Tumor Necrosis Factor-related Apoptosis-inducing Ligand Levels Research Articles

Defining age-specific reference intervals for biomarkers distinguishing bacterial from viral infection in paediatrics

Differentiating bacterial from viral infections in children is a common clinical challenge. Novel host immune biomarkers have the potential to aid thediagnosis of infection aetiology and identify children who require antibiotics. Data on novel infection biomarkers gender and age-specific correlations, and reference intervals in healthy paediatrics is lacking. This study reports the plasma levels of three novel biomarkers that can aid in the differentiation of bacterial and viral infection in a healthy group of paediatrics. The levels of (Interferon-Gamma Inducible Protein 10 kDa (IP-10), Lipocalin-2 (LCN2) and TNF-Related Apoptosis-Inducing Ligand (TRAIL) were quantified in 199 plasma samples from healthy paediatrics aged 2 to 16 years old from across the UK. Reference intervals (2.5th and 97.5th) were determined, and biomarker levels were examined for sex and age associations. Reference intervals for IP-10, LCN2 and TRAIL for ages 2–16 years were 36.7–168.1 pg/ml, 14.2–123.3 ng/ml, 57.4–71.4 pg/ml respectively. No biomarker showed an association with sex and IP-10 did not show any association with age. TRAIL levels had a weak continuous negative correlation with age and LCN2 levels had a continuous positive correlation with age. Specific cut-offs for LCN2 in two age categories were identified, while TRAIL did not require age partitions. This study provides age-appropriate reference intervals for three biomarkers of infection in healthy children. These findings have the potential to improve the impact of future research on these biomarkers, the accuracy of clinical decision-making in children with infection, paediatric patient care and outcomes, and antimicrobial stewardship.

Evaluating TRAIL and IP-10 alterations in vaccinated pregnant women after COVID-19 diagnosis and their correlation with neutralizing antibodies.

This study evaluates tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and interferon-γ-induced protein-10 (IP-10) in pregnant women with COVID-19 and their newborns, exploring the effects of antiviral treatments and vaccine-induced neutralizing antibody (Nab) inhibition on these key viral infection biomarkers. We studied 61 pregnant women with past COVID-19 and either three (n=56) or four (n=5) doses of vaccination, and 46 without COVID-19 but vaccinated. We analyzed them and their newborns' blood for TRAIL, IP-10, and Nab levels using enzyme-linked immunosorbent assays (ELISA), correlating these with other clinical factors. Our study found lower TRAIL but higher IP-10 levels in maternal blood than neonatal cord blood, irrespective of past COVID-19 diagnosis. Cases diagnosed with COVID-19 < 4 weeks previously had higher maternal blood TRAIL levels (16.49 vs. 40.81 pg/mL, p=0.0064) and IP-10 (154.68 vs. 225.81 pg/mL, p=0.0170) than those never diagnosed. Antiviral medication lowered TRAIL and IP-10 in maternal blood without affecting Nab inhibition (TRAIL: 19.24 vs. 54.53 pg/mL, p=0.028; IP-10: 158.36 vs. 255.47 pg/mL, p=0.0089). TRAIL and IP-10 levels were similar with three or four vaccine doses, but four doses increased Nab inhibition (p=0.0363). Previously COVID-19 exposed pregnant women had higher Nab inhibition (p < 0.0001). No obvious correlation was found among TRAIL, IP-10, and Nab inhibition level. Our study suggests that lower maternal TRAIL and higher IP-10 levels compared to neonatal cord blood coupled with a rise in both markers following COVID-19 diagnosis that could be reduced by antivirals indicates a correlation to infection severity. Higher vaccine doses enhance Nab inhibition, irrespective of antiviral medication use and independent of TRAIL or IP-10 levels, highlighting the significance and safety of adequate vaccination and antiviral use post-diagnosis in pregnant women.

Effects of intravenous pulse methylprednisolone in neuromyelitis optica during the acute phase.

Neuromyelitis optica spectrum disorder (NMOSD) is an anti-aquaporin 4 (anti-AQP4) autoantibodies-mediated idiopathic inflammatory demyelinating disease of the central nervous system. While intravenous pulse methylprednisolone (IVMP) is the recommended initial treatment option for acute onset NMOSD, its therapeutic mechanism remains unclear. We hypothesized that IVMP would reduce the expression of pro-inflammatory factors and increase the resolution of inflammation in patients with NMOSD. Mendelian randomization (MR) analysis was used to screen meaningful inflammatory and resolution factors for inclusion. Three MR methods with inverse variance weighting (IVW) were primarily used to identify positive results. Interleukin (IL)-10, IL-1β, IL-6, C-X-C motif chemokine ligand 12 (CXCL12), and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) were screened from 41 inflammatory factors, and resolvin D1 (RvD1), maresin 1 (MaR1), and lipoxin A4 (LXA4) were screened from 6 resolution markers for inclusion. Subsequently, 12 patients with NMOSD were enrolled and treated with IVMP. Serum levels of the aforementioned inflammatory and resolution markers were measured by enzyme-linked immunosorbent assay before and after IVMP treatment. High levels of TRAIL, CXCL12, and IL-1β were associated with an increased risk of NMOSD (TRAIL: odds ratio [OR], 1.582; 95% confidence interval [CI], 1.003-2.495; CXCL12: OR, 3.610; 95% CI, 1.011-12.889; IL-1β: OR, 4.500; 95% CI, 1.129-17.927). High levels of RvD1, MaR1, and LXA4 were associated with a reduced risk of NMOSD (RvD1: OR, 0.725; 95% CI, 0.538-0.976; MaR1: OR, 0.985; 95% CI, 0.970-0.999; LXA4: OR, 0.849; 95% CI, 0.727-0.993). Among patients with NMOSD, serum levels of IL-6, CXCL12, and TRAIL significantly decreased following IVMP treatment, compared with pretreatment levels, while levels of IL-1β, LXA4, and MaR1 significantly increased after IVMP treatment (p < 0.05). A significant positive correlation was observed between CXCL12 levels and Expanded Disability Status Scale (EDSS) scores (r = 0.451, p < 0.05). Several systemic inflammatory regulators associated with the pathogenesis of NMOSD were identified. The protective roles of LXA4 and MaR1 may be indispensable components of glucocorticoid treatment. Therefore, the use of resolution markers may be a potential strategy for improving central nervous system injury in individuals with NMOSD.

