Suppression Of Tumorigenicity Research Articles

The IL-33/ST2 Axis Affects Adipogenesis Through Regulating the TRAF6/RelA Pathway

Understanding the regulatory mechanisms of adipogenesis is essential for preventing obesity. Interleukin-33 (IL-33) has recently attracted increasing attention for its role in adipogenesis. The purpose of this study was to explore the function and regulatory mechanism of IL-33 and its receptor suppression of tumorigenicity 2 (ST2) on adipogenesis. Here, Oil Red O staining was used to detect the accumulation of intracellular lipid droplets. Molecular techniques such as qRT-PCR and Western blotting were used to detect the expression of pivotal genes and adipogenic marker genes. Gains and losses of function experiments were used to explore the potential regulatory mechanism of the IL-33/ST2 axis in adipogenesis. Functionally, IL-33 is negatively associated with adipogenesis in 3T3-L1 preadipocytes, while ST2 is positively associated with it, encompassing both the trans-membrane receptor ST2 (ST2L) and the soluble ST2 (sST2). Mechanistically, the IL-33/ST2 axis affects adipogenesis by regulating the expression of the TRAF6/RelA pathway in 3T3-L1 preadipocytes. Downregulating the expression of ST2 suppressed the activation of the IL-33/ST2 axis, which subsequently inhibits the expression of TRAF6. This further attenuates the expression of RelA, ultimately resulting in the suppression of adipogenesis in 3T3-L1 preadipocytes. This study reveals a new mechanism by which the IL-33/ST2 axis regulates the differentiation of preadipocytes and provides a new idea for improving obesity prevention.

ST2L promotes VEGFA-mediated angiogenesis in gastric cancer by activating TRAF6/PI3K/Akt/NF-κB pathway via IL-33

Suppression of Tumorigenicity 2 (ST2) is a member of the interleukin-1 receptor/ Toll-like receptor superfamily, and its specific ligand is Interleukin-33 (IL-33). IL-33/ ST2 signaling has been implicated in numerous inflammatory and allergic diseases, as well as in promoting malignant behavior of tumor cells and angiogenesis. However, the precise role of ST2 in gastric cancer angiogenesis remains incompletely elucidated. We observed a significant correlation between high expression of ST2 in gastric cancer tissues and poor prognosis, along with various clinicopathological features. In vitro experiments demonstrated that the IL-33/ ST2 axis activates the PI3K/AKT/NF-κB signaling pathway through TRAF6, thereby promoting VEGFA-mediated tumor angiogenesis; meanwhile sST2 acts as a decoy receptor to regulate the IL-33/ST2L axis. Consistent findings were also observed in subcutaneous xenograft tumor models in nude mice. Furthermore, we investigated the molecular mechanism by which IL-33 promotes ST2L expression in GC cells via upregulation of transcription factors YY1 and GATA2 through intracellular signaling pathways.

The role of fibrosis and inflammation for response and outcome prediction in candidates to cardiac resynchronization therapy: is response the right answer?

Abstract Background Cardiac resynchronization therapy (CRT) is an established treatment in selected patients suffering from heart failure with reduced ejection fraction (HFrEF). It has been proposed that myocardial fibrosis and inflammation could influence CRT "response" and outcome. Purpose Our study investigated the long-term prognostic significance of cardiac biomarkers in HFrEF patients with an indication for CRT. Methods 86 consecutive patients referred for CRT implantation were retrospectively evaluated. The soluble suppression of tumorigenicity 2 (sST2), galectin-3 (Gal-3), N-terminal portion of the B-type natriuretic peptide (NT-proBNP), and estimated glomerular filtration rate (eGFR) were measured at baseline and after 1 year of follow-up. An echocardiographic reduction of LV end-systolic volume ≥15% was used to define a patient as responder to CRT. Multivariate analyses were performed to evaluate their correlation with the primary composite outcome of cardiovascular mortality and heart failure hospitalizations at a mean follow-up of 9 ± 2 years. Results 44% of patients experienced the primary outcome. the mean baseline values of NT-proBNP, Gal-3, and sST2 were significantly higher compared with the patients without cardiovascular events. At the multivariate analyses, baseline Gal-3 [cut-off: 38.5 ng/ml, AUC: 0.63, p=0.03, (OR 7.13 [1.12;45.41], p=0.03), together with TAPSE>17.5 mm (OR 10.86 [3.15;37.44], p<0.001) significantly correlated with the structural response to CRT in several prediction models. Baseline Gal-3 [cut-off: 16.6 ng/ml, AUC: 0.91, p<0.001, HR 8.33 (1.88–33.33), p = 0.005] and sST2 [cut-off: 35.6 ng/ml AUC: 0.91, p<0.001, HR 333 (250–1,000), p = 0.003] significantly correlated with the composite outcome in the prediction models with high likelihood (Table). At Kaplan-Meyer curve patients with both high baseline sST2 and Gal-3 had the lowest survival probability (Figure). Among the parameters evaluated at 1-year follow-up, sST2, eGFR, and the variation from baseline to 1-year of Gal-3 levels showed a strong association with the primary outcome [HR 1.15 (1.08–1.22), p < 0.001; HR: 0.84 (0.74–0.91), p = 0.04; HR: 1.26 (1.10–1.43), p ≤ 0.001, respectively]. Conversely, the echocardiographic definition of CRT response did not correlate with any outcome. Conclusion In HFrEF patients with CRT, sST2, Gal-3, and renal function were associated with the combined endpoint of cardiovascular death and HF hospitalizations at long term follow-up, while the echocardiographic CRT response did not seem to influence the outcome of the patients.

