Showing papers by "Vanderbilt University published in 2019"
TL;DR: The Research Electronic Data Capture (REDCap) data management platform was developed in 2004 to address an institutional need at Vanderbilt University, then shared with a limited number of adopting sites beginning in 2006, and a broader consortium sharing and support model was created.
8,712 citations
Harvard University1, University of Western Australia2, University of Texas Health Science Center at San Antonio3, McMaster University4, University of Washington5, Centers for Disease Control and Prevention6, Primary Children's Hospital7, University of Utah8, University of Pittsburgh9, University of Michigan10, Vanderbilt University11, University of Connecticut12, United States Department of Veterans Affairs13, Baylor College of Medicine14
TL;DR: Although some recommendations remain unchanged from the 2007 guideline, the availability of results from new therapeutic trials and epidemiological investigations led to revised recommendations for empiric treatment strategies and additional management decisions.
Abstract: Background: This document provides evidence-based clinical practice guidelines on the management of adult patients with community-acquired pneumonia.Methods: A multidisciplinary panel conducted pra...
1,708 citations
University of Oklahoma1, University of Vermont2, University of Missouri–Kansas City3, Children's Mercy Hospital4, Harvard University5, Boston Children's Hospital6, University of North Carolina at Chapel Hill7, Ohio University8, American Academy of Pediatrics9, University of Cincinnati10, Cincinnati Children's Hospital Medical Center11, American Academy of Family Physicians12, Centers for Disease Control and Prevention13, Vanderbilt University14, Northwestern University15, American Academy of Child and Adolescent Psychiatry16
TL;DR: Attention-deficit/hyperactivity disorder (ADHD) is the most common neurobehavioral disorder of childhood and can profoundly affect the academic achievement, well-being, and social interactions of children.
Abstract: Attention-deficit/hyperactivity disorder (ADHD) is the most common neurobehavioral disorder of childhood and can profoundly affect the academic achievement, well-being, and social interactions of children; the American Academy of Pediatrics first published clinical recommendations for the diagnosis and evaluation of ADHD in children in 2000; recommendations for treatment followed in 2001.
1,657 citations
TL;DR: High-resolution density gradient fractionation and direct immunoaffinity capture are employed to precisely characterize the RNA, DNA, and protein constituents of exosomes and other non-vesicle material and show that small extracellular vesicles are not vehicles of active DNA release.
1,515 citations
VU University Amsterdam1, Karolinska Institutet2, deCODE genetics3, Vanderbilt University4, Jönköping University5, Oslo University Hospital6, University of Oslo7, King's College London8, Stavanger University Hospital9, Akershus University Hospital10, University of Tromsø11, Innlandet Hospital Trust12, Norwegian University of Science and Technology13, University of California, San Francisco14, Vanderbilt University Medical Center15, University of Iceland16, University of Cambridge17, University of Bergen18, University College London19, Namsos Hospital20, University of North Carolina at Chapel Hill21, Broad Institute22, Charité23, Harvard University24, VU University Medical Center25
TL;DR: A large genome-wide association study of clinically diagnosed AD and AD-by-proxy identifies new loci and functional pathways that contribute to AD risk and adds novel insights into the neurobiology of AD.
Abstract: Alzheimer's disease (AD) is highly heritable and recent studies have identified over 20 disease-associated genomic loci. Yet these only explain a small proportion of the genetic variance, indicating that undiscovered loci remain. Here, we performed a large genome-wide association study of clinically diagnosed AD and AD-by-proxy (71,880 cases, 383,378 controls). AD-by-proxy, based on parental diagnoses, showed strong genetic correlation with AD (rg = 0.81). Meta-analysis identified 29 risk loci, implicating 215 potential causative genes. Associated genes are strongly expressed in immune-related tissues and cell types (spleen, liver, and microglia). Gene-set analyses indicate biological mechanisms involved in lipid-related processes and degradation of amyloid precursor proteins. We show strong genetic correlations with multiple health-related outcomes, and Mendelian randomization results suggest a protective effect of cognitive ability on AD risk. These results are a step forward in identifying the genetic factors that contribute to AD risk and add novel insights into the neurobiology of AD.
1,460 citations
TL;DR: Treatment with alpelisib–fulvestrant prolonged progression‐free survival among patients with PIK3CA‐mutated, HR‐positive, HER2‐negative advanced breast cancer who had received endocrine therapy previously.
