Suppression Of Tumorigenicity Research Articles

Relation of Cigarette Smoking and Heart Failure in Adults ≥65 Years of Age (From the Cardiovascular Health Study)

Cigarette smoking is associated with adverse cardiac outcomes, including incident heart failure (HF). However, key components of potential pathways from smoking to HF have not been evaluated in older adults. In a community-based study, we studied cross-sectional associations of smoking with blood and imaging biomarkers reflecting mechanisms of cardiac disease. Serial nested, multivariable Cox models were used to determine associations of smoking with HF, and to assess the influence of biochemical and functional (cardiac strain) phenotypes on these associations. Compared with never smokers, smokers had higher levels of inflammation (C-reactive protein and interleukin-6), cardiomyocyte injury (cardiac troponin T [hscTnT]), myocardial "stress"/fibrosis (soluble suppression of tumorigenicity 2 [sST2], galectin 3), and worse left ventricle systolic and diastolic function. In models adjusting for age, gender, and race (DEMO) and for clinical factors potentially in the causal pathway (CLIN), smoking exposures were associated with C-reactive protein and interleukin-6, sST2, hscTnT, and with N-terminal pro-brain natriuretic protein (in Whites). In DEMO adjusted models, the cumulative burden of smoking was associated with worse left ventricle systolic strain. Current smoking and former smoking were associated with HF in DEMO models (hazard ratio 1.41, 95% confidence interval 1.22 to 1.64 and hazard ratio 1.14, 95% confidence interval 1.03 to 1.25, respectively), and with current smoking after CLIN adjustment. Adjustment for time-varying myocardial infarction, inflammation, cardiac strain, hscTnT, sST2, and galectin 3 did not materially alter the associations. Smoking was associated with HF with preserved and decreased ejection fraction. In conclusion, in older adults, smoking is associated with multiple blood and imaging biomarker measures of pathophysiology previously linked to HF, and to incident HF even after adjustment for clinical intermediates.

Novel Plasma Biomarker-Based Model for Predicting Acute Kidney Injury After Cardiac Surgery: A Case Control Study.

Introduction:Acute kidney injury (AKI) after cardiac surgery is independently associated with a prolonged hospital stay, increased cost of care, and increased post-operative mortality. Delayed elevation of serum creatinine (SCr) levels requires novel biomarkers to provide a prediction of AKI after cardiac surgery. Our objective was to find a novel blood biomarkers combination to construct a model for predicting AKI after cardiac surgery and risk stratification.Methods:This was a case-control study. Weighted Gene Co-expression Network Analysis (WGCNA) was applied to Gene Expression Omnibus (GEO) dataset GSE30718 to seek potential biomarkers associated with AKI. We measured biomarker levels in venous blood samples of 67 patients with AKI after cardiac surgery and 59 control patients in two cohorts. Clinical data were collected. We developed a multi-biomarker model for predicting cardiac-surgery-associated AKI and compared it with a traditional clinical-factor-based model.Results:From bioinformatics analysis and previous articles, we found 6 potential plasma biomarkers for the prediction of AKI. Among them, 3 biomarkers, such as growth differentiation factor 15 (GDF15), soluble suppression of tumorigenicity 2 (ST2, IL1RL1), and soluble urokinase plasminogen activator receptor (uPAR) were found to have prediction ability for AKI (area under the curve [AUC] > 0.6) in patients undergoing cardiac surgery. They were then incorporated into a multi-biomarker model for predicting AKI (C-statistic: 0.84, Brier 0.15) which outperformed the traditional clinical-factor-based model (C-statistic: 0.73, Brier 0.16).Conclusion:Our research validated a promising plasma multi-biomarker model for predicting AKI after cardiac surgery.

Paradoxical role of interleukin-33/suppressor of tumorigenicity 2 in colorectal carcinogenesis: Progress and therapeutic potential.

