Suppression Of Tumorigenicity 2 Levels Research Articles

Intestinal IL-33 promotes microbiota-derived trimethylamine N-oxide synthesis and drives metabolic dysfunction-associated steatotic liver disease progression by exerting dual regulation on HIF-1α.

Gut microbiota play a prominent role in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD). Interleukin-33 (IL-33) is highly expressed at mucosal barrier sites and regulates intestinal homeostasis. Herein, we aimed to investigate the role and mechanism of intestinal IL-33 in MASLD. In both human and mice with MASLD, hepatic expression of IL-33 and its receptor suppression of tumorigenicity 2 (ST2) showed no significant change compared to controls, while serum soluble ST2 levels in humans, as well as intestinal IL-33 and ST2 expression in mice were significantly increased in MASLD. Deletion of global or intestinal IL-33 in mice alleviated metabolic disorders, inflammation and fibrosis associated with MASLD by reducing intestinal barrier permeability and rectifying gut microbiota dysbiosis. Transplantation of gut microbiota from IL-33 deficiency mice prevented MASLD progression in wild type (WT) mice. Moreover, IL-33 deficiency resulted in a decrease in the abundance of trimethylamine N-oxide (TMAO)-producing bacteria. Inhibition of TMAO synthesis by 3,3-dimethyl-1-butanol (DMB) mitigated hepatic oxidative stress in mice with MASLD. Nuclear IL-33 bound to hypoxia inducible factor-1α (HIF-1α) and suppressed its activation, directly damaging the integrity of intestinal barrier. Extracellular IL-33 destroyed the balance of intestinal Th1/Th17 and facilitated Th1 differentiation through the ST2-Hif1a-Tbx21 axis. Knockout of ST2 resulted in a diminished MASLD phenotype resembling that observed in IL-33 deficiency mice. Intestinal IL-33 enhanced gut microbiota-derived TMAO synthesis and aggravated MASLD progression through dual regulation on HIF-1α. Targeting IL-33 and its associated microbiota may provide a potential therapeutic strategy for managing MASLD.

Soluble suppression of tumorigenicity 2 is a potential predictor of post-liver transplant renal outcomes.

Acute kidney injury is considered an independent prognostic factor for mortality in patients with liver cirrhosis. Non-treated acute kidney injury can progress to hepatorenal syndrome with a poor prognosis. As suppression of tumorigenicity 2 (ST2) is a member of the interleukin-1 receptor family that aggravates inflammation and fibrotic changes in multiple organs, we measured soluble ST2 (sST2) level in the serum and urine of liver-transplant recipients at the time of transplantation. The serum sST2 level significantly increased in liver-transplant recipients with suppressed kidney function compared with that in recipients with normal function. In recipients with severely decreased liver function (model for end-stage liver disease score ≥ 30), the serum sST2 level was higher than that in recipients with preserved liver function (model for end-stage liver disease score ≤ 20, P = 0.028). The serum sST2 level in recipients with hepatorenal syndrome was higher than that in liver-transplant recipients without hepatorenal syndrome (P = 0.003). The serum sST2 level in patients with hepatorenal syndrome was higher than that in recipients without a history of acute kidney injury (P = 0.004). Recipients with hepatorenal syndrome and recovered kidney function showed higher sST2 levels than those who did not recover (P = 0.034). Collectively, an increase in the serum sST2 level reflects a decrease in both kidney and liver functions. Thus, measuring sST2 level at the time of liver transplantation can help predict renal outcomes.

Salivary IL-33 and sST2 levels in relation to TLR2 rs111200466 polymorphism and periodontitis.

Toll-like receptor-2 (TLR2) signalling pathway is involved in the regulation of interleukin (IL)-33 and its receptor suppression of tumorigenicity-2 (ST2). This study aimed to compare salivary IL-33 and soluble ST2 (sST2) levels of periodontitis patients with those of periodontally healthy individuals in relation to their TLR2 rs111200466 23-bp insertion/deletion polymorphism within the promoter region. Unstimulated saliva samples were collected, and periodontal parameters were recorded from 35 periodontally healthy individuals and 44 periodontitis patients. Non-surgical treatments were applied to periodontitis patients, and sample collections and clinical measurements were repeated 3 months following therapy. Salivary IL-33 and sST2 levels were measured with enzyme-linked immunosorbent assay kits, and TLR2 rs111200466 polymorphism was detected by polymerase chain reaction. Elevated salivary IL-33 (p = 0.007) and sST2 (p = 0.020) levels were observed in periodontitis patients, in comparison to controls. sST2 levels declined 3-months following treatment (p < 0.001). Increased salivary IL-33 and sST2 levels were found to be associated with periodontitis, with no significant relation to the TLR2 polymorphism. Periodontitis, but not TLR2 rs111200466 polymorphism, is associated with elevated salivary sST2 and possibly IL-33 levels, and periodontal treatment is effective in reducing salivary sST2 levels.

