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3. Inherited and acquired errors of type I interferon immunity govern susceptibility to COVID-19 and multisystem inflammatory syndrome in children

Author

Giorgia Bucciol, Isabelle Meyts, Laurent Abel, Salah Al-Muhsen, Alessandro Aiuti, Fahd Al-Mulla, Evangelos Andreakos, Novelli Antonio, Andrés A. Arias, Sophie Trouillet-Assant, Alexandre Belot, Catherine M. Biggs, Ahmed A. Bousfiha, Alex Bolze, Alessandro Borghesi, Petter Brodin, John Christodoulou, Aurélie Cobat, Antonio Condino-Neto, Stefan Constantinescu, Clifton L. Dalgard, Sara Espinosa-Padilla, Jacques Fellay, Carlos Flores, José Luis Franco, Antoine Froidure, Guy Gorochov, Filomeen Haerynck, Rabih Halwani, Elena W.Y. Hsieh, Yuval Itan, Kai Kisand, Yu-Lung Lau, Davood Mansouri, Trine H. Mogensen, Lisa F.P. Ng, Luigi D. Notarangelo, Giuseppe Novelli, Satoshi Okada, Tayfun Ozcelik, Rebeca Perez de Diego, Carolina Prando, Aurora Pujol, Lluis Quintana-Murci, Laurent Renia, Igor Resnick, Lucie Roussel, Carlos Rodríguez-Gallego, Vanessa Sancho-Shimizu, Mohammed Shahrooei, Pere Soler-Palacín, András N. Spaan, Ivan Tancevski, Stuart G. Tangye, Ahmad Abou Tayoun, Şehime Gülsün Temel, Pierre Tiberghien, Jordi Perez Tur, Stuart E. Turvey, Furkan Uddin, Mohammed J. Uddin, Mateus Vidigal, Donald C. Vinh, Mayana Zatz, Keisuke Okamoto, David S. Perlin, Graziano Pesole, Christian Thorball, Diederik van de Beek, Roger Colobran, Joost Wauters, Shen-Ying Zhang, Qian Zhang, Helen C. Su, and Jean-Laurent Casanova

Subjects
Settore MED/03, SARS-CoV-2, Immunology, Immunology and Allergy, COVID-19, type I interferon, multisystem inflammatory syndrome in children
Abstract

Since the beginning of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)/coronavirus disease 2019 (COVID-19) pandemic, global sequencing efforts have led in the field of inborn errors of immunity, and inspired particularly by previous research on life-threatening influenza, they have revealed that known and novel inborn errors affecting type I interferon immunity underlie critical COVID-19 in up to 5% of cases. In addition, neutralizing autoantibodies against type I interferons have been identified in up to 20% of patients with critical COVID-19 who are older than 80 years and 20% of fatal cases, with a higher prevalence in men and individuals older than 70 years. Also, inborn errors impairing regulation of type I interferon responses and RNA degradation have been found as causes of multisystem inflammatory syndrome in children, a life-threatening hyperinflammatory condition complicating otherwise mild initial SARS-CoV-2 infection in children and young adults. Better understanding of these immunologic mechanisms can aid in designing treatments for severe COVID-19, multisystem inflammatory syndrome in children, long COVID, and neuro-COVID.

Published
2023

4. CCNE1 and survival of patients with tubo-ovarian high-grade serous carcinoma

Author

Eun-Young, Kang, Ashley, Weir, Nicola S, Meagher, Kyo, Farrington, Gregg S, Nelson, Prafull, Ghatage, Cheng-Han, Lee, Marjorie J, Riggan, Adelyn, Bolithon, Gordana, Popovic, Betty, Leung, Katrina, Tang, Neil, Lambie, Joshua, Millstein, Jennifer, Alsop, Michael S, Anglesio, Beyhan, Ataseven, Ellen, Barlow, Matthias W, Beckmann, Jessica, Berger, Christiani, Bisinotto, Hans, Bösmüller, Jessica, Boros, Alison H, Brand, Angela, Brooks-Wilson, Sara Y, Brucker, Michael E, Carney, Yovanni, Casablanca, Alicia, Cazorla-Jiménez, Paul A, Cohen, Thomas P, Conrads, Linda S, Cook, Penny, Coulson, Madeleine, Courtney-Brooks, Daniel W, Cramer, Philip, Crowe, Julie M, Cunningham, Cezary, Cybulski, Kathleen M, Darcy, Mona A, El-Bahrawy, Esther, Elishaev, Ramona, Erber, Rhonda, Farrell, Sian, Fereday, Anna, Fischer, María J, García, Simon A, Gayther, Aleksandra, Gentry-Maharaj, C Blake, Gilks, Marcel, Grube, Paul R, Harnett, Shariska Petersen, Harrington, Philipp, Harter, Arndt, Hartmann, Jonathan L, Hecht, Sebastian, Heikaus, Alexander, Hein, Florian, Heitz, Joy, Hendley, Brenda Y, Hernandez, Susanna Hernando, Polo, Sabine, Heublein, Akira, Hirasawa, Estrid, Høgdall, Claus K, Høgdall, Hugo M, Horlings, David G, Huntsman, Tomasz, Huzarski, Andrea, Jewell, Mercedes, Jimenez-Linan, Michael E, Jones, Scott H, Kaufmann, Catherine J, Kennedy, Dineo, Khabele, Felix K F, Kommoss, Roy F P M, Kruitwagen, Diether, Lambrechts, Nhu D, Le, Marcin, Lener, Jenny, Lester, Yee, Leung, Anna, Linder, Liselore, Loverix, Jan, Lubiński, Rashna, Madan, G Larry, Maxwell, Francesmary, Modugno, Susan L, Neuhausen, Alexander, Olawaiye, Siel, Olbrecht, Sandra, Orsulic, José, Palacios, Celeste Leigh, Pearce, Malcolm C, Pike, Carmel M, Quinn, Ganendra Raj, Mohan, Cristina, Rodríguez-Antona, Matthias, Ruebner, Andy, Ryan, Stuart G, Salfinger, Naoko, Sasamoto, Joellen M, Schildkraut, Minouk J, Schoemaker, Mitul, Shah, Raghwa, Sharma, Yurii B, Shvetsov, Naveena, Singh, Gabe S, Sonke, Linda, Steele, Colin J R, Stewart, Karin, Sundfeldt, Anthony J, Swerdlow, Aline, Talhouk, Adeline, Tan, Sarah E, Taylor, Kathryn L, Terry, Aleksandra, Tołoczko, Nadia, Traficante, Koen K, Van de Vijver, Maaike A, van der Aa, Toon, Van Gorp, Els, Van Nieuwenhuysen, Lilian, van-Wagensveld, Ignace, Vergote, Robert A, Vierkant, Chen, Wang, Lynne R, Wilkens, Stacey J, Winham, Anna H, Wu, Javier, Benitez, Andrew, Berchuck, Francisco J, Candido Dos Reis, Anna, DeFazio, Peter A, Fasching, Ellen L, Goode, Marc T, Goodman, Jacek, Gronwald, Beth Y, Karlan, Stefan, Kommoss, Usha, Menon, Hans-Peter, Sinn, Annette, Staebler, James D, Brenton, David D, Bowtell, Paul D P, Pharoah, Susan J, Ramus, Martin, Köbel, MUMC+: MA Obstetrie Gynaecologie (3), MUMC+: Vrouw Moeder en Kind Centrum (3), Obstetrie & Gynaecologie, MUMC+: MA Arts Assistenten Obstetrie Gynaecologie (6), RS: GROW - R2 - Basic and Translational Cancer Biology, and AOCS Group

Subjects
Cancer Research, ovarian cancer, Oncology, high-grade serous carcinoma, Human medicine, prognosis, CCNE1 amplification, cyclin E1 expression
Abstract

BACKGROUND: Cyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo-ovarian high-grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large-scale, histotype-specific validation has been performed. The hypothesis was that high-level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC. METHODS: Within the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated. RESULTS: High-level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high-level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08-1.47, p = .034, and HR, 1.18; 95% CI, 1.05-1.32, p = .015, respectively). This was also true for cases with combined high-level amplification/overexpression (HR, 1.26; 95% CI, 1.09-1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1-SD increase; 95% CI, 0.94-1.06; p = .58). CCNE1 high-level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss. CONCLUSION: This study provides large-scale validation that CCNE1 high-level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC. ispartof: CANCER vol:129 issue:5 pages:697-713 ispartof: location:United States status: published

Published
2023

6. Association Between Oral Bacteria and Alzheimer’s Disease: A Systematic Review and Meta-Analysis

Author

Sixin Liu, Stuart G. Dashper, and Rui Zhao

Subjects
Psychiatry and Mental health, Clinical Psychology, General Neuroscience, General Medicine, Geriatrics and Gerontology
Abstract