Pulmonary Congestion and Anemia in Hemodialysis: The Potential Link to Inflammation

Pulmonary congestion (PC) is common in hemodialysis (HD) patients. We explored the association of anemia and pulmonary congestion in HD patients. A prospective pilot observational study included 18 patients on maintenance HD. Individual B-lines scores (BLS; 8-sites method) were obtained by lung ultrasound, before and after the first two consecutive HD sessions of the week (HD1-HD2), with different inter-dialytic intervals (68 vs. 44 h). Bioimpedance spectroscopy body composition (BIS) was performed before each HD session. Hemoglobin (Hb) levels, in addition to circulating markers of chronic inflammation (soluble urokinase Plasminogen Activator Receptor [suPAR], soluble Suppression of Tumorigenicity 2 [sST2]) were obtained. Mean (±SD) BLS values were quite elevated at all time points: Pre-HD1 (16 ± 5.53), post-HD1 (15.3 ± 6.63), pre-HD2 (16.3 ± 5.26) and post-HD2 (13.6 ± 5.83), respectively. No direct significant correlation was found between inflammation markers levels and BLS. However, mean levels (±SD, ng/mL) of suPAR pre-HD1 (7.88 ± 3.07) and pre-HD2 (7.78 ± 3.02) remained significantly above the normal range (<4 ng/mL), and sST2 levels reached 2-fold the upper normal value in most patients (27.4 ± 17.8). Pulmonary congestion reflected by BLS was negatively correlated to Hb levels pre-HD1 (R² = 0.439, p = 0.003), and pre-HD2 (R² = 0.301, p = 0.018). In addition, Hb levels were negatively correlated to global volume status estimated by BIS (R² = 0.351, p = 0.009). Hemoglobin levels were negatively correlated to pulmonary congestion and to the global volume status evaluated by BIS. Chronic inflammation markers were increased in HD patients, suggesting a complex volume- and non-volume-dependent pathophysiology of pulmonary congestion in HD patients.

An elevated level of soluble suppression of tumorigenicity 2, but not galectin-3, is associated with the presence of coronary artery disease in hypertensive patients.

We investigated whether there were associations between coronary artery disease (CAD) and soluble suppression of tumorigenicity (sST2) and galectin-3 levels at the time of coronary artery computed tomography angiography (CCTA) for CAD screening. The subjects consisted of 429 patients who underwent CCTA examination. CAD was diagnosed when there was 50% or more stenosis in the coronary artery. Patient backgrounds were collected and plasma levels of sST2 and galectin-3 were measured. The presence or absence of CAD and factors that contributed to CAD were analyzed for all patients and for those with or without hypertension (HTN). The CAD group had significantly higher sST2 levels than the non-CAD group, whereas there was no significant difference in galectin-3 levels. The number of patients in the non-HTN and HTN groups was 174 and 255, respectively. In the HTN group, the CAD group was significantly older than the non-CAD group and had higher sST2 levels. Multivariate analysis showed that the factors that contributed to CAD in the HTN group were age and sST2 levels. On the other hand, in the non-HTN group, the CAD group was significantly older than the non-CAD group, and had a higher proportion of males and higher sST2 levels, while the contributing factors for the CAD group were age and male gender, but not sST2. In conclusion, a higher level of sST2, but not galectin-3, was a contributing factor for CAD in HTN patients. However, in non-HTN patients, a high level of sST2 was not a contributing factor for CAD.

