The reactome pathway knowledgebase 2022

Nucleic Acids Research, Год журнала: 2021, Номер 50(D1), С. D687 - D692

Опубликована: Окт. 14, 2021

The Reactome Knowledgebase (https://reactome.org), an Elixir core resource, provides manually curated molecular details across a broad range of physiological and pathological biological processes in humans, including both hereditary acquired disease processes. are annotated as ordered network transformations single consistent data model. thus functions digital archive human tool for discovering functional relationships such gene expression profiles or somatic mutation catalogs from tumor cells. Recent curation work has expanded our annotations normal disease-associated signaling the drugs that target them, particular infections caused by SARS-CoV-1 SARS-CoV-2 coronaviruses host response to infection. New tools support better simultaneous analysis high-throughput multiple sources placement understudied ('dark') proteins analyzed datasets context Reactome's pathways.

Язык: Английский

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The JAK/STAT signaling pathway: from bench to clinic

Signal Transduction and Targeted Therapy, Год журнала: 2021, Номер 6(1)

Опубликована: Ноя. 26, 2021

Abstract The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway was discovered more than a quarter-century ago. As fulcrum many vital cellular processes, the JAK/STAT constitutes rapid membrane-to-nucleus module induces expression various critical mediators cancer inflammation. Growing evidence suggests that dysregulation is associated with cancers autoimmune diseases. In this review, we discuss current knowledge about composition, activation, regulation pathway. Moreover, highlight role its inhibitors in

Язык: Английский

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Janus kinase-targeting therapies in rheumatology: a mechanisms-based approach

Nature Reviews Rheumatology, Год журнала: 2022, Номер 18(3), С. 133 - 145

Опубликована: Янв. 5, 2022

Язык: Английский

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Biomarkers in atopic dermatitis—a review on behalf of the International Eczema Council

Journal of Allergy and Clinical Immunology, Год журнала: 2021, Номер 147(4), С. 1174 - 1190.e1