Background: Pre-clinical evidence implicates oral bacteria in the pathogenesis of Alzheimer’s disease (AD), while clinical studies show diverse results. Objective: To comprehensively assess the association between oral bacteria and AD with clinical evidence. Methods: Studies investigating the association between oral bacteria and AD were identified through a systematic search of six databases PubMed, Embase, Cochrane Central Library, Scopus, ScienceDirect, and Web of Science. Methodological quality ratings of the included studies were performed. A best evidence synthesis was employed to integrate the results. When applicable, a meta-analysis was conducted using a random-effect model. Results: Of the 16 studies included, ten investigated periodontal pathobionts and six were microbiome-wide association studies. Samples from the brain, serum, and oral cavity were tested. We found over a ten-fold and six-fold increased risk of AD when there were oral bacteria (OR = 10.68 95% CI: 4.48–25.43; p

Published
2023

8. An analysis of published trials found that current use of pragmatic trial labels is uninformative

Author

Monica Taljaard, Stuart G. Nicholls, Alison H. Howie, Hayden P. Nix, Kelly Carroll, Paxton M. Moon, Natalie M. Nightingale, Bruno Giraudeau, Spencer P. Hey, Sandra M. Eldridge, Charles Weijer, and Merrick Zwarenstein

Subjects
Epidemiology
Abstract

Randomized trials labelled as "pragmatic" are attractive to funders, patients, and clinicians as the label implies that the results are directly applicable to clinical care. We examined how authors justify use of the label (e.g., by referring to one or more PRECIS [PRagmatic Explanatory Continuum Indicator Summary]-2 domains).We reviewed primary trial reports published 2014-2019, registered in ClinicalTrials.gov and using the pragmatic label anywhere in the report.Among 415 trials, the label was justified by reference to at least one design element in 282 (68.0%); of these, 240 (85.1%) referenced trial characteristics that can be mapped to one or more of the PRECIS-2 domains, most commonly eligibility (91, 32.3%), setting (90, 31.9%), flexibility delivery (89, 31.6%), and organization (75, 26.6%); 42 (14.9%) referenced characteristics that are not PRECIS-2 domains, most commonly type of intervention/comparator (48, 17%), recruitment without consent (22, 7.8%), routinely collected data (22, 7.8%), and cluster randomization (20, 7.1%). Most reports referenced only one or two design elements. Overall, 9/415 (2.2%) provided PRECIS wheels.Current use of pragmatic labels is uninformative. Authors should clarify the decision the trial is intended to support and include a PRECIS-2 table to make the design transparent.

Published
2022

11. The 2022 Update of IUIS Phenotypical Classification for Human Inborn Errors of Immunity

Author

Aziz Bousfiha, Abderrahmane Moundir, Stuart G. Tangye, Capucine Picard, Leïla Jeddane, Waleed Al-Herz, Charlotte C. Rundles, Jose Luis Franco, Steven M. Holland, Christoph Klein, Tomohiro Morio, Eric Oksenhendler, Anne Puel, Jennifer Puck, Mikko R. J. Seppänen, Raz Somech, Helen C. Su, Kathleen E. Sullivan, Troy R. Torgerson, and Isabelle Meyts

Subjects
Phenotype, Genotype, Neoplasms, Immunology, Immunologic Deficiency Syndromes, Hypersensitivity, Humans, Immunology and Allergy
Abstract

The International Union of Immunological Societies (IUIS) expert committee (EC) on Inborn Errors of Immunity (IEI) reports here the 2022 updated phenotypic classification, which accompanies and complements the most-recent genotypic classification. This phenotypic classification is aimed for clinicians at the bedside and focuses on clinical features and laboratory phenotypes of specific IEI. In this classification, 485 IEI underlying phenotypes as diverse as infection, malignancy, allergy, auto-immunity and auto-inflammation are described, including 55 novel monogenic defects and 1 autoimmune phenocopy. Therefore, all 485 diseases of the genetic classification are presented in this paper in the form of colored tables with essential clinical or immunological phenotype entries.

Published
2022

12. STAT5B restrains human B-cell differentiation to maintain humoral immune homeostasis

Author

Simon J. Pelham, Maria Soledad Caldirola, Danielle T. Avery, Joseph Mackie, Geetha Rao, Florian Gothe, Timothy J. Peters, Antoine Guerin, David Neumann, Doris Vokurkova, Vivian Hwa, Wenming Zhang, Shu-Chen Lyu, Iris Chang, Monali Manohar, Kari C. Nadeau, Maria Isabel Gaillard, Liliana Bezrodnik, Violeta Iotova, Norberto Walter Zwirner, Mavel Gutierrez, Waleed Al-Herz, Christopher C. Goodnow, Alexander Vargas-Hernández, Lisa R. Forbes Satter, Sophie Hambleton, Elissa K. Deenick, Cindy S. Ma, and Stuart G. Tangye

Subjects
Immunoglobulin Isotypes, Immunology, STAT5 Transcription Factor, Cytokines, Homeostasis, Humans, RNA, Immunology and Allergy, Cell Differentiation
Abstract

Lymphocyte differentiation is regulated by coordinated actions of cytokines and signaling pathways. IL-21 activates STAT1, STAT3, and STAT5 and is fundamental for the differentiation of human B cells into memory cells and antibody-secreting cells. While STAT1 is largely nonessential and STAT3 is critical for this process, the role of STAT5 is unknown.This study sought to delineate unique roles of STAT5 in activation and differentiation of human naive and memory B cells.STAT activation was assessed by phospho-flow cytometry cell sorting. Differential gene expression was determined by RNA-sequencing and quantitative PCR. The requirement for STAT5B in B-cell and CD4IL-21 activated STAT5 and strongly induced SOCS3 in human naive, but not memory, B cells. Deletion of STAT5B in B-cell lines diminished IL-21-mediated SOCS3 induction. PBMCs from STAT5B-null individuals contained expanded populations of immunoglobulin class-switched B cells, CD21These findings reveal novel roles for STAT5B in regulating IL-21-induced human B-cell differentiation. This is achieved by inducing SOCS3 to attenuate IL-21 signaling, and BCL6 to repress class switching and plasma cell generation. Thus, STAT5B is critical for restraining IL-21-mediated B-cell differentiation. These findings provide insights into mechanisms underpinning B-cell responses during primary and subsequent antigen encounter and explain autoimmunity and dysfunctional humoral immunity in STAT5B deficiency.

Published
2022

13. Coastal aeolian sediment transport in an active bed surface layer: Tracer study and conceptual model

Author

Charlotte F. K. Uphues, Christa O. van IJzendoorn, Caroline Hallin, Stuart G. Pearson, Bram C. van Prooijen, Graziela Miot da Silva, and Sierd de Vries

Subjects
field measurements, Geography, Planning and Development, armoring, sediment sorting, supply limited, Earth and Planetary Sciences (miscellaneous), beach, aeolian ripples, particle tracing, Earth-Surface Processes
Abstract

Coastal aeolian sediment transport is influenced by supply-limiting factors caused by sediment sorting by grain size. Sorting processes can lead to coarsening of the bed surface and influence the formation of aeolian ripples. However, the influence sorting processes and bedforms might have on the magnitude of the transport is not fully understood. This study explores sorting processes and their influence on the magnitude and mode of aeolian transport by using sediment tracers. Sand was painted in different colors according to particle size and placed on a supratidal beach in Noordwijk, the Netherlands. Several experiments were conducted with varying wind speeds. Surface sampling and cameras tracked the sand color movement on the bed surface, and wind velocity was measured. The tracer experiments showed that ripples developed in moderate wind conditions. Once the ripples had formed, the supply of finer tracer grains in the downwind direction decreased over time, while the supply of coarser grains remained constant. A linear relationship between ripple migration speed and wind speed was found. For higher wind speeds, no ripples or differences in transport of grain size fractions were observed. Instead, alternating phases of erosion and deposition of the bed surface were observed, which could not be related to local variations in wind velocity. Based on these results and literature, a conceptual model was developed for an active bed surface layer with two transport regimes corresponding to moderate (I) and high (II) wind speeds. The conceptual model is intended to guide the selection of aeolian sediment transport models as a function of wind speed, bed characteristics, and upwind sediment supply. For Regime I, transport could be modeled using a linear relationship between sediment transport and wind speed and for Regime II using a third power relationship in combination with a process-based model accounting for supply limitations.

