Plasma Gelsolin Inhibits Natural Killer Cell Function and Confers Chemoresistance in Epithelial Ovarian Cancer.

Plasma gelsolin (pGSN) overexpression in ovarian cancer (OVCA) disarms immune function, contributing to chemoresistance. The aim of this study was to investigate the immunoregulatory effects of pGSN expression on natural killer (NK) cell function in OVCA. OVCA tissues from primary surgeries underwent immunofluorescent staining of pGSN and the activated NK cell marker natural cytotoxicity triggering receptor 1 to analyze the prognostic impact of pGSN expression and activated NK cell infiltration. The immunoregulatory effects of pGSN on NK cells were assessed using apoptosis assay, cytokine secretion, immune checkpoint-receptor expression, and phosphorylation of STAT3. In OVCA tissue analyses, activated NK cell infiltration provided survival advantages to patients. However, high pGSN expression attenuated the survival benefits of activated NK cell infiltration. In the in vitro experiment, pGSN in OVCA cells induced NK cell death through cell-to-cell contact. pGSN increased T-cell immunoglobulin and mucin-domain-containing-3 expression (TIM-3) on activated NK cells. Further, it decreased interferon-γ production in activated TIM-3+ NK cells, attenuating their anti-tumor effects. Thus, increased pGSN expression suppresses the anti-tumor functions of NK cells. The study provides insights into why immunotherapy is rarely effective in patients with OVCA and suggests novel treatment strategies.

Hypogelsolinemia and Decrease in Blood Plasma Sphingosine-1-Phosphate in Patients Diagnosed with Severe Acute Pancreatitis.

BACKGROUND: Acute pancreatitis (AP) is a frequent hospitalization cause of patients suffering from gastrointestinal disorders. Gelsolin has an ability to bind bioactive lipids including different sphingolipids engaged in inflammatory response. Importantly, hypogelsolinemia was observed in patients with different states of acute and chronic inflammation. AIMS: The aim of the present study was to assess the interplay of blood plasma gelsolin and blood plasma sphingosine-1-phosphate (S1P) concentration in patients diagnosed with acute pancreatitis. MATERIALS AND METHODS: To assess the concentration of gelsolin and S1P, immunoblotting and HPLC technique were employed, respectively. Additionally, the concentrations of amylase, lipase, C-reactive protein (CRP), procalcitonin (PCT) and the number of white blood cells (WBC) and platelet (PLT) were recorded. RESULTS: We found that both pGSN and S1P concentrations in the plasma of the AP patients were significantly lower (pGSN ~ 15-165 mg/L; S1P ~ 100-360 pmol/mL) when compared to the levels of pGSN and S1P in a control group (pGSN ~ 130-240 mg/L; S1P ~ 260-400 pmol/mL). Additionally, higher concentrations of CRP, WBC, amylase and lipase were associated with low level of gelsolin in the blood of AP patients. No correlations between the level of PCT and PLT with gelsolin concentration were noticed. CONCLUSION: Plasma gelsolin and S1P levels decrease during severe acute pancreatitis. Simultaneous assessment of pGSN and S1P can be useful in development of more accurate diagnostic strategies for patients with severe acute pancreatitis.

Plasma Gelsolin Reinforces the Diagnostic Value of FGF-21 and GDF-15 for Mitochondrial Disorders.

Mitochondrial disorders (MD) comprise a group of heterogeneous clinical disorders for which non-invasive diagnosis remains a challenge. Two protein biomarkers have so far emerged for MD detection, FGF-21 and GDF-15, but the identification of additional biomarkers capable of improving their diagnostic accuracy is highly relevant. Previous studies identified Gelsolin as a regulator of cell survival adaptations triggered by mitochondrial defects. Gelsolin presents a circulating plasma isoform (pGSN), whose altered levels could be a hallmark of mitochondrial dysfunction. Therefore, we investigated the diagnostic performance of pGSN for MD relative to FGF-21 and GDF-15. Using ELISA assays, we quantified plasma levels of pGSN, FGF-21, and GDF-15 in three age- and gender-matched adult cohorts: 60 genetically diagnosed MD patients, 56 healthy donors, and 41 patients with unrelated neuromuscular pathologies (non-MD). Clinical variables and biomarkers' plasma levels were compared between groups. Discrimination ability was calculated using the area under the ROC curve (AUC). Optimal cut-offs and the following diagnostic parameters were determined: sensitivity, specificity, positive and negative predictive values, positive and negative likelihood ratios, and efficiency. Comprehensive statistical analyses revealed significant discrimination ability for the three biomarkers to classify between MD and healthy individuals, with the best diagnostic performance for the GDF-15/pGSN combination. pGSN and GDF-15 preferentially discriminated between MD and non-MD patients under 50 years, whereas FGF-21 best classified older subjects. Conclusion: pGSN improves the diagnosis accuracy for MD provided by FGF-21 and GDF-15.