297. ASSESSING BLOOD-BASED BIOMARKERS IN OESOPHAGEAL CANCER PATIENTS RECEIVING NEOADJUVANT CHEMORADIOTHERAPY

Abstract Background Oesophageal cancer is the sixth most common cause of cancer-related deaths globally. It has a significant rate of mortality despite the multimodal approach to treatment. Neo-adjuvant chemoradiotherapy is standard of care but there is a clinical need for new therapies. HER2-targeted therapies and immune checkpoint inhibitors targeting the PD-1/PD-L1 axis have emerged as treatment strategies of significant interest in recent years. This study focuses on exploring potential plasma-based biomarkers (growth factors, cytokines, soluble (s) PD-L1) in patients (pts) with oesophageal cancer receiving standard of care neo-adjuvant therapy and stratified based on HER2 expression and pathological complete response (pCR). Methods 50 pts with oesophageal cancer who are eligible for neoadjuvant therapy were recruited. Blood samples were taken pre-treatment, on the first day of the 2nd cycle and post-neoadjuvant treatment. Plasma was extracted within four hours of blood draw and stored at -800C. 20 matched pre- and post-treatment samples were included in this analysis. HER2 status (IHC 3+ (n=3), IHC 2+ (n=5), IHC 1+ (n=3), IHC 0 (n=6) was available for 17 pts. 3 pts achieved a pCR but no HER2 IHC data was available. The levels (pg/ml) of 21 analytes were assessed using the Human Growth Factor Luminex Performance Assay and a Luminex MagPix system. Changes were significant if p&amp;lt;0.05, paired student’s t test. Results Twenty-one biomarkers of response were assessed in the final analysis. Platelet-derived growth factor (PDGF)-AA and PDGF AA/BB displayed the highest concentration levels of the tested analytes but levels did not change pre-and post-treatment. GRO-b (CXCL2) and vascular endothelial growth factor (VEGF) displayed a numerical increase post-treatment but this did not prove significant (p&amp;lt;0.05). Tumour-necrosis factor-related apoptosis-inducing ligand (TRAIL) protein decreased significantly post-therapy (p=0.038). PD-L1 levels significantly increased in the post-treatment cycles (paired t-test p=0.0029), especially in pts with HER2+ status. TRAIL or sPD-L1 levels were not significantly different when categorised by HER2 IHC or pCR status. Conclusion The increase in sPD-L1 and reduction in TRAIL levels in the peripheral blood of oesophageal cancer patients following neoadjuvant therapy suggests treatment alters factors associated with immune-suppression and the induction of tumour cell death. Further investigation in a larger cohort is warranted.

TRAIL and IP-10 dynamics in pregnant women post COVID-19 vaccination: associations with neutralizing antibody potency.

The aim of this study is to investigate changes in TNF-related apoptosis-inducing ligand (TRAIL) and gamma interferon-induced protein 10 (IP-10) after COVID-19 vaccination in pregnant women and to explore their association with neutralizing antibody (Nab) inhibition. The study evaluated 93 pregnant women who had previously received two (n=21), three (n=55) or four (n=17) doses of COVID-19 vaccine. Also we evaluated maternal blood samples that were collected during childbirth. The levels of TRAIL, IP-10 and Nab inhibition were measured using enzyme-linked immunosorbent assays (ELISA). Our study revealed four-dose group resulted in lower TRAIL levels when compared to the two-dose and three-dose groups (4.78 vs. 16.07 vs. 21.61 pg/ml, p = 0.014). The two-dose group had reduced IP-10 levels than the three-dose cohort (111.49 vs. 147.89 pg/ml, p=0.013), with no significant variation compared to the four-dose group. In addition, the four-dose group showed stronger Nab inhibition against specific strains (BA.2 and BA.5) than the three-dose group. A positive correlation was observed between TRAIL and IP-10 in the two-dose group, while this relationship was not found in other dose groups or between TRAIL/IP-10 and Nab inhibition. As the doses of the COVID-19 vaccine increase, the levels of TRAIL and IP-10 generally increase, only by the fourth dose, the group previously vaccinated with AZD1222 showed lower TRAIL but higher IP-10. Despite these changes, more doses of the vaccine consistently reinforced Nab inhibition, apparently without any relation to TRAIL and IP-10 levels. The variation may indicate the induction of immunological memory in vaccinated mothers, which justifies further research in the future.

