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Sample records for multiple cytokine biomarkers

  1. Multiple Serum Cytokine Profiling to Identify Combinational Diagnostic Biomarkers in Attacks of Familial Mediterranean Fever

    PubMed Central

    Koga, Tomohiro; Migita, Kiyoshi; Sato, Shuntaro; Umeda, Masataka; Nonaka, Fumiaki; Kawashiri, Shin-Ya; Iwamoto, Naoki; Ichinose, Kunihiro; Tamai, Mami; Nakamura, Hideki; Origuchi, Tomoki; Ueki, Yukitaka; Masumoto, Junya; Agematsu, Kazunaga; Yachie, Akihiro; Yoshiura, Koh-Ichiro; Eguchi, Katsumi; Kawakami, Atsushi

    2016-01-01

    Abstract The precise cytokine networks in the serum of individuals with familial Mediterranean fever (FMF) that are associated with its pathogenesis have been unknown. Here, we attempted to identify specific biomarkers to diagnose or assess disease activity in FMF patients. We measured serum levels of 45 cytokines in 75 FMF patients and 40 age-matched controls by multisuspension cytokine array. FMF in “attack” or “remission” was classified by Japan College of Rheumatology-certified rheumatologists according to the Tel Hashomer criteria. Cytokines were ranked by their importance by a multivariate classification algorithm. We performed a logistic regression analysis to determine specific biomarkers for discriminating FMF patients in attack. To identify specific molecular networks, we performed a cluster analysis of each cytokine. Twenty-nine of the 45 cytokines were available for further analyses. Eight cytokines’ serum levels were significantly elevated in the FMF attack versus healthy control group. Nine cytokines were increased in FMF attack compared to FMF remission. Multivariate classification algorithms followed by a logistic regression analysis revealed that the combined measurement of IL-6, IL-18, and IL-17 distinguished FMF patients in attack from the controls with the highest accuracy (sensitivity 89.2%, specificity 100%, and accuracy 95.5%). Among the FMF patients, the combined measurement of IL-6, G-CSF, IL-10, and IL-12p40 discriminated febrile attack periods from remission periods with the highest accuracy (sensitivity 75.0%, specificity 87.9%, and accuracy 84.0%). Our data identified combinational diagnostic biomarkers in FMF patients based on the measurement of multiple cytokines. These findings help to improve the diagnostic performance of FMF in daily practice and extend our understanding of the activation of the inflammasome leading to enhanced cytokine networks. PMID:27100444

  2. Predictive cytokine biomarkers of clinical response to glatiramer acetate therapy in multiple sclerosis.

    PubMed

    Valenzuela, R M; Kaufman, M; Balashov, K E; Ito, K; Buyske, S; Dhib-Jalbut, S

    2016-11-15

    A prospective study of 62 patients with relapsing-remitting multiple sclerosis (RRMS) treated with Glatiramer acetate (GA) was conducted to evaluate the value of baseline and treatment-modulated cytokines in predicting the clinical response to the drug after 2years of therapy. There were 32 responders and 30 non-responders. GA upregulated Th2/regulatory cytokines and inhibited Th1 cytokines in sera or PBMC supernatants 3 and 6months into treatment. We found two prognostic models with clinical utility. A model based on IL-18 at baseline, the change in TNFa from baseline to 3months, the change in IL-4 from baseline to 6months, and the change in the log of the ratio of TNFa/IL-4 from baseline to 6months had an area under the curve (AUC) of 0.80. A high IL-18 level at baseline and a reduction of TNF-alpha over time are associated with a response to GA. Although the study identified predictive biomarkers of clinical response to GA, the results will need to be validated in other data sets. Copyright © 2016 Elsevier B.V. All rights reserved.

  3. Cytokines as Biomarkers in Rheumatoid Arthritis

    PubMed Central

    Burska, Agata; Boissinot, Marjorie; Ponchel, Frederique

    2014-01-01

    RA is a complex disease that develops as a series of events often referred to as disease continuum. RA would benefit from novel biomarker development for diagnosis where new biomarkers are still needed (even if progresses have been made with the inclusion of ACPA into the ACR/EULAR 2010 diagnostic criteria) and for prognostic notably in at risk of evolution patients with autoantibody-positive arthralgia. Risk biomarkers for rapid evolution or cardiovascular complications are also highly desirable. Monitoring biomarkers would be useful in predicting relapse. Finally, predictive biomarkers for therapy outcome would allow tailoring therapy to the individual. Increasing numbers of cytokines have been involved in RA pathology. Many have the potential as biomarkers in RA especially as their clinical utility is already established in other diseases and could be easily transferable to rheumatology. We will review the current knowledge's relation to cytokine used as biomarker in RA. However, given the complexity and heterogeneous nature of RA, it is unlikely that a single cytokine may provide sufficient discrimination; therefore multiple biomarker signatures may represent more realistic approach for the future of personalised medicine in RA. PMID:24733962

  4. Cytokines as biomarkers in rheumatoid arthritis.

    PubMed

    Burska, Agata; Boissinot, Marjorie; Ponchel, Frederique

    2014-01-01

    RA is a complex disease that develops as a series of events often referred to as disease continuum. RA would benefit from novel biomarker development for diagnosis where new biomarkers are still needed (even if progresses have been made with the inclusion of ACPA into the ACR/EULAR 2010 diagnostic criteria) and for prognostic notably in at risk of evolution patients with autoantibody-positive arthralgia. Risk biomarkers for rapid evolution or cardiovascular complications are also highly desirable. Monitoring biomarkers would be useful in predicting relapse. Finally, predictive biomarkers for therapy outcome would allow tailoring therapy to the individual. Increasing numbers of cytokines have been involved in RA pathology. Many have the potential as biomarkers in RA especially as their clinical utility is already established in other diseases and could be easily transferable to rheumatology. We will review the current knowledge's relation to cytokine used as biomarker in RA. However, given the complexity and heterogeneous nature of RA, it is unlikely that a single cytokine may provide sufficient discrimination; therefore multiple biomarker signatures may represent more realistic approach for the future of personalised medicine in RA.

  5. Circulating Cytokines as Biomarkers of Alcohol Abuse and Alcoholism

    PubMed Central

    Achur, Rajeshwara N.; Freeman, Willard M.; Vrana, Kent E.

    2010-01-01

    There are currently no consistent objective biochemical markers of alcohol abuse and alcoholism. Development of reliable diagnostic biomarkers that permit accurate assessment of alcohol intake and patterns of drinking is of prime importance to treatment and research fields. Diagnostic biomarker development in other diseases has demonstrated the utility of both open, systems biology, screening for biomarkers and more rational focused efforts on specific biomolecules or families of biomolecules. Long term alcohol consumption leads to altered inflammatory cell and adaptive immune responses with associated pathologies and increased incidence of infections. This has led researchers to focus attention on identifying cytokine biomarkers in models of alcohol abuse. Alcohol is known to alter cytokine levels in plasma and a variety of tissues including lung, liver, and very importantly brain. A number of cytokine biomarker candidates have been identified, including: TNF alpha, IL1-alpha, IL1-beta, IL6, IL8, IL12 and MCP-1. This is an emerging and potentially exciting avenue of research in that circulating cytokines may contribute to diagnostic biomarker panels and a combination of multiple biomarkers may significantly increase the sensitivity and specificity of the biochemical tests aiding reliable and accurate detection of excessive alcohol intake. PMID:20020329

  6. Cytokines as predictive biomarkers of alloreactivity.

    PubMed

    Brunet, M

    2012-09-08

    Clinical use of valid biomarkers enables the prediction of alloreactive response (risk of rejection) and personal susceptibility to immunosuppressive treatment could lead to personalized immunosuppressive therapy. In clinical transplantation, it has been reported that cytokine production and secretion could be modified by immunosuppressive drugs, as well as during the rejection process. Some cytokines such as interferon (IFN)-γ, interleukin (IL)-2, IL-10, and transforming growth factor (TGF)-β have been identified as candidate biomarkers that correlate with graft outcome and personal response to immunosuppressive agents. This review will focus on the current state of knowledge, indicating that monitoring changes in cytokine production could be used to predict the risk of rejection and to guide immunosuppression therapy in transplant recipients. In addition, many questions regarding the characteristics and standardization of the methods used for cytokine monitoring (ELISA; ELISPOT; Flow Cytometry) that need to be addressed before these assays can be clinically applied will be discussed in light of recent studies showing an association between the expression of some cytokines and genetic variants, the impact of immunosuppression, and the incidence of rejection. The clinical implementation of cytokine monitoring should be tested in prospective multicenter clinical trials with standard operating procedures and objective interpretation of the results obtained. Copyright © 2012 Elsevier B.V. All rights reserved.

  7. Cytokines as biomarkers of nanoparticle immunotoxicity

    PubMed Central

    Elsabahy, Mahmoud; Wooley, Karen L.

    2013-01-01

    Nanoscale objects, whether of biologic origin or synthetically created, are being developed into devices for a variety of bionanotechnology diagnostic and pharmaceutical applications. However, the potential immunotoxicity of these nanomaterials and mechanisms by which they may induce adverse reactions have not received sufficient attention. Nanomaterials, depending on their characteristics and compositions, can interact with the immune system in several ways and either enhance or suppress immune system function. Cytokines perform pleiotropic functions to mediate and regulate the immune response and are generally recognized as biomarkers of immunotoxicity. While the specificity and validity of certain cytokines as markers of adverse immune response has been established for chemicals, small and macromolecular drugs, research on their applicability for predicting and monitoring the immunotoxicity of engineered nanomaterials is still ongoing. The goal of this review is to provide guidelines as to important cytokines that can be utilized for evaluating the immunotoxicity of nanomaterials and to highlight the role of those cytokines in mediating adverse reactions, which is of particular importance for the clinical development of nanopharmaceuticals and other nanotechnology-based products. Importantly, the rational design of nanomaterials of low immunotoxicity will be discussed, focusing on synthetic nanodevices, with emphasis on both the nanoparticle-forming materials and the embedded cargoes. PMID:23549679

  8. Multiple Circulating Cytokines Are Coelevated in Chronic Obstructive Pulmonary Disease

    PubMed Central

    Todd, Ian; John, Michelle; Bolton, Charlotte E.; Harrison, Timothy

    2016-01-01

    Inflammatory biomarkers, including cytokines, are associated with COPD, but the association of particular circulating cytokines with systemic pathology remains equivocal. To investigate this, we developed a protein microarray system to detect multiple cytokines in small volumes of serum. Fourteen cytokines were measured in serum from never-smokers, ex-smokers, current smokers, and COPD patients (GOLD stages 1–3). Certain individual circulating cytokines (particularly TNFα and IL-1β) were significantly elevated in concentration in the serum of particular COPD patients (and some current/ex-smokers without COPD) and may serve as markers of particularly significant systemic inflammation. However, numerous circulating cytokines were raised such that their combined, but not individual, elevation was significantly associated with severity of disease, and these may be further indicators of, and contributors to, the systemic inflammatory manifestations of COPD. The coelevation of numerous circulating cytokines in COPD is consistent with the insidious development, chronic nature, and systemic comorbidities of the disease. PMID:27524865

  9. Multiple Circulating Cytokines Are Coelevated in Chronic Obstructive Pulmonary Disease.

    PubMed

    Selvarajah, Senthooran; Todd, Ian; Tighe, Patrick J; John, Michelle; Bolton, Charlotte E; Harrison, Timothy; Fairclough, Lucy C

    2016-01-01

    Inflammatory biomarkers, including cytokines, are associated with COPD, but the association of particular circulating cytokines with systemic pathology remains equivocal. To investigate this, we developed a protein microarray system to detect multiple cytokines in small volumes of serum. Fourteen cytokines were measured in serum from never-smokers, ex-smokers, current smokers, and COPD patients (GOLD stages 1-3). Certain individual circulating cytokines (particularly TNFα and IL-1β) were significantly elevated in concentration in the serum of particular COPD patients (and some current/ex-smokers without COPD) and may serve as markers of particularly significant systemic inflammation. However, numerous circulating cytokines were raised such that their combined, but not individual, elevation was significantly associated with severity of disease, and these may be further indicators of, and contributors to, the systemic inflammatory manifestations of COPD. The coelevation of numerous circulating cytokines in COPD is consistent with the insidious development, chronic nature, and systemic comorbidities of the disease.

  10. The inflammatory cytokines: molecular biomarkers for major depressive disorder?

    PubMed

    Martin, Charlotte; Tansey, Katherine E; Schalkwyk, Leonard C; Powell, Timothy R

    2015-01-01

    Cytokines are pleotropic cell signaling proteins that, in addition to their role as inflammatory mediators, also affect neurotransmitter systems, brain functionality and mood. Here we explore the potential utility of cytokine biomarkers for major depressive disorder. Specifically, we explore how genetic, transcriptomic and proteomic information relating to the cytokines might act as biomarkers, aiding clinical diagnosis and treatment selection processes. We advise future studies to investigate whether cytokine biomarkers might differentiate major depressive disorder patients from other patient groups with overlapping clinical characteristics. Furthermore, we invite future pharmacogenetic studies to investigate whether early antidepressant-induced changes to cytokine mRNA or protein levels precede behavioral changes and act as longer-term predictors of clinical antidepressant response.

  11. The Immune System, Cytokines, and Biomarkers in Autism Spectrum Disorder.

    PubMed

    Masi, Anne; Glozier, Nicholas; Dale, Russell; Guastella, Adam J

    2017-04-01

    Autism Spectrum Disorder (ASD) is a pervasive neurodevelopmental condition characterized by variable impairments in communication and social interaction as well as restricted interests and repetitive behaviors. Heterogeneity of presentation is a hallmark. Investigations of immune system problems in ASD, including aberrations in cytokine profiles and signaling, have been increasing in recent times and are the subject of ongoing interest. With the aim of establishing whether cytokines have utility as potential biomarkers that may define a subgroup of ASD, or function as an objective measure of response to treatment, this review summarizes the role of the immune system, discusses the relationship between the immune system, the brain, and behavior, and presents previously-identified immune system abnormalities in ASD, specifically addressing the role of cytokines in these aberrations. The roles and identification of biomarkers are also addressed, particularly with respect to cytokine profiles in ASD.

  12. CSF cytokines/chemokines as biomarkers in neuroinflammatory CNS disorders: A systematic review.

    PubMed

    Kothur, Kavitha; Wienholt, Louise; Brilot, Fabienne; Dale, Russell C

    2016-01-01

    Despite improved understanding of the pathogenesis of neuroinflammatory disorders of the brain and development of new diagnostic markers, our biomarker repertoire to demonstrate and monitor inflammation remains limited. Using PubMed database, we reviewed 83 studies on CSF cytokines and chemokines and describe the pattern of elevation and possible role of cytokines/chemokines as biomarkers in viral and autoimmune inflammatory neurological disorders of the CNS. Despite inconsistencies and overlap of cytokines and chemokines in different neuroinflammation syndromes, there are some trends regarding the pattern of cytokines/chemokine elevation. Namely B cell markers, such as CXCL13 and BAFF are predominantly investigated and found to be elevated in autoantibody-associated disorders, whereas interferon gamma (IFN-γ) is elevated mainly in viral encephalitis. Th2 and Th17 cytokines are frequently elevated in acute disseminated encephalomyelitis (ADEM) and neuromyelitis optica (NMO), whereas Th1 and Th17 cytokines are more commonly elevated in multiple sclerosis (MS). Cytokine/chemokine profiling might provide new insights into disease pathogenesis, and improve our ability to monitor inflammation and response to treatment. Copyright © 2015 Elsevier Ltd. All rights reserved.

