Showing papers by "Oregon Health & Science University published in 2018"
Clotilde Théry1, Kenneth W. Witwer2, Elena Aikawa3, María José Alcaraz4 +414 more•Institutions (209)
TL;DR: The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities, and a checklist is provided with summaries of key points.
Abstract: The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points.
5,988 citations
University of Pennsylvania1, University of Texas Southwestern Medical Center2, University of Oslo3, Boston Children's Hospital4, University of Utah5, Université de Montréal6, Goethe University Frankfurt7, University of Minnesota8, Children's Mercy Hospital9, Emory University10, Ghent University11, Kyoto University12, Stanford University13, Duke University14, Oregon Health & Science University15, University of Michigan16, Medical University of Vienna17, University of Paris18, Royal Children's Hospital19, University of Milan20, University of Toronto21, Novartis22, University of Southern California23
TL;DR: In this global study of CAR T‐cell therapy, a single infusion of tisagenlecleucel provided durable remission with long‐term persistence in pediatric and young adult patients with relapsed or refractory B‐cell ALL, with transient high‐grade toxic effects.
Abstract: Background In a single-center phase 1–2a study, the anti-CD19 chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel produced high rates of complete remission and was associated with serious but mainly reversible toxic effects in children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL) Methods We conducted a phase 2, single-cohort, 25-center, global study of tisagenlecleucel in pediatric and young adult patients with CD19+ relapsed or refractory B-cell ALL The primary end point was the overall remission rate (the rate of complete remission or complete remission with incomplete hematologic recovery) within 3 months Results For this planned analysis, 75 patients received an infusion of tisagenlecleucel and could be evaluated for efficacy The overall remission rate within 3 months was 81%, with all patients who had a response to treatment found to be negative for minimal residual disease, as assessed by means of flow cytometry The rates of event-f
3,237 citations
University of California, San Francisco1, Cold Spring Harbor Laboratory2, Icahn School of Medicine at Mount Sinai3, Oregon Health & Science University4, Wistar Institute5, Huntsman Cancer Institute6, University of Maryland, Baltimore County7, La Jolla Institute for Allergy and Immunology8, University of Pennsylvania9, Harvard University10, University of Michigan11, Massachusetts Institute of Technology12
TL;DR: By parsing the unique classes and subclasses of tumor immune microenvironment (TIME) that exist within a patient’s tumor, the ability to predict and guide immunotherapeutic responsiveness will improve, and new therapeutic targets will be revealed.
Abstract: The clinical successes in immunotherapy have been both astounding and at the same time unsatisfactory. Countless patients with varied tumor types have seen pronounced clinical response with immunotherapeutic intervention; however, many more patients have experienced minimal or no clinical benefit when provided the same treatment. As technology has advanced, so has the understanding of the complexity and diversity of the immune context of the tumor microenvironment and its influence on response to therapy. It has been possible to identify different subclasses of immune environment that have an influence on tumor initiation and response and therapy; by parsing the unique classes and subclasses of tumor immune microenvironment (TIME) that exist within a patient's tumor, the ability to predict and guide immunotherapeutic responsiveness will improve, and new therapeutic targets will be revealed.
2,920 citations
TL;DR: Examination of the oral and gut microbiome of melanoma patients undergoing anti-programmed cell death 1 protein (PD-1) immunotherapy suggested enhanced systemic and antitumor immunity in responding patients with a favorable gut microbiome as well as in germ-free mice receiving fecal transplants from responding patients.
Abstract: Preclinical mouse models suggest that the gut microbiome modulates tumor response to checkpoint blockade immunotherapy; however, this has not been well-characterized in human cancer patients. Here we examined the oral and gut microbiome of melanoma patients undergoing anti-programmed cell death 1 protein (PD-1) immunotherapy (n = 112). Significant differences were observed in the diversity and composition of the patient gut microbiome of responders versus nonresponders. Analysis of patient fecal microbiome samples (n = 43, 30 responders, 13 nonresponders) showed significantly higher alpha diversity (P < 0.01) and relative abundance of bacteria of the Ruminococcaceae family (P < 0.01) in responding patients. Metagenomic studies revealed functional differences in gut bacteria in responders, including enrichment of anabolic pathways. Immune profiling suggested enhanced systemic and antitumor immunity in responding patients with a favorable gut microbiome as well as in germ-free mice receiving fecal transplants from responding patients. Together, these data have important implications for the treatment of melanoma patients with immune checkpoint inhibitors.
2,791 citations
TL;DR: Improvements to Galaxy's core framework, user interface, tools, and training materials enable Galaxy to be used for analyzing tens of thousands of datasets, and >5500 tools are now available from the Galaxy ToolShed.
Abstract: Galaxy (homepage: https://galaxyproject.org, main public server: https://usegalaxy.org) is a web-based scientific analysis platform used by tens of thousands of scientists across the world to analyze large biomedical datasets such as those found in genomics, proteomics, metabolomics and imaging. Started in 2005, Galaxy continues to focus on three key challenges of data-driven biomedical science: making analyses accessible to all researchers, ensuring analyses are completely reproducible, and making it simple to communicate analyses so that they can be reused and extended. During the last two years, the Galaxy team and the open-source community around Galaxy have made substantial improvements to Galaxy's core framework, user interface, tools, and training materials. Framework and user interface improvements now enable Galaxy to be used for analyzing tens of thousands of datasets, and >5500 tools are now available from the Galaxy ToolShed. The Galaxy community has led an effort to create numerous high-quality tutorials focused on common types of genomic analyses. The Galaxy developer and user communities continue to grow and be integral to Galaxy's development. The number of Galaxy public servers, developers contributing to the Galaxy framework and its tools, and users of the main Galaxy server have all increased substantially.
