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1.
Plasma Proteomic Signatures in Early Chronic Obstructive Pulmonary Disease.
Baralla, A, Fois, AG, Sotgiu, E, Zinellu, E, Mangoni, AA, Sotgia, S, Zinellu, A, Pirina, P, Carru, C
Proteomics. Clinical applications. 2018;(3):e1700088
Abstract
PURPOSE Chronic obstructive pulmonary disease (COPD) is characterized by progressive airflow limitation and abnormal inflammatory response of the lungs to inhaled noxious particles or gases. We used a proteomic approach with 2-DE followed by MALDI TOF-MS analyses in order to identify potential biomarkers in the early stages of the disease: global initiative for chronic obstructive pulmonary disease (GOLD) stage mild and moderate. EXPERIMENTAL DESIGN Blood plasma was collected from 43 patients with mild and moderate COPD as well as from 43 age- and sex-matched control subjects. Proteome analysis was based on 2D-Page followed by MALDI-TOF MS identifications. Validation was made on two significant proteins by western blotting. RESULTS The analyses revealed 29 between-group differences in expressed spots, belonging to 20 unique proteins. These proteins are involved in inflammation (haptoglobin, Ig alpha-1 chain C), blood coagulation and complement pathways (prothrombin, complement 4-B, ApoH), oxidative stress (ceruloplasmin, vitamin D binding protein, and serotransferrin), and lipoprotein/lipid metabolism (apolipoprotein A-I, and apolipoprotein E). CONCLUSION AND CLINICAL RELEVANCE These results indicate that specific proteomic signatures can be detected and useful in terms of treatment selection and in early COPD patient monitoring.
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2.
iTRAQ-Based Proteomic Analysis Reveals Protein Profile in Plasma from Children with Autism.
Shen, L, Zhang, K, Feng, C, Chen, Y, Li, S, Iqbal, J, Liao, L, Zhao, Y, Zhai, J
Proteomics. Clinical applications. 2018;(3):e1700085
Abstract
PURPOSE Autism is a childhood neurological disorder with poorly understood etiology and pathology. This study is designed to identify differentially expressed proteins that might serve as potential biomarkers for autism. EXPERIMENTAL DESIGN We perform iTRAQ (isobaric tags for relative and absolute quantitation) analysis for normal and autistic children's plasma of the same age group. RESULTS The results show that 24 differentially expressed proteins were identified between autistic subjects and controls. For the first time, differential expression of complement C5 (C5) and fermitin family homolog 3 (FERMT3) are related to autism. Five proteins, that is, complement C3 (C3), C5, integrin alpha-IIb (ITGA2B), talin-1 (TLN1), and vitamin D-binding protein (GC) were validated via enzyme-linked immunosorbent assay (ELISA). By ROC (receiver operating characteristic) analysis, combinations of these five proteins C3, C5, GC, ITGA2B, and TLN1 distinguished autistic children from healthy controls with a high AUC (area under the ROC curve) value (0.982, 95% CI, 0.957-1.000, p < 0.000). CONCLUSION These above described proteins are found involved in different pathways that have previously been linked to the pathophysiology of autism spectrum disorders (ASDs). The results strongly support that focal adhesions, acting cytoskeleton, cell adhesion, motility and migration, synaptogenesis, and complement system are involved in the pathogenesis of autism, and highlight the important role of platelet function in the pathophysiology of autism.
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3.
Changes in Total Protein Concentration Due to Fluid Removal During and Shortly after Hemodialysis.