Serum biomarker discovery related to pathogenesis in acute coronary syndrome by proteomic approach.

Acute coronary syndrome (ACS) results from inadequate supply of blood flow from the coronary arteries to the heart or ischemia. ACS has an extremely high morbidity and mortality. The levels of biomarkers currently used for detection of ACS also increase in response to myocardial necrosis and other diseases and are not elevated immediately after symptoms appear, thus limiting their diagnostic capacity. Therefore, we aimed to discover new ACS diagnostic biomarkers with high sensitivity and specificity that are specifically related to ACS pathogenesis. Sera from 50 patients with ACS and healthy controls (discovery cohort) each were analyzed using mass spectrometry (MS) to identify differentially expressed proteins, and protein candidates were evaluated as ACS biomarkers in 120 people in each group (validation cohort). α-1-acid glycoprotein 1 (AGP1), complement C5 (C5), leucine-rich α-2-glycoprotein (LRG), and vitronectin (VN) were identified as biomarkers whose levels increase and gelsolin (GSN) as a biomarker whose levels decrease in patients with ACS. We concluded that these biomarkers are associated with the pathogenesis of ACS and can predict the onset of ACS prior to the appearance of necrotic biomarkers.

The gelsolin level in patients with primary Sjogren's syndrome.

OBJECTIVE: Gelsolin (GSN) is a multifunctional protein that can regulate cell proliferation, apoptosis, inflammation and infection. GSN has been reported to be involved in rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS) and many other diseases. The role of GSN in primary Sjogren's syndrome (pSS) remains still unclear. The aim of this study is to investigate the changes of GSN level in serum and whole blood cells of pSS patients and evaluate the relationship between GSN and fatigue or other clinical indicators. PATIENTS AND METHODS: The cross-sectional study included 47 pSS patients (1 male and 46 females, average age: 52.83±12.63 years) and 51 healthy controls (all females, average age: 50.61±9.86 years). The patients were collected from the Second Affiliated Hospital of Harbin Medical University, China, without the age and sex differences. The levels of GSN in serum of pSS patients and the healthy controls were measured by Western blotting. The sequencing gene expression omnibus (GEO) data from National Center for Biotechnology Information (NCBI) about GSN levels in the whole blood cells of pSS patients and the healthy controls were analyzed by R language. RESULTS: Compared with healthy controls, the level of GSN was significantly decreased in the serum of pSS patients (98.89 ± 28.94 vs. 131.6 ± 37.1 µg/ml, p<0.001). The expression of GSN in the whole blood cells of pSS patients was significantly lower than that in the healthy controls (6.4 ± 0.19 vs. 6.6 ± 0.17, p<0.01). Compared to non-fatigued pSS patients, the level of GSN was down-regulated in serum (85.69 ± 27.08 vs. 111.52 ± 24.71 µg/ml, p<0.01) and whole blood cells (6.43 ± 0.18 vs. 6.58 ± 0.21, p<0.001) in fatigue pSS patients. However, there was no significant correlation between the level of GSN and EULAR Sjogrens syndrome disease activity index (ESSDAI) in pSS patients (p=0.73). CONCLUSIONS: GSN is decreased in serum and whole blood cells of pSS patients, and it is much lower in fatigue patients than that in non-fatigue patients. The correlation between the level of GSN and ESSDAI was not significant in pSS patients.

Low Plasma Gelsolin Concentrations in Chronic Granulomatous Disease.