2,601 citations
University of Texas Southwestern Medical Center1, Stanford University2, University of Southern California3, University of California, Los Angeles4, West Virginia University5, Harvard University6, University of Colorado Boulder7, Vanderbilt University8, Case Western Reserve University9, Cincinnati Children's Hospital Medical Center10, Cleveland Clinic11, Fox Chase Cancer Center12, University of Pennsylvania13, University of Washington14, Seattle Children's15, University of Texas MD Anderson Cancer Center16, Nemours Foundation17, International University, Cambodia18, Oregon Health & Science University19
TL;DR: Larotrectinib had marked and durable antitumor activity in patients with TRK fusion–positive cancer, regardless of the age of the patient or of the tumor type.
Abstract: Background Fusions involving one of three tropomyosin receptor kinases (TRK) occur in diverse cancers in children and adults. We evaluated the efficacy and safety of larotrectinib, a highly selective TRK inhibitor, in adults and children who had tumors with these fusions. Methods We enrolled patients with consecutively and prospectively identified TRK fusion–positive cancers, detected by molecular profiling as routinely performed at each site, into one of three protocols: a phase 1 study involving adults, a phase 1–2 study involving children, or a phase 2 study involving adolescents and adults. The primary end point for the combined analysis was the overall response rate according to independent review. Secondary end points included duration of response, progression-free survival, and safety. Results A total of 55 patients, ranging in age from 4 months to 76 years, were enrolled and treated. Patients had 17 unique TRK fusion–positive tumor types. The overall response rate was 75% (95% confidence ...
1,773 citations
Oxford Health NHS Foundation Trust1, University of Oxford2, Kyoto University3, University of Bern4, Sorbonne5, Paris Descartes University6, Cochrane Collaboration7, Warneford Hospital8, Technische Universität München9, Radboud University Nijmegen Medical Centre10, Oregon Health & Science University11, University of Bristol12, Stanford University13
TL;DR: This work aimed to update and expand previous work to compare and rank antidepressants for the acute treatment of adults with unipolar major depressive disorder, and found that all antidepressants were more effective than placebo.
1,697 citations
Verneri Anttila1, Verneri Anttila2, Brendan Bulik-Sullivan2, Brendan Bulik-Sullivan1 +717 more•Institutions (270)
TL;DR: It is demonstrated that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine, and it is shown that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures.
Abstract: Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.
1,357 citations
Pierre-and-Marie-Curie University1, Paris Descartes University2, French Institute of Health and Medical Research3, Mayo Clinic4, Providence Portland Medical Center5, University of Bern6, University Hospital of Bern7, Radboud University Nijmegen8, University of Erlangen-Nuremberg9, Université catholique de Louvain10, University of Toronto11, University Health Network12, Memorial Sloan Kettering Cancer Center13, Karolinska Institutet14, First Faculty of Medicine, Charles University in Prague15, Humanitas University16, Keio University17, Yamaguchi University18, Kindai University19, Sapporo Medical University20, Kurume University21, Xi'an Jiaotong University22, Qatar Airways23, Oregon Health & Science University24
TL;DR: The immunoscore provides a reliable estimate of the risk of recurrence in patients with colon cancer and supports the implementation of the consensus Immunoscore as a new component of a TNM-Immune classification of cancer.
1,326 citations
Arthritis Research UK1, Public Health Research Institute2, Kaiser Permanente3, Oregon Health & Science University4, Johns Hopkins University5, Walter Reed National Military Medical Center6, University of Alberta7, University of Sydney8, University of Utah9, Erasmus University Medical Center10, Leiden University11, University of Washington12
TL;DR: Effective, promising, or emerging solutions that could offer new directions in the management of low back pain need greater attention and further research to determine if they are appropriate for large-scale implementation.
1,215 citations
University of Texas MD Anderson Cancer Center1, Memorial Sloan Kettering Cancer Center2, Institut Gustave Roussy3, Cornell University4, Northwestern University5, Ohio State University6, University of Miami7, University of Texas Southwestern Medical Center8, University of California, San Francisco9, Anschutz Medical Campus10, Sarah Cannon Research Institute11, Harvard University12, Centre Hospitalier Universitaire de Bordeaux13, University of Alabama at Birmingham14, Johns Hopkins University15, City of Hope National Medical Center16, Washington University in St. Louis17, Mayo Clinic18, Oregon Health & Science University19, Medical University of South Carolina20, Emory University21, Cleveland Clinic22, Agios Pharmaceuticals23
TL;DR: In patients with advanced IDH1‐mutated relapsed or refractory AML, ivosidenib at a dose of 500 mg daily was associated with a low frequency of grade 3 or higher treatment‐related adverse events and with transfusion independence, durable remissions, and molecular remissions in some patients with complete remission.
