Soluble TNF receptors predict acute kidney injury and mortality in critically ill COVID-19 patients: A prospective observational study.

BACKGROUND: Although pneumonia is the hallmark of coronavirus disease 2019 (COVID-19), multiple organ failure may develop in severe disease. TNFα receptors in their soluble form (sTNFR) are involved in the immune cascade in other systemic inflammatory processes such as septic shock, and could mediate the inflammatory activation of distant organs. The aim of this study is to analyse plasma levels of sTNFR 1 and 2 in association with organ failure and outcome in critically ill patients with COVID-19. METHODS: After informed consent, we included 122 adult patients with PCR-confirmed COVID-19 at ICU admission. Demographic data, illness severity scores, organ failure and survival at 30 days were collected. Plasma sTNFR 1 and 2 levels were quantified during the first days after ICU admission. Twenty-five healthy blood donors were used as control group. RESULTS: Levels of sTNFR were higher in severe COVID-19 patients compared to controls (p < 0.001). Plasma levels of sTNFR were associated to illness severity scores (SAPS 3 and SOFA), inflammation biomarkers such as IL-6, ferritin and PCT as well as development of AKI during ICU stay. sTNFR 1 higher than 2.29 ng/mL and? sTNFR 2 higher than 11.7 ng/mL were identified as optimal cut-offs to discriminate survivors and non-survivors 30 days after ICU admission and had an area under the curve in receiver operating characteristic curve of 0.75 and 0.67 respectively. CONCLUSION: Plasma levels of sTNFR 1 and 2 were higher in COVID-19 patients compared to controls and were strongly associated with other inflammatory biomarkers, severity of illness and acute kidney injury development during ICU stay. In addition, sTNFR 1 was an independent predictor of 30-day mortality after adjustment for age and respiratory failure.

Cytokine Signaling and Matrix Remodeling Pathways Associated with Cardiac Sarcoidosis Disease Activity Defined Using FDG PET Imaging.

While cardiac imaging has improved the diagnosis and risk assessment for cardiac sarcoidosis (CS), treatment regimens have consisted of generalized heart failure therapies and non-specific anti-inflammatory regimens. The overall goal of this study was to perform high-sensitivity plasma profiling of specific inflammatory pathways in patients with sarcoidosis and with CS.Specific inflammatory/proteolytic cascades were upregulated in sarcoidosis patients, and certain profiles emerged for CS patients.Plasma samples were collected from patients with biopsy-confirmed sarcoidosis undergoing F-18 fluorodeoxyglucose positron emission tomography (n = 47) and compared to those of referent control subjects (n = 6). Using a high-sensitivity, automated multiplex array, cytokines, soluble cytokine receptor profiles (an index of cytokine activation), as well as matrix metalloproteinase (MMP), and endogenous MMP inhibitors (TIMPs) were examined.The plasma tumor necrosis factor (TNF) and soluble TNF receptors sCD30 and sTNFRI were increased using sarcoidosis, and sTNFRII increased in CS patients (n = 18). The soluble interleukin sIL-2R and vascular endothelial growth factor receptors (sVEGFR2 and sVEGFR3) increased to the greatest degree in CS patients. When computed as a function of referent control values, the majority of soluble cytokine receptors increased in both sarcoidosis and CS groups. Plasma MMP-9 levels increased in sarcoidosis but not in the CS subset. Plasma TIMP levels declined in both groups.The findings from this study were the identification of increased activation of a cluster of soluble cytokine receptors, which augment not only inflammatory cell maturation but also transmigration in patients with sarcoidosis and patients with cardiac involvement.

Use of proteomics to identify biomarkers associated with chronic kidney disease and long-term outcomes in patients with myocardial infarction.

