tbuckley/cabot-search huggingface dataset:
Assessment of Cardiovascular Safety of Anti-Osteoporosis Drugs
Authors: N. R. Fuggle, C. Cooper, N. C. Harvey, N. Al-Daghri, M.-L. Brandi, O. Bruyere, A. Cano, E. M. Dennison, A. Diez-Perez, J.-M. Kaufman, S. Palacios, D. Prieto-Alhambra, S. Rozenberg, T. Thomas, F. Tremollieres, R. Rizzoli, J. A. Kanis, J. Y. Reginster
Journal: Drugs (2020)

The incidence of osteoporosis and cardiovascular disease increases with age, and there are potentially shared mechanistic associations between the two conditions. It is therefore highly relevant to understand the cardiovascular implications of osteoporosis medications. These are presented in this narrative review. Calcium supplementation could theoretically cause atheroma formation via calcium deposition, and in one study was found to be associated with myocardial infarction, but this has not been replicated. Vitamin D supplementation has been extensively investigated for cardiac benefit, but no consistent effect has been found. Despite findings in the early 21st century that menopausal hormone therapy was associated with coronary artery disease and venous thromboembolism (VTE), this therapy is now thought to be potentially safe (from a cardiac perspective) if started within the first 10 years of the menopause. Selective estrogen receptor modulators (SERMs) are associated with increased risk of VTE and may be related to fatal strokes (a subset of total strokes). Bisphosphonates could theoretically provide protection against atheroma. However, data from randomised trials and observational studies have neither robustly supported this nor consistently demonstrated the potential association with atrial fibrillation. Denosumab does not appear to be associated with cardiovascular disease and, although parathyroid hormone analogues are associated with palpitations and dizziness, no association with a defined cardiovascular pathology has been demonstrated. Finally, romosozumab has been shown to have a possible cardiovascular signal, and therefore post-market surveillance of this therapy will be vital.
Implications of ST Changes During Normal Echocardiography
Authors: Jesús Peteiro, Alberto Bouzas-Mosquera
Journal: JAMA Internal Medicine (2020)

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Child poverty, food insecurity, and respiratory health during the COVID-19 pandemic
Authors: Ian P Sinha, Alice R Lee, Davara Bennett, Louisa McGeehan, Elissa M Abrams, Sarah J Mayell, Rachel Harwood, Daniel B Hawcutt, Francis J Gilchrist, Marcus K H Auth, Justus M Simba, David C Taylor-Robinson
Journal: The Lancet Respiratory Medicine (2020)
Anti-alarmins in asthma: targeting the airway epithelium with next-generation biologics
Authors: Celeste M. Porsbjerg, Asger Sverrild, Clare M. Lloyd, Andrew N. Menzies-Gow, Elisabeth H. Bel
Journal: European Respiratory Journal (2020)