Soluble suppression of tumorigenicity 2 associated with contrast-induced acute kidney injury in patients with STEMI.

Contrast-induced acute kidney injury (CI-AKI) is a common complication after percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI). Soluble suppression of tumorigenicity 2 (sST2) is associated with AKI. However, the relationship between sST2 and CI-AKI is unclear. This study aimed to investigate the relationship between sST2 and CI-AKI in patients with STEMI. This was a single-center retrospective observational study. Patients diagnosed with STEMI in the Yichun People's Hospital from February 2020 to May 2024 were continuously included. CI-AKI was defined as an increase in serum creatinine of at least 50% or 0.3mg/dL from baseline within 48-72h after contrast exposure. The incidence of CI-AKI after PCI was 12.4% (98/791). Univariate analysis showed that age, fasting plasma glucose, diabetes mellitus, Killip class, left ventricular ejection fraction, estimated glomerular filtration rate, high sensitivity troponin T, N-terminal pro-B-type natriuretic peptide, and sST2 were associated with CI-AKI. The above factors were included in a multivariate analysis, which showed that sST2 was an independent factor for CI-AKI after PCI. The restricted cubic splines showed a nonlinear dose-response relationship between sST2 and CI-AKI (P < 0.001). The integration of the sST2 could significantly improve the ability of the model to identify CI-AKI (NRI 0.681, 95% CI 0.474-0.887; IDI 0.063, 95% CI 0.038-0.099). Elevated sST2 is an independent risk factor for CI-AKI after PCI in patients with STEMI. Integration of sST2 can significantly improve the risk model for CI-AKI.

O47 THE ROLE OF IL-33 AND ST2 IN THE MODULATION OF TARGET ORGAN DAMAGE IN ANGIOTENSIN II-DEPENDENT HYPERTENSION

Introduction: Hypertension is associated with a chronic inflammatory state and aberrant immune system activity. Interleukin-33/suppression of tumorigenicity 2 (IL-33/ST2) signalling axis is important in the modulation of atherosclerosis and cardiovascular fibrosis. We aimed to evaluate the modulation of IL-33 and ST2 in hypertensive mouse models and patients. Methods and Results: Hypertension was induced by a 14-day infusion of Ang-II (490ng/min/kg) in 12-week-old WT C57BL/6, ST2KO, IL33KO mice. IL-33 and ST2 mRNA and protein were evaluated using qPCR and Western blot in WT mice. Ang II-infusion significantly increased IL-33 and ST2 protein expression in target organs related to hypertension, particularly the aorta (1.0±0.1 vs 2.8±0.2, p&lt;0.0001, and 0.963±0.068 vs 2.094±0.231, p=0.002, respectively). Further, mRNA expression of IL-33 and ST2 was elevated in hypertensive aortas when compared with control (1.0±0.053 vs 1.76±0.271, p=0.0185 and 1.0±0.039 vs 1.978±0.221, p=0.0039, respectively). IHC from WT mice illustrated the localisation of IL-33 and ST2 in Ang-II aortas in ECs and SMCs. Further in human hypertensive mammary arteries, the localisation was. In-vivo, IL33KO and ST2KO mice showed no altered BP at baseline or after 14 days of Ang-II compared to WT littermates. ST2KO Ang-II mice showed protection against endothelial dysfunction compared to WT Ang-II mice through isometric tension studies (p=0.0317). Additionally, Ang-II-induced IL33KO and ST2KO mice worsen cardiac fibrosis compared to WT littermates (p=0.0005,p&lt;0.0001, respectively). Conclusion: Both IL-33 and its receptor, ST2 are increased in the vascular and perivascular tissues in hypertension. Additionally, the IL-33/ST2 axis has a role in regulating cardiac fibrosis.

Temporal trajectory and left ventricular ejection fraction association of eight circulating biomarkers in first acute myocardial infarction patients: a 12-month prospective cohort study.