Colorectal cancer (CRC) is presently the second most prevalent global mortality-inducing cancer. CRC carcinogenesis is a multifactorial process involving internal genetic mutations and the external environment. In addition, non-neoplastic cell activities within tumor microenvironments for CRC development have been established. However, interleukin (IL)-33, secreted by such cell types, plays a pivotal role in cancer progression due to interaction with cellular constituents within the tumor-inflammation microenvironment. IL-33 belongs to the IL-1 cytokine family and acts as binding attachments for the suppressor of tumorigenicity (ST)2 receptor. Therefore, how to coordinate tumor microenvironment, design and optimize treatment strategies suitable for CRC, based on IL-33/ST2 signal is a challenge. Even though it has established influences upon immunity-linked conditions, IL-33 effects on CRC progression and prevention and related mechanisms are still controversial. Our review depicts controversial activities for IL-33/ST2 within carcinogenesis and cancer prevention. Moreover, IL-33/ST2 signaling is a potential therapeutic target for CRC.

Interleukin-33/ Suppression of Tumorigenicity 2 in Renal Fibrosis: Emerging Roles in Prognosis and Treatment.

Chronic kidney disease (CKD) is a major public health problem that affects more than 10% of the population worldwide and has a high mortality rate. Therefore, it is necessary to identify novel treatment strategies for CKD. Incidentally, renal fibrosis plays a central role in the progression of CKD to end-stage renal disease (ESRD). The activation of inflammatory pathways leads to the development of renal fibrosis. In fact, interleukin-33 (IL-33), a newly discovered member of the interleukin 1 (IL-1) cytokine family, is a crucial regulator of the inflammatory process. It exerts pro-inflammatory and pro-fibrotic effects via the suppression of tumorigenicity 2 (ST2) receptor, which, in turn, activates other inflammatory pathways. Although the role of this pathway in cardiac, pulmonary, and hepatic fibrotic diseases has been extensively studied, its precise role in renal fibrosis has not yet been completely elucidated. Recent studies have shown that a sustained activation of IL-33/ST2 pathway promotes the development of renal fibrosis. However, with prolonged research in this field, it is expected that the IL-33/ST2 pathway will be used as a diagnostic and prognostic tool for renal diseases. In addition, the IL-33/ST2 pathway seems to be a new target for the future treatment of CKD. Here, we review the mechanisms and potential applications of the IL-33/ST2 pathway in renal fibrosis; such that it can help clinicians and researchers to explore effective treatment options and develop novel medicines for CKD patients.

Factors associated with cardiac allograft vasculopathy after heart transplantation.

Cardiac allograft vasculopathy (CAV) is a major threat to long-term survival after heart transplantation (HT). To determine factors associated with CAV detection in patients after HT. We analyzed 299 consecutive patients after HT who underwent routine visits at our institution between 2016 and 2018. Human interleukin 33 (IL-33) and suppression of tumorigenicity 2 (ST2) were measured by sandwich enzyme-linked immunosorbent assay with a commercially available kit (Human ST-2 and IL-33 ELISA, SunRedBio Technology Co, Ltd, Shanghai, China). The patients' median age was 59.00 years, and 74.2% were men. The frequency of CAV was 47.5%. Multivariable logistic regression analysis showed that IL-33 (odds ratio (OR) = 1.044 (1.029-1.059), p < 0.001) and ST2 (OR = 1.061 (1.040-1.083), p < 0.001) serum concentrations, donor age (OR = 1.046 (1.009-1.085), p = 0.015), left ventricular diastolic dimension (LVDD) (OR = 1.081 (1.016-1.149), p = 0.013), and time from HT to blood collection (OR = 1.256 (1.151-1.371), p < 0.001) were independent risk factors for CAV. The area under the receiver operating characteristics curve (AUC) indicated good prognostic power of IL-33 and ST2 concentrations (AUC = 0.779 and AUC = 0.784, respectively) and excellent prognostic power of the IL-33/ST2 score (AUC = 0.863). Lower IL-33 and higher ST2 serum concentrations, as well as older donor age, larger LVDD and longer time from HT to blood collection, are independently associated with CAV. IL-33 and ST2 have good discriminatory power and the IL-33/ST2 score has excellent strength for detecting CAV.

Sirtuin 7 super-enhancer drives epigenomic reprogramming in hepatocarcinogenesis.