Monoclonal antibody therapies have significantly improved treatment outcomes for patients with severe asthma; however, a significant disease burden remains. Available biologic treatments, including anti-immunoglobulin (Ig)E, anti-interleukin (IL)-5, anti-IL-5Rα and anti-IL-4Rα, reduce exacerbation rates in study populations by approximately 50% only. Furthermore, there are currently no effective treatments for patients with severe, type 2-low asthma. Existing biologics target immunological pathways that are downstream in the type 2 inflammatory cascade, which may explain why exacerbations are only partly abrogated. For example, type 2 airway inflammation results from several inflammatory signals in addition to IL-5. Clinically, this can be observed in how fractional exhaled nitric oxide ( F eNO ), which is driven by IL-13, may remain unchanged during anti-IL-5 treatment despite reduction in eosinophils, and how eosinophils may remain unchanged during anti-IL-4Rα treatment despite reduction in F eNO . The broad inflammatory response involving cytokines including IL-4, IL-5 and IL-13 that ultimately results in the classic features of exacerbations (eosinophilic inflammation, mucus production and bronchospasm) is initiated by release of “alarmins” thymic stromal lymphopoietin (TSLP), IL-33 and IL-25 from the airway epithelium in response to triggers. The central, upstream role of these epithelial cytokines has identified them as strong potential therapeutic targets to prevent exacerbations and improve lung function in patients with type 2-high and type 2-low asthma. This article describes the effects of alarmins and discusses the potential role of anti-alarmins in the context of existing biologics. Clinical phenotypes of patients who may benefit from these treatments are also discussed, including how biomarkers may help identify potential responders.
Avapritinib in advanced PDGFRA D842V-mutant gastrointestinal stromal tumour (NAVIGATOR): a multicentre, open-label, phase 1 trial
Authors: Michael C Heinrich, Robin L Jones, Margaret von Mehren, Patrick Schöffski, César Serrano, Yoon-Koo Kang, Philippe A Cassier, Olivier Mir, Ferry Eskens, William D Tap, Piotr Rutkowski, Sant P Chawla, Jonathan Trent, Meera Tugnait, Erica K Evans, Tamieka Lauz, Teresa Zhou, Maria Roche, Beni B Wolf, Sebastian Bauer, Suzanne George
Journal: The Lancet Oncology (2020)
Targeted Temperature Management for Cardiac Arrest
Authors: Nicolas Deye, Sebastian Voicu, Bruno Megarbane
Journal: New England Journal of Medicine (2020)

BACKGROUND
Moderate therapeutic hypothermia is currently recommended to improve neurologic outcomes in adults with persistent coma after resuscitated out-of-hospital
cardiac arrest. However, the effectiveness of moderate therapeutic hypothermia in
patients with nonshockable rhythms (asystole or pulseless electrical activity) is
debated.
METHODS
We performed an open-label, randomized, controlled trial comparing moderate
therapeutic hypothermia (33°C during the first 24 hours) with targeted normothermia (37°C) in patients with coma who had been admitted to the intensive care unit
(ICU) after resuscitation from cardiac arrest with nonshockable rhythm. The primary outcome was survival with a favorable neurologic outcome, assessed on day
90 after randomization with the use of the Cerebral Performance Category (CPC)
scale (which ranges from 1 to 5, with higher scores indicating greater disability).
We defined a favorable neurologic outcome as a CPC score of 1 or 2. Outcome
assessment was blinded. Mortality and safety were also assessed.
RESULTS
From January 2014 through January 2018, a total of 584 patients from 25 ICUs
underwent randomization, and 581 were included in the analysis (3 patients withdrew consent). On day 90, a total of 29 of 284 patients (10.2%) in the hypothermia
group were alive with a CPC score of 1 or 2, as compared with 17 of 297 (5.7%)
in the normothermia group (difference, 4.5 percentage points; 95% confidence
interval [CI], 0.1 to 8.9; P=0.04). Mortality at 90 days did not differ significantly
between the hypothermia group and the normothermia group (81.3% and 83.2%,
respectively; difference, −1.9 percentage points; 95% CI, −8.0 to 4.3). The incidence
of prespecified adverse events did not differ significantly between groups.
CONCLUSIONS
Among patients with coma who had been resuscitated from cardiac arrest with
nonshockable rhythm, moderate therapeutic hypothermia at 33°C for 24 hours led
to a higher percentage of patients who survived with a favorable neurologic outcome at day 90 than was observed with targeted normothermia. (Funded by the
French Ministry of Health and others; HYPERION ClinicalTrials.gov number,
NCT01994772.)
Design, synthesis, and biological evaluation of quinazolin-4(3H)-one derivatives co-targeting poly(ADP-ribose) polymerase-1 and bromodomain containing protein 4 for breast cancer therapy
Authors: Xiaosa Chang, Dejuan Sun, Danfeng Shi, Guan Wang, Yanmei Chen, Kai Zhang, Huidan Tan, Jie Liu, Bo Liu, Liang Ouyang
Journal: Acta Pharmaceutica Sinica B (2020)