Our study aimed to explore the temporal trajectory of eight circulating biomarkers, measured serially over 12 months, in a prospective observational cohort of patients with acute myocardial infarction (AMI) and to investigate the association between these biomarkers and left ventricular ejection fraction (LVEF) during follow-up assessments. We enrolled 155 patients admitted for a first AMI requiring percutaneous coronary intervention (PCI). Baseline characteristics, laboratory test results, and cardiac ultrasound examinations were collected at pre-PCI (H0), immediately post-PCI (H24), at discharge (D3), and at 6 months (M6) and 12 months (M12) post-PCI. Blood samples were analysed for established and emerging biomarkers described in left ventricular dysfunction: soluble suppression of tumorigenicity 2 (sST2), interleukin-6 (IL-6), osteopontin, angiopoietin-2, insulin-like growth factor-binding protein 2 (IGFBP-2), growth differentiation factor 15 (GDF-15), hepcidin, and galectin-3. Values at H24, D3, M6, and M12 were compared with value at H0. Three kinetic profiles were identified, with six biomarkers peaking during the acute MI phase. Crude relationships between clinical variables and the peak values (highest observed between H0 and D3) of each biomarker were studied. Peak levels of sST2, IL-6, osteopontin, and angiopoietin-2 demonstrated significant correlations with both baseline and follow-up LVEF values. The assessment of the temporal trajectories of these biomarkers and their associations with LVEF suggests that sST2, IL-6, osteopontin, and angiopoietin-2 hold significant promise as companion biomarkers. These biomarkers may improve the identification of patients at risk for developing impaired LVEF following AMI, thereby enabling more targeted and effective management strategies.

IL-33/sST2 signaling pathway in pulmonary thromboembolism: A clinical observational study

BackgroundPulmonary thromboembolism (PTE) is a cardiovascular emergency that can result in mortality. In the interleukin-33 (IL-33) /soluble suppression of tumorigenicity 2 (sST2) signaling pathway, increased sST2 is a cardiovascular risk factor. This study aimed to investigate the effectiveness of biomarkers in the IL-33/sST2 signaling pathway in determining PTE diagnosis, clinical severity, and mortality. MethodThis study was conducted as a single-center, prospective, observational study. Patients admitted to the emergency department and diagnosed with PTE constituted the patient group (n = 112), and healthy volunteers with similar sociodemographic characteristics constituted the control group (n = 62). Biomarkers in the IL-33/sST2 signaling pathway were evaluated for diagnosis, clinical severity, and prognosis. ResultsIL-33 was lower in the patient group than in the control group (275.89 versus 403.35 pg/mL), while sST2 levels were higher in the patient group than in the control group (53.16 versus 11.78 ng/mL) (p < 0.001 and p = 0.001; respectively). The AUC of IL-33 to diagnose PTE was 0.656 (95 % CI: 0.580–0.726). The optimal IL-33 cut-off point to diagnose PTE was ≤304.11 pg/mL (56.2 % sensitivity, 79 % specificity). The AUC of sST2 to diagnose PTE was 0.818 (95 % CI: 0.752–0.872). The optimal sST2 cut-off point to diagnose PTE was >14.48 ng/mL (83 % sensitivity, 71 % specificity).IL-33 levels were lower in patients with mortality (169.85 versus 332.04 pg/mL) compared to patients without mortality, whereas sST2 levels were higher in patients with mortality (118.32 versus 28.07 ng/mL) compared to patients without mortality (p > 0.001 for both). The AUC of IL-33 to predict the mortality of PTE was 0.801 (95 % CI: 0.715–0.870). The optimal IL-33 cut-off point to predict the mortality of PTE was ≤212.05 pg/mL (75 % sensitivity, 79.5 % specificity). The AUC of sST2 to predict the mortality of PTE was 0.824 (95 % CI: 0.740–0.889). The optimal sST2 cut-off point to predict the mortality of PTE was >81 ng/mL (95.8 % sensitivity, 78.4 % specificity). ConclusionIn the IL-33/ST2 signaling pathway, decreased IL-33 and increased sST2 are valuable biomarkers for diagnosis and prediction of mortality in patients with PTE.

Soluble Suppression of Tumorigenicity 2 for Predicting Need for Intubation and Mortality Outcomes in COVID-19

Soluble Suppression of Tumorigenicity 2 for Predicting Need for Intubation and Mortality Outcomes in COVID-19

Pericardial Fluid Accumulates microRNAs That Regulate Heart Fibrosis after Myocardial Infarction.