BACKGROUND: Patients with chronic kidney disease (CKD) have poor outcomes following myocardial infarction (MI). We performed an untargeted examination of 175 biomarkers to identify those with the strongest association with CKD and to examine the association of those biomarkers with long-term outcomes. METHODS: A total of 175 different biomarkers from MI patients enrolled in the Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies (SWEDEHEART) registry were analysed either by a multiple reaction monitoring mass spectrometry assay or by a multiplex assay (proximity extension assay). Random forests statistical models were used to assess the predictor importance of biomarkers, CKD and outcomes. RESULTS: A total of 1098 MI patients with a median estimated glomerular filtration rate of 85 mL min-1 /1.73 m2 were followed for a median of 3.2 years. The random forests analyses, without and with adjustment for differences in demography, comorbidities and severity of disease, identified six biomarkers (adrenomedullin, TNF receptor-1, adipocyte fatty acid-binding protein-4, TNF-related apoptosis-inducing ligand receptor 2, growth differentiation factor-15 and TNF receptor-2) to be strongly associated with CKD. All six biomarkers were also amongst the 15 strongest predictors for death, and four of them were amongst the strongest predictors of subsequent MI and heart failure hospitalization. CONCLUSION: In patients with MI, a proteomic approach could identify six biomarkers that best predicted CKD. These biomarkers were also amongst the most important predictors of long-term outcomes. Thus, these biomarkers indicate underlying mechanisms that may contribute to the poor prognosis seen in patients with MI and CKD.

Circulating Tumor Necrosis Factor Receptors: A Potential Biomarker for the Progression of Diabetic Kidney Disease.

Despite considerable advancements in medicine, the optimal treatment for chronic kidney disease (CKD), especially diabetic kidney disease (DKD), remains a major challenge. More patients with DKD succumb to death due to cardiovascular events than due to progression to end-stage renal disease (ESRD). Moreover, patients with DKD and ESRD have remarkably poor prognosis. Current studies have appreciated the contribution of inflammation and inflammatory mediators, such as tumor necrosis factor (TNF)-related biomarkers, on the development/progression of DKD. The present review focuses on molecular roles, serum concentrations of TNF receptors (TNFRs), and their association with increased albuminuria, eGFR decline, and all-cause mortality in diabetes. Experimental studies have suggested that DKD progression occurs through the TNFα-TNFR2 inflammatory pathway. Moreover, serum TNFR levels were positively associated with albuminuria and negatively associated with estimated glomerular filtration rate (eGFR), while circulating levels of TNFRs exhibited an independent effect on all-cause mortality and eGFR decline, including ESRD, even after adjusting for existing risk factors. However, their precise function has yet to be elucidated and requires further studies.

Predicting functional outcome of ischemic stroke patients in Romania based on plasma CRP, sTNFR-1, D-Dimers, NGAL and NSE measured using a biochip array.

In cerebral ischemia, evaluation of multiple biomarkers involved in various pathological pathways is a useful tool in assessing the outcome of the patients even from the early stages of the disease. In this study we investigated the utility of a panel of 5 peripheral biomarkers of inflammatory status, neuronal destruction and secondary fibrinolysis in the acute phase of ischemia, and evaluated the impact of these biomarkers on functional outcome after ischemic stroke. The 5 biomarkers (plasma CRP, D-Dimers, sTNFR-1, NGAL and NSE) were measured using a biochip array technology. Eighty nine patients in Romania were divided into 2 subgroups using the modified Rankin Scale evaluated at 3 months after ischemic stroke; the possible impact of analyzed biomarkers on unfavorable functional outcome was tested by binomial logistic regression. The subgroup with unfavorable outcome had higher concentrations of CRP, NGAL, sTNFR-1 and D-dimers, but CRP and NGAL values were not statistically different between the two subgroups. The univariate logistic regression analysis of plasma biomarkers revealed that CRP, D-Dimers, NGAL, sTNFR-1 were significant predictors of unfavorable clinical outcome. In the case of D-Dimers and sTNFR-1 we noticed an increased discrimination ability (versus baseline clinical model) to classify poor functional outcome with a tendency toward statistical signification. During the acute phase of the ischemic stroke, plasma concentrations of CRP, D-Dimers and sTNFR-1 were elevated in unfavorable outcome patients. D-Dimers and sTNFR-1 were independent predictors of poor outcome at 3 months after ischemic stroke. The biochip array technology offers the possibility to simultaneously measure several parameters involved in multiple pathophysiological pathways, in a small sample volume.

