tbuckley/cabot-search huggingface dataset:
AB0049C INFLAMMASOME DRIVES RELEASE OF MITOCHONDRIAL DNA ENCLOSED IN EXTRACELLULAR MEMBRANE VESICLES AND PROPAGATION OF INFLAMMATION IN BEHÇET’S DISEASE
Authors: Hachirou Konaka, Hyota Takamatsu, Jeong-Hoon Park, Yasuhiro Kato, Toru Hirano, Atsushi Kumanogoh
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> It has been reported that mitochondrial DNA (mtDNA) is released into the cytosol by mitochondrial stress and induces pro-inflammatory cytokine production via inflammasome and intracellular DNA sensors. Also, mtDNA in the extracellular space is known to result in sterile inflammation. However, the molecular mechanism of mtDNA release and its pathological significance in autoimmune diseases (ADs) has not been elucidated. <h3>Objectives:</h3> To clarify the molecular mechanism of mtDNA release and its pathological significance in ADs. <h3>Methods:</h3> We collected the serum from various AD patients and analyzed the levels of mtDNA in serum. We digested mtDNA in serum by DNase treatment. We purified the extracellular membrane vesicles (EMVs) and evaluated their inflammation-inducing potential. Also, we investigated the molecular mechanism behind mtDNA-induced inflammation by using inflammasome gene Knock out cell lines <h3>Results:</h3> We first measured the levels of mtDNA in serum of the various ADs by quantitative PCR and found that serum mtDNA levels were significantly high in BD. Interestingly, mtDNA in BD serum could not be digested by DNase treatment and was detected in the extracellular membrane vesicles (EMVs) purified by ultracentrifugation. Since EMVs are known to deliver various molecules from one cell to another, we stimulated monocytic cells with BD-derived EMVs and found that these EMVs could induce IL-1β production in an NLRP3 inflammasome-dependent manner. We then studied the mechanism of secretion of mtDNA in EMVs and found that both human primary monocyte and monocyte-like cell line released mtDNA-containing EMVs after stimulation with ATP or LPS. Further, BD-derived monocytes secreted more abundant mtDNA in EMVs than monocytes derived from healthy donors. Additionally, the inhibition of caspase-1 activity reduced the secretion of mtDNA in EMVs <h3>Conclusion:</h3> We revealed a novel mechanism of inflammation propagation involving inflammasome and mtDNA; activated inflammasome releases mtDNA-containing EMVs and subsequently leads to mtDNA-induced inflammation via NLRP3 inflammasome. Such inflammatory mechanism may contribute to the exacerbation of inflammation in BD. <h3>Disclosure of Interests:</h3> None declared
Jeffrey George Bissenden
Authors: Peter Weller, Doug Addy, Anne Aukett
Journal: BMJ (2020)

Jeffrey George Bissenden (“Jeff”) was born in Hyde, Cheshire, and attended Stockport Grammar School, where he excelled academically and in all sports. After graduating, he did his early postgraduate training at Southmead Hospital in Bristol and Great Ormond Street Hospital in London. He moved to Birmingham and was a registrar at Birmingham Children’s Hospital. This was …
A call for Essays: stories from the frontline during the COVID-19 pandemic
Authors: Sophie Woolven
Journal: The Lancet Respiratory Medicine (2020)

The year 2020 will no doubt be etched in the memory of health-care professionals around the world for many years to come. Doctors, nurses, paramedics, researchers, and many more working in health care have been challenged by the COVID-19 pandemic in many ways, but some positive outcomes have emerged in its wake. Collaborations have sprung up between private companies, public health bodies, and other stakeholders. There has been unprecedented research efforts and cooperation between clinical trialists to publish results in a timely manner and to inform the public and professionals in patient management. Finally, there has been a long-overdue, renewed appreciation of those who work on the frontline of health care. In 2013, The Lancet Respiratory Medicine's inaugural Essay competition led to some fantastic submissions from health-care professionals and students alike. To follow on from this, we would once again like to hear from those working on the frontline. We want to hear your story—the lessons you have learned, what you hope for the future, something that you have experienced that you wish to share. Whether it be about the COVID-19 pandemic or another experience that might have shaped how you approach your work or the outlook you have. Send us a piece of descriptive prose by Dec 6, 2020, on any topic related to respiratory medicine or critical care, no pictures necessary; just 1250 engaging, interesting, and striking words. Entries will be assessed anonymously by our editors, and the most pertinent essays will be published, in print and online, in 2021. To submit an Essay please go to https://www.editorialmanager.com/THELANCETRM To submit an Essay please go to https://www.editorialmanager.com/THELANCETRM
Selective SIRPα blockade reverses tumor T cell exclusion and overcomes cancer immunotherapy resistance
Authors: Vanessa Gauttier, Sabrina Pengam, Justine Durand, Kevin Biteau, Caroline Mary, Aurore Morello, Mélanie Néel, Georgia Porto, Géraldine Teppaz, Virginie Thepenier, Richard Danger, Nicolas Vince, Emmanuelle Wilhelm, Isabelle Girault, Riad Abes, Catherine Ruiz, Charlène Trilleaud, Kerry Ralph, E. Sergio Trombetta, Alexandra Garcia, Virginie Vignard, Bernard Martinet, Alexandre Glémain, Sarah Bruneau, Fabienne Haspot, Safa Dehmani, Pierre Duplouye, Masayuki Miyasaka, Nathalie Labarrière, David Laplaud, Stéphanie Le Bas-Bernardet, Christophe Blanquart, Véronique Catros, Pierre-Antoine Gouraud, Isabelle Archambeaud, Hélène Aublé, Sylvie Metairie, Jean-François Mosnier, Dominique Costantini, Gilles Blancho, Sophie Conchon, Bernard Vanhove, Nicolas Poirier
Journal: Journal of Clinical Investigation (2020)