Arsenic exposure and pulmonary function decline: Potential mediating role of TRAIL in chronic obstructive pulmonary disease patients

BackgroundEnvironmental arsenic (As) exposure is strongly related to the progression of chronic obstructive pulmonary disease (COPD). Pulmonary epithelial cells apoptosis is implicated in the pathophysiological mechanisms of COPD. However, the role of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), one biomarker of apoptosis, remains unclear in As-mediated pulmonary function alternations in COPD patients. MethodsThis study included 239 COPD patients. The serum level of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) was measured by enzyme-linked immunosorbent assay (ELISA). The blood As level was determined through inductively coupled plasma mass spectrometry (ICP-MS). ResultsBlood As levels exhibited a negative and dose-dependent correlation with pulmonary function. Per unit elevation of blood arsenic concentrations was related to reductions of 0.339 L in FEV1, 0.311 L in FVC, 1.171% in FEV1/FVC%, and 7.999% in FEV1% in COPD subjects. Additionally, a positive dose-response correlation of blood As with serum TRAIL was found in COPD subjects. Additionally, the level of serum TRAIL was negatively linked to lung function. Elevated TRAIL significantly mediated As-induced decreases of 11.05%, 13.35%, and 31.78% in FVC, FEV1, and FEV1%, respectively among the COPD patients. ConclusionBlood As level is positively correlated with pulmonary function decline and serum TRAIL increase in individuals with COPD. Our findings suggest that elevated TRAIL levels may serve as a mediating mechanism through which As contributes to declining lung function in COPD patients.

Plasma TRAIL and ANXA1 in diagnosis and prognostication of pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a rare vasculopathy, with high morbidity and mortality. The sensitivity of the current european society of cardiology/european respiratory society (ESC/ERS) risk assessment strategy may be improved by the addition of biomarkers related to PAH pathophysiology. Such plasma-borne biomarkers may also reduce time to diagnosis, if used as diagnostic tools in patients with unclear dyspnea, and in guiding treatment decisions. Plasma levels of proteins related to tumor necrosis factor (TNF), inflammation, and immunomodulation were analyzed with proximity extension assays in patients with PAH (n = 48), chronic thromboembolic pulmonary hypertension (PH; CTEPH, n = 20), PH due to left heart failure (HF) with preserved (HFpEF-PH, n = 33), or reduced (HFrEF-PH, n = 36) ejection fraction, HF without PH (n = 15), and healthy controls (n = 20). TNF-related apoptosis-inducing ligand (TRAIL) were lower in PAH versus the other disease groups and controls (p < 0.0082). In receiver operating characteristics analysis, TRAIL levels identified PAH from the other disease groups with a sensitivity of 0.81 and a specificity of 0.53 [area under the curve: 0.70; (95% confidence interval, CI: 0.61-0.79; p < 0.0001)]. In both single (p < 0.05) and multivariable Cox regression models Annexin A1 (ANXA1) [hazard ratio, HR: 1.0367; (95% CI: 1.0059-1.0684; p = 0.044)] and carcinoembryonic antigen-related cell adhesion molecule 8 [HR: 1.0603; (95% CI: 1.0004-1.1237; p = 0.0483)] were significant predictors of survival, adjusted for age, female sex and ESC/ERS-initial risk score. Low plasma TRAIL predicted PAH among patients with dyspnea and differentiated PAH from those with CTEPH, HF with and without PH; and healthy controls. Higher plasma ANXA1 was associated with worse survival in PAH. Larger multicenter studies are encouraged to validate our findings.

Novel protein biomarkers for pneumonia and acute exacerbations in COPD: a pilot study.

Community-acquired pneumonia (CAP) and acute exacerbations of chronic obstructive pulmonary disease (AECOPD) result in high morbidity, mortality, and socio-economic burden. The usage of easily accessible biomarkers informing on disease entity, severity, prognosis, and pathophysiological endotypes is limited in clinical practice. Here, we have analyzed selected plasma markers for their value in differential diagnosis and severity grading in a clinical cohort. A pilot cohort of hospitalized patients suffering from CAP (n = 27), AECOPD (n = 10), and healthy subjects (n = 22) were characterized clinically. Clinical scores (PSI, CURB, CRB65, GOLD I-IV, and GOLD ABCD) were obtained, and interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-2-receptor (IL-2R), lipopolysaccharide-binding protein (LBP), resistin, thrombospondin-1 (TSP-1), lactotransferrin (LTF), neutrophil gelatinase-associated lipocalin (NGAL), neutrophil-elastase-2 (ELA2), hepatocyte growth factor (HGF), soluble Fas (sFas), as well as TNF-related apoptosis-inducing ligand (TRAIL) were measured in plasma. In CAP patients and healthy volunteers, we found significantly different levels of ELA2, HGF, IL-2R, IL-6, IL-8, LBP, resistin, LTF, and TRAIL. The panel of LBP, sFas, and TRAIL could discriminate between uncomplicated and severe CAP. AECOPD patients showed significantly different levels of LTF and TRAIL compared to healthy subjects. Ensemble feature selection revealed that CAP and AECOPD can be discriminated by IL-6, resistin, together with IL-2R. These factors even allow the differentiation between COPD patients suffering from an exacerbation or pneumonia. Taken together, we identified immune mediators in patient plasma that provide information on differential diagnosis and disease severity and can therefore serve as biomarkers. Further studies are required for validation in bigger cohorts.

