Suppression Of Tumorigenicity 2 Research Articles

Biomarkers ST2 and interleukin 33 for assessing the severity of cardiac inflammation and fibrosis in patients with chronic heart failure

Chronic heart failure (CHF) is a pathology that affects more than 37 million people worldwide. Despite the introduction of new drugs into practice, that have proven their effectiveness in the treatment of patients with CHF, the life expectancy of these patients is growing at a slow pace. At the same time, the insufficient effect of neurohormonal blockers for the treatment of patients with CHF with preserved ejection fraction (CHFpEF), which prevails in the general structure of CHF, indicates a significant role of unidentified pathological processes in the development of this form of the disease. In recent years, the role of cardiac fibrosis has been actively studied within the framework of the investigation of the pathogenesis of CHFpEF, the probable biomarkers of which are interleukin (IL) 33 and suppression of tumorigenicity 2 (ST2). This literature review examines the influence of the IL-33/ ST2 interaction as a biomarker of cardiac fibrosis on the course of CHF and the possibilities of its practical application.

The predictive power of biomarker macrophage migration inhibitory factor in patients with st- segment elevation myocardial infarction

Abstract Biomarkers have been taken one of the first places as diagnostic and prognostic tools in acute myocardial infarction (AMI). They are used both in the acute and in the long-term periods of the disease to predict various adverse events Their especially important property is the ability to predict the long-term adverse events of the disease, which can significantly improve the outcome. One of the promising biomarkers for the early adverse outcome prediction is the proinflammatory cytokine macrophage migration inhibitory factor (MIF). Purpose To determine the MIF significance in 1-year adverse outcomes prognosis after AMI. Methods 130 ST-segment elevation myocardial infarction (STEMI) patients (72.6% male and 27.4% female) were enrolled, mean age was 58.25±1.22 years. Control group of 12 healthy volunteers included. All patients underwent a baseline investigation which includes standard electrocardiography, echocardiography with strain, angiography, and determination of marker of myocardial necrosis – cardiac troponin T. Also, the level of MIF, soluble suppression of tumorigenicity-2 (sST2), C-reactive protein determined during the first 12 hours after the STEMI, before the percutaneous coronary intervention (PCI), 6 hours, and 24 hours after the PCI. The endpoint was composite and included all-cause mortality, nonfatal myocardial infarction, nonfatal stroke, and hospitalization for unstable angina, acute decompensated heart failure. During 1-year follow-up 18% of patients reached the endpoint. Results The effect of several variables of clinical, instrumental and laboratory status were assessed on reaching the endpoint by patients. We have found that MIF level determined before PCI (AUC 0.73; p=0.003; 95% Cl: 0.613 – 0.826) might be a significant independent predictor of mortality with sensitivity (Se) 70% and specificity (Sp) 80%. MIF level 6 hours after PCI showed even better result (AUC 0.8; p=0.002; 95% Cl: 0.64 – 0.9; Se 74%, Sp 82%). MIF >3934 pg/ml associated with the highest risk of adverse events. For identification of the main risk factors for adverse outcome, we have used logistic regression method. The MIF level determined before the PCI was the most important to predict adverse outcomes (odds ratios is 1.0006, p=0,0038; x2=4.58). Areas under the ROC for the model was equal to 0.8; 95% Cl: 0.58 to 0.89). Neither sST2 nor CRP have not shown any significant results (p<0.05). According to the data of the Kaplan-Meier survival analysis, long-term survival after STEMI was significantly lower in patient with the level of MIF determined during the first 12 hours after the event more than 2988 pg/ml (Log-rank = −4,891, p=0.014). Conclusions Biomarker MIF has showed as an independent tool associated with the risk of adverse outcome 1 year after STEMI. MIF could be used in routine clinical practice to improve risk stratification of patients with STEMI. Funding Acknowledgement Type of funding sources: None.