T cell exclusion causes resistance to cancer immunotherapies via immune checkpoint blockade (ICB). Myeloid cells contribute to resistance by expressing signal regulatory protein-α (SIRPα), an inhibitory membrane receptor that interacts with ubiquitous receptor CD47 to control macrophage phagocytosis in the tumor microenvironment. Although CD47/SIRPα-targeting drugs have been assessed in preclinical models, the therapeutic benefit of selectively blocking SIRPα, and not SIRPγ/CD47, in humans remains unknown. We report a potent synergy between selective SIRPα blockade and ICB in increasing memory T cell responses and reverting exclusion in syngeneic and orthotopic tumor models. Selective SIRPα blockade stimulated tumor nest T cell recruitment by restoring murine and human macrophage chemokine secretion and increased anti-tumor T cell responses by promoting tumor-antigen crosspresentation by dendritic cells. However, nonselective SIRPα/SIRPγ blockade targeting CD47 impaired human T cell activation, proliferation, and endothelial transmigration. Selective SIRPα inhibition opens an attractive avenue to overcoming ICB resistance in patients with elevated myeloid cell infiltration in solid tumors.
Building Trust to Achieve Confidence in COVID-19 Vaccines
Authors: Douglas J. Opel, Daniel A. Salmon, Edgar K. Marcuse
Journal: JAMA Network Open (2020)

Peter G. Szilagyi, MD, MPH; Kyla Thomas, PhD; Megha D. Shah, MD, MPH, MS; Nathalie Vizueta, PhD; Yan Cui, MD, PhD; Sitaram Vangala, MS; Arie Kapteyn, PhD
7P Comparison of the clinical utility of two different size next generation sequencing (NGS) gene panels for solid tumours
Authors: B. Özdemir, M. Charrier, C.L. Gerard, A. Wicky, M. Caikovski, M. Cuendet, T. Olivier, P. Tsantoulis, O. Michielin
Journal: Annals of Oncology (2020)
High resolution photopolymer for 3D printing of personalised microneedle for transdermal delivery of anti-wrinkle small peptide
Authors: Seng Han Lim, Himanshu Kathuria, Muhd Hafiz Bin Amir, Xiyuan Zhang, Hien T.T. Duong, Paul Chi-Lui Ho, Lifeng Kang
Journal: Journal of Controlled Release (2020)
Promiscuous Structural Variants Drive Myeloma Initiation and Progression
Authors: P. Leif Bergsagel, W. Michael Kuehl
Journal: Blood Cancer Discovery (2020)

A comprehensive genomic analysis of structural variants in multiple myeloma in this issue highlights the key role of these events, involving primarily the immunoglobulin heavy chain locus in disease initiation and the MYC locus in disease progression. However, the current study reveals the large number of genomic hotspots, oncogenes, tumor suppressor genes, and recombination mechanisms that contribute to multiple myeloma heterogeneity. See related article by Rustad et al., p. 258.
Prospects for a safe COVID-19 vaccine
Authors: Barton F. Haynes, Lawrence Corey, Prabhavathi Fernandes, Peter B. Gilbert, Peter J. Hotez, Srinivas Rao, Michael R. Santos, Hanneke Schuitemaker, Michael Watson, Ann Arvin
Journal: Science Translational Medicine (2020)