Daugirdas, JT
American journal of nephrology. 2018;(2):118-126
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Abstract
BACKGROUND Changes in plasma volume during hemodialysis are complex and have been shown to depend on the rate of fluid removal and the degree of fluid overload. We examined changes in total protein concentration during and shortly after a dialysis treatment in archived data from the HEMO study. METHODS During follow-up months 4 and 36 of the HEMO study, additional blood samples were obtained during a typical dialysis session at 30 and 60 min after dialysis. In 315 studies from 282 patients where complete data were available, we calculated the concentration change in total protein and compared it to the modeled change in both total body water and extracellular fluid space as derived from 2-pool urea kinetic modeling. RESULTS The mean postdialysis modeled urea volume (V) was 31.1 ± 6.18 L. Mean fluid removal was 2.76 ± 1.27 kg, over a session length of 207 ± 28 min. The ratio of predialysis V to postdialysis V averaged 1.090 ± 0.040. The mean TP ratios (post/pre) at 0, 30, and 60 min postdialysis averaged 1.121 ± 0.070 (SD), 1.091 ± 0.090, and 1.091 ± 0.086. The dialysate to serum sodium gradient, studied in a different group of treatments where this information was available, had no impact on these findings, nor did the length of the interdialytic interval. CONCLUSIONS On average, after equilibration, the change in plasma volume due to fluid removal is similar to the modeled change in total body water (urea space), irrespective of dialysate to serum sodium gradient. This supports previous observations that during dialysis with ultrafiltration, plasma volume contracts to a lesser degree than the interstitial volume and that some fluid may be removed from spaces other than the extracellular fluid.
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Characteristics of fibrinolytic disorders in acute promyelocytic leukemia.
Wang, P, Zhang, Y, Yang, H, Hou, W, Jin, B, Hou, J, Li, H, Zhao, H, Zhou, J
Hematology (Amsterdam, Netherlands). 2018;(10):756-764
Abstract
OBJECTIVES Catastrophic hemorrhage remains the main cause of acute promyelocytic leukemia (APL) treatment failure. This study was aimed to study the pathogenesis of coagulopathy in patients with APL. METHODS Multiple procoagulant and profibrinolytic parameters in plasma and peripheral leukocytes from 24 patients with newly diagnosed APL accompanied by coagulopathy before and after arsenic trioxide (ATO) treatment were evaluated. RESULTS Prior to the treatment, the patients had elevated D-dimer and decreased fibrinogen levels. Plasma urokinase-type plasminogen activator receptor (uPAR) and plasmin-ɑ2 antiplasmin complexes (PAP) levels, plasmin (Pn) activity, and cell surface levels of urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA) were significantly higher; plasma plasminogen activator inhibitor-1 (PAI-1) levels and plasminogen (Pg) activity were significantly decreased; plasma plasminogen activator (PA) activity, uPA and tPA levels; and cell surface levels of uPAR and annexin II were not significantly different from levels in the control group. During ATO treatment, both patients' plasma PA activity and uPAR on leukocytes gradually increased, annexin II on leukocytes increased initially and decreased afterwards, and tPA and uPA on leukocytes remained consistently higher in the patients than in the controls. Other parameters gradually tended toward normal values. CONCLUSIONS In APL, activated coagulation system activated fibrinolytic system, and increased uPAR levels could contribute to the hyperfibrinolysis. Annexin II might not be involved in the coagulopathy.
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Conformational and Organizational Insights into Serum Proteins during Competitive Adsorption on Self-Assembled Monolayers.