Published
2022

14. Variants in mitochondrial amidoxime reducing component 1 and hydroxysteroid 17-beta dehydrogenase 13 reduce severity of nonalcoholic fatty liver disease in children and suppress fibrotic pathways through distinct mechanisms

Author

Christian A, Hudert, Leon A, Adams, Anna, Alisi, Quentin M, Anstee, Annalisa, Crudele, Laura G, Draijer, Samuel, Furse, Jan G, Hengstler, Benjamin, Jenkins, Kylie, Karnebeek, Deirdre A, Kelly, Bart G, Koot, Albert, Koulman, David, Meierhofer, Phillip E, Melton, Trevor A, Mori, Stuart G, Snowden, Indra, van Mourik, Anita, Vreugdenhil, Susanna, Wiegand, Jake P, Mann, MUMC+: MA Arts Assistenten Kindergeneeskunde (9), RS: NUTRIM - R2 - Liver and digestive health, Kindergeneeskunde, MUMC+: MA Medische Staf Kindergeneeskunde (9), RS: NUTRIM - R1 - Obesity, diabetes and cardiovascular health, Graduate School, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, ARD - Amsterdam Reproduction and Development, Paediatric Gastroenterology, and Pediatrics

Subjects
17-Hydroxysteroid Dehydrogenases, Hepatology, MARC1, Mitochondrial Proteins, INFLAMMATION, Non-alcoholic Fatty Liver Disease, NAFLD, Oximes, Humans, WIDE ASSOCIATION, Child, Oxidoreductases, PROTEIN STABILITY, CONFERS SUSCEPTIBILITY, Hydroxysteroids, PNPLA3, SYSTEM, Genome-Wide Association Study
Abstract

Genome-wide association studies in adults have identified variants in hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) and mitochondrial amidoxime reducing component 1 (MTARC1) as protective against nonalcoholic fatty liver disease (NAFLD). We aimed to test their association with pediatric NAFLD liver histology and investigate their function using metabolomics. A total of 1450 children (729 with NAFLD, 399 with liver histology) were genotyped for rs72613567T>TA in HSD17B13, rs2642438G>A in MTARC1, and rs738409C>G in patatin-like phospholipase domain-containing protein 3 (PNPLA3). Genotype-histology associations were tested using ordinal regression. Untargeted hepatic proteomics and plasma lipidomics were performed in a subset of children. We found rs72613567T>TA in HSD17B13 to be associated with lower odds of NAFLD diagnosis (odds ratio, 0.7; 95% confidence interval, 0.6-0.9) and a lower grade of portal inflammation (p < 0.001). rs2642438G>A in MTARC1 was associated with a lower grade of hepatic steatosis (p = 0.02). Proteomics found reduced expression of HSD17B13 in carriers of the protective -TA allele. MTARC1 levels were unaffected by genotype. Both variants were associated with down-regulation of fibrogenic pathways. HSD17B13 perturbs plasma phosphatidylcholines and triglycerides. In silico modeling suggested p.Ala165Thr disrupts the stability and metal binding of MTARC1. Conclusion: Both HSD17B13 and MTARC1 variants are associated with less severe pediatric NAFLD. These results provide further evidence for shared genetic mechanisms between pediatric and adult NAFLD.

Published
2022

15. Novel Metabolomic Approach for Identifying Pathology-Specific Biomarkers in Rare Diseases: A Case Study in Oculopharyngeal Muscular Dystrophy (OPMD)

Author

Snowden, Pradeep Harish, Alberto Malerba, Rosemarie H. M. J. M. Kroon, Milad Shademan, Baziel van Engelan, Vered Raz, Linda Popplewell, and Stuart G.

Subjects
biomarker, metabolomics, LC-MS, random forest, oculopharyngeal muscular dystrophy
Abstract

The identification of metabolomic biomarkers relies on the analysis of large cohorts of patients compared to healthy controls followed by the validation of markers in an independent sample set. Indeed, circulating biomarkers should be causally linked to pathology to ensure that changes in the marker precede changes in the disease. However, this approach becomes unfeasible in rare diseases due to the paucity of samples, necessitating the development of new methods for biomarker identification. The present study describes a novel approach that combines samples from both mouse models and human patients to identify biomarkers of OPMD. We initially identified a pathology-specific metabolic fingerprint in murine dystrophic muscle. This metabolic fingerprint was then translated into (paired) murine serum samples and then to human plasma samples. This study identified a panel of nine candidate biomarkers that could predict muscle pathology with a sensitivity of 74.3% and specificity of 100% in a random forest model. These findings demonstrate that the proposed approach can identify biomarkers with good predictive performance and a higher degree of confidence in their relevance to pathology than markers identified in a small cohort of human samples alone. Therefore, this approach has a high potential utility for identifying circulating biomarkers in rare diseases.

Published
2023
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17. Random number generation using spontaneous symmetry breaking in a Kerr resonator

Author

Quinn, Liam, Xu, Gang, Xu, Yiqing, Li, Zongda, Fatome, Julien, Murdoch, Stuart G., Coen, Stéphane, and Erkintalo, Miro

Subjects
FOS: Physical sciences, Optics (physics.optics), Physics - Optics
Abstract

We experimentally demonstrate an all-optical random number generator based on spontaneous symmetry breaking in a coherently-driven Kerr resonator. Random bit sequences are generated by repeatedly tuning a control parameter across a symmetry-breaking bifurcation that enacts random selection between two possible steady-states of the system. Experiments are performed in a fibre ring resonator, where the two symmetry-broken steady-states are associated with orthogonal polarization modes. Detrimental biases due to system asymmetries are completely suppressed by leveraging a recently-discovered self-symmetrization phenomenon that ensures the symmetry breaking acts as an unbiased coin toss, with a genuinely random selection between the two available steady-states. We optically generate bits at a rate of over 3~MHz without post-processing and verify their randomness using the National Institute of Standards and Technology and Dieharder statistical test suites., 5 pages, 4 figures

Published
2023

18. Virus taxonomy and the role of the International Committee on Taxonomy of Viruses (ICTV)

Author

Siddell, Stuart G., Smith, Donald B., Adriaenssens, Evelien M., Alfenas-Zerbini, Poliane, Dutilh, Bas E., Garcia, Maria Laura, Junglen, Sandra, Krupovic, Mart, Kuhn, Jens H., Lambert, Amy J., Lefkowitz, Elliot J., Lobocka, Malgorzata, Mushegian, Arcady R, Oksanen, Hanna M, Robertson, David L, Rubino, Luisa, Sabanadzovic, Sead, Simmonds, Peter, Suzuki, Nobuhiro, Van Doorslaer, Koenraad, Vandamme, A. -M., Varsani, Arvind, Zerbini, Francisco Murilo, Molecular and Integrative Biosciences Research Programme, and Molecular Principles of Viruses

Subjects
11832 Microbiology and virology, Virus taxonomy, International Committee of Virus Taxonomy
Published
2023

19. Virus taxonomy and the role of the International Committee on Taxonomy of Viruses (ICTV)

Author

Siddell, Stuart G., Smith, Donald B., Adriaenssens, Evelien, Alfenas-Zerbini, Poliane, Dutilh, Bas E., Garcia, Maria Laura, Junglen, Sandra, Krupovic, Mart, Kuhn, Jens H., Lambert, Amy J., Lefkowitz, Elliot J., Łobocka, Małgorzata, Mushegian, Arcady R., Oksanen, Hanna M., Robertson, David L., Rubino, Luisa, Sabanadzovic, Sead, Simmonds, Peter, Suzuki, Nobuhiro, Van Doorslaer, Koenraad, Vandamme, Anne-Mieke, Varsani, Arvind, Zerbini, F. Murilo, University of Bristol [Bristol], University of Oxford, Quadram Institute, Biotechnology and Biological Sciences Research Council (BBSRC), Universidade Federal de Viçosa = Federal University of Viçosa (UFV), Friedrich-Schiller-Universität = Friedrich Schiller University Jena [Jena, Germany], Utrecht University [Utrecht], Instituto de Biotecnología y Biología Molecular [La Plata] (IBBM), Consejo Nacional de Investigaciones Científicas y Técnicas [Buenos Aires] (CONICET)-Facultad de Ciencias Exactas [La Plata], Universidad Nacional de la Plata [Argentine] (UNLP)-Universidad Nacional de la Plata [Argentine] (UNLP), Free University of Berlin (FU), Virologie des archées - Archaeal Virology, Université Paris Cité (UPCité)-Microbiologie Intégrative et Moléculaire (UMR6047), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Integrated Research Facility at Fort Detrick (IRF-Frederick), National Institute of Allergy and Infectious Diseases [Bethesda] (NIAID-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), National Center for Emerging and Zoonotic Infectious Diseases (NCEZID), Centers for Disease Control and Prevention (CDC), University of Alabama at Birmingham [ Birmingham] (UAB), Institute of Biochemistry and Biophysics [Warsaw] (IBB), National Science Foundation [Arlington] (NSF), Helsingin yliopisto = Helsingfors universitet = University of Helsinki, MRC - University of Glasgow Centre for Virus Research, CNR Istituto per la Protezione Sostenibile delle Piante [Torino, Italia] (IPSP), National Research Council of Italy | Consiglio Nazionale delle Ricerche (CNR), Mississippi State University [Mississippi], Okayama University, University of Arizona, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Universidade Nova de Lisboa = NOVA University Lisbon (NOVA), Arizona State University [Tempe] (ASU), D.B.S. is supported by a grant from the Microbiology Society. B.E.D. is supported by the European Research Council (ERC) Consolidator grant 865694: DiversiPHI, the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany ́s Excellence Strategy – EXC 2051 – Project-ID 390713860, the Alexander von Humboldt Foundation in the context of an Alexander von Humboldt-Professorship founded by German Federal Ministry of Education and Research, and the European Union’s Horizon 2020 research and innovation programme, under the Marie Skłodowska-Curie Actions Innovative Training Networks grant agreement no. 955 974 (VIROINF). E.J.L. – this publication was supported by the National Institutes of Health (NIH) National Institute of Allergy And Infectious Diseases (NIAID), under Award Number U24AI162625. This work was also supported in part through the Laulima Government Solutions, LLC, prime contract with the NIH NIAID, under Contract No. HHSN272201800013C. J.H.K. performed this work as an employee of Tunnell Government Services (TGS), a subcontractor of Laulima Government Solutions, LLC, under Contract No. HHSN272201800013C. A.R.M. is a Program Director at the U.S. National Science Foundation (NSF), the statements and opinions expressed herein are made in a personal capacity and do not constitute endorsement by NSF or the government of the United States. H.M.O. was supported by the University of Helsinki and Academy of Finland funding for FINStruct, part of Biocenter Finland and Instruct-ERIC. D.L.R. is funded by the MRC (MC_UU_12014/12). S.S. acknowledges support from the Mississippi Agricultural and Forestry Experiment Station (MAFES), USDA-ARS project 58-6066-9-033 and the National Institute of Food and Agriculture, US Department of Agriculture, Hatch Project, under Accession Number 1021 494., European Project: 865694,H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC),DiversiPHI(2020), Instituto de Higiene e Medicina Tropical (IHMT), Global Health and Tropical Medicine (GHTM), and TB, HIV and opportunistic diseases and pathogens (THOP)