Опубликована: Янв. 28, 2021

Atopic dermatitis (AD) is a common yet complex skin disease, posing therapeutic challenge with increasingly recognized different phenotypes among variable patient populations. Because response may vary on the basis of heterogeneous clinical and molecular phenotypes, shift toward precision medicine approaches improve AD management. Herein, we will consider biomarkers as potential instruments in toolbox review process biomarker development validation, opinion experts use biomarkers, types encompassing that diagnosis, reflecting disease severity, those potentially predicting development, concomitant atopic diseases, or response, current practice AD. We found chemokine C-C motif ligand 17/thymus activation-regulated chemokine, chemoattractant TH2 cells, has currently greatest evidence for robust correlation at both baseline during therapy, by using recommendations, assessment, evaluation approach. Although to be fully elucidated, due complexity comprehensive approach taking into account reliable, AD-specific evaluations would further facilitate research disorder which gene-gene gene-environment interactions contribute generate highly phenotype.1Bieber T. Traidl-Hoffmann C. Schappi G. Lauener R. Akdis Schmid-Grendlmeier P. Unraveling dermatitis: CK-CARE towards medicine.Allergy. 2020; 75: 2936-2938Crossref PubMed Scopus (4) Google Scholar This heterogeneity likely reflects yet-to-be-defined mechanisms, coupled relevance are only beginning grasp. Progress our understanding role microbiome, epidermal barrier function, cytokines other immune mediators underlying chronic inflammation led an unprecedented number new compounds topical systemic therapy AD.2Renert-Yuval Y. Guttman-Yassky E. What's dermatitis.Dermatol Clin. 2019; 37: 205-213Abstract Full Text PDF However, thus far none can considered magic bullet, "one-size-fits-all" agent. When stringent end points such percent patients reaching investigator's global assessment 0/1 2-grade decrease Eczema Area Severity Index-90 monotherapy study design (ie, without adding topical/systemic anti-inflammatory medications), it appears biologics specifically target their receptors broad-acting Janus kinase inhibitors fail control most patients.3Han Chen Liu X. Zhang J. Su H. Wen et al.Efficacy safety dupilumab treatment adult meta-analysis randomized trials.J Allergy Clin Immunol. 2017; 140: 888-891.e6Abstract (38) Scholar, 4Wollenberg A. Howell M.D. Silverberg J.I. Kell Ranade K. al.Treatment tralokinumab, anti-IL-13 mAb.J 143: 135-141Abstract (133) 5Simpson E.L. Flohr Eichenfield L.F. Bieber Sofen Taieb lebrikizumab (an monoclonal antibody) adults moderate-to-severe inadequately controlled corticosteroids: randomized, placebo-controlled phase II trial (TREBLE).J Am Acad Dermatol. 2018; 78: 863-871.e11Abstract (140) 6Guttman-Yassky Nemoto O. Forman S.B. Wilke Prescilla al.Baricitinib 2 parallel, double-blinded, multiple-dose study.J 80: 913-921.e9Abstract (114) Hence, particularly considering AD, there need Biomarkers have always existed purposes medicine, principally diagnostic tool. diagnosis treatment, opposed many relies completely scores rather than biochemical markers. Thus, reliable reduce observatory differences. tremendous implications prevention strategies and, importantly, used upcoming background regulatory landscapes. In this regard, definition given organizations helpful but obviously not universal. The Food Drug Administration (FDA) adopted broad definition: "A defined characteristic measured indicator normal biologic processes, pathogenic responses exposure intervention, including interventions." FDA also adds following comment: "Molecular, histologic, radiographic, physiologic characteristics biomarkers. A how individual feels, functions, survives." Interestingly, European Medicines Agency another, more restrictive biological molecule blood, body fluids, tissues follow processes diseases humans animals." discovery, one should distinguish between kind material (or its origin) hand purpose/value hand. For first group, wide range (1) genomic information (eg, specific gene sequences epigenetic modification genes), (2) transcriptomic profiles obtained analysis mRNA miRNA, (3) proteins from fluids (whole serum, plasma, tissue fluids) tape stripping, morphological (immunohistochemical staining pictures thereof). distinguished 7 subtypes FDA-NIH Biomarker Working Group (www.ncbi.nlm.nih.gov/books/NBK326791/): susceptibility/risk, diagnostic, monitoring/severity, prognostic, (5) predictive, (6) pharmacodynamic/response, (7) safety. All these could importance context management Unfortunately, literature classical thereof scientific community generated idea easily described reality, bringing discovery acceptance and/or companion