Abstract: Background PIK3CA mutations occur in approximately 40% of patients with hormone receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2)–negative breast cancer. The PI3Kα-sp...
1,357 citations
University of South Florida1, Washington University in St. Louis2, Harvard University3, Stanford University4, University of Miami5, Vanderbilt University6, Mayo Clinic7, Albert Einstein College of Medicine8, Cleveland Clinic9, University of California, Los Angeles10, Wayne State University11, University of Rochester Medical Center12, Loyola University Chicago13, Sarah Cannon Research Institute14, University of Iowa15, University of Texas MD Anderson Cancer Center16, City of Hope National Medical Center17
TL;DR: Long-term activity and safety outcomes of the ZUMA-1 study suggest that axicabtagene ciloleucel can induce durable responses and a median overall survival of greater than 2 years, and has a manageable relapsed or refractory disease or relapsed after autologous stem-cell transplantation.
Abstract: Summary Background Axicabtagene ciloleucel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy. In the previous analysis of the ZUMA-1 registrational study, with a median follow-up of 15·4 months (IQR 13·7–17·3), 89 (82%) of 108 assessable patients with refractory large B-cell lymphoma treated with axicabtagene ciloleucel achieved an objective response, and complete responses were noted in 63 (58%) patients. Here we report long-term activity and safety outcomes of the ZUMA-1 study. Methods ZUMA-1 is a single-arm, multicentre, registrational trial at 22 sites in the USA and Israel. Eligible patients were aged 18 years or older, and had histologically confirmed large B-cell lymphoma—including diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, and transformed follicular lymphoma—according to the 2008 WHO Classification of Tumors of Hematopoietic and Lymphoid Tissue; refractory disease or relapsed after autologous stem-cell transplantation; an Eastern Cooperative Oncology Group performance status of 0 or 1; and had previously received an anti-CD20 monoclonal antibody containing-regimen and an anthracycline-containing chemotherapy. Participants received one dose of axicabtagene ciloleucel on day 0 at a target dose of 2 × 106 CAR T cells per kg of bodyweight after conditioning chemotherapy with intravenous fludarabine (30 mg/m2 body-surface area) and cyclophosphamide (500 mg/m2 body-surface area) on days −5, −4, and −3. The primary endpoints were safety for phase 1 and the proportion of patients achieving an objective response for phase 2, and key secondary endpoints were overall survival, progression-free survival, and duration of response. Pre-planned activity and safety analyses were done per protocol. ZUMA-1 is registered with ClinicalTrials.gov , number NCT02348216 . Although the registrational cohorts are closed, the trial remains open, and recruitment to extension cohorts with alternative endpoints is underway. Findings Between May 19, 2015, and Sept 15, 2016, 119 patients were enrolled and 108 received axicabtagene ciloleucel across phases 1 and 2. As of the cutoff date of Aug 11, 2018, 101 patients assessable for activity in phase 2 were followed up for a median of 27·1 months (IQR 25·7–28·8), 84 (83%) had an objective response, and 59 (58%) had a complete response. The median duration of response was 11·1 months (4·2–not estimable). The median overall survival was not reached (12·8–not estimable), and the median progression-free survival was 5·9 months (95% CI 3·3–15·0). 52 (48%) of 108 patients assessable for safety in phases 1 and 2 had grade 3 or worse serious adverse events. Grade 3 or worse cytokine release syndrome occurred in 12 (11%) patients, and grade 3 or worse neurological events in 35 (32%). Since the previous analysis at 1 year, additional serious adverse events were reported in four patients (grade 3 mental status changes, grade 4 myelodysplastic syndrome, grade 3 lung infection, and two episodes of grade 3 bacteraemia), none of which were judged to be treatment related. Two treatment-related deaths (due to haemophagocytic lymphohistiocytosis and cardiac arrest) were previously reported, but no new treatment-related deaths occurred during the additional follow-up. Interpretation These 2-year follow-up data from ZUMA-1 suggest that axicabtagene ciloleucel can induce durable responses and a median overall survival of greater than 2 years, and has a manageable long-term safety profile in patients with relapsed or refractory large B-cell lymphoma. Funding Kite and the Leukemia & Lymphoma Society Therapy Acceleration Program.