Hasan, A, Waibhaw, G, Pandey, LM
Langmuir : the ACS journal of surfaces and colloids. 2018;(28):8178-8194
Abstract
Physicochemical interactions of proteins with surfaces mediate the interactions between the implant and the biological system. Surface chemistry of the implant is crucial as it regulates the events at the interface. The objective of this study was to explore the performance of modified surfaces for such interactions relevant to various biomedical applications. Because of a wide range of surface wettability, we aimed to study protein behavior (i.e., conformational changes and their packing) during competitive protein adsorption. Three serum proteins (bovine serum albumin, BSA; fibrinogen, FB; and immunoglobulin G, IgG) were tested for their conformational changes and orientation upon adsorption on hydrophilic (COOH and amine), moderately hydrophobic (mixed and hybrid), and hydrophobic (octyl) surfaces generated via silanization. Modified surfaces were characterized using Fourier-transform infrared spectroscopy, contact angle, and atomic force microscopy (AFM) techniques. Adsorbed masses of proteins from single and binary protein solutions on different surfaces were quantified along with their secondary structure analyses. Maximum adsorbed protein masses were found to be on negatively charged and hydrophobic (octyl) surfaces because of ionic and hydrophobic interactions between protein molecules and surfaces, respectively. Side-on and end-on orientations of adsorbed protein molecules were analyzed using theoretical and AFM analyses. We observed compact and elongated forms of BSA molecules on hydrophilic and hydrophobic surfaces, respectively. We further found a linear increase in the α-helix content of BSA and β-sheet contents of FB and IgG proteins with the increasing side-on (%)-oriented protein molecules on the surfaces. This indicates that side-on orientations of adsorbed FB and IgG lead to the formation of β-sheets. Sodium dodecyl sulfate polyacrylamide gel electrophoresis was employed to quantify the protein types and their ratio in competitively adsorbed proteins on different surfaces. A theoretical analysis was also used to determine the % secondary structures of competitively adsorbed proteins from BSA/FB and BSA/IgG solutions, which very well agreed with experimental results. The competitive protein adsorption from both BSA/FB and BSA/IgG solutions was found to be entropy-driven, as revealed by thermodynamic studies performed using isothermal titration calorimetry.
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Novel Plasma Proteins in Nepalese School-aged Children are Associated with a Small Head Size at Birth.
Lee, SE, West, KP, Cole, RN, Schulze, KJ, Wu, LS, Yager, JD, Groopman, J, Christian, P
Scientific reports. 2018;(1):6390
Abstract
Fetal growth restriction increases the risk of poor childhood growth and development and chronic disease in adulthood. Yet, little is known about biological pathways that mediate the long-lasting effects of suboptimal intrauterine growth. We explored the plasma proteome in a cohort of 500 Nepalese children 6-8 years of age to identify plasma proteins associated with multiple anthropometric size indicators at birth. Among 982 proteins analyzed, no proteins differed by birth weight, length, or weight-for-length indicators. However, 25 proteins were differentially abundant in children with a small vs normal head circumference at birth (<-2 vs. ≥-2 z-scores of the WHO growth standards). Angiopoietin-like 6 was 19.4% more abundant and the other 24 proteins were 7-21% less abundant in children with a small vs normal head circumference at birth, adjusted for potential confounders. The less abundant proteins included actins, actin filament organizing proteins (α-actinin, talin, filamin, cofilin, profilin, and vinculin), proteins involved in muscle contraction, and glycolytic enzymes, which were all positively correlated with each other. A novel cluster of childhood plasma proteins involved in angiogenesis and cytoskeleton dynamics was associated with a small head size at birth. The prognostic value of an altered proteomic phenotype remains to be investigated.
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Physical Activity and Cognitive Function among Older Adults with an Elevated Gamma Gap.
Frith, E, Loprinzi, PD
Medical principles and practice : international journal of the Kuwait University, Health Science Centre. 2018;(6):531-536
Abstract
OBJECTIVE An elevated gamma gap is indicative of high serum concentrations of globulin proteins, some of which elicit acute inflammatory responses. An impaired cognitive function has been linked to central and peripheral inflammation, while exercise is associated with protective, anti-inflammatory benefits. In this study, we evaluated whether the gamma gap is associated with cognitive function among older adults and whether physical activity is favorably associated with cognitive function among those with an elevated gamma gap. MATERIALS AND METHODS Data from the 1999-2002 National Health and Nutrition Examination Survey (NHANES) were used to identify 2,352 older adults aged between 60 and 85 years. The gamma gap was evaluated by subtracting albumin from total protein, i.e., gamma gap = total protein (g/dL) - albumin (g/dL). Those at or above 3.1 g/dL (31.0 g/L) were considered to have an elevated gamma gap. The Digit Symbol Substitution Test (DSST) was used to assess cognitive function tasks of pairing and free recall among participants. Participants were asked open-ended questions about participation in leisure-time physical activity over the previous 30 days. RESULTS Those with an elevated gamma gap (DSST, 44.8) had a lower cognitive function score when compared to those without an elevated gamma gap (DSST, 50.1) (p < 0.001). After adjustments, and among those with an elevated gamma gap, those meeting the moderate-to-vigorous intensity physical activity (MVPA) guidelines (vs. not meeting them) had a DSST score of 6.42 units higher (β = 6.42, 95% CI 3.85-8.99, p < 0.001). CONCLUSION In this national sample of older adults, the gamma gap was associated with cognitive function, and among those with an elevated gamma gap, meeting the physical activity guidelines was associated with a higher cognitive function. Relevant clinical implications are discussed, as the gamma gap may be predictive of the risk for early mortality and reduced quality of life. Experimental work is needed to investigate whether physical activity training programs are effective in reducing an elevated gamma gap and preserving optimal cognitive functioning among at-risk individuals.
