tbuckley/cabot-search huggingface dataset:
Cross-Neutralization of a SARS-CoV-2 Antibody to a Functionally Conserved Site Is Mediated by Avidity
Authors: Hejun Liu, Nicholas C. Wu, Meng Yuan, Sandhya Bangaru, Jonathan L. Torres, Tom G. Caniels, Jelle van Schooten, Xueyong Zhu, Chang-Chun D. Lee, Philip J.M. Brouwer, Marit J. van Gils, Rogier W. Sanders, Andrew B. Ward, Ian A. Wilson
Journal: Immunity (2020)

Most antibodies isolated from individuals with coronavirus disease 2019 (COVID-19) are specific to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, COVA1-16 is a relatively rare antibody that also cross-neutralizes SARS-CoV. Here, we determined a crystal structure of the COVA1-16 antibody fragment (Fab) with the SARS-CoV-2 receptor-binding domain (RBD) and negative-stain electron microscopy reconstructions with the spike glycoprotein trimer to elucidate the structural basis of its cross-reactivity. COVA1-16 binds a highly conserved epitope on the SARS-CoV-2 RBD, mainly through a long complementarity-determining region (CDR) H3, and competes with the angiotensin-converting enzyme 2 (ACE2) receptor because of steric hindrance rather than epitope overlap. COVA1-16 binds to a flexible up conformation of the RBD on the spike and relies on antibody avidity for neutralization. These findings, along with the structural and functional rationale for epitope conservation, provide insights for development of more universal SARS-like coronavirus vaccines and therapies.
Arginine and Old MACE: Small Molecules in Atherogenesis Support the Concept of Coronary Artery Disease as a Complex Trait⁎⁎Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
Authors: Richard I. Levin
Journal: Journal of the American College of Cardiology (2009)
Electronic Nicotine Delivery Systems Use and Cigarette Smoking Frequency and Intensity Among Young Adult Smokers
Authors: Cristian I. Meghea
Journal: JAMA Network Open (2020)

Jennifer L. Pearson, MPH, PhD; Eva Sharma, PhD; Ning Rui, PhD; Michael J. Halenar, MPH; Amanda L. Johnson, MHS; K. Michael Cummings, PhD, MPH; Hoda T. Hammad, MS, MPH; Annette R. Kaufman, PhD; Cindy Tworek, PhD, MPH; Maciej L. Goniewicz, PharmD, PhD; Heather L. Kimmel, PhD; Susanne Tanski, MD; Wilson M. Compton, MD, MPE; Hannah Day, PhD; Bridget K. Ambrose, PhD; Maansi Bansal-Travers, PhD; Marushka L. Silveira, BDS, MPH, PhD; David Abrams, PhD; Jeannie Limpert, MD; Mark J. Travers, PhD; Nicolette Borek, PhD; Andrew J. Hyland, PhD; Cassandra A. Stanton, PhD
Abstract 17677: An Acute Prmt5 Response Activates Epicardium During Myocardial Infarction and Protects Heart From Ischemic Damage
Authors: Jian Wu, Olan Jackson-Weaver, Rahul Gupta, Jian Xu
Journal: Circulation (2017)

Introduction: Arginine methylation has emerged as a key post-translational modification as prevalent as phosphorylation in mammals owing to generation of new methylarginine antibodies, advanced pro...
AB1356-HPR GOUT IN SPANISH PRIMARY HEALHCARE CENTERS: STILL A LONG WAY TO GO
Authors: M. A. Pou, S. Jeria, A. Prada-Ojeda, S. Ferrer, A. García-Guillén, H. Corominas, C. Diaz Torne
Journal: Annals of the Rheumatic Diseases (2020)

