Soluble Receptor Research Articles

Relationship of cerebrospinal fluid and serum levels of SIL-2R, eNOS, and CD93 with the progression and prognosis of viral encephalitis in children

To investigate the relationship of cerebrospinal fluid and serum levels of soluble interleukin-2 receptor (SIL-2R), endothelial nitric oxide synthase (eNOS), and cluster of differentiation 93 (CD93) with the progression and prognosis of viral encephalitis (VE) in children. Prospectively, 102 children with VE admitted from January 2021 to January 2024 were selected as the VE group. The patients were divided into a mild subgroup (64 patients) and a severe subgroup (38 patients) according to disease progression. The patients were also divided into a good prognosis subgroup (29 patients) and a poor prognosis subgroup (73 patients) according to prognosis. A control group of 102 children with central nervous system diseases who were examined and found not to have VE during the same period was selected. The factors contributing to the poor prognosis of children with VE and the predictive value of SIL-2R, eNOS, and CD93 in cerebrospinal fluid and serum for the poor prognosis of children with VE were evaluated. Cerebrospinal fluid and serum SIL-2R, eNOS, and CD93 levels were significantly increased in the VE group, severe subgroup, and poor prognosis subgroup (P<0.05). Multivariate logistic regression analysis showed that high SIL-2R, eNOS, and CD93 levels in cerebrospinal fluid and serum were risk factors for poor prognosis in children with VE (P<0.05). Receiver operating characteristic curve analysis showed that the combination of cerebrospinal fluid SIL-2R, eNOS, and CD93 was superior to these individual indicators in prediction of poor prognosis in children with VE (P<0.05). Similarly, the combination of serum SIL-2R, eNOS, and CD93 was superior to these individual indicators in prediction of poor prognosis in children with VE (P<0.05). The cerebrospinal fluid and serum levels of SIL-2R, eNOS, and CD93 are significantly elevated in children with VE, and they are associated with VE progression and prognosis.

Host Response Markers of Inflammation and Endothelial Activation Associated with COVID-19 Severity and Mortality: A GeoSentinel Prospective Observational Cohort

Background: The effect of the COVID-19 pandemic on healthcare systems emphasized the need for rapid and effective triage tools to identify patients at risk of severe or fatal infection. Measuring host response markers of inflammation and endothelial activation at clinical presentation may help to inform appropriate triage and care practices in patients with SARS-CoV-2 infection. Methods: We enrolled patients with COVID-19 across five GeoSentinel clinical sites (in Italy, Belgium, Canada, and the United States) from September 2020 to December 2021, and analyzed the association of plasma markers, including soluble urokinase-type plasminogen activator receptor (suPAR), soluble tumor necrosis factor receptor-1 (sTREM-1), interleukin-6 (IL-6), interleukin-8 (IL-8), complement component C5a (C5a), von Willebrand factor (VWF-a2), and interleukin-1 receptor antagonist (IL-1Ra), with 28-day (D28) mortality and 7-day (D7) severity (discharged, hospitalized on ward, or died/admitted to the ICU). Results: Of 193 patients, 8.9% (16 of 180) died by D28. Higher concentrations of suPAR were associated with increased odds of mortality at D28 and severity at D7 in univariable and multivariable regression models. The biomarkers sTREM-1 and IL-1Ra showed bivariate associations with mortality at D28 and severity at D7. IL-6, VWF, C5a, and IL-8 were not as indicative of progression to severe disease or death. Conclusions: Our findings confirm previous studies’ assertions that point-of-care tests for suPAR and sTREM-1 could facilitate the triage of patients with SARS-CoV-2 infection, which may help guide hospital resource allocation.

Diagnostic Value of sLR11 and sIL-2R in the Cerebrospinal Fluid for Malignant Central Nervous System Lymphoma.

Objective We previously reported that patients with acute leukemia and malignant lymphoma (ML) demonstrated significantly increased serum soluble LR11 (sLR11) levels compared to normal controls. Accurately diagnosing ML of the central nervous system (CNS ML) using cytology is frequently difficult. Therefore, we evaluated the use of cerebrospinal fluid (CSF) sLR11 and soluble interleukin-2 receptor (sIL-2R) as diagnostic and treatment response markers for CNS ML. Methods We retrospectively evaluated the CSF results for CNS ML using clinical data at our institution, and then analyzed the usefulness of sLR11 and sIL-2R in CSF for both the diagnosis and as surrogate markers that reflect the therapeutic effect. Patients We enrolled patients with CNS ML who received intrathecal anticancer drugs between 2017 and 2023. We analyzed the sLR11 and sIL-2R levels in CSF and cytological malignant grades. We studied 22 patients, including 17 with central nervous system (CNS) clinical conditions and five who received prevention treatment. Results The CSF sLR11 levels were significantly and positively correlated with CSF sIL-2R levels. The CSF sLR11 and sIL-2R levels in patients with CNS ML were significantly higher than those in the prevention group. A receiver operating characteristic (ROC) curve analysis showed the cut-off value of sLR11 for CNS invasion to be 21.7 ng/mL. Moreover, the chemotherapy-responder group demonstrated significantly decreased CSF sLR11 and sIL-2R levels after treatment. Conclusion CSF sLR11 and sIL-2R of CSF were found to be useful biomarkers for the diagnostic and treatment response evaluation in patients with CNS ML.