Hepatocellular carcinoma (HCC) is a major cancer burden worldwide with increasing incidence in many developed countries. Super-enhancers (SEs) drive gene expressions required for cell type-specificity and tumor cell identity. However, their roles in HCC remain unclear because of data scarcity from primary tumors. Herein, chromatin profiling of non-alcoholic fatty liver disease (NAFLD)-associated HCCs and matched liver tissues uncovered an average of ∼500 somatically-acquired SEs per patient. The identified SE-target genes were functionally enriched for aberrant metabolism and cancer phenotypes, especially chromatin regulators including deacetylases and Polycomb repressive complexes. Notably, all examined tumors exhibited SE activation of Sirtuin 7 (SIRT7), genome-wide promoter H3K18 deacetylation and concurrent H3K27me3, as well as tumor-suppressor gene silencing. Depletion of SIRT7 SE in hepatoma cells induced global H3K18 acetylation and reactivated key metabolic and immune regulators, leading to marked suppression of tumorigenicity in vitro and in vivo. In concordance, SIRT7 physically interacted with the methyltransferase EZH2, and they were co-expressed in primary HCCs. In summary, our integrative analysis establishes a compendium of SEs in NAFLD-associated HCCs and uncovers SIRT7-driven chromatin regulatory network as potential druggable vulnerability of this increasingly prevalent cancer.

Evaluation of serum interleukin-33 and soluble suppression of tumorigenicity 2 (sST2) receptors in patients with and without periodontal disease.

: Interleukin-33 and its receptor soluble suppression of tumorigenicity 2. sST2) play an important role in inflammation and its role in periodontal disease is yet unclear. The role of both IL-33 and sST2 together in periodontal disease as biomarkers has never been studied. : To assess the levels of IL-33 and sST2 in serum samples of patients with periodontitis and healthy subjects. : A total of 71 subjects (30 healthy subjects and 41 patients with periodontal disease) were included in the cross-sectional study. Community Periodontal Index (CPI) was used to assess periodontal health by utilizing a mouth mirror and a CPI probe. Venous blood was collected and serum was separated. Serum levels of IL-33 and sST2 were determined by the enzyme-linked immunosorbent assay (ELISA) assay. Graph Pad Prism 5 was used for statistical analysis. Mann Whitney test was applied to compare the two groups. : The level of IL-33 was not found to be elevated among healthy subjects and sST2 was found elevated among patients with periodontal disease. The serum concentration of IL-33 was found at 472 ± 114 pg/ml and 282 ± 77 pg/ml among healthy subjects and patients with periodontal disease respectively. Significantly higher values of sST2 at 28 ± 2 ng/ml were found among periodontal patients as compared to healthy subjects with values of 18 ± 1 ng/ml. No significant differences were noted between mild to moderate and severe periodontitis for IL-33 and sST2 between the two groups. This study shows alteration in serum levels of IL-33 and sST2 in periodontitis patients. IL-33 and sST2 may be potential inflammatory markers of periodontitis. Further studies are required on a large sample size for better understanding. This pilot study is the first to assess the serum levels of both IL-33 and sST2 together among patients with and without periodontal disease.

Interleukin-33 as a Potential Diagnostic and Prognostic Factor in Human Brucellosis.

The balance between T-helper 1 (Th1) and T-helper 2 (Th2) cells plays an important role in the pathogenesis of brucellosis. Interleukin (IL)-33 induces the activation of Th2 cells while soluble suppression of tumorigenicity 2 (sST2) is a decoy receptor to antagonize the effect of IL-33. Herein, we aimed to identify whether plasma IL-33/sST2 levels could reflect the state of brucellosis and help to monitor the treatment. A total of 78 patients were recruited and divided into acute, subacute, and chronic groups. The chronic group was further divided into chronic active brucellosis and chronic stable brucellosis according to the clinical manifestation. Twenty-six volunteers were assigned to the healthy control (HC) group. Plasma IL-33/sST2 levels were detected by enzyme linked immunosorbent assay (ELISA) and other routine laboratory parameters were obtained from the clinical central laboratory. The level of IL-33 in acute (49.48 ± 18.92), subacute (41.35 ± 17.12), chronic active (44.99 ± 16.80), and the chronic stable (28.92 ± 13.12) groups were higher than that in the HC group (11.66 ± 3.26) (p < 0.001). The IL-33 level in the acute group decreased significantly after treatment (49.48 ± 18.92 vs. 29.89 ± 12.92) (p < 0.001). Furthermore, the IL-33 level in the chronic active group (44.99 ± 16.80) was higher than that in the chronic stable group (28.92 ± 13.12) (p < 0.01). Interestingly, IL-33 correlated with white blood cells (WBC) (r = 0.268, p < 0.05) and C-reactive protein (CRP) (r = 0.272, p < 0.05). The level of sST2 increased in the acute (3,717.76 ± 2,036.25), subacute (3,130.41 ± 1,931.71), chronic active (3,381.43 ± 1,394.83), and the chronic stable group (2,707.03 ± 1,260.26) groups compared with the HC group (297.76 ± 290.93) (p < 0.001). However, the sST2 plasma level showed no differences among the groups and did not significantly change after treatment in the acute group. IL-33 can reflect the state of brucellosis and may be a potential biomarker for diagnosis and monitoring treatment for brucellosis.