procedure, widely underestimated scientists, often comparable drug process. There several crucial steps evolution before reaches status qualification practice. nutshell, life starts either chance product hypothesis-driven program based registry collecting high-quality phenotypical data linked biobank hundreds specimens patients. next step (internal) analytical validation limited cases. Thereafter, must undergo another (external) step, ideally independent institutions, large cohort where reproducibility key. Once goal internal external reached, subjected qualification, supported guidance documents agencies (FDA, Agency). developing newly discovered stage accepted demanding Grading Recommendations, Assessment, Development, Evaluation (GRADE) offers system rating quality evidence, structured presenting summary.7Guyatt Oxman A.D. Akl E.A. Kunz Vist Brozek al.GRADE guidelines, 1: introduction—GRADE summary findings tables.J Epidemiol. 2011; 64: 383-394Abstract (3344) searched AD-related publications included significant (P < .05) coefficient greater equal 0.4 severity blood/skin various treatments, across pediatric were robustly correlate 3 review. Next, summarized GRADE approach, accumulated per each (separated adults, treatments) was graded strength overall published data, inclusion threshold. International Council (IEC) consists 100 councilors associates (https://www.eczemacouncil.org/), all Before IEC meeting Society Investigative Dermatology 2019 Chicago, invitation internet-based survey sent email examine regarding (Table I; detailed questions, see article's Online Repository www.jacionline.org). Monkey software collection. Overall, believe least help stratify compliance, future developments focus predictors response.Table IResults expertsQuestionYes (N)No (N)Follow-up questions (N)Do you think disease?97.52% (41)2.38% (1)How there? (38)•>3 (92.7%)•<3 (7.3%)How phenotypes? (38)•Combining features (92.7%)•Only (7.3%)Which groups patients' stratification? (36)•Blood (70%)•Skin (genomics/transcriptomics) (50%)•Proteomics (28%)•Genomics transcriptomics tape-strips (28%)•Physiological properties TEWL Raman spectroscopy) (25%)Are blood tests/biomarkers AD?29.55% (13)70.45% (31)Which using? (13)•IgE (100%)•Eosinophils (92.3%)•Other (FLG, LDH, CCL17/TARC) (30.8%)Do useful assessing AD?59.09% (25)40.91% (18)Why not?•Lack reliability, validity, commercial availabilityWhy yes?•Improve selection therapies trials•Improve comparability trials•Allow better follow-up tool daily practice•Improve compliance encouragement.Could test/biomarkers compliance?76.74% (33)23.26% (10)Which suggest? (17)•CCL17/TARC (52.9%)•IgE (47.1%)•p-EASI (formula containing CCL17/TARC, sIL-2R, IL-22) (35.3%)•Eosinophils (35.3%)•IL-13 (23.5%)•Other markers (CCL22, CCL26, IL-22—selected <23.5%)How prioritize needs test/biomarkers?Top-rated priorities: (40)•Biomarkers general, identification endo/phenotypes predict identifying responders particular initiationLower priority development:•The less-invasive (all ranked almost equally)EASI, Index; lactate dehydrogenase; TEWL, transepidermal water loss. Open table tab EASI, Potential subdivided suggested use. Some seem reliably psoriasis (namely NOS2 [CCL]27/cutaneous T-cell–attracting [CTACK]),8Garzorz-Stark N. Krause L. Lauffer F. Atenhan Thomas Stark S.P. al.A novel classifier eczema.Exp 2016; 25: 767-774Crossref (27) 9He Bissonnette Wu Diaz Saint-Cyr Proulx Maari al.Tape strips detect distinct psoriasis.J 2021; 147: 199-212Abstract (9) 10Quaranta M. Knapp B. Garzorz Mattii Pullabhatla V. Pennino D. al.Intraindividual genome expression reveals signature eczema.Sci Transl Med. 2014; 6244ra90Crossref (116) improving psoriasiform II).Table IIBiomarkers classifiers, differentiating psoriasisBiomarkerFull nameFunctional effectAbnormalitiesNOS2Inducible nitric oxidase synthaseCatalyzing production oxide, toxic defense against infections, regulator functional activity, growth, death cells T antigen-presenting mast neutrophils, natural killer cellsUpregulated psoriasis, downregulated ADCCL27/CTACKChemokine (C-C motif) 27/cutaneous chemokineExpressed keratinocytes. Mediates migration lymphocytes binding CCR10Upregulated These include related general serum dehydrogenase,11Vekaria A.S. Brunner P.M. Aleisa A.I. Bonomo Lebwohl M.G. Israel al.Moderate-to-severe show increases C-reactive protein levels, correlating activity.F1000Res. 6: 1712PubMed 12Morishima Kawashima Takekuma Hoshika Changes dehydrogenase activity children dermatitis.Pediatr Int. 2010; 52: 171-174Crossref (0) 13Kou Aihara Matsunaga Taguri Morita S. al.Association interleukin-18 dermatitis.Arch Dermatol Res. 2012; 304: 305-312Crossref (48) 14Mizawa Yamaguchi Ueda Makino Shimizu Stress salivary cortisol.Biomed Res 2013; 2013138027Crossref (17) protein,11Vekaria along allergy peripheral eosinophil counts).11Vekaria Scholar,12Morishima Scholar,15Thijs Krastev Weidinger Buckens C.F. de Bruin-Weller Bruijnzeel-Koomen al.Biomarkers systematic meta-analysis.Curr Opin 2015; 15: 453-460Crossref (97) 16Kagi M.K. Joller-Jemelka Wuthrich Correlation eosinophils, cationic soluble interleukin-2 receptor dermatitis.Dermatology. 