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Article ; Online: Achieving Precision Medicine in Allergic Disease: Progress and Challenges.

Proper, Steven P / Azouz, Nurit P / Mersha, Tesfaye B

2021 Volume 12, Page(s) 720746

Abstract: Allergic diseases (atopic dermatitis, food allergy, eosinophilic esophagitis, asthma and allergic rhinitis), perhaps more than many other traditionally grouped disorders, share several overlapping inflammatory pathways and risk factors, though we are ... ...

Abstract	Allergic diseases (atopic dermatitis, food allergy, eosinophilic esophagitis, asthma and allergic rhinitis), perhaps more than many other traditionally grouped disorders, share several overlapping inflammatory pathways and risk factors, though we are still beginning to understand how the relevant patient and environmental factors uniquely shape each disease. Precision medicine is the concept of applying multiple levels of patient-specific data to tailor diagnoses and available treatments to the individual; ideally, a patient receives the right intervention at the right time, in order to maximize effectiveness but minimize morbidity, mortality and cost. While precision medicine in allergy is in its infancy, the recent success of biologics, development of tools focused on large data set integration and improved sampling methods are encouraging and demonstrates the utility of refining our understanding of allergic endotypes to improve therapies. Some of the biggest challenges to achieving precision medicine in allergy are characterizing allergic endotypes, understanding allergic multimorbidity relationships, contextualizing the impact of environmental exposures (the "exposome") and ancestry/genetic risks, achieving actionable multi-omics integration, and using this information to develop adequately powered patient cohorts and refined clinical trials. In this paper, we highlight several recently developed tools and methods showing promise to realize the aspirational potential of precision medicine in allergic disease. We also outline current challenges, including exposome sampling and building the "knowledge network" with multi-omics integration.
MeSH term(s)	Allergens/immunology ; Animals ; Biomarkers ; Computational Biology/methods ; Diagnosis, Differential ; Disease Management ; Disease Susceptibility ; Genomics/methods ; Humans ; Hypersensitivity/diagnosis ; Hypersensitivity/etiology ; Hypersensitivity/therapy ; Machine Learning ; Phenotype ; Precision Medicine/methods ; Proteomics/methods
Chemical Substances	Allergens ; Biomarkers
Language	English
Publishing date	2021-08-18
Publishing country	Switzerland
Document type	Research Support, N.I.H., Extramural ; Systematic Review
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2021.720746
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Mechanisms of gastrointestinal allergic disorders.

Azouz, Nurit P / Rothenberg, Marc E

The Journal of clinical investigation

2019 Volume 129, Issue 4, Page(s) 1419–1430

Abstract: Gastrointestinal (GI) allergic disease is an umbrella term used to describe a variety of adverse, food antigen-driven, immune-mediated diseases. Although these diseases vary mechanistically, common elements include a breakdown of immunologic tolerance, a ...

Abstract	Gastrointestinal (GI) allergic disease is an umbrella term used to describe a variety of adverse, food antigen-driven, immune-mediated diseases. Although these diseases vary mechanistically, common elements include a breakdown of immunologic tolerance, a biased type 2 immune response, and an impaired mucosal barrier. These pathways are influenced by diverse factors such as diet, infections, exposure to antibiotics and chemicals, GI microbiome composition, and genetic and epigenetic elements. Early childhood has emerged as a critical period when these factors have a dramatic impact on shaping the immune system and therefore triggering or protecting against the onset of GI allergic diseases. In this Review, we will discuss the latest findings on the molecular and cellular mechanisms that govern GI allergic diseases and how these findings have set the stage for emerging preventative and treatment strategies.
MeSH term(s)	Animals ; Epigenesis, Genetic/immunology ; Gastrointestinal Diseases/immunology ; Gastrointestinal Diseases/microbiology ; Gastrointestinal Diseases/pathology ; Gastrointestinal Microbiome/immunology ; Humans ; Hypersensitivity/immunology ; Hypersensitivity/microbiology ; Hypersensitivity/pathology ; Intestinal Mucosa/immunology ; Intestinal Mucosa/microbiology ; Intestinal Mucosa/pathology ; Th2 Cells/immunology ; Th2 Cells/pathology
Language	English
Publishing date	2019-03-11
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI124604
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Article ; Online: Aryl hydrocarbon receptor and IL-13 signaling crosstalk in human keratinocytes and atopic dermatitis.