The Effect of Elective Ligation of the Arteriovenous Fistula on Cardiac and Renal Functions in Kidney Transplant Recipients.

Kidney transplantation (KTx) is considered as the best kidney replacement therapy and arteriovenous fistula (AVF) is the preferred vascular access for hemodialysis. The systematic ligation of a functioning AVF in stable kidney transplant recipients remains debatable. In this prospective study, we investigated the hemodynamic impact of the surgical closure of AVF in KTRs. Forty-three KTRs underwent an ambulatory blood pressure monitoring (24h-ABPM) before surgical closure of AVF (T0) and 12 months later (M12), as well as measurement of serum cardiac biomarkers (i.e., soluble suppression of tumorigenicity 2 (ST2), N-terminal pro b-type natriuretic peptide (NT-proBNP) and Galectin-3). Serum tests were also performed 6 months after AVF closure (M6). An echocardiographic exam was done at each time-point. All serum creatinine values were collected to compare the individual eGFR slopes before versus after AVF closure. The latest measure of the AVF flow (QAVF) prior to KTx was recorded. Diastolic blood pressure (DBP) significantly raised from T0 to M12: + 4.4±7.3 mmHg (p=0.0003) for 24h, + 3.8±7.4 mmHg (p=0.0018) during the day, and + 6.3±9.9 mmHg (p=0.0002) during the night, leading to an increased proportion of KTRs with ESH-defined arterial hypertension after AVF ligation. No change was observed for systolic BP. NT-proBNP significantly dropped between T0 and M6 (345 [190; 553] to 230 [118; 458] pg/mL, p=0.0001) and then remained stable from M6 to M12, while ST2 and Galectin-3 levels did not change from T0 to M12. We observed a significant decrease of left ventricular (LV) end-diastolic volume, LV end-systolic volume, LV mass, interventricular septum diameter, left atrial (LA) volume, and tricuspid annular plane systolic excursion from T0 to M6, and then a stability from M6 to M12. LV ejection fraction and eGFR slope remained stable during the whole study. These observations remained unchanged after adjustment for QAVF. The closure of a patent AVF in KTRs is associated with elevation of DBP, drop of serum NT-proBNP levels, reduction of LV/LA dimensions, and stable eGFR slope.

ST2 and CSF-1 as potential druggable targets of inflammatory bowel diseases: Results from two-sample Mendelian randomization study.

Novel druggable targets are warranted for inflammatory bowel disease (IBD) treatment. We aimed to identify novel circulating proteins with causal associations with the risk of IBDs and provide potential therapeutic targets for IBD treatment. We performed a two-sample Mendelian randomization (MR) study to explore the associations of 55 circulating biomarkers on the risk of IBD, Crohn's disease (CD), and ulcerative colitis (UC) by leveraging the summary statistics from large genomewide association studies and protein quantitative trait loci studies. The individual estimate was pooled together by meta-analyses to estimate the causal effects of each outcome. In univariable MR, we identified several circulating proteins showed potential correlation with IBD, UC, and CD. Of note, we observed that a genetically proxied increased level of suppression of tumorigenicity 2 (ST2) was associated with an elevated risk of IBD (odds ratios [ORs] 1.133, 95% confidence interval [CI] 1.091-1.176, p < 0.0001), CD (ORs 1.188, 95% CI 1.103-1.281, p < 0.0001), and UC cohorts (ORs 1.087, 95% CI 1.050-1.125, p < 0.0001). Additionally, we observed a consistent positive correlation between the level of CSF-1 and the increased risk of IBD in individual MR, with statistically significant causal associations in the meta-analyses with ORs equal to 1.217 (IBD, 95% CI 1.115-1.328, p < 0.0001), 1.223 (CD, 95% CI 1.082-1.382, p=0.0013), and 1.179 (UC, 95% CI 1.055-1.317, p=0.0037). This study provided evidence for potential casual associations between circulating ST2 and CSF-1 levels, and increased risks of IBD, UC, and CD, implicating potential treatment targets for IBD and subtypes.