The biomarker macrophage migration inhibitory factor as a predictor of no-reflow phenomenon and other adverse events in patients with ST-segment elevation myocardial infarction

Abstract Major adverse cardiovascular events (MACE) in patients with ST-segment elevation myocardial infarction (STEMI) after percutaneous coronary intervention (PCI) may be caused by the “no-reflow” phenomenon. Biomarkers for the “no-reflow” phenomenon prediction is being actively studied. Proinflammatory cytokine macrophage migration inhibitory factor (MIF) is one of the promising biomarkers. Purpose To estimate the role of MIF in the prediction of early reperfusion myocardial injury and MACE in patients with STEMI. Methods The study involved 341 STEMI patients (78.6% male and 21.4% female) with an average age of 59.08±9.65 years. Control group of 12 healthy volunteers included. All patients were made to undergo a baseline investigation. In addition, the level of MIF and soluble suppression of tumorigenicity-2 (sST2) determined twice during the first 12 hours of STEMI, before the PCI and 24 hours after the procedure. Coronary blood flow evaluated using TIMI flow grade and myocardial blush grade (MBG). All patients had epicardial blood flow TIMI 3. The criteria for “no-reflow” diagnosis were myocardial perfusion at MBG 0 or MBG 1 level with complete recovery of epicardial blood flow or ST-segment resolution (rST) of less than 70% from baseline within 2 hours after PCI. All patients were divided into two groups according to MBG and rST after PCI more and less than 70%: 147 patients in the first group with MBG stage 0–1, 182 patients with MBG stage 2–3. Results The level of MIF biomarker determined before PCI was significantly higher in the group of patients with MBG 0–1 in comparison to MBG 2–3. (4386,750±676 pg/ml vs 2935±350 pg/ml; p=0,05). Also, the level of sST2, left ventricular mass index and blood glucose were significantly higher in the group of MBG 0–1 (p=0.03, p=0.006 and p=0.0085, respectively). The difference in left ventricle posterior wall thickness and early to late diastolic transmitral flow velocity (p=0.045) was found between two groups. In the group of MBG 0–1 and rST<70% these parameters were significantly lower (p=0,04 and p=0,05, respectively). Using the multivariate regression analysis, the dependency of the biomarker MIF on the parameters of the reperfusion myocardial injuries were obtained. MIF measured before revascularization was an independent predictor of MBG 0–1 and rST less than 70% (coefficients Beta 0,00057; odd ratio 1,0; 95%confidential interval (CI) 1,0–1,001; p=0,038). The Kaplan-Meier survival analysis showed that long-term adverse outcomes rate after STEMI was significantly higher in patient with the level of MIF determined during the first 12 hours after the event more than 2988 pg/ml (Log-rank = −4,891, p=0.014). Conclusions Biomarkers MIF has a capacity as predictive tool for MACE and “no-reflow” phenomenon in STEMI patients. Funding Acknowledgement Type of funding sources: None.

Role of Interleukin 33 in Immune Response Process of Vitiligo Disease

Background: When melanocytes cease to operate, vitiligo develops. It is a skin and mucosa depigmentation condition. Any area of the body can develop well-circumscribed white macules or patches in this disease. Approximately 1-2 percent of the population is affected by Vitiligo. Suppression of tumorigenicity 2 (ST2), a newly discovered member of the interleukin-1 (IL-1) family, acts as a receptor for the IL-1 receptor-like 1 protein (also known as IL-1RL1) while also acting as a ligand for the interleukin-1 receptor-like 1 protein (also known as IL-1RL1) and suppressing tumorigenicity 2. Objective: To study Interleukin 33 (IL-33) in generalized and localized vitiligo patients and to assess their relationship with disease activity. Conclusion: Vitiligo could be associated with increased serum levels of IL-33, which could help as predictor marker of disease activity in vitiligo.

IL-33 Enhances IFNγ and TNFα Production by Human MAIT Cells: A New Pro-Th1 Effect of IL-33.

Mucosal-associated invariant T (MAIT) cells represent a distinct T cell population restricted by the MHC-class-I-related molecule, MR1, which recognizes microbial-derived vitamin B2 (riboflavin) metabolites. Their abundance in humans, together with their ability to promptly produce distinct cytokines including interferon γ (IFNγ) and tumor necrosis factor α (TNFα), are consistent with regulatory functions in innate as well as adaptive immunity. Here, we tested whether the alarmin interleukin 33 (IL-33), which is secreted following inflammation or cell damage, could activate human MAIT cells. We found that MAIT cells stimulated with IL-33 produced high levels of IFNγ, TNFα and Granzyme B (GrzB). The action of IL-33 required IL-12 but was independent of T cell receptor (TCR) cross-linking. MAIT cells expressed the IL-33 receptor ST2 (suppression of tumorigenicity 2) and upregulated Tbet (T-box expressed in T cells) in response to IL-12 or IL-33. Electronically sorted MAIT cells also upregulated the expression of CCL3 (Chemokine C-C motif ligand 3), CD40L (CD40 Ligand), CSF-1 (Colony Stimulating Factor 1), LTA (Lymphotoxin-alpha) and IL-2RA (IL-2 receptor alpha chain) mRNAs in response to IL-33 plus IL-12. In conclusion, IL-33 combined with IL-12 can directly target MAIT cells to induce their activation and cytokine production. This novel mechanism of IL-33 activation provides insight into the mode of action by which human MAIT cells can promote inflammatory responses in a TCR-independent manner.