Effect of penetrative needling of "Zhibian" (BL54) through "Shuidao" (ST28) on expression of TRAIL and its receptors in rats with premature ovarian insufficiency

To observe the effect of penetrative needling of "Zhibian" (BL54) through "Shuidao" (ST28) on the expressions of death receptor pathway-related protein tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its receptors, as death receptor 4 (DR4), death receptor 5 (DR5), decoy receptor 1 (DcR1) and decoy receptor 2 (DcR2) in premature ovarian insufficiency (POI) rats, so as to explore its mechanisms underlying improvement of POI. Forty female SD rats were randomly divided into blank control, model, penetrative needling and medication (estradiol valerate) groups, with 10 rats in each group. The POI model was established by intraperitoneal injection of cyclophosphamide (D1: 50 mg·kg-1·d-1, D2 to D15: 8 mg·kg-1·d-1, for a total of 15 d). After successful modeling, the rats in the penetrative needling group received penetrative needling of BL54 through ST28, with the needle retained for 30 min, once a day for a total of 4 weeks. Rats of the medication group received gavage of estradiol valerate (0.09 mg·kg-1·d-1) once daily for 4 weeks. After the intervention, the content of serum follicles of stimulation hormone (FSH),lateinizing hormone (LH),estradiol (E2) and vascular endothelial growth factor (VEGF) were assayed using enzyme-linked immunosorbent assay, and histopathological changes of ovarian tissue and the number of follicles were observed under light microscope after H.E. staining. The expression levels of TRAIL, DR4, DR5, DcR1, DcR2, and Fas-associated death domain (FADD) in ovarian tissues were detected using quantitative real-time PCR, and the immunoactivity of ovarian TRAIL, DR4 and DR5 detected using immunohistochemistry. The body weight and the damp weight of ovary were measured for calculating the ovarian coefficient. Compared with the blank control group, the E2 and VEGF contents, ovarian coefficient, and the number of the primary, secondary and sinus follicles were significantly decreased (P<0.01) in the model group, whereas FSH and LH contents, the atretic follicle number, TRAIL, DR4 and DR5 immunoactivity, and the expression levels of TRAIL, DR4, DR5 and FADD mRNAs considerably increased in the model group (P<0.01). In comparison with the model group, the decrease of the VEGF content, ovarian coefficient, and the number of the primary, secondary and sinus follicles, and the increase of the atretic follicle number, TRAIL, DR4 and DR5 immunoactivity, and expression levels of TRAIL, DR4, DR5 and FADD mRNAs were reversed in both penetrative needling and medication groups (P<0.01, P<0.05). The number of primary follicles was significantly more in the medication group than in the penetrative needling group (P<0.01). Penetrative needling of BL54 and ST28 can improve ovarian weight and promote follicular development in POI rats, which may be associated with its function in down-regulating the expression of pro-apoptotic proteins TRAIL, DR4, DR5 and FADD of the death receptor pathway to inhibit apoptosis of ovarian granulosa cells.

TRAIL or TRAIL-R2 as a Predictive Biomarker for Mortality or Cardiovascular Events: A Systematic Review and Meta-analysis.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and TRAIL-receptor-2 (TRAIL-R2) are associated with atherosclerosis. This meta-analysis aimed to investigate the potential association between TRAIL/TRAIL-R2 with mortality or cardiovascular (CV) events. PubMed, Embase, and Cochrane Library were searched for reports published up to May 2021. Reports were included when the association between TRAIL or TRAIL-R2 and mortality or CV events was reported. Considering the heterogeneity between studies, we used the random-effects model for all analyses. Ultimately, the meta-analysis included 18 studies (16,295 patients). The average follow-up ranged from 0.25 to 10 years. Decreased TRAIL levels were negatively associated with all-cause mortality [rank variable, hazard ratio (HR), 95% CI, 2.93, 1.94-4.42; I2 = 0.0%, Pheterogeneity = 0.835]. Increased TRAIL-R2 levels were positively associated with all-cause mortality (continuous variable, HR, 95% CI, 1.43, 1.23-1.65; I2 = 0.0%, Pheterogeneity = 0.548; rank variable, HR, 95% CI, 7.08, 2.70-18.56; I2 = 46.5%, Pheterogeneity = 0.154), CV mortality (continuous variable, HR, 95% CI, 1.33, 1.14-1.57; I2 = 0.0%, Pheterogeneity = 0.435), myocardial infarction (continuous variable, HR, 95% CI, 1.23, 1.02-1.49; rank variable, HR, 95% CI, 1.49, 1.26-1.76; I2 = 0.7%, Pheterogeneity = 0.402), and new-onset heart failure (rank variable, HR, 95% CI, 3.23, 1.32-7.87; I2 = 83.0%, Pheterogeneity = 0.003). In conclusion, decreased TRAIL was negatively associated with all-cause mortality, and increased TRAIL-R2 was positively associated with all-cause mortality, CV mortality, myocardial infarction, and heart failure.

