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Sahakian, E.,Powers, J.J.,Chen, J.,Deng, S.L.,Cheng, F.,Distler, A.,Woods, D.M.,Rock-Klotz, J.,Sodre, A.L.,Youn, J.I.,Woan, K.V.,Villagra, A.,Gabrilovich, D.,Sotomayor, E.M.,Pinilla-Ibarz, J. Pergamon Press 2015 Molecular immunology Vol.63 No.2
Myeloid-derived suppressor cells (MDSCs), a heterogeneous population of cells capable of suppressing anti-tumor T cell function in the tumor microenvironment, represent an imposing obstacle in the development of cancer immunotherapeutics. Thus, identifying elements essential to the development and perpetuation of these cells will undoubtedly improve our ability to circumvent their suppressive impact. HDAC11 has emerged as a key regulator of IL-10 gene expression in myeloid cells, suggesting that this may represent an important targetable axis through which to dampen MDSC formation. Using a murine transgenic reporter model system where eGFP expression is controlled by the HDAC11 promoter (Tg-HDAC11-eGFP), we provide evidence that HDAC11 appears to function as a negative regulator of MDSC expansion/function in vivo. MDSCs isolated from EL4 tumor-bearing Tg-HDAC11-eGFP display high expression of eGFP, indicative of HDAC11 transcriptional activation at steady state. In striking contrast, immature myeloid cells in tumor-bearing mice display a diminished eGFP expression, implying that the transition of IMC to MDSC's require a decrease in the expression of HDAC11, where we postulate that it acts as a gate-keeper of myeloid differentiation. Indeed, tumor-bearing HDAC11-knockout mice (HDAC11-KO) demonstrate a more suppressive MDSC population as compared to wild-type (WT) tumor-bearing control. Notably, the HDAC11-KO tumor-bearing mice exhibit enhanced tumor growth kinetics when compare to the WT control mice. Thus, through a better understanding of this previously unknown role of HDAC11 in MDSC expansion and function, rational development of targeted epigenetic modifiers may allow us to thwart a powerful barrier to efficacious immunotherapies.
Daniele de Ávila Dalmora,Patrícia Miranda Lago,Jordana Vaz Hendler,Milton Gross Junior,Juliana Ritondale Sodré de Castro,João Carlos Batista Santana,Liane Esteves Daudt 대한소아응급의학회 2024 대한소아응급의학회지 Vol.11 No.3
Purpose: Magnesium sulfate (MgSO4) emerged as an adjunctive therapy to help manage acute severe asthma refractory to the first-line therapy, such as oxygen, ipratropium, corticosteroids, and bronchodilators. Despite the known benefits of MgSO4, limited information is available regarding potential adverse effects (AEs). We aimed to investigate potential AEs and clinical response of intravenous MgSO4 by assessing vital signs and the modified Wood-Downes score (mWDS), a relevant clinical scoring system. Methods: This investigation constitutes a prospective, single- arm study, conducted from June 2022 through May 2023, in a pediatric emergency department of the quaternary public hospital in Brazil. This study included all children aged 3-14 years who visited the pediatric emergency department during the period and underwent a 6-hour continuous infusion of MgSO4 at 50 mg/kg/hour, against acute severe asthma, a case refractory to the first-line therapies. We evaluated the safety and efficacy of the infusion by using vital signs and the mWDS. Clinical response was defined as a reduction of at least 1 point in the scoring system. Results: We analyzed a total of 42 children including 24 boys (57.1%), whose mean age was 5.7 ± 2.4 years. The 6- hour continuous infusion of MgSO4 reduced mWDS from 3 (interquartile range, 3-4) to 2 (2-3) (P < 0.001) and resulted in the clinical response in 30 children (71.4%) without an AE. After the infusion, 13 of the 15 children (86.7%) classified as having moderate asthma exacerbation (mWDS, 4-6) were improved to having mild asthma exacerbation (mWDS, 1-3) (P < 0.001). The mean serum magnesium concentration after the infusion was 4.7 mg/dL. Pneumonia and viral infection did not predict the clinical response. Conclusion: This study indicates the safety and efficacy of the 6-hour continuous infusion of MgSO4 as a therapeutic option for acute severe asthma, which is refractory to the first-line therapy.