1992; 185: 88-92Crossref 17Ariens L.F.M. van der Schaft Bakker D.S. Balak Romeijn M.L.E. Kouwenhoven al.Dupilumab very effective difficult-to-treat patients: results BioDay registry.Allergy. 116-126Crossref (29) 18Kou Okawa Ono Inoue Kohno al.Periostin levels chronicity dermatitis.Br J 171: 283-291Crossref (57) 19Czech W. Krutmann Schopf Kapp Serum (ECP) sensitive measure 126: 351-355Crossref TH2/TH22-centered, chemokines pathways correlated untreated posttreated (either serum) investigated possible (Tables III IV Fig 1). Such key marker IL-1341Tintle Shemer Suarez-Farinas Fujita Gilleaudeau Sullivan-Whalen al.Reversal narrow-band UVB phototherapy response.J 128: 583-593.e1-4Abstract (138) Scholar,58Ungar Garcet Gonzalez Dhingra Correa da Rosa al.An integrated model highlights nature disease.J Invest 137: 603-613Abstract Scholar,59Sanyal R.D. Pavel A.B. Glickman Chan T.C. Zheng al.Atopic African American TH2/TH22-skewed TH1/TH17 attenuation.Ann Asthma 122: 99-110.e6Abstract (50) Scholar,66Koning Neijens H.J. Baert M.R. Oranje A.P. Savelkoul H.F. cell subsets allergic non-allergic children, I: IL-4, IFN-gamma IL-13 production.Cytokine. 1997; 9: 416-426Crossref Scholar,67Szegedi Lutter P.C. Bos J.D. Luiten R.M. Kezic al.Cytokine interstitial fluid skin.J Eur Venereol. 29: 2136-2144Crossref (37) Scholar,95Pavel Song Kim Del Duca Krueger J.G. Dubin al.Oral kinase/SYK inhibition (ASN002) suppresses improves dermatitis.J 144: 1011-1024Abstract Scholar,100Simon Vassina Yousefi Kozlowski Braathen L.R. Simon H.U. Reduced dermal infiltration cytokine-expressing inflammatory after short-term tacrolimus treatment.J 2004; 114: 887-895Abstract (72) TH22-related cytokine IL-22.41Tintle Scholar,64Nograles K.E. Zaba L.C. Fuentes-Duculan Cardinale I. Kikuchi al.IL-22-producing "T22" upregulated IL-22 despite reduced IL-17-producing TH17 cells.J 2009; 123: 1244-1252.e2Abstract (434) Scholar,84Gittler J.K. Gulewicz K.J. Wang C.Q. al.Progressive activation T(H)2/T(H)22 selective characterizes acute 130: 1344-1354Abstract (421) TH2-related CCL17/thymus (TARC),13Kou Scholar,14Mizawa Scholar,20Kakinuma Nakamura Wakugawa Mitsui Tada Saeki al.Thymus thymus level closely activity.J 2001; 107: 535-541Abstract (426) Scholar,24Fujisawa Fujisawa Kato Nakayama Katsumata al.Presence high contents platelets elevated plasma macrophage-derived 2002; 110: 139-146Abstract (134) Scholar,27Hijnen De Oosting Lebre Jong al.Serum (TARC) cutaneous cell-attracting (CTACK) diseases: TARC CTACK disease-specific 113: 334-340Abstract (187) 28Jahnz-Rozyk Targowski Paluchowska Owczarek Kucharczyk eotaxin dermatitis.Allergy. 2005; 60: 685-688Crossref 29Song T.W. Sohn M.H. E.S. K.W. Increased dermatitis.Clin Exp Allergy. 2006; 36: 346-351Crossref (31) 30Nakazato Kishida Kuroiwa Fujiwara Shimoda Shinomiya Th2 chemokines, CCL17, CCL22, CCL27, important infantile 2008; 19: 605-613PubMed 31Fujisawa Nagao Hiraguchi Nishimori Iguchi measurement chemokine/CCL17 infancy age-specific 20: 633-641Crossref (46) 32van Velsen S.G. Knol M.J. Haeck I.M. C.A. Pasmans Self-administered Index moderate severe estimation surface area severity.Pediatr 27: 470-475Crossref (22) 33Machura Rusek-Zychma Jachimowicz Wrzask Mazur Kasperska-Zajac concentrations dermatitis, asthma, urticaria.Pediatr 23: 278-284Crossref Scholar,35Kataoka Thymus 41: 221-229Crossref (58) 36Landheer Boonacker Hijnen Rockmann Utility monitoring severity.J 71: 1160-1166Abstract (14) 37Ahrens Schulz Bellach Niggemann Beyer Chemokine regard sensitization status.Pediatr 26: 634-640Crossref (10) 38Gu C.Y. Gu Dou dermatitis.Int 54: e261-e265Crossref 39Hulshof Overbeek S.A. Wyllie A.L. Chu Bogaert Jager al.Exploring infants dermatitis.Front 630Crossref Scholar,94Beck L.A. Thaci Hamilton Graham N.M. Rocklin dermatitis.N Engl 371: 130-139Crossref (715) Scholar,101Yasukochi Nakahara Abe Kido-Nakahara Kohda Takeuchi al.Reduction treatments.Asian Pac 32: 240-245PubMed 102Kyoya Kawakami Soma interleukin-31 Sci. 204-207Abstract 103Gohar Atta A.H. Nasr M.M. Hussein D.N. regulated (TARC), IL-18 polymorphism associative factors dermatitis.Egypt 24: 9-22PubMed 104Bogaczewicz Malinowska Sysa-Jedrzejowska Wozniacka Medium-dose ultraviolet A1 TSLP, TARC, IL-5, lesions 55: 856-863Crossref CCL26/eosinophil-attracting (eotaxin-3),43Wen H.C. Czarnowicki Noda Malik Nakajima Asian characterized TH2/TH22 activation, nonlesional measures.J 142: 324-328.e11Abstract (20) F