Suppression of Tumorigenicity 2 Pro-Inflammatory Biomarker Linking Diabetes Mellitus and Periodontitis: A Pilot Study.

BACKGROUND Suppression of tumorigenicity 2 (ST2) is a member of the interleukin (IL)-1 family and has 2 isoforms: ST2L, a transmembrane form, and ST2, a soluble form. IL-33 can act as an immune system alarm signal when released by damaged cells, which in turn activates other cells expressing the ST2 receptor. This can cause inflammatory cytokines to be released and produced, as well as trigger osteoclastogenesis. This study aimed to investigate the levels of soluble ST2 in gingival samples. MATERIAL AND METHODS The study population consisted of 30 individuals. The participants were divided into 3 groups: healthy participants, patients with periodontitis, and patients with periodontitis and diabetes mellitus. Periodontitis was determined using probing depth, clinical attachment loss, and gingival index. Patients with stage 2 to 4 periodontitis met the inclusion criteria. Gingival crevicular fluid (GCF) was collected for quantification of samples for ST2 levels by using an enzyme immunoassay. RESULTS The mean±standard deviation of ST2 GCF concentrations was relatively high (558.87±68.99) in the group with periodontitis and diabetes mellitus, compared with that of the periodontitis group (452.06±54.18) and healthy group (252.82±87.9). CONCLUSIONS GCF ST2 values were found to be a marker of inflammatory activities. Thus, GCF ST2 could be a potential biomarker for the diagnosis of periodontitis as well as systemic diseases, such as diabetes mellitus. This pilot study was limited by a small number of participants. To confirm the associations, more large-scale investigations should be conducted.

The Interleukin-33/ST2 Axis Enhances Lung-Resident CD14+ Monocyte Function in Patients with Non-Small Cell Lung Cancer

ABSTRACT Interleukin-33 (IL-33) binds to its cognate receptor suppression of tumorigenicity 2 (ST2), leading to critical modulatory roles in immune responses during inflammation and cancers. The aim of this study was to investigate the role of IL-33/ST2 signaling in monocyte function in non-small cell lung cancer (NSCLC). Sixty-two NSCLC patients and nineteen controls were enrolled. IL-33 levels and ST2 expression were measured in peripheral blood and bronchoalveolar lavage fluid (BALF) by ELISA and flow cytometry. HLA-DR expression by CD14+ monocytes, granzyme B and proinflammatory cytokine secretion were also investigated in lipopolysaccharide-stimulated cells. CD14+ monocytes purified from BALF in the tumor site were stimulated with IL-33 in vitro, and co-cultured with a lung cancer cell line A549 cells. The cytotoxicity of monocytes with IL-33 stimulation was then assessed. IL-33 levels were lower in the peripheral blood and tumor microenvironment of NSCLC patients. There was no significant difference in peripheral ST2 expression between NSCLC patients and controls. Soluble ST2 levels were increased but membrane-bound ST2 expression in CD14+ monocytes was decreased in tumor microenvironment of NSCLC patients. There were no remarkable differences in either HLA-DR expression or proinflammatory cytokine secretion by circulating CD14+ monocytes between NSCLC patients and controls. CD14+ monocytes in the tumor microenvironment revealed a dysfunctional phenotype, which presented as lower HLA-DR expression and reduced granzyme B and proinflammatory cytokines. A higher concentration of IL-33 stimulation promoted tumor-resident CD14+ monocyte-induced target cell death. The present study indicates that IL-33/ST2 signaling pathway might enhance the activity of tumor-resident CD14+ monocytes in NSCLC.

Association of ST2 Elevation in the Early Third Trimester with Heart Failure and Pre-Eclampsia in the Peripartum Period.