A novel biomarker for bacteremia in acute pyelonephritis during pregnancy

Sepsis is a leading cause of maternal death and its diagnosis during the golden hour is critical to improve survival. Acute pyelonephritis, a leading cause of sepsis, is a risk factor for ARDS, renal failure, and DIC. Bacteremia occurs in 15-20% of pregnant patients with pyelonephritis and its recognition depends on the availability of cultures, which takes time. A test for the rapid detection of blood-borne infections is needed. Soluble suppression of tumorigenicity 2 (sST2) has been proposed as a biomarker for sepsis in adults and children (GREAT Network, Ann Lab Med, 2015).

Can biomarkers help identify women who will have progressively worsening hypertensive disorders of pregnancy?

To determine if soluble fms-like tyrosine kinase-1 (sFLT-1), erythropoietin (EPO), soluble suppression of tumorigenicity 2 (sST2), and brain natriuretic peptide (BNP) levels at 34 to 36 6/7 weeks can predict progression from gestational (gHTN) or chronic hypertension (cHTN) to preeclampsia with severe features (PEC with SF) or superimposed preeclampsia (SI PEC).

Soluble ST2 and All-Cause Mortality in Patients with Chronic Obstructive Pulmonary Disease-A 10-Year Cohort Study.

Chronic obstructive pulmonary disease (COPD) is an inflammatory condition with constantly increasing mortality rates. Interleukin (IL)-33 and its decoy receptor, soluble suppression of tumorigenicity 2 (sST2), play a central role in the inflammatory response during infection. sST2 was suggested as a factor in the pathogenesis of COPD and emerged as a predictor of mortality in other non-communicable diseases. The role of sST2 as a predictor of mortality remains unclear in COPD yet. In this cohort study, we measured circulating concentrations of IL-33 and sST2 in the serum of patients with stable COPD (n = 59), patients with acute exacerbation of COPD (n = 29) and smoking (n = 20) and non-smoking controls (n = 20), using commercially available ELISAs, and investigated the prognostic role of sST2 in stable COPD. sST2 levels were significantly higher in COPD patients and smokers compared with non-smoking controls. We identified systolic blood pressure, forced expiratory volume in 1 s (FEV1% predicted), neutrophil count, lactate dehydrogenase and pack-years index as independent predictors of sST2 levels. During a median follow-up time of 10.6 years, 28 patients (47.5%) died. sST2 was an independent predictor of all-cause mortality in patients with COPD with a hazard ratio of 2.9 (95% CI 1.1–8.4, p = 0.035) per one standard deviation after adjustment for age, sex, pack-years, FEV1% predicted and C-reactive protein (CRP). sST2 concentrations are associated with severity of disease and long-term outcome in patients with COPD.

Correlation between Levels of Serum Lipoprotein-Associated Phospholipase A2 and Soluble Suppression of Tumorigenicity 2 and Condition of Acute Heart Failure Patients and Their Predictive Value for Prognosis.