Background: Gout has a prevalence &gt;2.5% in the Spanish adult population. It is a chronic disease that without proper treatment causes pain, joint deformity and increased cardiovascular risk and mortality. Recent advances have demonstrated that if correctly treated the disease can be controlled and even ‘cured’. Most gouty patients are diagnosed and treated by general practitioners (GPs). There is evidence that the management if these patients is not good neither at Rheumatology Units nor at Primary Healthcare (PHC) centers.Several causes of this mismanagement can be found in the literature. Objectives: Design and evaluation of the results of a questionnaire created from a bibliographic search focused on areas of improvement of gout management in PHC. Methods: A search was made in Pubmed to identify the main barriers described in the management of patients with gout in primary care. The terms used were: “Gout”, “primary healthcare” and “education”. A Google Form of gout knowledge and management questionnaire was designed, taking into account what is described in the literature. The Google Form was sent to all GP from an urban area via mail and to other contacts via WhatsApp and twitter. Results: Responses were obtained from 224 GPs; 69.5% were women; 73.1% had between 11 and 30 years of professional experience; 96.4% answered that gouty are mostly controlled in primary care; 99.6% performs the diagnosis of gout without analysis of synovial fluid and 17% diagnosed only by clinics without urate levels; 55.9% of GPs do not use any reference guide. Of those who use, the 73% use GUIPCLINGOT and 40% use SEMGs one; 80.5% have not done any gout course in the last 5 years; 26% did not have access to a rheumatologist to confirm the gout diagnosis; only 30.8% knew the therapeutic objective of the urate lowering therapy (ULT); 28.6% considered the beginning of ULT after the first attack; 62% believed that the most important part of the treatment was changing diet and lifestyles; 88.8% did not perform any specific education for these patients by the nurse; just 37.2% carried out a treat-to-target strategy to lower urate levels. Conclusion: The questionnaire identifies multiple points of improvement for the management of this pathology in accordance with the described in the literature. Most GPs are unaware of the therapeutic objective of the ULT. Disclosure of Interests: None declared
Patient-reported wellbeing and clinical disease measures over time captured by multivariate trajectories of disease activity in individuals with juvenile idiopathic arthritis in the UK: a multicentre prospective longitudinal study
Authors: Stephanie J W Shoop-Worrall, Kimme L Hyrich, Lucy R Wedderburn, Wendy Thomson, Nophar Geifman, Eileen Baildam, Michael Barnes, Michael W Beresford, Emil Carlsson, Alice Chieng, Coziana Ciurtin, Gavin Cleary, Joyce Davidson, Fatjon Dekaj, Sally-Anne Dews, Andrew Dick, Gil Reynolds Diogo, Teresa Duerr, Joanna Fairlie, Helen Foster, Jenna F Gritzfeld, Yiannis Ioannou, Beth Jebson, Melissa Kartawinata, Toby Kent, Aline Kimonyo, Saskia Lawson-Tovey, Wei-Yu Lin, Paul Martin, Flora McErlane, Fatema Merali, Andrew Morris, Helen Neale, Jessica Neisen, Sandra Ng, Elizabeth Ralph, Athimalaipet V Ramanan, Soumya Raychaudhuri, Emily Robinson, Samantha Smith, Emma Sumner, Damian Tarasek, Chris Wallace, Zoe Wanstall, Annie Yarwood
Journal: The Lancet Rheumatology (2020)

Juvenile idiopathic arthritis (JIA) is a heterogeneous disease, the signs and symptoms of which can be summarised with use of composite disease activity measures, including the clinical Juvenile Arthritis Disease Activity Score (cJADAS). However, clusters of children and young people might experience different global patterns in their signs and symptoms of disease, which might run in parallel or diverge over time. We aimed to identify such clusters in the 3 years after a diagnosis of JIA. The identification of these clusters would allow for a greater understanding of disease progression in JIA, including how physician-reported and patient-reported outcomes relate to each other over the JIA disease course.
133P Which patient subgroup needs more attention in early treatment failure? A matched cohort study of treatment failure patterns in locally advanced gastric cancer
Authors: D. Wu, L-L. Shen, S-J. Que, J. Lu, C-H. Zheng, P. Li, J-W. Xie, J-B. Wang, J-X. Lin, Q-Y. Chen, L-L. Cao, M. Lin, R-H. Tu, Z-N. Huang, J-L. Lin, H-L. Zheng, C. Huang
Journal: Annals of Oncology (2020)
Targeting autophagy to overcome drug resistance: further developments
Authors: Haocai Chang, Zhengzhi Zou
Journal: Journal of Hematology & Oncology (2020)