IL-33/ST2 Axis Plays a Protective Effect in Streptococcus pyogenes Infection through Strengthening of the Innate Immunity.

Group A Streptococcus (GAS) causes invasive human diseases with the cytokine storm. Interleukin-33 (IL-33)/suppression of tumorigenicity 2 (ST2) axis is known to drive TH2 response, while its effect on GAS infection is unclear. We used an air pouch model to examine the effect of the IL-33/ST2 axis on GAS-induced necrotizing fasciitis. GAS infection induced IL-33 expression in wild-type (WT) C57BL/6 mice, whereas the IL-33- and ST2-knockout mice had higher mortality rates, more severe skin lesions and higher bacterial loads in the air pouches than those of WT mice after infection. Surveys of infiltrating cells in the air pouch of GAS-infected mice at the early stage found that the number and cell viability of infiltrating cells in both gene knockout mice were lower than those of WT mice. The predominant effector cells in GAS-infected air pouches were neutrophils. Absence of the IL-33/ST2 axis enhanced the expression of inflammatory cytokines, but not TH1 or TH2 cytokines, in the air pouch after infection. Using in vitro assays, we found that the IL-33/ST2 axis not only enhanced neutrophil migration but also strengthened the bactericidal activity of both sera and neutrophils. These results suggest that the IL-33/ST2 axis provided the protective effect on GAS infection through enhancing the innate immunity.

Serum Expression of IL-33 and ST2 in Patients with Psoriasis Vulgaris.

Psoriasis vulgaris (PsV) is an immune-mediated skin disease of unknown mechanism. Interleukin 33 (IL-33) is a member of IL-1 cytokine family and suppression of tumorigenicity 2 (ST2) is the specific ligand of IL-33. It has been found that IL-33 and ST2 are increased in psoriatic lesions, but the expression levels in serum and their relationship to clinical features are still unclear. The aim of this study is to assess IL-33, ST2, IL-17 and IL-5 serum levels as well as serum concentration of blood glucose and blood lipids in PsV patients and their relationship with clinical characteristics. Sixty-eight PsV samples and 60 healthy individuals were recruited. Serum levels of IL-33, ST2, IL-17 and IL-5 were measured by enzyme-linked immunosorbent assay and blood glucose and blood lipid were assayed by automatic biochemical analyzer. Serum levels of IL-33, ST2, IL-17 and IL-5 were increased significantly in PsV patients compared with controls (P<0.01). Cytokines were overexpressed in PsV patients during active stages compared with controls (P<0.05). Expression levels of IL-33, ST2 and IL-17 confirmed a significance in different severity groups of PsV patients (P<0.05). Serum concentration of triglyceride (TG) was also increased compared with controls (P=0.024). IL-33 levels were positively correlated with total cholesterol (TC) levels (r=0.319, P=0.008). IL-33/ST2 could generally reflect the activity and disease severity in PsV patients, which indicates that the IL-33/ST2 signaling pathway plays an important role in the pathogenesis of PsV.

Suppression of tumorigenicity 2 after exercise: a systematic review.