Objective To explore the correlation between levels of serum lipoprotein-associated phospholipase A2 (LP-PLA2) and soluble suppression of tumorigenicity 2 (sST2) and condition of acute heart failure (AHF) patients and their predictive value for prognosis. Methods The data of patients who complained of acute dyspnea and were treated in our hospital (January 2018–January 2020) were selected for review analysis, and those diagnosed with AHF by means of chest films, physical examination, cardiogram, and color Doppler ultrasonography (CDS) were selected as the study objects. The patients were split into the mild group (I or II, 55 cases) and the severe group (III or IV, 50 cases) according to the clinical condition grading standard in Guidelines for Diagnosis and Treatment of Acute Heart Failure. In addition, 105 healthy individuals examined in our medical center in the same period were selected as the control group. The serum LP-PLA2 and sST2 levels of all study objects were measured to analyze the correlation between these levels and AHF condition. Readmission due to heart failure and all-cause death were regarded as the endpoint events, and after one year of follow-up visits, the occurrence of the endpoint events in patients of the two groups was recorded, and with the endpoint events as the variable, the patients were divided into the event group and nonevent group to establish a logistic regression analysis model and analyze the merit of serum LP-PLA2 and sST2 in evaluating patient outcome. Results The patients' general information such as age and gender between the severe group and the mild group were not statistically different (P > 0.05), and the levels of high-sensitivity c-reactive protein (CRP), hemoglobin, creatinine, and uric acid of the severe group were greatly different from those of the mild group (P < 0.001), the comparison result of serum LP-PLA2 and sST2 levels was severe group > mild group > control group (P all <0.001), and the serum LP-PLA2 and sST2 levels of the severe group were, respectively, 275.98 ± 50.68 ng/ml and 2,122.65 ± 568.65 ng/ml; among 105 AHF patients, 50 of them had endpoint events (47.6%), including 36 in the severe group (36/50, 72.0%) and 14 in the mild group (14/55, 25.5%), and the event group presented greatly higher serum LP-PLA2 and sST2 levels than in the nonevent group (P < 0.001); according to the logistic regression analysis, serum LP-PLA2 and sST2 had independent predictive value for prognosis of AHF patients, which could be used as the independent predictive factors for 1-year prognosis. Conclusion Serum LP-PLA2 and sST2 have a good diagnosis value for the condition and prognosis of AHF patients, which shall be promoted and applied in practice.

Breast cancer in schizophrenia could be interleukin-33-mediated.

Recent epidemiological and genetic studies have revealed an interconnection between schizophrenia and breast cancer. The mutual underlying pathophysiological mechanisms may be immunologically driven. A new cluster of molecules called alarmins may be involved in sterile brain inflammation, and we have already reported the potential impact of interleukin-33 (IL-33) on positive symptoms onset and the role of its soluble trans-membranes full length receptor (sST2) on amelioration of negative symptoms in schizophrenia genesis. Furthermore, these molecules have already been shown to be involved in breast cancer etiopathogenesis. In this review article, we aim to describe the IL-33/suppressor of tumorigenicity 2 (ST2) axis as a crossroad in schizophrenia-breast cancer comorbidity. Considering that raloxifene could be tissue-specific and improve cognition and that tamoxifen resistance in breast carcinoma could be improved by strategies targeting IL-33, these selective estrogen receptor modulators could be useful in complementary treatment. These observations could guide further somatic, as well as psychiatric therapeutical protocols by incorporating what is known about immunity in schizophrenia.

Clinical Relevance of Elevated Soluble ST2, HSP27 and 20S Proteasome at Hospital Admission in Patients with COVID-19.