1,285 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
Roswell Park Cancer Institute1, Johns Hopkins University2, Duke University3, Brigham and Women's Hospital4, Mayo Clinic5, City of Hope National Medical Center6, Memorial Sloan Kettering Cancer Center7, Fred Hutchinson Cancer Research Center8, Fox Chase Cancer Center9, Yale Cancer Center10, Washington University in St. Louis11, University of California, San Diego12, University of Wisconsin-Madison13, University Hospitals of Cleveland14, University of Alabama at Birmingham15, Vanderbilt University16, Moffitt Cancer Center17, University of Colorado Boulder18, University of Tennessee Health Science Center19, University of California, San Francisco20, Northwestern University21, Ohio State University22, University of Michigan23, Stanford University24, University of Utah25, National Comprehensive Cancer Network26
TL;DR: The NCCN Guidelines for Prostate Cancer include recommendations regarding diagnosis, risk stratification and workup, treatment options for localized disease, and management of recurrent and advanced disease for clinicians who treat patients with prostate cancer.
Abstract: The NCCN Guidelines for Prostate Cancer include recommendations regarding diagnosis, risk stratification and workup, treatment options for localized disease, and management of recurrent and advanced disease for clinicians who treat patients with prostate cancer. The portions of the guidelines included herein focus on the roles of germline and somatic genetic testing, risk stratification with nomograms and tumor multigene molecular testing, androgen deprivation therapy, secondary hormonal therapy, chemotherapy, and immunotherapy in patients with prostate cancer.
1,218 citations
Fraunhofer Society1, University of Manchester2, ETH Zurich3, Eindhoven University of Technology4, Erasmus University Rotterdam5, Chalmers University of Technology6, Lund University7, Vanderbilt University8, Aalto University9, University of Brighton10, University of Sussex11, École Polytechnique Fédérale de Lausanne12, Stockholm Environment Institute13, Université libre de Bruxelles14, Monash University15, Linköping University16, King's College London17, Cardiff University18
TL;DR: In this article, the authors provide an extensive review and an updated research agenda for the field, classified into nine main themes: understanding transitions; power, agency and politics; governing transitions; civil society, culture and social movements; businesses and industries; transitions in practice and everyday life; geography of transitions; ethical aspects; and methodologies.
Abstract: Research on sustainability transitions has expanded rapidly in the last ten years, diversified in terms of topics and geographical applications, and deepened with respect to theories and methods. This article provides an extensive review and an updated research agenda for the field, classified into nine main themes: understanding transitions; power, agency and politics; governing transitions; civil society, culture and social movements; businesses and industries; transitions in practice and everyday life; geography of transitions; ethical aspects; and methodologies. The review shows that the scope of sustainability transitions research has broadened and connections to established disciplines have grown stronger. At the same time, we see that the grand challenges related to sustainability remain unsolved, calling for continued efforts and an acceleration of ongoing transitions. Transition studies can play a key role in this regard by creating new perspectives, approaches and understanding and helping to move society in the direction of sustainability.
1,099 citations
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.
Daniel Taliun1, Daniel N. Harris2, Michael D. Kessler2, Jedidiah Carlson1 +191 more•Institutions (61)
TL;DR: The nearly complete catalog of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and non-coding sequence variants to phenotypic variation as well as resources and early insights from the sequence data.
Abstract: Summary paragraph The Trans-Omics for Precision Medicine (TOPMed) program seeks to elucidate the genetic architecture and disease biology of heart, lung, blood, and sleep disorders, with the ultimate goal of improving diagnosis, treatment, and prevention. The initial phases of the program focus on whole genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here, we describe TOPMed goals and design as well as resources and early insights from the sequence data. The resources include a variant browser, a genotype imputation panel, and sharing of genomic and phenotypic data via dbGaP. In 53,581 TOPMed samples, >400 million single-nucleotide and insertion/deletion variants were detected by alignment with the reference genome. Additional novel variants are detectable through assembly of unmapped reads and customized analysis in highly variable loci. Among the >400 million variants detected, 97% have frequency
Nasim Mavaddat1, Kyriaki Michailidou1, Kyriaki Michailidou2, Joe Dennis1 +307 more•Institutions (105)
TL;DR: This PRS, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset is developed and empirically validated and is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs.