This study was aimed to design the first dual-target small-molecule inhibitor co-targeting poly (ADP-ribose) polymerase-1 (PARP1) and bromodomain containing protein 4 (BRD4), which had important cross relation in the global network of breast cancer, reflecting the synthetic lethal effect. A series of new BRD4 and PARP1 dual-target inhibitors were discovered and synthesized by fragment-based combinatorial screening and activity assays that together led to the chemical optimization. Among these compounds, 19d was selected and exhibited micromole enzymatic potencies against BRD4 and PARP1, respectively. Compound 19d was further shown to efficiently modulate the expression of BRD4 and PARP1. Subsequently, compound 19d was found to induce breast cancer cell apoptosis and stimulate cell cycle arrest at G1 phase. Following pharmacokinetic studies, compound 19d showed its antitumor activity in breast cancer susceptibility gene 1/2 (BRCA1/2) wild-type MDA-MB-468 and MCF-7 xenograft models without apparent toxicity and loss of body weight. These results together demonstrated that a highly potent dual-targeted inhibitor was successfully synthesized and indicated that co-targeting of BRD4 and PARP1 based on the concept of synthetic lethality would be a promising therapeutic strategy for breast cancer.
Alendronate loaded graphene oxide functionalized collagen sponge for the dual effects of osteogenesis and anti-osteoclastogenesis in osteoporotic rats
Authors: Yuyang Zeng, Muran Zhou, Lifeng Chen, Huimin Fang, Shaokai Liu, Chuchao Zhou, Jiaming Sun, Zhenxing Wang
Journal: Bioactive Materials (2020)

Graphene Oxide (GO)-related hydrogels have been extensively studied in hard tissue repair, because GO can not only enhance the mechanical properties of polymers but also promote osteogenic differentiation of mesenchymal stem cells. However, simple GO-related hydrogels are not ideal for the repair of osteoporotic bone defects as the overactive osteoclasts in osteoporosis. Alendronate (Aln) is known to inhibit osteoclasts and may bind to GO through covalent connection. Therefore, delivering Aln in GO-related hydrogels may be effective to repair osteoporotic bone defects. Here, we developed a control-released system which is constructed by collagen (Col)-GO sponges loaded with Aln (Col-GO-Aln) for osteoporotic bone defect repair. In vitro, Col-GO-Aln sponges prolonged the release period of Aln, and the sponge containing 0.05% (w/v) GO released Aln faster than sponge with 0.2% GO. Furthermore, tartrate-resistant acid phosphatase (TRAP) and F-actin staining demonstrated that Col-GO-Aln sponges effectively inhibited osteoclastogenesis of monocyte-macrophages. In vivo, micro-CT scan showed that the volume of newborn bone in defect site by 0.05% GO sponge was nearly three times larger than that of other groups. Moreover, the CT and histological examinations of rat femur proved that Col-GO-Aln sponges decreased the number of osteoclasts and suppressed the systemic bone loss in osteoporotic rats. These findings reveal that the application of GO as carriers of anti-osteoporosis drugs is a viable treatment for osteoporosis. The results also underscore the potential of GO-related hydrogels with Aln-releasing capacity for bone regeneration in osteoporosis.
Glycolipid-peptide vaccination induces liver-resident memory CD8 <sup>+</sup> T cells that protect against rodent malaria
Authors: Lauren E. Holz, Yu Cheng Chua, Maria N. de Menezes, Regan J. Anderson, Sarah L. Draper, Benjamin J. Compton, Susanna T. S. Chan, Juby Mathew, Jasmine Li, Lukasz Kedzierski, Zhongfang Wang, Lynette Beattie, Matthias H. Enders, Sonia Ghilas, Rose May, Thiago M. Steiner, Joshua Lange, Daniel Fernandez-Ruiz, Ana Maria Valencia-Hernandez, Taryn L. Osmond, Kathryn J. Farrand, Rebecca Seneviratna, Catarina F. Almeida, Kirsteen M. Tullett, Patrick Bertolino, David G. Bowen, Anton Cozijnsen, Vanessa Mollard, Geoffrey I. McFadden, Irina Caminschi, Mireille H. Lahoud, Katherine Kedzierska, Stephen J. Turner, Dale I. Godfrey, Ian F. Hermans, Gavin F. Painter, William R. Heath
Journal: Science Immunology (2020)