Tumor necrosis factor-related apoptosis-inducing ligand gene polymorphism and its plasma phenotype in relation to Crohn's disease

Objectives: To investigate the associations of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene polymorphism and plasma soluble TRAIL level (sTRAIL) with Crohn's disease (CD) and to retrospectively analyze the effects of TRAIL gene variants and plasma sTRAIL levels on clinical response to infliximab (IFX). Methods: From January 2012 to January 2021, 312 CD patients [205 males, 107 females, average age (33.9±9.8) years] and 514 age-and gender-matched healthy controls [304 males, 210 females, average age (34.9±9.4) years] were recruited from the Department of Gastroenterology, the Second Affiliated Hospital of Wenzhou Medical University. Among them, 72 patients with active CD who were ineffective or intolerant to traditional drug therapy regularly received IFX (5 mg/kg) treatment. According to the changes in the Harvey-Bradshaw index (HBI) and the Simplified Endoscopic Score for Crohn's Disease (SES-CD) in the 14th week, these patients were classified into response group (a decrease in HBI≥3 or a decrease in SES-CD≥50%) and non-response group. TRAIL (rs1131568) gene polymorphism was analyzed by matrix-assisted laser desorption/ionization time of flight mass spectrometry technique. The plasma sTRAIL level was examined by enzyme-linked immunosorbent assay (ELISA). Based on the Montreal CD classification criteria, all CD patients were divided into different subgroups. Finally, a comprehensive analysis was performed to investigate the relationship between TRAIL (rs1131568) gene polymorphism, the plasma sTRAIL level and the risk of CD, the clinicopathological characteristics of CD patients, and the clinical response to IFX. Results: The recessive model analysis showed that the homozygous variant genotype (CC) was more prevalent in patients with moderately to severely active CD than in those with mildly active CD (45.34% vs 29.23%, P=0.005). Both variant allele (C) and homozygous variant genotype (CC) in patients with stricturing and penetrating CD were more frequent than those in patients with non-stricturing and non-penetrating CD (65.48% vs 57.53%, P=0.046; 49.21% vs 31.18%, P=0.001). The dominant model analysis showed that variant allele (C) and variant genotype (TC+CC) was higher in CD patients with perianal lesions than in those without perianal lesions (66.83% vs 58.17%, P=0.037; 92.31% vs 78.37%, P=0.002). The average plasma sTRAIL level was higher in CD patients than in healthy controls [(243.04±42.74) ng/L vs (194.16±31.14) ng/L, P<0.001]. Compared with the patients with mildly active CD, the plasma sTRAIL level was increased in those with moderately to severely active CD [263.47(242.09, 281.91) ng/L vs 231.13(211.11, 247.11) ng/L, P<0.001]. The same conclusion was also drawn for the patients with stricturing and penetrating CD in contrast to those with non-stricturing and non-penetrating CD [266.18 (246.68, 289.91) ng/L vs 227.19 (204.57, 249.59) ng/L, P<0.001]. The plasma sTRAIL level was also higher in patients with perianal disease than in those without perianal disease [(261.40±41.51) ng/L vs (233.86±40.41) ng/L, P<0.001]. Multiple linear regression analysis further showed that disease activity (β=22.640, P<0.001) and homozygous variant genotype (CC) (β=16.814, P<0.001) may be positively related to the plasma sTRAIL level in CD patients independently. At the 14th week of IFX treatment, the plasma sTRAIL level in the response group was lower than that in the non-response group [205.98(190.72, 214.56) ng/L vs (238.33±29.38) ng/L, P<0.001]. Compared with week 0, the plasma sTRAIL level was decreased in the response group in the 14th week [(205.98 (190.72, 214.56) ng/L vs (239.89±42.43) ng/L, P<0.001]. Non-conditional logistic regression analysis showed that variant allele (C) and variant genotype (TC+CC) were less frequent in the response group than in the non-response group (53.33% vs 70.83%, P=0.037; 70.00% vs 91.67%, P=0.036). Conclusions: The increased plasma sTRAIL level may be a risk factor for CD. TRAIL (rs1131568) gene variation and the increase of plasma sTRAIL level may be associated with the increased disease activity of CD and may be the risk factors for stenosis, penetration, and perianal lesions in CD patients. In addition, TRAIL (rs1131568) gene variation or the increase of plasma sTRAIL level may be related to no response to IFX treatment in CD patients.

Electronic Cigarette Exposure Increases the Severity of Influenza a Virus Infection via TRAIL Dysregulation in Human Precision-Cut Lung Slices.