Abstract Inhibiting cell survival and inducing cell death are the main approaches of tumor therapy. Autophagy plays an important role on intracellular metabolic homeostasis by eliminating dysfunctional or unnecessary proteins and damaged or aged cellular organelles to recycle their constituent metabolites that enable the maintenance of cell survival and genetic stability and even promotes the drug resistance, which severely limits the efficacy of chemotherapeutic drugs. Currently, targeting autophagy has a seemingly contradictory effect to suppress and promote tumor survival, which makes the effect of targeting autophagy on drug resistance more confusing and fuzzier. In the review, we summarize the regulation of autophagy by emerging ways, the action of targeting autophagy on drug resistance and some of the new therapeutic approaches to treat tumor drug resistance by interfering with autophagy-related pathways. The full-scale understanding of the tumor-associated signaling pathways and physiological functions of autophagy will hopefully open new possibilities for the treatment of tumor drug resistance and the improvement in clinical outcomes.
Abstract 15194: The Usefulness of Geriatric Nutritional Risk Index as a Short Term Cardiovascular Prognostic Indicator in Elderly Dialysis Patients
Authors: Akihiro Tokushige, Yoshiyuki Ikeda, Daisuke Kanda, Ippei Kosedo, Akiko Yoshikawa, Masakazu Imamura, Mitsuru Ohishi
Journal: Circulation (2019)

Introduction: The nutritional status of dialysis patients is often poor, and its evaluation is important because the malnutrition affects the vital prognosis. GNRI (geriatric nutritional risk index...
The Advisory Committee on Immunization Practices’ Ethical Principles for Allocating Initial Supplies of COVID-19 Vaccine — United States, 2020
Authors: Nancy McClung, Mary Chamberland, Kathy Kinlaw, Dayna Bowen Matthew, Megan Wallace, Beth P. Bell, Grace M. Lee, H. Keipp Talbot, José R. Romero, Sara E. Oliver, Kathleen Dooling
Journal: MMWR Morbidity and Mortality Weekly Report (2020)

Abbreviations: COVID-19 = coronavirus disease 2019; HCP = health care personnel.* Health care personnel: paid and unpaid persons serving in health care settings who have the potential for direct or indirect exposure to patients or infectious materials; other essential workers: person who conduct operations vital for continuing critical infrastructure, such as food, agriculture, transportation, education, and law enforcement; adults with high risk medical conditions: adults who have one or more high-risk medical conditions, such as obesity, diabetes, and cardiovascular disease; adults aged ≥65 years: includes adults living at home and approximately 3 million living in long-term care facilities.There is considerable overlap between groups, for example, many adults aged ≥65 years also have high-risk medical conditions.† Essential workers during the COVID-19 response have been defined by the U.S. Department of Homeland Security Cybersecurity and Infrastructure Security
15640 Effectiveness and safety of oral dutasteride for male androgenetic alopecia in real clinical practice: A descriptive unicenter study
Authors: Sergio Vañó-Galván, David Saceda-Corralo, Oscar Muñoz Moreno Arrones, Rita Rodrigues-Barata, Carlos Morales, Rocío Gil-Redondo, Caudia Bernárdez
Journal: Journal of the American Academy of Dermatology (2020)
Abstract PO-12: Activity of ASTX660, a small-molecule IAP antagonist, reveals a novel, immune-based therapeutic approach in T-cell lymphoma
Authors: Simone Jueliger, Nicola Ferrari, George Ward, Joanne Munck, Tomoko Smyth, Matthew Davis, Christina Gewinner, Roberta Ferraldeschi, John Lyons, Martin Sims
Journal: Blood Cancer Discovery (2020)