Background: Although high-risk pregnancies are common in clinical practice, there are limited data on the association of soluble suppression of tumorigenicity 2 (ST2) with pregnancy-related complications. The rates of maternal complications, including heart failure (HF) during the peripartum period, were evaluated according to the ST2 level. Materials and Methods: A single-center retrospective cohort study included and stratified 259 women with high-risk pregnancies in their early third trimester according to the ST2 levels. The primary endpoint was the occurrence of peripartum HF based on symptoms, N-terminal pro-brain natriuretic peptide, or echocardiography associated with fluid retention. The secondary endpoints consisted of pre-eclampsia, silent pleural effusion, and pericardial effusion during the peripartum period. We performed a logistic model for the association between ST2 and maternal complications. Results: Of the 259 patients (mean age: 36.4 years, mean gestational duration: 31.6 weeks), advanced age ≥35 years and twin gestation were the most prevalent risk factors. Patients with ST2 ≥ 35 ng/mL showed enlarged cardiac chambers. Peripartum HF occurred in 2 (1.6%) out of 121 patients with ST2 < 35 ng/mL and in 47 (34%) out of 138 patients with ST2 ≥ 35 ng/mL. Those with ST2 ≥ 35 ng/mL were more likely to have the secondary endpoints (40.6% vs. 5.8%, p < 0.001). After adjustment, ST2 ≥ 35 ng/mL was associated with a six-fold occurrence of peripartum HF and a four-fold increase in the secondary endpoints. Conclusions: In women with high-risk pregnancies, peripartum HF and pre-eclampsia were not uncommon, and ST2 ≥ 35 ng/mL in the third trimester was independently related to maternal complications.

Diagnostic efficacy of serum ST2 in patients with ASC.

BackgroundSoluble suppression of tumorigenicity 2 (ST2) is closely related to the development of cardiovascular disease, but the level of acute coronary syndrome (ACS) and the relationship between ST2 and ACS are unclear.Patients and MethodsPatients with the acute coronary syndrome were divided into the unstable angina pectoris (USAP) group (n = 65) and non‐ST‐segment elevation myocardial infarction (NSTEMI) group (n = 58), and the healthy population, without chest pain and with normal coronary CT, was included as a control group (n = 55). Laboratory index levels were collected from each participant. The baseline information was reviewed and analyzed. The binary logistic regression was used to explore the relation of ST2 levels with the occurrence of ACS and NSTEMI, and the diagnostic performance of ST2 for diagnosing ACS or NSTEMI was evaluated using a receiver‐operating characteristic (ROC) curve.ResultsThe level of ST2 was found significantly higher in NSTEMI than in USAP and was higher in USAP than in control (p < 0.01). ST2 levels were positively correlated with ALT, AST, and BNP in the control group, were negatively correlated with HGB and TG in the USAP group, and were positively correlated with WBC, GLU, BNP, and Gensini scores in the NSTEMI group. Multivariate analysis revealed that the occurrence of ACS was associated with ST2, BNP, GLU, TC, BUN, WBC, and PLT, and the occurrence of NSTEMI was associated with AST, WBC, LDL‐C, and ST2. Meanwhile, ST2 levels achieved good performance for ACS and NSTEMI diagnostician.ConclusionST2 could be used as an auxiliary diagnostic indicator for the occurrence of ACS and NSTEMI.

General Rehabilitation Program after Knee or Hip Replacement Significantly Influences Erythrocytes Oxidative Stress Markers and Serum ST2 Levels.

The survival of erythrocytes in the circulating blood depends on their membranes' structural and functional integrity. One of the mechanisms that may underlie the process of joint degeneration is the imbalance of prooxidants and antioxidants, promoting cellular oxidative stress. The study is aimed at observing the effects of the 21-day general rehabilitation program on the erythrocytes redox status and serum ST2 marker in patients after knee or hip replacement in the course of osteoarthritis. Erythrocytes and serum samples were collected from 36 patients. We analyzed the selected markers of the antioxidant system in the erythrocytes: catalase (CAT), glutathione reductase (glutathione disulfide reductase (GR, GSR)), total superoxide dismutase activity (SOD), glutathione peroxidase (GPx), glutathione transferase (GST) activity, and cholesterol and lipofuscin (LPS) concentration. In serum, we analyzed the concentration of the suppression of tumorigenicity 2 (ST2) marker. After the 21-day general rehabilitation program, the total SOD and GPx activity, measured in the hemolysates, significantly increased (p < 0.001) while LPS, cholesterol, and ST2 levels in serum significantly decreased (p < 0.001). General rehabilitation reduces oxidative stress in patients after knee or hip replacement in the course of osteoarthritis. Individually designed, regular physical activity is the essential element of the postoperative protocol, which improves the redox balance helping patients recover after the s4urgery effectively.

