@article{bitting_hedgespeth_ehrhardt-humbert_arthur_schubert_bradding_tilley_cruse_2022, title={Identification of redundancy between human Fc epsilon RI beta and MS4A6A proteins points toward additional complex mechanisms for Fc epsilon RI trafficking and signaling}, volume={12}, ISSN={["1398-9995"]}, url={https://doi.org/10.1111/all.15595}, DOI={10.1111/all.15595}, abstractNote={AbstractBackgroundAllergic diseases are triggered by signaling through the high‐affinity IgE receptor, FcεRI. In both mast cells (MCs) and basophils, FcεRI is a tetrameric receptor complex comprising a ligand‐binding α subunit (FcεRIα), a tetraspan β subunit (FcεRIβ, MS4A2) responsible for trafficking and signal amplification, and a signal transducing dimer of single transmembrane γ subunits (FcεRIγ). However, FcεRI also exists as presumed trimeric complexes that lack FcεRIβ and are expressed on several cell types outside the MC and basophil lineages. Despite known differences between humans and mice in the presence of the trimeric FcεRI complex, questions remain as to how it traffics and whether it signals in the absence of FcεRIβ. We have previously reported that targeting FcεRIβ with exon‐skipping oligonucleotides eliminates IgE‐mediated degranulation in mouse MCs, but equivalent targeting in human MCs was not effective at reducing degranulation.ResultsHere, we report that the FcεRIβ‐like protein MS4A6A exists in human MCs and compensates for FcεRIβ in FcεRI trafficking and signaling. Human MS4A6A promotes surface expression of FcεRI complexes and facilitates degranulation. MS4A6A and FcεRIβ are encoded by highly related genes within the MS4A gene family that cluster within the human gene loci 11q12‐q13, a region linked to allergy and asthma susceptibility.ConclusionsOur data suggest the presence of either FcεRIβ or MS4A6A is sufficient for degranulation, indicating that MS4A6A could be an elusive FcεRIβ‐like protein in human MCs that performs compensatory functions in allergic disease.}, number={5}, journal={ALLERGY}, author={Bitting, Katie and Hedgespeth, Barry and Ehrhardt-Humbert, Lauren C. and Arthur, Greer K. and Schubert, Alicia G. and Bradding, Peter and Tilley, Stephen L. and Cruse, Glenn}, year={2022}, month={Dec} }
 @article{arthur_cruse_2022, title={Regulation of Trafficking and Signaling of the High Affinity IgE Receptor by Fc epsilon RI beta and the Potential Impact of Fc epsilon RI beta Splicing in Allergic Inflammation}, volume={23}, ISSN={["1422-0067"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85122521799&partnerID=MN8TOARS}, DOI={10.3390/ijms23020788}, abstractNote={Mast cells are tissue-resident immune cells that function in both innate and adaptive immunity through the release of both preformed granule-stored mediators, and newly generated proinflammatory mediators that contribute to the generation of both the early and late phases of the allergic inflammatory response. Although mast cells can be activated by a vast array of mediators to contribute to homeostasis and pathophysiology in diverse settings and contexts, in this review, we will focus on the canonical setting of IgE-mediated activation and allergic inflammation. IgE-dependent activation of mast cells occurs through the high affinity IgE receptor, FcεRI, which is a multimeric receptor complex that, once crosslinked by antigen, triggers a cascade of signaling to generate a robust response in mast cells. Here, we discuss FcεRI structure and function, and describe established and emerging roles of the β subunit of FcεRI (FcεRIβ) in regulating mast cell function and FcεRI trafficking and signaling. We discuss current approaches to target IgE and FcεRI signaling and emerging approaches that could target FcεRIβ specifically. We examine how alternative splicing of FcεRIβ alters protein function and how manipulation of splicing could be employed as a therapeutic approach. Targeting FcεRI directly and/or IgE binding to FcεRI are promising approaches to therapeutics for allergic inflammation. The characteristic role of FcεRIβ in both trafficking and signaling of the FcεRI receptor complex, the specificity to IgE-mediated activation pathways, and the preferential expression in mast cells and basophils, makes FcεRIβ an excellent, but challenging, candidate for therapeutic strategies in allergy and asthma, if targeting can be realized.}, number={2}, journal={INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES}, author={Arthur, Greer K. and Cruse, Glenn}, year={2022}, month={Jan} }