  13. Cytokines and other immunological biomarkers in children's environmental health studies

    PubMed Central

    Duramad, Paurene; Tager, Ira B.; Holland, Nina T.

    2007-01-01

    Environmental exposures (e.g. pesticides, air pollution, and environmental tobacco smoke) during prenatal and early postnatal development have been linked to a growing number of childhood diseases including allergic disorders and leukemia. Because the immune response plays a critical role in each of these diseases, it is important to study the effects of toxicants on the developing immune system. Children's unique susceptibility to environmental toxicants has become an important focus of the field of immunotoxicology and the use of immune biomarkers in molecular epidemiology of children's environmental health is a rapidly expanding field of research. In this review, we discuss how markers of immune status and immunotoxicity are being applied to pediatric studies, with a specific focus on the various methods used to analyze T-helper-1/2 (Th1/Th2) cytokine profiles. Furthermore, we review recent data on the effects of children's environmental exposures to volatile organic compounds, metals, and pesticides on Th1/Th2 cytokine profiles and the associations of Th1/Th2 profiles with adverse health outcomes such as pediatric respiratory diseases, allergies, cancer and diabetes. Although cytokine profiles are increasingly used in children's studies, there is still a need to acquire distribution data for different ages and ethnic groups of healthy children. These data will contribute to the validation and standardization of cytokine biomarkers for future studies. Application of immunological markers in epidemiological studies will improve the understanding of mechanisms that underlie associations between environmental exposures and immune-mediated disorders. PMID:17624696

  14. Cytokines as Biomarkers of Pancreatic Ductal Adenocarcinoma: A Systematic Review.

    PubMed

    Yako, Yandiswa Yolanda; Kruger, Deirdré; Smith, Martin; Brand, Martin

    2016-01-01

    A systematic review of the role of cytokines in clinical medicine as diagnostic, prognostic, or predictive biomarkers in pancreatic ductal adenocarcinoma was undertaken. A systematic review was conducted according to the 2009 PRISMA guidelines. PubMed database was searched for all original articles on the topic of interest published until June 2015, and this was supplemented with references cited in relevant articles. Studies were evaluated for risk of bias using the Quality in Prognosis Studies tools. Forty one cytokines were investigated with relation to pancreatic ductal adenocarcinoma (PDAC) in 65 studies, ten of which were analyzed by more than three studies. Six cytokines (interleukin[IL]-1β, -6, -8, -10, vascular endothelial growth factor, and transforming growth factor) were consistently reported to be increased in PDAC by more than four studies; irrespective of sample type; method of measurement; or statistical analysis model used. When evaluated as part of distinct panels that included CA19-9, IL-1β, -6 and -8 improved the performance of CA19-9 alone in differentiating PDAC from healthy controls. For example, a panel comprising IL-1β, IL-8, and CA 19-9 had a sensitivity of 94.1% vs 85.9%, specificity of 100% vs 96.3%, and area under the curve of 0.984 vs 0.925. The above-mentioned cytokines were associated with the severity of PDAC. IL-2, -6, -10, VEGF, and TGF levels were reported to be altered after patients received therapy or surgery. However, studies did not show any evidence of their ability to predict treatment response. Our review demonstrates that there is insufficient evidence to support the role of individual cytokines as diagnostic, predictive or prognostic biomarkers for PDAC. However, emerging evidence indicates that a panel of cytokines may be a better tool for discriminating PDAC from other non-malignant pancreatic diseases or healthy individuals.

  15. Cytokines as Biomarkers of Pancreatic Ductal Adenocarcinoma: A Systematic Review

    PubMed Central

    Yako, Yandiswa Yolanda; Kruger, Deirdré; Smith, Martin; Brand, Martin

    2016-01-01

    Objectives A systematic review of the role of cytokines in clinical medicine as diagnostic, prognostic, or predictive biomarkers in pancreatic ductal adenocarcinoma was undertaken. Materials and Methods A systematic review was conducted according to the 2009 PRISMA guidelines. PubMed database was searched for all original articles on the topic of interest published until June 2015, and this was supplemented with references cited in relevant articles. Studies were evaluated for risk of bias using the Quality in Prognosis Studies tools. Results Forty one cytokines were investigated with relation to pancreatic ductal adenocarcinoma (PDAC) in 65 studies, ten of which were analyzed by more than three studies. Six cytokines (interleukin[IL]-1β, -6, -8, -10, vascular endothelial growth factor, and transforming growth factor) were consistently reported to be increased in PDAC by more than four studies; irrespective of sample type; method of measurement; or statistical analysis model used. When evaluated as part of distinct panels that included CA19-9, IL-1β, -6 and -8 improved the performance of CA19-9 alone in differentiating PDAC from healthy controls. For example, a panel comprising IL-1β, IL-8, and CA 19–9 had a sensitivity of 94.1% vs 85.9%, specificity of 100% vs 96.3%, and area under the curve of 0.984 vs 0.925. The above-mentioned cytokines were associated with the severity of PDAC. IL-2, -6, -10, VEGF, and TGF levels were reported to be altered after patients received therapy or surgery. However, studies did not show any evidence of their ability to predict treatment response. Conclusion Our review demonstrates that there is insufficient evidence to support the role of individual cytokines as diagnostic, predictive or prognostic biomarkers for PDAC. However, emerging evidence indicates that a panel of cytokines may be a better tool for discriminating PDAC from other non-malignant pancreatic diseases or healthy individuals. PMID:27170998

  16. Cytokines as biomarkers of Crimean-Congo hemorrhagic fever.

    PubMed

    Papa, Anna; Tsergouli, Katerina; Çağlayık, Dilek Yağcı; Bino, Silvia; Como, Najada; Uyar, Yavuz; Korukluoglu, Gulay

    2016-01-01

    Crimean-Congo hemorrhagic fever (CCHF) is a potentially severe disease caused by CCHF virus. As in other viral hemorrhagic fevers, it is considered that the course and outcome of the disease depend on the viral load and the balance among the immune response mediators, and that a fatal outcome is the result of a "cytokine storm." The level of 27 cytokines was measured in serum samples taken from 29 patients during the acute phase of the disease. Two cases were fatal. Among survivors, significant differences between severe and non-severe cases were observed in the levels of IP-10, and MCP-1, while the levels of IL-1b, IL-5, IL-6, IL-8, IL-9, IL-10, IL-15, IP-10, MCP-1, TNF-α, and RANTES differed significantly between fatal and non-fatal cases (P < 0.05). RANTES was negatively correlated with the outcome of the disease. A striking similarity with the cytokine patterns seen in Ebola virus disease was observed. A weak Th1 immune response was seen. The viral load was positively correlated with IL-10, IP-10, and MCP-1 levels, and negatively correlated with the ratio IL-12/IL-10. Especially IP-10 and MCP-1 were significantly associated with the viral load, the severity and outcome of the disease, and they could act as biomarkers and, probably, as potential targets for treatment strategies design.

  17. Translational implications of inflammatory biomarkers and cytokine networks in psychoneuroimmunology.

    PubMed

    Yan, Qing

    2012-01-01

    Developments in psychoneuroimmunology (PNI) need to be translated into personalized medicine to achieve better clinical outcomes. One of the most critical steps in this translational process is to identify systemic biomarkers for better diagnosis and treatment. Applications of systems biology approaches in PNI would enable the insights into the correlations among various systems and different levels for the identification of the basic elements of the psychophysiological framework. Among the potential PNI biomarkers, inflammatory markers deserve special attention as they play a pivotal role linking various health conditions and disorders. The elucidation of inflammatory markers, cytokine networks, and immune-brain-behavior interactions may help establish PNI profiles for the identification of potential targets for personalized interventions in at risk populations. The understanding of the general systemic pathways among different disorders may contribute to the transition from the disease-centered medicine to patient-centered medicine. Integrative strategies targeting these factors and pathways would be useful for the prevention and treatment of a spectrum of diseases that share the common links. Examples of the translational implications of potential PNI biomarkers and networks in diseases including depression, Alzheimer's disease, obesity, cardiovascular disease, stroke, and HIV are discussed in details.

  18. Cerebrospinal fluid biomarkers in multiple sclerosis.

    PubMed

    Tumani, Hayrettin; Hartung, Hans-Peter; Hemmer, Bernhard; Teunissen, Charlotte; Deisenhammer, Florian; Giovannoni, Gavin; Zettl, Uwe K

    2009-08-01

    In patients with multiple sclerosis (MS) intensive efforts are directed at identifying biomarkers in bodily fluids related to underlying disease mechanisms, disease activity and progression, and therapeutic response. Besides MR imaging parameters cerebrospinal fluid (CSF) biomarkers provide important and specific information since changes in the CSF composition may reflect disease mechanisms inherent to MS. The different cellular and protein-analytical methods of the CSF and the recommended standard of the diagnostic CSF profile in MS are described. A brief update on possible CSF biomarkers that might reflect key pathological processes of MS such as inflammation, demyelination, neuroaxonal loss, gliosis and regeneration is provided.

  19. Blood Cytokines as Biomarkers of In Vivo Toxicity in Preclinical Safety Assessment: Considerations for Their Use

    PubMed Central

    Tarrant, Jacqueline M.

    2010-01-01

    In the drive to develop drugs with well-characterized and clinically monitorable safety profiles, there is incentive to expand the repertoire of safety biomarkers for toxicities without routine markers or premonitory detection. Biomarkers in blood are pursued because of specimen accessibility, opportunity for serial monitoring, quantitative measurement, and the availability of assay platforms. Cytokines, chemokines, and growth factors (here referred to collectively as cytokines) show robust modulation in proximal events of inflammation, immune response, and repair. These are key general processes in many toxicities; therefore, cytokines are commonly identified during biomarker discovery studies. In addition, multiplexed cytokine immunoassays are easily applied to biomarker discovery and routine toxicity studies to measure blood cytokines. However, cytokines pose several challenges as safety biomarkers because of a short serum half-life; low to undetectable baseline levels; lack of tissue-specific or toxicity-specific expression; complexities related to cytokine expression with multiorgan involvement; and species, strain, and interindividual differences. Additional challenges to their application are caused by analytical, methodological, and study design–related variables. A final consideration is the strength of the relationship between changes in cytokine levels and the development of phenotypic or functional manifestations of toxicity. These factors should inform the integrated judgment-based qualification of novel biomarkers in preclinical, and potentially clinical, risk assessment. The dearth of robust, predictive cytokine biomarkers for specific toxicities is an indication of the significant complexity of these challenges. This review will consider the current state of the science and recommendations for appropriate application of cytokines in preclinical safety assessment. PMID:20447938

  20. Plasma Biomarkers Discriminate Clinical Forms of Multiple Sclerosis

    PubMed Central

    Tejera-Alhambra, Marta; Casrouge, Armanda; de Andrés, Clara; Seyfferth, Ansgar; Ramos-Medina, Rocío; Alonso, Bárbara; Vega, Janet; Fernández-Paredes, Lidia; Albert, Matthew L.; Sánchez-Ramón, Silvia

    2015-01-01

    Multiple sclerosis, the most common cause of neurological disability in young population after trauma, represents a significant public health burden. Current challenges associated with management of multiple sclerosis (MS) patients stem from the lack of biomarkers that might enable stratification of the different clinical forms of MS and thus prompt treatment for those patients with progressive MS, for whom there is currently no therapy available. In the present work we analyzed a set of thirty different plasma cytokines, chemokines and growth factors present in circulation of 129 MS patients with different clinical forms (relapsing remitting, secondary progressive and primary progressive MS) and 53 healthy controls, across two independent cohorts. The set of plasma analytes was quantified with Luminex xMAP technology and their predictive power regarding clinical outcome was evaluated both individually using ROC curves and in combination using logistic regression analysis. Our results from two independent cohorts of MS patients demonstrate that the divergent clinical and histology-based MS forms are associated with distinct profiles of circulating plasma protein biomarkers, with distinct signatures being composed of chemokines and growth/angiogenic factors. With this work, we propose that an evaluation of a set of 4 circulating biomarkers (HGF, Eotaxin/CCL11, EGF and MIP-1β/CCL4) in MS patients might serve as an effective tool in the diagnosis and more personalized therapeutic targeting of MS patients. PMID:26039252

  1. Cytokines as biomarkers in depressive disorder: current standing and prospects.

    PubMed

    Lichtblau, Nicole; Schmidt, Frank M; Schumann, Robert; Kirkby, Kenneth C; Himmerich, Hubertus

    2013-10-01

    The frequently observed co-occurrence of depressive disorders and inflammatory diseases suggests a close connection between the nervous and the immune systems. Increased pro-inflammatory and type 1 cytokines, such as interleukin (IL)-1, tumour necrosis factor (TNF)-α and interferon (IFN)-γ, appear to be an important link. Cytokines are synthesized by immune cells in the blood and peripheral tissues and by glial cells in the central nervous system (CNS). Evidence suggests that the blood-brain barrier (BBB) is permeable to cytokines and immune cells, and that afferent nerves, e.g. the vagus nerve, mediate the communication between peripheral inflammatory processes and CNS. Cytokines such as IL-1ß, TNF-α and IFN-γ seem to contribute to the pathophysiology of depression by activating monoamine reuptake, stimulating the hypothalamic-pituitary-adrenocortical (HPA) axis and decreasing production of serotonin due to increased activity of indolamine-2,3-dioxygenase (IDO). However, critical appraisal of these hypotheses is required, because cytokine elevation is not specific to depression. Moreover, several effective antidepressants such as amitriptyline and mirtazapine have been shown to increase cytokine production. When applying immunomodulatory therapies, these drugs may increase the risk of specific side effects such as infections or interact with antidepressant drugs on important functions of the body such as the coagulation system.