Soluble Urokinase-Type Plasminogen Activator Receptor (suPAR), Growth Differentiation Factor-15 (GDF-15), and Soluble C5b-9 (sC5b-9) Levels Are Significantly Associated with Endothelial Injury Indices in CAR-T Cell Recipients

Endothelial injury indices, such as Endothelial Activation and Stress Index (EASIX), modified EASIX (m-EASIX), and simplified EASIX (s-EASIX) scores, have been previously associated with chimeric antigen receptor-T (CAR-T) cell immunotherapy complications. Soluble urokinase-type plasminogen activator receptor (suPAR), growth differentiation factor-15 (GDF-15), and soluble C5b-9 (sC5b-9) have been described as markers of endothelial injury post-hematopoietic stem cell transplantation. In the current study, we examined whether suPAR, GDF-15, and sC5b-9 levels were associated with endothelial injury indices in adult CAR-T cell recipients. The levels of these markers were measured in patients before CAR-T cell infusion and in healthy individuals with immunoenzymatic methods. We studied 45 CAR-T cell recipients and 20 healthy individuals as the control group. SuPAR, GDF-15, and sC5b-9 levels were significantly higher in the patients’ group compared to the healthy control group (p &lt; 0.001, in all comparisons). SuPAR levels at baseline were associated with the m-EASIX scores calculated at the same time point (p = 0.020), while suPAR and GDF-15 concentrations were correlated with EASIX scores at day 14 post-infusion (p &lt; 0.001 in both comparisons). Moreover, sC5b-9 levels were correlated with the s-EASIX scores at infusion (p = 0.008) and the EASIX scores at day 14 (p = 0.005). In our study, sC5b9, suPAR, and GDF-15 levels were found to reflect endothelial injury in CAR-T cell recipients.

A novel ER stress regulator ARL6IP5 induces reticulophagy to ameliorate the prion burden

ABSTRACT Prion disease is a fatal and infectious neurodegenerative disorder caused by the trans-conformation conversion of PRNP/PrPC to PRNP/PrPSc. Accumulated PRNP/PrPSc-induced ER stress causes chronic unfolded protein response (UPR) activation, which is one of the fundamental steps in prion disease progression. However, the role of various ER-resident proteins in prion-induced ER stress is elusive. This study demonstrated that ARL6IP5 is compensatory upregulated in response to chronically activated UPR in the cellular prion disease model (RML-ScN2a). Furthermore, overexpression of ARL6IP5 overcomes ER stress by lowering the expression of chronically activated UPR pathway proteins. We discovered that ARL6IP5 induces reticulophagy to reduce the PRNP/PrPSc burden by releasing ER stress. Conversely, the knockdown of ARL6IP5 leads to inefficient macroautophagic/autophagic flux and elevated PRNP/PrPSc burden. Our study also uncovered that ARL6IP5-induced reticulophagy depends on Ca2+-mediated AMPK activation and can induce 3 MA-inhibited autophagic flux. The detailed mechanistic study revealed that ARL6IP5-induced reticulophagy involves interaction with soluble reticulophagy receptor CALCOCO1 and lysosomal marker LAMP1, leading to degradation in lysosomes. Here, we delineate the role of ARL6IP5 as a novel ER stress regulator and reticulophagy inducer that can effectively reduce the misfolded PRNP/PrPSc burden. Our research opens up a new avenue of selective autophagy in prion disease and represents a potential therapeutic target.