Abstract: Background Mutations in the gene encoding isocitrate dehydrogenase 1 (IDH1) occur in 6 to 10% of patients with acute myeloid leukemia (AML). Ivosidenib (AG-120) is an oral, targeted, small-molecule inhibitor of mutant IDH1. Methods We conducted a phase 1 dose-escalation and dose-expansion study of ivosidenib monotherapy in IDH1-mutated AML. Safety and efficacy were assessed in all treated patients. The primary efficacy population included patients with relapsed or refractory AML receiving 500 mg of ivosidenib daily with at least 6 months of follow-up. Results Overall, 258 patients received ivosidenib and had safety outcomes assessed. Among patients with relapsed or refractory AML (179 patients), treatment-related adverse events of grade 3 or higher that occurred in at least 3 patients were prolongation of the QT interval (in 7.8% of the patients), the IDH differentiation syndrome (in 3.9%), anemia (in 2.2%), thrombocytopenia or a decrease in the platelet count (in 3.4%), and leukocytosis (in 1.7%...
Institute for Health Metrics and Evaluation1, University of Louisville2, Kermanshah University of Medical Sciences3, Karolinska Institutet4, University of Queensland5, Centre for Mental Health6, Tehran University of Medical Sciences7, South African Medical Research Council8, University of KwaZulu-Natal9, University of Colorado Boulder10, University of California, Irvine11, Fred Hutchinson Cancer Research Center12, Montefiore Medical Center13, Northeastern University14, University of Alabama at Birmingham15, Brown University16, San Diego State University17, University of Melbourne18, Albert Einstein College of Medicine19, Cambridge Health Alliance20, Johns Hopkins University21, University of Cape Town22, University of Pittsburgh23, Marshall University24, Case Western Reserve University25, University of London26, University of Illinois at Urbana–Champaign27, National Drug and Alcohol Research Centre28, Harvard University29, University of California, San Diego30, Yale University31, Georgetown University32, Veterans Health Administration33, Jackson State University34, University of Massachusetts Boston35, State University of New York System36, Simmons College37, Charles R. Drew University of Medicine and Science38, University of California, Los Angeles39, University of Oxford40, Norwegian Institute of Public Health41, Pacific Institute42, Curtin University43, Heidelberg University44, Jimma University45, Northwestern University46, Washington University in St. Louis47, Howard University48, University of New Mexico49, University at Buffalo50, University of Washington51, University of South Florida52, Tufts University53, University of Rochester Medical Center54, Kosin University55, Central South University56, Michigan State University57, Ball State University58, Nova Southeastern University59, Dalhousie University60, Mayo Clinic61, University of British Columbia62, Ohio State University63, Baylor University64, Wrocław Medical University65, Jagiellonian University Medical College66, Dartmouth College67, University of Western Ontario68, Oregon Health & Science University69, Virginia Commonwealth University70, Columbia University71, University of Canberra72, Aga Khan University73
TL;DR: There are wide differences in the burden of disease at the state level and specific diseases and risk factors, such as drug use disorders, high BMI, poor diet, high fasting plasma glucose level, and alcohol use disorders are increasing and warrant increased attention.
Abstract: Introduction Several studies have measured health outcomes in the United States, but none have provided a comprehensive assessment of patterns of health by state. Objective To use the results of the Global Burden of Disease Study (GBD) to report trends in the burden of diseases, injuries, and risk factors at the state level from 1990 to 2016. Design and Setting A systematic analysis of published studies and available data sources estimates the burden of disease by age, sex, geography, and year. Main Outcomes and Measures Prevalence, incidence, mortality, life expectancy, healthy life expectancy (HALE), years of life lost (YLLs) due to premature mortality, years lived with disability (YLDs), and disability-adjusted life-years (DALYs) for 333 causes and 84 risk factors with 95% uncertainty intervals (UIs) were computed. Results Between 1990 and 2016, overall death rates in the United States declined from 745.2 (95% UI, 740.6 to 749.8) per 100 000 persons to 578.0 (95% UI, 569.4 to 587.1) per 100 000 persons. The probability of death among adults aged 20 to 55 years declined in 31 states and Washington, DC from 1990 to 2016. In 2016, Hawaii had the highest life expectancy at birth (81.3 years) and Mississippi had the lowest (74.7 years), a 6.6-year difference. Minnesota had the highest HALE at birth (70.3 years), and West Virginia had the lowest (63.8 years), a 6.5-year difference. The leading causes of DALYs in the United States for 1990 and 2016 were ischemic heart disease and lung cancer, while the third leading cause in 1990 was low back pain, and the third leading cause in 2016 was chronic obstructive pulmonary disease. Opioid use disorders moved from the 11th leading cause of DALYs in 1990 to the 7th leading cause in 2016, representing a 74.5% (95% UI, 42.8% to 93.9%) change. In 2016, each of the following 6 risks individually accounted for more than 5% of risk-attributable DALYs: tobacco consumption, high body mass index (BMI), poor diet, alcohol and drug use, high fasting plasma glucose, and high blood pressure. Across all US states, the top risk factors in terms of attributable DALYs were due to 1 of the 3 following causes: tobacco consumption (32 states), high BMI (10 states), or alcohol and drug use (8 states). Conclusions and Relevance There are wide differences in the burden of disease at the state level. Specific diseases and risk factors, such as drug use disorders, high BMI, poor diet, high fasting plasma glucose level, and alcohol use disorders are increasing and warrant increased attention. These data can be used to inform national health priorities for research, clinical care, and policy.