Plasma gelsolin (pGSN) is the secreted isoform of an intracellular actin remodeling protein found in high concentrations in human plasma. Clinical studies demonstrate reduced pGSN concentrations in several disease states, including severe trauma, burns, and sepsis. Markedly decreased pGSN concentrations in these conditions precede and predict adverse clinical outcomes. In this study, we measured pGSN in patients with chronic granulomatous disease (CGD), a primary immunodeficiency characterized by recurrent infections and dysregulated inflammation. pGSN was quantified using a sandwich ELISA in plasma from healthy volunteers, clinically stable CGD patients, and X-linked CGD carriers and in sera from 12 CGD patients undergoing bone marrow transplantation. pGSN was also quantified in healthy volunteers challenged with intravenous endotoxin. pGSN concentrations were lower in CGD patients without active infection or systemic inflammation compared with healthy control subjects. In CGD patients undergoing bone marrow transplantation, pGSN concentrations increased significantly following successful transplant. X-linked carriers of CGD had normal pGSN. Despite reduction of pGSN in CGD patients, we did not detect significant changes in pGSN over 24 h following challenge of healthy volunteers with intravenous endotoxin (4 ng/kg) that elicited a febrile response. We describe, for the first time, significantly lower pGSN in clinically stable patients with CGD compared with age- and sex-matched healthy volunteers. Low pGSN levels in CGD patients significantly increased following bone marrow transplantation. X-linked carriers of CGD had normal pGSN. In healthy volunteers challenged with intravenous endotoxin, pGSN is not an acute phase reactant.

Large-Scale Multi-omic Analysis of COVID-19 Severity.

We performed RNA-seq and high-resolution mass spectrometry on 128 blood samples from COVID-19-positive and COVID-19-negative patients with diverse disease severities and outcomes. Quantified transcripts, proteins, metabolites, and lipids were associated with clinical outcomes in a curated relational database, uniquely enabling systems analysis and cross-ome correlations to molecules and patient prognoses. We mapped 219 molecular features with high significance to COVID-19 status and severity, many of which were involved in complement activation, dysregulated lipid transport, and neutrophil activation. We identified sets of covarying molecules, e.g., protein gelsolin and metabolite citrate or plasmalogens and apolipoproteins, offering pathophysiological insights and therapeutic suggestions. The observed dysregulation of platelet function, blood coagulation, acute phase response, and endotheliopathy further illuminated the unique COVID-19 phenotype. We present a web-based tool (covid-omics.app) enabling interactive exploration of our compendium and illustrate its utility through a machine learning approach for prediction of COVID-19 severity.

Role of Plasma Gelsolin Protein in the Final Stage of Erythropoiesis and in Correction of Erythroid Dysplasia In Vitro.

Gelsolin, an actin-remodeling protein, is involved in cell motility, cytoskeletal remodeling, and cytokinesis and is abnormally expressed in many cancers. Recently, human recombinant plasma gelsolin protein (pGSN) was reported to have important roles in cell cycle and maturation of primary erythroblasts. However, the role of human plasma gelsolin in late stage erythroblasts prior to enucleation and putative clinical relevance in patients with myelodysplastic syndrome (MDS) and hemato-oncologic diseases have not been reported. Polychromatic and orthochromatic erythroblasts differentiated from human cord blood CD34+ cells, and human bone marrow (BM) cells derived from patients with MDS, were cultured in serum-free medium containing pGSN. Effects of pGSN on mitochondria, erythroid dysplasia, and enucleation were assessed in cellular and transcriptional levels. With pGSN treatment, terminal maturation at the stage of poly- and ortho-chromatic erythroblasts was enhanced, with higher numbers of orthochromatic erythroblasts and enucleated red blood cells (RBCs). pGSN also significantly decreased dysplastic features of cell morphology. Moreover, we found that patients with MDS with multi-lineage dysplasia or with excess blasts-1 showed significantly decreased expression of gelsolin mRNA (GSN) in their peripheral blood. When BM erythroblasts of MDS patients were cultured with pGSN, levels of mRNA transcripts related to terminal erythropoiesis and enucleation were markedly increased, with significantly decreased erythroid dysplasia. Moreover, pGSN treatment enhanced mitochondrial transmembrane potential that is unregulated in MDS and cultured cells. Our findings demonstrate a key role for plasma gelsolin in erythropoiesis and in gelsolin-depleted MDS patients, and raises the possibility that pGSN administration may promote erythropoiesis in erythroid dysplasia.

Actin is associated with tissue injury in trauma patients and produces a hypercoagulable profile in vitro.