Diagnostic challenge: Combination of magnetic resonance imaging and serum soluble Interleukin-2 receptor in soft tissue non-hodgkin lymphoma

PurposeNon-Hodgkin lymphoma (NHL) sometimes occurs in soft tissue (referred to as soft tissue lymphoma or soft tissue NHL), often mimicking soft tissue tumors. Despite some clinical indicators, accurate diagnosis of soft tissue NHL before biopsy remains challenging. We investigated the diagnostic value of serum soluble interleukin-2 receptor (sIL-2R) levels and magnetic resonance imaging (MRI) as an initial tool to assess the likelihood of soft tissue NHL. MethodsWe analyzed 36 cases of pathologically proven soft tissue NHL initially suspected as soft tissue tumors alongside 48 control cases of soft tissue sarcoma or carcinoma. Patient medical charts and MRI scans were retrospectively reviewed and statistically analyzed, focusing on assessing the diagnostic efficacy of soft tissue NHL. ResultsThe diagnostic accuracy of soft tissue NHL combining the appearance of homogeneity on MRI (T2-weighted and/or short-time inversion recovery [STIR] images) and sIL-2R value (≧ 904 U/mL) yielded a sensitivity of 78 % and 86 %, and specificity of 83 % and 88 %, respectively. Meeting one or both criteria increased the sensitivity to a maximum of 92 %, albeit with a specificity of 71 %. When both criteria were met, sensitivity and specificity were 72 % and 100 %, respectively. ConclusionThe integrated approach of combining MRI and sIL-2R demonstrated excellent efficacy in predicting the diagnosis of soft tissue NHL, which was initially referred to as soft tissue tumor.

Obesity Human Soluble Prorenin Receptor Expressed in Adipose Tissue Improves Insulin Sensitivity and Endothelial Function in Obese Female Mice.

Soluble prorenin receptor (sPRR) is a component of the renin-angiotensin system (RAS) identified as a plasma biomarker for human metabolic disease. However, what tissue source of sPRR is implicated in the modulation of metabolic function remains unclear. This study investigated the contribution of human sPRR (HsPRR) produced in the adipose tissue (Adi) on the metabolic and cardiovascular function of lean and obese male and female mice. Adi-HsPRR mice, generated by crossing human sPRR-Myc-tag and Adiponectin/Cre mice, were fed a low-fat or high-fat diet (10% and 60% kCal from fat, respectively) for 20 weeks. Obese Adi-HsPRR mice showed elevated sPRR levels in adipose tissue without affecting adipocyte size or fat depot weight. Despite plasma sPRR being similar between obese Adi-HsPRR and control female mice, a positive correlation between plasma sPRR and adiposity was present only in controls. Obese Adi-HsPRR male mice showed elevated plasma sPRR compared with controls, but no correlation with adiposity was found in either group. Nevertheless, Adi-HsPRR expression improved insulin sensitivity and endothelial function, reduced adipogenic genes mRNA abundance (PPARg, SEBP1C and CD36), and increased plasma Angiotensin 1-7 levels only in obese HsPPR female mice. Taken together, elevated HsPRR in adipose tissue improved metabolic and vascular function in obese female mice despite normal circulating levels of sPRR, whereas increased local and circulating levels of HsPRR did not influence metabolic and cardiovascular function in obese male mice. Our data suggest that increased plasma sPRR associated with metabolic disease could be produced by other tissues rather than adipocytes.

Soluble TREM-1 is not a useful biomarker in the diagnosis of early-onset neonatal sepsis.

Aim: Sepsis remains a significant cause of morbidity and mortality in neonates. We aimed to investigate the use and reliability of the soluble triggering receptor expressed on myeloid cells (sTREM-1) biomarker for suspected early onset of neonatal sepsis (EONS).Materials & methods: 52 patients with suspected EONS and 30 healthy newborns were analyzed for sTREM-1 and other biomarkers.Results: It revealed that elevated levels of C-reactive protein (CRP), neutrophil (%), red cell distribution width (RDW), neutrophil/lymphocyte ratio (NLR) and lactate, as well as decreased lymphocyte (%) were statistically significant for EONS. However, there was no statistically significant difference in sTREM-1 levels between the groups.Conclusion: Although no significant difference in sTREM-1 levels was found between the groups, further research involving repeated measurements and larger sample sizes is necessary to evaluate its practical utility in clinical settings.