Kaiser Permanente1, University of Iowa2, Veterans Health Administration3, Stanford University4, University of California, San Francisco5, Oregon Health & Science University6, Columbia University7, University of Pennsylvania8, University of Georgia9, Virginia Tech10, Nationwide Children's Hospital11, Virginia Commonwealth University12, Temple University13, University of Alabama at Birmingham14, University of California, Los Angeles15, Boston University16, Northwestern University17, Icahn School of Medicine at Mount Sinai18, University of Hawaii19
TL;DR: The USPSTF concludes with moderate certainty that the net benefit of PSA-based screening for prostate cancer in men aged 55 to 69 years is small for some men.
Abstract: Importance In the United States, the lifetime risk of being diagnosed with prostate cancer is approximately 11%, and the lifetime risk of dying of prostate cancer is 2.5%. The median age of death from prostate cancer is 80 years. Many men with prostate cancer never experience symptoms and, without screening, would never know they have the disease. African American men and men with a family history of prostate cancer have an increased risk of prostate cancer compared with other men. Objective To update the 2012 US Preventive Services Task Force (USPSTF) recommendation on prostate-specific antigen (PSA)–based screening for prostate cancer. Evidence Review The USPSTF reviewed the evidence on the benefits and harms of PSA-based screening for prostate cancer and subsequent treatment of screen-detected prostate cancer. The USPSTF also commissioned a review of existing decision analysis models and the overdiagnosis rate of PSA-based screening. The reviews also examined the benefits and harms of PSA-based screening in patient subpopulations at higher risk of prostate cancer, including older men, African American men, and men with a family history of prostate cancer. Findings Adequate evidence from randomized clinical trials shows that PSA-based screening programs in men aged 55 to 69 years may prevent approximately 1.3 deaths from prostate cancer over approximately 13 years per 1000 men screened. Screening programs may also prevent approximately 3 cases of metastatic prostate cancer per 1000 men screened. Potential harms of screening include frequent false-positive results and psychological harms. Harms of prostate cancer treatment include erectile dysfunction, urinary incontinence, and bowel symptoms. About 1 in 5 men who undergo radical prostatectomy develop long-term urinary incontinence, and 2 in 3 men will experience long-term erectile dysfunction. Adequate evidence shows that the harms of screening in men older than 70 years are at least moderate and greater than in younger men because of increased risk of false-positive results, diagnostic harms from biopsies, and harms from treatment. The USPSTF concludes with moderate certainty that the net benefit of PSA-based screening for prostate cancer in men aged 55 to 69 years is small for some men. How each man weighs specific benefits and harms will determine whether the overall net benefit is small. The USPSTF concludes with moderate certainty that the potential benefits of PSA-based screening for prostate cancer in men 70 years and older do not outweigh the expected harms. Conclusions and Recommendation For men aged 55 to 69 years, the decision to undergo periodic PSA-based screening for prostate cancer should be an individual one and should include discussion of the potential benefits and harms of screening with their clinician. Screening offers a small potential benefit of reducing the chance of death from prostate cancer in some men. However, many men will experience potential harms of screening, including false-positive results that require additional testing and possible prostate biopsy; overdiagnosis and overtreatment; and treatment complications, such as incontinence and erectile dysfunction. In determining whether this service is appropriate in individual cases, patients and clinicians should consider the balance of benefits and harms on the basis of family history, race/ethnicity, comorbid medical conditions, patient values about the benefits and harms of screening and treatment-specific outcomes, and other health needs. Clinicians should not screen men who do not express a preference for screening. (C recommendation) The USPSTF recommends against PSA-based screening for prostate cancer in men 70 years and older. (D recommendation)
TL;DR: Among men with nonmetastatic castration‐resistant prostate cancer, metastasis‐free survival and time to symptomatic progression were significantly longer with apalutamide than with placebo.
Abstract: Background Apalutamide, a competitive inhibitor of the androgen receptor, is under development for the treatment of prostate cancer. We evaluated the efficacy of apalutamide in men with nonmetastatic castration-resistant prostate cancer who were at high risk for the development of metastasis. Methods We conducted a double-blind, placebo-controlled, phase 3 trial involving men with nonmetastatic castration-resistant prostate cancer and a prostate-specific antigen doubling time of 10 months or less. Patients were randomly assigned, in a 2:1 ratio, to receive apalutamide (240 mg per day) or placebo. All the patients continued to receive androgen-deprivation therapy. The primary end point was metastasis-free survival, which was defined as the time from randomization to the first detection of distant metastasis on imaging or death. Results A total of 1207 men underwent randomization (806 to the apalutamide group and 401 to the placebo group). In the planned primary analysis, which was performed after ...
Indiana University – Purdue University Indianapolis1, Federal University of Rio de Janeiro2, Boston University3, Johns Hopkins University4, Mayo Clinic5, University of California, Irvine6, University of Pavia7, Columbia University8, University College London9, University of Pennsylvania10, Oregon Health & Science University11, University of Lisbon12, University of Münster13, University of Messina14, University of Barcelona15, Auckland City Hospital16
TL;DR: Inotersen improved the course of neurologic disease and quality of life in patients with hereditary transthyretin amyloidosis and improvements were independent of disease stage, mutation type, or the presence of cardiomyopathy.