  2. Tear Cytokine Profile as a Noninvasive Biomarker of Inflammation for Ocular Surface Diseases: Standard Operating Procedures

    PubMed Central

    Wei, Yi; Gadaria-Rathod, Neha; Epstein, Seth; Asbell, Penny

    2013-01-01

    Purpose. To provide standard operating procedures (SOPs) for measuring tear inflammatory cytokine concentrations and to validate the resulting profile as a minimally invasive objective metric and biomarker of ocular surface inflammation for use in multicenter clinical trials on dry eye disease (DED). Methods. Standard operating procedures were established and then validated with cytokine standards, quality controls, and masked tear samples collected from local and distant clinical sites. The concentrations of the inflammatory cytokines in tears were quantified using a high-sensitivity human cytokine multiplex kit. Results. A panel of inflammatory cytokines was initially investigated, from which four key inflammatory cytokines (IL-1β, IL-6, INF-γ, and TNF-α) were chosen. Results with cytokine standards statistically satisfied the manufacturer's quality control criteria. Results with pooled tear samples were highly reproducible and reliable with tear volumes ranging from 4 to 10 μL. Incorporation of the SOPs into clinical trials was subsequently validated. Tear samples were collected at a distant clinical site, stored, and shipped to our Biomarker Laboratory, where a masked analysis of the four tear cytokines was successfully performed. Tear samples were also collected from a feasibility study on DED. Inflammatory cytokine concentrations were decreased in tears of subjects who received anti-inflammatory treatment. Conclusions. Standard operating procedures for human tear cytokine assessment suitable for multicenter clinical trials were established. Tear cytokine profiling using these SOPs may provide objective metrics useful for diagnosing, classifying, and analyzing treatment efficacy in inflammatory conditions of the ocular surface, which may further elucidate the mechanisms involved in the pathogenesis of ocular surface disease. PMID:24204044

  3. The Systemic Cytokine Environment Is Permanently Altered in Multiple Myeloma

    PubMed Central

    Bemis, Kyle; Belch, Andrew R.; Pilarski, Linda M.; Shively, John E.; Kirshner, Julia

    2013-01-01

    Multiple myeloma (MM) is an incurable bone marrow malignancy of the B cell lineage. Utilizing multiplex Luminex technology we measured levels of 25 cytokines in the plasma of normal donors (n = 177), those with monoclonal gammopathy of undetermined significance (n = 8), and MM patients (n = 55) with either active disease, on treatment, or in remission. The cytokine levels were compared between normal donors and MM patients as well as between various phases of MM, and discriminant analysis was used to create a predictive classification model based on the differentially expressed cytokines. Evaluating age- and gender-dependence of cytokine expression, we determined that with age there is a shift toward a pro-inflammatory environment. Moreover, we observed a strong gender bias in cytokine expression. However, the profile of differentially expressed cytokines was heavily skewed toward an anti-inflammatory, pro-tumorigenic response in patients with MM. Significantly, our predictive model placed all patients in remission in the same category as those with active disease. Thus, our study demonstrates that the homeostasis of systemic cytokines is not restored when MM patients enter remission, suggesting that once an individual has cancer, the microenvironment is permanently altered and the system is primed for a relapse. PMID:23544044

  4. Cytokine biomarkers in tear film for primary open-angle glaucoma

    PubMed Central

    Gupta, Divakar; Wen, Joanne C; Huebner, Janet L; Stinnett, Sandra; Kraus, Virginia B; Tseng, Henry C; Walsh, Molly

    2017-01-01

    Purpose To determine the utility of tear film cytokines as biomarkers for early primary open-angle glaucoma (POAG). Methods Patients without POAG and eye drop-naïve patients with newly diagnosed POAG were recruited from an academic hospital-based glaucoma practice. Tear films of recruited patients were obtained and analyzed using a multiplex, high-sensitivity electrochemiluminescent enzyme-linked immunosorbent assay for proinflammatory cytokines (IFNγ, IL-10, IL-12p70, IL-13, IL-1β, IL-2, IL-4, IL-6, IL-8, and TNFα). Results Mean concentrations of tear film cytokines were lower in the glaucoma group for 8 of 10 cytokines tested. IL-12p70 (3.94±2.19 pg/mL in control vs 2.31±1.156 pg/mL in POAG; P=0.035) was significantly lower in the tear film of patients with newly diagnosed POAG. Conclusion Proinflammatory cytokines were lower in eye drop-naïve newly diagnosed glaucoma patients. Tear film cytokine profiles may be used as biomarkers of early POAG. PMID:28260854

  5. Biomarker Qualification: Toward a Multiple Stakeholder Framework for Biomarker Development, Regulatory Acceptance, and Utilization.

    PubMed

    Amur, S; LaVange, L; Zineh, I; Buckman-Garner, S; Woodcock, J

    2015-07-01

    The discovery, development, and use of biomarkers for a variety of drug development purposes are areas of tremendous interest and need. Biomarkers can become accepted for use through submission of biomarker data during the drug approval process. Another emerging pathway for acceptance of biomarkers is via the biomarker qualification program developed by the Center for Drug Evaluation and Research (CDER, US Food and Drug Administration). Evidentiary standards are needed to develop and evaluate various types of biomarkers for their intended use and multiple stakeholders, including academia, industry, government, and consortia must work together to help develop this evidence. The article describes various types of biomarkers that can be useful in drug development and evidentiary considerations that are important for qualification. A path forward for coordinating efforts to identify and explore needed biomarkers is proposed for consideration.

  6. Cytokines as biomarkers to monitoring the impact of multidrug therapy in immune response of leprosy patients.

    PubMed

    Cassirer-Costa, Fábio; Medeiros, Nayara I; Chaves, Ana T; Lyon, Sandra; Coelho-Dos-Reis, Jordana G A; Ribeiro-Junior, Atvaldo F; Correa-Oliveira, Rodrigo; Rocha, Manoel O C; Gomes, Juliana A S

    2017-09-01

    Leprosy or Hansen's disease is a chronic infectious disease of the skin and nerves, caused by the intracellular bacilli Mycobacterium leprae. It is characterized by a spectrum of clinical forms depending on the host's immune response to M. leprae. Patients with tuberculoid (TT) leprosy have strong cell-mediated immunity (CMI) with elimination of the bacilli, whereas patients with lepromatous (LL) leprosy exhibit defective CMI to M. leprae. Despite advances in the understanding of the pathogenesis of leprosy and the development of new therapeutic strategies, there is a need for the identification of biomarkers which be used for early diagnosis and to discrimination between different forms of the disease, as prognostic markers. Here, we analyzed the serum levels of IL-1β, IL-6, IL-8, IL-10, IL-12p70, IL-13, IL-17A, IFN-γ and TNF in order to address the contribution of these cytokines in late phase of M. leprae infection, and the impact of multidrug therapy (MDT). Our results demonstrated that patients of LL group presented higher expression of serum levels of inflammatory cytokines before MDT, while TT patients presented a balance between inflammatory and regulatory cytokines. MDT changes the profile of serum cytokines in M. leprae infected patients, as evidenced by the cytokine network, especially in TT patients. LL patients displayed a multifaceted cytokine system characterized by strong connecting axes involving inflammatory/regulatory molecules, while TT patients showed low involvement of regulatory cytokines in network overall. Cytokines can be identified as good biomarkers of the impact of MDT on the immune system and the effectiveness of treatment. Copyright © 2017 Elsevier Ltd. All rights reserved.

  7. Detection of multiple cytokines by protein arrays from cell lysate and tissue lysate.

    PubMed

    Lin, Ying; Huang, Ruochun; Cao, Xuan; Wang, Shen-Ming; Shi, Qing; Huang, Ruo-Pan

    2003-02-01

    Previously we demonstrated that multiple cytokines could be simultaneously detected using an antibody-based protein array system with high sensitivity and specificity from conditioned medium and serum. Here, we created a higher density array system to simultaneously detect 35 cytokines from cell lysates and tissue lysates. This assay combines the advantages of the specificity of enzyme-linked immunosorbent assays (ELISA), sensitivity of enhanced chemiluminescence (ECL), and high-throughput of microspot. In this system, capture antibodies dissolved in methanol were spotted onto polyvinylidene difluoride (PVDF) membranes. The membranes were then incubated with tissue lysates or cell lysates. After removing unbound proteins by extensive washing, the membranes were exposed to horseradish peroxidase (HRP)-conjugated antibody(ies). The signals were visualized with an ECL system. High specificity, sensitivity, and accuracy of this approach were demonstrated. This approach can be used in any general laboratory setting without any sophisticated equipment. It should be feasible to extend this concept to develop a high-throughput protein array system. Combining nitrocellulose membrane-based and PVDF membrane-based approaches, the human cytokine array system can be applied to detect multiple cytokine expression from cell lysate, tissue lysate, serum, plasma, and conditioned medium. Future applications of this new approach include direct protein expression profiling, immunological disease diagnostics, and discovery of new biomarkers.

  8. Cancer Cells Hijack PRC2 to Modify Multiple Cytokine Pathways

    PubMed Central

    Zhao, Michael; Song, Lan; Yu, Tao; Liu, Yu; Liu, Jeffrey C.; McCurdy, Sean; Ma, Anqi; Wither, Joan; Jin, Jian; Zacksenhaus, Eldad; Wrana, Jeffrey L.; Bremner, Rod

    2015-01-01

    Polycomb Repressive Complex 2 (PRC2) is an epigenetic regulator induced in many cancers. It is thought to drive tumorigenesis by repressing division, stemness, and/or developmental regulators. Cancers evade immune detection, and diverse immune regulators are perturbed in different tumors. It is unclear how such cell-specific effects are coordinated. Here, we show a profound and cancer-selective role for PRC2 in repressing multiple cytokine pathways. We find that PRC2 represses hundreds of IFNγ stimulated genes (ISGs), cytokines and cytokine receptors. This target repertoire is significantly broadened in cancer vs non-cancer cells, and is distinct in different cancer types. PRC2 is therefore a higher order regulator of the immune program in cancer cells. Inhibiting PRC2 with either RNAi or EZH2 inhibitors activates cytokine/cytokine receptor promoters marked with bivalent H3K27me3/H3K4me3 chromatin, and augments responsiveness to diverse immune signals. PRC2 inhibition rescues immune gene induction even in the absence of SWI/SNF, a tumor suppressor defective in ~20% of human cancers. This novel PRC2 function in tumor cells could profoundly impact the mechanism of action and efficacy of EZH2 inhibitors in cancer treatment. PMID:26030458

  9. Cytokines and disability in interferon-β-1b treated and untreated women with multiple sclerosis.

    PubMed

    Trenova, Anastasiya G; Slavov, Georgy S; Manova, Maria G; Kostadinova, Ivanka I

    2014-08-01

    T-helper (Th) cells involved in the pathogenesis of multiple sclerosis (MS) represent a functionally heterogeneous population defined by their cytokine secretion profile. The effects of immunotherapeutic drugs on the cytokine network are still not fully clarified. This study aimed to investigate serum levels of IFN-γ, TNF-α, IL-4, IL-10 in interferon-β-1b-treated and untreated women with relapsing-remitting MS (RRMS) in comparison with healthy controls and the relationship between cytokine concentrations and the degree of disability. The study included 35 women with RRMS and 35 age-matched healthy controls. The patients were divided in two groups: Group A-without disease modifying treatment; Group B-treated with interferon-β-1b. Degree of disability was assessed by the Expanded Disability Status Scale (EDSS). Serum cytokine concentrations were measured by ELISA during relapse and remission. Group A showed higher IFN-γ in remission (p = 0.0239) than the controls; Group B had lower IFN-γ during relapse (p = 0.0226) than controls. EDSS in relapse correlated with the levels of IL-10 for Group A (p = 0.015) and with the concentration of IFN-γ for Group B (p = 0.039). Nontreated patients showed higher EDSS in relapse compared to the interferon-β-1b-treated group (p = 0.005). We found an imbalance in the patients' cytokine profile, which may be seen as supportive of the hypothesis that demyelination in the central nervous system is mediated by Th1 lymphocytes. IFN-γ is probably one of the important indicators for intensity of the immune reaction and shows promise as a potential biomarker for the therapeutic effect of interferon-β-1b. The role of IL-10 in the autoimmune process needs further investigation. Copyright © 2014 IMSS. Published by Elsevier Inc. All rights reserved.

  10. Regulation network of serum cytokines induced by tuberculosis-specific antigens reveals biomarkers for tuberculosis diagnosis.

    PubMed

    Wei, M; Wu, Z Y; Lin, J H; Li, Y; Qian, Z X; Xie, Y Q; Su, H; Zhou, W

    2015-12-17

    In this study, we identified potential serum biomarkers for the diagnosis of active tuberculosis (TB) and screening for latent TB infections (LTBIs). Peripheral blood samples from 40 healthy individuals, 40 patients with TB, and 40 LTBI individuals were stimulated with the TB-specific antigens ESAT-6 and CFP-10. Human inflammatory cytokine arrays were used to detect the expression of inflammatory cytokines. Cytokines with significant changes were screened to construct a cytokine regulation network. The levels of the cytokines CCL1 (I-309), CXCL9 (MIG), IL-10, IL-6, CSF2, CSF3, IL-8, IL-1α, IL-7, TGF-β1, CCL2, IL-2, IL-13, and TNFα were significantly upregulated in the active TB group. The levels of CCL3, IL-1β, CCL8, IFNγ, and CXCL10 were significantly increased in the TB groups compared to those in the healthy control group. sTNF RII was upregulated in the LTBI group. CCL4 and MIP1d were significantly increased in all groups.The upregulated cytokines were mainly found in the IFNγ and IL-1α regulatory networks. Importantly, we found that CXCL10 (IP-10), CCL3, CCL8, and IL-1β may be more suitable than IFNγ for active or latent TB infection screening. Furthermore, we found that levels of CCL1 (I-309), CXCL9 (MIG), IL-10, IL-6, CSF2, CSF3, IL-8, IL-1α, IL-7, TGF-β1, CCL2, IL-2, and IL-13 after TB antigen stimulation may help distinguish between active and latent TB.

  11. Cytokines and MicroRNAs as Candidate Biomarkers for Systemic Lupus Erythematosus

    PubMed Central

    Stypińska, Barbara; Paradowska-Gorycka, Agnieszka

    2015-01-01

    Systemic lupus erythematosus (SLE) is a systemic autoimmune disease, with varied course and symptoms. Its etiology is very complex and not clearly understood. There is growing evidence of the important role of cytokines in SLE pathogenesis, as well as their utility as biomarkers and targets in new therapies. Other potential new SLE biomarkers are microRNAs. Recently, over one hundred different microRNAs have been demonstrated to have a significant impact on the immune system. Various alterations in these microRNAs, associated with disease pathogenesis, have been described. They influence the signaling pathways and functions of immune response cells. Here, we aim to review the emerging new data on SLE etiology and pathogenesis. PMID:26473848

  12. The role of cytokines in the pathogenesis of rheumatoid arthritis--Practical and potential application of cytokines as biomarkers and targets of personalized therapy.

    PubMed

    Brzustewicz, Edyta; Bryl, Ewa

    2015-12-01

    Rheumatoid arthritis (RA), as a common chronic disease leading to severe disability, requires early diagnosis and introduction of proper treatment. Deregulation in the cytokine network plays an undoubtedly crucial role in the pathogenesis of RA. The understanding of the role of cytokines in RA can be used for patients' benefit. Technological advances had already allowed introduction of the tailor-made cytokine-targeted therapies (so far anti-TNF, anti-IL-1 and anti-IL-6) into clinical practice. This type of treatment is currently developing very fast. Moreover, cytokines are considered to be potential powerful biomarkers of RA with roles predicted to grow in the future. Detailed understanding of the cytokine balance in RA may assist both the diagnostic process and therapy.

  13. Cytokines are early diagnostic biomarkers of graft-versus-host disease in liver recipients.

    PubMed

    Meng, Xue-Qin; Chen, Xin-Hua; Sahebally, Zayd; Xu, Yu-Ning; Yin, Sheng-Yong; Wu, Li-Ming; Zheng, Shu-Sen

    2017-02-01

    Graft-versus-host disease (GVHD) is associated with high mortality. Early diagnosis is essential to start treatment and to improve outcomes. Because of the inflammatory nature, we hypothesis that cytokine profile of patients with GVHD may serve as diagnostic markers. The present study was to evaluate the role of cytokine profile in the diagnosis of GVHD. An immunoassay was used to detect 29 cytokines simultaneously in the serum; the measuring sensitivity of all cytokines was pg/mL. Healthy subjects undergoing annual routine physical examinations served as negative controls; 23 patients with hepatocellular carcinoma (HCC) who had undergone liver transplantation (the LT group) comprised the test subjects. A total of 22 kidney recipients with biopsy-confirmed GVHD (the RT group) were included for comparison. HCC patients with radical surgery (the HCC group, n=22) served as positive control. The liver contents of the three cytokines, IL-2, IL-18, and IFN-gamma, were detected with immunohistochemistry. Serum granzyme B and perforin were measured by flow cytometry. Of the 29 cytokines, the levels of IL-2 and IL-18 were increased significantly in liver recipients with GVHD compared with healthy controls (P<0.05). The serum levels of these three cytokines in the healthy, HCC, LT, and RT groups were IL-2: 0.90+/-0.02, 4.14+/-0.61, 5.10+/-0.89, and 1.48+/-0.09 pg/mL; IL-18: 80.61+/-9.35, 109.51+/-10.93, 230.11+/-12.92, and 61.98+/-7.88 pg/mL; IFN-gamma: 24.06+/-3.88, 24.84+/-3.21, 40.37+/-5.88, and 15.33+/-4.72 pg/mL, respectively. Immunohistochemistry showed that these 3 cytokines expressions in the liver were parallel to the serum cytokine. After standard anti-GVHD treatment, the expressions of IL-2, IL-18, and IFN-gamma were decreased in the liver (P<0.05). Serum granzyme B and perforin were significantly increased in GVHD patients (P<0.05). IL-2, IL-18 and IFN-gamma were from liver and might serve as biomarkers for monitoring GVHD development and the effects of anti

  14. miRNA in multiple sclerosis: search for novel biomarkers.