Язык: Английский

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The CCL20-CCR6 Axis in Cancer Progression

International Journal of Molecular Sciences, Год журнала: 2020, Номер 21(15), С. 5186 - 5186

Опубликована: Июль 22, 2020

Chemokines, which are basic proteins that exert their effects via G protein-coupled receptors and a subset of the cytokine family, mediators deeply involved in leukocyte migration during an inflammatory reaction. Chemokine (C-C motif) ligand 20 (CCL20), also known as macrophage protein (MIP)-3α, liver activation regulated chemokine (LARC), Exodus-1, is small physiologically expressed liver, colon, skin, tissue inflammation homeostasis, has specific receptor C-C 6 (CCR6). The CCL20-CCR6 axis long been to be infectious diseases, such rheumatoid arthritis human immunodeficiency virus infections. Recently, however, reports have shown associated with several cancers, including hepatocellular carcinoma, colorectal cancer, breast pancreatic cervical kidney cancer. promotes cancer progression directly by enhancing proliferation cells indirectly remodeling tumor microenvironment through immune cell control. present article reviewed role its potential therapeutic target.

Язык: Английский

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Delgocitinib ointment, a topical Janus kinase inhibitor, in adult patients with moderate to severe atopic dermatitis: A phase 3, randomized, double-blind, vehicle-controlled study and an open-label, long-term extension study

Journal of the American Academy of Dermatology, Год журнала: 2020, Номер 82(4), С. 823 - 831

Опубликована: Фев. 3, 2020

BackgroundPrevious studies showed the potential effectiveness of delgocitinib ointment, a novel topical Janus kinase inhibitor, in atopic dermatitis (AD).ObjectiveThis study aimed to evaluate efficacy and safety 0.5% ointment.MethodsIn part 1, 4-week double-blind period, Japanese patients aged 16 years or older with moderate severe AD were randomly assigned 2:1 ratio ointment vehicle ointment. Eligible entered 2, 24-week extension receive ointment.ResultsAt end treatment least-squares mean percent changes from baseline modified Eczema Area Severity Index score, primary endpoint, significantly greater group than (-44.3% vs 1.7%, P < .001). The improvement score was maintained 2. Most adverse events mild unrelated across periods.LimitationsOnly included. vehicle-controlled period lasted only 4 weeks. In corticosteroids allowed for worsening AD.ConclusionDelgocitinib effective well tolerated adult up 28 Previous (AD). This At periods. Only AD. Delgocitinib