Glycolipid-peptide conjugate vaccines protect against rodent malaria by generating large numbers of liver CD8 + T RM cells.
Author Correction: NADPH oxidase subunit NOXO1 is a target for emphysema treatment in COPD
Authors: Michael Seimetz, Natascha Sommer, Mariola Bednorz, Oleg Pak, Christine Veith, Stefan Hadzic, Marija Gredic, Nirmal Parajuli, Baktybek Kojonazarov, Simone Kraut, Jochen Wilhelm, Fenja Knoepp, Ingrid Henneke, Alexandra Pichl, Zeki I. Kanbagli, Susan Scheibe, Athanasios Fysikopoulos, Cheng-Yu Wu, Walter Klepetko, Peter Jaksch, Christina Eichstaedt, Ekkehard Grünig, Katrin Hinderhofer, Miklós Geiszt, Niklas Müller, Flavia Rezende, Giulia Buchmann, Ilka Wittig, Matthias Hecker, Andreas Hecker, Winfried Padberg, Peter Dorfmüller, Stefan Gattenlöhner, Claus F. Vogelmeier, Andreas Günther, Srikanth Karnati, Eveline Baumgart-Vogt, Ralph T. Schermuly, Hossein A. Ghofrani, Werner Seeger, Katrin Schröder, Friedrich Grimminger, Ralf P. Brandes, Norbert Weissmann
Journal: Nature Metabolism (2020)
Selective Neuronal Vulnerability in Alzheimer’s Disease: A Network-Based Analysis
Authors: Jean-Pierre Roussarie, Vicky Yao, Patricia Rodriguez-Rodriguez, Rose Oughtred, Jennifer Rust, Zakary Plautz, Shirin Kasturia, Christian Albornoz, Wei Wang, Eric F. Schmidt, Ruth Dannenfelser, Alicja Tadych, Lars Brichta, Alona Barnea-Cramer, Nathaniel Heintz, Patrick R. Hof, Myriam Heiman, Kara Dolinski, Marc Flajolet, Olga G. Troyanskaya, Paul Greengard
Journal: Neuron (2020)

A major obstacle to treating Alzheimer's disease (AD) is our lack of understanding of the molecular mechanisms underlying selective neuronal vulnerability, a key characteristic of the disease. Here, we present a framework integrating high-quality neuron-type-specific molecular profiles across the lifetime of the healthy mouse, which we generated using bacTRAP, with postmortem human functional genomics and quantitative genetics data. We demonstrate human-mouse conservation of cellular taxonomy at the molecular level for neurons vulnerable and resistant in AD, identify specific genes and pathways associated with AD neuropathology, and pinpoint a specific functional gene module underlying selective vulnerability, enriched in processes associated with axonal remodeling, and affected by amyloid accumulation and aging. We have made all cell-type-specific profiles and functional networks available at http://alz.princeton.edu. Overall, our study provides a molecular framework for understanding the complex interplay between Aβ, aging, and neurodegeneration within the most vulnerable neurons in AD.
Platelet-Specific PDGFB Ablation Impairs Tumor Vessel Integrity and Promotes Metastasis
Authors: Yanyu Zhang, Jessica Cedervall, Anahita Hamidi, Melanie Herre, Kati Viitaniemi, Gabriela D'Amico, Zuoxiu Miao, Ragaseema Valsala Madhavan Unnithan, Alessandra Vaccaro, Luuk van Hooren, Maria Georganaki, Åsa Thulin, Qi Qiao, Johanna Andrae, Agneta Siegbahn, Carl-Henrik Heldin, Kari Alitalo, Christer Betsholtz, Anna Dimberg, Anna-Karin Olsson
Journal: Cancer Research (2020)