 @article{slobodiuk_niven_arthur_thakur_ercumen_2021, title={Does Irrigation with Treated and Untreated Wastewater Increase Antimicrobial Resistance in Soil and Water: A Systematic Review}, volume={18}, ISSN={1660-4601}, url={http://dx.doi.org/10.3390/ijerph182111046}, DOI={10.3390/ijerph182111046}, abstractNote={Population growth and water scarcity necessitate alternative agriculture practices, such as reusing wastewater for irrigation. Domestic wastewater has been used for irrigation for centuries in many historically low-income and arid countries and is becoming more widely used by high-income countries to augment water resources in an increasingly dry climate. Wastewater treatment processes are not fully effective in removing all contaminants, such as antimicrobial resistant bacteria (ARB) and antimicrobial resistance genes (ARGs). Literature reviews on the impact of wastewater irrigation on antimicrobial resistance (AMR) in the environment have been inconclusive and mostly focused on treated wastewater. We conducted the first systematic review to assess the impact of irrigation with both treated or untreated domestic wastewater on ARB and ARGs in soil and adjacent water bodies. We screened titles/abstracts of 3002 articles, out of which 41 were screened in full text and 26 were included in this review. Of these, thirteen investigated irrigation with untreated wastewater, and nine found a positive association with ARB/ARGs in soil. Out of thirteen studies focused on treated wastewater, six found a positive association with ARB/ARGs while six found mixed/negative associations. Our findings demonstrate that irrigation with untreated wastewater increases AMR in soil and call for precautionary action by field workers, their families, and consumers when untreated wastewater is used to irrigate crops. The effect of irrigation with treated wastewater was more variable among the studies included in our review, highlighting the need to better understand to what extent AMR is disseminated through this practice. Future research should assess factors that modify the effect of wastewater irrigation on AMR in soil, such as the degree and type of wastewater treatment, and the duration and intensity of irrigation, to inform guidelines on the reuse of wastewater for irrigation.}, number={21}, journal={INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH}, publisher={MDPI AG}, author={Slobodiuk, Stacy and Niven, Caitlin and Arthur, Greer and Thakur, Siddhartha and Ercumen, Ayse}, year={2021}, month={Nov}, pages={11046} }
 @article{snider_arthur_falduto_olivera_ehrhardt-humbert_smith_smith_metcalfe_cruse_2022, title={Targeting KIT by frameshifting mRNA transcripts as a therapeutic strategy for aggressive mast cell neoplasms}, volume={30}, ISSN={["1525-0024"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85114708401&partnerID=MN8TOARS}, DOI={10.1016/j.ymthe.2021.08.009}, abstractNote={Activating mutations in c-KIT are associated with the mast cell (MC) clonal disorders cutaneous mastocytosis and systemic mastocytosis and its variants, including aggressive systemic mastocytosis, MC leukemia, and MC sarcoma. Currently, therapies inhibiting KIT signaling are a leading strategy to treat MC proliferative disorders. However, these approaches may have off-target effects, and in some patients, complete remission or improved survival time cannot be achieved. These limitations led us to develop an approach using chemically stable exon skipping oligonucleotides (ESOs) that induce exon skipping of precursor (pre-)mRNA to alter gene splicing and introduce a frameshift into mature KIT mRNA transcripts. The result of this alternate approach results in marked downregulation of KIT expression, diminished KIT signaling, inhibition of MC proliferation, and rapid induction of apoptosis in neoplastic HMC-1.2 MCs. We demonstrate that in vivo administration of