The use of electronic nicotine dispensing systems (ENDS), also known as electronic cigarettes (ECs), is common among adolescents and young adults with limited knowledge about the detrimental effects on lung health such as respiratory viral infections and underlying mechanisms. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a protein of the TNF family involved in cell apoptosis, is upregulated in COPD patients and during influenza A virus (IAV) infections, but its role in viral infection during EC exposures remains unclear. This study was aimed to investigate the effect of ECs on viral infection and TRAIL release in a human lung precision-cut lung slices (PCLS) model, and the role of TRAIL in regulating IAV infection. PCLS prepared from lungs of nonsmoker healthy human donors were exposed to EC juice (E-juice) and IAV for up to 3 days during which viral load, TRAIL, lactate dehydrogenase (LDH), and TNF-α in the tissue and supernatants were determined. TRAIL neutralizing antibody and recombinant TRAIL were utilized to determine the contribution of TRAIL to viral infection during EC exposures. E-juice increased viral load, TRAIL, TNF-α release and cytotoxicity in IAV-infected PCLS. TRAIL neutralizing antibody increased tissue viral load but reduced viral release into supernatants. Conversely, recombinant TRAIL decreased tissue viral load but increased viral release into supernatants. Further, recombinant TRAIL enhanced the expression of interferon-β and interferon-λ induced by E-juice exposure in IAV-infected PCLS. Our results suggest that EC exposure in human distal lungs amplifies viral infection and TRAIL release, and that TRAIL may serve as a mechanism to regulate viral infection. Appropriate levels of TRAIL may be important to control IAV infection in EC users.

Bacterial vs viral etiology of fever: A prospective study of a host score for supporting etiologic accuracy of emergency department physicians.

A host-protein score (BV score) that combines the circulating levels of TNF-related apoptosis-inducing ligand (TRAIL), interferon gamma-induced protein 10 (IP-10) and C-reactive protein (CRP) was developed for distinguishing bacterial from viral infection. This study assessed the potential of the BV score to impact decision making and antibiotic stewardship at the emergency department (ED), by comparing BV score's performance to physician's etiological suspicion at patient presentation. Rosetta study participants, aged 3 months to 18 years with febrile respiratory tract infection or fever without source, were prospectively recruited in a tertiary care pediatric ED. 465 patients were recruited, 298 met eligibility criteria and 287 were enrolled. ED physician's etiological suspicion was recorded in a questionnaire. BV score was measured retrospectively with results interpreted as viral, bacterial or equivocal and compared to reference standard etiology, which was adjudicated by three independent experts based on all available data. Experts were blinded to BV scores. Median age was 1.3 years (interquartile range 1.7), 39.7% females. 196 cases were reference standard viral and 18 cases were reference standard bacterial. BV score attained sensitivity of 88.9% (95% confidence interval: 74.4-100), specificity 92.1% (88.1-96.0), positive predictive value 53.3% (35.5-71.2) and negative predictive value 98.8% (97.1-100). Positive likelihood ratio was 11.18 (6.59-18.97) and negative likelihood ratio was 0.12 (0.03-0.45). The rate of BV equivocal scores was 9.4%. Comparing physician's suspicion to BV score and to the reference standard, and assuming full adoption, BV score could potentially correct the physician's diagnosis and reduce error ~2-fold, from 15.9% to 8.2%. BV score has potential to aid the diagnostic process. Future studies are warranted to assess the impact of real-time BV results on ED practice.

Serum TRAIL predicts severity and prognosis in patients with community-acquired pneumonia: a prospective cohort study.

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) can trigger the apoptosis pathways through binding to relative death receptors. However, the relationship of TRAIL with community-acquired pneumonia (CAP) was unclear. This study aims at exploring the relationships between circulatory TRAIL with severity and prognosis in CAP patients through a prospective cohort study. The whole of 239 CAP patients was enrolled. Demographic characteristics and clinical information were analyzed. TRAIL and inflammatory cytokines were measured using enzyme-linked immunosorbent assay (ELISA). Circulatory TRAIL was gradually increased in accord with CAP severity scores. Spearman or Pearson correlative analysis indicated that circulatory TRAIL was strongly associated with physiologic indicators among CAP patients. Mixed logistic and linear regression models revealed that circulatory TRAIL was positively correlated with the severity scores in CAP patients. After adjusting for confounders, higher levels of circulatory TRAIL on admission significantly elevated the risks of ICU admission, mechanical ventilation, longer hospital stays, or even death during hospitalization. The predictive capacities of serum TRAIL for death were higher compared with CAP severity scores, inflammatory and infectious indicators. There are obviously positive dose-response relationships between circulatory TRAIL on admission with the severity and poor prognostic outcomes in CAP patients. Circulatory TRAIL on admission may be used as a potential biomarker in predicting the severity and poor prognosis for CAP patients.Supplementary InformationThe online version contains supplementary material available at 10.1007/s11739-022-03086-7.

Preterm newborns exposed to early-onset preeclampsia have altered postnatal Tumor Necrosis Factor-related apoptosis-inducing ligand trends versus controls.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a protein with anti-atherogenic and vasoprotective effects that has never been studied in newborns exposed to preeclampsia. Our aim was to examine TRAIL serum concentrations in such neonates after birth and during the transitional period. Serum TRAIL levels were measured on the first and fifth day of life (DOL1 and DOL5, respectively) in 38 newborns exposed to early-onset preeclampsia and 38 controls born of normotensive mothers. TRAIL values on DOL1 and DOL5 did not differ between cases and controls. However, from DOL1 to DOL5 TRAIL levels increased in controls (from 20.54 ± 7.35 to 23.93 ± 11.02 pg/ml, p = 0.044) but decreased in those exposed to preeclampsia (from 25.58 ± 15.74 to 20.53 ± 10.72 pg/ml, p = 0.035). Overall, the relative change of TRAIL values from DOL1 to DOL5 was positively related to birth weight (beta coefficient 0.234, p = 0.042) and inversely related to preeclampsia (beta coefficient -0.241, p = 0.036). Newborns exposed to early-onset preeclampsia present a decrease in serum TRAIL levels during the transitional period. This pattern is exactly the opposite from what is observed in neonates born to normotensive mothers, and most likely points towards a defective mechanism of extrauterine adaptation related to preeclampsia exposure in utero. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) levels during the transitional period do not differ between infants exposed to early-onset preeclampsia and controls The pattern of change of TRAIL levels after birth is different; TRAIL decreases in newborns exposed to preeclampsia but increases in controls The decrease of TRAIL levels during the transitional period points towards a defective mechanism of extrauterine adaptation and an altered cardiometabolic profile in newborns exposed to early-onset preeclampsia.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is associated with cardiac injury and stroke severity in patients after acute ischemic stroke