Platelet-derived growth factor B (PDGFB) plays a crucial role in recruitment of PDGF receptor β-positive pericytes to blood vessels. The endothelium is an essential source of PDGFB in this process. Platelets constitute a major reservoir of PDGFB and are continuously activated in the tumor microenvironment, exposing tumors to the plethora of growth factors contained in platelet granules. Here, we show that tumor vascular function, as well as pericyte coverage is significantly impaired in mice with conditional knockout of PDGFB in platelets. A lack of PDGFB in platelets led to enhanced hypoxia and epithelial-to-mesenchymal transition in the primary tumors, elevated levels of circulating tumor cells, and increased spontaneous metastasis to the liver or lungs in two mouse models. These findings establish a previously unknown role for platelet-derived PDGFB, whereby it promotes and maintains vascular integrity in the tumor microenvironment by contributing to the recruitment of pericytes. SIGNIFICANCE: Conditional knockout of PDGFB in platelets demonstrates its previously unknown role in the maintenance of tumor vascular integrity and host protection against metastasis.
Distinct synovial tissue macrophage subsets regulate inflammation and remission in rheumatoid arthritis
Authors: Stefano Alivernini, Lucy MacDonald, Aziza Elmesmari, Samuel Finlay, Barbara Tolusso, Maria Rita Gigante, Luca Petricca, Clara Di Mario, Laura Bui, Simone Perniola, Moustafa Attar, Marco Gessi, Anna Laura Fedele, Sabarinadh Chilaka, Domenico Somma, Stephen N. Sansom, Andrew Filer, Charles McSharry, Neal L. Millar, Kristina Kirschner, Alessandra Nerviani, Myles J. Lewis, Costantino Pitzalis, Andrew R. Clark, Gianfranco Ferraccioli, Irina Udalova, Christopher D. Buckley, Elisa Gremese, Iain B. McInnes, Thomas D. Otto, Mariola Kurowska-Stolarska
Journal: Nature Medicine (2020)
The Role of the TL1A/DR3 Axis in the Activation of Group 2 Innate Lymphoid Cells in Subjects with Eosinophilic Asthma
Authors: Kentaro Machida, Michael Aw, Brittany M. A. Salter, Xiaotian Ju, Manali Mukherjee, Gail M. Gauvreau, Paul M. O’Byrne, Parameswaran Nair, Roma Sehmi
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

Rationale: Group 2 innate lymphoid cells (ILC2s) are critical for type 2 inflammation. In murine models of asthma, some ILC2s remain activated in the absence of epithelial cell-derived cytokine signaling, implicating alternate stimulatory pathways. DR3 (death receptor 3), a member of the tumor necrosis factor receptor superfamily, is expressed on ILC2s. Genome-wide association studies report an association between DR3 ligand, TL1A (tumor necrosis factor-like protein 1A), and chronic inflammatory conditions.Objectives: We investigated the TL1A/DR3 axis in airway ILC2 biology in eosinophilic asthma.Methods: Stable subjects with mild asthma were subject to allergen inhalation challenge, and DR3 expression on sputum cells was assessed. We investigated cytokine regulation of DR3 expression on ILC2s and steroid sensitivity. Airway TL1A was assessed in sputum from subjects with mild asthma and subjects with prednisone-dependent severe eosinophilic asthma.Measurements and Main Results: There was a significant increase in sputum DR3+ ILC2s 24 hours after allergen challenge, and DR3 expression on ILC2s was upregulated by IL-2, IL-33, or TSLP in vitro. Stimulation with TL1A significantly increased IL-5 expression by ILC2s and was attenuated by dexamethasone, an effect that was negated in the presence of TSLP. Airway TL1A levels were increased 24 hours after allergen challenge in subjects with mild asthma but were significantly greater in those with severe eosinophilic asthma. The highest levels were detected in subjects with severe asthma with airway autoimmune responses. C1q+ immune complexes from the sputa of subjects with severe asthma with high autoantibody levels stimulated TL1A production by monocytes.Conclusions: The TL1A/DR3 axis is a costimulator of ILC2s in asthma, particularly in the airways of patients with a predisposition to autoimmune responses.
Assessment of Acute Acral Lesions in a Case Series of Children and Adolescents During the COVID-19 Pandemic
Authors: Juncal Roca-Ginés, Ignacio Torres-Navarro, Javier Sánchez-Arráez, Carlos Abril-Pérez, Oihana Sabalza-Baztán, Sergio Pardo-Granell, Vicent Martínez i Cózar, Rafael Botella-Estrada, Montserrat Évole-Buselli
Journal: JAMA Dermatology (2020)