Detection of Thrombosis Using Soluble C-Type Lectin-like Receptor-2 with D-Dimer Level and Platelet Count

Introduction: Soluble C-type lectin-like receptor -2 (sCLEC-2) has been recognized as a marker of platelet activation, and attention has been drawn to formulas combining sCLEC-2 levels with platelet count and D-dimer levels. Methods: In this study, sCLEC-2 levels, as well as sCLEC-2/platelet count (sCLEC-2/PLT), sCLEC-2 × D-dimer (sCLEC-2xDD), and sCLEc-2xDD/PLT formulas were used to detect thrombotic diseases, including microvascular thrombosis (MVT), arterial thromboembolism (ATE), and venous thromboembolism (VTE), with the aim of evaluating the ability of the three parameters combined in these formulas to diagnose thrombotic diseases. Results: The plasma sCLEC-2 levels were significantly higher in patients with infectious or thrombotic diseases than in those with neither thrombosis nor infection; however, there was no significant difference among patients with infection, ATE, VTE, and MVT; the correlations among sCLEC-2, platelet count, and D-dimer level were poor. The sCLEC-2/PLT ratio was the highest in patients with MVT, and the sCLEC-2 × D-dimer value was higher in patients with MVT and VTE than in those with neither thrombosis nor infection. Although receiver operating characteristic (ROC) analysis shows the differential diagnosis of thrombotic diseases from non-thrombosis without infection, the sCLEC-2 × D-dimer/platelet count was useful for differential diagnosis among MVT and infection or non-thrombotic diseases. Conclusions: sCLEC-2 is useful for the diagnosis of thrombosis, and the formulas of sCLEC-2 with platelet count or D-dimer are useful for the diagnosis of thrombosis using ROC analyses for the thrombosis group vs. the non-thrombosis group without infection.

Iron status, anemia, and birth outcomes among pregnant women in urban Bloemfontein, South Africa: the NuEMI study

BackgroundDespite routine iron supplementation for pregnant women in South Africa, anaemia and iron deficiency (ID) in pregnancy remain a public health concern.ObjectiveTo determine the associations between iron status and birth outcomes of pregnant women attending antenatal clinic at a regional hospital in Bloemfontein.MethodsIn this cross-sectional study of 427 pregnant women, blood was taken to analyze biomarkers of anaemia (haemoglobin), iron status (ferritin and soluble transferrin receptor) and inflammation (C-reactive protein and α-1-acid glycoprotein). A questionnaire was used to collect information about birth outcomes (birth weight and gestational age at birth), HIV exposure, sociodemographics, iron supplement intake, and maternal dietary iron intake using a validated quantified food frequency questionnaire.ResultsThe median (Q1, Q3) weeks of gestation of participants was 32 (26, 36) at enrolment. Anaemia, iron deficiency (ID), ID anaemia (IDA) and ID erythropoiesis (IDE) were present in 42%, 31%, 19% and 9.8% of participants, respectively. Median (Q1, Q3) dietary and supplemental iron intake during pregnancy was 16.8 (12.7, 20.5) mg/d and 65 (65, 65) mg/d, respectively. The median (max-min) total iron intake (diet and supplements) was 81 (8.8-101.8) mg/d, with 88% of participants having a daily intake above the tolerable upper intake level of 45 mg/d. No significant associations of anaemia and iron status with low birth weight and prematurity were observed. However, infants born to participants in the third hemoglobin (Hb) quartile (Hb > 11.3–12.2 g/dL) had a shorter gestation by 1 week than those in the fourth Hb quartile (Hb > 12.2 g/dL) (p = 0.009). Compared to pregnant women without HIV, women with HIV had increased odds of being anaemic (OR:2.14, 95%CI: 1.41, 3.247), having ID (OR:2.19, 95%CI: 1.42, 3.37), IDA (OR:2.23, 95%CI: 1.36, 3.67), IDE (OR:2.22, 95%CI: 1.16, 4.22) and delivering prematurely (OR:2.39, 95%CI: 1.01, 5.64).ConclusionIn conclusion, anaemia, ID, and IDA were prevalent in this sample of pregnant women, despite the reported intake of prescribed iron supplements, with HIV-infected participants more likely to be iron deficient and anaemic. Research focusing on the best formulation and dosage of iron supplementation to enhance iron absorption and status, and compliance to supplementation is recommended, especially for those living with HIV infection.Graphical

Disentangling Anemia in Frailty: Exploring the role of Inflammation.

In older patients, frailty and anemia frequently coexist. However, only few studies have been conducted in older patients with multimorbidity and several overlapping causes of anemia, such as inflammation, inadequate nutrition or certain pathologies. This analysis aims to decipher potential factors associated with anemia in older hospital patients with frailty. Patients (n=208, age: 62-98 years) were categorized as pre-frail (n=68) and frail (n=140) using the Fried frailty phenotype. We quantified serum concentrations of markers of iron-metabolism (iron, ferritin, transferrin, soluble transferrin receptor, hepcidin), inflammation (interleukin (IL) 6, IL-10 C-reactive protein) and haematology (hemoglobin). Principal component analysis was conducted to evaluate biomarker patterns and associations with frailty were assessed with logistic regression analysis. Anemia prevalence was higher in patients with frailty (84.3% versus 70.6%, p=0.021). Three principal components (PC1-3) were identified. PC1 was characterized by high factor loadings representing inflammation and factor scores differed between patients with pre-frailty and frailty [-0.04 (IQR:1.45) versus -0.51 (IQR:0.87), p<0.001]. PC2 represents macrocytic anemia and thus vitamin B12 or folate deficiency, whereas PC3 indicates hematological pathologies. Only PC1 was associated with frailty status when controlled for age, sex, number of drugs and comorbidities (OR: 2.018, 95%CI: 1.316; 3.094, p=0.001). PC2 and PC3 were not associated with frailty. Our results suggest that anemia in patients with frailty is driven by inflammation rather than being disease-related or solely the result of micronutrient deficiencies.