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Relationship Between Central Venous Catheter Protein Adsorption and Water Infused Surface Protection Mechanisms.
Sutherland, DW, Blanks, ZD, Zhang, X, Charest, JL
Artificial organs. 2018;(11):E369-E379
Abstract
Central venous catheters (CVCs) are implanted in the majority of dialysis patients despite increased patient risk due to thrombotic occlusion and biofilm formation. Current solutions remain ineffective at preventing these complications and treatment options are limited and often harmful. We present further analysis of the previously proposed water infused surface protection (WISP) technology, an active method to reduce protein adsorption and effectively disrupt adsorbed protein sheaths on the inner surface of CVCs. A WISP CVC is modeled by a hollow fiber membrane (HFM) in a benchtop device which continuously infuses a saline solution across the membrane wall into the blood flow, creating a blood-free boundary layer at the lumen surface. Total protein adsorption is measured under various experimental conditions to further test WISP performance. The WISP device shows reduced protein adsorption as blood and WISP flow rates increase (P < 0.040) with up to a 96% reduction in adsorption over the no WISP condition. When heparin is added to the WISP flow, protein adsorption (0.097[+0.035/-0.055] µg/mm2 ) is reduced when compared to both bolus administration and nondoped WISP, 0.406(+0.056/-0.065) µg/mm2 (P = 0.001) and 0.191 (+0.076/-0.126) (P = 0.029), respectively. Additionally, when heparinized WISP is applied to a preadsorbed protein layer, 0.375(+0.114/-0.164) µg/mm2 , it displays the ability to reduce the previously-adsorbed protein, 0.186(+0.058/-0.084) µg/mm2 (P = 0.0012), suggesting aptitude for intermittent treatments. The WISP technology not only shows the ability to reduce protein adsorption, but also the ability to remove preadsorbed material by effectively delivering drugs to the point of adsorption; functionalities that could greatly improve clinical outcomes.
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Plasma proteome analysis in patients with pulmonary arterial hypertension: an observational cohort study.
Rhodes, CJ, Wharton, J, Ghataorhe, P, Watson, G, Girerd, B, Howard, LS, Gibbs, JSR, Condliffe, R, Elliot, CA, Kiely, DG, et al
The Lancet. Respiratory medicine. 2017;(9):717-726
Abstract
BACKGROUND Idiopathic and heritable pulmonary arterial hypertension form a rare but molecularly heterogeneous disease group. We aimed to measure and validate differences in plasma concentrations of proteins that are associated with survival in patients with idiopathic or heritable pulmonary arterial hypertension to improve risk stratification. METHODS In this observational cohort study, we enrolled patients with idiopathic or heritable pulmonary arterial hypertension from London (UK; cohorts 1 and 2), Giessen (Germany; cohort 3), and Paris (France; cohort 4). Blood samples were collected at routine clinical appointment visits, clinical data were collected within 30 days of blood sampling, and biochemical data were collected within 7 days of blood sampling. We used an aptamer-based assay of 1129 plasma proteins, and patient clinical details were concealed to the technicians. We identified a panel of prognostic proteins, confirmed with alternative targeted assays, which we evaluated against the established prognostic risk equation for pulmonary arterial hypertension derived from the REVEAL registry. All-cause mortality was the primary endpoint. FINDINGS 20 proteins differentiated survivors and non-survivors in 143 consecutive patients with idiopathic or heritable pulmonary arterial hypertension with 2 years' follow-up (cohort 1) and in a further 75 patients with 2·5 years' follow-up (cohort 2). Nine proteins were both prognostic independent of plasma