Severity of Plasma Leakage Is Associated With High Levels of Interferon γ-Inducible Protein 10, Hepatocyte Growth Factor, Matrix Metalloproteinase 2 (MMP-2), and MMP-9 During Dengue Virus Infection.

BACKGROUND: Dengue virus infection typically causes mild dengue fever, but, in severe cases, life-threatening dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) occur. The pathophysiological hallmark of DHF and DSS is plasma leakage that leads to enhanced vascular permeability, likely due to a cytokine storm. METHODS: Ninety patients with dengue during 2010-2012 in Singapore were prospectively recruited and stratified according to their disease phase, primary and secondary infection status, and disease severity, measured by plasma leakage. Clinical parameters were recorded throughout the disease progression. The levels of various immune mediators were quantified using comprehensive multiplex microbead-based immunoassays for 46 immune mediators. RESULTS: Associations between clinical parameters and immune mediators were analyzed using various statistical methods. Potential immune markers, including interleukin 1 receptor antagonist, interferon γ-inducible protein 10, hepatocyte growth factor, soluble p75 tumor necrosis factor α receptor, vascular cell adhesion molecule 1, and matrix metalloproteinase 2, were significantly associated with significant plasma leakage. Secondary dengue virus infections were also shown to influence disease outcome in terms of disease severity. CONCLUSIONS: This study identified several key markers for exacerbated dengue pathogenesis, notably plasma leakage. This will allow a better understanding of the molecular mechanisms of DHF and DSS in patients with dengue.

[Endothelial immune activation and functional state in patients with hypertensive disease]. / Immunnaia aktivatsiia i funktsional'noe sostoianie éndoteliia u bol'nykh gipertonicheskoi bolezn'iu.

AIM: To investigate the nitric oxide (NO) system, the activity of endothelial NO synthase (e-NOS) and inducible NO synthase (i-NOS) in relation to the levels of tumor necrosis factor-α (TNF- α) and its soluble receptor type I (sTNFRI) depending on the grade of hypertensive disease (HD). SUBJECTS AND METHODS: A total of 317 patients, including 284 patients aged 30 to 65 years (mean age 54.7±0.58 years) with Grades 1-3 HD who had not previously received regular antihypertensive therapy and 33 apparently healthy individuals, were examined at Kharkov City Clinical Hospital Eleven. Immune activation was judged by the serum levels of the proinflammatory cytokine TNF-α in all the examinees and y those of sTNFRI, which were measured by enzyme immunoassay. To study the endothelial functional state, the level of stable end metabolites of nitric oxide, that of S-nitrosothiol and the activity of NO synthases were biochemically determined in 100 patients from this group. A control group consisted of 16 apparently healthy individuals. RESULTS: There were increases in the circulating levels of proinflammatory cytokines (TNF-α, sTNFRI), the content of S-nitrosothiol and the activity of i-NOS. At the same time, there were decreases in the activity of e-NOS and the level of end nitric oxide metabolites, such as nitrites and nitrates. CONCLUSION: In patients with HD, the end metabolites of nitric oxide decrease, which indirectly shows a reduction in its vasoactive part, and the stable NO metabolite S-nitrosothiol increases. This is associated with enhanced NO oxidation under conditions of oxidative stress and endothelial dysfunction. The higher amount of S-nitrosothiol in the examinees may be associated with increased i-NOS. The immunoinflammatory activation mediated by the proinflammatory cytokines, particularly by the enhanced activity of TNF-α and sTNFRI, has been proven to play a role.

Associations of total and free 25OHD and 1,25(OH)2D with serum markers of inflammation in older men.