Exercise is a pivotal physiological activity, associated with benefits. Whilst the importance of physical activity is consensual along different steps of the cardiovascular (CV) continuum, there has been interest in assessing the CV adaptations to vigorous exercise. Indeed, exercise can be associated with increases in cardiac biomarkers, though the scope of this observation remains elusive. Interleukin 1 receptor related protein, Suppression of tumorigenicity 2 (ST2) is a biomarker related to the pathophysiology of fibrosis, having shown promise in the study of heart failure. Knowledge of ST2 kinetics could improve understanding of the mechanistic pathways related to CV adaptations to exercise. To assess the current state-of-the-art concerning ST2 levels after exercise in healthy individuals. A systematic review was carried out on three databases (Pubmed, ISI Web of Science and Scopus), up to October 2020, using the queries "ST2" or "ST-2" + "exercise" or "running". A total of six studies were included in the review, encompassing 349 subjects (73% male gender) in which ST2 was assessed. Most studies reported increases in ST2 levels after exercise. Three studies, encompassing a total of 219 individuals, described a cut-off level of 35 ng/dL for ST2. In these, 92.7% of subjects had ST2 levels above this cut-off after exercise (running in all studies). Most studies report increased levels of ST2 after exercise, with an important number of individuals exceeding the 35 ng/dL threshold. Given the small number of individuals represented and the lack of imaging data and long-term follow-up, further prospective larger studies should target this.

Sex-specific cut-off values for soluble suppression of tumorigenicity 2 (ST2) biomarker increase its cardiovascular prognostic value in the community

Background Suppression of tumorigenicity 2 (ST2) has important cardiovascular prognostic value in community patients; however, previous analyses have utilized non-sex specific cut-off values. We assessed whether sex-specific ST2 cut-off values would improve the prognostic utility of ST2 in the asymptomatic community. Methods A total of 2042 participants underwent clinical assessment and echocardiographic evaluation. Baseline measurements of high sensitivity troponin, natriuretic peptides and ST2 were obtained in 1681 individuals. ST2, cardiac biomarkers and associated co-morbidities were evaluated by sex-specific ST2 quartile analysis. ST2 concentrations were also analysed as dichotomous variables defined as being above the sex-specific cut-off for each the outcomes of heart failure (HF), major adverse cardiac event (MACE) and mortality. Results Median ST2 concentration was 29.4 ng/mL in male subjects and 24.1 ng/mL in female subjects. Higher ST2 concentrations were associated with incident HF (p<0.001; preserved ejection fraction (EF) p<0.001, reduced EF p=0.23), MACE (p=0.003) and mortality (p<0.001) across sex-specific quartiles. Event-based, hazard ratio (HR) analysis revealed sex-specific ST2 cut-offs were significantly more predictive of incident HF, MACE and mortality compared to non-sex-specific analysis even following adjustment for cardiac co-morbidities and traditional biomarkers. Conclusions These data suggest that sex-specific cut-offs, greater than non-sex specific cut-offs, significantly impact the prognostic value of the biomarker ST2 in the asymptomatic community cohort. Clinical Significance Suppression of tumorigenicity 2 (ST2) is a biomarker which has known associations with heart failure (HF), major adverse cardiac events (MACEs) and mortality in the general population. Recent data support the concept of sex-specific cut off values and individualized approaches based on sex to predict cardiovascular disease. Given the difference in pathobiology between the sexes, the fact that such approaches improve risk stratification is understandable. Thus, when sex-specific treatments are developed, this may similarly lead to improved outcomes. The use of sex-specific ST2 cut-off values significantly improved the prognostic value in predicting HF, MACE, and mortality in an asymptomatic community. This prognostication was particularly strong for HF with preserved ejection fraction and remained clinically significant following adjustment for cardiac co-morbidities and other traditional cardiac biomarkers (NTproBNP and hscTnI).

Efficiency and Toxicity of Ruxolitinib as a Salvage Treatment for Steroid-Refractory Chronic Graft-Versus-Host Disease.