Abstract Background Patients after acute stroke frequently show signs of myocardial injury. The pathophysiology and impact on patient's outcome are not fully understood. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is cytokine known to be associated with cardiovascular events. Purpose We aimed to assess TRAIL level dynamic changes in patients after acute ischemic stroke and its relations to cardiac injury, stroke severity and impact on short-term outcome. Methods Between August 2020 and August 2021, 104 consecutive patients after acute ischemic stroke (AIS) were enrolled in our study. Blood samples were obtained from patients at the time of admission, 24- and 48-hours later to determine levels of Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), N-terminal prohormone of brain natriuretic peptide (NT-proBNP), and high-sensitive Troponin I (hs-cTnI). Twelve lead ECG at admission, 24-, 48-hours later and at the release of the patients were obtained. Patients underwent echocardiographic examination within first 5 days of hospitalization, if eligible. National Institutes of Health Stroke Scale (NIHSS) at admission and modified Rankin Scale (mRS) at 90 days following the patient's discharge from the hospital were performed. Chi-square, Fishers exact test and regression analysis were performed to detect differences between variables using SPSS statistics. Results were considered statistically significant at a significance level of p&amp;lt;0.05. Results We found significant negative association between TRAIL and NT-proBNP at admission (p=0.039), after 24 (p=0.043) and 48 hours (p=0.023) of hospitalization. There was significant negative association between TRAIL and hs-cTnI at admission (p=0.04). Moreover, we found significant negative association between TRAIL and stroke severity evaluated by NIHSS at admission (p=0.044) and negative association with severe disability or death evaluated by mRS at 90 days both after 24 (p=0.0022) and 48 hours (p=0.044) of hospitalization. In ECG analysis, lower TRAIL levels were associated with the occurrence of premature ventricular extrasystoles (p=0.043), and there was a near statistically significant association with prolonged QTc interval (p=0.07). Two patients presented with new left ventricular regional wall motion abnormality. Conclusions Lower TRAIL levels are associated with laboratory markers of cardiac injury, stroke severity and unfavorable functional outcome in patients after acute ischemic stroke. Funding Acknowledgement Type of funding sources: Public grant(s) – EU funding. Main funding source(s): Charles University Research Program Cooperatio – Cardiovascular sciences

Temporal Dynamics of Host Immune Response Associated With Disease Severity and Time to Recovery in Patients Hospitalized for COVID-19.

The objective of this study was to compare the temporal dynamics of two viral-induced inflammatory proteins interferon gamma inducible protein-10 (IP-10) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), as well as C-reactive protein (CRP) among patients hospitalized for COVID-19 and examine their prognostic significance. Prospective observational cohort study. Multicenter, inpatient. Adult patients infected with severe acute respiratory syndrome coronavirus 2 between March 2021 and October 2021. Patient sera were collected on days 1, 3, 5, and 7 of hospitalization. Levels of IP-10, TRAIL, and CRP were measured using a point-of-need diagnostic immunoassay platform (MeMed BV, MeMed, Haifa, Israel) and compared between patients grouped by disease severity (severe vs nonsevere). Baseline characteristics were similar regardless of severity except for a higher prevalence of diabetes and heart failure among severe patients. The immune profile at admission was similar between groups; IP-10 and CRP levels generally decreased while TRAIL levels increased over time in all patients. However, the severe group had higher IP-10 (median 713 vs 328 pg/mL; p = 0.045) and lower TRAIL levels (median 21 vs 30 pg/mL; p = 0.003) on day 3 compared with nonsevere patients. A breakpoint IP-10 level of greater than or equal to 570 pg/mL and TRAIL level of less than 25 pg/mL on day 3 were associated with COVID-19 severity. Patients with elevated day 3 IP-10 levels (≥ 570 pg/mL) were more likely to experience prolonged recovery time (median 12 vs 3 d; p < 0.001). The severe group had prolonged use of corticosteroids (12 vs 5 d; p < 0.001) and had a higher rate of secondary infections (20% vs 6%; p = 0.04) and in-hospital mortality (20% vs 0%; p < 0.001) as compared with nonsevere patients. The observed patterns in host immune response revealed a turning point in COVID-19 disease on hospital day 3 and the potential utility of IP-10 and TRAIL as sensitive markers associated with disease severity and time to recovery.

Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL): A Novel Biomarker for Prognostic Assessment and Risk Stratification of Acute Pulmonary Embolism.