BACKGROUND: While tissue injury provokes fibrinolysis shutdown in trauma, the mechanism remains elusive. Cellular death causes release of structural proteins, including actin and myosin, which may interact with clot formation and structure. We hypothesized that tissue injury is associated with high circulating actin and that actin produces a hypercoagulable profile with decreased fibrinolysis in vitro. METHODS: Blood was collected from trauma activation patients at a single Level I trauma center for thrombelastography and proteomics. Proteomic analyses were performed through targeted liquid chromatography coupled with mass spectrometry using isotope-labeled standards for quantification of actin and its endogenous inhibitor gelsolin. Based on the results, we added physiologic concentrations of cytoskeletal G-actin to whole blood from healthy volunteers and analyzed changes in thrombelastography, as well as to plasma and examined clot architecture using confocal microscopy of fluorescently labeled fibrinogen. RESULTS: Overall, 108 trauma patients were included: majority (71%) men, median age of 32.7 years, 66% blunt mechanism, median New Injury Severity Score (NISS) of 41. Compared with patients without severe tissue injury (NISS < 15, n = 10), patients with severe tissue injury (NISS > 15, n = 98) had higher levels of circulating actin (0.0428 vs. 0.0301, p = 0.02). Further, there was a trend toward lower gelsolin levels in patients with fibrinolysis shutdown (0.1844 vs. 0.2052, p = 0.17) and tissue plasminogen activator resistance (0.1676 vs. 0.2188, p = 0.06).Ten healthy volunteers were included in the in vitro experiments (50% male; median age, 31.3 years). Actin significantly increased angle (40.0° to 52.9°, p = 0.002) and decreased fibrinolysis (percent clot lysis 30 minutes after reaching maximum amplitude, 4.0% to 1.6%; p = 0.002), provoking fibrinolytic shutdown in three patients. The addition of actin to control plasma decreased fiber resolvability of fibrin clots, monitored by microscopy, and decreased plasmin-mediated fibrinolysis. CONCLUSION: Actin increases clot propagation and provokes fibrinolysis shutdown in vitro, through a mechanism of plasmin inhibition. High circulating levels of actin are present in trauma patients with severe tissue injury, suggesting actin contributes to fibrinolysis shutdown in the setting of tissue injury.

Designing new diagnostic systems for the early detection of tobacco-associated chronic renal damage in patients of a primary care centre in Salamanca, Spain: an observational, prospective study protocol.

INTRODUCTION: Tobacco causes kidney damage that can progress to chronic kidney disease. However, the diagnostic parameters used in clinics are not effective in identifying smokers at risk. Our first objective is to more effectively detect subclinical renal damage in smokers. In addition, we hypothesise that tobacco consumption can predispose smokers to renal damage on exposure to other potentially nephrotoxic events (drugs, diagnostic procedures and so on). We will test this hypothesis in our second objective by investigating whether certain predisposition markers (GM2 ganglioside activator protein (GM2AP), transferrin and t-gelsolin) are able to detect smokers who are predisposed to kidney damage. Finally, in our third objective, we will study whether smoking cessation reduces subclinical and/or predisposition to renal damage. METHODS AND ANALYSIS: For our first objective, a prospective cross-sectional study will be carried out with patients from a primary healthcare centre. The influence of tobacco on renal damage, in patients both with and without additional risk factors, will be studied using a panel of early biomarkers (albuminuria, N-acetyl-beta-D-glucosaminidase, kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin). For our second objective, a prospective longitudinal study will be carried out with patients recruited for our first objective. We will study whether certain predisposition biomarkers (GM2AP, transferrin and t-gelsolin) are able to detect smokers predisposed to renal damage. For our third objective, a prospective longitudinal study will be carried out with patients from a smoking cessation unit. We will study the evolution of the markers described above following smoking cessation. ETHICS AND DISSEMINATION: The study has been approved by the Clinical Research Ethics Committee of the Healthcare Area of Salamanca. All study participants will sign an informed consent form in compliance with the Declaration of Helsinki and the WHO standards for observational studies. Results will be presented at conferences and submitted to peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03850756.

Plasma gelsolin levels in patients with psoriatic arthritis: a possible novel marker.