Abstract Introduction: ASTX660 is a potent, non-peptidomimetic antagonist of the cellular and X-linked inhibitors of apoptosis proteins (cIAP1/2 and XIAP), which is currently being tested in a first-in-human phase I-II study in patients with advanced solid tumors and lymphomas (NCT02503423). IAP antagonists are known regulators of cell death and have been reported to modulate immune responses (1). Herein, we describe the profile of ASTX660 in preclinical models with a specific focus on ASTX660's ability to harness a particular form of regulated cell death in T-cell lymphoma that directs an effective immune response and leads to sustained tumor regressions. Methods: ASTX660 was profiled across a panel of T-cell lymphoma lines, assessing apoptosis, necroptosis, and immunogenic cell death (ICD). ASTX660 was tested in vitro with or without caspase-8/RIPK1 inhibitors to demonstrate mechanism of action. Target engagement along with induction of apoptosis, necroptosis, and ICD markers were analyzed by Western blotting and flow cytometry. Murine tumor models in immunocompetent and immunocompromised mice were utilized to evaluate the efficacy of ASTX660 in the presence or absence of an adaptive immune response. Results: ASTX660 antagonized IAPs in cell lines, as indicated by a decrease in cIAP1 protein levels. In certain murine T-cell lymphoma cell lines, ASTX660 treatment was associated with an increase in cell death and release of biomarkers of ICD. Use of caspase and RIPK1 inhibitors indicated the cell death was via necroptosis. In a syngeneic model of T-cell lymphoma, administration of ASTX660 resulted in complete and sustained tumor regressions which were not seen in mice deficient in T and B cells. Mice cured of T-cell lymphoma by ASTX660 were resistant to a second inoculation of the same lymphoma. Conclusion: These data add to the description of ASTX660's mode of action and our ongoing understanding of the preliminary clinical efficacy in T-cell lymphoma (2). We describe a new role for ASTX660 as an immunomodulatory molecule with potential to deliver a novel immune-based therapeutic approach in T-cell lymphoma. References: 1. Michie J et al. Cells 2020;9(1). 2. Hollebecque A et al. 2019 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics. Citation Format: Simone Jueliger, Nicola Ferrari, George Ward, Joanne Munck, Tomoko Smyth, Matthew Davis, Christina Gewinner, Roberta Ferraldeschi, John Lyons, Martin Sims. Activity of ASTX660, a small-molecule IAP antagonist, reveals a novel, immune-based therapeutic approach in T-cell lymphoma [abstract]. In: Proceedings of the AACR Virtual Meeting: Advances in Malignant Lymphoma; 2020 Aug 17-19. Philadelphia (PA): AACR; Blood Cancer Discov 2020;1(3_Suppl):Abstract nr PO-12.
Preclinical Characterization of HPN536, a Trispecific, T-Cell–Activating Protein Construct for the Treatment of Mesothelin-Expressing Solid Tumors
Authors: Mary Ellen Molloy, Richard J. Austin, Bryan D. Lemon, Wade H. Aaron, Vaishnavi Ganti, Adrie Jones, Susan D. Jones, Kathryn L. Strobel, Purbasa Patnaik, Kenneth Sexton, Laurie Tatalick, Timothy Z. Yu, Patrick A. Baeuerle, Che-Leung Law, Holger Wesche
Journal: Clinical Cancer Research (2020)

Mesothelin (MSLN) is a glycophosphatidylinositol-linked tumor antigen overexpressed in a variety of malignancies, including ovarian, pancreatic, lung, and triple-negative breast cancer. Early signs of clinical efficacy with MSLN-targeting agents have validated MSLN as a promising target for therapeutic intervention, but therapies with improved efficacy are still needed to address the significant unmet medical need posed by MSLN-expressing cancers.We designed HPN536, a 53-kDa, trispecific, T-cell-activating protein-based construct, which binds to MSLN-expressing tumor cells, CD3ε on T cells, and to serum albumin. Experiments were conducted to assess the potency, activity, and half-life of HPN536 in in vitro assays, rodent models, and in nonhuman primates (NHP).HPN536 binds to MSLN-expressing tumor cells and to CD3ε on T cells, leading to T-cell activation and potent redirected target cell lysis. A third domain of HPN536 binds to serum albumin for extension of plasma half-life. In cynomolgus monkeys, HPN536 at doses ranging from 0.1 to 10 mg/kg demonstrated MSLN-dependent pharmacologic activity, was well tolerated, and showed pharmacokinetics in support of weekly dosing in humans.HPN536 is potent, is well tolerated, and exhibits extended half-life in NHPs. It is currently in phase I clinical testing in patients with MSLN-expressing malignancies (NCT03872206).
Myeloid-Derived Suppressor Cells Are a Major Source of Wnt5A in the Melanoma Microenvironment and Depend on Wnt5A for Full Suppressive Activity
Authors: Stephen M. Douglass, Mitchell E. Fane, Emilio Sanseviero, Brett L. Ecker, Curtis H. Kugel, Reeti Behera, Vinit Kumar, Evgenii N. Tcyganov, Xiangfan Yin, Qin Liu, Yash Chhabra, Gretchen M. Alicea, Rejji Kuruvilla, Dmitry I. Gabrilovich, Ashani T. Weeraratna
Journal: Cancer Research (2020)