Correlation of serum ST2 levels with severity of diastolic dysfunction on echocardiography and findings on cardiac MRI in patients with heart failure with preserved ejection fraction

ObjectiveThe aim of the present study was to find a correlation of serum Suppression of tumorigenicity 2 (ST2) levels with severity of diastolic dysfunction on echocardiography and cardiac magnetic resonance imaging (CMRI) in heart failure with preserved ejection fraction (HFpEF) patients. MethodsFifty patients aged ≥18 years fulfilling diagnostic criteria for HFpEF were included. ST2 levels, 2D echocardiography and CMRI were performed. Left ventricular ejection fraction, E/A, Septal E/E’, left atrial volume index (LAVI), tricuspid regurgitation (TR), assessment of diastolic dysfunction, T1 mapping in milliseconds and late gadolinium enhancement (LGE) in percentage were noted. The primary outcome measure was to study correlation of ST2 levels with severity of diastolic dysfunction, whereas the secondary outcome measures were to study correlation of ST2 levels with native T1 mapping and LGE on CMRI. ResultsST2 levels showed statistically significant and positive correlation with E/E’ (r = 0.837), peak TR velocity (r = 0.373), LAVI (r = 0.74), E/A (r = 0.420), and T1 values in milliseconds (r = 0.619). There was no statistically significant correlation between ST2 level and LGE in % (r = 0.145). The median ST2 levels in patients with E/E’ > 14 and E/E’ ≤ 14 were 110.8 and 36.1 respectively (p-value < 0.05). The mean ST2 levels were significantly higher in patients who had diastolic dysfunction grade III (126.4) and New York Heart Association class IV (133.3). ConclusionsEvaluation of ST2 adds important information to support the diagnosis of left ventricular diastolic dysfunction in patients with HFpEF.

Validation of Pre-Transplantation Plasma ST2 Levels As a Prognostic Marker of 1-Year Non-Relapse Mortality after Allogeneic Hematopoietic Cell Transplantation

Introduction: Accurate assessment of the risk of non-relapse mortality (NRM) is important for making the shared decision about treatment with allogeneic hematopoietic cell transplantation (allo-HCT). We have shown that the pre-transplantation plasma level of suppression of tumorigenicity 2 (ST2)-a protein that is released to the bloodstream upon inflammation, cellular stress and endothelial damage-was associated with NRM after myeloablative allo-HCT [Gjærde et al., ASH Annual Meeting 2020, abstract #1524]. In an expanded cohort of both myeloablative- and non-myeloablative conditioned patients, we aimed to validate the value of pre-transplant ST2 in predicting 1-year NRM after allo-HCT.Methods: Pre-transplantation plasma ST2 levels were measured by enzyme-linked immunosorbent assays in 374 adult patients who underwent allo-HCT at Rigshospitalet between July 2015 and December 2019 (Table 1), using stored plasma samples collected at a median (Q1, Q3) of 23 (21, 24) days before allo-HCT. All patients were followed-up for at least 1 year after transplant. NRM was defined as all deaths in relapse-free patients. Given our sample size and outcome proportion, we could include four parameters in a logistic regression model of 1-year NRM to avoid severe overfitting [Riley et al., BMJ, 2020]. Based on our current clinical risk assessment practice, we included age (linear), comorbidity index (HCT-CI [Sorror et al., Blood, 2005], linear) and conditioning intensity (myeloablative vs. non-myeloablative) in a base model, to which we added the pre-transplantation ST2 level (linear) and assessed its incremental prognostic value [Steyerberg et al., Epidemiology, 2019]. The internal validity of the full model was estimated by bootstrapping [Steyerberg et al., J Clin Epidemiol, 2001].Results: The median (Q1, Q3) pre-transplantation plasma ST2 level was 20.4 (15.2, 27.2) ng/mL. NRM at 1-year was 9% (N = 33). The main causes of NRM were organ failure (39%), infection (23%) and acute graft-versus-host disease (21%). Relapse risk at 1-year was 18%. The patients who constituted the 33 cases of 1-year NRM had a 2.7 ng/mL higher median pre-transplantation ST2 level than the remaining 341 patients (95% bootstrap confidence interval [CI] of the difference: -1.9, 6.2 ng/mL, Figure Panel A). In the full logistic regression model-including age, HCT-CI, conditioning intensity and ST2-ST2 was associated with 1-year NRM with an odds ratio of 1.32 (CI: 1.05, 1.65) per 10 ng/mL increase. Adding ST2 to the base model increased the model likelihood ratio χ 2 from 12.1 to 17.3 (p = 0.02), i.e. ST2 added a fraction of 30% (12.1/17.3) of new predictive information to age, HCT-CI and conditioning intensity. However, the ability of the full model to discriminate cases of NRM at 1-year remained poor with minimal improvement after adding ST2 (AUC up to 0.675 from 0.674 in the base model). The bootstrap-corrected AUC (the expected AUC of the full model used in a new population) was 0.63. Moreover, bootstrap-corrected estimates of predicted vs. observed risk revealed slight model miscalibration: lower predicted risks were generally underestimated, while higher predicted risks were overestimated (Figure Panel B).Conclusion: Pre-transplantation plasma levels of ST2 was a prognostic biomarker of 1-year NRM after allo-HCT, adding new predictive information to age, HCT-CI and conditioning intensity. However, internal validation of the full ST2-based prediction model revealed poor overall performance, precluding further validation and use of the model in clinical practice. When identifying prognostic biomarkers, investigation of overall predictive performance (in addition to already known prognostic factors) is needed before clinical usefulness can be evaluated. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