Graft-versus-host disease (GVHD), especially steroid-refractory GVHD, remains a life-threatening complication after hematopoietic stem cell transplantation (HSCT). The effect of the JAK1/2 kinase inhibitor ruxolitinib on treating steroid-refractory acute GVHD has been verified by the REACH1/2 study; however, its safety and efficacy in patients with steroid-refractory chronic GVHD (SR-cGVHD) remain unclear. In this retrospective study, 70 patients received ruxolitinib as a salvage therapy for SR-cGVHD. Twenty-four weeks after ruxolitinib treatment, the overall response rate (ORR) was 74.3% (52/70), including 34 patients who achieved complete remission (CR) and 18 who achieved partial remission (PR). The main adverse event was cytopenia, which occurred in 51.4% (36/70) of patients. After ruxolitinib treatment, the percentage of CD4 cells increased from 18.20% to 23.22% (P<0.001), while the percentages of NK (CD16+CD56+) cells and regulatory T cells (CD4+CD127 ± CD25+) decreased (P<0.001, P<0.001). Among the B cell subsets, the proportion of total B cells approximately tripled from 3.69% to 11.16% (P<0.001). Moreover, we observed a significant increase in IL-10 levels after ruxolitinib treatment (P=0.025) and a remarkable decrease in levels of suppression of tumorigenicity 2 (ST2) from 229.90 ng/ml to 72.65 ng/ml. The median follow-up after the initiation of ruxolitinib treatment was 401 (6-1076) days. The estimated one-year overall survival rate of the whole group was 66.0% (54.4–77.6%, 95% CI), and the one-year overall survival rate of patients with mild and moderate cGVHD was 69.6% (57.4–81.8%, 95% CI), which was better than that of patients with severe cGVHD (31.3%, 0.0–66.2%, 95% CI) (P=0.002). Patients who achieved a CR and PR achieved better survival outcomes (84.5%, 73.9–95.1%, 95% CI) than those who showed NR to ruxolitinib treatments (16.7%, 0–34.3%, 95% CI) (P<0.001). At the final follow-up, cGVHD relapse occurred in six patients after they reduced or continued their ruxolitinib doses. Collectively, our results suggest that ruxolitinib is potentially a safe and effective treatment for SR-cGVHD.

ST2 As a Biomarker of Non-Relapse Mortality after HLA-Haploidentical SCT with High-Dose Post-Transplantation Cyclophosphamide

Intoduction:Allogenic hematopoietic stem cell transplantation (allo-SCT) is a curative procedure for several hematological malignancies. However, this treatment presents a significant morbidity and mortality, mainly related to infection, graft-versus-host disease (GVHD), and conditioning-related toxicity.In recent years, a number of tissue-specific proteins have been described as biomarkers that could contribute to anticipate post allo-SCT complications. ST2 (suppression of tumorigenicity 2)is a member of the interleukin-1 receptor family and It has been directly related to response to therapy of acute GVHD (aGVHD) and non-relapse mortality (NRM). Our objective was to analyze plasma levels of ST2 at days +15 and +30 post allo-SCT in patients who underwent unmanipulated haploidentical transplantation (HAPLO-HSCT), and to correlate with the NRM and GVHD.Material an methods:We retrospectively analyzed 110 consecutive patients (2009-2016) who underwent HAPLO-HSCT with post-transplant cyclophosfamide (days +3, +4), MMF and CsA as GVHD prophylaxis. A total of 23 cases were escluded, 9 cases due to early death (before day +30) and 14 cases due lack plasma sample. Characteristics of the 87 patients included in the analysis are described in Table 1. ST2 detection was performed by ELISA (Critical Diagnostics, San Diego, California) according to manufacturer's instructions on 200 μl of plasma obtained at day +15 and +30.The association of the incidence of aGVHD with known clinical variables and plasma ST2 levels were performed by Cox regression and Mann-Whitney U-test, respectively. The determination of the best cut-off of ST2 levels to stratified patients who died due to toxicity was performed with ROC curves. The statistical program used was R v2.15.0.Results:The cumulative incidence (CI) of grade II-IV and grade III-IV aGVHD at 100 days was 51.5% and 14.2%, respectively. CI of relapse and NRM at 2 years was 30% and 22.2% respectively.No association was found between usual clinical variables (stem cells source, age, sex, conditioning regimen intensity, disease status at trasplant, donor sex, and number of infused CD34 + cells) and NRM and with plasma ST2 levels at day +15 and +30. No differences were found between ST2 levels at day +15 and +30 and II-IV aGVHD, overal survival and steroid-resistant aGVHD.Highlight, plasma ST2 levels at day +30 were slightly higher in patients who devolped grade III-IV aGVHD compared to patients who did not (median and range, 2503 (524-5275) vs . 2146 (809-4572) ng/ml, p=0.12) with no stadistical significance.On the other hand, plasma ST2 levels at day +30 were significantly higher in patients with NRM compared to patients who did not (median and range, 2972 (1352-6072) vs. 2015 (809-5275) ng/ml, p= 0.022, Figure 1). Characteristics of NRM are shown in Table 2.The best cut-off selected on day +30 was 3230 ng/ml (E 82%, S 50%). Patients with higher levels than 3230 ng/ml at day +30 presented a significantly higher incidence of NRM (HR 10.4, p = 0.001, Figure 2).Conclusion:Plasma levels of ST2 at day +30 after HAPLO-HSCT correlated with the occurrence of NRM. Prospective studies are needed to better understand the kinetics of ST2 and its possible clinical application. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Role of the IL-33/ST2 pathway in renal allograft rejection