B-070 Supar: what UACR and GFR don't say…

Abstract Background Soluble urokinase-type plasminogen activator receptor (suPAR) is the circulating form of a three domain membrane protein expressed on a variety of cells, including immunologically active cells, endothelial cells, and podocytes. Diabetic nephropathy (DN) typically manifests with impaired glomerular filtration and microalbuminuria and progresses to end-stage renal disease. The study investigated whether high levels of suPAR may be added to KDIGO models that includes estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR) to give more information about diabetic patients at higher risk of DN occurrence. Methods We measured plasma suPAR levels in 142 patients (67F/75M, median age 67 years) admitted to our hospital to check their glucose and glycated A1c hemoglobin (HbA1c) levels. We also recorded information about UACR and eGFR, and the relationship between suPAR levels and these parameters was investigated together with the distribution of suPAR levels according to KDIGO category risk of CKD. Results Among our study population, according to KDIGO risk category, 80 patients were at low risk, 47 were at moderate risk and 13 were at high risk of CKD. Mean plasma suPAR levels are 4.613±3.331 ng/mL, and significant correlation between suPAR and eGFR (P=0.0001) and between suPAR and HbA1c (P=0.0026) were found, while there is not a significant correlation with UACR (p=0.207) . According to KDIGO category risk, suPAR levels significantly increased from low to high risk, in particular, the increase is higher between the first two category (4.176 vs 6.285 ng/mL) risk compared to the highest (7.557 vs 7.427 ng/mL). We classified the 80 patients at low risk for KDIGO according suPAR levels divided into 4 quartiles according to literature (S. Salim Hayek et Al 2015) and 52 of them had suPAR levels in the third and fourth quartiles. Moreover, among these 52 patients, only 5 had HbA1c levels over the therapeutic target of 53 mmol/mol. Conclusions We identified an association between elevated plasma suPAR levels and a decline in the eGFR. However, we did not find a correlation with UACR, this is because suPAR levels are associated with a prospective membrane damage through interference with podocyte migration and apoptosis. According to this analysis, suPAR is a possible best candidate marker to stratify those patients who, according to the KDIGO criteria, are at low risk and have good glycemic compensation, but suPAR levels suggest a more careful follow-up.

A-088 Clinically Significant Errors Using the Diazyme Total Bile Acid Assay on the Roche c502 Analyzer: Investigating a Result Error Identifies a Novel Large-Scale Testing Error Caused by Reagent Carryover

