluate the effect of intensive blood pressure control on risk of dementia. Design, Setting, and Participants Randomized clinical trial conducted at 102 sites in the United States and Puerto Rico among adults aged 50 years or older with hypertension but without diabetes or history of stroke. Randomization began on November 8, 2010. The trial was stopped early for benefit on its primary outcome (a composite of cardiovascular events) and all-cause mortality on August 20, 2015. The final date for follow-up of cognitive outcomes was July 22, 2018. Interventions Participants were randomized to a systolic blood pressure goal of either less than 120 mm Hg (intensive treatment group; n = 4678) or less than 140 mm Hg (standard treatment group; n = 4683). Main Outcomes and Measures The primary cognitive outcome was occurrence of adjudicated probable dementia. Secondary cognitive outcomes included adjudicated mild cognitive impairment and a composite outcome of mild cognitive impairment or probable dementia. Results Among 9361 randomized participants (mean age, 67.9 years; 3332 women [35.6%]), 8563 (91.5%) completed at least 1 follow-up cognitive assessment. The median intervention period was 3.34 years. During a total median follow-up of 5.11 years, adjudicated probable dementia occurred in 149 participants in the intensive treatment group vs 176 in the standard treatment group (7.2 vs 8.6 cases per 1000 person-years; hazard ratio [HR], 0.83; 95% CI, 0.67-1.04). Intensive BP control significantly reduced the risk of mild cognitive impairment (14.6 vs 18.3 cases per 1000 person-years; HR, 0.81; 95% CI, 0.69-0.95) and the combined rate of mild cognitive impairment or probable dementia (20.2 vs 24.1 cases per 1000 person-years; HR, 0.85; 95% CI, 0.74-0.97). Conclusions and Relevance Among ambulatory adults with hypertension, treating to a systolic blood pressure goal of less than 120 mm Hg compared with a goal of less than 140 mm Hg did not result in a significant reduction in the risk of probable dementia. Because of early study termination and fewer than expected cases of dementia, the study may have been underpowered for this end point. Trial Registration ClinicalTrials.gov Identifier:NCT01206062
01 Oct 2019
TL;DR: SPIN as discussed by the authors uses a deep network to initialize an iterative optimization routine that fits the body model to 2D joints within the training loop, and the fitted estimate is subsequently used to supervise the network.
Abstract: Model-based human pose estimation is currently approached through two different paradigms. Optimization-based methods fit a parametric body model to 2D observations in an iterative manner, leading to accurate image-model alignments, but are often slow and sensitive to the initialization. In contrast, regression-based methods, that use a deep network to directly estimate the model parameters from pixels, tend to provide reasonable, but not pixel accurate, results while requiring huge amounts of supervision. In this work, instead of investigating which approach is better, our key insight is that the two paradigms can form a strong collaboration. A reasonable, directly regressed estimate from the network can initialize the iterative optimization making the fitting faster and more accurate. Similarly, a pixel accurate fit from iterative optimization can act as strong supervision for the network. This is the core of our proposed approach SPIN (SMPL oPtimization IN the loop). The deep network initializes an iterative optimization routine that fits the body model to 2D joints within the training loop, and the fitted estimate is subsequently used to supervise the network. Our approach is self-improving by nature, since better network estimates can lead the optimization to better solutions, while more accurate optimization fits provide better supervision for the network. We demonstrate the effectiveness of our approach in different settings, where 3D ground truth is scarce, or not available, and we consistently outperform the state-of-the-art model-based pose estimation approaches by significant margins. The project website with videos, results, and code can be found at https://seas.upenn.edu/~nkolot/projects/spin.
University of Texas MD Anderson Cancer Center1, Duke University2, Northwestern University3, City of Hope National Medical Center4, University of California, San Francisco5, Fox Chase Cancer Center6, Brigham and Women's Hospital7, University of California, San Diego8, Fred Hutchinson Cancer Research Center9, Memorial Sloan Kettering Cancer Center10, Vanderbilt University11, University of Utah12, University of Michigan13, Roswell Park Cancer Institute14, Mayo Clinic15, Yale Cancer Center16, Johns Hopkins University17, University of Colorado Boulder18, University of Wisconsin-Madison19, University Hospitals of Cleveland20, Washington University in St. Louis21, Ohio State University22, University of South Florida23, Stanford University24, University of Pennsylvania25, Harvard University26, National Comprehensive Cancer Network27
TL;DR: This selection from the NCCN Guidelines for Esophageal and Esophagogastric Junction Cancers focuses on recommendations for the management of locally advanced and metastatic adenocarcinoma of the esophagus and EGJ.
Abstract: Esophageal cancer is the sixth leading cause of cancer-related deaths worldwide. Squamous cell carcinoma is the most common histology in Eastern Europe and Asia, and adenocarcinoma is most common in North America and Western Europe. Surgery is a major component of treatment of locally advanced resectable esophageal and esophagogastric junction (EGJ) cancer, and randomized trials have shown that the addition of preoperative chemoradiation or perioperative chemotherapy to surgery significantly improves survival. Targeted therapies including trastuzumab, ramucirumab, and pembrolizumab have produced encouraging results in the treatment of patients with advanced or metastatic disease. Multidisciplinary team management is essential for all patients with esophageal and EGJ cancers. This selection from the NCCN Guidelines for Esophageal and Esophagogastric Junction Cancers focuses on recommendations for the management of locally advanced and metastatic adenocarcinoma of the esophagus and EGJ.