UNLABELLED: Vitamin D is hypothesized to suppress inflammation. We tested total and free vitamin D metabolites and their association with inflammatory markers. Interleukin-6 levels were lower with higher 25-hydroxyvitamin D. 1,25-dihydroxyvitamin D and free 25OHD associations mirrored those of 25OHD. However, associations for the two metabolites diverged for tumor necrosis factor alpha (TNF-α) soluble receptors. INTRODUCTION: Vitamin D is hypothesized to suppress inflammation, and circulating 25-hydroxyvitamin D (25OHD) and inflammatory markers are inversely correlated. However, total serum 25OHD may not be the best indicator of biologically active vitamin D. METHODS: We tested serum total 25OHD, total 1,25(OH)2D, vitamin D binding protein (DBP), and estimated free 25OHD and free 1,25(OH)2D associations with inflammatory markers serum interleukin-6 (IL-6), TNF-α and their soluble receptors, interleukin-10 (IL-10), and C-reactive protein (CRP) as continuous outcomes and the presence of ≥2 inflammatory markers in the highest quartile as a dichotomous outcome, in a random subcohort of 679 men in the Osteoporotic Fractures in Men (MrOS) study. RESULTS: IL-6 was lower in men with higher 25OHD (-0.23 µg/mL per standard deviation (SD) increase in 25OHD, 95 % confidence intervals (CI) -0.07 to -0.38 µg/mL) and with higher 1,25(OH)2D (-0.20 µg/mL, 95 % CI -0.0004 to -0.39 µg/mL); free D associations were slightly stronger. 25OHD and DBP, but not 1,25(OH)2D, were independently associated with IL-6. TNF-α soluble receptors were inversely associated with 1,25(OH)2D but positively associated with 25OHD, and each had independent effects. The strongest association with ≥2 inflammatory markers in the highest quartile was for free 1,25(OH)2D (odds ratios (OR) 0.70, 95 % CI 0.54 to 0.89 per SD increase in free 1,25(OH)2D). CONCLUSIONS: Associations of 1,25(OH)2D and free 25OHD with IL-6 mirrored those of 25OHD, suggesting that 1,25(OH)2D and free D do not improve upon 25OHD in population-based IL-6 studies. However, associations for the two metabolites diverged for TNF-α soluble receptor, warranting examination of both metabolites in studies of TNF-α and its antagonists.

The assessment of the prognostic value of tumor markers and cytokines as SCCAg, CYFRA 21.1, IL-6, VEGF and sTNF receptors in patients with squamous cell cervical cancer, particularly with early stage of the disease.

The aim of this study is to determine the prognostic value of tumor markers, as squamous cell carcinoma antigen (SCCAg) and cytokeratin-19 fragment (CYFRA 21.1) and interleukin 6 (IL-6), vascular endothelial growth factor (VEGF), soluble tumor necrosis factor receptor I (sTNF RI), and sTNF RII in patients with squamous cell carcinoma of the cervix. The subjects of analysis were 138 patients with stage I-IVA according to the International Federation of Gynecology and Obstetrics (FIGO) classification. The collected research material comes from one oncology center. During the 10 years of follow-up, 56 relapses and 53 deaths were observed, and recurrent disease in early stage was confirmed in 45 % of patients. The pretreatment serum levels of SCCAg and CYFRA 21.1, and cytokines IL-6, VEGF, sTNF RI, and sTNF RII were determined in all patients. The probability of disease-free survival (DFS) and overall survival (OS) was evaluated using the log-rank test and the Cox regression model. Based on the ROC curve analysis for patients with recurrence, the largest area under the curve was demonstrated for SCCAg and IL-6 and for patients who died, for SCCAg and VEGF. Cox analysis demonstrated that independent prognostic factor for DFS was only SCCAg and for OS cytokine IL-6 and SCCAg, but in patients with early stage the prognostic value for DFS was VEGF, whereas IL-6 and CYFRA 21.1 for OS. Serum level of VEGF, CYFRA 21.1 and IL-6 before treatment in patients with early stage cervical cancer appears to be an important prognostic factor.

Diagnostic value of apoptosis biomarkers in severe sepsis-A pilot study.