Abstract Background Thoroughly investigating single patient result errors may identify systemic, large-scale testing errors. The laboratory observed an event where a revision to a Total Bile Acid (TBA, Diazyme Laboratories, Inc.) patient result following a 22S quality control (QC) failure displayed a larger than expected difference (52 to 5mcmol/L). TBA is primarily used for diagnosis and monitoring of intrahepatic cholestasis of pregnancy with results &amp;gt;10mcmol/L considered elevated. Retrospective review of result revisions following QC failures (3/15/2017-5/30/2023) revealed that 50%(20/40) yielded result differences of &amp;gt;10mcmol/L(&amp;gt;20SD based on assay imprecision). The aim of this study was to apply a systematic approach to i) estimate the rate of TBA errors, ii) ensure accurate result reporting during investigation period, iii) perform root cause analysis (RCA), and iv) determine corrective and preventative action(s). Methods Residual samples from TBA testing (6/24-7/5/2023) were retested(n=158), differences &amp;gt;+/-3.0mcmol/L or 15% were confirmed on an alternate analyzer, and reports were revised. Automated repeat testing of TBA samples &amp;gt;10mcmol/L was operationalized 7/6/2023. Initial and repeat TBA results were compared(n=448) and results differing by &amp;gt;+/-20% were remeasured on an alternate analyzer. RCA was conducted using a fishbone diagram. NaOH reagent probe washes were implemented for TBA and the error rate was re-assessed. Assays run prior to TBA samples with errors (n=15) were identified. To assess reagent carryover a residual serum pool (TBA ∼5mcmol/L) was aliquoted into 5 tubes in a sample rack. The first sample in the rack was programmed to run an assay suspected of causing carryover followed by 4 TBA measurements. Mean±standard deviation(SD) TBA concentrations were calculated. TBA was also measured in the liquid reagent for amylase, lipase, acetylcholinesterase (ACE) and fructosamine. Results Initial TBA retesting yielded no errors when initial TBA was ≤10mcmol/L(n=51). For samples with TBA &amp;gt;10mcmol/L(n=107), 9(8.4%) had differences exceeding criteria with 8/9 being revised to ≤10mcmol/L. Analysis of automated patient repeat data showed a 3.8%(17/448) error rate when initial TBA &amp;gt;10mcmol/L. After NaOH reagent probe washes were implemented, the error rate decreased to 0.7%(3/448). Assays run directly before an erroneously high TBA result included: lactate, fructosamine, soluble transferrin receptor(STFR), lipase, and ACE. A serum TBA pool(mean±SD=5.1±0.4 mcmol/L,n=15) measured 37.6±1.2mcmol/L(n=3) and 6.7±0.7mcmol/L(n=3) after lipase and fructosamine, respectively. No other assays demonstrated carryover. TBA in lipase reagent compartment B and C was 653 and 649mcmol/L, respectively, and 653mcmol/L in fructosamine reagent compartment B. Conclusions A single patient TBA result revision was investigated and led to identification of reagent carryover causing erroneously high TBA results on the Roche c502 analyzer. Automatic, real-time, repeat testing was implemented to prevent reporting incorrect patient results until RCA could identify the cause. Occurrence rate of erroneous high TBA results decreased from 3.8% to 0.7% after implementation of NaOH washes on the instruments. Carryover experiments confirmed that lipase and fructosamine assays cause carryover when run prior to a TBA sample due to measurable TBA in the reagent. The lab is pursuing moving the fructosamine and lipase reagent to the Roche Cobas c701 to prevent the issue.

The Relationship Between Soluble Interleukin-17 Receptor Levels and CD3-Positive T Cells and Lymphocytes in Patients with Sepsis and Their Predictive Clinical Significance.

To assess the relationship between soluble interleukin-17 receptor (sIL-7R) levels and CD3-positive t cells and lymphocytes in patients with sepsis and their predictive clinical significance. The study cohort comprised individuals diagnosed with sepsis based on the Third International Consensus Definitions for Sepsis and Septic Shock, treated in the emergency and critical care medicine departments at Beijing Chuiyangliu Hospital and Baoding No. 1 Central Hospital between December 2020 and June 2022. Patient outcomes were classified based on survival or mortality. Biomarkers, including sIL-7R levels and illness severity scores, were documented. All statistical analyses, including predictive modeling and comparisons were carried out using SPSS v.23.0 software and R software. On the fifth day post-admission, sIL-7R levels significantly decreased in both the survival and death groups, compared with levels on day one (2.09 ± 0.65 vs 1.07 ± 0.53 ng/mL, P < 0.01). There was a significant correlation between the sIL-7R level and the CD3+ T-lymphocyte count (CD3+) (r = 0.44) and lymphocyte count (LYM) (r = 0.42). The combination of the sIL-7R level with the Sequential Organ Failure Assessment (SOFA) score demonstrated optimal predictive value for clinical outcomes in patients with sepsis, demonstrated by an area under the receiver operating characteristic curve of 0.998. sIL-7R levels are correlated with CD3+ and LYM counts. Additionally, the combination of serum sIL-7R level and SOFA score provides a robust method for predicting sepsis outcomes.