Subjects
ICTV, Infectious Diseases, Science & Technology, SDG 3 - Good Health and Well-being, Biotechnology & Applied Microbiology, Virology, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, virus nomenclature, virus taxonomy, virus classification, QR355 Virology, Life Sciences & Biomedicine, International Committee on Taxonomy of Viruses
Abstract

The taxonomy of viruses is developed and overseen by the International Committee on Taxonomy of Viruses (ICTV), which scrutinizes, approves and ratifies taxonomic proposals, and maintains a list of virus taxa with approved names (https://ictv.global). The ICTV has approximately 180 members who vote by simple majority. Taxon-specific Study Groups established by the ICTV have a combined membership of over 600 scientists from the wider virology community; they provide comprehensive expertise across the range of known viruses and are major contributors to the creation and evaluation of taxonomic proposals. Proposals can be submitted by anyone and will be considered by the ICTV irrespective of Study Group support. Thus, virus taxonomy is developed from within the virology community and realized by a democratic decision-making process. The ICTV upholds the distinction between a virus or replicating genetic element as a physical entity and the taxon category to which it is assigned. This is reflected by the nomenclature of the virus species taxon, which is now mandated by the ICTV to be in a binomial format (genus + species epithet) and is typographically distinct from the names of viruses. Classification of viruses below the rank of species (such as, genotypes or strains) is not within the remit of the ICTV. This article, authored by the ICTV Executive Committee, explains the principles of virus taxonomy and the organization, function, processes and resources of the ICTV, with the aim of encouraging greater understanding and interaction among the wider virology community.

Published
2023

22. Humans with inherited MyD88 and IRAK-4 deficiencies are predisposed to hypoxemic COVID-19 pneumonia

Author

García-García, Ana, Pérez de Diego, Rebeca, Flores, Carlos, Rinchai, Darawan, Solé-Violán, Jordi, Deyà-Martínez, Àngela, García-Solis, Blanca, Lorenzo-Salazar, José M., Hernández-Brito, Elisa, Lanz, Anna-Lisa, Moens, Leen, Bucciol, Giorgia, Almuqamam, Mohamed, Domachowske, Joseph B., Colino, Elena, Santos-Perez, Juan Luis, Marco, Francisco M., Pignata, Claudio, Bousfiha, Aziz, Turvey, Stuart E., Bauer, Stefanie, Haerynck, Filomeen, Ocejo-Vinyals, Javier Gonzalo, Lendinez, Francisco, Prader, Seraina, Naumann-Bartsch, Nora, Pachlopnik Schmid, Jana, Biggs, Catherine M., Hildebrand, Kyla, Dreesman, Alexandra, Cárdenes, Miguel Ángel, Ailal, Fatima, Benhsaien, Ibtihal, Giardino, Giuliana, Molina-Fuentes, Agueda, Fortuny, Claudia, Madhavarapu, Swetha, Conway, Daniel H., Prando, Carolina, Schidlowski, Laire, Martínez de Saavedra Álvarez, María Teresa, Alfaro, Rafael, Rodríguez de Castro, Felipe, Kindle, Gerhard, Mahlaoui, Nizar, Seidel, Markus G., Vassilios, Lougaris, Seppänen, Mikko R.J., Abel, Laurent, Aiuti, Alessandro, Al-Muhsen, Saleh, Al-Mulla, Fahd, Anderson, Mark S., Andreakos, Evangelos, Arias, Andrés A., Baris Feldman, Hagit, Belot, Alexandre, Bogunovic, Dusan, Bolze, Alexandre, Bondarenko, Anastasiia, Bousfiha, Ahmed A., Brodin, Petter, Bryceson, Yenan, Bustamante, Carlos D., Butte, Manish J., Casari, Giorgio, Christodoulou, John, Condino-Neto, Antonio, Constantinescu, Stefan N., Cooper, Megan A., Dalgard, Clifton L., Desai, Murkesh, Drolet, Beth A., El Baghdadi, Jamila, Espinosa-Padilla, Sara, Fellay, Jacques, Franco, José Luis, Froidure, Antoine, Gregersen, Peter K., Grimbacher, Bodo, Hagin, David, Halwani, Rabih, Hammarström, Lennart, Heath, James R., Henrickson, Sarah E., Hsieh, Elena W.Y., Husebye, Eystein, Imai, Kohsuke, Itan, Yuval, Jarvis, Erich D., Karamitros, Timokratis, Kisand, Kai, Ku, Cheng-Lung, Lau, Yu-Lung, Ling, Yun, Lucas, Carrie L., Maniatis, Tom, Mansouri, Davood, Meyts, Isabelle, Milner, Joshua D., Mironska, Kristina, Mogensen, Trine H., Morio, Tomohiro, Ng, Lisa F.P., Notarangelo, Luigi D., Novelli, Antonio, Novelli, Giuseppe, O’Farrelly, Cliona, Okada, Satoshi, Okamoto, Keisuke, Ozcelik, Tayfun, Pan-Hammarström, Qiang, Pape, Jean W., Perez de Diego, Rebecca, Perlin, David S., Pesole, Graziano, Planas, Anna M., Pujol, Aurora, Quintana-Murci, Lluis, Ramaswamy, Sathishkumar, Renia, Laurent, Resnick, Igor, Rodríguez-Gallego, Carlos, Sancho-Shimizu, Vanessa, Sediva, Anna, Seppänan, Mikko R.J., Shahrooei, Mohammed, Shcherbina, Anna, Slaby, Ondrej, Snow, Andrew L., Soler-Palacín, Pere, Spaan, András N., Tancevski, Ivan, Tangye, Stuart G., Tayoun, Ahmad Abou, Uddin, K M Furkan, Uddin, Mohammed J., van de Beek, Diederik, Vinh, Donald C., von Bernuth, Horst, Wauters, Joost, Zatz, Mayana, Zawadzki, Pawel, Su, Helen C., Casanova, Jean-Laurent, Hauck, Fabian, Puel, Anne, Bastard, Paul, Boisson, Bertrand, Jouanguy, Emmanuelle, Cobat, Aurélie, Zhang, Qian, Alsina, Laia, ESID Registry Working Party, [missing], COVID Human Genetic Effort, [missing], AII - Infectious diseases, Amsterdam Neuroscience - Neuroinfection & -inflammation, and Neurology

Subjects
SARS-CoV-2, Immunology, Signal Transducing, COVID-19, Adaptor Proteins, Settore MED/03, Toll-Like Receptor 7, Myeloid Differentiation Factor 88, Medicine and Health Sciences, COVID-19/complications, Immunology and Allergy, Humans, Myeloid Differentiation Factor 88/genetics, Child, Adaptor Proteins, Signal Transducing
Abstract

X-linked recessive deficiency of TLR7, a MyD88- and IRAK-4-dependent endosomal ssRNA sensor, impairs SARS-CoV-2 recognition and type I IFN production in plasmacytoid dendritic cells (pDCs), thereby underlying hypoxemic COVID-19 pneumonia with high penetrance. We report 22 unvaccinated patients with autosomal recessive MyD88 or IRAK-4 deficiency infected with SARS-CoV-2 (mean age: 10.9 yr; 2 mo to 24 yr), originating from 17 kindreds from eight countries on three continents. 16 patients were hospitalized: six with moderate, four with severe, and six with critical pneumonia, one of whom died. The risk of hypoxemic pneumonia increased with age. The risk of invasive mechanical ventilation was also much greater than in age-matched controls from the general population (OR: 74.7, 95% CI: 26.8-207.8, P < 0.001). The patients' susceptibility to SARS-CoV-2 can be attributed to impaired TLR7-dependent type I IFN production by pDCs, which do not sense SARS-CoV-2 correctly. Patients with inherited MyD88 or IRAK-4 deficiency were long thought to be selectively vulnerable to pyogenic bacteria, but also have a high risk of hypoxemic COVID-19 pneumonia. ispartof: JOURNAL OF EXPERIMENTAL MEDICINE vol:220 issue:5 ispartof: location:United States status: published