Pericardial fluid (PF) has been suggested as a reservoir of molecular targets that can be modulated for efficient repair after myocardial infarction (MI). Here, we set out to address the content of this biofluid after MI, namely in terms of microRNAs (miRs) that are important modulators of the cardiac pathological response. PF was collected during coronary artery bypass grafting (CABG) from two MI cohorts, patients with non-ST-segment elevation MI (NSTEMI) and patients with ST-segment elevation MI (STEMI), and a control group composed of patients with stable angina and without previous history of MI. The PF miR content was analyzed by small RNA sequencing, and its biological effect was assessed on human cardiac fibroblasts. PF accumulates fibrotic and inflammatory molecules in STEMI patients, namely causing the soluble suppression of tumorigenicity 2 (ST-2), which inversely correlates with the left ventricle ejection fraction. Although the PF of the three patient groups induce similar levels of fibroblast-to-myofibroblast activation in vitro, RNA sequencing revealed that PF from STEMI patients is particularly enriched not only in pro-fibrotic miRs but also anti-fibrotic miRs. Among those, miR-22-3p was herein found to inhibit TGF-β-induced human cardiac fibroblast activation in vitro. PF constitutes an attractive source for screening diagnostic/prognostic miRs and for unveiling novel therapeutic targets in cardiac fibrosis.

Difamilast, a Topical Phosphodiesterase 4 Inhibitor, Produces Soluble ST2 via the AHR-NRF2 Axis in Human Keratinocytes.

Difamilast, a phosphodiesterase 4 (PDE4) inhibitor, has been shown to be effective in the treatment of atopic dermatitis (AD), although the mechanism involved remains unclear. Since IL-33 plays an important role in the pathogenesis of AD, we investigated the effect of difamilast on IL-33 activity. Since an in vitro model of cultured normal human epidermal keratinocytes (NHEKs) has been utilized to evaluate the pharmacological potential of adjunctive treatment of AD, we treated NHEKs with difamilast and analyzed the expression of the suppression of tumorigenicity 2 protein (ST2), an IL-33 receptor with transmembrane (ST2L) and soluble (sST2) isoforms. Difamilast treatment increased mRNA and protein levels of sST2, a decoy receptor suppressing IL-33 signal transduction, without affecting ST2L expression. Furthermore, supernatants from difamilast-treated NHEKs inhibited IL-33-induced upregulation of TNF-α, IL-5, and IL-13 in KU812 cells, a basophil cell line sensitive to IL-33. We also found that difamilast activated the aryl hydrocarbon receptor (AHR)-nuclear factor erythroid 2-related factor 2 (NRF2) axis. Additionally, the knockdown of AHR or NRF2 abolished the difamilast-induced sST2 production. These results indicate that difamilast treatment produces sST2 via the AHR-NRF2 axis, contributing to improving AD symptoms by inhibiting IL-33 activity.

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 plays a prominent role in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD). 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 humans 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 mice. Moreover, IL-33 deficiency resulted in a decrease in the abundance of trimethylamine N -oxide-producing bacteria. Inhibition of trimethylamine N -oxide synthesis by 3,3-dimethyl-1-butanol mitigated hepatic oxidative stress in mice with MASLD. Nuclear IL-33 bound to hypoxia-inducible factor-1α and suppressed its activation, directly damaging the integrity of the 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 trimethylamine N -oxide synthesis and aggravated MASLD progression through dual regulation on hypoxia-inducible factor-1α. Targeting IL-33 and its associated microbiota may provide a potential therapeutic strategy for managing MASLD.

Ruxolitinib for the treatment of acute graft-versus-host disease: a retrospective analysis