    PubMed

    Gandhi, Roopali

    2015-08-01

    A major challenge in multiple sclerosis (MS) is to develop biomarkers that could help in understanding individual MS patients, i.e. whether they are a responder or non-responder to therapy, which medicine is more effective, and the degree to which they may be entering the progressive phase of disease. In the last few years, a lot of attention has been drawn toward identification of diagnostic, prognostic, process-specific, and treatment-related biomarkers for MS. In this review, we will focus on the micro RNAs (miRNAs) as potential candidates for MS biomarkers.

  15. Netrin-1 and multiple sclerosis: a new biomarker for neuroinflammation?

    PubMed

    Mulero, P; Córdova, C; Hernández, M; Martín, R; Gutiérrez, B; Muñoz, J C; Redondo, N; Gallardo, I; Téllez, N; Nieto, M L

    2017-09-01

    Netrin-1, an axon guidance protein, reduces serum levels of pro-inflammatory mediators and stabilizes the blood-brain barrier limiting the entrance of immune cells into the central nervous system. The aim was to investigate its presence in the experimental autoimmune encephalomyelitis (EAE) model and in multiple sclerosis (MS) patients with and without clinical activity. Netrin-1 levels were evaluated in EAE mouse tissues. Afterwards, serum netrin-1 was cross-sectionally quantified in 90 patients with different MS phenotypes and 30 control subjects. An additional group of 10 relapsing-remitting MS (RRMS) patients was longitudinally evaluated throughout a relapse (RRMSr) with an interval of 60 days. Tumour necrosis factor α (TNFα), a reference inflammatory cytokine, and netrin-1 were quantified by enzyme-linked immunosorbent assay. Experimental autoimmune encephalomyelitis mice showed significantly lower netrin-1 levels and higher TNFα amounts in sera, spinal cord and cerebella than healthy control mice. MS patients showed significantly lower serum netrin-1 levels than controls (511.62 ± 209.30 and 748.32 ± 103.24 pg/ml, respectively; P ≤ 0.005). The lowest protein levels were found in RRMSr, remaining significantly lower throughout the relapse. TNFα serum concentrations were higher in MS patients compared to controls, and negatively correlated with netrin-1 levels (r = -0.3734, P ≤ 0.0001). Netrin-1 decreased in EAE and in MS patients, mainly during relapse, suggesting an anti-inflammatory role of netrin-1. Further research should be performed in a larger cohort of patients to validate netrin-1 as a biomarker of MS inflammatory activity. © 2017 EAN.

  16. Colostrum proinflammatory cytokines as biomarkers of bovine immune response to bovine tuberculosis (bTB).

    PubMed

    Sánchez-Soto, Eduardo; Ponce-Ramos, Rosa; Hernández-Gutiérrez, Rodolfo; Gutiérrez-Ortega, Abel; Álvarez, Angel H; Martínez-Velázquez, Moisés; Absalón, Angel E; Ortiz-Lazareno, Pablo; Limón-Flores, Alberto; Estrada-Chávez, Ciro; Herrera-Rodríguez, Sara E

    2017-02-01

    Bovine colostrum contains compounds, which provide passive immune protection from mother to newborn calves. Little is known about cytokine levels and their role in bovine colostrum. Moreover, the capacity of bovine colostrum cells to mount specific immune responses after natural exposure to bovine tuberculosis (bTB) antigens in dairy herds has not been studied, thus far. The purpose of this study was to identify biomarkers for bTB infection measurable in bovine colostrum. The present study reveals that isolated-immune colostrum cells can mount a specific immune response against bTB antigens, by measuring the novo IFN-γ release in cell culture. We found that IFN-γ levels in the responders (Bov(+)) to bTB antigen were higher than in non-responders (Bov(-)). On the other hand, proinflammatory cytokines contained in colostrum's whey were tested in Tuberculin Skin Test (TST) reactor (TST(+)) and non-reactor (TST(-)) animals to assess their potential role as biomarker. We observed that IFN-γ levels were lower or undetectable, as opposed to IL4 levels were measurable, the TNF-α level was higher in TST(-) than TST(+), while IL-6 levels showed the opposite reaction and with no statistical significance. Moreover, IL-1α mRNA expression levels were higher in colostrum mononuclear cells (CMC) in Bov(+) cattle. Collectively, these data suggest that the differential expression of pro and anti-inflammatory cytokines could have relevant value to diagnose bTB in cattle. Copyright © 2016 Elsevier Ltd. All rights reserved.

  17. Inflammatory Cytokines: Potential Biomarkers of Immunologic Dysfunction in Autism Spectrum Disorders

    PubMed Central

    Li, Xiaohong; Zhong, Yan

    2015-01-01

    Autism is a disorder of neurobiological origin characterized by problems in communication and social skills and repetitive behavior. After more than six decades of research, the etiology of autism remains unknown, and no biomarkers have been proven to be characteristic of autism. A number of studies have shown that the cytokine levels in the blood, brain, and cerebrospinal fluid (CSF) of autistic subjects differ from that of healthy individuals; for example, a series of studies suggests that interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) are significantly elevated in different tissues in autistic subjects. However, the expression of some cytokines, such as IL-1, IL-2, transforming growth factor-β (TGF-β), and granulocyte-macrophage colony-stimulating factor (GM-CSF), is controversial, and different studies have found various results in different tissues. In this review, we focused on several types of proinflammatory and anti-inflammatory cytokines that might affect different cell signal pathways and play a role in the pathophysiological mechanism of autistic spectrum disorders. PMID:25729218

  18. Fluid biomarkers in multiple system atrophy: A review of the MSA Biomarker Initiative.

    PubMed

    Laurens, Brice; Constantinescu, Radu; Freeman, Roy; Gerhard, Alexander; Jellinger, Kurt; Jeromin, Andreas; Krismer, Florian; Mollenhauer, Brit; Schlossmacher, Michael G; Shaw, Leslie M; Verbeek, Marcel M; Wenning, Gregor K; Winge, Kristian; Zhang, Jing; Meissner, Wassilios G

    2015-08-01

    Despite growing research efforts, no reliable biomarker currently exists for the diagnosis and prognosis of multiple system atrophy (MSA). Such biomarkers are urgently needed to improve diagnostic accuracy, prognostic guidance and also to serve as efficacy measures or surrogates of target engagement for future clinical trials. We here review candidate fluid biomarkers for MSA and provide considerations for further developments and harmonization of standard operating procedures. A PubMed search was performed until April 24, 2015 to review the literature with regard to candidate blood and cerebrospinal fluid (CSF) biomarkers for MSA. Abstracts of 1760 studies were retrieved and screened for eligibility. The final list included 60 studies assessing fluid biomarkers in patients with MSA. Most studies have focused on alpha-synuclein, markers of axonal degeneration or catecholamines. Their results suggest that combining several CSF fluid biomarkers may be more successful than using single markers, at least for the diagnosis. Currently, the clinically most useful markers may comprise a combination of the light chain of neurofilament (which is consistently elevated in MSA compared to controls and Parkinson's disease), metabolites of the catecholamine pathway and proteins such as α-synuclein, DJ-1 and total-tau. Beyond future efforts in biomarker discovery, the harmonization of standard operating procedures will be crucial for future success.

  19. Biomarkers and cytokines of bone turnover: extensive evaluation in a cohort of patients with ankylosing spondylitis

    PubMed Central

    2012-01-01

    Background Ankylosing spondylitis (AS) is a chronic inflammatory disease of spine and sacroiliac joints; it is characterized by new bone formation, and the disease processes can be accompanied by osteoporosis. In the present study, we investigated changes in bone mineral density (BMD) and in the levels of various bone turnover-related biomarkers and cytokines in a cohort of AS patients, with regard to clinical parameters, disease activity, and treatment regimen. Methods 55 AS patients and 33 healthy controls included in the study. Spinal mobility was assessed by the Bath Ankylosing Spondylitis Metrology Index (BASMI), and radiologic changes were scored by the Bath Ankylosing Spondylitis Radiologic Index (BASRI). Patients were also evaluated with the Bath Ankylosing Spondylitis Functional Index (BASFI) and the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). Bone mineral density (BMD) assessed by dual energy X-ray absorptiometry. Various biomarkers and cytokines of bone turnover including osteoprotegerin (OPG), serum band 5 tartrate-resistant acid phosphatase (TRAP-5), soluble receptor activator of nuclear factor kappa-B ligand (sRANKL), secreted frizzled-related protein 1 (sFRP-1), Dickkopf-related protein 1 (DKK-1), and sclerostin were studied. Results The levels of TRAP-5, NTX, sRANKL, sclerostin, sFRP-1, DKK-1, and IFNγ, were similar between the patients and controls (p > 0.05), while BMD of femoral neck, and OPG levels were significantly lower in AS patients (p < 0.05). In a subgroup analysis, patients with active disease had significantly higher concentrations of OPG compared with the inactive group. Rest of the biomarkers and cytokines of bone turnover were similar between the active and inactive disease groups. Subgroup analysis of patients receiving anti-TNFα agents and conventional therapy revealed that OPG concentrations were significantly lower in the patients receiving biological drugs, while BAP and DKK-1 were significantly higher

  20. Rapid simultaneous measurement of multiple cytokines using 100 µl sample volumes – association with neonatal sepsis

    PubMed Central

    Hodge, G; Hodge, S; Haslam, R; McPhee, A; Sepulveda, H; Morgan, E; Nicholson, I; Zola, H

    2004-01-01

    Early diagnosis of neonatal infection has proved problematic due to the inadequacy of currently available laboratory tests. Neonatal sepsis is associated with an increase in plasma-derived cytokine levels, but an increase of a single cytokine cannot identify neonatal sepsis specifically and multiple cytokine levels are required. The time constraints and relatively large volume of plasma required to measure multiple cytokines from newborn infants by conventional enzyme-linked immunosorbent assay (ELISA) techniques is prohibitive. We therefore applied cytometric bead array (CBA) technology for simultaneous measurement of multiple cytokines from a group of 18 term neonates with infection confirmed by culture and a control group. ‘Normal’ ranges were established for each cytokine from 1–7-, 8–14- and 15–21-day-old newborns. There was no significant change in the levels of cytokines from infants in different control age groups, suggesting that basal cytokine levels are unchanged in the first 3 weeks of life. In the patient groups, however, there was a significant difference in several cytokines between the different age groups. Interleukin (IL)-6, IL-10 and IL-12 were increased significantly in the 1–7-day-old patient group compared to either the 8–14 and 15–21 age group, suggesting that infection in utero is associated with increased levels of these cytokines compared to infection acquired following birth. When individual patient cytokine levels were compared to normal control reference ranges, two patients failed to show significant elevation of any cytokine tested. All other patients showed elevated levels of between one and nine cytokines tested (mean of 4·6). There was no correlation between elevated cytokine levels and types of infective organism or patient age. In conclusion, neonatal sepsis is associated with the elevation of multiple plasma cytokines. The use of CBA kits is a rapid, easy, low sample volume and sensitive method to measure

  1. Cytokines and Chemokines as Biomarkers of Community-Acquired Bacterial Infection

    PubMed Central

    Lawrence, David A.; Andersen, Nancy; Beran, Ondřej; Marešová, Vilma

    2013-01-01

    Routinely used biomarkers of bacterial etiology of infection, such as C-reactive protein and procalcitonin, have limited usefulness for evaluation of infections since their expression is enhanced by a number of different conditions. Therefore, several inflammatory cytokines and chemokines were analyzed with sera from patients hospitalized for moderate bacterial and viral infectious diseases. In total, 57 subjects were enrolled: 21 patients with community-acquired bacterial infections, 26 patients with viral infections, and 10 healthy subjects (control cohorts). The laboratory analyses were performed using Luminex technology, and the following molecules were examined: IL-1Ra, IL-2, IL-4, IL-6, IL-8, TNF-α, INF-γ, MIP-1β, and MCP-1. Bacterial etiology of infection was associated with significantly (P < 0.001) elevated serum concentrations of IL-1Ra, IL-2, IL-6, and TNF-α in comparison to levels observed in the sera of patients with viral infections. In the patients with bacterial infections, IL-1Ra and IL-8 demonstrated positive correlation with C-reactive protein, whereas, IL-1Ra, TNF-α, and MCP-1 correlated with procalcitonin. Furthermore, elevated levels of IL-1Ra, IL-6, and TNF-α decreased within 3 days of antibiotic therapy to levels observed in control subjects. The results show IL-1Ra as a potential useful biomarker of community-acquired bacterial infection. PMID:23690657

  2. Cytokines and chemokines as biomarkers of community-acquired bacterial infection.

    PubMed

    Holub, Michal; Lawrence, David A; Andersen, Nancy; Davidová, Alžběta; Beran, Ondřej; Marešová, Vilma; Chalupa, Pavel

    2013-01-01

    Routinely used biomarkers of bacterial etiology of infection, such as C-reactive protein and procalcitonin, have limited usefulness for evaluation of infections since their expression is enhanced by a number of different conditions. Therefore, several inflammatory cytokines and chemokines were analyzed with sera from patients hospitalized for moderate bacterial and viral infectious diseases. In total, 57 subjects were enrolled: 21 patients with community-acquired bacterial infections, 26 patients with viral infections, and 10 healthy subjects (control cohorts). The laboratory analyses were performed using Luminex technology, and the following molecules were examined: IL-1Ra, IL-2, IL-4, IL-6, IL-8, TNF- α , INF- γ , MIP-1 β , and MCP-1. Bacterial etiology of infection was associated with significantly (P < 0.001) elevated serum concentrations of IL-1Ra, IL-2, IL-6, and TNF- α in comparison to levels observed in the sera of patients with viral infections. In the patients with bacterial infections, IL-1Ra and IL-8 demonstrated positive correlation with C-reactive protein, whereas, IL-1Ra, TNF- α , and MCP-1 correlated with procalcitonin. Furthermore, elevated levels of IL-1Ra, IL-6, and TNF- α decreased within 3 days of antibiotic therapy to levels observed in control subjects. The results show IL-1Ra as a potential useful biomarker of community-acquired bacterial infection.