KIT targeting ESOs significantly inhibits tumor growth and systemic organ infiltration using both an allograft mastocytosis model and a humanized xenograft MC tumor model. We propose that our innovative approach, which employs well-tolerated, chemically stable oligonucleotides to target KIT expression through unconventional pathways, has potential as a KIT-targeted therapeutic alone, or in combination with agents that target KIT signaling, in the treatment of KIT-associated malignancies. Activating mutations in c-KIT are associated with the mast cell (MC) clonal disorders cutaneous mastocytosis and systemic mastocytosis and its variants, including aggressive systemic mastocytosis, MC leukemia, and MC sarcoma. Currently, therapies inhibiting KIT signaling are a leading strategy to treat MC proliferative disorders. However, these approaches may have off-target effects, and in some patients, complete remission or improved survival time cannot be achieved. These limitations led us to develop an approach using chemically stable exon skipping oligonucleotides (ESOs) that induce exon skipping of precursor (pre-)mRNA to alter gene splicing and introduce a frameshift into mature KIT mRNA transcripts. The result of this alternate approach results in marked downregulation of KIT expression, diminished KIT signaling, inhibition of MC proliferation, and rapid induction of apoptosis in neoplastic HMC-1.2 MCs. We demonstrate that in vivo administration of KIT targeting ESOs significantly inhibits tumor growth and systemic organ infiltration using both an allograft mastocytosis model and a humanized xenograft MC tumor model. We propose that our innovative approach, which employs well-tolerated, chemically stable oligonucleotides to target KIT expression through unconventional pathways, has potential as a KIT-targeted therapeutic alone, or in combination with agents that target KIT signaling, in the treatment of KIT-associated malignancies.}, number={1}, journal={MOLECULAR THERAPY}, author={Snider, Douglas B. and Arthur, Greer K. and Falduto, Guido H. and Olivera, Ana and Ehrhardt-Humbert, Lauren C. and Smith, Emmaline and Smith, Cierra and Metcalfe, Dean D. and Cruse, Glenn}, year={2022}, month={Jan}, pages={295–310} }
 @article{ozpinar_frey_arthur_mora-navarro_biehl_snider_cruse_freytes_2021, title={Dermal Extracellular Matrix-Derived Hydrogels as an In Vitro Substrate to Study Mast Cell Maturation}, volume={27}, ISSN={["1937-335X"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85110277858&partnerID=MN8TOARS}, DOI={10.1089/ten.tea.2020.0142}, abstractNote={Mast cells (MCs) are pro-inflammatory tissue-resident immune cells that play a key role in inflammation. MCs circulate in peripheral blood as progenitors and undergo terminal differentiation in the tissue microenvironment where they can remain for many years. This in situ maturation results in tissue- and species-specific MC phenotypes, culminating in significant variability in response to environmental stimuli. There are many challenges associated with studying mature tissue-derived MCs, particularly in humans. In cases where cultured MCs are able to differentiate in two-dimensional in vitro cultures, there remains an inability for full maturation. Extracellular matrix (ECM) scaffolds provide for a more physiologically relevant environment for cells in vitro and have been shown to modulate the response of other immune cells such as T cells, monocytes, and macrophages. To improve current in vitro testing platforms of MCs and to assess future use of ECM scaffolds for MC regulation, we studied the in vitro response of human MCs cultured on decellularized porcine dermis hydrogels (dermis extracellular matrix hydrogel [dECM-H]). This study investigated the effect of dECM-H on cellular metabolic activity, cell viability, and receptor expression compared to collagen type I hydrogel (Collagen-H). Human MCs showed different metabolic activity when cultured in the dECM-H and also upregulated immunoglobulin E (IgE) receptors associated with MC maturation/activation compared to collagen type I. These results suggest an overall benefit in the long-term culture of human MCs in the dECM-H compared to