BACKGROUND: Psoriatic arthritis (PsA) is an inflammatory disorder affecting the joints of psoriatic patients. Gelsolin regulated the actin assembly and disassembly. Reduction in plasma gelsolin levels was detected in tissue damages, including trauma, sepsis, and chronic inflammatory disorders. OBJECTIVES: The study aims to investigate the potential role of gelsolin in PsA and to determine the association between gelsolin and the disease activity. METHODS: Plasma gelsolin levels were measured in 76 PsA patients in comparison with 40 patients having psoriasis only and 40 age- and sex -matched healthy controls. RESULTS: Plasma gelsolin levels were decreased in PsA patients compared to controls and psoriasis-only patients (p Ë‚ 0.0001). The optimal cutoff point of gelsolin was 172.5 mg/L. Gelsolin showed 92.1% sensitivity and 95% specificity in detecting PsA. But, it had 92.1% sensitivity and 80% specificity in differentiating between psoriasis and PsA. Plasma gelsolin showed a significant negative correlation with inflammatory markers as C-reactive protein and erythrocyte sedimentation rate (p < 0.0001 and p = 0.039; respectively). A significant negative correlation between plasma gelsolin and PsA activity was detected (p < 0.0001). The PsA activity was defined by the Disease Activity for Psoriatic Arthritis Score and the Composite Psoriatic Disease Activity Index. CONCLUSIONS: The plasma gelsolin levels were decreased in PsA patients, suggesting that gelsolin may be implicated in the chronic joint inflammation process. Plasma gelsolin seems to be a useful predictive biomarker for diagnosing PsA and monitoring the disease activity.Key Points• This study introduces an unprecedented focus within which the relationship between the levels of plasma gelsolin and PsA is investigated• The study examines the potential role of gelsolin in PsA, and detects the association between gelsolin and the arthritis activity.• There were decreased plasma gelsolin levels in PsA patients. So, gelsolin can constitute a role in the chronic joint inflammation process.• Gelsolin may be a useful biomarker for diagnosing of PsA and monitoring the disease activity.

Gelsolin: a new biomarker of disease activity in SLE patients associated with HDL-c.

OBJECTIVES: To identify potential biomarkers of disease activity analysing the proteome of high-density lipoprotein (HDL) particles from SLE patients in clinical remission and when they develop a flare compared with a healthy control group. METHODS: Quantitative proteomic analyses of purified HDL were performed using Tandem Mass Tag isobaric tag-labelling and nanoLC-Orbitrap (nLC-MS/MS) from nine SLE patients in clinical remission when they developed a flare and from nine healthy controls (9-9-9). We verified the identified proteins by Western blot and ELISA in a cohort of 104 SLE women patients, 46 healthy women and 14 SLE patients when a flare developed. RESULTS: We found 17 proteins with a significant fold-change (>1.1) compared with the control group. In lupus patients experiencing a flare compared with those in remission, we identified four proteins with a significant fold-change (C4, Indian Hedgehog protein, S100A8 and gelsolin). Plasma gelsolin (pGSN) levels were decreased in the 104 SLE patients (176.02(74.9) mcg/l) compared with the control group (217.13(86.7) mcg/l); P=0.005 and when they developed a clinical flare (104.84(41.7) mcg/l); P=0.002). pGSN levels were associated with HDL cholesterol levels (r = 0.316, P<0.001). Antimalarial treated patients showed significant higher levels of pGSN (214.56(88.94) mcg/l regarding 170.35(66.36) mcg/l); P = 0.017. CONCLUSION: Decreased pGSN are associated with clinical disease activity in SLE patients. Antimalarial treatment and HDL cholesterol are associated with higher levels of pGSN.

The exosome-mediated autocrine and paracrine actions of plasma gelsolin in ovarian cancer chemoresistance.

Ovarian cancer (OVCA) is the most lethal gynecological cancer, due predominantly to late presentation, high recurrence rate and common chemoresistance development. The expression of the actin-associated protein cytosolic gelsolin (GSN) regulates the gynecological cancer cell fate resulting in dysregulation in chemosensitivity. In this study, we report that elevated expression of plasma gelsolin (pGSN), a secreted isoform of GSN and expressed from the same GSN gene, correlates with poorer overall survival and relapse-free survival in patients with OVCA. In addition, it is highly expressed and secreted in chemoresistant OVCA cells than its chemosensitive counterparts. pGSN, secreted and transported via exosomes (Ex-pGSN), upregulates HIF1α-mediated pGSN expression in chemoresistant OVCA cells in an autocrine manner as well as confers cisplatin resistance in otherwise chemosensitive OVCA cells. These findings support our hypothesis that exosomal pGSN promotes OVCA cell survival through both autocrine and paracrine mechanisms that transform chemosensitive cells to resistant counterparts. Specifically, pGSN transported via exosomes is a determinant of chemoresistance in OVCA.