The interleukin-33 (IL-33)/suppression of tumorigenicity 2 (ST2) pathway modulates immune response and inflammation, associated with allograft dysfunction and rejection. We hypothesized that IL-33/ST2 is a marker of renal allograft rejection and IL-33/ST2 expression may differ according to rejection type. IL-33/ST2 expression was measured in sera and kidney tissues from recipients with acute antibody-mediated rejection (AAMR), acute cell-mediated rejection (ACMR), chronic antibody-mediated rejection (CAMR), and healthy controls. The soluble ST2 and IL-33/ST2 expression levels were higher in participants with all three rejection types than in controls. Although the expression levels in recipients with AAMR and ACMR were significantly higher than those with CAMR, there was no significant difference between the expression levels in AAMR and ACMR. Although IL-33, IL-8, and fibronectin expression were significantly increased after the addition of the recipients’ serum in primary cultured human renal proximal tubular epithelial cells, the levels decreased after treatment with an anti-ST2 antibody. Furthermore, the anti-ST2 antibody specifically suppressed the upregulation of the mixed lymphocyte reaction. Boyden chamber assays demonstrated that anti-ST2 antibody abrogated chemotaxis induced by recombinant IL-33. Thus, IL-33 and ST2 are potent mediators of rejection. Treatment with an anti-ST2 antibody ameliorates rejection and could be a potential therapeutic strategy for renal allograft rejection.

SERUM LEVEL OF IL-33 IN GOUTY RENAL PATIENTS

Background: Gout is a form of inflammatory arthritis and the most common metabolic disease in humans. It may result in tophi, kidney stones, or even kidney damage. It has become more common in recent decades due to increasing risk factors in the population, such as metabolic syndrome. Interleukin-33, the latest discovery in IL-1 cytokine family, acts as an early alerter of inflammation, it has been linked to several human pathologies including autoimmune diseases, sepsis, and allergy through its specific IL-1 receptor ST2 (suppression of tumorigenicity 2). However, there is little information regarding the role of IL-33 in gout.Aim of the Work: Our study aimed to examine the clinical utility of IL-33 level in serum among gouty patients and correlating its concentration with renal affection.Patients and Methods: Our case-control study was conducted on 90 subjects divided into three groups. Group I: included thirty gout patients, with no evidence of kidney affection, Group II: included thirty gout patients with kidney affection, their diagnosis based on the American College of Rheumatology classification criteria, Group III: thirty age and sex-matched, apparently healthy subjects included in the study as a control group. All individuals were subjected to detailed medical history, clinical examination including weight measurement and body mass index (BMI), and laboratory parameters including serum uric acid, creatinine, urea, lipid profile, and serum level of IL-33 measured by ELISA.Results: Serum IL-33 was predominantly increased in gout patients (with or without kidney affection) compared to healthy controls and was even higher in patients without kidney injury compared to gout patients with kidney injury. IL-33 was positively correlated with serum HDL, BMI, although it was negatively correlated with LDL and cholesterol.In Conclusion: IL-33 might have a protective role in kidney injury among gout patients.

Serum Soluble ST2 Correlated with Symptom Severity and Clinical Response of Sublingual Immunotherapy for House Dust Mite-Induced Allergic Rhinitis Patients.