Rapid development of an efficacious vaccine against the viral pathogen severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the cause of the coronavirus disease 2019 (COVID-19) pandemic, is essential, but rigorous studies are required to determine the safety of candidate vaccines. Here, on behalf of the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) Working Group, we evaluate research on the potential risk of immune enhancement of disease by vaccines and viral infections, including coronavirus infections, together with emerging data about COVID-19 disease. Vaccine-associated enhanced disease has been rarely encountered with existing vaccines or viral infections. Although animal models of SARS-CoV-2 infection may elucidate mechanisms of immune protection, we need observations of enhanced disease in people receiving candidate COVID-19 vaccines to understand the risk of immune enhancement of disease. Neither principles of immunity nor preclinical studies provide a basis for prioritizing among the COVID-19 vaccine candidates with respect to safety at this time. Rigorous clinical trial design and postlicensure surveillance should provide a reliable strategy to identify adverse events, including the potential for enhanced severity of COVID-19 disease, after vaccination.
Radionuclide therapy using ABD-fused ADAPT scaffold protein: Proof of Principle
Authors: Javad Garousi, Emma von Witting, Jesper Borin, Anzhelika Vorobyeva, Mohamed Altai, Olga Vorontsova, Mark W. Konijnenberg, Maryam Oroujeni, Anna Orlova, Vladimir Tolmachev, Sophia Hober
Journal: Biomaterials (2020)

Molecular recognition in targeted therapeutics is typically based on immunoglobulins. Development of engineered scaffold proteins (ESPs) has provided additional opportunities for the development of targeted therapies. ESPs offer inexpensive production in prokaryotic hosts, high stability and convenient approaches to modify their biodistribution. In this study, we demonstrated successful modification of the biodistribution of an ESP known as ADAPT (Albumin-binding domain Derived Affinity ProTein). ADAPTs are selected from a library based on the scaffold of ABD (Albumin Binding Domain) of protein G. A particular ADAPT, the ADAPT6, binds to human epidermal growth factor receptor type 2 (HER2) with high affinity. Preclinical and early clinical studies have demonstrated that radiolabeled ADAPT6 can image HER2-expression in tumors with high contrast. However, its rapid glomerular filtration and high renal reabsorption have prevented its use in radionuclide therapy. To modify the biodistribution, ADAPT6 was genetically fused to an ABD. The non-covalent binding to the host's albumin resulted in a 14-fold reduction of renal uptake and appreciable increase of tumor uptake for the best variant, 177Lu-DOTA-ADAPT6-ABD035. Experimental therapy in mice bearing HER2-expressing xenografts demonstrated more than two-fold increase of median survival even after a single injection of 18 MBq 177Lu-DOTA-ADAPT6-ABD035. Thus, a fusion with ABD and optimization of the molecular design provides ADAPT derivatives with attractive targeting properties for radionuclide therapy.
Impulse Dispersion of Aerosols during Singing and Speaking: A Potential COVID-19 Transmission Pathway
Authors: Matthias Echternach, Sophia Gantner, Gregor Peters, Caroline Westphalen, Tobias Benthaus, Bernhard Jakubaß, Liudmila Kuranova, Michael Döllinger, Stefan Kniesburges
Journal: American Journal of Respiratory and Critical Care Medicine (2020)
32P High levels of stromal tumour infiltrating lymphocytes, CD3, CD8 cells and Immunoscore® are associated with pathological CR and time to progression in TNBC patients undergoing neo-adjuvant chemotherapy
Authors: B.L. Rapoport, J. Galon, S. Nayler, A. Fugon, I. Boquet, B. Mlecnik, M. Martel, C.A. Benn, T. Smit, L. Heyman, F. Moosa, R. Anderson
Journal: Annals of Oncology (2020)
Chromatin interactions in differentiating keratinocytes reveal novel atopic dermatitis– and psoriasis-associated genes
Authors: Pelin Sahlén, Rapolas Spalinskas, Samina Asad, Kunal Das Mahapatra, Pontus Höjer, Anandashankar Anil, Jesper Eisfeldt, Ankit Srivastava, Pernilla Nikamo, Anaya Mukherjee, Kyu-Han Kim, Otto Bergman, Mona Ståhle, Enikö Sonkoly, Andor Pivarcsi, Carl-Fredrik Wahlgren, Magnus Nordenskjöld, Fulya Taylan, Maria Bradley, Isabel Tapia-Páez
Journal: Journal of Allergy and Clinical Immunology (2020)

