IGF1 deficiency integrates stunted growth and neurodegeneration in Down syndrome

Araya, Paula; Kinning, Kohl T; Coughlan, Christina; Smith, Keith P; Granrath, Ross E; Enriquez-Estrada, Belinda; Worek, Kayleigh; Sullivan, Kelly D.; Rachubinski, Angela L.; Wolter‐Warmerdam, Kristine; Hickey, Francis; Galbraith, Matthew D.; Potter, Huntington; Espinosa, Joaquín M.

doi:10.1016/j.celrep.2022.111883

Cited by 17 publications

(7 citation statements)

References 95 publications

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“…Transcriptome data from murine tissues can be accessed through the Gene Expression Omnibus under accession numbers GSE229762 and GSE229737. Targeted plasma proteomics data for inflammatory markers using MSD assays for 470+ research participants ( 81 ) can be accessed through Synapse ( https://doi.org/10.7303/syn31475487 ) and the INCLUDE Data Hub. Plasma proteomics data using the SOMAscan platform for 410+ research participants ( 81 ) are available through Synapse ( https://doi.org/10.7303/syn31488781 ).…”

Section: Acknowledgmentsmentioning

confidence: 99%

“…Targeted plasma proteomics data for inflammatory markers using MSD assays for 470+ research participants ( 81 ) can be accessed through Synapse ( https://doi.org/10.7303/syn31475487 ) and the INCLUDE Data Hub. Plasma proteomics data using the SOMAscan platform for 410+ research participants ( 81 ) are available through Synapse ( https://doi.org/10.7303/syn31488781 ). Plasma metabolomics data for 410+ participants can be accessed through Synapse ( https://doi.org/10.7303/syn31488782 ), Metabolomics Workbench (study ID ST002200; http://dev.metabolomicsworkbench.org:22222/data/DRCCMetadata.php?Mode=Study&StudyID=ST002200&Access=UrlT3545 ), and the INCLUDE Data Hub.…”

Section: Acknowledgmentsmentioning

confidence: 99%

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Multidimensional definition of the interferonopathy of Down syndrome and its response to JAK inhibition

et al. 2023

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Individuals with Down syndrome (DS) display chronic hyperactivation of interferon signaling. However, the clinical impacts of interferon hyperactivity in DS are ill-defined. Here, we describe a multiomics investigation of interferon signaling in hundreds of individuals with DS. Using interferon scores derived from the whole blood transcriptome, we defined the proteomic, immune, metabolic, and clinical features associated with interferon hyperactivity in DS. Interferon hyperactivity associates with a distinct proinflammatory phenotype and dysregulation of major growth signaling and morphogenic pathways. Individuals with the highest interferon activity display the strongest remodeling of the peripheral immune system, including increased cytotoxic T cells, B cell depletion, and monocyte activation. Interferon hyperactivity accompanies key metabolic changes, most prominently dysregulated tryptophan catabolism. High interferon signaling stratifies a subpopulation with elevated rates of congenital heart disease and autoimmunity. Last, a longitudinal case study demonstrated that JAK inhibition normalizes interferon signatures with therapeutic benefit in DS. Together, these results justify the testing of immune-modulatory therapies in DS.

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Section: Acknowledgmentsmentioning

confidence: 99%

Section: Acknowledgmentsmentioning

confidence: 99%

Multidimensional definition of the interferonopathy of Down syndrome and its response to JAK inhibition

et al. 2023

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“…In the field of paediatric allergy, novel proteomics methods have been used to identify the presence of 36 digested cow’s milk proteins in breast milk which would be missed by immunochemical methods, and thus may help to improve our understanding of cow’s milk protein allergy in exclusively breast-fed infants and to support new approaches to allergy prevention (Zhu et al, 2019 ). Recently, proteomics profiling as part of a multi-omics approach has been used to predict neurodegeneration in children with Down’s syndrome pointing to a disruption of IGF1 signalling as a potential contributor to or biomarker to the neurodegenerative process, again potentially providing novel pathways for targeted treatments (Araya et al, 2022 ). In paediatric oncology, proteogenomic studies are furthering our understanding of relapse and treatment resistance in children with acute myeloid leukaemia, providing new approaches to predict relapse during disease progression, novel biomarkers and new targets for novel drug therapies (Stratmann et al, 2022 ).…”

Section: Developing Biomarkers and Targeted Therapies To Treat Childh...mentioning

confidence: 99%

Precision diagnostics in children

Dimitri¹

2023

Camb. prisms Precis. med.