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.

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.

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.

Pre-Transplantation ST2 Levels and Non-Relapse Mortality after Myeloablative Allogeneic Hematopoietic Cell Transplantation

Introduction: Suppression of tumorigenicity 2 (ST2) is a prognostic plasma marker of non-relapse mortality (NRM) after allogeneic hematopoietic cell transplantation (allo-HCT) when measured at day +14 [Vander Lugt MT et al., N Engl J Med, 2013] and at day +7 in combination with regenerating islet-derived 3α (REG3α) [Hartwell MJ et al., JCI Insight, 2017]. We hypothesized that also pre-transplantation ST2 levels would be associated with NRM in the first 6 months after allo-HCT. Methods: We studied 112 adult patients who underwent allo-HCT with myeloablative conditioning at Rigshospitalet between July 2015 and August 2018 (Table 1). ST2 levels were measured by enzyme-linked immunosorbent assays using stored EDTA plasma samples obtained at the patients' scheduled pre-transplantation visit around day -23 (±11 days) and post-transplantation at days +7 and +14 (±3 days, n = 76 and 66). Univariable linear models and Spearman's ρ were used to evaluate associations and correlations between pre-transplantation ST2 levels and patient characteristics and other prognostic markers, respectively. Cause-specific Cox regression models were used to estimate hazard ratios (HR) with 95% confidence intervals (CI) for NRM in the first 6 months after allo-HCT (relapse as competing risk) and grade II-IV acute graft-versus-host disease (GvHD) in the first 100 days after allo-HCT (NRM and relapse as competing risks) according to pre-transplantation ST2 levels. Gray's test was used to test differences in the cumulative incidence of NRM in the first 6 months after allo-HCT according to quartiles of pre-transplantation ST2 levels. Results: The median pre-transplantation plasma ST2 level was 19.9 ng/mL (inter-quartile range: 14.6-25.7 ng/mL, Figure Panel A); levels were higher in males (β = 8.7 ng/mL, p &amp;lt; 0.01), but did not differ by age (p = 0.81) or by being transplanted for acute leukemia (p = 0.89). ST2 was correlated with C-reactive protein (ρ = 0.24, p = 0.01), the endothelial activation and stress index (EASIX, calculated as creatinine x lactate dehydrogenase/thrombocytes, ρ = 0.27, p &amp;lt; 0.01) and ferritin (ρ = 0.28, p &amp;lt; 0.01). Longitudinally, pre-transplantation ST2 levels were strongly correlated with ST2 levels on day +7 (ρ = 0.57, p &amp;lt; 0.01) and day +14 (ρ = 0.48, p &amp;lt; 0.01). The cumulative incidence of NRM at 6 months was 11% (n = 12); causes of death were organ failure (75%), acute graft-versus-host disease (GvHD, 17%) and infection (8%). Higher pre-transplantation ST2 levels were associated with increased hazard of NRM in the first 6 months after allo-HCT (HR 1.73 per 10 ng/mL increase, 95% CI: 1.28-2.33, p &amp;lt; 0.01, area under the receiver operating characteristics curve = 0.61). Despite a significantly higher NRM in patients with pre-transplantation ST2 levels in the highest quartile (cumulative incidence at 6 months: 21% vs. 7% in patients with levels in the three lower quartiles, p = 0.03), there was no overall significant difference in NRM according to quartiles of pre-transplantation ST2 levels (p = 0.15, Figure Panel B). No significant association was found between pre-transplantation ST2 levels and grade II-IV acute GvHD (HR 0.88, 95% CI: 0.61-1.26, p = 0.48). Conclusion: Pre-transplantation ST2 levels were associated with increased NRM in the first 6 months after myeloablative allo-HCT, mainly driven by higher NRM in patients with pre-transplantation ST2 levels in the highest quartile. Larger studies are warranted to validate pre-transplantation ST2 levels as a prognostic marker of NRM after allo-HCT, which potentially could be used to support the choice of conditioning intensity. Disclosures No relevant conflicts of interest to declare.