  3. Cytokine levels as biomarkers of radiation fibrosis in patients treated with breast radiotherapy

    PubMed Central

    2014-01-01

    Background Radiation fibrosis is not easily measurable although clinical scores have been developed for this purpose. Biomarkers present an alternative more objective approach to quantification, and estimation in blood provides accessible samples. We investigated if blood cytokines could be used to measure established fibrosis in patients who have undergone radiotherapy for breast cancer. Methods We studied two cohorts treated by breast-conserving surgery and radiotherapy in the UK START Trial A, one with breast fibrosis (cases) and one with no or minimal fibrosis (controls). Two candidate cytokines, plasma connective tissue growth factor (CTGF) and serum interleukin-6 (IL6) were estimated by ELISA. Comparisons between cases and controls used the t-test or Mann–Whitney test and associations between blood concentration and clinical factors were assessed using the Spearman rank correlation coefficient. Results Seventy patients were included (26 cases, 44 controls). Mean time since radiotherapy was 9.9 years (range 8.3-12.0). No statistically significant differences between cases and controls in serum IL6 (median (IQR) 0.84 pg/ml (0.57-1.14), 0.75 pg/ml (0.41-1.43) respectively) or plasma CTGF (331.4 pg/ml (234.8-602.9), 334.5 pg/ml (270.0-452.8) were identified. There were no significant associations between blood cytokine concentration and age, fibrosis severity, breast size or time since radiotherapy. Conclusions No significant difference in IL6 or CTGF concentrations was detected between patients with breast fibrosis and controls with minimal or no fibrosis. PMID:24885397

  4. COPD Exacerbation Biomarkers Validated Using Multiple Reaction Monitoring Mass Spectrometry

    PubMed Central

    Leung, Janice M.; Chen, Virginia; Hollander, Zsuzsanna; Dai, Darlene; Tebbutt, Scott J.; Aaron, Shawn D.; Vandemheen, Kathy L.; Rennard, Stephen I.; FitzGerald, J. Mark; Woodruff, Prescott G.; Lazarus, Stephen C.; Connett, John E.; Coxson, Harvey O.; Miller, Bruce; Borchers, Christoph; McManus, Bruce M.; Ng, Raymond T.; Sin, Don D.

    2016-01-01

    Background Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) result in considerable morbidity and mortality. However, there are no objective biomarkers to diagnose AECOPD. Methods We used multiple reaction monitoring mass spectrometry to quantify 129 distinct proteins in plasma samples from patients with COPD. This analytical approach was first performed in a biomarker cohort of patients hospitalized with AECOPD (Cohort A, n = 72). Proteins differentially expressed between AECOPD and convalescent states were chosen using a false discovery rate <0.01 and fold change >1.2. Protein selection and classifier building were performed using an elastic net logistic regression model. The performance of the biomarker panel was then tested in two independent AECOPD cohorts (Cohort B, n = 37, and Cohort C, n = 109) using leave-pair-out cross-validation methods. Results Five proteins were identified distinguishing AECOPD and convalescent states in Cohort A. Biomarker scores derived from this model were significantly higher during AECOPD than in the convalescent state in the discovery cohort (p<0.001). The receiver operating characteristic cross-validation area under the curve (CV-AUC) statistic was 0.73 in Cohort A, while in the replication cohorts the CV-AUC was 0.77 for Cohort B and 0.79 for Cohort C. Conclusions A panel of five biomarkers shows promise in distinguishing AECOPD from convalescence and may provide the basis for a clinical blood test to diagnose AECOPD. Further validation in larger cohorts is necessary for future clinical translation. PMID:27525416

  5. Biomarkers in Multiple Sclerosis: An Up-to-Date Overview

    PubMed Central

    Katsavos, Serafeim; Anagnostouli, Maria

    2013-01-01

    During the last decades, the effort of establishing satisfactory biomarkers for multiple sclerosis has been proven to be very difficult, due to the clinical and pathophysiological complexities of the disease. Recent knowledge acquired in the domains of genomics-immunogenetics and neuroimmunology, as well as the evolution in neuroimaging, has provided a whole new list of biomarkers. This variety, though, leads inevitably to confusion in the effort of decision making concerning strategic and individualized therapeutics. In this paper, our primary goal is to provide the reader with a list of the most important characteristics that a biomarker must possess in order to be considered as reliable. Additionally, up-to-date biomarkers are further divided into three subgroups, genetic-immunogenetic, laboratorial, and imaging. The most important representatives of each category are presented in the text and for the first time in a summarizing workable table, in a critical way, estimating their diagnostic potential and their efficacy to correlate with phenotypical expression, neuroinflammation, neurodegeneration, disability, and therapeutical response. Special attention is given to the “gold standards” of each category, like HLA-DRB1∗ polymorphisms, oligoclonal bands, vitamin D, and conventional and nonconventional imaging techniques. Moreover, not adequately established but quite promising, recently characterized biomarkers, like TOB-1 polymorphisms, are further discussed. PMID:23401777

  6. Enhancing cytokine-induced killer cell therapy of multiple myeloma.

    PubMed

    Liu, Chunsheng; Suksanpaisan, Lukkana; Chen, Yun-Wen; Russell, Stephen J; Peng, Kah-Whye

    2013-06-01

    Cytokine-induced killer (CIK) cells are in clinical testing against various tumor types, including multiple myeloma. In this study, we show that CIK cells have activity against subcutaneous and disseminated models of human myeloma (KAS-6/1), which can be enhanced by infecting the CIK cells with an oncolytic measles virus (MV) or by pretreating the myeloma cells with ionizing radiation (XRT). KAS-6/1 cells were killed by coculture with CIK or MV-infected CIK (CIK/MV) cells, and the addition of an anti-NKG2D antibody inhibited cytolysis by 50%. However, human bone marrow stromal cells can reduce CIK and CIK/MV mediated killing of myeloma cells (RPMI 8226, JJN-3 and MM1). In vivo, CIK and CIK/MV prolonged the survival of mice with systemic myeloma, although CIK/MV showed enhanced antitumor activity compared with CIK. Irradiation of the KAS-6/1 cells induced mRNA and protein expression of NKG2D ligands, MICA, and MICB in a dose-dependent manner and enhanced delivery of CIK/MV to the irradiated tumors. In both subcutaneous and disseminated myeloma models, XRT at 2 Gy resulted in superior prolongation of the survival of mice given CIK/MV therapy compared with CIK/MV with no XRT. This study demonstrates the potential of CIK against myeloma and that the combination of virotherapy with radiation could be used to further enhance therapeutic outcome using CIK cells.

  7. Effect of catechin/epicatechin dietary intake on endothelial dysfunction biomarkers and proinflammatory cytokines in aorta of hyperhomocysteinemic mice.

    PubMed

    Noll, Christophe; Lameth, Julie; Paul, Jean-Louis; Janel, Nathalie

    2013-04-01

    Hyperhomocysteinemia is well recognized as an independent risk factor for the development of premature atherosclerosis. Atherosclerosis, however, may be prevented by polyphenols, potent antioxidant compounds with anti-atherogenic properties. Previously, we used cystathionine beta synthase-deficient mice [Cbs (±)] fed a high-methionine diet-a murine model of hyperhomocysteinemia-to show that daily intake of a red wine polyphenolic extract, mainly comprised of catechin and epicatechin, has a beneficial effect on aortic expression of endothelial dysfunction biomarkers and pro-inflammatory cytokines. The aim of the present study was to understand whether catechin and epicatechin, in purified forms, have anti-atherogenic effects in hyperhomocysteinemia. Cbs (±) mice received 50 μg of catechin and/or epicatechin daily in drinking water for 1 month. Plasma homocysteine (Hcy) level and aortic expression of several endothelial dysfunction biomarkers (Vcam-1, Icam-1, E-selectin, and Lox-1) and pro-inflammatory cytokines (Tnf-α, Il-6) were assessed. We found that both catechin and epicatechin had a beneficial effect on plasma homocysteine levels and endothelial dysfunction biomarker expression; however, only catechin had a beneficial effect on pro-inflammatory cytokine expression. Further, when both polyphenols were given, a beneficial effect was observed only on pro-inflammatory cytokine expression. Catechin seems to be a more potent anti-atherogenic compound than epicatechin in hyperhomocysteinemia and should be considered as a novel therapeutic approach against endothelial dysfunction induced by this condition.

  8. Suppressor of cytokine signaling 1 gene mutation status as a prognostic biomarker in classical Hodgkin lymphoma.

    PubMed

    Lennerz, Jochen K; Hoffmann, Karl; Bubolz, Anna-Maria; Lessel, Davor; Welke, Claudia; Rüther, Nele; Viardot, Andreas; Möller, Peter

    2015-10-06

    Suppressor of cytokine signaling 1 (SOCS1) mutations are among the most frequent somatic mutations in classical Hodgkin lymphoma (cHL), yet their prognostic relevance in cHL is unexplored. Here, we performed laser-capture microdissection of Hodgkin/Reed-Sternberg (HRS) cells from tumor samples in a cohort of 105 cHL patients. Full-length SOCS1 gene sequencing showed mutations in 61% of all cases (n = 64/105). Affected DNA-motifs and mutation pattern suggest that many of these SOCS1 mutations are the result of aberrant somatic hypermutation and we confirmed expression of mutant alleles at the RNA level. Contingency analysis showed no significant differences of patient-characteristics with HRS-cells containing mutant vs. wild-type SOCS1. By predicted mutational consequence, mutations can be separated into those with non-truncating point mutations ('minor' n = 49/64 = 77%) and those with length alteration ('major'; n = 15/64 = 23%). Subgroups did not differ in clinicopathological characteristics; however, patients with HRS-cells that contained SOCS1 major mutations suffered from early relapse and significantly shorter overall survival (P = 0.03). The SOCS1 major status retained prognostic significance in uni-(P = 0.016) and multivariate analyses (P = 0.005). Together, our data indicate that the SOCS1 mutation type qualifies as a single-gene prognostic biomarker in cHL.

  9. Serum levels of oncostatin M (a gp 130 cytokine): an inflammatory biomarker in periodontal disease.

    PubMed

    Pradeep, A R; S, Thorat Manojkumar; Garima, Garg; Raju, Arjun

    2010-05-01

    Periodontitis is considered to be a risk factor for systemic diseases such as atherosclerosis, diabetes, etc., and cytokines play a key role. The present study was carried out to measure the level of serum oncostatin M (OSM) in patients with chronic periodontitis, and to evaluate the effect of non-surgical periodontal therapy on the serum OSM concentration. Sixty subjects were divided into three groups (each group n = 20) based on the gingival index (GI), probing pocket depth (PPD) and clinical attachment level (CAL): group I healthy; group II gingivitis; and group III chronic periodontitis. Group III patients were followed for 8 weeks after non-surgical periodontal therapy as the after-treatment group (group IV). Estimation of serum OSM was done using an enzyme-linked immunosorbent assay. The mean OSM concentrations in serum were highest in the chronic periodontitis group (mean 68.05 pg ml(-1)) and decreased following treatment (39.65 pg ml(-1)) while OSM was undetectable in healthy subjects or in patients with gingivitis. Increased serum OSM concentration in patients with chronic periodontitis and its positive correlation with PPD and CAL, suggest its role as an inflammatory biomarker in periodontal disease and it may exaggerate other systemic conditions such as atherosclerosis and rheumatoid arthritis.

  10. Impact of child obesity on adipose tissue physiology: assessment of adipocytokines and inflammatory cytokines as biomarkers of obesity

    PubMed Central

    Leoni, Maria Chiara; Valsecchi, Chiara; Mantelli, Melissa; Marastoni, Laura; Tinelli, Carmine; Marchi, Antonietta; Castellazzi, Annamaria

    2010-01-01

    Obesity could be interpreted as a low grade inflammatory state. The role of cytokines for innate and acquired immune response and adipocytokines in pathogenesis of obesity is not completely understood. The aim of the study was to evaluate anthropometric parameters, adipocytokines and inflammatory cytokine levels as biomarkers of childhood obesity. This investigation was designed as a longitudinal observational study. Forty-seven obese children (19 males and 28 females) were enrolled by Pediatric Clinic of the Foundation IRCCS Policlinico San Matteo, Pavia, Italy. For each patients a blood sample, used for other biochemical evaluations, was collected. Cytokines and adipocytokines plasmatic levels were determined using an ELISA method. Plasma leptin levels are in correlation with age (r=0.5; P<0.001) and BMI-z score (r=0.36; P<0.001), particularly in girls; plasma resistin levels are in inverse correlation with age, particularly in boys (r=-0.67; P<0.001) and in correlation with BMI-z score (r=0.52; P=0.002). Plasma leptin and resistin levels show a good correlation with antrophometric parameters of child obesity (sex and BMI z score). This study suggests that leptin and resistin can be considered as biomarker of childhood obesity and its comorbility. We observed a statistically significant correlation between plasma leptin and resistin levels and antrophometric parameters of child obesity (sex and BMI z score). This study suggests that adipocytokines, such as leptin and resistin, can be considered as biomarkers of childhood obesity. PMID:21589832

  11. Addressing small sample size bias in multiple-biomarker trials: Inclusion of biomarker-negative patients and Firth correction.

    PubMed

    Habermehl, Christina; Benner, Axel; Kopp-Schneider, Annette

    2017-08-01

    In recent years, numerous approaches for biomarker-based clinical trials have been developed. One of these developments are multiple-biomarker trials, which aim to investigate multiple biomarkers simultaneously in independent subtrials. For low-prevalence biomarkers, small sample sizes within the subtrials have to be expected, as well as many biomarker-negative patients at the screening stage. The small sample sizes may make it unfeasible to analyze the subtrials individually. This imposes the need to develop new approaches for the analysis of such trials. With an expected large group of biomarker-negative patients, it seems reasonable to explore options to benefit from including them in such trials. We consider advantages and disadvantages of the inclusion of biomarker-negative patients in a multiple-biomarker trial with a survival endpoint. We discuss design options that include biomarker-negative patients in the study and address the issue of small sample size bias in such trials. We carry out a simulation study for a design where biomarker-negative patients are kept in the study and are treated with standard of care. We compare three different analysis approaches based on the Cox model to examine if the inclusion of biomarker-negative patients can provide a benefit with respect to bias and variance of the treatment effect estimates. We apply the Firth correction to reduce the small sample size bias. The results of the simulation study suggest that for small sample situations, the Firth correction should be applied to adjust for the small sample size bias. Additional to the Firth penalty, the inclusion of biomarker-negative patients in the analysis can lead to further but small improvements in bias and standard deviation of the estimates. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  12. Biomarkers in Ocular Chronic Graft Versus Host Disease: Tear Cytokine- and Chemokine-Based Predictive Model.

    PubMed

    Cocho, Lidia; Fernández, Itziar; Calonge, Margarita; Martínez, Verónica; González-García, María J; Caballero, Dolores; López-Corral, Lucía; García-Vázquez, Carmen; Vázquez, Lourdes; Stern, Michael E; Enríquez-de-Salamanca, Amalia

    2016-02-01

    To develop a tear molecule level-based predictive model based on a panel of tear cytokines and their correlation with clinical features in ocular chronic graft versus host disease (cGVHD). Twenty-two ocular cGVHD patients and 21 healthy subjects were evaluated in a controlled environmental research laboratory (CERLab). Clinical parameters were recorded, and tears were collected. Levels of 15 molecules (epidermal growth factor [EGF], IL receptor antagonist [IL-1Ra], IL-1β, IL-2, IL-6, IL-8/CXCL8, IL-10, IL-12p70, IL-17A, interferon inducible protein [IP]-10/CXCL10, IFN-γ, VEGF, TNF-α, eotaxin 1, and regulated on activation normal T cell expressed and secreted [RANTES]) were measured by multiplex-bead assay and correlated with clinical parameters. Logistic regression was used to develop a predictive model. Leave-one-out cross-validation was applied. Classification capacity was evaluated in a cohort of individuals with dry eye (DE) of other etiologies different from GVHD. Epidermal growth factor and IP-10/CXCL10 levels were significantly decreased in ocular cGVHD, positively correlating with tear production and stability and negatively correlating with symptoms, hyperemia, and vital staining. Interleukin-1Ra, IL-8/CXCL8, and IL-10 were significantly increased in ocular cGVHD, and the first two correlated positively with symptoms, hyperemia, and ocular surface integrity while negatively correlating with tear production and stability. Predictive models were generated, and the best panel was based on IL-8/CXCL8 and IP-10/CXCL10 tear levels along with age and sex, with an area under the receiving operating curve of 0.9004, sensitivity of 86.36%, and specificity of 95.24%. A predictive model based on tear levels of IL-8/CXCL8 and IP-10/CXCL10 resulted in optimal sensitivity and specificity. These results add further knowledge to the search for potential biomarkers in this devastating ocular inflammatory disease.