Steroid-refractory acute graft-versus-host disease (aGvHD) is a serious complication after allogeneic hematopoietic stem cell transplantation, associated with significant mortality. Ruxolitinib was the first drug approved for aGvHD, based on results of the REACH2 trial; however, real-world data are limited. We retrospectively analyzed the safety and efficacy of ruxolitinib for treatment of aGvHD at our center from March 2016 to August 2022 and assessed biomarkers of risk. We identified 49 patients receiving ruxolitinib as second- (33/49), third- (11/49), fourth- (3/49), or fifth-line (2/49) treatment. Ruxolitinib was started on median day 11 (range, 7–21) after aGvHD onset; median duration of administration was 37 days (range, 20–86), with 10 patients continuing treatment at last follow-up. Median follow-up period was 501 days (range, 95–905). In the primary analysis at the 1-month assessment, overall response rate was 65%, and failure-free survival was 78%. Infectious complications ≥ CTCAE Grade III were observed in 10/49 patients within 1-month followup. Patients responding to ruxolitinib therapy required fewer steroids and exhibited lower levels of the serum biomarkers regenerating islet-derived protein 3-alpha, suppression of tumorigenicity 2, and the Mount Sinai Acute GVHD International Consortium algorithm probability. A univariate regression model revealed steroid-dependent aGvHD as a significant predictor of better response to ruxolitinib. Within 6-months follow-up, four patients experienced recurrence of underlying malignancy, and eight died due to treatment-related mortality. Overall, ruxolitinib was welltolerated and showed response in heavily pretreated patients, with results comparable to those of the REACH2 trial. Biomarkers may be useful predictors of response to ruxolitinib.

Repeated Infusions of Bone-Marrow-Derived Mesenchymal Stem Cells over 8 Weeks for Steroid-Refractory Chronic Graft-versus-Host Disease: A Prospective, Phase I/II Clinical Study.

Chronic graft-versus-host disease (cGVHD) is a long-term complication of allogeneic hematopoietic stem cell transplantation associated with poor quality of life and increased morbidity and mortality. Currently, there are several approved treatments for patients who do not respond to steroids, such as ruxolitinib. Nevertheless, a significant proportion of patients fail second-line treatment, indicating the need for novel approaches. Mesenchymal stem cells (MSCs) have been considered a potential treatment approach for steroid-refractory cGVHD. To evaluate the safety and efficacy of repeated infusions of MSCs, we administered intravenous MSCs every two weeks to ten patients with severe steroid-refractory cGVHD in a prospective phase I clinical trial. Each patient received a total of four doses, with each dose containing 1 × 106 cells/kg body weight from the same donor and same passage. Patients were assessed for their response to treatment using the 2014 National Institutes of Health (NIH) response criteria during each visit. Ten patients with diverse organ involvement were enrolled, collectively undergoing 40 infusions as planned. Remarkably, the MSC infusions were well tolerated without severe adverse events. Eight weeks after the initial MSC infusion, all ten patients showed partial responses characterized by the amelioration of clinical symptoms and enhancement of their quality of life. The overall response rate was 60%, with a complete response rate of 20% and a partial response (PR) rate of 40% at the last follow-up. Overall survival was 80%, with a median follow-up of 381 days. Two patients died due to relapse of their primary disease. Immunological analyses revealed a reduction in inflammatory markers, including Suppression of Tumorigenicity 2 (ST2), C-X-C motif chemokine ligand (CXCL)10, and Secreted phosphoprotein 1(SPP1), following the MSC treatment. Repeated MSC infusions proved to be both feasible and safe, and they may be an effective salvage therapy in patients with steroid-refractory cGVHD. Further large-scale clinical studies with long-term follow-up are needed in the future to determine the role of MSCs in cGVHD.

Multimarkers approach in chest pain management in Emergency department: a focus on the prognostic role of sST2 and suPAR

Chest pain is one of the most prevalent causes of Emergency Department (ED) admission and could be a presenting symptom of Acute Coronary Syndrome (ACS). The aim of this review was to provide an overview of the research about troponin and its limitations and new biomarkers used in patients with cardiovascular diseases, with a special focus on soluble Suppression of Tumorigenicity 2 (sST2) and Soluble Urokinase Plasminogen Activator Receptor (suPAR). In January 2024, a PubMed and Reviews in Cardiovascular Medicine (RCM) search was carried out to identify all relevant papers in the past five years. 80 articles were included in the final review. ssT2 and suPAR are involved in both acute and chronic cardiovascular disease and can predict the risk of adverse events. sST2 and suPAR are promising biomarkers that, in combination with troponin, could help in the management of patients with chest pain in the ED. Further studies are needed to validate their role in management of ACS in this specific setting.

Does the ST2 Level in Pediatric Heart Failure Patients Correlate with Cardiovascular Events and Mortality?