Published
2023

24. Comparison of the Lipidomic Signature of Fatty Liver in Children and Adults

Author

Jake P. Mann, Benjamin Jenkins, Samuel Furse, Stuart G. Snowden, Anna Alisi, Laura G. Draijer, Kylie Karnebeek, Deirdre A. Kelly, Bart G. Koot, Antonella Mosca, Camilla Salvestrini, Indra van Mourik, Anita Vreugdenhil, Matthias Zilbauer, Albert Koulman, Graduate School, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam Reproduction & Development (AR&D), Paediatric Gastroenterology, Pediatrics, Nutrition and Movement Sciences, Kindergeneeskunde, MUMC+: MA Medische Staf Kindergeneeskunde (9), and RS: NUTRIM - R1 - Obesity, diabetes and cardiovascular health

Subjects
Adult, OUTCOMES, diabetes, NONALCOHOLIC STEATOHEPATITIS, hepatic steatosis, BIOMARKERS, fibrosis, Gastroenterology, ACIDS, DISEASE, Cross-Sectional Studies, Liver, MARKERS, Cardiovascular Diseases, Non-alcoholic Fatty Liver Disease, NAFLD, Pediatrics, Perinatology and Child Health, Lipidomics, ADOLESCENTS, YOUNG, Humans, biomarker, Child, Triglycerides
Abstract

OBJECTIVE: Non-alcoholic fatty liver disease (NAFLD) is an increasingly common condition in children characterized by insulin resistance and altered lipid metabolism. Affected patients are at increased risk of cardiovascular disease (CVD) and children with NAFLD are likely to be at risk of premature cardiac events. Evaluation of the plasma lipid profile of children with NAFLD offers the opportunity to investigate these perturbations and understand how closely they mimic the changes seen in adults with cardiometabolic disease.METHODS: We performed untargeted liquid chromatography mass spectrometry (LC-MS) plasma lipidomics on 287 children: 19 lean controls, 146 from an obese cohort, and 122 NAFLD cases who had undergone liver biopsy. Associations between lipid species and liver histology were assessed using regression adjusted for age and sex. Results were then replicated using data from 9,500 adults with metabolic phenotyping.RESULTS: More severe paediatric NAFLD was associated with lower levels of long chain, polyunsaturated phosphatidylcholines (PC) and triglycerides (TG). Similar trends in PC and TG chain length and saturation were seen in adults with hepatic steatosis. However, many of the specific lipids associated with NAFLD differed between children and adults. Five lipids replicated in adults (including PC(36:4)) have been directly linked to death and cardiometabolic disease, as well as indirectly via genetic variants.CONCLUSION: These findings suggest that, whilst similar pathways of lipid metabolism are perturbed in paediatric NAFLD as in cardiometabolic disease in adults, the specific lipid signature in children is different.

Published
2022

26. Multicenter Evaluation of Multiparametric MRI Clear Cell Likelihood Scores in Solid Indeterminate Small Renal Masses

Author

Nicola Schieda, Matthew S. Davenport, Stuart G. Silverman, Barun Bagga, Daniel Barkmeier, Zane Blank, Nicole E. Curci, Ankur M. Doshi, Ryan T. Downey, Elizabeth Edney, Elon Granader, Isha Gujrathi, Rebecca M. Hibbert, Nicole Hindman, Cynthia Walsh, Tim Ramsay, Atul B. Shinagare, and Ivan Pedrosa

Subjects
Male, Cross-Sectional Studies, Humans, Radiology, Nuclear Medicine and imaging, Middle Aged, Multiparametric Magnetic Resonance Imaging, Magnetic Resonance Imaging, Carcinoma, Renal Cell, Article, Kidney Neoplasms, Retrospective Studies
Abstract

BACKGROUND: Solid small renal masses (SRMs, ≤4 cm) represent benign and malignant tumors. Among SRMs, clear cell renal cell carcinoma (ccRCC) is frequently aggressive. Compared to invasive percutaneous biopsies, a proposed clear cell likelihood score (ccLS) aims to diagnose ccRCC non-invasively using multiparametric MRI (mpMRI), but lacks external validation. PURPOSE: To evaluate the performance of and interobserver agreement for ccLS to diagnose ccRCC among solid SRMs. MATERIALS AND METHODS: This retrospective, multicenter, cross-sectional study included patients with consecutive solid (≥25% approximate volume enhancement) SRMs undergoing mpMRI between December 2012 and December 2019 at five academic medical centers with histological confirmation of diagnosis. Masses with macroscopic fat were excluded. After a 1.5-hour training session, two abdominal radiologists per center independently rendered a ccLS for 50 masses. The diagnostic performance for ccRCC was calculated using random-effects logistic regression modeling. The distribution of ccRCC by ccLS was tabulated. Interobserver agreement for ccLS was evaluated with Fleiss Kappa. RESULTS: 241 patients (mean±SD age, 60 ± 13 years, 174 men) with 250 solid SRMs were evaluated. The mean ±SD size was 25±8 mm (range 10–39 mm). 48% (119/250) of SRMs were ccRCC. The sensitivity, specificity, and positive predictive value for the diagnosis of ccRCC (95% CI) when ccLS≥4 were 75% (68%, 81%), 78% (72%, 84%), and 76% (69%, 81%), respectively. The negative predictive value of ccLS≤2 was 88% (81%, 93%). The percentages of ccRCC according to the ccLS were 6% (range, 0%–18%), 38% (range, 0%–100%), 32% (range, 18%–53%), 72% (range, 20%–100%), and 81% (range, 50%–100%) for ccLS 1–5, respectively. The mean interobserver agreement was moderate (Kappa=0.58 [95% CI: 0.42, 0.75]). CONCLUSION: The clear cell likelihood score applied to multiparametric MRI had moderate interobserver agreement and differentiated clear cell renal cell carcinoma from other solid renal masses with a negative predictive value of 88%. SUMMARY: Clear cell likelihood scores provide a framework for standardized multiparametric MRI assessment of solid small renal masses with moderate diagnostic accuracy for clear cell renal cell carcinoma.

Published
2022

27. Platform for isolation and characterization of SARS-CoV-2 variants enables rapid characterization of Omicron in Australia

Author

Anupriya Aggarwal, Alberto Ospina Stella, Gregory Walker, Anouschka Akerman, Camille Esneau, Vanessa Milogiannakis, Deborah L. Burnett, Samantha McAllery, Mariana Ruiz Silva, Yonghui Lu, Charles S. P. Foster, Fabienne Brilot, Aleha Pillay, Sabastiaan Van Hal, Vennila Mathivanan, Christina Fichter, Andrea Kindinger, Alexandra Carey Hoppe, Mee Ling Munier, Supavadee Amatayakul-Chantler, Nathan Roth, Germano Coppola, Geoff P. Symonds, Peter Schofield, Jennifer Jackson, Helen Lenthall, Jake Y. Henry, Ohan Mazigi, Hans-Martin Jäck, Miles P. Davenport, David R. Darley, Gail V. Matthews, David S. Khoury, Deborah Cromer, Christopher C. Goodnow, Daniel Christ, Roselle Robosa, Damien J. Starck, Nathan W. Bartlett, William D. Rawlinson, Anthony D. Kelleher, and Stuart G. Turville

Subjects
Microbiology (medical), SARS-CoV-2, Immunology, Australia, Genetics, COVID-19, Humans, Cell Biology, Pandemics, Applied Microbiology and Biotechnology, Microbiology
Abstract

Genetically distinct variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have emerged since the start of the COVID-19 pandemic. Over this period, we developed a rapid platform (R-20) for viral isolation and characterization using primary remnant diagnostic swabs. This, combined with quarantine testing and genomics surveillance, enabled the rapid isolation and characterization of all major SARS-CoV-2 variants circulating in Australia in 2021. Our platform facilitated viral variant isolation, rapid resolution of variant fitness using nasopharyngeal swabs and ranking of evasion of neutralizing antibodies. In late 2021, variant of concern Omicron (B1.1.529) emerged. Using our platform, we detected and characterized SARS-CoV-2 VOC Omicron. We show that Omicron effectively evades neutralization antibodies and has a different entry route that is TMPRSS2-independent. Our low-cost platform is available to all and can detect all variants of SARS-CoV-2 studied so far, with the main limitation being that our platform still requires appropriate biocontainment.