Background Suppressor of tumorigenicity 2 (ST2) is a key biomarker in inflammation and cardiovascular diseases, but limited data is available on its role in allergic rhinitis (AR). Objective The aim of this study is to explore the role of serum soluble ST2 (sST2) in evaluating disease severity and predicting the efficacy of sublingual immunotherapy (SLIT) in house dust mite- (HDM-) induced AR patients. Methods Eighty healthy controls (HC group) and 160 HDM-induced AR patients, including 40 mild patients (MAR group) and 120 moderate-severe patients (MSAR group), were recruited in this study. Serum was collected from all participants and levels of sST2 were determined by ELISA and the relationship between sST2 levels and disease severity was assessed. In the MSAR group, 109 patients received 3 years of SLIT, and the relationship between serum levels of sST2 and efficacy of SLIT was exampled. Results Serum sST2 levels were increased in HDM-induced AR patients compared to the HC group (P < 0.001), and the concentrations were higher in the MSAR group than in the MAR group and HC group (all P < 0.05). Moreover, sST2 levels positively correlated with the total nasal symptom score (TNSS), visual analogue scale (VAS), and specific IgE levels (P < 0.05). Seventy-eight MSAR patients accomplished SLIT, and they were divided into an effective group (n = 40) and an ineffective group (n = 38). The serum sST2 levels in the effective group were lower than those in the ineffective group (P < 0.001). In addition, patients in the effective group levels exhibited significantly lower sST2 levels post-SLIT than pre-SLIT (P < 0.001), but no statistic difference was observed in the ineffective group (P > 0.05). Receiver operating characteristic (ROC) curve showed promising accuracy for predicting clinical efficacy of SLIT in AR patients (area under the curve = 0.839, P < 0.001). Conclusion Serum sST2 is a potential biomarker for assessing disease severity and may serve as a sensitive biomarker for predicting the therapeutic response of SLIT in HDM-induced AR patients.

Therapeutic Opportunities of Interleukin-33 in the Central Nervous System.

Interleukin-33 (IL-33), a member of the IL-1 cytokine family, is involved in various diseases. IL-33 exerts its effects via its heterodimeric receptor complex, which comprises suppression of tumorigenicity 2 (ST2) and the IL-1 receptor accessory protein (IL-1RAP). Increasing evidence has demonstrated that IL-33/ST2 signaling plays diverse but crucial roles in the homeostasis of the central nervous system (CNS) and the pathogenesis of CNS diseases, including neurodegenerative diseases, cerebrovascular diseases, infection, trauma, and ischemic stroke. In the current review, we focus on the functional roles and cellular signaling mechanisms of IL-33 in the CNS and evaluate the potential for diagnostic and therapeutic applications.

Role of the IL-33/ST2 receptor axis in ovarian cancer progression.

Ovarian cancer remains a significant health problem for women in the world due to its diagnosis at advanced stages of disease and the high mortality rate of patients. To date, ovarian cancer is frequently treated with tumor reduction surgery followed by platinum/paclitaxel-based chemotherapy; however, most patients eventually develop relapsed disease. The mRNA expression levels of interleukin-33 (IL-33) and the suppressor of tumorigenicity 2 (ST2) receptor are significantly upregulated in ovarian cancer tissues and metastatic tumor lesions. In addition, IL-33 and ST2 expression has been associated with a poor overall survival in patients with epithelial ovarian cancer. The IL-33 receptor ST2 is expressed as both a membrane-anchored receptor (ST2L) activated by IL-33, and as a soluble variant that exhibits anti-inflammatory properties. In the present review, the functions of the IL-33/ST2L axis in cells and their aberrant expression levels in ovarian cancer were discussed. In addition, targeting their expression as a novel strategy for the control of ovarian cancer progression was emphasized.

Circulating microbial cell-free DNA is associated with inflammatory host-responses in severe pneumonia

Host inflammatory responses predict worse outcome in severe pneumonia, yet little is known about what drives dysregulated inflammation. We performed metagenomic sequencing of microbial cell-free DNA (mcfDNA) in 83 mechanically...

Elevated levels of soluble ST2 but not galectin-3 are associated with increased risk of mortality in hemodialysis patients.