Abstract: Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. Samples were genotyped using genome-wide arrays, and single-nucleotide polymorphisms (SNPs) were selected by stepwise regression or lasso penalized regression. The best performing PRSs were validated in an independent test set comprising 11,428 case subjects and 18,323 control subjects from 10 prospective studies and 190,040 women from UK Biobank (3,215 incident breast cancers). For the best PRSs (313 SNPs), the odds ratio for overall disease per 1 standard deviation in ten prospective studies was 1.61 (95%CI: 1.57-1.65) with area under receiver-operator curve (AUC) = 0.630 (95%CI: 0.628-0.651). The lifetime risk of overall breast cancer in the top centile of the PRSs was 32.6%. Compared with women in the middle quintile, those in the highest 1% of risk had 4.37- and 2.78-fold risks, and those in the lowest 1% of risk had 0.16- and 0.27-fold risks, of developing ER-positive and ER-negative disease, respectively. Goodness-of-fit tests indicated that this PRS was well calibrated and predicts disease risk accurately in the tails of the distribution. This PRS is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs.
Seattle Cancer Care Alliance1, Memorial Sloan Kettering Cancer Center2, Duke University3, University of Wisconsin-Madison4, Brigham and Women's Hospital5, University of Michigan6, University of South Florida7, Fox Chase Cancer Center8, Harvard University9, Ohio State University10, Vanderbilt University11, Yale Cancer Center12, Stanford University13, University of Texas MD Anderson Cancer Center14, University of Colorado Boulder15, Roswell Park Cancer Institute16, University of Utah17, City of Hope National Medical Center18, University of Alabama at Birmingham19, Northwestern University20, Mayo Clinic21, Washington University in St. Louis22, Case Western Reserve University23, Johns Hopkins University24, University of Nebraska Medical Center25, University of Tennessee Health Science Center26, University of California, San Francisco27, University of California, San Diego28, National Comprehensive Cancer Network29
TL;DR: This manuscript discusses guiding principles for the workup, staging, and treatment of early stage and locally advanced cervical cancer, as well as evidence for these recommendations.
Abstract: Cervical cancer is a malignant epithelial tumor that forms in the uterine cervix. Most cases of cervical cancer are preventable through human papilloma virus (HPV) vaccination, routine screening, and treatment of precancerous lesions. However, due to inadequate screening protocols in many regions of the world, cervical cancer remains the fourth-most common cancer in women globally. The complete NCCN Guidelines for Cervical Cancer provide recommendations for the diagnosis, evaluation, and treatment of cervical cancer. This manuscript discusses guiding principles for the workup, staging, and treatment of early stage and locally advanced cervical cancer, as well as evidence for these recommendations. For recommendations regarding treatment of recurrent or metastatic disease, please see the full guidelines on NCCN.org.
University of California, Los Angeles1, Memorial Sloan Kettering Cancer Center2, Columbia University Medical Center3, Princess Margaret Cancer Centre4, Samsung Medical Center5, Yale University6, University of Pennsylvania7, Vanderbilt University8, University of California, San Francisco9, Emory University10, Hebron University11, Merck & Co.12, University of Sydney13
TL;DR: Pembrolizumab monotherapy provided durable antitumor activity and high 5-year OS rates in patients with treatment-naive or previously treated advanced NSCLC and had a tolerable long-term safety profile with little evidence of late-onset or new toxicity.
Abstract: PURPOSEPembrolizumab monotherapy has demonstrated durable antitumor activity in advanced programmed death ligand 1 (PD-L1)–expressing non‒small-cell lung cancer (NSCLC). We report 5-year outcomes f...
Ghent University1, University of California, San Diego2, Leiden University3, Dresden University of Technology4, Stanford University5, University of Maryland, College Park6, Indiana University7, University of Cambridge8, Cardiff University9, University of Western Ontario10, Monash University, Clayton campus11, University of Toronto12, University of Vermont13, University of Oregon14, University of Tasmania15, University of Oslo16, Utrecht University17, Katholieke Universiteit Leuven18, Yale University19, Vanderbilt University20, University of Amsterdam21, Anglia Ruskin University22, Indian Institute of Science23, Queen's University24, King's College London25, Michigan State University26, University of Iowa27, Trinity College, Dublin28
TL;DR: The goal is to facilitate a more accurate use of the stop-signal task and provide user-friendly open-source resources intended to inform statistical-power considerations, facilitate the correct implementation of the task, and assist in proper data analysis.