Dysregulation of the actin scavenging system and inhibition of DNase activity following severe thermal injury.

BACKGROUND: Circulating cell-free DNA (cfDNA) is not found in healthy subjects, but is readily detected after thermal injury and may contribute to the risk of multiple organ failure. The hypothesis was that a postburn reduction in DNase protein/enzyme activity could contribute to the increase in cfDNA following thermal injury. METHODS: Patients with severe burns covering at least 15 per cent of total body surface area were recruited to a prospective cohort study within 24 h of injury. Blood samples were collected from the day of injury for 12 months. RESULTS: Analysis of blood samples from 64 patients revealed a significant reduction in DNase activity on days 1-28 after injury, compared with healthy controls. DNase protein levels were not affected, suggesting the presence of an enzyme inhibitor. Further analysis revealed that actin (an inhibitor of DNase) was present in serum samples from patients but not those from controls, and concentrations of the actin scavenging proteins gelsolin and vitamin D-binding protein were significantly reduced after burn injury. In a pilot study of ten military patients with polytrauma, administration of blood products resulted in an increase in DNase activity and gelsolin levels. CONCLUSION: The results of this study suggest a novel biological mechanism for the accumulation of cfDNA following thermal injury by which high levels of actin released by damaged tissue cause a reduction in DNase activity. Restoration of the actin scavenging system could therefore restore DNase activity, and reduce the risk of cfDNA-induced host tissue damage and thrombosis.

ANTECEDENTES: El ADN libre de las células circulantes (circulating cell-free DNA, cfDNA) no se encuentra en sujetos sanos, pero se detecta fácilmente después de una lesión térmica y puede contribuir al riesgo de fallo multiorgánico. La hipótesis fue que una disminución en la actividad de la proteína/enzima ADNasa tras la lesión térmica podría contribuir a la elevación del cfDNA que ocurre tras la misma. MÉTODOS: Los pacientes con quemaduras graves con una extensión ≥ 15% del área de superficie corporal total (total body surface area, TBSA) se incluyeron en un estudio prospectivo de cohortes durante las primeras 24 horas posteriores a la lesión. Se recogieron muestras de sangre desde el día de la lesión hasta los 12 meses posteriores a la misma. RESULTADOS: El análisis de muestras de sangre de 64 pacientes reveló una reducción significativa de la actividad de la ADNasa en los días 1 a 28 después de la lesión, en comparación con los controles sanos. Los niveles de proteína ADNasa no se vieron afectados, lo que sugiere la presencia de un inhibidor enzimático. Un análisis adicional reveló que la actina (un inhibidor de la ADNasa) estaba presente en las muestras de suero de los pacientes, pero no en los controles, y las concentraciones de la gelsolina, proteína que causa la disociación de la actina, y la proteína de unión a la vitamina D se redujeron significativamente después de la lesión térmica. En un estudio piloto de 10 pacientes con politrauma por lesiones militares, la administración de hemoderivados produjo un aumento en la actividad de la ADNasa y de los niveles de gelsolina. CONCLUSIÓN: Este estudio sugiere un nuevo mecanismo biológico para la acumulación de cfDNA después de una lesión térmica, por el cual los altos niveles de actina liberada por el tejido dañado causarían una reducción en la actividad de la ADNasa. La restauración del sistema eliminador de actina podría, por lo tanto, restaurar la actividad de la ADNasa y reducir el riesgo de daño tisular y trombosis en el huésped inducido por el cfDNA.

Pre-operative Circulating Plasma Gelsolin Predicts Residual Disease and Detects Early Stage Ovarian Cancer.

Ovarian cancer (OVCA) patients with suboptimal residual disease (RD) and advanced stages have poor survival. pGSN is an actin binding protein which protects OVCA cells from cisplatin-induced death. There is an urgent need to discover reliable biomarkers to optimize individualized treatment recommendations. 99 plasma samples with pre-determined CA125 were collected from OVCA patients and pGSN assayed using sandwich-based ELISA. Associations between CA125, pGSN and clinicopathological parameters were examined using Fisher's exact test, T test and Kruskal Wallis Test. Univariate and multivariate Cox proportional hazard models were used to statistically analyze clinical outcomes. At 64 µg/ml, pGSN had sensitivity and specificity of 60% and 60% respectively, for the prediction of RD where as that of CA125 at 576.5 U/mL was 43.5% and 56.5% respectively. Patients with stage 1 tumor had increased levels of pre-operative pGSN compared to those with tumor stage >1 and healthy subjects (P = 0.005). At the value of 81 µg/mL, pGSN had a sensitivity and specificity of 75% and 78.4%, respectively for the detection of early stage OVCA. At the value of 0.133, the Indicator of Stage 1 OVCA (ISO1) provided a sensitivity of 100% at a specificity of 67% (AUC, 0.89; P < 0.001). In the multivariate Cox regression analysis, pGSN (HR, 2.00; CI, 0.99-4.05; P = 0.05) was an independent significant predictor of progression free survival (PFS) but not CA125 (HR, 0.68; CI, 0.41-1.13; P = 0.13). Pre-operative circulating pGSN is a favorable and independent biomarker for early disease detection, RD prediction and patients' prognosis.