  13. MAG-DPA curbs inflammatory biomarkers and pharmacological reactivity in cytokine-triggered hyperresponsive airway models.

    PubMed

    Khaddaj-Mallat, Rayan; Hiram, Roddy; Sirois, Chantal; Sirois, Marco; Rizcallah, Edmond; Marouan, Sofia; Morin, Caroline; Rousseau, Éric

    2016-12-01

    Bronchial inflammation contributes to a sustained elevation of airway hyperresponsiveness (AHR) in asthma. Conversely, omega-3 fatty acid derivatives have been shown to resolve inflammation in various tissues. Thus, the effects of docosapentaenoic acid monoacylglyceride (MAG-DPA) were assessed on inflammatory markers and reactivity of human distal bronchi as well as in a cultured model of guinea pig tracheal rings. Human bronchi were dissected and cultured for 48 h with 10 ng/mL TNF-α or IL-13. Guinea pig tracheas were maintained in organ culture for 72 h which was previously shown to trigger spontaneous AHR. All tissues were treated with increasing concentrations of MAG-DPA (0.1, 0.3, and 1 μmol/L). Pharmacomechanical reactivity, Ca(2+) sensitivity, and western blot analysis for specific phosphoproteins and transcription factors were performed to assess the effects of both cytokines, alone or in combination with MAG-DPA, on human and guinea pig airway preparations. Although 0.1 μmol/L MAG-DPA did not significantly reduce inflammatory biomarkers, the higher concentrations of MAG-DPA (0.3 and 1 μmol/L) blunted the activation of the TNF-α/NF κB pathway and abolished COX-2 expression in human and guinea pig tissues. Moreover, 0.3 and 1 μmol/L MAG-DPA consistently decreased the Ca(2+) sensitivity and pharmacological reactivity of cultured bronchial explants. Furthermore, in human bronchi, IL-13-stimulated phosphorylation of CPI-17 was reversed by 1 μmol/L MAG-DPA. This effect was further amplified in the presence of 100 μmol/L aspirin. MAG-DPA mediates antiphlogistic effects by increasing the resolution of inflammation, while resetting Ca(2+) sensitivity and contractile reactivity.

  14. Biomarkers in multiple sclerosis: an update for 2014.

    PubMed

    Fernandez, Oscar; Martin, Roland; Rovira, Alex; Llufriu, Sara; Vidal-Jordana, Angela; Fernandez-Sanchez, Victoria E; Alvarez-Cermeno, José C; Izquierdo, Guillermo; Arroyo-Gonzalez, Rafael; Rodriguez-Antiguedad, Alfredo; Casanova-Estruch, Bonaventura; Montalban, Xavier

    2014-06-16

    Multiple sclerosis is a chronic, demyelinating and inflammatory disease of the central nervous system that mainly affects young adults. It is characterised by processes involving inflammation, demyelination and axonal destruction, and as a result the pathogenic aspects and response to treatment of the disease vary widely. It is therefore difficult to establish a prognosis for these patients or to determine the effectiveness of the different drugs that are employed. Current clinical research into the development of new biomarkers has advanced a great deal in recent years, especially in the early stages of the disease. Yet, it is essential to further our knowledge about novel markers of the disease, and not only in the more advanced stages, so as to be able to stop disability from progressing and to establish new therapy regimens in these patients. This review presents an update on the information available about the biomarkers that are currently validated and used in multiple sclerosis, together with the possible candidates for utilisation in routine clinical practice.

  15. Oxidative stress biomarkers and their relationship with cytokine concentrations in overweight/obese pregnant women and their neonates.

    PubMed

    Hernández-Trejo, María; Montoya-Estrada, Araceli; Torres-Ramos, Yessica; Espejel-Núñez, Aurora; Guzmán-Grenfell, Alberto; Morales-Hernández, Rosa; Tolentino-Dolores, Maricruz; Laresgoiti-Servitje, Estibalitz

    2017-01-07

    Oxidative damage present in obese/overweight mothers may lead to further oxidative stress conditions or inflammation in maternal and cord blood samples. Thirty-four pregnant women/newborn pairs were included in this study to assess the presence of oxidative stress biomarkers and their relationship with serum cytokine concentrations. Oxidative stress biomarkers and antioxidant enzymes were compared between the mother/offspring pairs. The presence of 27 cytokines was measured in maternal and cord blood samples. Analyses were initially performed between all mothers and newborns and later between normal weight and mothers with overweight and obesity, and diabetic/non-diabetic women. Significant differences were found in biomarker concentrations between mothers and newborns. Additionally, superoxide-dismutase activity was higher in pre-pregnancy overweight mothers compared to those with normal weight. Activity for this enzyme was higher in neonates born from mothers with normal pregestational weight compared with their mothers. Nitrites in overweight/obese mothers were statistically lower than in their offspring. Maternal free fatty acids, nitrites, carbonylated proteins, malondialdehyde and superoxide dismutase predicted maternal serum concentrations of IL-4, IL-13, IP-10 and MIP-1β. Arginase activity in maternal plasma was related to decreased concentrations of IL-4 and IL-1β in cord arterial blood. Increased maternal malondialdehyde plasma was associated with higher levels of IL-6 and IL-7 in the offspring. Oxidative stress biomarkers differ between mothers and offspring and can predict maternal and newborn cytokine concentrations, indicating a potential role for oxidative stress in foetal metabolic and immunologic programming. Moreover, maternal obesity and diabetes may affect maternal microenvironments, and oxidative stress related to these can have an impact on the placenta and foetal growth.

  16. Sublineage structure analysis of Mycobacterium tuberculosis complex strains using multiple-biomarker tensors

    PubMed Central

    2011-01-01

    Background Strains of Mycobacterium tuberculosis complex (MTBC) can be classified into major lineages based on their genotype. Further subdivision of major lineages into sublineages requires multiple biomarkers along with methods to combine and analyze multiple sources of information in one unsupervised learning model. Typically, spacer oligonucleotide type (spoligotype) and mycobacterial interspersed repetitive units (MIRU) are used for TB genotyping and surveillance. Here, we examine the sublineage structure of MTBC strains with multiple biomarkers simultaneously, by employing a tensor clustering framework (TCF) on multiple-biomarker tensors. Results Simultaneous analysis of the spoligotype and MIRU type of strains using TCF on multiple-biomarker tensors leads to coherent sublineages of major lineages with clear and distinctive spoligotype and MIRU signatures. Comparison of tensor sublineages with SpolDB4 families either supports tensor sublineages, or suggests subdivision or merging of SpolDB4 families. High prediction accuracy of major lineage classification with supervised tensor learning on multiple-biomarker tensors validates our unsupervised analysis of sublineages on multiple-biomarker tensors. Conclusions TCF on multiple-biomarker tensors achieves simultaneous analysis of multiple biomarkers and suggest a new putative sublineage structure for each major lineage. Analysis of multiple-biomarker tensors gives insight into the sublineage structure of MTBC at the genomic level. PMID:21988942

  17. Looking for new biomarkers of skin wound vitality with a cytokine-based multiplex assay: preliminary study.

    PubMed

    Peyron, Pierre-Antoine; Baccino, Éric; Nagot, Nicolas; Lehmann, Sylvain; Delaby, Constance

    2017-02-01

    Determination of skin wound vitality is an important issue in forensic practice. No reliable biomarker currently exists. Quantification of inflammatory cytokines in injured skin with MSD(®) technology is an innovative and promising approach. This preliminary study aims to develop a protocol for the preparation and the analysis of skin samples. Samples from ante mortem wounds, post mortem wounds, and intact skin ("control samples") were taken from corpses at the autopsy. After an optimization of the pre-analytical protocol had been performed in terms of skin homogeneisation and proteic extraction, the concentration of TNF-α was measured in each sample with the MSD(®) approach. Then five other cytokines of interest (IL-1β, IL-6, IL-10, IL-12p70 and IFN-γ) were simultaneously quantified with a MSD(®) multiplex assay. The optimal pre-analytical conditions consist in a proteic extraction from a 6 mm diameter skin sample, in a PBS buffer with triton 0,05%. Our results show the linearity and the reproductibility of the TNF-α quantification with MSD(®), and an inter- and intra-individual variability of the concentrations of proteins. The MSD(®) multiplex assay is likely to detect differential skin concentrations for each cytokine of interest. This preliminary study was used to develop and optimize the pre-analytical and analytical conditions of the MSD(®) method using injured and healthy skin samples, for the purpose of looking for and identifying the cytokine, or the set of cytokines, that may be biomarkers of skin wound vitality.

  18. Investigation of cytokines, oxidative stress, metabolic, and inflammatory biomarkers after orange juice consumption by normal and overweight subjects

    PubMed Central

    Dourado, Grace K. Z. S.; Cesar, Thais B.

    2015-01-01

    Background Abdominal adiposity has been linked to metabolic abnormalities, including dyslipidemia, oxidative stress, and low-grade inflammation. Objective To test the hypothesis that consumption of 100% orange juice (OJ) would improve metabolic, oxidative, and inflammatory biomarkers and cytokine levels in normal and overweight subjects with increased waist circumference. Design Subjects were divided into two groups in accordance with their body mass index: normal and overweight. Both groups of individuals consumed 750 mL of OJ daily for 8 weeks. Body composition (weight, height, percentage of fat mass, and waist circumference); metabolic biomarkers (total cholesterol, low-density lipoprotein-cholesterol [LDL-C], high-density lipoprotein-cholesterol [HDL-C], triglycerides, glucose, insulin, HOMA-IR, and glycated hemoglobin); oxidative biomarkers (malondialdehyde and DPPH•); inflammatory biomarkers (high-sensitivity C-reactive protein [hsCRP]); cytokines (IL-4, IL-10, IL-12, TNF-α, and IFN-γ); and diet were evaluated before and after consumption of OJ for 8 weeks. Results The major findings of this study were: 1) no alteration in body composition in either group; 2) improvement of the lipid profile, evidenced by a reduction in total cholesterol and LDL-C; 3) a potential stimulation of the immune response due to increase in IL-12; 4) anti-inflammatory effect as a result of a marked reduction in hsCRP; and 5) antioxidant action by the enhancement of total antioxidant capacity and the reduction of lipid peroxidation, in both normal and overweight subjects. Conclusions OJ consumption has a positive effect on important biomarkers of health status in normal and overweight subjects, thereby supporting evidence that OJ acts as functional food and could be consumed as part of a healthy diet to prevent metabolic and chronic diseases. PMID:26490535

  19. Molecular biomarkers in cerebrospinal fluid of multiple sclerosis patients.

    PubMed

    Fitzner, Brit; Hecker, Michael; Zettl, Uwe Klaus

    2015-10-01

    Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system, usually occurring in young adults and leading to disability. Despite the progress in technology and intensive research work of the last years, diagnosing MS can still be challenging. A heterogenic and complex pathophysiology with various types of disease courses makes MS unique for each patient. There is an urgent need to identify markers facilitating rapid and accurate diagnosis and prognostic assessments with regard to optimal therapy for each MS patient. Cerebrospinal fluid (CSF) is an outstanding source of specific markers related to MS pathology. Molecules reflecting specific pathological processes, such as inflammation, cellular damage, and loss of blood-brain-barrier integrity, are detectable in CSF. Clinically used biomarkers of CSF are oligoclonal bands, IgG-index, measles-rubella-zoster-reaction, anti-aquaporin 4 antibodies, and antibodies against John Cunningham virus. Many other potential biomarkers have been proposed in recent years. In this review we examine the current scientific knowledge on CSF molecular markers that could guide diagnosis and discrimination of different MS forms, support treatment decisions, or be helpful in monitoring and predicting disease progression, therapy response, and complications such as opportunistic infections. Copyright © 2015 Elsevier B.V. All rights reserved.

  20. Acute-phase proteins, oxidative stress biomarkers, proinflammatory cytokines, and cardiac troponin in Arabian mares affected with pyometra.

    PubMed

    El-Bahr, S M; El-Deeb, W M

    2016-09-01

    New biomarkers are essential for diagnosis of pyometra in mares. In this context, 12 subfertile Arabian mares suffered from pyometra were admitted to the Veterinary Teaching Hospital. The basis for diagnosis of pyometra was positive findings of clinical examination and rectal palpation. Blood samples were collected from diseased animals and from five Arabian healthy mares, which were considered as control group. Acute-phase proteins (APP), oxidative stress biomarkers, proinflammatory cytokines, and cardiac troponin I were estimated in the harvested sera of both groups. Clinical examination revealed purulent yellowish fluid discharged from vagina of affected animals and rectal palpation of the reproductive tract revealed uterine distention. The biochemical analysis of the serum revealed significant increase in cardiac troponin I, creatin kinase, alkaline phosphatase, malondialdehyde, tumor necrosis factor α, interleukins 6, prostaglandin F2α, haptoglobin, and serum amyloid A and significant decrease in reduced glutathione, superoxide dismutase (SOD), total antioxidant capacity, and nitric oxide (NO) of mares affected with pyometra compare to control. Cardiac troponin I was positively correlated with aspartate aminotransferase, creatin kinase, malondialdehyde, alkaline phosphatase, tumor necrosis factor α, interleukins 6, prostaglandin F2α, haptoglobin and serum amyloid A and negatively correlated with glutathione, superoxide dismutase, total antioxidant capacity and nitric oxide in serum of mares affected with pyometra. Moreover, there was high positive correlation between proinflammatory cytokines and APP in serum of mares affected with pyometra. The present study suggests cardiac troponin I together with APP, proinflammatory cytokines, and oxidative stress parameters as biomarkers for pyometra in Arabian mares. Copyright © 2016 Elsevier Inc. All rights reserved.

  1. Fatigue in patients with multiple sclerosis: is it related to pro- and anti-inflammatory cytokines?

    PubMed

    Malekzadeh, Arjan; Van de Geer-Peeters, Wietske; De Groot, Vincent; Teunissen, Charlotte Elisabeth; Beckerman, Heleen

    2015-01-01

    To investigate the pathophysiological role of pro- and anti-inflammatory cytokines in primary multiple sclerosis-related fatigue. Fatigued and non-fatigued patients with multiple sclerosis (MS) were recruited and their cytokine profiles compared. Patients with secondary fatigue were excluded. Fatigue was assessed with the self-reported Checklist Individual Strength (CIS20r), subscale fatigue. A CIS20r fatigue cut-off score of 35 was applied to differentiate between non-fatigued (CIS20r fatigue ≤34) and fatigued (CIS20r fatigue ≥35) patients with MS. Blood was collected to determine the serum concentrations of pro-inflammatory cytokines (IL-1β, IL-2, IL-6, IL-8, IL-12p70, IL-17, TNFα, and IFN-γ) and anti-inflammatory cytokines (IL-4, IL-5, IL-10, and IL-13). We controlled for the confounding effect of age, gender, duration of MS, disease severity, type of MS, and use of immunomodulatory drugs. Similar cytokine levels were observed between MS patients with (n = 21) and without fatigue (n = 14). Adjusted multiple regression analyses showed a single significant positive relationship, that of IL-6 with CIS20r fatigue score. The explained variance of the IL-6 model was 21.1%, once adjusted for the confounding effect of age. The pro-inflammatory cytokine interleukin-6 (IL-6) may play a role in the pathophysiology of primary fatigue in patients with MS. ISRCTN69520623, ISRCTN58583714, and ISRCTN82353628.