NT-proBNP concentrations and confirmed by targeted assays. The functions of these proteins relate to myocardial stress, inflammation, pulmonary vascular cellular dysfunction and structural dysregulation, iron status, and coagulation. A cutoff-based score using the panel of nine proteins provided prognostic information independent of the REVEAL equation, improving the C statistic from area under the curve 0·83 (for REVEAL risk score, 95% CI 0·77-0·89; p<0·0001) to 0·91 (for panel and REVEAL 0·87-0·96; p<0·0001) and improving reclassification indices without detriment to calibration. Poor survival was preceded by an adverse change in panel score in paired samples from 43 incident patients with pulmonary arterial hypertension in cohort 3 (p=0·0133). The protein panel was validated in 93 patients with idiopathic or heritable pulmonary arterial hypertension in cohort 4, with 4·4 years' follow-up and improved risk estimates, providing complementary information to the clinical risk equation. INTERPRETATION A combination of nine circulating proteins identifies patients with pulmonary arterial hypertension with a high risk of mortality, independent of existing clinical assessments, and might have a use in clinical management and the evaluation of new therapies. FUNDING National Institute for Health Research, Wellcome Trust, British Heart Foundation, Assistance Publique-Hôpitaux de Paris, Inserm, Université Paris-Sud, and Agence Nationale de la Recherche.
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The Role of Protein Z and Protein Z-Dependent Protease Inhibitor Polymorphisms in the Development of Prosthetic Heart Valve Thrombosis.
Karakoyun, S, Ozan Gürsoy, M, Kalçık, M, Yesin, M, Gündüz, S, Ali Astarcıoğlu, M, Bayram, Z, Çakal, B, Bayam, E, Özkan, M
The Journal of heart valve disease. 2017;(4):460-466
Abstract
BACKGROUND AND AIM OF THE STUDY Protein Z (PZ) is a vitamin K-dependent factor that is synthesized mainly by the liver. It acts as an activator of serpin, the protein Z-dependent inhibitor (ZPI), which inhibits factor Xa. The potential role of alterations in protein Z and/or ZPI levels in the pathogenesis of thrombotic and/or hemorrhagic diseases has been previously investigated, but results have been conflicting. The study aim was to evaluate the role of PZ/ZPI polymorphisms in the development of prosthetic valve thrombosis (PVT). METHODS This prospective, observational cross-sectional study included 50 consecutive patients with PVT [non-obstructive thrombosis (NOT) in 35 patients; obstructive thrombosis (OT) in 15] and 50 consecutive healthy subjects with normally functioning prostheses. gDNA was extracted from ca. 5 × 106 leukocytes, using the QIAamp DNA Mini Kit (Qiagen), according to the manufacturer's recommendations. For mutational analysis, a minisequencing method was employed. Results of the analyses were compared between the PVT and control groups, and also between the OT and NOT subgroups. RESULTS The frequency of A allele (mutant type) of PZG79A was equal in all PVT patients and in controls. With regards to PZ-A13G polymorphisms, frequency of the mutant G allele was 22% in PVT patients and 19% in controls. Serpina-R67X polymorphism was observed in 8% of PVT patients and 6% of controls. Normal variant CC was present in 47 controls (94%), whereas a heterozygotic mutation (CT) was detected in four PVT patients (8%). Frequency of the ZPI-R67X mutation was significantly higher in patients with OT than in those with NOT (p = 0.041). CONCLUSIONS The present study was the first to evaluate the potential impact of PZ (PZ-A13G, PZG79A) and ZPI (R-67X, W303X) polymorphisms in the development of PVT. Based on the results of this small observational case-control study, PZ/ZPI polymorphisms do not appear to play an active role in the development of PVT. Hence, further extensive studies are necessary.