Effect of Remestemcel-L Treatment in Pediatric Steroid Refractory Acute Graft-Versus-Host Disease: A Biomarker Substudy

Introduction: Steroid-refractory acute graft-versus-host dose disease (SR-aGVHD) is a common, potentially fatal complication of hematopoietic stem cell transplantation (HSCT) with no approved therapies for use in children &amp;lt; 12 years old with SR-aGVHD. We recently reported the results from a phase 3 pivotal single arm study of remestemcel-L, human, culture-expanded, allogeneic mesenchymal stromal cells as first line therapy after failure to respond to steroids (NCT02336230). Subjects (n=54) received 8 intravenous infusions of remestemcel-L (2 x 106 cells/kg) twice weekly for 4 weeks. The primary endpoint, overall response at day 28 was achieved in 38/54 (70%) of patients and 40/54 (74%) survived through day 100. To explore further the biologic, mechanistic basis for effects of remestemcel-L in SR-aGVHD, we assessed a panel of soluble and cellular biomarkers in a subset of subjects (N=40) who participated in an elective biomarker substudy. The aim of the biomarker substudy was to explore the effect of remestemcel-L treatment on biomarkers involved in disease processes in aGVHD and which have established prognostic and/or predictive value in aGVHD Methods: Whole blood samples for biomarker analyses were collected at baseline, and days 28, 100, 160 and 180. Circulating levels of NK cells, T and B lymphocytes and of activated T cells (CD25+, HLA-DR+), key effectors of aGVHD development and progression, were measured by multicolor flow cytometry. Plasma levels of regenerating islet-derived protein 3α (REG3α) were measured using a multiplexed immunoassay; soluble suppression of tumorigenicity 2 (ST2) levels were measured by ELISA. REG3α and ST2 were used to derive the MAGIC algorithm probability (MAP) score at each time point as an index of gastrointestinal disease burden and risk of 6-month non-relapse mortality (NRM), with a threshold probability of 0.291 cut-off for GVHD low and high risk of NRM. Least-Squares Means (LSM) were calculated for longitudinal biomarker analyses using the restricted maximum likelihood (REML) approach followed by post-hoc pairwise comparisons between days using the Tukey-Kramer HSD significance test. These analyses were exploratory, so no adjustment was made for multiplicity. Results: Biomarker data were collected in 40 subjects. At baseline, the mean age was 8.5 years, aGVHD severity by IBMTR grade C or D, median MAP was 0.369, with a MAP ≥ 0.291 in 60% of subjects, reflecting active gastrointestinal inflammation and high risk for 6-month NRM. In this biomarker cohort day 28 (N=40) overall response was 70% and survival was 78% and 70% through day 100 and 180, respectively. Baseline biomarker profile was consistent with an inflammatory state characteristic of SR-aGVHD, with elevated plasma levels of Reg3α, ST2 and frequencies of activated CD4+ and CD8+ T cells. MAP decreased from ≥0.291 to &amp;lt;0.291 by day 100 with further reductions through day 180, P&amp;lt;0.0001; baseline MAP = 0.36, 95% CI [0.30, 0.41] vs day 100 = 0.26, 95% CI [0.20-0.32], P=0.0037; baseline MAP vs day 180 = 0.20, 95% CI [0.14, 0.26], P&amp;lt;0.0001). These changes in MAP were attributable to significant reductions in ST2 levels. Levels of activated T cells declined over the course of the study (CD3+CD4+CD25+HLA-DR+ (%), F(4, 83.8) = 6.84, P&amp;lt;0.0001; CD3+CD8+ HLA-DR+ (%), F(4, 72.65) = 8.00, P&amp;lt;0.0001) The frequency of CD3+CD4+CD25+HLA-DR+ T cells significantly decreased from baseline (26.57%, 95% CI [22.02, 31.06]) to day 28 (17.70%, 95% CI [13.40-22.00], P=0.0084), plateaued through day 100 and remained significantly below baseline at day 180 (12.74%, 95% CI [7.29-18.19], P=0.0004 vs baseline). The percentage of CD3+CD8+HLA-DR+ T cells significantly decreased from baseline (67.81%, 95% CI [60.21, 75.42]) to day 100 (54.14%, 95% CI [45.99, 62.29], P=0.0075) and decreased further by day 180 (47.10%, 95% CI [38.49, 55.72], P=0.0001 vs baseline). In contrast, levels of T, B and NK cells generally increased over time suggesting no long-term impairment of hematopoietic reconstitution following remestemcel-L treatment. Conclusions: Clinically meaningful overall response and survival with remestemcel-L-treatment in pediatric SR-aGVHD are associated with changes in soluble and cellular biomarkers consistent with reduced inflammation and risk of mortality. These observed changes in biomarkers provide mechanistic evidence of immunomodulation. Disclosures See: Mesoblast, Inc,: Current Employment. Segal:Mesoblast, Inc,: Current Employment. Simmons:Mesoblast, LTD: Current Employment. Kurtzberg:Mesoblast, Inc,: Consultancy, Honoraria.