  2. Analysis of complex biomarkers for human immune-mediated disorders based on cytokine responsiveness of peripheral blood cells123

    PubMed Central

    Davis, John M.; Knutson, Keith L.; Strausbauch, Michael A.; Crowson, Cynthia S.; Therneau, Terry M.; Wettstein, Peter J.; Matteson, Eric L.; Gabriel, Sherine E.

    2010-01-01

    The advent of improved biomarkers promises to enhance the clinical care for patients with rheumatoid arthritis (RA) and other immune-mediated disorders. We have developed an innovative approach to broadly assess the cytokine responsiveness of human PBMC using a multi-stimulant panel and multiplexed immunoassays. The objective of this study was to demonstrate this concept by determining whether cytokine profiles could discriminate RA patients according to disease stage (early vs. late) or severity. A 10-cytokine profile, consisting of IL-12, CCL4, TNFα, IL-4, and IL-10 release in response to stimulation with anti-CD3/anti-CD28, CXCL8 and IL-6 in response to CMV/EBV lysate, and IL-17A, GM-CSF, and CCL2 in response to HSP60, easily discriminated the early RA group from controls. These data were used to create an immune response score, which performed well in distinguishing the early RA patients from controls and also correlated with several markers of disease severity among the patients with late RA. In contrast, the same 10-cytokine profile assessed in serum was far less effective in discriminating the groups. Thus, our approach lays the foundation for the development of immunologic ‘signatures’ that could be useful in predicting disease course and monitoring the outcomes of therapy among patients with immune-mediated diseases. PMID:20495063

  3. Identification of Predictive Biomarkers for Cytokine Release Syndrome after Chimeric Antigen Receptor T cell Therapy for Acute Lymphoblastic Leukemia

    PubMed Central

    Teachey, David T.; Lacey, Simon F.; Shaw, Pamela A.; Melenhorst, J. Joseph; Maude, Shannon L.; Frey, Noelle; Pequignot, Edward; Gonzalez, Vanessa E.; Chen, Fang; Finklestein, Jeffrey; Barrett, David M.; Weiss, Scott L.; Fitzgerald, Julie C.; Berg, Robert A.; Aplenc, Richard; Callahan, Colleen; Rheingold, Susan R.; Zheng, Zhaohui; Rose-John, Stefan; White, Jason C.; Nazimuddin, Farzana; Wertheim, Gerald; Levine, Bruce L.; June, Carl H.; Porter, David L.; Grupp, Stephan A.

    2017-01-01

    Chimeric antigen receptor (CAR)-modified T cells with anti-CD19 specificity are a highly effective novel immune therapy for relapsed/refractory acute lymphoblastic leukemia (ALL). Cytokine release syndrome (CRS) is the most significant and life-threatening toxicity. To improve understanding of CRS, we measured cytokines and clinical biomarkers in 51 CTL019-treated patients. Peak levels of 24 cytokines, including IFNγ, IL6, sgp130, and sIL6R in the first month after infusion were highly associated with severe CRS. Using regression modeling, we could accurately predict which patients would develop severe CRS with a signature composed of three cytokines. Results validated in an independent cohort. Changes in serum biochemical markers, including C-reactive protein and ferritin, were associated with CRS but failed to predict development of severe CRS. These comprehensive profiling data provide novel insights into CRS biology, and importantly represent the first data that can accurately predict which patients have a high probability of becoming critically ill. PMID:27076371

  4. Putative transcriptomic biomarkers in the inflammatory cytokine pathway differentiate major depressive disorder patients from control subjects and bipolar disorder patients.

    PubMed

    Powell, Timothy R; McGuffin, Peter; D'Souza, Ursula M; Cohen-Woods, Sarah; Hosang, Georgina M; Martin, Charlotte; Matthews, Keith; Day, Richard K; Farmer, Anne E; Tansey, Katherine E; Schalkwyk, Leonard C

    2014-01-01

    Mood disorders consist of two etiologically related, but distinctly treated illnesses, major depressive disorder (MDD) and bipolar disorder (BPD). These disorders share similarities in their clinical presentation, and thus show high rates of misdiagnosis. Recent research has revealed significant transcriptional differences within the inflammatory cytokine pathway between MDD patients and controls, and between BPD patients and controls, suggesting this pathway may possess important biomarker properties. This exploratory study attempts to identify disorder-specific transcriptional biomarkers within the inflammatory cytokine pathway, which can distinguish between control subjects, MDD patients and BPD patients. This is achieved using RNA extracted from subject blood and applying synthesized complementary DNA to quantitative PCR arrays containing primers for 87 inflammation-related genes. Initially, we use ANOVA to test for transcriptional differences in a 'discovery cohort' (total n = 90) and then we use t-tests to assess the reliability of any identified transcriptional differences in a 'validation cohort' (total n = 35). The two most robust and reliable biomarkers identified across both the discovery and validation cohort were Chemokine (C-C motif) ligand 24 (CCL24) which was consistently transcribed higher amongst MDD patients relative to controls and BPD patients, and C-C chemokine receptor type 6 (CCR6) which was consistently more lowly transcribed amongst MDD patients relative to controls. Results detailed here provide preliminary evidence that transcriptional measures within inflammation-related genes might be useful in aiding clinical diagnostic decision-making processes. Future research should aim to replicate findings detailed in this exploratory study in a larger medication-free sample and examine whether identified biomarkers could be used prospectively to aid clinical diagnosis.

  5. Inflammatory cytokines in an experimental model for the multiple organ dysfunction syndrome.

    PubMed

    Jansen, M J; Hendriks, T; Vogels, M T; van der Meer, J W; Goris, R J

    1996-07-01

    To investigate the alterations in circulating pro-inflammatory cytokines and cytokine production by peritoneal macrophages during the development of multiple organ dysfunction syndrome. Prospective, controlled laboratory study on zymosan-induced generalized inflammation in mice. Single intraperitoneal administration of zymosan induces, over a 12-day period, a triphasic illness in mice; the third phase, from day 6 onward, resembles multiple organ dysfunction syndrome. Animal research laboratory. C57BL/6CRW mice received a single intraperitoneal dose of zymosan on day 0, and standard numbers of animals were killed at different time points up until day 12. Plasma concentrations of interleukin (IL)-1 alpha and IL-1 beta, IL-6, and tumor necrosis factor (TNF)-alpha were measured from 3 hrs to 12 days after administration of zymosan. At the same time points, both lipopolysaccharide-stimulated and unstimulated production of these cytokines by peritoneal macrophages were measured in vitro. Plasma TNF and IL-6 concentrations transiently increased during the first 24 hrs after administration of zymosan. After 8 days, a prominent peak of biologically inactive TNF was observed. Both unstimulated and lipopolysaccharide-stimulated cytokine production by peritoneal cells showed profound changes during the experimental period. These findings seem to confirm our hypothesis that the macrophages are in a continuously activated state and altered in their function, when the animals develop multiple organ dysfunction syndrome. Further studies are needed to elucidate what happens with these cytokines at the tissue level, to better understand the pathophysiology of multiple organ dysfunction syndrome.

  6. Genomic analysis, cytokine expression, and microRNA profiling reveal biomarkers of human dietary zinc depletion and homeostasis

    PubMed Central

    Ryu, Moon-Suhn; Langkamp-Henken, Bobbi; Chang, Shou-Mei; Shankar, Meena N.; Cousins, Robert J.

    2011-01-01

    Implementation of zinc interventions for subjects suspected of being zinc-deficient is a global need, but is limited due to the absence of reliable biomarkers. To discover molecular signatures of human zinc deficiency, a combination of transcriptome, cytokine, and microRNA analyses was applied to a dietary zinc depletion/repletion protocol with young male human subjects. Concomitant with a decrease in serum zinc concentration, changes in buccal and blood gene transcripts related to zinc homeostasis occurred with zinc depletion. Microarray analyses of whole blood RNA revealed zinc-responsive genes, particularly, those associated with cell cycle regulation and immunity. Responses of potential signature genes of dietary zinc depletion were further assessed by quantitative real-time PCR. The diagnostic properties of specific serum microRNAs for dietary zinc deficiency were identified by acute responses to zinc depletion, which were reversible by subsequent zinc repletion. Depression of immune-stimulated TNFα secretion by blood cells was observed after low zinc consumption and may serve as a functional biomarker. Our findings introduce numerous novel candidate biomarkers for dietary zinc status assessment using a variety of contemporary technologies and which identify changes that occur prior to or with greater sensitivity than the serum zinc concentration which represents the current zinc status assessment marker. In addition, the results of gene network analysis reveal potential clinical outcomes attributable to suboptimal zinc intake including immune function defects and predisposition to cancer. These demonstrate through a controlled depletion/repletion dietary protocol that the illusive zinc biomarker(s) can be identified and applied to assessment and intervention strategies. PMID:22171008

  7. Chemokine biomarkers in central nervous system tissue and cerebrospinal fluid in the Theiler's virus model mirror those in multiple sclerosis.

    PubMed

    Pachner, Andrew R; Li, Libin; Gilli, Francesca

    2015-12-01

    Chemokines have increasingly been implicated in inflammatory and infectious disease of the central nervous system, both as biomarkers and as molecules important in pathogenesis. Multiple sclerosis is a disabling disease of unknown etiology, and recently chemokines have been identified as being upregulated molecules in the disease. We were interested in how the chemokine expression patterns in the central nervous system of a viral model of multiple sclerosis, Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD), compared to that in humans with multiple sclerosis. Cerebrospinal fluid and spinal cord tissue were analyzed for expression of a range of cytokines and chemokines. Three chemokines, CXCL10, CXCL9, and CCL5 were strongly and specifically upregulated in both the cerebrospinal fluid and spinal cord in chronic disease, a pattern identical to that in multiple sclerosis. These data, the first study of cytokines in central nervous system tissue and cerebrospinal fluid in TMEV-IDD, support the hypothesis that multiple sclerosis is caused by chronic infection with an as-yet unidentified pathogen, possibly a picornavirus.

  8. DNA Repair and Cytokines: TGF-β, IL-6, and Thrombopoietin as Different Biomarkers of Radioresistance

    PubMed Central

    Centurione, Lucia; Aiello, Francesca B.

    2016-01-01

    Double strand breaks (DSBs) induced by radiotherapy are highly cytotoxic lesions, leading to chromosomal aberrations and cell death. Ataxia-telangiectasia-mutated (ATM)-dependent DNA-damage response, non-homologous end joining, and homologous recombination pathways coordinately contribute to repairing DSBs in higher eukaryotes. It is known that the expression of DSB repair genes is increased in tumors, which is one of the main reasons for radioresistance. The inhibition of DSB repair pathways may be useful to increase tumor cell radiosensitivity and may target stem cell-like cancer cells, known to be the most radioresistant tumor components. Commonly overexpressed in neoplastic cells, cytokines confer radioresistance by promoting proliferation, survival, invasion, and angiogenesis. Unfortunately, tumor irradiation increases the expression of various cytokines displaying these effects, including transforming growth factor-beta and interleukin-6. Recently, the capabilities of these cytokines to support DNA repair pathways and the ATM-dependent DNA response have been demonstrated. Thrombopoietin, essential for megakaryopoiesis and very important for hematopoietic stem cell (HSC) homeostasis, has also been found to promote DNA repair in a highly selective manner. These findings reveal a novel mechanism underlying cytokine-related radioresistance, which may be clinically relevant. Therapies targeting specific cytokines may be used to improve radiosensitivity. Specific inhibitors may be chosen in consideration of different tumor microenvironments. Thrombopoietin may be useful in fending off irradiation-induced loss of HSCs. PMID:27500125

  9. Kidney tumor biomarkers revealed by simultaneous multiple matrix metabolomics analysis.

    PubMed

    Ganti, Sheila; Taylor, Sandra L; Abu Aboud, Omran; Yang, Joy; Evans, Christopher; Osier, Michael V; Alexander, Danny C; Kim, Kyoungmi; Weiss, Robert H

    2012-07-15

    Metabolomics is increasingly being used in cancer biology for biomarker discovery and identification of potential novel therapeutic targets. However, a systematic metabolomics study of multiple biofluids to determine their interrelationships and to describe their use as tumor proxies is lacking. Using a mouse xenograft model of kidney cancer, characterized by subcapsular implantation of Caki-1 clear cell human kidney cancer cells, we examined tissue, serum, and urine all obtained simultaneously at baseline (urine) and at, or close to, animal sacrifice (urine, tissue, and plasma). Uniform metabolomics analysis of all three "matrices" was accomplished using gas chromatography- and liquid chromatography-mass spectrometry. Of all the metabolites identified (267 in tissue, 246 in serum, and 267 in urine), 89 were detected in all 3 matrices, and the majority was altered in the same direction. Heat maps of individual metabolites showed that alterations in serum were more closely related to tissue than was urine. Two metabolites, cinnamoylglycine and nicotinamide, were concordantly and significantly (when corrected for multiple testing) altered in tissue and serum, and cysteine-glutathione disulfide showed the highest change (232.4-fold in tissue) of any metabolite. On the basis of these and other considerations, three pathways were chosen for biologic validation of the metabolomic data, resulting in potential therapeutic target identification. These data show that serum metabolomics analysis is a more accurate proxy for tissue changes than urine and that tryptophan degradation (yielding anti-inflammatory metabolites) is highly represented in renal cell carcinoma, and support the concept that PPAR-α antagonism may be a potential therapeutic approach for this disease.

  10. Cytokine profiles show heterogeneity of interferon-β response in multiple sclerosis patients

    PubMed Central

    Hegen, Harald; Adrianto, Indra; Lessard, Christopher J.; Millonig, Alban; Bertolotto, Antonio; Comabella, Manuel; Giovannoni, Gavin; Guger, Michael; Hoelzl, Martina; Khalil, Michael; Fazekas, Franz; Killestein, Joep; Lindberg, Raija L.P.; Malucchi, Simona; Mehling, Matthias; Montalban, Xavier; Rudzki, Dagmar; Schautzer, Franz; Sellebjerg, Finn; Sorensen, Per Soelberg; Deisenhammer, Florian; Steinman, Lawrence

    2016-01-01

    Objective: To evaluate serum cytokine profiles for their utility to determine the heterogeneous responses to interferon (IFN)–β treatment in patients with multiple sclerosis (MS). Methods: Patients with relapsing-remitting MS (RRMS) or clinically isolated syndrome receiving de novo IFN-β treatment were included in this prospective, observational study. Number of relapses and changes in disability were assessed 2 years prior to and 2 years after initiation of treatment. Sera were collected at baseline and after 3 months on therapy. Cytokine levels in sera were assessed by Luminex multiplex assays. Baseline cytokine profiles were grouped by hierarchical clustering analysis. Demographic features, changes in cytokines, and clinical outcome were then assessed in the clustered patient groups. Results: A total of 157 patients were included in the study and clustered into 6 distinct subsets by baseline cytokine profiles. These subsets differed significantly in their clinical and biological response to IFN-β therapy. Two subsets were associated with patients who responded poorly to therapy. Two other subsets, associated with a good response to therapy, showed a significant reduction in relapse rates and no worsening of disability. Each subset also had differential changes in cytokine levels after 3 months of IFN-β treatment. Conclusions: There is heterogeneity in the immunologic pathways of the RRMS population, which correlates with IFN-β response. PMID:26894205

  11. Targeting the Binding Interface on a Shared Receptor Subunit of a Cytokine Family Enables the Inhibition of Multiple Member Cytokines with Selectable Target Spectrum*

    PubMed Central

    Nata, Toshie; Basheer, Asjad; Cocchi, Fiorenza; van Besien, Richard; Massoud, Raya; Jacobson, Steven; Azimi, Nazli; Tagaya, Yutaka

    2015-01-01

    The common γ molecule (γc) is a shared signaling receptor subunit used by six γc-cytokines. These cytokines play crucial roles in the differentiation of the mature immune system and are involved in many human diseases. Moreover, recent studies suggest that multiple γc-cytokines are pathogenically involved in a single disease, thus making the shared γc-molecule a logical target for therapeutic intervention. However, the current therapeutic strategies seem to lack options to treat such cases, partly because of the lack of appropriate neutralizing antibodies recognizing the γc and, more importantly, because of the inherent and practical limitations in the use of monoclonal antibodies. By targeting the binding interface of the γc and cytokines, we successfully designed peptides that not only inhibit multiple γc-cytokines but with a selectable target spectrum. Notably, the lead peptide inhibited three γc-cytokines without affecting the other three or non-γc-cytokines. Biological and mutational analyses of our peptide provide new insights to our current understanding on the structural aspect of the binding of γc-cytokines the γc-molecule. Furthermore, we provide evidence that our peptide, when conjugated to polyethylene glycol to gain stability in vivo, efficiently blocks the action of one of the target cytokines in animal models. Collectively, our technology can be expanded to target various combinations of γc-cytokines and thereby will provide a novel strategy to the current anti-cytokine therapies against immune, inflammatory, and malignant diseases. PMID:26183780

  12. Targeting the binding interface on a shared receptor subunit of a cytokine family enables the inhibition of multiple member cytokines with selectable target spectrum.

