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Arlauckas, Sean

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Arlauckas

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Arlauckas, Sean

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Author's Publications: search.filters.isAuthorOfPublication.76b5c76e-64b1-4c1a-8259-31394acf125e

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    Prediction of Anti-cancer Nanotherapy Efficacy by Imaging
    (Ivyspring International Publisher, 2017) Miller, Miles; Arlauckas, Sean; Weissleder, Ralph
    Anticancer nanotherapeutics have shown mixed results in clinical trials, raising the questions of whether imaging should be used to i) identify patients with a higher likelihood of nanoparticle accumulation, ii) assess nanotherapeutic efficacy before traditional measures show response, and iii) guide adjuvant treatments to enhance therapeutic nanoparticle (TNP) delivery. Here we review the use of a clinically approved MRI nanoparticle (ferumoxytol, FMX) to predict TNP delivery and efficacy. It is becoming increasingly apparent that nanoparticles used for imaging, despite clearly distinct physicochemical properties, often co-localize with TNP in tumors. This evidence offers the possibility of using FMX as a generic “companion diagnostic” nanoparticle for multiple TNP formulations, thus potentially allowing many of the complex regulatory and cost challenges of other approaches to be avoided.
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    IRF3 and type I interferons fuel a fatal response to myocardial infarction
    (Springer Nature, 2017) King, Kevin R; Aguirre, Aaron; Ye, Yu-Xiang; Sun, Yuan; Roh, Jason; Ng, Richard; Kohler, Rainer; Arlauckas, Sean; Iwamoto, Yoshiko; Savol, Andrej J; Sadreyev, Ruslan; Kelly, Mark; Fitzgibbons, Timothy P; Fitzgerald, Katherine A; Mitchison, Timothy; Libby, Peter; Nahrendorf, Matthias; Weissleder, Ralph
    Interferon regulatory factor 3 (IRF3) and type I interferons (IFNs) protect against infections and cancer, but excessive IRF3 activation and type I IFN production cause autoinflammatory conditions such as Aicardi–Goutières syndrome and STING-associated vasculopathy of infancy (SAVI)3. Myocardial infarction (MI) elicits inflammation5, but the dominant molecular drivers of MI-associated inflammation remain unclear. Here we show that ischemic cell death and uptake of cell debris by macrophages in the heart fuel a fatal response to MI by activating IRF3 and type I IFN production. In mice, single-cell RNA-seq analysis of 4,215 leukocytes isolated from infarcted and non-infarcted hearts showed that MI provokes activation of an IRF3–interferon axis in a distinct population of interferon-inducible cells (IFNICs) that were classified as cardiac macrophages. Mice genetically deficient in cyclic GMP-AMP synthase (cGAS), its adaptor STING, IRF3, or the type I IFN receptor IFNAR exhibited impaired interferon-stimulated gene (ISG) expression and, in the case of mice deficient in IRF3 or IFNAR, improved survival after MI as compared to controls. Interruption of IRF3-dependent signaling resulted in decreased cardiac expression of inflammatory cytokines and chemokines and decreased inflammatory cell infiltration of the heart, as well as in attenuated ventricular dilation and improved cardiac function. Similarly, treatment of mice with an IFNAR-neutralizing antibody after MI ablated the interferon response and improved left ventricular dysfunction and survival. These results identify IRF3 and the type I IFN response as a potential therapeutic target for post-MI cardioprotection.