NEUROINFLAMMATION IN PARKINSON’S DISEASE: A STUDY WITH [11C]PBR28 PET AND CEREBROSPINAL FLUID MARKERS

ObjectiveTo investigate neuroinflammation in Parkinson’s disease (PD) with [11C]PBR28 positron emission tomography (PET) and cerebrospinal fluid (CSF) biomarkers, and the relationship to dopaminergic functioning measured with 6-[18F]-fluoro-L-dopa ([18F]FDOPA) PET. MethodsThe clinical cohort consisted of 20 subjects with PD and 51 healthy controls (HC). All HC and 15 PD participants underwent [11C]PBR28 High Resolution Research Tomograph (HRRT) PET for the quantitative assessment of cerebral binding to the translocator protein (TSPO), a neuroinflammation marker. CSF samples were available from 17 subjects with PD and 21 HC and were examined for soluble triggering receptor expressed on myeloid cells 2 (sTREM2), chitinase 3-like 1 protein (YKL-40), neurogranin (NG), alpha-synuclein (aSyn) and oligo-alpha-synuclein. All subjects with PD underwent [18F]FDOPA HRRT PET. ResultsWhile the subjects with PD and HC did not differ in the total volume of distribution (VT) of [11C]PBR28 in any studied brain regions, higher levels of neuroinflammation and neurodegeneration CSF biomarkers sTREM2 and NG, respectively were associated with more severe motor symptoms evaluated by The Unified Parkinson’s Disease Rating Scale motor part (UPDRS-III) (r = 0.52, p=0.041 and r = 0.59, p=0.016 respectively). Additionally, in the PD group increased [11C]PBR28 VT in the basal ganglia and substantia nigra (SN) was related to higher levels of neuroinflammation biomarker YKL-40 (p <0.01). ConclusionAssociations between CSF biomarkers, motor disability and [11C]PBR28 VT in the striatum and SN may support a role for neuroinflammation in PD.

Clinical significance of serum soluble scavenger receptor CD163 in patients with lupus nephritis.

The soluble CD163 (sCD163) was elevated in systemic lupus erythematosus (SLE) patients. To study whether serum sCD163 could be used to predict the occurrence and prognosis of lupus nephritis (LN). The recruited patients were classified into different groups according to standard identification criteria. The patients with LN. 11 indices were analyzed and compared in SLE and LN patients. Furthermore, the level of serum sCD163 was detected using an enzyme-linked immunosorbent assay. Meanwhile, the receiver operating characteristic analysis was performed to evaluate the prediction effect of sCD163. Additionally, spearman correlation analysis of serum sCD163 with indices was conducted. There were six positive indices and one negative risk factor correlated to LN. sCD163 was elevated in LN patients and could be used to diagnose LN. Importantly, sCD163 was increased in LN patients with a heavy SLE disease activity index. Finally, it was revealed that the level of sCD163 was higher in the LN patients with no response than that with complete or partial response, which also could predict the prognosis of LN. Serum sCD163 was elevated in LN patients than in SLE patients, which could be used to predict the occurrence and prognosis of LN.

New insights in the mechanisms of opioid analgesia and tolerance: ultramicronized palmitoylethanolamide down-modulates vascular endothelial growth factor-A in the nervous system

Growing evidence suggest that opioid analgesics modulate angiogenesis during pathophysiological processes. Vascular endothelial growth factor-A (VEGF-A) was recently proposed to be involved in pain development. To date, no anti-angiogenic drug is used for pain management. When administered in a bioavailable formulation, (i.e., ultramicronized) N-palmitoylethanolamine (PEA) delays the onset of morphine tolerance, improves morphine analgesic activity and reduces angiogenesis in in vivo models. This study aimed at investigating whether VEGF-A is involved in PEA-induced delay of morphine tolerance. The anti-VEGF-A monoclonal antibody bevacizumab was used as a reference drug. Preemptive and concomitant treatment with ultramicronized PEA delayed morphine tolerance and potentiated the analgesic effect of morphine, while counteracting morphine-induced increase of VEGF-A in the nervous system. Similar results were obtained when bevacizumab was administered together with morphine. Of note, bevacizumab showed an analgesic effect per se. In equianalgesic treatment regimens (obtained through increasing morphine doses and associating PEA), PEA resulted in lower expression of VEGF-A in dorsal root ganglia (DRG) and spinal cord compared to morphine alone. Similar results were observed for plasma levels of the soluble VEGF receptor 1 (sFLT-1). Moreover, in morphine treated animals, two pain related genes (i.e., Serpina3n and Eaat2) showed a more than 3-fold increase in their expression at spinal cord and DRG level, with the increase being significantly counteracted by PEA treatment. This study supports the hypothesis that the effects of PEA on morphine analgesia and tolerance may be mediated by the down-modulation of VEGF-A and sFLT-1 in the nervous system and plasma, respectively.

The mechanosensitive ion channel Piezo1 contributes to podocyte cytoskeleton remodeling and development of proteinuria in lupus nephritis.