Comprehensive proteomic profiling of plasma-derived Extracellular Vesicles from dementia with Lewy Bodies patients.

Proteins and nucleic acids contained in extracellular vesicles (EVs) are considered a feasible source of putative biomarkers for physiological and pathological conditions. Within the nervous system, not only neurons but also other brain cells are able to produce EVs, which have been involved in their physiological processes and also in the development and course of several neurodegenerative diseases. Among these, dementia with Lewy bodies (DLB) is the second cause of dementia worldwide, though most cases are missed or misdiagnosed as Alzheimer's disease (AD) due to the important clinical and pathological overlap between both diseases. In an attempt to find reliable biomarkers for DLB diagnosis, our group characterized the proteome of plasma-derived EVs from DLB patients compared to aged-matched healthy controls (HCs) using two different proteomic LC-MS/MS approaches. Remarkably, we found that gelsolin and butyrylcholinesterase were differentially identified between DLB and HCs. Further validation of these results using conventional ELISA techniques, and including an additional group of AD patients, pointed to decreased levels of gelsolin in plasma-EVs from DLB compared to HCs and to AD samples. Thus, gelsolin may be considered a possible biomarker for the differentiation between DLB and AD.

Hypogelsolinemia in Patients Diagnosed with Acute Myeloid Leukemia at Initial Stage of Sepsis.

BACKGROUND Gelsolin (GSN) is an actin-binding and PIP2/Ca²âº-regulated protein found in the cytoplasm and blood plasma. Hypogelsolinemia occurs in a wide range of traumatic injuries and inflammatory reactions. We hypothesize that blood GSN levels will be altered in patients diagnosed with acute myeloid leukemia (AML) that develop sepsis, and assessment of GSN concentration will be a useful marker to determine their clinical outcome. To achieve this task, we evaluated the plasma gelsolin concentration in blood samples collected from patients diagnosed with acute myeloid leukemia (AML) at initial stages of sepsis. MATERIAL AND METHODS To assess if AML patients might be at risk of sepsis, a SOFA score was determined. Plasma gelsolin concentration was evaluated using an immunoblotting technique. RESULTS We found that GSN concentration in the blood of the AML group with developing sepsis was significantly lower (32±41 µg/ml; p<0.05) compared to the AML group (65±35 µg/ml) and control group (176±37 µg/ml; p<0.001). Additionally, low gelsolin concentration in the blood of AML patients developing sepsis was associated with a high SOFA score. A decrease of GSN concentration in the blood of AML subjects with developing sepsis suggests that GSN level in blood reflects not only chronic inflammation stage associated with leukemia, but that GSN depletion also manifests the inflammation associated with sepsis development. CONCLUSIONS The results presented here suggest the possible utility of GSN evaluation for diagnostic purposes. Overall, these data support the that reversing plasma GSN deficiency might be a possible new strategy in sepsis treatment.

Altered plasma-type gelsolin and amyloid-ß in neonates with hypoxic-ischaemic encephalopathy under therapeutic hypothermia.