Published
2022

28. Rational engineering of lung alveolar epithelium

Author

Katherine L. Leiby, Yifan Yuan, Ronald Ng, Micha Sam Brickman Raredon, Taylor S. Adams, Pavlina Baevova, Allison M. Greaney, Karen K. Hirschi, Stuart G. Campbell, Naftali Kaminski, Erica L. Herzog, and Laura E. Niklason

Subjects
Biomedical Engineering, Medicine (miscellaneous), Cell Biology, Developmental Biology
Abstract

Engineered whole lungs may one day expand therapeutic options for patients with end-stage lung disease. However, the feasibility of ex vivo lung regeneration remains limited by the inability to recapitulate mature, functional alveolar epithelium. Here, we modulate multimodal components of the alveolar epithelial type 2 cell (AEC2) niche in decellularized lung scaffolds in order to guide AEC2 behavior for epithelial regeneration. First, endothelial cells coordinate with fibroblasts, in the presence of soluble growth and maturation factors, to promote alveolar scaffold population with surfactant-secreting AEC2s. Subsequent withdrawal of Wnt and FGF agonism synergizes with tidal-magnitude mechanical strain to induce the differentiation of AEC2s to squamous type 1 AECs (AEC1s) in cultured alveoli, in situ. These results outline a rational strategy to engineer an epithelium of AEC2s and AEC1s contained within epithelial-mesenchymal-endothelial alveolar-like units, and highlight the critical interplay amongst cellular, biochemical, and mechanical niche cues within the reconstituting alveolus.

Published
2023

30. Enhanced functional detection of synaptic calcium-permeable AMPA receptors using intracellular NASPM

Author

Ian Coombs, Cécile Bats, Craig A Sexton, Dorota Studniarczyk, Stuart G Cull-Candy, and Mark Farrant

Subjects
General Immunology and Microbiology, General Neuroscience, General Medicine, General Biochemistry, Genetics and Molecular Biology
Abstract

Calcium-permeable AMPA-type glutamate receptors (CP-AMPARs) contribute to many forms of synaptic plasticity and pathology. They can be distinguished from GluA2-containing calcium-impermeable AMPARs by the inward rectification of their currents, which reflects voltage-dependent channel block by intracellular spermine. However, the efficacy of this weakly permeant blocker is differentially altered by the presence of AMPAR auxiliary subunits – including transmembrane AMPAR regulatory proteins, cornichons, and GSG1L – which are widely expressed in neurons and glia. This complicates the interpretation of rectification as a measure of CP-AMPAR expression. Here, we show that the inclusion of the spider toxin analog 1-naphthylacetyl spermine (NASPM) in the intracellular solution results in a complete block of GluA1-mediated outward currents irrespective of the type of associated auxiliary subunit. In neurons from GluA2-knockout mice expressing only CP-AMPARs, intracellular NASPM, unlike spermine, completely blocks outward synaptic currents. Thus, our results identify a functional measure of CP-AMPARs, that is unaffected by their auxiliary subunit content.

Published
2023

31. MAF file for CNVs from Real-time Genomic Characterization of Advanced Pancreatic Cancer to Enable Precision Medicine

Author

Brian M. Wolpin, Scott L. Carter, Ryan B. Corcoran, William C. Hahn, Jen Jen Yeh, Nikhil Wagle, David A. Tuveson, Paul B. Shyn, Jeffrey W. Miller, Robert J. Mayer, Matthew H. Kulke, Bruce E. Johnson, Jason L. Hornick, Gad Getz, Levi A. Garraway, Charles S. Fuchs, Matthew B. Yurgelun, Dean J. Welsch, Deborah Knoerzer, Richard B. Lanman, Rebecca J. Nagy, Stuart G. Silverman, Ewa Sicinska, Geoffrey I. Shapiro, Marvin Ryou, Douglas A. Rubinson, Michael H. Rosenthal, Kimberly Perez, Anuj K. Patel, Kimmie Ng, Janet E. Murphy, Jeffrey A. Meyerhardt, Nadine J. McCleary, Kunal Jajoo, Leona A. Doyle, James M. Cleary, Thomas Clancy, Kelly P. Burke, Joseph P. St. Pierre, Heather A. Shahzade, Emily E. Van Seventer, Brandon Nadres, Annacarolina Da Silva, Ana Babic, Nelly Oliver, Karla Helvie, Kristin Anderka, Lori Marini, Devin McCabe, Emma Reilly, Marisa W. Welch, Dorisanne Ragon, Lauren K. Brais, Jaegil Kim, Srivatsan Raghavan, Mehlika Hazar-Rethinam, Arezou A. Ghazani, Richard A. Moffitt, Nicholas D. Camarda, Jonathan A. Nowak, and Andrew J. Aguirre

Abstract

MAF file for copy number variations identified in the cohort

Published
2023

32. Supplementary Table S4 from Real-time Genomic Characterization of Advanced Pancreatic Cancer to Enable Precision Medicine

Author

Brian M. Wolpin, Scott L. Carter, Ryan B. Corcoran, William C. Hahn, Jen Jen Yeh, Nikhil Wagle, David A. Tuveson, Paul B. Shyn, Jeffrey W. Miller, Robert J. Mayer, Matthew H. Kulke, Bruce E. Johnson, Jason L. Hornick, Gad Getz, Levi A. Garraway, Charles S. Fuchs, Matthew B. Yurgelun, Dean J. Welsch, Deborah Knoerzer, Richard B. Lanman, Rebecca J. Nagy, Stuart G. Silverman, Ewa Sicinska, Geoffrey I. Shapiro, Marvin Ryou, Douglas A. Rubinson, Michael H. Rosenthal, Kimberly Perez, Anuj K. Patel, Kimmie Ng, Janet E. Murphy, Jeffrey A. Meyerhardt, Nadine J. McCleary, Kunal Jajoo, Leona A. Doyle, James M. Cleary, Thomas Clancy, Kelly P. Burke, Joseph P. St. Pierre, Heather A. Shahzade, Emily E. Van Seventer, Brandon Nadres, Annacarolina Da Silva, Ana Babic, Nelly Oliver, Karla Helvie, Kristin Anderka, Lori Marini, Devin McCabe, Emma Reilly, Marisa W. Welch, Dorisanne Ragon, Lauren K. Brais, Jaegil Kim, Srivatsan Raghavan, Mehlika Hazar-Rethinam, Arezou A. Ghazani, Richard A. Moffitt, Nicholas D. Camarda, Jonathan A. Nowak, and Andrew J. Aguirre

Abstract

Treatment history for patients enrolled on the PancSeq protocol.

Published
2023

33. Supplementary Table S3 from Real-time Genomic Characterization of Advanced Pancreatic Cancer to Enable Precision Medicine

Author

Brian M. Wolpin, Scott L. Carter, Ryan B. Corcoran, William C. Hahn, Jen Jen Yeh, Nikhil Wagle, David A. Tuveson, Paul B. Shyn, Jeffrey W. Miller, Robert J. Mayer, Matthew H. Kulke, Bruce E. Johnson, Jason L. Hornick, Gad Getz, Levi A. Garraway, Charles S. Fuchs, Matthew B. Yurgelun, Dean J. Welsch, Deborah Knoerzer, Richard B. Lanman, Rebecca J. Nagy, Stuart G. Silverman, Ewa Sicinska, Geoffrey I. Shapiro, Marvin Ryou, Douglas A. Rubinson, Michael H. Rosenthal, Kimberly Perez, Anuj K. Patel, Kimmie Ng, Janet E. Murphy, Jeffrey A. Meyerhardt, Nadine J. McCleary, Kunal Jajoo, Leona A. Doyle, James M. Cleary, Thomas Clancy, Kelly P. Burke, Joseph P. St. Pierre, Heather A. Shahzade, Emily E. Van Seventer, Brandon Nadres, Annacarolina Da Silva, Ana Babic, Nelly Oliver, Karla Helvie, Kristin Anderka, Lori Marini, Devin McCabe, Emma Reilly, Marisa W. Welch, Dorisanne Ragon, Lauren K. Brais, Jaegil Kim, Srivatsan Raghavan, Mehlika Hazar-Rethinam, Arezou A. Ghazani, Richard A. Moffitt, Nicholas D. Camarda, Jonathan A. Nowak, and Andrew J. Aguirre

Abstract

PancSeq protocol gene list for CLIA-certified somatic and germline analysis from whole exome sequencing data.