TL;DR: These guidelines are a consensus work of a considerable number of members of the immunology and flow cytometry community providing the theory and key practical aspects offlow cytometry enabling immunologists to avoid the common errors that often undermine immunological data.
Abstract: These guidelines are a consensus work of a considerable number of members of the immunology and flow cytometry community. They provide the theory and key practical aspects of flow cytometry enabling immunologists to avoid the common errors that often undermine immunological data. Notably, there are comprehensive sections of all major immune cell types with helpful Tables detailing phenotypes in murine and human cells. The latest flow cytometry techniques and applications are also described, featuring examples of the data that can be generated and, importantly, how the data can be analysed. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid, all written and peer-reviewed by leading experts in the field, making this an essential research companion.
Netherlands Cancer Institute1, Merck & Co.2, University of Lausanne3, La Jolla Institute for Allergy and Immunology4, University of California, San Diego5, University of Melbourne6, Vanderbilt University Medical Center7, Memorial Sloan Kettering Cancer Center8, National Institutes of Health9, Harvard University10, University of Pennsylvania11, St. Jude Children's Research Hospital12, Technische Universität München13
TL;DR: In this Viewpoint article, 18 experts in the field tell us what exhaustion means to them, ranging from complete lack of effector function to altered functionality to prevent immunopathology, with potential differences between cancer and chronic infection.
Abstract: 'T cell exhaustion' is a broad term that has been used to describe the response of T cells to chronic antigen stimulation, first in the setting of chronic viral infection but more recently in response to tumours. Understanding the features of and pathways to exhaustion has crucial implications for the success of checkpoint blockade and adoptive T cell transfer therapies. In this Viewpoint article, 18 experts in the field tell us what exhaustion means to them, ranging from complete lack of effector function to altered functionality to prevent immunopathology, with potential differences between cancer and chronic infection. Their responses highlight the dichotomy between terminally differentiated exhausted T cells that are TCF1- and the self-renewing TCF1+ population from which they derive. These TCF1+ cells are considered by some to have stem cell-like properties akin to memory T cell populations, but the developmental relationships are unclear at present. Recent studies have also highlighted an important role for the transcriptional regulator TOX in driving the epigenetic enforcement of exhaustion, but key questions remain about the potential to reverse the epigenetic programme of exhaustion and how this might affect the persistence of T cell populations.
University of Pennsylvania1, University of Texas MD Anderson Cancer Center2, University of Marburg3, Memorial Sloan Kettering Cancer Center4, University of Bologna5, Carlos III Health Institute6, University of Maryland, Baltimore7, University of Chicago8, University of Minnesota9, University of Alabama at Birmingham10, Medical University of South Carolina11, University of California, San Francisco12, Thomas Jefferson University13, National Taiwan University14, Yale University15, Centre Hospitalier Universitaire de Toulouse16, University of Fukui17, Seoul National University18, University of Ulsan19, Wake Forest University20, Harvard University21, Astellas Pharma22, Johns Hopkins University23
TL;DR: Gilteritinib resulted in significantly longer survival and higher percentages of patients with remission than salvage chemotherapy among patients with relapsed or refractory FLT3-mutated AML.
Abstract: Background Patients with relapsed or refractory acute myeloid leukemia (AML) with mutations in the FMS-like tyrosine kinase 3 gene (FLT3) infrequently have a response to salvage chemothera...
University of Tübingen1, Novo Nordisk2, Imperial College London3, Duke University4, Lunenfeld-Tanenbaum Research Institute5, Ulster University6, University of Cambridge7, University of Pennsylvania8, Harvard University9, University of Copenhagen10, ETH Zurich11, Ruhr University Bochum12, University of Cincinnati Academic Health Center13, Janssen Pharmaceutica14, University of Michigan15, University of Cincinnati16, Indiana University17, Technische Universität München18
TL;DR: The numerous beneficial effects of GLP-1 render this hormone an interesting candidate for the development of pharmacotherapies to treat obesity, diabetes, and neurodegenerative disorders.
Abstract: Background The glucagon-like peptide-1 (GLP-1) is a multifaceted hormone with broad pharmacological potential. Among the numerous metabolic effects of GLP-1 are the glucose-dependent stimulation of insulin secretion, decrease of gastric emptying, inhibition of food intake, increase of natriuresis and diuresis, and modulation of rodent β-cell proliferation. GLP-1 also has cardio- and neuroprotective effects, decreases inflammation and apoptosis, and has implications for learning and memory, reward behavior, and palatability. Biochemically modified for enhanced potency and sustained action, GLP-1 receptor agonists are successfully in clinical use for the treatment of type-2 diabetes, and several GLP-1-based pharmacotherapies are in clinical evaluation for the treatment of obesity. Scope of review In this review, we provide a detailed overview on the multifaceted nature of GLP-1 and its pharmacology and discuss its therapeutic implications on various diseases. Major conclusions Since its discovery, GLP-1 has emerged as a pleiotropic hormone with a myriad of metabolic functions that go well beyond its classical identification as an incretin hormone. The numerous beneficial effects of GLP-1 render this hormone an interesting candidate for the development of pharmacotherapies to treat obesity, diabetes, and neurodegenerative disorders