Collagen-H providing important steps toward a model that is more representative of in vivo conditions. Mast cells (MCs) are difficult to culture in vitro as current culture conditions and substrates fail to promote similar phenotypic features observed in vivo. Extracellular matrix (ECM)-based biomaterials offer three-dimensional, tissue-specific environments that more closely resemble in vivo conditions. Our study explores the use of dermal ECM hydrogels for MC culture and shows significant upregulation of metabolic activity, cell viability, and gene expression of markers associated with MC maturation or activation compared to collagen type I-hydrogel and tissue culture plastic controls at 7 days. These results are among the first to describe MC behavior in response to ECM hydrogels.}, number={15-16}, journal={TISSUE ENGINEERING PART A}, author={Ozpinar, Emily W. and Frey, Ariana L. and Arthur, Greer K. and Mora-Navarro, Camilo and Biehl, Andreea and Snider, Douglas B. and Cruse, Glenn and Freytes, Donald O.}, year={2021}, month={Aug}, pages={1008–1022} }
 @article{arthur_cruse_2018, title={Exon Skipping of Fc epsilon RI beta for Allergic Diseases}, volume={1828}, ISBN={["978-1-4939-8650-7"]}, ISSN={["1940-6029"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85052966676&partnerID=MN8TOARS}, DOI={10.1007/978-1-4939-8651-4_33}, abstractNote={Mast cells are key effector cells in allergic inflammation and consequently are ideal targets for new therapeutics. The high-affinity IgE receptor complex, FcεRI, plays a critical role in mast cell and basophil activation by allergens to drive the immediate allergic inflammatory response. The β subunit of FcεRI is critical for trafficking the FcεRI complex to the cell membrane and amplifies the FcεRI signaling cascade. We have utilized splice switching antisense oligonucleotides to force expression of a truncated isoform of FcεRIβ, which we have shown does not associate with the FcεRI complex. This approach eliminates surface FcεRI expression in mast cells by targeting protein-protein interactions. Exon skipping has several therapeutic applications, and our findings demonstrate a novel application to alter receptor trafficking and dampen allergic inflammation. Here, we describe the methods of exon skipping in mast cells and the assays used to examine the responses of mast cells in vitro and in vivo.}, journal={EXON SKIPPING AND INCLUSION THERAPIES: METHODS AND PROTOCOLS}, author={Arthur, Greer K. and Cruse, Glenn}, year={2018}, pages={503–518} }
 @article{dickey_arthur_2017, title={Big data meets materials science: Training the future generation}, volume={96}, number={6}, journal={American Ceramic Society Bulletin}, author={Dickey, E. and Arthur, G.}, year={2017}, pages={40–44} }
 @article{cruse_yin_fukuyama_desai_arthur_baumer_beaven_metcalfe_2016, title={Exon skipping of Fc epsilon RI beta eliminates expression of the high-affinity IgE receptor in mast cells with therapeutic potential for allergy}, volume={113}, ISSN={["0027-8424"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85002784626&partnerID=MN8TOARS}, DOI={10.1073/pnas.1608520113}, abstractNote={Significance
          We identified an innovative use for the technique of antisense oligonucleotide-mediated exon skipping to specifically target and down-regulate IgE receptor expression in mast cells. Exon skipping is typically used as part of personalized medicine, where a mutant exon is skipped after sequencing the patients’ affected genes. Our approach, however, targets a nonmutated gene and an exon that is critical for surface IgE receptor expression. It does not require a personalized approach with genetic sequencing or multiple iterations of oligonucleotides that would require clinical trials. Furthermore, the diseases to be treated with this technology are ideal for local delivery of the oligonucleotides by aerosols or topical cream formulations.}, number={49}, journal={PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA}, author={Cruse, Glenn and Yin, Yuzhi and Fukuyama, Tomoki and Desai, Avanti and Arthur, Greer K. and Baumer, Wolfgang and Beaven, Michael A. and Metcalfe, Dean D.}, year={2016}, month={Dec}, pages={14115–14120} }