Abstract: Response inhibition is essential for navigating everyday life. Its derailment is considered integral to numerous neurological and psychiatric disorders, and more generally, to a wide range of behavioral and health problems. Response-inhibition efficiency furthermore correlates with treatment outcome in some of these conditions. The stop-signal task is an essential tool to determine how quickly response inhibition is implemented. Despite its apparent simplicity, there are many features (ranging from task design to data analysis) that vary across studies in ways that can easily compromise the validity of the obtained results. Our goal is to facilitate a more accurate use of the stop-signal task. To this end, we provide 12 easy-to-implement consensus recommendations and point out the problems that can arise when they are not followed. Furthermore, we provide user-friendly open-source resources intended to inform statistical-power considerations, facilitate the correct implementation of the task, and assist in proper data analysis.
Stanford University1, University of North Carolina at Chapel Hill2, Fred Hutchinson Cancer Research Center3, Vanderbilt University4, Anschutz Medical Campus5, University of Southern California6, Icahn School of Medicine at Mount Sinai7, University of California, San Francisco8, University of Hawaii9, University of Washington10, University of Texas Health Science Center at Houston11, University of Potsdam12, Johns Hopkins University13, Pennsylvania State University14, National Institutes of Health15, University of California, Davis16, Ohio State University17, Cancer Prevention Institute of California18, University of Vermont19, Rutgers University20
TL;DR: The value of diverse, multi-ethnic participants in large-scale genomic studies is demonstrated and evidence of effect-size heterogeneity across ancestries for published GWAS associations, substantial benefits for fine-mapping using diverse cohorts and insights into clinical implications are shown.
Abstract: Genome-wide association studies (GWAS) have laid the foundation for investigations into the biology of complex traits, drug development and clinical guidelines. However, the majority of discovery efforts are based on data from populations of European ancestry1-3. In light of the differential genetic architecture that is known to exist between populations, bias in representation can exacerbate existing disease and healthcare disparities. Critical variants may be missed if they have a low frequency or are completely absent in European populations, especially as the field shifts its attention towards rare variants, which are more likely to be population-specific4-10. Additionally, effect sizes and their derived risk prediction scores derived in one population may not accurately extrapolate to other populations11,12. Here we demonstrate the value of diverse, multi-ethnic participants in large-scale genomic studies. The Population Architecture using Genomics and Epidemiology (PAGE) study conducted a GWAS of 26 clinical and behavioural phenotypes in 49,839 non-European individuals. Using strategies tailored for analysis of multi-ethnic and admixed populations, we describe a framework for analysing diverse populations, identify 27 novel loci and 38 secondary signals at known loci, as well as replicate 1,444 GWAS catalogue associations across these traits. Our data show evidence of effect-size heterogeneity across ancestries for published GWAS associations, substantial benefits for fine-mapping using diverse cohorts and insights into clinical implications. In the United States-where minority populations have a disproportionately higher burden of chronic conditions13-the lack of representation of diverse populations in genetic research will result in inequitable access to precision medicine for those with the highest burden of disease. We strongly advocate for continued, large genome-wide efforts in diverse populations to maximize genetic discovery and reduce health disparities.
TL;DR: QuanTIseq as discussed by the authors is a method to quantify the fractions of ten immune cell types from bulk RNA-sequencing data, which is extensively validated in blood and tumor samples using simulated, flow cytometry, and immunohistochemistry data.
Abstract: We introduce quanTIseq, a method to quantify the fractions of ten immune cell types from bulk RNA-sequencing data. quanTIseq was extensively validated in blood and tumor samples using simulated, flow cytometry, and immunohistochemistry data. quanTIseq analysis of 8000 tumor samples revealed that cytotoxic T cell infiltration is more strongly associated with the activation of the CXCR3/CXCL9 axis than with mutational load and that deconvolution-based cell scores have prognostic value in several solid cancers. Finally, we used quanTIseq to show how kinase inhibitors modulate the immune contexture and to reveal immune-cell types that underlie differential patients’ responses to checkpoint blockers. Availability: quanTIseq is available at http://icbi.at/quantiseq.