Severe sepsis is associated with significant mortality and massive immune cell lose, or apoptosis. It is unclear whether plasma apoptosis biomarkers could be used as a diagnostic test for severe sepsis. Forty patients with severe sepsis and 35 healthy controls were enrolled. The percentage and apoptosis of monocytes and lymphocytes were detected by flow cytometric analysis. Plasma levels of tumor necrosis factor (TNF)-α, soluble TNF receptor (sTNFR), soluble Fas (sFas), Fas ligand (FasL), caspase-1, and procalcitonin (PCT) were measured. Plasma caspase-1 level was positively correlated with CD4 lymphocyte apoptosis in controls and patients, and with CD8 lymphocyte apoptosis in all subjects. Plasma FasL level was negatively correlated with CD4 and CD8 lymphocyte apoptosis in all subjects. The sFas/FasL ratio was positively correlated with CD4 and CD8 lymphocyte apoptosis and negatively with monocyte apoptosis in all subjects. Compared with PCT, caspase-1, FasL, and sFas/FasL ratio had better negative predictive value and likelihood ratio for a negative test. PCT had better positive predictive value and likelihood ratio for a positive test. This work demonstrated caspase-1, FasL, and sFas/FasL ratio could be candidates for diagnosis of severe sepsis and their diagnostic value was not inferior to that of PCT.

Enhancement of Ovarian Tumor Detection by DR6-Targeted Ultrasound Imaging Agents in Laying Hen Model of Spontaneous Ovarian Cancer.

OBJECTIVE: The lack of an effective early detection test leads to high case to death ratio of women with ovarian cancer (OVCA). To improve early detection, tumor-associated imaging targets need to be established and imaging agents to image these targets need to be developed. Targeted imaging agents offer potential for improvement of signal intensities from their targets. Expression of death receptor 6 (DR6) by ovarian malignant cells and tumor-associated microvessels increases during OVCA development and represents a novel target for ultrasound imaging. The goal of this study was to examine the feasibility of newly developed DR6-targeted ultrasound imaging agents in enhancing early detection of ovarian tumors in laying hen model of spontaneous OVCA. MATERIALS AND METHODS: The study was conducted in an exploratory cross-sectional design using 4-year-old laying hens (n = 130). DR6-targeted imaging agents were developed by conjugating microbubbles with rabbit anti-chicken DR6 antibodies. Changes in signal intensity of ultrasound imaging were determined before and after injection of targeted imaging agents in hens with or without spontaneous OVCA. Following targeted imaging, normal or tumor ovaries were processed for histopathological and immunohistochemical studies. RESULTS: DR6-targeted imaging agents bound with their targets expressed by malignant cells and tumor-associated microvessels in the ovary. Compared with pretargeted imaging, targeted imaging is enhanced by approximately 40% ultrasound echo signal intensity (P < 0.001) from early- and late-stage OVCA. Differences in signal enhancement were not observed among different histological subtypes of OVCA at early or late stages. Higher imaging signal intensities were associated with enhancement in DR6 expression by ovarian malignant cells and increase in the frequency of DR6-expressing microvessels during OVCA development. CONCLUSIONS: The results of this study suggest that DR6-targeted imaging agents enhance the visualization of ovarian tumors and tumor-associated microvessels in hens with early-stage OVCA and will form a foundation for clinical studies.

Frailty Phenotypes, Disability, and Outcomes in Adult Candidates for Lung Transplantation.

RATIONALE: Frailty is associated with morbidity and mortality in abdominal organ transplantation but has not been examined in lung transplantation. OBJECTIVES: To examine the construct and predictive validity of frailty phenotypes in lung transplant candidates. METHODS: In a multicenter prospective cohort, we measured frailty with the Fried Frailty Phenotype (FFP) and Short Physical Performance Battery (SPPB). We evaluated construct validity through comparisons with conceptually related factors. In a nested case-control study of frail and nonfrail subjects, we measured serum IL-6, tumor necrosis factor receptor 1, insulin-like growth factor I, and leptin. We estimated the association between frailty and disability using the Lung Transplant Valued Life Activities disability scale. We estimated the association between frailty and risk of delisting or death before transplant using multivariate logistic and Cox models, respectively. MEASUREMENTS AND MAIN RESULTS: Of 395 subjects, 354 completed FFP assessments and 262 completed SPPB assessments; 28% were frail by FFP (95% confidence interval [CI], 24-33%) and 10% based on the SPPB (95% CI, 7-14%). By either measure, frailty correlated more strongly with exercise capacity and grip strength than with lung function. Frail subjects tended to have higher plasma IL-6 and tumor necrosis factor receptor 1 and lower insulin-like growth factor I and leptin. Frailty by either measure was associated with greater disability. After adjusting for age, sex, diagnosis, and transplant center, both FFP and SPPB were associated with increased risk of delisting or death before lung transplant. For every 1-point worsening in score, hazard ratios were 1.30 (95% CI, 1.01-1.67) for FFP and 1.53 (95% CI, 1.19-1.59) for SPPB. CONCLUSIONS: Frailty is prevalent among lung transplant candidates and is independently associated with greater disability and an increased risk of delisting or death.