Proper, Steven P / Dwyer, Alexander T / Appiagyei, Andrews / Felton, Jennifer M / Ben-Baruch Morgenstern, Netali / Marlman, Justin M / Kotliar, Michael / Barski, Artem / Troutman, Ty D / Rothenberg, Marc E / Mersha, Tesfaye B / Azouz, Nurit P

Frontiers in allergy

2024 Volume 5, Page(s) 1323405

Abstract: Introduction: Atopic dermatitis (AD) is an allergic skin disease mediated by skin barrier impairment and IL-13-driven immune response. Activation of the aryl hydrocarbon receptor (AHR) has shown promise in early clinical trials for AD; however, the ... ...

Abstract	Introduction: Atopic dermatitis (AD) is an allergic skin disease mediated by skin barrier impairment and IL-13-driven immune response. Activation of the aryl hydrocarbon receptor (AHR) has shown promise in early clinical trials for AD; however, the mechanism by which AHR partially ameliorates AD is not well known. Methods: Gene expression data from human biopsies were analyzed, and compared to gene expression from RNA-sequencing in our Results: The AHR target gene Discussion: Together, these data suggest that the AHR pathway is dysregulated in AD and that AHR modulates IL-13 downstream signaling in keratinocytes through genome-wide, transcriptional regulatory effects.
Language	English
Publishing date	2024-01-26
Publishing country	Switzerland
Document type	Journal Article
ISSN	2673-6101
ISSN (online)	2673-6101
DOI	10.3389/falgy.2024.1323405
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Article ; Online: Measurement of Exocytosis in Genetically Manipulated Mast Cells.

Klein, Ofir / Azouz, Nurit P / Sagi-Eisenberg, Ronit

Methods in molecular biology (Clifton, N.J.)

2020 Volume 2233, Page(s) 181–192

Abstract: The hallmark of mast cell activation is secretion of immune mediators by regulated exocytosis. Measurements of mediator secretion from mast cells that are genetically manipulated by transient transfections provide a powerful tool for deciphering the ... ...

Abstract	The hallmark of mast cell activation is secretion of immune mediators by regulated exocytosis. Measurements of mediator secretion from mast cells that are genetically manipulated by transient transfections provide a powerful tool for deciphering the underlying mechanisms of mast cell exocytosis. However, common methods to study regulated exocytosis in bulk culture of mast cells suffer from the drawback of high signal-to-noise ratio because of their failure to distinguish between the different mast cell populations, that is, genetically modified mast cells versus their non-transfected counterparts. In particular, the low transfection efficiency of mast cells poses a significant limitation on the use of conventional methodologies. To overcome this hurdle, we developed a method, which discriminates and allows detection of regulated exocytosis of transfected cells based on the secretion of a fluorescent secretory reporter. We used a plasmid encoding for Neuropeptide Y (NPY) fused to a monomeric red fluorescent protein (NPY-mRFP), yielding a fluorescent secretory granule-targeted reporter that is co-transfected with a plasmid encoding a gene of interest. Upon cell trigger, NPY-mRFP is released from the cells by regulated exocytosis, alongside the endogenous mediators. Therefore, using NPY-mRFP as a reporter for mast cell exocytosis allows either quantitative, via a fluorimeter assay, or qualitative analysis, via confocal microscopy, of the genetically manipulated mast cells. Moreover, this method may be easily modified to accommodate studies of regulated exocytosis in any other type of cell.
MeSH term(s)	Cell Count ; Cell Degranulation/genetics ; Exocytosis/genetics ; Humans ; Luminescent Proteins/genetics ; Luminescent Proteins/pharmacology ; Mast Cells/metabolism ; Secretory Vesicles/genetics ; Transfection/methods ; Red Fluorescent Protein
Chemical Substances	Luminescent Proteins
Language	English
Publishing date	2020-11-22
Publishing country	United States
Document type	Journal Article
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-0716-1044-2_12
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Article ; Online: Recent advances in potential targets for eosinophilic esophagitis treatments.