Background: Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is associated with poor prognosis in cardiovascular diseases. However, the predictive value of TRAIL for the short-term outcome and risk stratification of acute pulmonary embolism (PE) remains unknown. Methods: This study prospectively included 151 normotensive patients with acute PE. The study outcome was a composite of 30-day adverse events, defined as PE-related death, shock, mechanical ventilation, cardiopulmonary resuscitation, and major bleeding. Results: Overall, nine of 151 (6.0%) patients experienced 30-day adverse composite events. Multivariable logistic regression showed that TRAIL was an independent predictor of study outcome (OR 0.19 per SD; 95% CI 0.04–0.90). An ROC curve revealed that TRAIL’s area under the curve (AUC) was 0.83 (95% CI 0.76–0.88). The optimal cut-off value for TRAIL was 18 pg/mL, with a sensitivity, specificity, negative predictive value, positive predictive value, positive likelihood ratio, and negative likelihood ratio of 89%, 69%, 99%, 15%, 2.87, and 0.16, respectively. Compared with the risk stratification algorithm outlined in the 2019 ESC guidelines, our biomarker-based risk stratification strategy (combining TRAIL and hs-cTnI) has a similar risk classification effect. Conclusion: Reduced plasma TRAIL levels predict short-term adverse events in normotensive patients with acute PE. The combination of the 2019 ESC algorithm and TRAIL aids risk stratification in normotensive patients with acute PE.

TNF-related apoptosis-inducing ligand, interferon gamma-induced protein 10, and C-reactive protein in predicting the progression of SARS-CoV-2 infection: a prospective cohort study

BackgroundEarly prognostication of COVID-19 severity will potentially improve patient care. Biomarkers, such as TNF-related apoptosis-inducing ligand (TRAIL), interferon gamma-induced protein 10 (IP-10), and C-reactive protein (CRP), might represent possible tools for point-of-care testing and severity prediction.MethodsIn this prospective cohort study, we analyzed serum levels of TRAIL, IP-10, and CRP in patients with COVID-19, compared them with control subjects, and investigated the association with disease severity.ResultsA total of 899 measurements were performed in 132 patients (mean age 64 years, 40.2% females). Among patients with COVID-19, TRAIL levels were lower (49.5 vs 87 pg/ml, P = 0.0142), whereas IP-10 and CRP showed higher levels (667.5 vs 127 pg/ml, P <0.001; 75.3 vs 1.6 mg/l, P <0.001) than healthy controls. TRAIL yielded an inverse correlation with length of hospital and intensive care unit (ICU) stay, Simplified Acute Physiology Score II, and National Early Warning Score, and IP-10 showed a positive correlation with disease severity. Multivariable regression revealed that obesity (adjusted odds ratio [aOR] 5.434, 95% confidence interval [CI] 1.005-29.38), CRP (aOR 1.014, 95% CI 1.002-1.027), and peak IP-10 (aOR 1.001, 95% CI 1.00-1.002) were independent predictors of in-ICU mortality.ConclusionsWe demonstrated a correlation between COVID-19 severity and TRAIL, IP-10, and CRP. Multivariable regression showed a role for IP-10 in predicting unfavourable outcomes, such as in-ICU mortality.Trial registrationClinicaltrials.gov, NCT04655521

Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) in Patients after Acute Stroke: Relation to Stroke Severity, Myocardial Injury, and Impact on Prognosis.

Background: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is known to be associated with poor prognosis after cardiovascular events. We aimed to assess the dynamic changes in TRAIL levels and the relation of TRAIL level to stroke severity, its impact on the short-term outcomes, and its association with markers of cardiac injury in patients after acute stroke. Methods: Between August 2020 and August 2021, 120 consecutive patients, 104 after acute ischemic stroke (AIS), 76 receiving reperfusion therapy, and 16 patients after intracerebral hemorrhage (ICH) were enrolled in our study. Blood samples were obtained from patients at the time of admission, 24 h later, and 48 h later to determine the plasma level of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), N-terminal prohormone of brain natriuretic peptide (NT-proBNP), and high-sensitive Troponin I (hs-TnI). Twelve-lead ECGs were obtained at the time of admission, 24 h later, 48 h later, and at the release of the patients. Evaluations were performed using the National Institutes of Health Stroke Scale (NIHSS) at the time of admission and using the modified Rankin Scale (mRS) 90 days following the patient’s discharge from the hospital. Results: We observed a connection between lower TRAIL levels and stroke severity evaluated using the NIHSS (p = 0.044) on the first day. Lower TRAIL showed an association with severe disability and death as evaluated using the mRS at 90 days, both after 24 (p = 0.0022) and 48 h (p = 0.044) of hospitalization. Moreover, we observed an association between lower TRAIL and NT-proBNP elevation at the time of admission (p = 0.039), after 24 (p = 0.043), and after 48 h (p = 0.023) of hospitalization. In the ECG analysis, lower TRAIL levels were associated with the occurrence of premature ventricular extrasystoles (p = 0.043), and there was an association with prolonged QTc interval (p = 0.052). Conclusions: The results show that lower TRAIL is associated with stroke severity, unfavorable functional outcome, and short-term mortality in patients after acute ischemic stroke. Moreover, we described the association with markers of cardiac injury and ECG changes.