Johns Hopkins University1, Seattle Cancer Care Alliance2, University of Pennsylvania3, University of Colorado Boulder4, University of Utah5, Fox Chase Cancer Center6, Northwestern University7, Case Western Reserve University8, University of Texas MD Anderson Cancer Center9, Brigham and Women's Hospital10, Duke University11, University of South Florida12, Yale University13, Washington University in St. Louis14, University of California, San Francisco15, Roswell Park Cancer Institute16, Vanderbilt University17, University of Nebraska Medical Center18, Harvard University19, University of Wisconsin-Madison20, University of Michigan21, Stanford University22, Ohio State University23, University of California, San Diego24, City of Hope National Medical Center25, Memorial Sloan Kettering Cancer Center26, Mayo Clinic27, University of Tennessee Health Science Center28, National Comprehensive Cancer Network29
TL;DR: The NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC) as discussed by the authors address all aspects of management for NSCLC, focusing on recent updates in immunotherapy.
Abstract: The NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC) address all aspects of management for NSCLC. These NCCN Guidelines Insights focus on recent updates in immunotherapy. For the 2020 update, all of the systemic therapy regimens have been categorized using a new preference stratification system; certain regimens are now recommended as "preferred interventions," whereas others are categorized as either "other recommended interventions" or "useful under certain circumstances."
TL;DR: Hexagonal boron nitride (hBN) is a natural hyperbolic material in the mid-IR range, in which photonic material options are sparse as discussed by the authors.
Abstract: For more than seven decades, hexagonal boron nitride (hBN) has been employed as an inert, thermally stable engineering ceramic; since 2010, it has also been used as the optimal substrate for graphene in nanoelectronic and optoelectronic devices. Recent research has revealed that hBN exhibits a unique combination of optical properties that enable novel (nano)photonic functionalities. Specifically, hBN is a natural hyperbolic material in the mid-IR range, in which photonic material options are sparse. Furthermore, hBN hosts defects that can be engineered to obtain room-temperature, single-photon emission; exhibits strong second-order nonlinearities with broad implications for practical devices; and is a wide-bandgap semiconductor well suited for deep UV emitters and detectors. Inspired by these promising attributes, research on the properties of hBN and the development of large-area bulk and thin-film growth techniques has dramatically expanded. This Review offers a snapshot of current research exploring the properties underlying the use of hBN for future photonics functionalities and potential applications, and covers some of the remaining obstacles. Hexagonal boron nitride (hBN) is highly sought after for mid-IR nanophotonics, nonlinear and quantum optics, and as an efficient UV emitter. This Review surveys its fundamental physical properties, applications and synthesis.
F. Kyle Satterstrom1, Jack A. Kosmicki1, Jiebiao Wang2, Michael S. Breen3 +150 more•Institutions (45)
TL;DR: Using an enhanced Bayesian framework to integrate de novo and case-control rare variation, 102 risk genes are identified at a false discovery rate of ≤ 0.1, consistent with multiple paths to an excitatory/inhibitory imbalance underlying ASD.
Abstract: We present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n=35,584 total samples, 11,986 with ASD). Using an enhanced Bayesian framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate ≤ 0.1. Of these genes, 49 show higher frequencies of disruptive de novo variants in individuals ascertained for severe neurodevelopmental delay, while 53 show higher frequencies in individuals ascertained for ASD; comparing ASD cases with mutations in these groups reveals phenotypic differences. Expressed early in brain development, most of the risk genes have roles in regulation of gene expression or neuronal communication (i.e., mutations effect neurodevelopmental and neurophysiological changes), and 13 fall within loci recurrently hit by copy number variants. In human cortex single-cell gene expression data, expression of risk genes is enriched in both excitatory and inhibitory neuronal lineages, consistent with multiple paths to an excitatory/inhibitory imbalance underlying ASD.
TL;DR: Venetoclax plus LDAC has a manageable safety profile, producing rapid and durable remissions in older adults with AML ineligible for intensive chemotherapy, and high remission rate and low early mortality combined with rapid and Durable remission make venetoclAX and LDAC an attractive and novel treatment for older adults not suitable forintensive chemotherapy.
Abstract: PURPOSEEffective treatment options are limited for patients with acute myeloid leukemia (AML) who cannot tolerate intensive chemotherapy. An international phase Ib/II study evaluated the safety and...
TL;DR: Combined measurements of the production and decay rates of the Higgs boson, as well as its couplings to vector bosons and fermions, are presented and constraints are placed on various two Higgs doublet models.