Abstract: Background Hereditary transthyretin amyloidosis is caused by pathogenic single-nucleotide variants in the gene encoding transthyretin (TTR) that induce transthyretin misfolding and systemi...
Oregon Health & Science University1, Howard Hughes Medical Institute2, Oregon State University3, University of Florida4, University of Texas Southwestern Medical Center5, Fox Chase Cancer Center6, University of Utah7, National Institutes of Health8, University of Colorado Denver9, University of Kansas10, University of Miami11, Stanford University12
TL;DR: Analyses of samples from patients with acute myeloid leukaemia reveal that drug response is associated with mutational status and gene expression; the generated dataset provides a basis for future clinical and functional studies of this disease.
Abstract: The implementation of targeted therapies for acute myeloid leukaemia (AML) has been challenging because of the complex mutational patterns within and across patients as well as a dearth of pharmacologic agents for most mutational events. Here we report initial findings from the Beat AML programme on a cohort of 672 tumour specimens collected from 562 patients. We assessed these specimens using whole-exome sequencing, RNA sequencing and analyses of ex vivo drug sensitivity. Our data reveal mutational events that have not previously been detected in AML. We show that the response to drugs is associated with mutational status, including instances of drug sensitivity that are specific to combinatorial mutational events. Integration with RNA sequencing also revealed gene expression signatures, which predict a role for specific gene networks in the drug response. Collectively, we have generated a dataset—accessible through the Beat AML data viewer (Vizome)—that can be leveraged to address clinical, genomic, transcriptomic and functional analyses of the biology of AML. Analyses of samples from patients with acute myeloid leukaemia reveal that drug response is associated with mutational status and gene expression; the generated dataset provides a basis for future clinical and functional studies of this disease.
University of Iowa1, Virginia Commonwealth University2, Veterans Health Administration3, Stanford University4, Harvard University5, Oregon Health & Science University6, Columbia University7, University of Pennsylvania8, Virginia Tech9, Nationwide Children's Hospital10, Temple University11, University of Alabama at Birmingham12, University of California, Los Angeles13, Brown University14, Boston University15, Northwestern University16, University of Hawaii17, Tufts University18
TL;DR: The USPSTF concludes with high certainty that the benefits of screening every 3 years with cytology alone in women aged 21 to 29 years substantially outweigh the harms and screening women younger than 21 years does not provide significant benefit.
Abstract: Importance The number of deaths from cervical cancer in the United States has decreased substantially since the implementation of widespread cervical cancer screening and has declined from 2.8 to 2.3 deaths per 100 000 women from 2000 to 2015. Objective To update the US Preventive Services Task Force (USPSTF) 2012 recommendation on screening for cervical cancer. Evidence Review The USPSTF reviewed the evidence on screening for cervical cancer, with a focus on clinical trials and cohort studies that evaluated screening with high-risk human papillomavirus (hrHPV) testing alone or hrHPV and cytology together (cotesting) compared with cervical cytology alone. The USPSTF also commissioned a decision analysis model to evaluate the age at which to begin and end screening, the optimal interval for screening, the effectiveness of different screening strategies, and related benefits and harms of different screening strategies. Findings Screening with cervical cytology alone, primary hrHPV testing alone, or cotesting can detect high-grade precancerous cervical lesions and cervical cancer. Screening women aged 21 to 65 years substantially reduces cervical cancer incidence and mortality. The harms of screening for cervical cancer in women aged 30 to 65 years are moderate. The USPSTF concludes with high certainty that the benefits of screening every 3 years with cytology alone in women aged 21 to 29 years substantially outweigh the harms. The USPSTF concludes with high certainty that the benefits of screening every 3 years with cytology alone, every 5 years with hrHPV testing alone, or every 5 years with both tests (cotesting) in women aged 30 to 65 years outweigh the harms. Screening women older than 65 years who have had adequate prior screening and women younger than 21 years does not provide significant benefit. Screening women who have had a hysterectomy with removal of the cervix for indications other than a high-grade precancerous lesion or cervical cancer provides no benefit. The USPSTF concludes with moderate to high certainty that screening women older than 65 years who have had adequate prior screening and are not otherwise at high risk for cervical cancer, screening women younger than 21 years, and screening women who have had a hysterectomy with removal of the cervix for indications other than a high-grade precancerous lesion or cervical cancer does not result in a positive net benefit. Conclusions and Recommendation The USPSTF recommends screening for cervical cancer every 3 years with cervical cytology alone in women aged 21 to 29 years. (A recommendation) The USPSTF recommends screening every 3 years with cervical cytology alone, every 5 years with hrHPV testing alone, or every 5 years with hrHPV testing in combination with cytology (cotesting) in women aged 30 to 65 years. (A recommendation) The USPSTF recommends against screening for cervical cancer in women younger than 21 years. (D recommendation) The USPSTF recommends against screening for cervical cancer in women older than 65 years who have had adequate prior screening and are not otherwise at high risk for cervical cancer. (D recommendation) The USPSTF recommends against screening for cervical cancer in women who have had a hysterectomy with removal of the cervix and do not have a history of a high-grade precancerous lesion or cervical cancer. (D recommendation)
TL;DR: The development and validation of dLight1 is reported, a novel suite of intensity-based genetically encoded dopamine indicators that enables ultrafast optical recording of neuronal dopamine dynamics in behaving mice and permits robust detection of physiologically and behaviorally relevant dopamine transients.