Correlation between Suppression of Tumorigenicity-2 with Left Ventricular Geometry, Left Ventricular Ejection Fraction and Quality of Life in Systolic Heart Failure Patients

BACKGROUND: Heart failure (HF) is a clinical syndrome caused by structural or functional cardiac disorders and is the final stage of every heart disease, marked by decreased functional capacity and patients’ quality of life (QoL). Suppression of tumorigenicity-2 (ST2) is a biomarker depicting heart fibrosis and remodeling that altered left ventricular geometry, which in turn decreases left ventricular contractility, decreases functional capacity, and ultimately affects the QoL of the HF patient.METHODS: An observational study was conducted with a cross-sectional approach involving 60 patients with systolic heart failure. Left ventricular geometry, left ventricular ejection fraction (LVEF), ST2 level, and other biomarkers were examined, continued by QoL assessment.RESULTS: The ST2 level (33.25±23.55 ng/mL) was negatively correlated with LVEF (r=-0.257; p=0.024) and was positively correlated with QoL (r=0.255; p=0.05). The LVEF was negatively correlated with QoL (r=-0.224; p=0.031). However, no significant correlation was found between left ventricular geometry with ST2 level or patients’ QoL.CONCLUSION: Elevated ST2 levels are correlated with decreased LVEF and worse QoL in systolic heart failure subjects. Therefore, ST2 together with LVEF can be used as prognostic tools for patients with HF.KEYWORDS: heart failure, ST2, left ventricular geometry, left ventricular ejection fraction, quality of life

High Expression of Interleukin-33/ST2 Predicts the Progression and Poor Prognosis in Chronic Hepatitis B Patients with Hepatic Flare

BackgroundInterleukin-33 (IL-33), along with its receptor suppression of tumorigenicity 2 (ST2), is capable of regulating immune responses. Immunologically mediated events play a critical role in the acute phase of chronic hepatitis B (CHB) infection. The present study primarily aimed to determine whether the IL-33/ST2 axis could be used as a reliable biomarker to predict disease progression and prognosis. MethodsThe study included 130 cases of CHB, with 48 cases in stable condition, 50 cases of progression to hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF), and 32 cases of progression to HBV related pre-ACLF. The demographic data and laboratory test results were recorded and compared among the groups. The blood samples for the measurement of serum IL-33 and soluble ST2 (sST2) levels were collected at admission and evaluated twice using the ELISA method. ResultsThe patients in which the disease progressed to HBV-ACLF had the highest serum IL-33 and sST2 levels among the three groups (p<0.001). The correlation analysis showed that the serum IL-33 levels were associated with the levels of ALT (r = 0.367, p<0.001), AST (r = 0.456, p<0.001) and the MELD score (r = 0.377, p = 0.001). The area under the curve (AUC) of IL-33 and sST2 levels for differentiation of disease progression were 0.861 (95% CI: 0.787–0.934, p<0.001) and 0.788 (95% CI: 0.692–0.884, p<0.001), respectively. The serum IL-33 levels combined with the MELD score had the highest 90-day mortality prediction efficiency, with an AUC of 0.918 (95% CI: 0.859–0.977, p<0.001), a sensitivity of 92.3%, and a specificity of 88.7%. ConclusionsThe IL-33/sST2 axis could be used to evaluate the progression and mortality in CHB patients with hepatic flare. The combinatorial use of multiple indicators could achieve the highest diagnostic and predictive accuracy.