Abstract: Combined measurements of the production and decay rates of the Higgs boson, as well as its couplings to vector bosons and fermions, are presented. The analysis uses the LHC proton–proton collision data set recorded with the CMS detector in 2016 at $\sqrt{s}=13\,\text {Te}\text {V} $ , corresponding to an integrated luminosity of 35.9 ${\,\text {fb}^{-1}} $ . The combination is based on analyses targeting the five main Higgs boson production mechanisms (gluon fusion, vector boson fusion, and associated production with a $\mathrm {W}$ or $\mathrm {Z}$ boson, or a top quark-antiquark pair) and the following decay modes: $\mathrm {H} \rightarrow \gamma \gamma $ , $\mathrm {Z}\mathrm {Z}$ , $\mathrm {W}\mathrm {W}$ , $\mathrm {\tau }\mathrm {\tau }$ , $\mathrm {b} \mathrm {b} $ , and $\mathrm {\mu }\mathrm {\mu }$ . Searches for invisible Higgs boson decays are also considered. The best-fit ratio of the signal yield to the standard model expectation is measured to be $\mu =1.17\pm 0.10$ , assuming a Higgs boson mass of $125.09\,\text {Ge}\text {V} $ . Additional results are given for various assumptions on the scaling behavior of the production and decay modes, including generic parametrizations based on ratios of cross sections and branching fractions or couplings. The results are compatible with the standard model predictions in all parametrizations considered. In addition, constraints are placed on various two Higgs doublet models.
University of Tennessee Health Science Center1, University College London2, Harvard University3, Mayo Clinic4, Johns Hopkins University5, University of São Paulo6, Duke University7, University of California, Los Angeles8, Cleveland Clinic9, University of Pittsburgh10, Peking Union Medical College11, University of Arizona12, University of Sydney13, Vanderbilt University14, Medical University of South Carolina15, University of British Columbia16, University of Texas Southwestern Medical Center17, Anschutz Medical Campus18, University of Pavia19, Nippon Medical School20, Utrecht University21, University of Amsterdam22, Columbia University23, University of Rochester24
TL;DR: This expert consensus statement provides the clinician with guidance on evaluation and management of ACM and includes clinically relevant information on genetics and disease mechanisms.
TL;DR: Comparative proteomic and phosphoproteomic analysis of paired tumor and normal adjacent tissues produced a catalog of colon cancer-associated proteins and phosphosites, including known and putative new biomarkers, drug targets, and cancer/testis antigens, which suggested glycolysis as a potential target to overcome the resistance of MSI-H tumors to immune checkpoint blockade.
Yale University1, University of South Florida2, University of Miami3, University of Florida4, Virginia Mason Medical Center5, University of California, San Francisco6, Indiana University – Purdue University Indianapolis7, University of Colorado Boulder8, Children's Mercy Hospital9, University of Minnesota10, Vanderbilt University11, University of Iowa12, University of Toronto13, Technische Universität München14
TL;DR: Teplizumab delayed progression to clinical type 1 diabetes in high-risk participants and among the participants who were Hla-DR3-negative, HLA-DR4-positive, or anti-zinc transporter 8 antibody- negative, fewer participants in the teplizuab group than in the placebo group had diabetes diagnosed.
Abstract: Background Type 1 diabetes is a chronic autoimmune disease that leads to destruction of insulin-producing beta cells and dependence on exogenous insulin for survival. Some interventions ha...
TL;DR: The minimum values of n and E (and subsequently the minimum number of events per predictor parameter, EPP) should be calculated to meet the following three criteria: small optimism in predictor effect estimates as defined by a global shrinkage factor of ≥0.9, aim to reduce overfitting conditional on a chosen p, and require prespecification of the model's anticipated Cox‐Snell R2.
Abstract: When designing a study to develop a new prediction model with binary or time-to-event outcomes, researchers should ensure their sample size is adequate in terms of the number of participants (n) and outcome events (E) relative to the number of predictor parameters (p) considered for inclusion. We propose that the minimum values of n and E (and subsequently the minimum number of events per predictor parameter, EPP) should be calculated to meet the following three criteria: (i) small optimism in predictor effect estimates as defined by a global shrinkage factor of ≥0.9, (ii) small absolute difference of ≤ 0.05 in the model's apparent and adjusted Nagelkerke's R2 , and (iii) precise estimation of the overall risk in the population. Criteria (i) and (ii) aim to reduce overfitting conditional on a chosen p, and require prespecification of the model's anticipated Cox-Snell R2 , which we show can be obtained from previous studies. The values of n and E that meet all three criteria provides the minimum sample size required for model development. Upon application of our approach, a new diagnostic model for Chagas disease requires an EPP of at least 4.8 and a new prognostic model for recurrent venous thromboembolism requires an EPP of at least 23. This reinforces why rules of thumb (eg, 10 EPP) should be avoided. Researchers might additionally ensure the sample size gives precise estimates of key predictor effects; this is especially important when key categorical predictors have few events in some categories, as this may substantially increase the numbers required.