Abstract: Neuromodulatory systems exert profound influences on brain function. Understanding how these systems modify the operating mode of target circuits requires measuring spatiotemporally precise neuromodulator release. We developed dLight1, an intensity-based genetically encoded dopamine indicator, to enable optical recording of dopamine dynamics with high spatiotemporal resolution in behaving mice. We demonstrated the utility of dLight1 by imaging dopamine dynamics simultaneously with pharmacological manipulation, electrophysiological or optogenetic stimulation, and calcium imaging of local neuronal activity. dLight1 enabled chronic tracking of learning-induced changes in millisecond dopamine transients in striatum. Further, we used dLight1 to image spatially distinct, functionally heterogeneous dopamine transients relevant to learning and motor control in cortex. We also validated our sensor design platform for developing norepinephrine, serotonin, melatonin, and opioid neuropeptide indicators.
TL;DR: By applying sci-CAR to lung adenocarcinoma cells and mouse kidney tissue, the authors demonstrate precision in assessing expression and genome accessibility at a genome-wide scale and provide an improvement over bulk analysis, which can be confounded by differing cellular subgroups.
Abstract: Although we can increasingly measure transcription, chromatin, methylation, and other aspects of molecular biology at single-cell resolution, most assays survey only one aspect of cellular biology. Here we describe sci-CAR, a combinatorial indexing–based coassay that jointly profiles chromatin accessibility and mRNA (CAR) in each of thousands of single cells. As a proof of concept, we apply sci-CAR to 4825 cells, including a time series of dexamethasone treatment, as well as to 11,296 cells from the adult mouse kidney. With the resulting data, we compare the pseudotemporal dynamics of chromatin accessibility and gene expression, reconstruct the chromatin accessibility profiles of cell types defined by RNA profiles, and link cis-regulatory sites to their target genes on the basis of the covariance of chromatin accessibility and transcription across large numbers of single cells.
University of South Florida1, Washington University in St. Louis2, University of Texas MD Anderson Cancer Center3, Oregon Health & Science University4, University of Kansas5, Cornell University6, Medical University of South Carolina7, Vanderbilt University8, Northside Hospital9, Harvard University10, University of Michigan11, University of California, Los Angeles12, University of California, San Diego13, University of Rochester14, Fred Hutchinson Cancer Research Center15, Stanford University16
TL;DR: CPX-351 treatment is associated with significantly longer survival compared with conventional 7+3 in older adults with newly diagnosed sAML, and improved outcomes were observed across age-groups and AML subtypes.
Abstract: Purpose CPX-351 is a dual-drug liposomal encapsulation of cytarabine and daunorubicin that delivers a synergistic 5:1 drug ratio into leukemia cells to a greater extent than normal bone marrow cells Prior clinical studies demonstrated a sustained drug ratio and exposure in vivo and prolonged survival versus standard-of-care cytarabine plus daunorubicin chemotherapy (7+3 regimen) in older patients with newly diagnosed secondary acute myeloid leukemia (sAML) Patients and Methods In this open-label, randomized, phase III trial, 309 patients age 60 to 75 years with newly diagnosed high-risk/sAML received one to two induction cycles of CPX-351 or 7+3 followed by consolidation therapy with a similar regimen The primary end point was overall survival Results CPX-351 significantly improved median overall survival versus 7+3 (956 v 595 months; hazard ratio, 069; 95% CI, 052 to 090; one-sided P = 003) Overall remission rate was also significantly higher with CPX-351 versus 7+3 (477% v 333%; two-sided P = 016) Improved outcomes were observed across age-groups and AML subtypes The incidences of nonhematologic adverse events were comparable between arms, despite a longer treatment phase and prolonged time to neutrophil and platelet count recovery with CPX-351 Early mortality rates with CPX-351 and 7+3 were 59% and 106% (two-sided P = 149) through day 30 and 137% and 212% (two-sided P = 097) through day 60 Conclusion CPX-351 treatment is associated with significantly longer survival compared with conventional 7+3 in older adults with newly diagnosed sAML The safety profile of CPX-351 was similar to that of conventional 7+3 therapy
Vanderbilt University1, Van Andel Institute2, University of North Carolina at Chapel Hill3, Memorial Sloan Kettering Cancer Center4, University of Texas MD Anderson Cancer Center5, Massachusetts Institute of Technology6, Harvard University7, Baylor College of Medicine8, University of Kansas9, Brigham and Women's Hospital10, Washington University in St. Louis11, Mayo Clinic12, Leidos13, Yale University14, Oregon Health & Science University15
TL;DR: Comprehensive genomic and phenotypic analysis of the RCC subtypes reveals distinctive features of each subtype that provide the foundation for the development of subtype-specific therapeutic and management strategies for patients affected with these cancers.
TL;DR: The Multi-Center Mutation Calling in Multiple Cancers project, an effort to generate a comprehensive encyclopedia of somatic mutation calls for the TCGA data to enable robust cross-tumor-type analyses, is described.