Published
2023

34. Supplementary Figures from Real-time Genomic Characterization of Advanced Pancreatic Cancer to Enable Precision Medicine

Author

Brian M. Wolpin, Scott L. Carter, Ryan B. Corcoran, William C. Hahn, Jen Jen Yeh, Nikhil Wagle, David A. Tuveson, Paul B. Shyn, Jeffrey W. Miller, Robert J. Mayer, Matthew H. Kulke, Bruce E. Johnson, Jason L. Hornick, Gad Getz, Levi A. Garraway, Charles S. Fuchs, Matthew B. Yurgelun, Dean J. Welsch, Deborah Knoerzer, Richard B. Lanman, Rebecca J. Nagy, Stuart G. Silverman, Ewa Sicinska, Geoffrey I. Shapiro, Marvin Ryou, Douglas A. Rubinson, Michael H. Rosenthal, Kimberly Perez, Anuj K. Patel, Kimmie Ng, Janet E. Murphy, Jeffrey A. Meyerhardt, Nadine J. McCleary, Kunal Jajoo, Leona A. Doyle, James M. Cleary, Thomas Clancy, Kelly P. Burke, Joseph P. St. Pierre, Heather A. Shahzade, Emily E. Van Seventer, Brandon Nadres, Annacarolina Da Silva, Ana Babic, Nelly Oliver, Karla Helvie, Kristin Anderka, Lori Marini, Devin McCabe, Emma Reilly, Marisa W. Welch, Dorisanne Ragon, Lauren K. Brais, Jaegil Kim, Srivatsan Raghavan, Mehlika Hazar-Rethinam, Arezou A. Ghazani, Richard A. Moffitt, Nicholas D. Camarda, Jonathan A. Nowak, and Andrew J. Aguirre

Abstract

Supplementary Figure S1: Overview of workflow and data generation. Supplementary Figure S2: Analysis of neoplastic cellularity. Supplementary Figure S3: Recurrent copy number alterations. Supplementary Figure S4: Mutational signature analysis. Supplementary Figure S5: Analysis of PDAC gene expression signatures. Supplementary Figure S6: Clinically relevant alterations in the cohort.

Published
2023

35. Supplementary Experimental Methods from Real-time Genomic Characterization of Advanced Pancreatic Cancer to Enable Precision Medicine

Author

Brian M. Wolpin, Scott L. Carter, Ryan B. Corcoran, William C. Hahn, Jen Jen Yeh, Nikhil Wagle, David A. Tuveson, Paul B. Shyn, Jeffrey W. Miller, Robert J. Mayer, Matthew H. Kulke, Bruce E. Johnson, Jason L. Hornick, Gad Getz, Levi A. Garraway, Charles S. Fuchs, Matthew B. Yurgelun, Dean J. Welsch, Deborah Knoerzer, Richard B. Lanman, Rebecca J. Nagy, Stuart G. Silverman, Ewa Sicinska, Geoffrey I. Shapiro, Marvin Ryou, Douglas A. Rubinson, Michael H. Rosenthal, Kimberly Perez, Anuj K. Patel, Kimmie Ng, Janet E. Murphy, Jeffrey A. Meyerhardt, Nadine J. McCleary, Kunal Jajoo, Leona A. Doyle, James M. Cleary, Thomas Clancy, Kelly P. Burke, Joseph P. St. Pierre, Heather A. Shahzade, Emily E. Van Seventer, Brandon Nadres, Annacarolina Da Silva, Ana Babic, Nelly Oliver, Karla Helvie, Kristin Anderka, Lori Marini, Devin McCabe, Emma Reilly, Marisa W. Welch, Dorisanne Ragon, Lauren K. Brais, Jaegil Kim, Srivatsan Raghavan, Mehlika Hazar-Rethinam, Arezou A. Ghazani, Richard A. Moffitt, Nicholas D. Camarda, Jonathan A. Nowak, and Andrew J. Aguirre

Abstract

Supplementary Experimental Methods

Published
2023

36. MAF file for mutations from Real-time Genomic Characterization of Advanced Pancreatic Cancer to Enable Precision Medicine

Author

Brian M. Wolpin, Scott L. Carter, Ryan B. Corcoran, William C. Hahn, Jen Jen Yeh, Nikhil Wagle, David A. Tuveson, Paul B. Shyn, Jeffrey W. Miller, Robert J. Mayer, Matthew H. Kulke, Bruce E. Johnson, Jason L. Hornick, Gad Getz, Levi A. Garraway, Charles S. Fuchs, Matthew B. Yurgelun, Dean J. Welsch, Deborah Knoerzer, Richard B. Lanman, Rebecca J. Nagy, Stuart G. Silverman, Ewa Sicinska, Geoffrey I. Shapiro, Marvin Ryou, Douglas A. Rubinson, Michael H. Rosenthal, Kimberly Perez, Anuj K. Patel, Kimmie Ng, Janet E. Murphy, Jeffrey A. Meyerhardt, Nadine J. McCleary, Kunal Jajoo, Leona A. Doyle, James M. Cleary, Thomas Clancy, Kelly P. Burke, Joseph P. St. Pierre, Heather A. Shahzade, Emily E. Van Seventer, Brandon Nadres, Annacarolina Da Silva, Ana Babic, Nelly Oliver, Karla Helvie, Kristin Anderka, Lori Marini, Devin McCabe, Emma Reilly, Marisa W. Welch, Dorisanne Ragon, Lauren K. Brais, Jaegil Kim, Srivatsan Raghavan, Mehlika Hazar-Rethinam, Arezou A. Ghazani, Richard A. Moffitt, Nicholas D. Camarda, Jonathan A. Nowak, and Andrew J. Aguirre

Abstract

MAF file for mutations identified in the cohort

Published
2023

37. Supplementary Table S2 from Real-time Genomic Characterization of Advanced Pancreatic Cancer to Enable Precision Medicine

Author

Brian M. Wolpin, Scott L. Carter, Ryan B. Corcoran, William C. Hahn, Jen Jen Yeh, Nikhil Wagle, David A. Tuveson, Paul B. Shyn, Jeffrey W. Miller, Robert J. Mayer, Matthew H. Kulke, Bruce E. Johnson, Jason L. Hornick, Gad Getz, Levi A. Garraway, Charles S. Fuchs, Matthew B. Yurgelun, Dean J. Welsch, Deborah Knoerzer, Richard B. Lanman, Rebecca J. Nagy, Stuart G. Silverman, Ewa Sicinska, Geoffrey I. Shapiro, Marvin Ryou, Douglas A. Rubinson, Michael H. Rosenthal, Kimberly Perez, Anuj K. Patel, Kimmie Ng, Janet E. Murphy, Jeffrey A. Meyerhardt, Nadine J. McCleary, Kunal Jajoo, Leona A. Doyle, James M. Cleary, Thomas Clancy, Kelly P. Burke, Joseph P. St. Pierre, Heather A. Shahzade, Emily E. Van Seventer, Brandon Nadres, Annacarolina Da Silva, Ana Babic, Nelly Oliver, Karla Helvie, Kristin Anderka, Lori Marini, Devin McCabe, Emma Reilly, Marisa W. Welch, Dorisanne Ragon, Lauren K. Brais, Jaegil Kim, Srivatsan Raghavan, Mehlika Hazar-Rethinam, Arezou A. Ghazani, Richard A. Moffitt, Nicholas D. Camarda, Jonathan A. Nowak, and Andrew J. Aguirre

Abstract

Characteristics of biopsies obtained on PancSeq protocol.