Simple SummarySince the outbreak of the Coronavirus Disease (COVID-19) disease in 2019 immunological research is continuing to debunk contingent pathomechanistic interpretations. Currently the COVID-2019 infection is described in humans as a state of hyperinflammation. As the COVID-2019 pandemic continued we collected serum (first blood draw) from patients that were admitted to the hospital (2020/21). Here we show that proteins that indicate “immune decay” (heat shock protein 27 and 20S proteasome) and immune suppressive soluble suppression of tumorigenicity 2 (sST2) were massively increased in those COVID-19 patients. In addition, we demonstrated that those proteins were associated with mortality, invasive ventilation, and oxygen support. Facit: Our results indicate that COVID-19 disease can also be construed as disease that causes an immunological disintegration. Historically it is notable to report that sepsis pathophysiology underwent a similar metamorphosis. Until 2003 the clinical picture of sepsis was seen as a consequence of a hyperactive immune system. This scientific interpretation tottered, and clinical research has evidenced that septic patients are in a state of immunologic default. Based on our serological data we believe that the concept of “COVID-19 induced hyperinflammation” is ready to undergo a critical appraisal and calls for cytoprotective therapeutic interventions.Although, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) represents one of the biggest challenges in the world today, the exact immunopathogenic mechanism that leads to severe or critical Coronavirus Disease 2019 (COVID-19) has remained incompletely understood. Several studies have indicated that high systemic plasma levels of inflammatory cytokines result in the so-called “cytokine storm”, with subsequent development of microthrombosis, disseminated intravascular coagulation, and multiorgan-failure. Therefore, we reasoned those elevated inflammatory molecules might act as prognostic factors. Here, we analyzed 245 serum samples of patients with COVID-19, collected at hospital admission. We assessed the levels of heat shock protein 27 (HSP27), soluble suppressor of tumorigenicity-2 (sST2) and 20S proteasome at hospital admission and explored their associations with overall-, 30-, 60-, 90-day- and in-hospital mortality. Moreover, we investigated their association with the risk of ventilation. We demonstrated that increased serum sST2 was uni- and multivariably associated with all endpoints. Furthermore, we also identified 20S proteasome as independent prognostic factor for in-hospital mortality (sST2, AUC = 0.73; HSP27, AUC = 0.59; 20S proteasome = 0.67). Elevated sST2, HSP27, and 20S proteasome levels at hospital admission were univariably associated with higher risk of invasive ventilation (OR = 1.8; p < 0.001; OR = 1.1; p = 0.04; OR = 1.03, p = 0.03, respectively). These findings could help to identify high-risk patients early in the course of COVID-19.

Recent research trends in fluorescent reporters‐based lateral flow immunoassay for protein biomarkers specific to acute myocardial infarction

AbstractA rapid and sensitive method is urgently required for the detection of acute myocardial infarction (AMI), a major cause of death globally. As a user‐friendly diagnostic platform, the lateral flow immunoassay (LFIA) has been considered as a rapid and low‐cost tool for point‐of‐care testing. Among the available LFIAs, fluorescent nanoparticles have been widely used as reporters to improve the sensitivity of detection targets. This review describes the basic principle of fluorescence‐based LFIA and various fluorescent nanoparticles used as a signal readout. Recently, various studies on fluorescent reporters‐based LFIAs for diagnosing potential AMI have been outlined by determining the level of AMI‐specific protein biomarkers, including cardiac troponins I and T, heart‐type fatty acid‐binding protein, myoglobin, brain natriuretic peptide, suppression of tumorigenicity 2, creatine kinase‐MB, and C‐reactive protein. The challenges of the used fluorescent reporters in LFIA are discussed to achieve affordable and excellent performances for clinical applications.

Easix before Conditioning Therapy Predicts Sepsis after Allogeneic Stem Cell Transplantation