Association between serum soluble tumor necrosis factor-α receptors and early childhood obesity.

This study aimed to characterize the inflammatory cytokine profiles and further validate the significantly different cytokines in the serum obtained from obese children aged 36-48 months. Four obese children and four lean controls were randomly selected for inflammatory cytokine array assay, in which two cytokines [soluble tumor necrosis factor-α receptors (sTNFRs) 1 and 2] were found to be significantly different. Both cytokines (sTNFR1 and sTNFR2) were then further validated through enzyme-linked immunosorbent assay (ELISA) in 61 obese children and 52 lean children. ELISA results revealed that serum sTNFR1 level in obese children significantly increased (p = 0.003), whereas sTNFR2 did not change significantly (p = 0.069). Stratified analysis by gender showed that only obese girls presented increased sTNFR1 (p = 0.005) and sTNFR2 (p = 0.049) levels. We conclude that serum sTNFR1 is elevated in early childhood obesity. Moreover, serum sTNFR1 and sTNFR2 are associated with obese girls but not obese boys, thereby suggesting that serum sTNFRs in early childhood obesity may be sex related.

Significant associations of antidrug antibody levels with serum drug trough levels and therapeutic response of adalimumab and etanercept treatment in rheumatoid arthritis.

OBJECTIVE: To evaluate the associations between (1) antidrug antibody (ADAb) and therapeutic response, (2) ADAb and serum drug trough levels and (3) serum drug levels and therapeutic responses in rheumatoid arthritis (RA) patients receiving adalimumab or etanercept. Secondarily, we aim (1) to evaluate the concordance between radioimmunoassay and bridging ELISA for ADAb assessment and to evaluate the correlation between two different ELISA methods for detecting drug levels, and (2) to determine the optimal cut-off drug levels for good European League Against Rheumatism (EULAR) response. METHODS: ADAb levels were determined by bridging ELISA and radioimmunoassay, and drug levels evaluated using sandwich ELISA among 36 adalimumab-treated patients and 34 etanercept-treated patients at the 6th and 12th month. The optimal cut-off drug levels for EULAR responses were determined by receiver-operating characteristic curve analysis. RESULTS: ADAb was detected in 10 (27.8%) and 13 (36.1%) of adalimumab-treated patients after 12-month therapy using bridging ELISA and radioimmunoassay respectively, but not detected in any of etanercept-treated patients. The presence of ADAb was associated with lower EULAR response and lower drug levels compared with those without ADAb (both p<0.001). Drug trough levels were positively associated with DAS28 decrement (ΔDAS28) (all p<0.001). The optimal cut-off trough levels for adalimumab were 1.274 µg/mL and 1.046 µg/mL, and those for etanercept were 1.242 µg/mL and 0.800 µg/mL for good EULAR response assessed at the 6th and 12th month, respectively. CONCLUSIONS: ADAb levels were inversely correlated with therapeutic response and drug levels. The positive correlation between drug levels and ΔDAS28 indicates that drug monitoring would be useful to evaluate therapeutic response of TNF-α inhibitors.

TWEAK/Fn14 system and crescent formation in IgA nephropathy.