The suppression of tumorigenicity 2 (ST2) is a receptor member belonging to the interleukin-1 (IL-1) family. The ligand and soluble versions are its two isoforms. The IL-33-ST2L ligand complex's development provides protection against heart fibrosis and hypertrophy. Investigations on heart failure in adults have demonstrated that it does not change by age, body mass index (BMI), creatinine, hemoglobin, and albumin levels, in contrast to NT pro BNP. In adult heart failure patients, it has been demonstrated to be an independent predictor of mortality and cardiovascular events. The most recent guideline recommends using it as class 2b in the diagnosis of adult heart failure. Studies on ST2 in children are rare. The purpose of this study is to assess the prognostic value of ST2 for cardiovascular events in young individuals suffering from heart failure. This study included pediatric patients (0-18 years old) with congenital heart disease or cardiomyopathy who needed medical care, as well as surgical or interventional treatment. Height, weight, gender, saturation, heart failure classification (Ross or NYHA), medications, the electrocardiogram, echocardiography, pro BNP, and sST2 values of the patients, as well as any hospitalization, lower respiratory tract infection, organ dysfunction, or need for angiography or surgery during follow-up data on arrhythmia and death were gathered during a 1-year follow-up. The SPSS software version 25 application was used to carry out the statistical analysis. This study included 59 patients, of whom 27 (46.6%) were male. The average age of the patients was 55.5 months (1-228 months) and the average body weight was 16 kg (2.6-90 kg). Major cardiovascular events occurred in 45 of 59 patients (76.3%). Twenty-four patients experienced one MACE, while twenty-one patients experienced multiple MACEs. Pro BNP and sST2 levels were similar in the groups that developed MACE compared to those that did not. Pro BNP was discovered to be significantly higher in patients with hospitalization, growth retardation, lower respiratory tract infection, and organ failure, however, when assessing each situation (p = 0.001, p = 0.011, p = 0.001, p = 0.007, respectively). Soluble ST2 was found to be higher in patients with growth retardation than in those without (p = 0.037). Although the soluble ST2 level failed to demonstrate a correlation with pro BNP, it did show a positive correlation (r = 0.437) with the Ross score. When compared to other groups, it was discovered to be higher in patients with valvular insufficiency type heart disease. In this study, higher sST2 levels were discovered, particularly in the group with valve insufficiency and children with growth retardation. It was associated with the Ross score, but not with the pro BNP level. Although it increases in correlation with clinical heart failure, its predictive value for MACE is low. Similarly, pro BNP is not proven to be predictive; nonetheless, its high levels in patients with hospitalization, growth retardation, lower respiratory tract infection, and organ failure demonstrate that pro BNP may increase for a variety of causes. Long-term studies with more patients are needed for ST2 to be suitable for clinical use in pediatric patients.

Diagnostic and prognostic values of serum Selenoprotein P and soluble St2 levels in pulmonary embolism

AimPulmonary Thromboembolism (PTE) occurs as a result of occlusion of one or more of the pulmonary artery branches by thrombus and is an important cause of right heart failure and pulmonary hypertension. Selenoprotein P (SePP) and soluble suppression of tumorigenicity 2 protein (sST2) are two new biomarkers that have previously been the subject of various studies in heart failure. The aim of this study was to determine the diagnostic and prognostic potential of SePP and soluble sST2 levels in patients with acute PTE. Materials and MethodsThe study included 135 patients diagnosed with acute non-massive PTE and 43 healthy volunteers. Clinical, laboratory, and radiological patient data were recorded. SePP and sST2 levels were measured in the patient and control groups. Patients were followed at 1, 3, and 6 months of treatment via the death notification system and telemedicine. ResultsSePP and sST2 levels were significantly lower in the patient group compared with the control group (SePP: 17.65 ng/ml vs. 43.06 ng/ml and sST2: 10.86 ng/ml vs. 16.20 ng/ml, both p < 0.001). No correlation was found at 1, 3, and 6 months of follow-up with prognosis and mortality. ConclusionSePP and sST2 values were significantly lower in patients with acute PTE compared with the control group. Low levels of these biomarkers may be diagnostically valuable.

Biomarkers in a phase 1b study of investigational microbiome therapeutic SER-155 in adults undergoing allogeneic hematopoietic cell transplantation (allo-HCT).