<h3>Importance</h3> A novel coronavirus named<i>severe acute respiratory syndrome coronavirus 2</i>(SARS-CoV-2) has recently been identified as the cause of a pandemic called<i>coronavirus disease 2019</i>(COVID-19). In this context, some associated skin diseases have been described. Cutaneous lesions referred to as<i>acute acro-ischemia</i>have been reported as a possible sign of COVID-19 in adolescents and children. <h3>Objective</h3> To evaluate the pathogenesis of these newly described acute acral lesions. <h3>Design, Setting, and Participants</h3> This prospective case series was conducted at La Fe University Hospital, a tertiary referral hospital in Valencia, Spain, between April 9 and April 15, 2020. Among 32 referred patients, 20 children and adolescents with new-onset inflammatory lesions did not have a diagnosis. <h3>Exposures</h3> Patients were not exposed to any drug or other intervention. <h3>Main Outcomes and Measures</h3> We performed reverse transcriptase–polymerase chain reaction for SARS-CoV-2 and a range of blood tests for possible origins of the lesions. Skin biopsies were performed in 6 patients. <h3>Results</h3> Of the 20 patients enrolled, 7 were female and 13 were male, with an age range of 1 to 18 years. Clinical findings fit into the following patterns: acral erythema (6 patients), dactylitis (4 patients), purpuric maculopapules (7 patients), and a mixed pattern (3 patients). None of the patients had remarkable hematologic or serologic abnormalities, including negative antibodies to SARS-CoV-2. Biopsies performed in 6 patients showed histologic findings characteristic of perniosis. <h3>Conclusions and Relevance</h3> The clinical, histologic, and laboratory test results were compatible with a diagnosis of perniosis, and no evidence was found to support the implication of SARS-CoV-2 infection.
Rapidly scalable mechanical ventilator for the COVID-19 pandemic
Authors: Albert H. Kwon, Alexander H. Slocum, Dirk Varelmann, Christoph G. S. Nabzdyk, Brandon Araki, Murad Abu-Kalaf, Mike Detienne, David Hagan, Nevan Hanumara, Kimberly Jung, Teddy Ort, Aaron Ramirez, Folkers Rojasv, Daniela Rus, Amelia Servi, Shakti Shaligram, Alexander Slocum, Jonathan Slocum, Coby Unger, Jay Connor, Bon Ku, Albert Kwon, Christoph Nabzdyk, Dirk Varelmann, John Callahan, Sergey Karamnov, Keith G. Lurie, Niels Olson, Neil Ray, Mark Rosen, Steven Shafer, Scott Sparks, Leena Pradhan-Nabzdyk, Abdul Mohsen Al Husseini, Justin Negrete, Stephen Powelson, Heon Ju Lee
Journal: Intensive Care Medicine (2020)
Validation of a commercially available SARS-CoV-2 serological immunoassay
Authors: B. Meyer, G. Torriani, S. Yerly, L. Mazza, A. Calame, I. Arm-Vernez, G. Zimmer, T. Agoritsas, J. Stirnemann, H. Spechbach, I. Guessous, S. Stringhini, J. Pugin, P. Roux-Lombard, L. Fontao, C.-A. Siegrist, I. Eckerle, N. Vuilleumier, L. Kaiser
Journal: Clinical Microbiology and Infection (2020)