Oliva, Salvatore / Azouz, Nurit P / Stronati, Laura / Rothenberg, Marc E

Expert review of clinical immunology

2020 Volume 16, Issue 4, Page(s) 421–428

Abstract: ... ...

Abstract	Introduction
MeSH term(s)	Animals ; Anti-Inflammatory Agents/therapeutic use ; Biological Products/therapeutic use ; Drug Discovery ; Eosinophilic Esophagitis/drug therapy ; Humans ; Inflammation/drug therapy ; Molecular Targeted Therapy/trends ; Practice Guidelines as Topic ; Precision Medicine
Chemical Substances	Anti-Inflammatory Agents ; Biological Products
Language	English
Publishing date	2020-03-18
Publishing country	England
Document type	Journal Article ; Meta-Analysis ; Review
ZDB-ID	2274260-8
ISSN	1744-8409 ; 1744-666X
ISSN (online)	1744-8409
ISSN	1744-666X
DOI	10.1080/1744666X.2020.1742110
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Article ; Online: Achieving Precision Medicine in Allergic Disease

Steven P. Proper / Nurit P. Azouz / Tesfaye B. Mersha

Frontiers in Immunology, Vol

Progress and Challenges

2021 Volume 12

Abstract	Allergic diseases (atopic dermatitis, food allergy, eosinophilic esophagitis, asthma and allergic rhinitis), perhaps more than many other traditionally grouped disorders, share several overlapping inflammatory pathways and risk factors, though we are still beginning to understand how the relevant patient and environmental factors uniquely shape each disease. Precision medicine is the concept of applying multiple levels of patient-specific data to tailor diagnoses and available treatments to the individual; ideally, a patient receives the right intervention at the right time, in order to maximize effectiveness but minimize morbidity, mortality and cost. While precision medicine in allergy is in its infancy, the recent success of biologics, development of tools focused on large data set integration and improved sampling methods are encouraging and demonstrates the utility of refining our understanding of allergic endotypes to improve therapies. Some of the biggest challenges to achieving precision medicine in allergy are characterizing allergic endotypes, understanding allergic multimorbidity relationships, contextualizing the impact of environmental exposures (the “exposome”) and ancestry/genetic risks, achieving actionable multi-omics integration, and using this information to develop adequately powered patient cohorts and refined clinical trials. In this paper, we highlight several recently developed tools and methods showing promise to realize the aspirational potential of precision medicine in allergic disease. We also outline current challenges, including exposome sampling and building the “knowledge network” with multi-omics integration.
Keywords	precision medicine ; allergic disease ; atopic march ; omics ; endotypes ; exposome ; Immunologic diseases. Allergy ; RC581-607
Subject code	610
Language	English
Publishing date	2021-08-01T00:00:00Z
Publisher	Frontiers Media S.A.
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Epithelial origin of eosinophilic esophagitis.

Rochman, Mark / Azouz, Nurit P / Rothenberg, Marc E

The Journal of allergy and clinical immunology

2018 Volume 142, Issue 1, Page(s) 10–23

Abstract: Eosinophilic esophagitis (EoE) is a chronic, allergen-driven inflammatory disease of the esophagus characterized predominantly by eosinophilic inflammation, leading to esophageal dysfunction. Converging data have placed the esophageal epithelium at the ... ...