Abstract: The Cancer Genome Atlas (TCGA) cancer genomics dataset includes over 10,000 tumor-normal exome pairs across 33 different cancer types, in total >400 TB of raw data files requiring analysis. Here we describe the Multi-Center Mutation Calling in Multiple Cancers project, our effort to generate a comprehensive encyclopedia of somatic mutation calls for the TCGA data to enable robust cross-tumor-type analyses. Our approach accounts for variance and batch effects introduced by the rapid advancement of DNA extraction, hybridization-capture, sequencing, and analysis methods over time. We present best practices for applying an ensemble of seven mutation-calling algorithms with scoring and artifact filtering. The dataset created by this analysis includes 3.5 million somatic variants and forms the basis for PanCan Atlas papers. The results have been made available to the research community along with the methods used to generate them. This project is the result of collaboration from a number of institutes and demonstrates how team science drives extremely large genomics projects.
University of Bern1, Institute of Cancer Research2, Oregon Health & Science University3, Cornell University4, Princess Margaret Cancer Centre5, Yonsei University6, University of Salford7, University of Copenhagen8, Monash University9, University of São Paulo10, Columbia University11, The Royal Marsden NHS Foundation Trust12, University of Texas MD Anderson Cancer Center13, University of California, Davis14, University of Bologna15, University of California, San Francisco16, University of Paris-Sud17, University of British Columbia18, Duke University19, University of Cologne20, Fred Hutchinson Cancer Research Center21, University of Birmingham22, Memorial Sloan Kettering Cancer Center23, University of Tampere24, American University of Beirut25, Medical University of Vienna26, Vanderbilt University27, Tata Memorial Hospital28, Icahn School of Medicine at Mount Sinai29, Ghent University30, University of Washington31, Université de Montréal32, Tulane University33, Tel Aviv University34, Harvard University35, Prostate Cancer Foundation36, Toho University37, University College London38, University of Toronto39, Université catholique de Louvain40, University of Milan41, University of Ulm42
TL;DR: The presented expert voting results can be used for support in areas of management of men with APC where there is no high-level evidence, but individualised treatment decisions should as always be based on all of the data available.
TL;DR: Cicero is introduced, an algorithm that identifies co-accessible pairs of DNA elements using single-cell chromatin accessibility data and so connects regulatory elements to their putative target genes and is applied to investigate how dynamically accessible elements orchestrate gene regulation in differentiating myoblasts.
Louisiana State University1, University of Washington2, Mayo Clinic3, George Washington University4, Northwestern University5, University of Colorado Boulder6, University of Pennsylvania7, Kaiser Permanente8, Harvard University9, University of Pittsburgh10, Oregon Health & Science University11, Anschutz Medical Campus12, Boston Children's Hospital13
TL;DR: Clinicians should consider body fat distribution and individual health risks in addition to body mass index when making treatment decisions, especially when treatment is discontinued.
Abstract: The prevalence of obesity, measured by body mass index, has risen to unacceptable levels in both men and women in the United States and worldwide with resultant hazardous health implications. Genetic, environmental, and behavioral factors influence the development of obesity, and both the general public and health professionals stigmatize those who suffer from the disease. Obesity is associated with and contributes to a shortened life span, type 2 diabetes mellitus, cardiovascular disease, some cancers, kidney disease, obstructive sleep apnea, gout, osteoarthritis, and hepatobiliary disease, among others. Weight loss reduces all of these diseases in a dose-related manner-the more weight lost, the better the outcome. The phenotype of "medically healthy obesity" appears to be a transient state that progresses over time to an unhealthy phenotype, especially in children and adolescents. Weight loss is best achieved by reducing energy intake and increasing energy expenditure. Programs that are effective for weight loss include peer-reviewed and approved lifestyle modification programs, diets, commercial weight-loss programs, exercise programs, medications, and surgery. Over-the-counter herbal preparations that some patients use to treat obesity have limited, if any, data documenting their efficacy or safety, and there are few regulatory requirements. Weight regain is expected in all patients, especially when treatment is discontinued. When making treatment decisions, clinicians should consider body fat distribution and individual health risks in addition to body mass index.
TL;DR: General measures in patients hospitalized with ALD include inpatient management of liver disease complications, management of alcohol withdrawal syndrome, surveillance for infections and early effective antibiotic therapy, nutritional supplementation, and treatment of the underlying alcohol-use disorder.
TL;DR: There are gaps in the authors' knowledge of the prevalence of adult atopic dermatitis (AD) and the need to investigate these gaps more fully.
Abstract: Background There are gaps in our knowledge of the prevalence of adult atopic dermatitis (AD). Objective To estimate the prevalence of AD in adults and by disease severity. Methods This international, cross-sectional, web-based survey was performed in the United States, Canada, France, Germany, Italy, Spain, United Kingdom, and Japan. Adult members of online respondent panels were sent a questionnaire for AD identification and severity assessment; demographic quotas ensured population representativeness for each country. A diagnosis of AD required subjects to be positive on the modified UK Working Party/ISAAC criteria and self-report of ever having an AD diagnosis by a physician. The proportion of subjects with AD who reported being treated for their condition was determined and also used to estimate prevalence. Severity scales were Patient-Oriented SCORAD, Patient-Orientated Eczema Measure, and Patient Global Assessment. Results Among participants by region, the point prevalence of adult AD in the overall/treated populations was 4.9%/3.9% in the US, 3.5%/2.6% in Canada, 4.4%/3.5% in the EU, and 2.1%/1.5% in Japan. The prevalence was generally lower for males vs females, and decreased with age. Regional variability was observed within countries. Severity varied by scale and region; however, regardless of the scale or region, proportion of subjects reporting severe disease was lower than mild or moderate disease. Conclusions Prevalence of adult AD ranged from 2.1% to 4.9% across countries. Severe AD represented a small proportion of the overall AD population regardless of measure or region.