Piezo1 functions as a special transducer of mechanostress into electrochemical signals and is implicated in the pathogenesis of various diseases across different disciplines. However, whether Piezo1 contributes to the pathogenesis of lupus nephritis (LN) remains elusive. To study this, we applied an agonist and antagonist of Piezo1 to treat lupus-prone MRL/lpr mice. Additionally, a podocyte-specific Piezo1 knockout mouse model was also generated to substantiate the role of Piezo1 in podocyte injury induced by pristane, a murine model of LN. A marked upregulation of Piezo1 was found in podocytes in both human and murine LN. The Piezo1 antagonist, GsMTx4, significantly alleviated glomerulonephritis and tubulointerstitial damage, improved kidney function, decreased proteinuria, and mitigated podocyte foot process effacement in MRL/lpr mice. Moreover, podocyte-specific Piezo1 deletion showed protective effects on the progression of proteinuria and podocyte foot process effacement in the murine LN model. Mechanistically, Piezo1 expression was upregulated by inflammatory cytokines (IL-6, TNF-α and IFN-γ), soluble urokinase Plasminogen Activator Receptor and its own activation. Activation of Piezo1 elicited calcium influx, which subsequently enhanced Rac1 activity and increased active paxillin, thereby promoting cytoskeleton remodeling and decreasing podocyte motility. Thus, our work demonstrated that Piezo1 contributed to podocyte injury and proteinuria progression in LN. Hence, targeted therapy aimed at decreasing or inhibiting Piezo1 could represent a novel strategy to treat LN.

Interleukin-2 receptor α (IL-2Rα/CD25) shedding is differentially regulated by N- and O-glycosylation

The cytokine interleukin-2 (IL-2) is a critical regulator of immune responses, with an especially well-characterized role in regulating T-cell homeostasis. IL-2 signaling involves three distinct receptor subunits: the IL-2Rα (CD25), IL-2Rβ, and IL-2Rγ. The intracellular transduction of IL-2-induced signals is strictly dependent on IL-2Rβ and IL-2Rγ, while the IL-2Rα is not directly involved in signaling. Instead, it has the highest affinity towards IL-2 and is thus responsible for regulating the affinity of a cell for IL-2. In addition to the membrane-bound IL-2Rα, a soluble form of the receptor (sIL-2Rα) has been described, which is present in the blood of healthy individuals, increased under various pathological conditions, and able to bind IL-2 and thus modulate its function. The sIL-2Rα is generated by proteolytic cleavage of the membrane-bound receptor. Here, we analyze whether glycosylation of the IL-2Rα regulates its proteolysis. We find that constitutive IL-2Rα shedding is affected by glycosylation and discover distinct roles for N- and O-glycosylation. Furthermore, we show that induced shedding by the metalloproteases ADAM10 and ADAM17 is also differentially regulated by distinct types of glycans. Finally, we identify a specific role for an N-glycan at an exosite in ADAM17-mediated proteolysis that does not affect ADAM10, indicating distinct substrate recognition mechanisms. These results further the understanding of the mechanisms leading to sIL-2Rα generation, and thus offer the opportunity to specifically modulate the generation of the soluble receptor.

Regulation of plasma soluble receptors of TNF and IL-1 in patients with COVID-19 differs from that observed in sepsis

IL-1α/β and TNF are closely linked to the pathology of severe COVID-19 and sepsis. The soluble forms of their receptors, functioning as decoy receptors, exhibit inhibitory effects. However, little is known about their regulation in severe bacterial and viral infections, which we aimed to investigate in this study. The circulating soluble receptors of TNF (sTNFR1 and sTNFR2) and IL-1α/β (sIL-1R1, sIL-1R2) were evaluated in the plasma of patients with COVID-19, severe bacterial infections, and sepsis and compared with healthy controls. Additionally, IL1R1, IL1R2, TNFRSF1A, and TNFRSF1B expression was evaluated at the single cell level in PBMCs derived from COVID-19 or sepsis patients. Plasma concentrations of sIL-1R1, sTNFR1, and sTNFR2 were significantly higher in COVID-19 patients compared to healthy subjects. Notably, sIL-1R1 levels were particularly elevated in ICU COVID-19 patients, and transcriptome analysis indicated heightened IL1R1 expression in PBMCs from severe COVID-19 patients. In severe bacterial infections, only sTNFR1 and sTNFR2 exhibited increased levels compared to healthy controls. Sepsis patients had decreased sIL-1R1 plasma concentrations but elevated sIL-1R2, sTNFR1, and sTNFR2 levels compared to healthy individuals, reflecting the heightened expression due to the increased numbers of monocytes present in sepsis. Finally, elevated concentrations of sIL-1R2, sTNFR1, and sTNFR2 were moderately associated with reduced 28-day survival in sepsis patients. Our study reveals distinct regulation of plasma concentrations of soluble IL-1 receptors in COVID-19 and sepsis. Moreover, soluble TNF receptors 1 and 2 consistently rise in all conditions and show a positive correlation with disease severity in sepsis.