Abstract	Eosinophilic esophagitis (EoE) is a chronic, allergen-driven inflammatory disease of the esophagus characterized predominantly by eosinophilic inflammation, leading to esophageal dysfunction. Converging data have placed the esophageal epithelium at the center of disease pathogenesis. In particular, the main EoE disease susceptibility loci at 2p23 and 5p22 encode for gene products that are produced by the esophageal epithelium: the intracellular protease calpain 14 and thymic stromal lymphopoietin, respectively. Furthermore, genetic and functional data establish a primary role for impaired epithelial barrier function in disease susceptibility and pathoetiology. Additionally, the EoE transcriptome, a set of genes dysregulated in the esophagi of patients with EoE, is enriched in genes that encode for proteins involved in esophageal epithelial cell differentiation. This transcriptome has a high proportion of esophagus-specific epithelial genes that are notable for the unexpected enrichment in genes encoding for proteases and protease inhibitors, as well as in IL-1 family genes, demonstrating a previously unappreciated role for innate immunity responses in the esophagus under homeostatic conditions. Among these pathways, basal production of the serine protease inhibitor, Kazal-type 7 (SPINK7) has been demonstrated to be part of the normal differentiation program of esophageal epithelium. Profound lost expression of SPINK7 occurs in patients with EoE and is sufficient for unleashing increased proteolytic activity (including urokinase plasminogen activator), impaired barrier function, and production of large quantities of proinflammatory and proallergic cytokines, including thymic stromal lymphopoietin. Collectively, we put forth a model in which the esophagus is normally equipped as an anti-inflammatory sensing organ and that defects in this pathway, mediated by epithelial protease/protease inhibitor imbalances, unleash inflammatory responses resulting in disorders, such as EoE.
MeSH term(s)	Eosinophilic Esophagitis ; Epithelial Cells/enzymology ; Epithelial Cells/immunology ; Epithelial Cells/pathology ; Epithelium/enzymology ; Epithelium/immunology ; Epithelium/pathology ; Humans ; Peptide Hydrolases/metabolism ; Protease Inhibitors/metabolism
Chemical Substances	Protease Inhibitors ; Peptide Hydrolases (EC 3.4.-)
Language	English
Publishing date	2018-05-26
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	121011-7
ISSN	1097-6825 ; 1085-8725 ; 0091-6749
ISSN (online)	1097-6825 ; 1085-8725
ISSN	0091-6749
DOI	10.1016/j.jaci.2018.05.008
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Article ; Online: Alpha 1 Antitrypsin is an Inhibitor of the SARS-CoV2–Priming Protease TMPRSS2

Azouz, Nurit P. / Klingler, Andrea M. / Rothenberg, Marc E.

bioRxiv

Abstract: The transmembrane serine protease TMPRSS2 is indispensable for S protein priming of the MERS, SARS-CoV, and SARS-CoV2 coronaviruses, a process that is necessary for entry of the virus into host cells. Therefore, inhibiting TMPRSS2 holds promise as an ... ...

Abstract	The transmembrane serine protease TMPRSS2 is indispensable for S protein priming of the MERS, SARS-CoV, and SARS-CoV2 coronaviruses, a process that is necessary for entry of the virus into host cells. Therefore, inhibiting TMPRSS2 holds promise as an approach toward preventing transmission of coronaviruses. Herein, we developed an in vitro system to measure TMPRSS2 activity and tested the inhibition of TMPRSS2 by several synthetic and natural protease inhibitors. Camostat mesylate and bromhexine hydrochloride (BHH) inhibited TMPRSS2 proteolytic function. In addition, we identified the small molecule 4-(2-aminomethyl)benzenesulfonyl fluoride (AEBSF) and the human, anti-inflammatory protein alpha 1 antitrypsin (A1AT) as inhibitors of TMPRSS2. AEBSF and A1AT inhibited TMPRSS2 activity in a dose-dependent manner. AEBSF and A1AT inhibited TMPRSS2 in the same range of concentrations (100-0.1 μM). We suggest that treatment with these inhibitors, particularly A1AT, which is an FDA-approved drug, might be effective in limiting SARS-CoV and SARS-CoV2 transmissibility and as a COVID-19 treatment.
Keywords	covid19
Publisher	BioRxiv
Document type	Article ; Online
DOI	10.1101/2020.05.04.077826
Database	COVID19