BACKGROUND: The TNF-like weak inducer of apoptosis (TWEAK) contributes to kidney inflammation producing secretion by renal cells. The present study examined whether the level of TWEAK is associated with histologic findings in patients with IgA nephropathy (IgAN). METHODS: The levels of urinary TWEAK (uTWEAK) from 116 IgAN patients, 50 non-IgA kidney disease patients, and 50 healthy individuals were measured by ELISA. Histological findings of renal biopsy specimens of patients with IgAN were evaluated according to the Oxford classification and histological classification for IgAN in Japan. We investigated the expression of TWEAK/Fn14 in renal tissues of those patients and assessed the effect of TWEAK in glomerular mesangial cells and podocytes. RESULTS: The levels of uTWEAK in the patients with IgAN and other renal diseases were significantly higher than in the healthy controls (P < 0.001). In the IgAN patients, the levels of uTWEAK correlated significantly with urinary protein excretion and extracapillary proliferation (r = 0.54, P < 0.001 and r = 0.32, P < 0.001, respectively). In a comparison of the levels of uTWEAK at diagnosis with that of follow-up, the levels of uTWEAK in patients with clinical and partial remission decreased significantly. We showed not only increased expression of both TWEAK and Fn14 in IgAN patients with glomerular crescents but also TWEAK-induced cell motility in podocytes. CONCLUSIONS: The relationship between the levels of uTWEAK and clinicopathological findings observed in this study suggests that TWEAK/Fn14 system affects crescent formation and proteinuria in patients with IgAN.

Elevated Serum Levels of Soluble TNF Receptors and Adhesion Molecules Are Associated with Diabetic Retinopathy in Patients with Type-1 Diabetes.

AIMS: To examine the association of the serum levels of TNF receptors, adhesion molecules, and inflammatory mediators with diabetic retinopathy (DR) in T1D patients. METHODS: Using the multiplex immunoassay, we measured serum levels of eight proteins in 678 T1D subjects aged 20-75 years. Comparisons were made between 482 T1D patients with no complications and 196 T1D patients with DR. RESULTS: The levels of sTNFR-I, sTNFR-II, CRP, SAA, sgp130, sIL6R, sVCAM1, and sICAM1 were significantly higher in the T1D patients with DR as compared to T1D patients with no complications. Multivariate logistic regression analysis revealed significant association for five proteins after adjustment for age, sex, and disease duration (sTNFR-I: OR = 1.57, sgp130: OR = 1.43, sVCAM1: OR = 1.27, sICAM1: OR = 1.42, and CRP: OR = 1.15). Conditional logistic regression on matched paired data revealed that subjects in the top quartile for sTNFR-I (OR = 2.13), sTNFR-II (OR = 1.66), sgp130 (OR = 1.82), sIL6R (OR = 1.75), sVCAM1 (OR = 1.98), sICAM1 (OR = 2.23), CRP (OR = 2.40) and SAA (OR = 2.03), had the highest odds of having DR. CONCLUSIONS: The circulating markers of inflammation, endothelial injury, and TNF signaling are significantly associated with DR in patients with T1D. TNFR-I and TNFR-II receptors are highly correlated, but DR associated more strongly with TNFR-I in these patients.

Low blood levels of sTWEAK are related to locoregional failure in head and neck cancer.

Identifying serum pre-treatment molecular markers that can predict response to therapy is of great interest in head and neck oncology and is required to develop personalized treatments that maximize survival while minimizing morbidity. The main aim was to investigate the potential prognostic significance of tumor necrosis factor-like weak inducer of apoptosis (TWEAK), and its receptors, fibroblast growth factor-inducible 14 (Fn14) and CD163, in head and neck squamous cell carcinoma (HNSCC). The study comprised 37 consecutive patients with pathologically confirmed, untreated HNSCC. Serum and tissue samples from these patients were available for study. We determined sTWEAK and sCD163 levels in serum from 37 HNSCC patients by ELISA. TWEAK, CD163, Fn14 and TNF-α gene expression were detected by real-time RT-PCR in 111 matched tissue samples (tumoral, adjacent and distal/normal mucosa). Our results showed a significant relationship between low sTWEAK levels and poor locoregional control of the disease. Kaplan-Meier curves indicated that the locoregional recurrence-free survival rate in patients with low sTWEAK circulating levels was significantly lower than in patients with high levels, and that high CD136/TWEAK expression ratio in tumors was also related to poor prognosis. sTWEAK pre-treatment serum levels might be used as prognostic non-invasive biomarkers for locoregional control in patients with HNSCC. Future investigations are warranted to determine the potential prognostic significance of this non-invasive biomarker in the rapid discrimination according to the locoregional control achieved in patients who received a non-surgical organ preservation treatment.