Hypoxic-ischemic encephalopathy (HIE) is a severe neonatal complication responsible for ∼23% of all neonatal deaths. Also, 30-70% of these patients will suffer lifetime disabilities, including learning impairment, epilepsy or cerebral palsy. However, biomarkers for HIE screening, or monitoring disease progression are limited. Herein, we sought to evaluate the clinical usefulness of plasma-type gelsolin (pGSN) and amyloid-beta (Aß) 40 and 42 as prognostic biomarkers for HIE. pGSN has been previously suggested as a feasible marker in other brain injuries and amyloid-beta 40 and 42 are classically assessed in neurodegenerative diseases. However, to our knowledge, they have not been previously assessed in HIE patients. We have analyzed plasma pGSN and Aß 40 and 42 levels in 55 newborns (16 controls, 16 mild and 23 moderate-severe HIE) at birth, during 72 h of therapeutic hypothermia, a gold-standard treatment for HIE, and 24 h after hypothermia. Aß levels were lower in HIE patients, and pGSN levels were progressively reduced in mild and moderate-severe HIE patients. The fact that pGSN reductions could predict the severity of HIE and significantly correlated with the time to undergo hypothermia supports the prognostic value of plasmatic pGSN. Further studies are warranted to investigate the role of pGSN in neonatal HIE.

Acute Lung Injury in Critically Ill Patients: Actin-Scavenger Gelsolin Signals Prolonged Respiratory Failure.

BACKGROUND: Gelsolin is an actin-scavenger controlling the tissue damage from actin in the blood. Gelsolin levels in circulation drops when tissue damage and corresponding actin release is pronounced due to catabolic conditions. The purpose of this study was to determine if low plasma gelsolin independently predicts a reduced chance of weaning from ventilator-demanding respiratory failure in critically ill patients within 28 days from admission. RESULTS: This cohort study included 746 critically ill patients with ventilator-demanding respiratory failure from the randomized clinical trial, "Procalcitonin And Survival Study (PASS)." Primary end point was successful weaning from mechanical ventilation within 28 days. We used multivariable Cox regression adjusted for age, sepsis, PaO2/FiO2 ratio and other known and suspected predictors of persistent respiratory failure. Follow-up was complete.For medical patients, baseline-gelsolin below the 25th percentile independently predicted a 40% lower chance of successful weaning within 28 days (HR 0.60, 95% CI 0.46-0.79, P = 0.0002); among surgical patients this end point was not predicted. Low gelsolin levels predicted chance of being "alive and out of intensive care at day 14" for both medical and surgical patients (HR 0.69, 95% CI 0.54-0.89, P = 0.004). Gelsolin levels did not predict 28 day mortality for surgical or medical patients. CONCLUSIONS: Low levels of serum gelsolin independently predict a decreased chance of successful weaning from ventilator within 28 days among medical intensive care patients. This finding has implications for identifying patients who need individualized intervention early in intensive care course to prevent unfavorable lung prognosis in acute respiratory failure. TRIAL REGISTRATION: This is a substudy to the PASS, Clinicaltrials.gov ID: NCT00271752, first registered January 1, 2006.

Low Admission Plasma Gelsolin Concentrations Identify Community-acquired Pneumonia Patients at High Risk for Severe Outcomes.

BACKGROUND: Plasma gelsolin (pGSN) is an abundant circulating protein that neutralizes actin exposed by damaged cells, modulates inflammatory responses, and enhances alveolar macrophage antimicrobial activity. We investigated whether adults with low pGSN at hospital admission for community-acquired pneumonia (CAP) were at high risk for severe outcomes. METHODS: Admission pGSN concentrations in 455 adults hospitalized with CAP were measured using enzyme-linked immunosorbent assay. Patients were grouped into the following 4 hierarchical, mutually exclusive categories based on maximum clinical severity experienced during their hospitalization: general floor care without intensive care unit (ICU) admission, invasive respiratory or vasopressor support (IRVS), or death; ICU care without IRVS or death; IRVS without death; or death. Admission pGSN concentrations were compared across these discrete outcome categories. Additionally, outcomes among patients in the lowest quartile of pGSN concentration were compared to those in the upper 3 quartiles. RESULTS: Overall, median (interquartile range) pGSN concentration was 38.1 (32.1, 45.7) µg/mL. Patients with more severe outcomes had lower pGSN concentrations (P = .0001); median values were 40.3 µg/mL for floor patients, 36.7 µg/mL for ICU patients, 36.5 µg/mL for patients receiving IRVS, and 25.7 µg/mL for patients who died. Compared to patients with higher pGSN concentrations, patients in the lowest quartile (pGSN ≤ 32.1 µg/mL) more often required IRVS (21.2% vs 11.7%, P = .0114) and died (8.8% vs 0.9%, P < .0001). CONCLUSIONS: Among adults hospitalized with CAP, lower pGSN concentrations were associated with more severe clinical outcomes. Future studies are planned to investigate possible therapeutic benefits of recombinant human pGSN in this population.