Hundreds of variants associated with atopic dermatitis (AD) and psoriasis, 2 common inflammatory skin disorders, have previously been discovered through genome-wide association studies (GWASs). The majority of these variants are in noncoding regions, and their target genes remain largely unclear.We sought to understand the effects of these noncoding variants on the development of AD and psoriasis by linking them to the genes that they regulate.We constructed genomic 3-dimensional maps of human keratinocytes during differentiation by using targeted chromosome conformation capture (Capture Hi-C) targeting more than 20,000 promoters and 214 GWAS variants and combined these data with transcriptome and epigenomic data sets. We validated our results with reporter assays, clustered regularly interspaced short palindromic repeats activation, and examination of patient gene expression from previous studies.We identified 118 target genes of 82 AD and psoriasis GWAS variants. Differential expression of 58 of the 118 target genes (49%) occurred in either AD or psoriatic lesions, many of which were not previously linked to any skin disease. We highlighted the genes AFG1L, CLINT1, ADO, LINC00302, and RP1-140J1.1 and provided further evidence for their potential roles in AD and psoriasis.Our work focused on skin barrier pathology through investigation of the interaction profile of GWAS variants during keratinocyte differentiation. We have provided a catalogue of candidate genes that could modulate the risk of AD and psoriasis. Given that only 35% of the target genes are the gene nearest to the known GWAS variants, we expect that our work will contribute to the discovery of novel pathways involved in AD and psoriasis.
Circular RNAs in renal cell carcinoma: implications for tumorigenesis, diagnosis, and therapy
Authors: Ying Wang, Yunjing Zhang, Ping Wang, Xianghui Fu, Weiqiang Lin
Journal: Molecular Cancer (2020)

Abstract Renal cell carcinoma (RCC) is the most common malignant kidney tumor and has a high incidence rate. Circular RNAs (circRNAs) are noncoding RNAs with widespread distribution and diverse cellular functions. They are highly stable and have organ- and tissue-specific expression patterns. CircRNAs have essential functions as microRNA sponges, RNA-binding protein- and transcriptional regulators, and protein translation templates. Recent reports have shown that circRNAs are abnormally expressed in RCC and act as important regulators of RCC carcinogenesis and progression. Moreover, circRNAs have emerged as potential biomarkers for RCC diagnosis and prognosis and targets for developing new treatments. However, further studies are needed to better understand the functions of circRNAs in RCC. In this review, we summarize and discuss the recent research progress on RCC-associated circRNAs, with a focus on their potential for RCC diagnosis and targeted therapy.
Analysis of 16S rRNA genes reveals reduced Fusobacterial community diversity when translocating from saliva to GI sites
Authors: Miles Richardson, Jihui Ren, Mara Roxana Rubinstein, Jamila A. Taylor, Richard A. Friedman, Bo Shen, Yiping W. Han
Journal: Gut Microbes (2020)

Fusobacterium nucleatum is a Gram-negative oral commensal anaerobe which has been increasingly implicated in various gastrointestinal (GI) disorders, including inflammatory bowel disease, appendicitis, GI cancers. The oral cavity harbors a diverse group of Fusobacterium, and it is postulated that F. nucleatum in the GI tract originate from the mouth. It is not known, however, if all oral Fusobacterium translocate to the GI sites with equal efficiencies. Therefore, we amplified 16S rRNA genes of F. nucleatum and F. periodonticum, two closely related oral species from matched saliva, gastric aspirates, and colon or ileal pouch aspirates of three patients with inflammatory bowel disease (IBD) and three healthy controls, and saliva alone from seven patients with either active IBD or IBD in remission. The 16S rRNA gene amplicons were cloned, and the DNA sequences determined by Sanger sequencing. The results demonstrate that fusobacterial community composition differs more significantly between the oral and GI sites than between different individuals. The oral communities demonstrate the highest level of variation and have the richest pool of unique sequences, with certain nodes/strains enriched in the GI tract and others diminished during translocation. The gastric and colon/pouch communities exhibit reduced diversity and are more closely related, possibly due to selective pressure in the GI tract. This study elucidates selective translocation of oral fusobacteria to the GI tract. Identification of specific transmissible clones will facilitate risk assessment for developing Fusobacterium-implicated GI disorders.
HTLV-1 targets human placental trophoblasts in seropositive pregnant women
Authors: Kenta Tezuka, Naoki Fuchi, Kazu Okuma, Takashi Tsukiyama, Shoko Miura, Yuri Hasegawa, Ai Nagata, Nahoko Komatsu, Hiroo Hasegawa, Daisuke Sasaki, Eita Sasaki, Takuo Mizukami, Madoka Kuramitsu, Sahoko Matsuoka, Katsunori Yanagihara, Kiyonori Miura, Isao Hamaguchi
Journal: Journal of Clinical Investigation (2020)