BackgroundThe soluble forms of suppression of tumorigenicity-2 (ST2) and galectin-3 have been proposed as novel biomarkers for cardiac fibrosis and heart failure, as well as predictors of cardiovascular events and mortality. However, there are limited data on the association between soluble ST2 and galectin-3 and clinical outcomes in patients with kidney failure on replacement therapy. To determine this, we examined the associations between soluble ST2 and galectin-3 and all-cause mortality and cardiovascular events in patients on hemodialysis.MethodsThis study included maintenance hemodialysis patients (over 18 years old) who consented to preserve their serum in the Biobank at our institution between March 2014 and March 2015. We used Cox proportional hazards regression analysis to evaluate the associations between soluble ST2, galectin-3 levels, and clinical outcomes. The primary outcome was all-cause mortality, the secondary outcome was cardiovascular disease, and patients were followed for both outcomes until March 2018.ResultsA total of 296 patients were analyzed in this study. The mean age was 57 ± 13 years, and 53.0% were male. Serum concentration of soluble ST2 was significantly associated with higher mortality, after adjustment for confounding factors, but was not associated with cardiovascular disease. Serum galectin-3 level was not independently associated with either outcome after adjustment.ConclusionElevated soluble ST2 is independently associated with an increased risk of mortality, but not with cardiovascular disease, in patients on hemodialysis. Elevated galectin-3 was not associated with mortality or cardiovascular disease.

Assessment of ST2 and Reg3a levels in patients with acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation

Background/aim Graft-versus-host disease (GVHD) is a crucial complication leading to significant morbidity and mortality allogeneic hematopoietic stem cell transplantation which occurs in approximately half of the transplant recipients. Suppression of tumorigenicity 2 (ST2) and regenerating islet-derived 3-alpha(Reg3a) might be important biomarkers to predict acute GVHD.Materials and methods In the present study, blood samples were collected from 17 patients with acute GVHD and 12 control patients after allogeneic stem cell transplantation. ST2 and Reg3a were measured in plasma samples compared in patients with acute GVHD and the controls. ResultsMedian age of the study population was 42 years (range 19–49). When compared to controls, the mean ST2 levels was significant higher in acute GVHD (9794 ng/dL vs. 2646 ng/dL, P = 0.008). Mean Reg3a level did not show significant difference between control and acute GVHD group (8848 ng/dL vs. 5632 ng/dL, respectively, P = 0.190).Conclusion The ST2 level might be used as a significant biomarker for predicting acute GVHD.

Associations Between Blood Biomarkers, Cardiac Function, and Adverse Outcome in a Young Fontan Cohort.

BackgroundPatients who have undergone the Fontan procedure are at high risk of circulatory failure. In an exploratory analysis we aimed to determine the prognostic value of blood biomarkers in a young cohort who have undergone the Fontan procedure.Methods and ResultsIn multicenter prospective studies patients who have undergone the Fontan procedure underwent blood sampling, cardiopulmonary exercise testing, and stress cardiac magnetic resonance imaging. Several biomarkers including NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide), GDF‐15 (growth differentiation factor 15), Gal‐3 (galectin‐3), ST2 (suppression of tumorigenicity 2), DLK‐1 (protein delta homolog 1), FABP‐4 (fatty acid‐binding protein 4), IGFBP‐1 (insulin‐like growth factor‐binding protein 1), IGFBP‐7, MMP‐2 (matrix metalloproteinase 2), and vWF (von Willebrand factor) were assessed in blood at 9.6 (7.1–12.1) years after Fontan completion. After this baseline study measurement, follow‐up information was collected on the incidence of adverse cardiac events, including cardiac death, out of hospital cardiac arrest, heart transplantation (listing), cardiac reintervention (severe events), hospitalization, and cardioversion/ablation for arrhythmias was collected and the relation with blood biomarkers was assessed by Cox proportional hazard analyses. The correlation between biomarkers and other clinical parameters was evaluated. We included 133 patients who have undergone the Fontan procedure, median age 13.2 (25th, 75th percentile 10.4–15.9) years, median age at Fontan 3.2 (2.5–3.9) years. After a median follow‐up of 6.2 (4.9–6.9) years, 36 (27.1%) patients experienced an event of whom 13 (9.8%) had a severe event. NT‐proBNP was associated with (all) events during follow‐up and remained predictive after correction for age, sex, and dominant ventricle (hazard ratio, 1.89; CI, 1.32–2.68). The severe event‐free survival was better in patients with low levels of GDF‐15 (P=0.005) and vWF (P=0.008) and high levels of DLK‐1 (P=0.041). There was a positive correlation (β=0.33, P=0.003) between DLK‐1 and stress cardiac magnetic resonance imaging functional reserve.ConclusionsNT‐proBNP, GDF‐15, vWF, DLK‐1, ST‐2 FABP‐4, and IGFBP‐7 levels relate to long‐term outcome in young patients who have undergone the Fontan procedure.