Purpose: Endothelial complications are principal causes of non-relapse mortality (NRM) after allogeneic stem cell transplantation (alloSCT). Sepsis is a dysfunctional endothelial response to harmful microorganisms with increased risk of microvascular damage and organ failure. We hypothesized that the endothelial activation and stress index (EASIX) predicts risk of sepsis after alloSCT.Methods: In this retrospective evaluation, 1290 patients (random 1:1 allocation into a training cohort and a validation cohort while balancing for sepsis events) were assessed for presence of neutropenic fever, sepsis and infectious pathogens within 50 days after alloSCT. Sepsis and septic shock were defined according to the modified Sepsis-3 guidelines by the Infectious Diseases Working Party (AGIHO) and Intensive Care Working Party (iCHOP) of the German Society of Hematology and Medical Oncology (DGHO) for neutropenic cancer patients. EASIX and additional serum markers were assessed longitudinally before and after transplantation and correlated with outcome. Established clinical risk scores (EBMT, HCT-CI and VOD-CIBMTR) were raised and compared to EASIX.Results: Within the full cohort of 1290 patients transplanted since 01/2004, neutropenic fever episodes until day+50 after alloSCT were reported in 989 (76.7%), sepsis in 93 (7.2%), catecholamine use in 35 (2.7%), and mechanical ventilation in 31 (2.4%) patients. Patients who developed sepsis until day+50 differed from patients without early sepsis in more frequently having a higher disease score (58% vs 33%, p<0.001), more often receiving ATG prophylaxis (77% vs 64%, p=0.007), myeloablative or aplasia conditioning (44% vs 20%, p<0.001), and less likely receiving MTX prophylaxis (33% vs 43%, p=0.06).Prior to conditioning therapy, EASIX(-pre) was the only marker to predict the hazard of early sepsis irrespective of pathogen detection in time-dependent ROC (AUC 0.85 at day 50) and multivariable cause-specific Cox regression analyses (HR per two-fold increase 2.3 (1.9-2.8, p<0.001). The prognostic value of uni- and multivariable models were evaluated in the second cohort. An optimized cutoff for EASIX defined in the training cohort (2.32) strongly predicted sepsis in multivariable cause-specific Cox regression in the second cohort (HR 16.3 (7.0-37.5), p<0.001). Although Ferritin significantly predicted time to death without sepsis (HR per two-fold increase 1.11 (1.03-1.19), p=0.008), EASIX performed superior to other scores in univariate analysis when predicting time to early sepsis with respect to predictive accuracy measured by the time-dependent Brier score (Figure 1). Accordingly, EASIX was the strongest pre-transplantation score to predict early non-relapse mortality (NRM) within 6 months after alloSCT.Pre-conditioning leukocyte counts, CRP or endothelial serum markers did not associate with early sepsis. After transplantation starting with day 0, sepsis associated with EASIX at any time point until day+28, and in addition with suppressor of tumorigenicity (ST)2 and interleukin-18.Conclusions: EASIX is a powerful predictor of early sepsis and 6-months NRM, irrespective of detected pathogens. Patients with EASIX-pre>2.32 represent a high-risk cohort requiring intensive prophylaxis and endothelial protective treatment strategies. [Display omitted] DisclosuresSchönland: Pfizer: Honoraria; Janssen: Honoraria, Other: Travel grants, Research Funding; Prothena: Honoraria, Other: Travel grants; Sanofi: Research Funding; Takeda: Honoraria, Other: Travel grants. Hegenbart: Pfizer: Consultancy, Honoraria; Janssen: Consultancy, Research Funding; Alnylam: Honoraria; Akcea: Honoraria; Prothena: Research Funding. Schmitt: Apogenix: Research Funding; Hexal: Other: Travel grants, Research Funding; Novartis: Other: Travel grants, Research Funding; Kite Gilead: Other: Travel grants; Bluebird Bio: Other: Travel grants; MSD: Membership on an entity's Board of Directors or advisory committees; TolerogenixX: Current holder of individual stocks in a privately-held company. Dreger: Novartis: Consultancy, Speakers Bureau; Bluebird Bio: Consultancy; Janssen: Consultancy; Gilead Sciences: Consultancy, Speakers Bureau; BMS: Consultancy; AbbVie: Consultancy, Speakers Bureau; AstraZeneca: Consultancy, Speakers Bureau; Riemser: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Speakers Bureau.

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.

Soluble suppression of tumorigenicity 2 as outcome predictor after cardiopulmonary resuscitation: an observational prospective study

Prognostication after cardiopulmonary resuscitation (CPR) is complex. Novel biomarkers like soluble suppression of tumorigenicity 2 (sST2) may provide an objective approach. A total of 106 post-CPR patients were included in this single-center observational prospective study. Serum sST2 levels were obtained 24 h after admission. Individuals were assigned to two groups: patients below and above the overall cohort’s median sST2 concentration. Primary outcome was a combined endpoint at 6 months (death or Cerebral Performance Category > 2); secondary endpoint 30-day mortality. A uni- and multivariate logistic regression analysis were conducted. Elevated sST2-levels were associated with an increased risk for the primary outcome (OR 1.011, 95% CI 1.004–1.019, p = 0.004), yet no patients with poor neurological outcome were observed at 6 months. The optimal empirical cut-off for sST2 was 46.15 ng/ml (sensitivity 81%, specificity 53%, AUC 0.69). Levels above the median (> 53.42 ng/ml) were associated with higher odds for both endpoints (death or CPC > 2 after 6 months: 21% vs. 49%, OR 3.59, 95% CI 1.53–8.45, p = 0.003; death after 30 days: 17% vs. 43.3%, OR 3.75, 95% CI 1.52–9.21, p = 0.003). A positive correlation of serum sST2 after CPR with mortality at 30 days and 6 months after cardiac arrest could be demonstrated.