Human T cell leukemia virus type 1 (HTLV-1) is mainly transmitted vertically through breast milk. The rate of mother-to-child transmission (MTCT) through formula feeding, although significantly lower than through breastfeeding, is approximately 2.4%–3.6%, suggesting the possibility of alternative transmission routes. MTCT of HTLV-1 might occur through the uterus, birth canal, or placental tissues; the latter is known as transplacental transmission. Here, we found that HTLV-1 proviral DNA was present in the placental villous tissues of the fetuses of nearly half of pregnant carriers and in a small number of cord blood samples. An RNA ISH assay showed that HTLV-1–expressing cells were present in nearly all subjects with HTLV-1–positive placental villous tissues, and their frequency was significantly higher in subjects with HTLV-1–positive cord blood samples. Furthermore, placental villous trophoblasts expressed HTLV-1 receptors and showed increased susceptibility to HTLV-1 infection. In addition, HTLV-1–infected trophoblasts expressed high levels of viral antigens and promoted the de novo infection of target T cells in a humanized mouse model. In summary, during pregnancy of HTLV-1 carriers, HTLV-1 was highly expressed in placental villous tissues, and villous trophoblasts showed high HTLV-1 sensitivity, suggesting that MTCT of HTLV-1 occurs through the placenta.
Leveraging the Capabilities of the FDA’s Sentinel System To Improve Kidney Care
Authors: Sruthi Adimadhyam, Erin F. Barreto, Noelle M. Cocoros, Sengwee Toh, Jeffrey S. Brown, Judith C. Maro, Jacqueline Corrigan-Curay, Gerald J. Dal Pan, Robert Ball, David Martin, Michael Nguyen, Richard Platt, Xiaojuan Li
Journal: Journal of the American Society of Nephrology (2020)

The Sentinel System is a national electronic postmarketing resource established by the US Food and Drug Administration to support assessment of the safety and effectiveness of marketed medical products. It has built a large, multi-institutional, distributed data network that contains comprehensive electronic health data, covering about 700 million person-years of longitudinal observation time nationwide. With its sophisticated infrastructure and a large selection of flexible analytic tools, the Sentinel System permits rapid and secure analyses, while preserving patient privacy and health-system autonomy. The Sentinel System also offers enhanced capabilities, including accessing full-text medical records, supporting randomized clinical trials embedded in healthcare delivery systems, and facilitating effective collection of patient-reported data using mobile devices, among many other research programs. The nephrology research community can use the infrastructure, tools, and data that this national resource offers for evidence generation. This review summarizes the Sentinel System and its ability to rapidly generate high-quality, real-world evidence; discusses the program’s experience in, and potential for, addressing gaps in kidney care; and outlines avenues for conducting research, leveraging this national resource in collaboration with Sentinel investigators.
LRRK2 mediates microglial neurotoxicity via NFATc2 in rodent models of synucleinopathies
Authors: Changyoun Kim, Alexandria Beilina, Nathan Smith, Yan Li, Minhyung Kim, Ravindran Kumaran, Alice Kaganovich, Adamantios Mamais, Anthony Adame, Michiyo Iba, Somin Kwon, Won-Jae Lee, Soo-Jean Shin, Robert A. Rissman, Sungyong You, Seung-Jae Lee, Andrew B. Singleton, Mark R. Cookson, Eliezer Masliah
Journal: Science Translational Medicine (2020)

LRRK2 modulates nucleus translocation of NFATc2 in microglia.
Asthma Exacerbations in Patients with Type 2 Diabetes and Asthma on Glucagon-like Peptide-1 Receptor Agonists
Authors: Dinah Foer, Patrick E. Beeler, Jing Cui, Elizabeth W. Karlson, David W. Bates, Katherine N. Cahill
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

GLP-1R (glucagon-like peptide-1 receptor) agonists are approved to treat type 2 diabetes mellitus and obesity. GLP-1R agonists reduce airway inflammation and hyperresponsiveness in preclinical models.
Answering Key Questions About COVID-19 Vaccines
Authors: Jesse L. Goodman, John D. Grabenstein, M. Miles Braun
Journal: JAMA (2020)

Answering Key Questions About COVID-19 VaccinesThe US government is investing in rapid development of vaccinesagainstcoronavirusdisease2019(COVID-19),several relying on new technologies. 1In the US, 4 vaccine candidates are in phase 3 studies with initial results expected soon.If studies succeed, 1 or more vaccines may become available within a few months.Clinicians are likely among the first to be offered COVID-19 vaccines and have a key role in helping patients make decisions about vaccination. 2Providing evidence-based information will be particularly important in an environment of polarization and mistrust.This Viewpoint focuses on common questions patients are likely to ask about COVID-19 vaccines.