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Medical practice is transforming from a reactive to a pro-active and preventive discipline that is underpinned by precision medicine. The advances in technologies in such fields as genomics, proteomics, metabolomics, transcriptomics and artificial intelligence have resulted in a paradigm shift in our understanding of specific diseases in childhood, greatly enhanced by our ability to combine data from changes within cells to the impact of environmental and population changes. Diseases in children have been reclassified as we understand more about their genomic origin and their evolution. Genomic discoveries, additional 'Omics' data and advances such as optical genome mapping have driven rapid improvements in the precision and speed of diagnoses of diseases in children, and are now being incorporated into newborn screening, have improved targeted therapies in childhood, and have supported the development of predictive biomarkers to assess therapeutic impact and determine prognosis in congenital and acquired diseases of childhood.New medical device technologies are facilitating data capture at a population level to support higher diagnostic accuracy and tailored therapies in children according to predicted population outcome, and digital ecosystems now tailor therapies and provide support for their specific needs. By capturing biological and environmental data as early as possible in childhood, we can understand factors that predict disease or maintain health, and track changes across a more extensive longitudinal path. Data from multiple health and external sources over long time periods starting from birth or even in the in-utero environment will provide further clarity about how to sustain health and prevent or predict disease. In this respect, we will not only use data to diagnose disease, but precision diagnostics will aid the 'diagnosis of good health'. The principle of 'start early and gain more' will thus underpin the value of applying a personalised medicine approach early in life.

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“…Human insulin-like growth factor-1 (IGF-1) is an important protein biomarker produced by the liver, which not only performs an extremely important role in regulating endocrine balance, nerve excitation conduction, and the growing development of humans − but is also related to neuropathic pain, growth hormone deficiency, prostate cancer, and other diseases. − Furthermore, because its aberrant expression levels have been connected to a variety of human illnesses, it is crucial in the early phases of clinical diagnosis and treatment. Consequently, it is vitally significant to quickly analyze and sensitively detect IGF-1 .…”

Section: Introductionmentioning

confidence: 99%

Antibody-Protein-Aptamer Electrochemical Biosensor based on Highly Efficient Proximity-Induced DNA Hybridization on Tetrahedral DNA Nanostructure for Sensitive Detection of Insulin-like Growth Factor-1

Long,

Hu,

Wang

et al. 2024

Anal. Chem.

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Herein, an antibody-protein-aptamer electrochemical biosensor was designed by highly efficient proximity-induced DNA hybridization on a tetrahedral DNA nanostructure (TDN) for ultrasensitive detection of human insulin-like growth factor-1 (IGF-1). Impressively, the IGF-1 antibody immobilized on the top vertex of the TDN could effectively capture the target protein with less steric effect, and the ferrocene-labeled signal probe (SP) bound on the bottom vertex of the TDN was close to the electrode surface for generating a strong initial signal. In the presence of target protein IGF-1 and an aptamer strand, an antibody-proteinaptamer sandwich could be formed on the top vertex of TDN, which would trigger proximity-induced DNA hybridization to release the SP on the bottom vertex of TDN; therefore, the signal response would decrease dramatically, enhancing the sensitivity of the biosensor. As a result, the linear range of the proposed biosensor for target IGF-1 was 1 fM to 1 nM with the limit of detection down to 0.47 fM, which was much lower than that of the traditional TDN designs on electrochemical biosensors. Surprisingly, the use of this approach offered an innovative approach for the sensitive detection of biomarkers and illness diagnosis.

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IGF1 deficiency integrates stunted growth and neurodegeneration in Down syndrome

Cited by 17 publications

References 95 publications

Multidimensional definition of the interferonopathy of Down syndrome and its response to JAK inhibition

Multidimensional definition of the interferonopathy of Down syndrome and its response to JAK inhibition

Precision diagnostics in children

Antibody-Protein-Aptamer Electrochemical Biosensor based on Highly Efficient Proximity-Induced DNA Hybridization on Tetrahedral DNA Nanostructure for Sensitive Detection of Insulin-like Growth Factor-1

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