Modulation of TNF-α, TNF-α receptors and IL-6 after treatment with AM3 in professional cyclists.

AIM: Changes in IL-6, TNF-α, and TNF-α receptors - sTNFRI and sTNFRII - were evaluated in a group of professional cyclists treated with immunomodulator AM3 (Inmunoferón®) for 6 months of training and competition. METHODS: Sixteen male professional cyclists with a similar training program participated in the study which was designed as a randomized, placebo-controlled, double-blind clinical trial. Venous blood samples were collected in basal conditions, before beginning the supplementation program, and after 90 and 180 days of training and competition season. RESULTS: No significant differences in biochemical parameters or in IL-6 were evidenced between placebo and AM3-treated groups throughout the study. Plasma TNF-α levels significantly decreased (P<0.05) after 90 days of training in the AM3 treated group. TNF-α receptors increased during training season in both placebo and AM3 treated groups, although the increase was significantly higher (P<0.05) in the AM3 group with respect to the placebo group. CONCLUSION: The changes produced by regular training and competition were modified throughout the season by AM3 treatment which could reduce the inflammatory response to excessive exercise.

Plasma levels of soluble tumor necrosis factor receptors are associated with cognitive performance in Parkinson's disease.

Inflammatory mechanisms have been implicated in a series of neuropsychiatric conditions, including behavioral disturbances, cognitive dysfunction, and affective disorders. Accumulating evidence also strongly suggests their involvement in the pathophysiology of Parkinson's disease (PD). This study aimed to evaluate plasma levels of inflammatory biomarkers, and their association with cognitive performance and other non-motor symptoms of PD. PD patients and control individuals were subjected to various psychometric tests, including the Mini-Mental State Examination (MMSE), Frontal Assessment Battery (FAB), and Beck's Depression Inventory (BDI). Biomarker plasma levels were measured by enzyme-linked immunosorbent assay (ELISA). PD patients exhibited worse performance on MMSE and the programming task of FAB, and presented higher soluble tumor necrosis factor receptor (sTNFR) plasma levels than control individuals. Among PD patients, increased sTNFR1 and sTNFR2 concentrations were associated with poorer cognitive test scores. After multiple linear regression, sTNFR1 and education remained a significant predictor for FAB scores. Our data suggest that PD is associated with a proinflammatory profile, and sTNFRs are putative biomarkers of cognitive performance, with elevated sTNFR1 levels predicting poorer executive functioning in PD patients.

Differential risk of tuberculosis reactivation among anti-TNF therapies is due to drug binding kinetics and permeability.

Increased rates of tuberculosis (TB) reactivation have been reported in humans treated with TNF-α (TNF)-neutralizing drugs, and higher rates are observed with anti-TNF Abs (e.g., infliximab) as compared with TNF receptor fusion protein (etanercept). Mechanisms driving differential reactivation rates and differences in drug action are not known. We use a computational model of a TB granuloma formation that includes TNF/TNF receptor dynamics to elucidate these mechanisms. Our analyses yield three important insights. First, drug binding to membrane-bound TNF critically impairs granuloma function. Second, a higher risk of reactivation induced from Ab-type treatments is primarily due to differences in TNF/drug binding kinetics and permeability. Apoptotic and cytolytic activities of Abs and pharmacokinetic fluctuations in blood concentration of drug are not essential to inducing TB reactivation. Third, we predict specific host factors that, if augmented, would improve granuloma function during anti-TNF therapy. Our findings have implications for the development of safer anti-TNF drugs to treat inflammatory diseases.