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Pierson, Sheila K.; Shenoy, Sushila; Oromendia, Ana B.; Gorzewski, Alexander M.; Langan Pai, Ruth-Anne; Nabel, Christopher Shield; Ruth, Jason R.; Parente, Sophia A.T.; Arenas, Daniel J.; Guilfoyle, Mary; Reddy, Manjula; Weinblatt, Michael; Shadick, Nancy; Bower, Mark; Pria, Alessia Dalla; Masaki, Yasufumi; Katz, Laura; Mezey, Jason; Beineke, Philip; Lee, David; Tendler, Craig; Kambayashi, Taku; Fosså, Alexander; van Rhee, Frits; Fajgenbaum, David C.
Blood advances, 09/2021, Letnik: 5, Številka: 17Journal Article
Idiopathic multicentric Castleman disease (iMCD) is a poorly understood hematologic disorder involving cytokine-induced polyclonal lymphoproliferation, systemic inflammation, and potentially fatal multiorgan failure. Although the etiology of iMCD is unknown, interleukin-6 (IL-6) is an established disease driver in approximately one-third of patients. Anti–IL-6 therapy, siltuximab, is the only US Food and Drug Administration–approved treatment. Few options exist for siltuximab nonresponders, and no validated tests are available to predict likelihood of response. We procured and analyzed the largest-to-date cohort of iMCD samples, which enabled classification of iMCD into disease categories, discovery of siltuximab response biomarkers, and identification of therapeutic targets for siltuximab nonresponders. Proteomic quantification of 1178 analytes was performed on serum of 88 iMCD patients, 60 patients with clinico-pathologically overlapping diseases (human herpesvirus-8–associated MCD, N = 20; Hodgkin lymphoma, N = 20; rheumatoid arthritis, N = 20), and 42 healthy controls. Unsupervised clustering revealed iMCD patients have heterogeneous serum proteomes that did not cluster with clinico-pathologically overlapping diseases. Clustering of iMCD patients identified a novel subgroup with superior response to siltuximab, which was validated using a 7-analyte panel (apolipoprotein E, amphiregulin, serum amyloid P-component, inactivated complement C3b, immunoglobulin E, IL-6, erythropoietin) in an independent cohort. Enrichment analyses and immunohistochemistry identified Janus kinase (JAK)/signal transducer and activator of transcription 3 signaling as a candidate therapeutic target that could potentially be targeted with JAK inhibitors in siltuximab nonresponders. Our discoveries demonstrate the potential for accelerating discoveries for rare diseases through multistakeholder collaboration. •Clustering analysis from proteomic quantification of iMCD serum identified a novel subgroup with superior siltuximab response.•Enrichment analyses and immunohistochemistry identified JAK-STAT3 signaling as a candidate therapeutic target in iMCD. Display omitted
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Dostop do baze podatkov JCR je dovoljen samo uporabnikom iz Slovenije. Vaš trenutni IP-naslov ni na seznamu dovoljenih za dostop, zato je potrebna avtentikacija z ustreznim računom AAI.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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Povezave do osebnih bibliografij avtorjev | Povezave do podatkov o raziskovalcih v sistemu SICRIS |
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Vir: Osebne bibliografije
in: SICRIS
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