Prognosis value of serum soluble ST2 level in acute ischemic stroke and STEMI patients in the era of mechanical reperfusion therapy.

Soluble form suppression of tumorigenicity 2 (sST2) is known to have prognostic value in ST-elevation myocardial infarction (STEMI) and could impact mortality after acute ischemic stroke (AIS). However, before considering sST2 as a therapeutic target, the kinetics of release and its association with adverse clinical events in both STEMI and AIS patients have to be determined. We prospectively enrolled 251 STEMI patients, treated with primary percutaneous coronary intervention, and 152 AIS patients treated with mechanical thrombectomy. We evaluated the level of sST2 in patient sera at five time point (admission, 4, 24, 48h and 1month from admission for STEMI patients and admission, 6, 24, 48h and 3months from admission for AIS patients). Major adverse clinical events (MACE) (all-cause death, acute myocardial infarction, stroke or hospitalization for heart failure) in STEMI patients and all-cause death in AIS patients were recorded during a 12-month follow-up. Mean age of the study population was 59 ± 12 and 69 ± 15years in STEMI and AIS patients, respectively. In STEMI patients, sST2 peaked 24h after admission (25.5ng/mL interquartile range (IQR) [14.9-29.1]) whereas an earlier and lower peak was observed in AIS patients (16.8ng/mL IQR [15.2-18.3] at 6h). Twenty-five (10.0%) STEMI patients experienced a MACE and 12 (7.9%) AIS patients had all-cause death within the first 12months. A high level of sST2 at 24h was associated with MACE in STEMI patients (hazard ratio (HR) = 2.5; 95% confidence interval (CI) [1.1-5.6], p = 0.03) and all-cause death in AIS patients (HR = 11.7; 95% CI [3.8-36.2], p < 0.01) within the first 12months. The study highlights that sST2 levels at 24h are associated with an increased risk to adverse clinical events in both diseases.

Soluble suppression of tumorigenicity 2 (sST2) for predicting disease severity or mortality outcomes in cardiovascular diseases: A systematic review and meta-analysis

ObjectivesSoluble suppression of tumorigenicity 2 (sST2) is a member of the interleukin-1 receptor family. It is raised in various cardiovascular diseases, but its value in predicting disease severity or mortality outcomes has been controversial. Therefore, we conducted a systematic review and meta-analysis to determine whether sST2 levels differed between survivors and non-survivors of patients with cardiovascular diseases, and whether elevated sST2 levels correlated with adverse outcomes.MethodsPubMed and Embase were searched until 23rd June 2021 for studies that evaluated the relationship between sST2 levels and cardiovascular disease severity or mortality.ResultsA total of 707 entries were retrieved from both databases, of which 14 studies were included in the final meta-analysis. In acute heart failure, sST2 levels did not differ between survivors and non-survivors (mean difference [MD]: 24.2 ± 13.0 ng/ml; P = 0.06; I2: 95%). Elevated sST2 levels tend to be associated with increased mortality risk (hazard ratio [HR]: 1.12, 95 %CI: 0.99–1.27, P = 0.07; I2: 88%). In chronic heart failure, sST2 levels were higher in non-survivors than in survivors (MD: 0.19 ± 0.04 ng/ml; P = 0.001; I2: 0%) and elevated levels were associated with increased mortality risk (HR: 1.64, 95% CI: 1.27–2.12, P < 0.001; I2: 82%). sST2 levels were significantly higher in severe disease compared to less severe disease (MD: 1.56 ± 0.46 ng/ml; P = 0.001; I2: 98%). Finally, in stable coronary artery disease, sST2 levels were higher in non-survivors than survivors (MD: 3.0 ± 1.1 ng/ml; P = 0.005; I2: 80%) and elevated levels were significantly associated with increased mortality risk (HR: 1.32, 95% CI: 1.04–1.68, P < 0.05; I2: 57%).ConclusionssST2 significantly predicts disease severity and mortality in cardiovascular disease and is a good predictor of mortality in patients with stable coronary artery disease and chronic heart failure.