Vanderbilt University1, Fisk University2, Harvard University3, Lehigh University4, Northern Kentucky University5, Boston University6, Vassar College7, Andrés Bello National University8, Space Telescope Science Institute9, Ames Research Center10, University of California, Riverside11, University of Maryland, Baltimore County12, Goddard Space Flight Center13, University of Chicago14, University of Florida15, University of North Carolina at Chapel Hill16, George Mason University17, Massachusetts Institute of Technology18, University of Sydney19, INAF20, Aarhus University21, University of New South Wales22
Seattle Cancer Care Alliance1, University of Michigan2, Johns Hopkins University3, University of South Florida4, Brigham and Women's Hospital5, City of Hope National Medical Center6, University of Alabama at Birmingham7, Yale Cancer Center8, Roswell Park Cancer Institute9, Harvard University10, University of Colorado Boulder11, Case Western Reserve University12, Memorial Sloan Kettering Cancer Center13, Northwestern University14, Fox Chase Cancer Center15, Vanderbilt University16, University of California, San Diego17, Stanford University18, Mayo Clinic19, Duke University20, University of Texas MD Anderson Cancer Center21, National Comprehensive Cancer Network22
TL;DR: The content featured in this issue is an excerpt of the recommendations for managing toxicity related to immune checkpoint blockade and a review of existing evidence.
Abstract: The aim of the NCCN Guidelines for Management of Immunotherapy-Related Toxicities is to provide guidance on the management of immune-related adverse events resulting from cancer immunotherapy. The NCCN Management of Immunotherapy-Related Toxicities Panel is an interdisciplinary group of representatives from NCCN Member Institutions and ASCO, consisting of medical and hematologic oncologists with expertise in a wide array of disease sites, and experts from the fields of dermatology, gastroenterology, neuro-oncology, nephrology, emergency medicine, cardiology, oncology nursing, and patient advocacy. Several panel representatives are members of the Society for Immunotherapy of Cancer (SITC). The initial version of the NCCN Guidelines was designed in general alignment with recommendations published by ASCO and SITC. The content featured in this issue is an excerpt of the recommendations for managing toxicity related to immune checkpoint blockade and a review of existing evidence. For the full version of the NCCN Guidelines, including recommendations for managing toxicities related to chimeric antigen receptor T-cell therapy, visit NCCN.org.
Duke University1, Memorial Sloan Kettering Cancer Center2, Harvard University3, Ohio State University4, Hackensack University Medical Center5, Fox Chase Cancer Center6, Vanderbilt University7, Johns Hopkins University8, University of New Mexico9, University of Louisville10, Sarah Cannon Research Institute11, Princess Alexandra Hospital12, Complutense University of Madrid13, Bristol-Myers Squibb14, Emory University15
TL;DR: TMB of 10 or more mut/Mb was associated with improved response and prolonged progression-free survival in both tumor PD-L1 expression 1% or greater and less than 1% subgroups and was thus identified as a potentially relevant cutoff in the assessment of TMB as a biomarker for first-line nivolumab plus ipilimumab.
Abstract: PURPOSECheckMate 568 is an open-label phase II trial that evaluated the efficacy and safety of nivolumab plus low-dose ipilimumab as first-line treatment of advanced/metastatic non–small-cell lung cancer (NSCLC). We assessed the association of efficacy with programmed death ligand 1 (PD-L1) expression and tumor mutational burden (TMB).PATIENTS AND METHODSTwo hundred eighty-eight patients with previously untreated, recurrent stage IIIB/IV NSCLC received nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks. The primary end point was objective response rate (ORR) in patients with 1% or more and less than 1% tumor PD-L1 expression. Efficacy on the basis of TMB (FoundationOne CDx assay) was a secondary end point.RESULTSOf treated patients with tumor available for testing, 252 patients (88%) of 288 were evaluable for PD-L1 expression and 98 patients (82%) of 120 for TMB. ORR was 30% overall and 41% and 15% in patients with 1% or greater and less than 1% tumor PD-L1 expression, respectively. ORR...