Metastatic dissemination remains a significant barrier to successful therapy for melanoma. Wnt5A is a potent driver of invasion in melanoma and is believed to be secreted from the tumor microenvironment (TME). Our data suggest that myeloid-derived suppressor cells (MDSC) in the TME are a major source of Wnt5A and are reliant upon Wnt5A for multiple actions. Knockdown of Wnt5A specifically in the myeloid cells demonstrated a clear decrease in Wnt5A expression within the TME
307P Development of circulating free DNA methylation markers for thyroid nodule diagnostics
Authors: S. Hong, Z. Su, J. Li, S. Yu, B. Lin, Z. Ke, Q. Zhang, Z. Guo, W. Lv, S. Peng, L. Cheng, Q. He, R. Liu, H. Xiao
Journal: Annals of Oncology (2020)
Parkinson’s disease and translational research
Authors: Elisabeth Dinter, Theodora Saridaki, Leonie Diederichs, Heinz Reichmann, Björn H. Falkenburger
Journal: Translational Neurodegeneration (2020)

Abstract Parkinson’s disease (PD) is diagnosed when patients exhibit bradykinesia with tremor and/or rigidity, and when these symptoms respond to dopaminergic medications. Yet in the last years there was a greater recognition of additional aspects of the disease including non-motor symptoms and prodromal states with associated pathology in various regions of the nervous system. In this review we discuss current concepts of two major alterations found during the course of the disease: cytoplasmic aggregates of the protein α-synuclein and the degeneration of dopaminergic neurons. We provide an overview of new approaches in this field based on current concepts and latest literature. In many areas, translational research on PD has advanced the understanding of the disease but there is still a need for more effective therapeutic options based on the insights into the basic biological phenomena.
Pik3c3 deficiency in myeloid cells imparts partial resistance to experimental autoimmune encephalomyelitis associated with reduced IL-1β production
Authors: Guan Yang, Wenqiang Song, Jielin Xu, J. Luke Postoak, Feixiong Cheng, Jennifer Martinez, Jianhua Zhang, Lan Wu, Luc Van Kaer
Journal: Cellular and Molecular Immunology (2020)
Beat-by-Beat Cardiomyocyte T-Tubule Deformation Drives Tubular Content Exchange
Authors: Eva A. Rog-Zielinska, Marina Scardigli, Remi Peyronnet, Callum M. Zgierski-Johnston, Joachim Greiner, Josef Madl, Eileen T. O’Toole, Mary Morphew, Andreas Hoenger, Leonardo Sacconi, Peter Kohl
Journal: Circulation Research (2020)