Sarah Cannon Research Institute1, National Foundation for Cancer Research2, University of Arizona3, University of Oklahoma4, Medical University of South Carolina5, Seoul National University Bundang Hospital6, Oregon Health & Science University7, Katholieke Universiteit Leuven8, Henry Ford Hospital9, Merck Serono10, National Institutes of Health11
TL;DR: Avelumab showed antitumour activity in the treatment of patients with platinum-refractory metastatic urothelial carcinoma and it has received accelerated US FDA approval in this setting on this basis.
Abstract: Summary Background The approval of anti-programmed death ligand 1 (PD-L1) and anti-programmed death 1 agents has expanded treatment options for patients with locally advanced or metastatic urothelial carcinoma. Avelumab, a human monoclonal anti-PD-L1 antibody, has shown promising antitumour activity and safety in this disease. We aimed to assess the safety profile in patients (both post-platinum therapy and cisplatin-naive) treated with avelumab and to assess antitumour activity of this drug in post-platinum patients. Methods In this pooled analysis of two cohorts from the phase 1 dose-expansion JAVELIN Solid Tumor study, patients aged 18 years and older with histologically or cytologically confirmed locally advanced or metastatic urothelial carcinoma that had progressed after at least one previous platinum-based chemotherapy were enrolled from 80 cancer treatment centres or hospitals in the USA, Europe, and Asia. Eligible patients had adequate end-organ function, an Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of at least 3 months, and at least one measurable lesion. Cisplatin-ineligible patients who might have been previously treated in the perioperative setting, including platinum-naive patients, were also eligible. Patients unselected for PD-L1 expression received avelumab (10 mg/kg, 1 h intravenous infusion) every 2 weeks until confirmed disease progression, unacceptable toxicity, or other criterion for withdrawal. The primary endpoint for this efficacy expansion cohort was confirmed best overall response (according to RECIST version 1.1), adjudicated by independent review. Safety analysis was done in all patients who received at least one dose of avelumab. Antitumour activity was assessed in post-platinum patients who received at least one dose of avelumab. This trial is registered with ClinicalTrials.gov, number NCT01772004; enrolment in this cohort of patients with metastatic urothelial carcinoma is closed and the trial is ongoing. Findings Between Sept 3, 2014, and March 15, 2016, 329 patients with advanced metastatic urothelial carcinoma were screened for enrolment into this study; 249 patients were eligible and received treatment with avelumab for a median of 12 weeks (IQR 6·0–19·7) and followed up for a median of 9·9 months (4·3–12·1). Safety and antitumour activity were evaluated at data cutoff on June 9, 2016. In 161 post-platinum patients with at least 6 months of follow-up, a best overall response of complete or partial response was recorded in 27 patients (17%; 95% CI 11–24), including nine (6%) complete responses and 18 (11%) partial responses. The most frequent treatment-related adverse events (any grade in ≥10% patients) were infusion-related reaction (73 [29%]; all grade 1–2) and fatigue (40 [16%]). Grade 3 or worse treatment-related adverse events occurred in 21 (8%) of 249 patients, the most common of which were fatigue (four [2%]), and asthenia, elevated lipase, hypophosphataemia, and pneumonitis in two (1%) patients each. 19 (8%) of 249 patients had a serious adverse event related to treatment with avelumab, and one treatment-related death occurred (pneumonitis). Interpretation Avelumab showed antitumour activity in the treatment of patients with platinum-refractory metastatic urothelial carcinoma; a manageable safety profile was reported in all avelumab-treated patients. These data provide the rationale for therapeutic use of avelumab in metastatic urothelial carcinoma and it has received accelerated US FDA approval in this setting on this basis. Funding Merck KGaA, and Pfizer Inc.
University of California, San Francisco1, Washington University in St. Louis2, University of Michigan3, Oregon Health & Science University4, University of British Columbia5, United States Department of Veterans Affairs6, University of California, Los Angeles7, University of Minnesota8, University of California, Davis9, University of California, Santa Cruz10, Illumina11, Thomas Jefferson University12, Princess Margaret Cancer Centre13, Duke University14
TL;DR: Integrative deep whole-genome and -transcriptome analysis of 101 castration-resistant prostate cancer metastases identified structural variants altering critical regulators of tumorigenesis and progression not detectable by exome approaches, providing a comprehensive view of how structural variations affect critical regulators in metastatic prostate cancer.
TL;DR: A library of congenic tumor cell clones from an autochthonous mouse model of pancreatic adenocarcinoma is established, identifying heterogeneous and multifactorial pathways regulating tumor‐cell‐intrinsic mechanisms that dictate the immune microenvironment and thereby responses to immunotherapy.