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Article ; Online: Alpha 1 Antitrypsin is an Inhibitor of the SARS-CoV2-Priming Protease TMPRSS2

Azouz, Nurit P / Klingler, Andrea M / Rothenberg, Marc E

bioRxiv

Abstract: The transmembrane serine protease TMPRSS2 is indispensable for S protein priming of the MERS, SARS-Cov, and SARS-CoV2 coronaviruses, a process that is necessary for entry of the virus into host cells. Therefore, inhibiting TMPRSS2 holds promise as an ... ...

Abstract	The transmembrane serine protease TMPRSS2 is indispensable for S protein priming of the MERS, SARS-Cov, and SARS-CoV2 coronaviruses, a process that is necessary for entry of the virus into host cells. Therefore, inhibiting TMPRSS2 holds promise as an approach toward preventing transmission of coronaviruses. Herein, we developed an in vitro system to measure TMPRSS2 activity and tested the inhibition of TMPRSS2 by several synthetic and natural protease inhibitors. Camostat mesylate and bromhexine hydrochloride (BHH) inhibited TMPRSS2 proteolytic function. In addition, we identified the small molecule 4-(2-aminomethyl)benzenesulfonyl fluoride (AEBSF) and the human, anti-inflammatory protein alpha 1 antitrypsin (A1AT) as inhibitors of TMPRSS2. AEBSF and A1AT inhibited TMPRSS2 activity in a dose-dependent manner. AEBSF and A1AT inhibited TMPRSS2 in the same range of concentrations (100-0.1 uM). We suggest that treatment with these inhibitors, particularly A1AT, which is an FDA-approved drug, might be effective in limiting SARS-CoV and SARS-CoV2 transmissibility and as a COVID-19 treatment.
Keywords	covid19
Language	English
Publishing date	2020-05-05
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2020.05.04.077826
Database	COVID19

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Article ; Online: Uncovering the secretes of allergic inflammation.

Brusilovsky, Michael / Rochman, Mark / Azouz, Nurit P / Mack, Lydia E / Rothenberg, Marc E

The Journal of clinical investigation

2020 Volume 130, Issue 7, Page(s) 3419–3421

Abstract: Allergic asthma is a chronic inflammatory lung disease associated with increased cytokine secretion. Aspects of airway inflammation are also linked to a common genetic variant that corresponds to the small GTPase, Rab27, a protein involved in vesicular ... ...

Abstract	Allergic asthma is a chronic inflammatory lung disease associated with increased cytokine secretion. Aspects of airway inflammation are also linked to a common genetic variant that corresponds to the small GTPase, Rab27, a protein involved in vesicular trafficking in immune cells. However, the mechanisms by which Rab27 contributes to airway inflammation and cytokine release remain ambiguous. In this issue of the JCI, Okunishi et al. explored the role that the Rab27 effector, exophilin-5, has in allergic inflammation. Exophilin-5-deficient mice and asthma mouse models revealed that exophilin-5 regulates IL-33 production and the Th2 response. Notably, exophilin-5 deletion enhanced IL-33 release and pathogenic Th2 responsiveness through the mTOR pathway and altered intracellular IL-33 trafficking. This work provides insights into the molecular mechanisms that underlie inflammatory lung disease.
MeSH term(s)	Animals ; Asthma/genetics ; Cytokines ; Disease Models, Animal ; Inflammation/genetics ; Interleukin-33 ; Lung ; Mice ; Th2 Cells
Chemical Substances	Cytokines ; Interleukin-33
Language	English
Publishing date	2020-06-16
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI138343
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