6554 Background: Acute graft- versus-host disease (aGvHD) is a life-threatening complication following allo-HCT. Microbiome dysfunction and associated GI barrier disruption may contribute to aGvHD via activation of inflammatory immune responses. Circulating biomarkers in the peri-transplant period are correlated with risk of severe aGvHD, including suppression of tumorigenicity 2 (ST2), regenerating islet-derived 3-alpha (Reg3a) and inflammatory cytokines (IL6, IFNϒγ &amp; TNFα). SER-155 is an investigational cultivated oral microbiome therapeutic designed to restructure the GI microbiome, improve GI barrier integrity and reduce GI inflammation and is being assessed in a 2-part Phase 1b study in adults undergoing allo-HCT. We present preliminary safety, GvHD, PK, and exploratory biomarker data from the completed open-label Cohort 1 through Day 100 post-HCT. Methods: Adult recipients of allo-HCT were eligible. HCT conditioning and aGvHD prophylaxis were per investigator discretion. Patients received 2 courses of SER-155 (pre-HCT and post-neutrophil engraftment, each comprised of 4 days of microbiome conditioning with oral vancomycin followed by 10 days oral SER-155. The primary endpoint was safety. Strain engraftment (PK) and biomarkers were assessed in stool and plasma samples. Results: Fifteen adults enrolled; 13 received at least 1 course of study drug (median age 67; 54% male), and 11 underwent allo-HCT. Following each course, the majority of the 16 SER-155 strains were detected in stool. Treatment-emergent adverse events (AEs) were reported in all patients with GI AEs the most common. No serious AEs (SAEs) were deemed related to SER-155. Most SAEs and AEs of special interest (ie, BSIs, invasive or GI infections) occurred between HCT and the 2nd SER-155 course. There were no deaths before Day 100. No BSIs were attributable to SER-155 strains. The rate of grade 2-4 aGvHD based on MAGIC criteria through Day 100 was 45.5%; no severe grade 3-4 aGvHD was observed. Median levels of plasma biomarkers REG3α, ST2 and inflammatory cytokines were not elevated relative to a reference range (Table). Conclusions: In this small open-label cohort, SER-155 was generally well-tolerated through Day 100 without drug-related SAEs and no severe aGvHD. Plasma biomarkers were not elevated at HCT Day 0 or neutrophil recovery. These preliminary observations align with the design and preclinical evaluation of SER-155. Clinical trial information: NCT04995653 . [Table: see text]

Association of suPAR, ST2, and galectin-3 with eGFR decline and mortality in patients with advanced heart failure with reduced ejection fraction.

Patients with heart failure with reduced ejection fraction (HFrEF) are at risk for chronic kidney disease (CKD). Elevated levels of circulating biomarkers soluble urokinase plasminogen activator receptor (suPAR), galectin-3, soluble suppression of tumorigenicity 2 (ST2), and N-terminal prohormone B-type natriuretic peptide (NT-proBNP) are associated with CKD progression and mortality. The predictive value of these biomarkers in a population with HFrEF and kidney disease is relatively unknown. We sought to determine whether these biomarkers were associated with longitudinal trajectory of estimated glomerular filtration rate (eGFR) in HFrEF and assess their association with mortality using a joint model to account for competing risks of ventricular assist device (VAD) implantation and heart transplantation. We included participants from the Registry Evaluation of Vital Information for Ventricular Assist Devices in Ambulatory Life with repeated eGFR measures over 2 years. Of 309 participants, mean age was 59 years, median eGFR 60 ml/min/1.73 m2, 45 participants died, 33 received VAD, and 25 received orthotopic heart transplantation. Higher baseline serum standardized suPAR (β coefficient = -0.36 √(ml/min/1.73 m2), 95% confidence interval (-0.48 to -0.24), p < 0.001), standardized galectin-3 (-0.14 √(ml/min/1.73 m2) (-0.27 to -0.02), p = 0.02), and log NT-proBNP (-0.23 √(ml/min/1.73 m2) (-0.31 to -0.15), p < 0.001) were associated with eGFR decline. ST2 and log NT-proBNP were associated with mortality. Higher baseline suPAR, galectin-3, and NT-proBNP are associated with eGFR decline in patients with HFrEF. Only ST2 and NT-proBNP are associated with greater mortality after controlling for other factors including change in eGFR. These biomarkers may provide prognostic value for kidney disease progression in HFrEF and inform candidacy for advanced heart failure therapies.