Published
2023

40. Monogenic early-onset lymphoproliferation and autoimmunity: Natural history of STAT3 gain-of-function syndrome

Author

Jennifer W. Leiding, Tiphanie P. Vogel, Valentine G.J. Santarlas, Rahul Mhaskar, Madison R. Smith, Alexandre Carisey, Alexander Vargas-Hernández, Manuel Silva-Carmona, Maximilian Heeg, Anne Rensing-Ehl, Bénédicte Neven, Jérôme Hadjadj, Sophie Hambleton, Timothy Ronan Leahy, Kornvalee Meesilpavikai, Charlotte Cunningham-Rundles, Cullen M. Dutmer, Svetlana O. Sharapova, Mervi Taskinen, Ignatius Chua, Rosie Hague, Christian Klemann, Larysa Kostyuchenko, Tomohiro Morio, Akaluck Thatayatikom, Ahmet Ozen, Anna Scherbina, Cindy S. Bauer, Sarah E. Flanagan, Eleonora Gambineri, Lisa Giovannini-Chami, Jennifer Heimall, Kathleen E. Sullivan, Eric Allenspach, Neil Romberg, Sean G. Deane, Benjamin T. Prince, Melissa J. Rose, John Bohnsack, Talal Mousallem, Rohith Jesudas, Maria Marluce Dos Santos Vilela, Michael O’Sullivan, Jana Pachlopnik Schmid, Štěpánka Průhová, Adam Klocperk, Matthew Rees, Helen Su, Sami Bahna, Safa Baris, Lisa M. Bartnikas, Amy Chang Berger, Tracy A. Briggs, Shannon Brothers, Vanessa Bundy, Alice Y. Chan, Shanmuganathan Chandrakasan, Mette Christiansen, Theresa Cole, Matthew C. Cook, Mukesh M. Desai, Ute Fischer, David A. Fulcher, Silvanna Gallo, Amelie Gauthier, Andrew R. Gennery, José Gonçalo Marques, Frédéric Gottrand, Bodo Grimbacher, Eyal Grunebaum, Emma Haapaniemi, Sari Hämäläinen, Kaarina Heiskanen, Tarja Heiskanen-Kosma, Hal M. Hoffman, Luis Ignacio Gonzalez-Granado, Anthony L. Guerrerio, Leena Kainulainen, Ashish Kumar, Monica G. Lawrence, Carina Levin, Timi Martelius, Olaf Neth, Peter Olbrich, Alejandro Palma, Niraj C. Patel, Tamara Pozos, Kahn Preece, Saúl Oswaldo Lugo Reyes, Mark A. Russell, Yael Schejter, Christine Seroogy, Jan Sinclair, Effie Skevofilax, Daniel Suan, Daniel Suez, Paul Szabolcs, Helena Velasco, Klaus Warnatz, Kelly Walkovich, Austen Worth, Mikko R.J. Seppänen, Troy R. Torgerson, Georgios Sogkas, Stephan Ehl, Stuart G. Tangye, Megan A. Cooper, Joshua D. Milner, Lisa R. Forbes Satter, Svetlana Aleshkevich, Luis M. Allende, T. Prescott Atkinson, Faranaz Atschekzei, Sezin Aydemir, Utku Aygunes, Vincent Barlogis, Ulrich Baumann, John Belko, Liliana Bezrodnik, Ariane Biebl, Lori Broderick, Nancy J. Bunin, Maria Soledad Caldirola, Martin Castelle, Fatih Celmeli, Louis-Marie Charbonnier, Talal A. Chatila, Deepak Chellapandian, Haluk Cokugras, Niall Conlon, Fionnuala Cox, Etienne Crickx, Buket Dalgic, Virgil ASH Dalm, Silvia Danielian, Nerea Dominguez-Pinilla, Tal Dujovny, Mikael Ebbo, Ahmet Eken, Brittany Esty, Alexandre Fabre, Alain Fischer, Mark Hannibal, Laura Huppert, Marc D. Ikeda, Stephen Jolles, Kent W. Jolly, Neil Jones, Maria Kanariou, Elif Karakoc-Aydiner, Theoni Karamantziani, Charikleia Kelaidi, Mary Keogan, Ayşenur Pac Kisaarslan, Ayca Kiykim, Kosmas Kotsonis, Natalia Kuzmenko, Sylvie Leroy, Dimitra Lianou, Hilary Longhurst, Myriam Ricarda Lorenz, Patrick Maffucci, Ania Manson, Sarah Marchal, Marion Malphettes, Lia Furlaneto Marega, Andrea A. Mauracher, Holly Miller, Joy Mombourquette, Noel G. Morgan, Anna Mukhina, Aladjidi Nathalie, Brigitte Nelken, David Nolan, Anna-Carin Norlin, Matias Oleastro, Alper Ozcan, Marlene Pasquet, José Roberto Pegler, Capucine Picard, Sophia Polychronopoulou, Pierre Quartier, Juan Francisco Quesada, Jan Ramakers, Katrina L. Randall, V. Koneti Rao, Allison Remiker, Geraldine Resin, Peter Richmond, Frederic Rieux-Laucat, Yulia Rodina, Pierre Rohrlich, Johnathan Sachs, Inga Sakovich, Christopher Santarlas, Sinan Sari, Gregory Sawicki, Uwe Schauer, Selma C. Scheffler Mendoza, Oksana Schvetz, Reinhold Ernst Schmidt, Klaus Schwarz, Anna Sediva, Kyle Sinclair, Mary Slatter, John Sleasman, Katerina Stergiou, Narissara Suratannon, Kay Tanita, Grace Thompson, Stephen Travis, Timothy Trojan, Maria Tsinti, Ekrem Unal, Luciano Urdinez, Felisa Vazquez-Gomez, Mariana Villa, Michael Weinrich, Mitchell J. Weiss, Benjamin Wright, Ebru Yilmaz, Radana Zachova, Yu Zhang, Internal Medicine, and Immunology

Subjects
SDG 3 - Good Health and Well-being, Immunology, Immunology and Allergy
Abstract

Background: In 2014, germline signal transducer and activator of transcription (STAT) 3 gain-of-function (GOF) mutations were first described to cause a novel multisystem disease of early-onset lymphoproliferation and autoimmunity. Objective: This pivotal cohort study defines the scope, natural history, treatment, and overall survival of a large global cohort of patients with pathogenic STAT3 GOF variants. Methods: We identified 191 patients from 33 countries with 72 unique mutations. Inclusion criteria included symptoms of immune dysregulation and a biochemically confirmed germline heterozygous GOF variant in STAT3. Results: Overall survival was 88%, median age at onset of symptoms was 2.3 years, and median age at diagnosis was 12 years. Immune dysregulatory features were present in all patients: lymphoproliferation was the most common manifestation (73%); increased frequencies of double-negative (CD4−CD8−) T cells were found in 83% of patients tested. Autoimmune cytopenias were the second most common clinical manifestation (67%), followed by growth delay, enteropathy, skin disease, pulmonary disease, endocrinopathy, arthritis, autoimmune hepatitis, neurologic disease, vasculopathy, renal disease, and malignancy. Infections were reported in 72% of the cohort. A cellular and humoral immunodeficiency was observed in 37% and 51% of patients, respectively. Clinical symptoms dramatically improved in patients treated with JAK inhibitors, while a variety of other immunomodulatory treatment modalities were less efficacious. Thus far, 23 patients have undergone bone marrow transplantation, with a 62% survival rate. Conclusion:: STAT3 GOF patients present with a wide array of immune-mediated disease including lymphoproliferation, autoimmune cytopenias, and multisystem autoimmunity. Patient care tends to be siloed, without a clear treatment strategy. Thus, early identification and prompt treatment implementation are lifesaving for STAT3 GOF syndrome.

Published
2023

47. Improving social justice in observational studies: protocol for the development of a global and Indigenous STROBE-equity reporting guideline

Author

Sarah Funnell, Janet Jull, Lawrence Mbuagbaw, Vivian Welch, Omar Dewidar, Xiaoqin Wang, Miranda Lesperance, Elizabeth Ghogomu, Anita Rizvi, Elie A. Akl, Marc T. Avey, Alba Antequera, Zulfiqar A. Bhutta, Catherine Chamberlain, Peter Craig, Luis Gabriel Cuervo, Alassane Dicko, Holly Ellingwood, Cindy Feng, Damian Francis, Regina Greer-Smith, Billie-Jo Hardy, Matire Harwood, Janet Hatcher-Roberts, Tanya Horsley, Clara Juando-Prats, Mwenya Kasonde, Michelle Kennedy, Tamara Kredo, Alison Krentel, Elizabeth Kristjansson, Laurenz Langer, Julian Little, Elizabeth Loder, Olivia Magwood, Michael Johnson Mahande, G. J. Melendez-Torres, Ainsley Moore, Loveline Lum Niba, Stuart G. Nicholls, Miriam Nguilefem Nkangu, Daeria O. Lawson, Ekwaro Obuku, Patrick Okwen, Tomas Pantoja, Jennifer Petkovic, Mark Petticrew, Kevin Pottie, Tamara Rader, Jacqueline Ramke, Alison Riddle, Larissa Shamseer, Melissa Sharp, Bev Shea, Peter Tanuseputro, Peter Tugwell, Janice Tufte, Erik Von Elm, Hugh Sharma Waddington, Harry Wang, Laura Weeks, George Wells, Howard White, Charles Shey Wiysonge, Luke Wolfenden, and Taryn Young

Subjects
Health Policy, Public Health, Environmental and Occupational Health
Abstract

Background Addressing persistent and pervasive health inequities is a global moral imperative, which has been highlighted and magnified by the societal and health impacts of the COVID-19 pandemic. Observational studies can aid our understanding of the impact of health and structural oppression based on the intersection of gender, race, ethnicity, age and other factors, as they frequently collect this data. However, the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline, does not provide guidance related to reporting of health equity. The goal of this project is to develop a STROBE-Equity reporting guideline extension. Methods We assembled a diverse team across multiple domains, including gender, age, ethnicity, Indigenous background, disciplines, geographies, lived experience of health inequity and decision-making organizations. Using an inclusive, integrated knowledge translation approach, we will implement a five-phase plan which will include: (1) assessing the reporting of health equity in published observational studies, (2) seeking wide international feedback on items to improve reporting of health equity, (3) establishing consensus amongst knowledge users and researchers, (4) evaluating in partnership with Indigenous contributors the relevance to Indigenous peoples who have globally experienced the oppressive legacy of colonization, and (5) widely disseminating and seeking endorsement from relevant knowledge users. We will seek input from external collaborators using social media, mailing lists and other communication channels. Discussion Achieving global imperatives such as the Sustainable Development Goals (e.g., SDG 10 Reduced inequalities, SDG 3 Good health and wellbeing) requires advancing health equity in research. The implementation of the STROBE-Equity guidelines will enable a better awareness and understanding of health inequities through better reporting. We will broadly disseminate the reporting guideline with tools to enable adoption and use by journal editors, authors, and funding agencies, using diverse strategies tailored to specific audiences.

Published
2023

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