Rationale: The sarcolemma of cardiomyocytes contains many proteins that are essential for electromechanical function in general, and excitation-contraction coupling in particular. The distribution of these proteins is nonuniform between the bulk sarcolemmal surface and membrane invaginations known as transverse tubules (TT). TT form an intricate network of fluid-filled conduits that support electromechanical synchronicity within cardiomyocytes. Although continuous with the extracellular space, the narrow lumen and the tortuous structure of TT can form domains of restricted diffusion. As a result of unequal ion fluxes across cell surface and TT membranes, limited diffusion may generate ion gradients within TT, especially deep within the TT network and at high pacing rates. Objective: We postulate that there may be an advective component to TT content exchange, wherein cyclic deformation of TT during diastolic stretch and systolic shortening serves to mix TT luminal content and assists equilibration with bulk extracellular fluid. Methods and Results: Using electron tomography, we explore the 3-dimensional nanostructure of TT in rabbit ventricular myocytes, preserved at different stages of the dynamic cycle of cell contraction and relaxation. We show that cellular deformation affects TT shape in a sarcomere length-dependent manner and on a beat-by-beat time-scale. Using fluorescence recovery after photobleaching microscopy, we show that apparent speed of diffusion is affected by the mechanical state of cardiomyocytes, and that cyclic contractile activity of cardiomyocytes accelerates TT diffusion dynamics. Conclusions: Our data confirm the existence of an advective component to TT content exchange. This points toward a novel mechanism of cardiac autoregulation, whereby the previously implied increased propensity for TT luminal concentration imbalances at high electrical stimulation rates would be countered by elevated advection-assisted diffusion at high mechanical beating rates. The relevance of this mechanism in health and during pathological remodeling (eg, cardiac hypertrophy or failure) forms an exciting target for further research.
Is Treatment in Patients With Suspected Nonradiographic Axial Spondyloarthritis Effective? Six‐Month Results of a Placebo‐Controlled Trial
Authors: Tamara Rusman, Mignon A. C. van der Weijden, Michael T. Nurmohamed, Robert B. M. Landewé, Janneke J. H. de Winter, Bouke J. H. Boden, Pierre M. Bet, Carmella M. A. van der Bijl, Conny van der Laken, Irene E. van der Horst‐Bruinsma
Journal: Arthritis & Rheumatology (2020)

To investigate the efficacy of 16-week treatment with etanercept (ETN) in patients with suspected nonradiographic axial spondyloarthritis (SpA).Tumor necrosis factor inhibitor-naive patients with inflammatory back pain with at least 2 SpA features and high disease activity (Bath Ankylosing Spondylitis Disease Activity Index score ≥4), without the requirement of a positive finding on magnetic resonance imaging (MRI) of the sacroiliac (SI) joint and/or elevated C-reactive protein (CRP) level, were randomized (1:1) to receive ETN (n = 40) or placebo (n = 40) for 16 weeks and subsequently were followed up for a further 8 weeks (to 24 weeks from baseline) without study medication. The primary end point was the Assessment of SpondyloArthritis international Society 20 (ASAS20) response at 16 weeks. Secondary end points included the Ankylosing Spondylitis Disease Activity Score (ASDAS) and changes in disease parameters, including the Bath Ankylosing Spondylitis Metrology Index (BASMI), CRP level, erythrocyte sedimentation rate (ESR), and Spondyloarthritis Research Consortium of Canada index scores (MRI of the SI joint), after 16 and 24 weeks.Patient characteristics at baseline were comparable between the ETN and placebo groups. At 16 weeks, there was no significant difference in the percentage of patients exhibiting ASAS20 response between the ETN group (6 patients [16.7%]) and the placebo group (4 patients [11.1%]) (relative risk 0.7 [95% confidence interval 0.2-2.2], P = 0.5). Only the ESR showed more improvement in the ETN group compared to the placebo group at 16 weeks (decreases of 2.2 mm/hour and 1.4 mm/hour, respectively), but the difference did not reach statistical significance. Between 16 and 24 weeks, without study medication, the BASMI, CRP level, and ESR had worsened to a greater extent in the ETN group compared to the placebo group, with the difference being significant for the CRP level.This study shows that in patients with suspected nonradiographic axial SpA with high disease activity but without the requirement of a positive finding on SI joint MRI and/or elevated CRP level, treatment with ETN is not effective.
141P Low expression of CDK5RAP3 and UFM1 indicates poor prognosis in patients with gastric cancer
Authors: N-Z. Lian, Q-Z. Qiu, Y-X. Gao, J-B. Wang, C-H. Zheng, P. Li, J-W. Xie, J-X. Lin, J. Lu, Q-Y. Chen, L-L. Cao, M. Lin, R-H. Tu, Z-N. Huang, J-L. Lin, H-L. Zheng, C. Huang
Journal: Annals of Oncology (2020)