Язык: Английский

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Type 2 Inflammation Contributes to Skin Barrier Dysfunction in Atopic Dermatitis

JID Innovations, Год журнала: 2022, Номер 2(5), С. 100131 - 100131

Опубликована: Апрель 26, 2022

Язык: Английский

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JAK–STAT signaling pathway in the pathogenesis of atopic dermatitis: An updated review

Frontiers in Immunology, Год журнала: 2022, Номер 13

Опубликована: Дек. 8, 2022

Atopic dermatitis (AD) is a chronic, inflammatory, pruritic form of dermatosis with heterogeneous manifestations that can substantially affect patients' quality life. AD has complex pathogenesis, making treatment challenging for dermatologists. The Janus kinase (JAK)–signal transducer and activator transcription (STAT) pathway plays central role in modulating multiple immune axes involved the immunopathogenesis AD. In particular, Th2 cytokines, including interleukin (IL)-4, IL-5, IL-13, IL-31, thymic stromal lymphopoietin, which contribute to symptoms chronic inflammation pruritus AD, are mediated by JAK–STAT signal transduction. Furthermore, regulation epidermal barrier modulation peripheral nerves related transduction pruritus. Targeting may attenuate these signals show clinical efficacy through suppression various pathways associated Topical oral JAK inhibitors variable selectivity have emerged as promising therapeutic options Notably, topical ruxolitinib, upadacitinib, abrocitinib were approved U.S. Food Drug Administration treating patients Accordingly, present study reviewed pathogenesis explored updated applications

Язык: Английский

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The translational revolution in atopic dermatitis: the paradigm shift from pathogenesis to treatment

Cellular and Molecular Immunology, Год журнала: 2023, Номер 20(5), С. 448 - 474

Опубликована: Март 16, 2023

Atopic dermatitis (AD) is the most common inflammatory skin disease, and it considered a complex heterogeneous condition. Different phenotypes of AD, defined according to patient age at onset, race, ethnic background; disease duration; other characteristics, have been recently described, underlying need for personalized treatment approach. Recent advancements in understanding AD pathogenesis resulted real translational revolution led exponential expansion therapeutic pipeline. The study biomarkers clinical studies emerging treatments helping clarify role each cytokine immune pathway will allow addressing unique fingerprints subset. Personalized medicine be ultimate goal this targeted research. In review, we discuss changes concepts both approach highlight scientific rationale behind report recent efficacy data.

Язык: Английский

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Neuroimmune communication regulating pruritus in atopic dermatitis

Journal of Allergy and Clinical Immunology, Год журнала: 2022, Номер 149(6), С. 1875 - 1898

Опубликована: Март 23, 2022

Atopic dermatitis (AD) is a common, chronic-relapsing inflammatory skin disease with significant burden. Genetic and environmental trigger factors contribute to AD, activating 2 of our largest organs, the nervous system immune system. Dysregulation neuroimmune circuits plays key role in pathophysiology causing inflammation, pruritus, pain, barrier dysfunction. Sensory nerves can be activated by or endogenous factors, transmitting itch stimuli brain. On stimulation, sensory nerve endings also release neuromediators into skin, contributing again dysfunction, itch. In addition, dysfunctional peripheral central neuronal structures neuroinflammation, sensitization, elongation, neuropathic itch, thus chronification therapy resistance. Consequently, may targets treat pruritus AD. Cytokines, chemokines, proteases, lipids, opioids, ions excite/sensitize endings, which not only induces but further aggravates/perpetuates disruption, as well. Thus, targeted therapies for well pathway inhibitors (eg, kinase inhibitors) beneficial control AD either systemic and/or topical form. Understanding signaling will optimize approach all pathological mechanisms pruritus.

Язык: Английский

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