    PubMed

    Nata, Toshie; Basheer, Asjad; Cocchi, Fiorenza; van Besien, Richard; Massoud, Raya; Jacobson, Steven; Azimi, Nazli; Tagaya, Yutaka

    2015-09-11

    The common γ molecule (γc) is a shared signaling receptor subunit used by six γc-cytokines. These cytokines play crucial roles in the differentiation of the mature immune system and are involved in many human diseases. Moreover, recent studies suggest that multiple γc-cytokines are pathogenically involved in a single disease, thus making the shared γc-molecule a logical target for therapeutic intervention. However, the current therapeutic strategies seem to lack options to treat such cases, partly because of the lack of appropriate neutralizing antibodies recognizing the γc and, more importantly, because of the inherent and practical limitations in the use of monoclonal antibodies. By targeting the binding interface of the γc and cytokines, we successfully designed peptides that not only inhibit multiple γc-cytokines but with a selectable target spectrum. Notably, the lead peptide inhibited three γc-cytokines without affecting the other three or non-γc-cytokines. Biological and mutational analyses of our peptide provide new insights to our current understanding on the structural aspect of the binding of γc-cytokines the γc-molecule. Furthermore, we provide evidence that our peptide, when conjugated to polyethylene glycol to gain stability in vivo, efficiently blocks the action of one of the target cytokines in animal models. Collectively, our technology can be expanded to target various combinations of γc-cytokines and thereby will provide a novel strategy to the current anti-cytokine therapies against immune, inflammatory, and malignant diseases.

  13. Increased urinary levels of podocyte glycoproteins, matrix metallopeptidases, inflammatory cytokines, and kidney injury biomarkers in women with preeclampsia.

    PubMed

    Wang, Yuping; Gu, Yang; Loyd, Susan; Jia, Xiuyue; Groome, Lynn J

    2015-12-15

    To investigate kidney injury in preeclampsia, we analyzed 14 biomarkers in urine specimen from 4 groups of pregnant women (normotensive pregnant women and those with pregnancy complicated with chronic hypertension or mild or severe preeclampsia). These biomarkers included 1) podocyte glycoproteins nephrin and podocalyxin, 2) matrix metallopeptidase (MMP)-2 and MMP-9 and their inhibitor tissue inhibitor of metalloproteinase-2, 3) inflammatory molecules and cytokines soluble VCAM-1, TNF-α, soluble TNF receptor receptor-1, IL-6, IL-8, IL-10, and IL-18, and 4) kidney injury biomarkers neutrophil gelatinase-associated lipocalin and kidney injury molecule-1. Postpartum urine specimens (6-8 wk) from normotensive women and those with severe preeclampsia were also evaluated. We found that, first, urine levels of nephrin, MMP-2, MMP-9, and kidney injury molecule-1 were significantly higher before delivery in severe preeclampsia than normotensive groups. The increased levels were all reduced to levels similar to those of the normotensive control group in postpartum specimens from the severe preeclampsia group. Second, soluble VCAM-1, soluble TNF receptor-1, and neutrophil gelatinase-associated lipocalin levels were significantly increased in the severe preeclampsia group compared with the normotensive control group before delivery, but levels of these molecules were significantly reduced in postpartum specimens in both groups. Third, IL-6 and IL-8 levels were not different between preeclampsia and normotensive groups but significantly increased in pregnancy complicated with chronic hypertension. Finally, tissue inhibitor of metalloproteinase-2 and IL-18 levels were not different among the study groups before delivery but were significantly reduced in postpartum specimens from normotensive controls. Our results indicate that the kidney experiences an increased inflammatory response during pregnancy. Most interestingly, tubular epithelial cell injury may also occur in severe

  14. Fatigue in Patients with Multiple Sclerosis: Is It Related to Pro- and Anti-Inflammatory Cytokines?

    PubMed Central

    Malekzadeh, Arjan; Van de Geer-Peeters, Wietske; De Groot, Vincent; Elisabeth Teunissen, Charlotte; Beckerman, Heleen; TREFAMS-ACE Study Group

    2015-01-01

    Objective. To investigate the pathophysiological role of pro- and anti-inflammatory cytokines in primary multiple sclerosis-related fatigue. Methods. Fatigued and non-fatigued patients with multiple sclerosis (MS) were recruited and their cytokine profiles compared. Patients with secondary fatigue were excluded. Fatigue was assessed with the self-reported Checklist Individual Strength (CIS20r), subscale fatigue. A CIS20r fatigue cut-off score of 35 was applied to differentiate between non-fatigued (CIS20r fatigue ≤34) and fatigued (CIS20r fatigue ≥35) patients with MS. Blood was collected to determine the serum concentrations of pro-inflammatory cytokines (IL-1β, IL-2, IL-6, IL-8, IL-12p70, IL-17, TNFα, and IFN-γ) and anti-inflammatory cytokines (IL-4, IL-5, IL-10, and IL-13). We controlled for the confounding effect of age, gender, duration of MS, disease severity, type of MS, and use of immunomodulatory drugs. Results. Similar cytokine levels were observed between MS patients with (n = 21) and without fatigue (n = 14). Adjusted multiple regression analyses showed a single significant positive relationship, that of IL-6 with CIS20r fatigue score. The explained variance of the IL-6 model was 21.1%, once adjusted for the confounding effect of age. Conclusion. The pro-inflammatory cytokine interleukin-6 (IL-6) may play a role in the pathophysiology of primary fatigue in patients with MS. Trial Registrations. ISRCTN69520623, ISRCTN58583714, and ISRCTN82353628. PMID:25722532

  15. Multiple Biomarkers for the Prediction of First Major Cardiovascular Events and Death

    USDA-ARS?s Scientific Manuscript database

    Few investigations have evaluated the incremental usefulness of multiple biomarkers from distinct biologic pathways for predicting the risk of cardiovascular events. We measured 10 biomarkers in 3209 participants attending a routine examination cycle of the Framingham Heart Study: the levels of C-r...

  16. Network-Based Identification of Biomarkers Coexpressed with Multiple Pathways

    PubMed Central

    Guo, Nancy Lan; Wan, Ying-Wooi

    2014-01-01

    Unraveling complex molecular interactions and networks and incorporating clinical information in modeling will present a paradigm shift in molecular medicine. Embedding biological relevance via modeling molecular networks and pathways has become increasingly important for biomarker identification in cancer susceptibility and metastasis studies. Here, we give a comprehensive overview of computational methods used for biomarker identification, and provide a performance comparison of several network models used in studies of cancer susceptibility, disease progression, and prognostication. Specifically, we evaluated implication networks, Boolean networks, Bayesian networks, and Pearson’s correlation networks in constructing gene coexpression networks for identifying lung cancer diagnostic and prognostic biomarkers. The results show that implication networks, implemented in Genet package, identified sets of biomarkers that generated an accurate prediction of lung cancer risk and metastases; meanwhile, implication networks revealed more biologically relevant molecular interactions than Boolean networks, Bayesian networks, and Pearson’s correlation networks when evaluated with MSigDB database. PMID:25392692

  17. Factors Associated with Multiple Biomarkers of Systemic Inflammation†

    PubMed Central

    Navarro, Sandi L.; Kantor, Elizabeth D.; Song, Xiaoling; Milne, Ginger L.; Lampe, Johanna W.; Kratz, Mario; White, Emily

    2016-01-01

    Background While much is known about correlates of C-reactive protein (CRP), little is known about correlates of other inflammation biomarkers. As these measures are increasingly being used in epidemiologic studies, it is important to determine what factors affect inflammation biomarker concentrations. Methods Using age, sex and body mass index (BMI) adjusted linear regression, we examined 38 exposures (demographic and anthropometric measures, chronic disease history, NSAIDs, dietary factors, supplement use) of 8 inflammation biomarkers [CRP, interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor-alpha (TNF-α), and soluble TNF receptors (sTNFR) in plasma; and prostaglandin E2 –metabolite (PGE-M) in urine] in 217 adults, aged 50-76 years. Results Increasing age was associated with higher concentrations of all biomarkers except IL-1β. BMI was positively associated with CRP and sTNFR I and II. Saturated fat intake was associated with increased CRP, sTNFRII, TNF-α, and IL-1β, while EPA+DHA intake (diet or total) was associated with decreased CRP, TNF-α, and IL-1β. Results for sex were varied: CRP and IL-6 were lower among men, whereas PGE-M and sTNFRI were higher. Higher CRP was also associated with smoking, HRT use, and γ-tocopherol intake; lower CRP with physical activity, and intakes of dietary vitamin C and total fiber. Conclusions Although the associations varied by biomarker, the factors having the greatest number of significant associations (p<=0.05) with the inflammation biomarkers were age, BMI, dietary saturated fat and EPA+DHA omega 3 fatty acids. Impact Our results suggest that potential confounders in epidemiologic studies assessing associations with inflammation biomarkers vary across specific biomarkers. PMID:26908433

  18. Prediction of graft-versus-host disease: a biomarker panel based on lymphocytes and cytokines.

    PubMed

    Budde, Holger; Papert, Susanne; Maas, Jens-Holger; Reichardt, Holger M; Wulf, Gerald; Hasenkamp, Justin; Riggert, Joachim; Legler, Tobias J

    2017-07-01

    Graft-versus-host disease (GvHD) still belongs to the major challenges after allogeneic hematopoietic stem cell transplantation (HSCT). Immune-suppressive therapy against GvHD is a double-edged sword due to risk of infections and relapse. The ability to adapt prophylactic treatment according to the probability of severe GvHD would be an essential advantage for the patients. We analyzed different biomarkers for their potential to predict the development of GvHD in 28 patients who underwent allogeneic HSCT. Blood was taken once directly after hematopoietic engraftment. In this study, patients were monitored for 12 months after HSCT for the occurrence of acute GvHD or acute/chronic GvHD overlap syndrome. Soluble IL-2 receptor and CD4/CD8 T cell ratio were independently associated with the occurrence of GvHD in the observation period. However, the largest area under the receiver operating characteristic curve with 0.90 was observed when a 5-parameter biomarker score based on CD4(+) T cells, CD8(+) T cells, CD19(-) CD21(+) precursor B cells, CD4/CD8 T cell ratio, and soluble IL-2 receptor was used to predict GvHD. In addition, CD8(+) T cell levels above 2.3% of all mononuclear cells after engraftment may predict relapse-free survival at least for 12 months. In summary, we found a new biomarker panel for prediction of GvHD which is featured by established laboratory assays and high statistical significance. In order to introduce the biomarker panel into routine clinical protocols, we suggest performing a larger multi-center study.

  19. Effect of Black Tea Consumption on Intracellular Cytokines, Regulatory T Cells and Metabolic Biomarkers in Type 2 Diabetes Patients.

    PubMed

    Mahmoud, Fadia; Haines, David; Al-Ozairi, Ebaa; Dashti, Ali

    2016-03-01

    The present study was undertaken to evaluate the effects of black tea intake on inflammatory cytokines and metabolic biomarkers in Type 2 diabetes mellitus (T2DM). Thirty patients with T2DM were randomly assigned either to a High Intake (HI) group, consuming three cups (600 mL) of black tea per day; and a Low Intake (LI) group, administered 1 cup (200 mL) per day, each during a 12-week period. Intracellular cytokine expression, regulatory T cells (Treg), glycemic and lipid profiles were measured at baseline and following the tea intake period. Tea consumption correlated with major effects measured in peripheral blood of subjects that included significantly reduced glycated hemoglobin (HbA1c) levels, along with increased regulatory T cells CD3+ CD4+ CD25+ FOXP3, CD3+ CD4+ IL-10+ cells (an immunosuppressive phenotype), reduced (pro-inflammatory) CD3+ CD4+ IL-17+ cells and reduced Th1-associated CD3+ CD4+ IFN-Υ+ cells. Tea consumption was also observed to abolish the significance of an inverse correlation between total serum cholesterol and representation of CD4+ IL-4+ T cells, which may reflect protection against atopy-related oxidative stress. Outcomes of this study describe both advantages and limitations to consumption of black tea as an aid to sustained health maintenance by persons at-risk for TD2M and related obesity-associated metabolic syndromes.

  20. Non-invasive skin biomarkers quantification of psoriasis and atopic dermatitis: cytokines, antioxidants and psoriatic skin auto-fluorescence.

    PubMed

    Portugal-Cohen, Meital; Horev, Liran; Ruffer, Claas; Schlippe, Gerrit; Voss, Werner; Ma'or, Ze'evi; Oron, Miriam; Soroka, Yoram; Frušić-Zlotkin, Marina; Milner, Yoram; Kohen, Ron

    2012-06-01

    Psoriasis and atopic dermatitis (AD) are challenging to treat due to the absence of suitable monitoring procedure and their recurrences. Alteration of skin hydrophilic biomarkers (SHB) and structural elements occur in both disorders and may possess a distinct profile for each clinical condition. To quantify skin cytokines and antioxidants non-invasively in psoriatic and in AD patients and to evaluate skin auto-fluorescence in psoriatic patients. A skin wash sampling technique was utilized to detect the expression of SHB on psoriatic and AD patients and healthy controls. Inflammatory cytokine (TNFα, IL-1α and IL-6) levels, total antioxidant scavenging capacity and uric acid content were estimated. Additionally, measurement of the fluorescent emission spectra of tryptophan moieties, collagen cross-links and elastin cross-links were performed on psoriatic patients and healthy controls. Our findings demonstrate significant alterations of the SHB levels among psoriasis, AD and healthy skin. Differences were also observed between lesional and non-lesional areas in patients with psoriasis and AD. Ultra-structural changes were found in psoriatic patients both in lesional and non-lesional areas. Employing non-invasive measurements of skin wash sampling and skin auto-fluorescence might serve as complementary analysis for improved diagnosis and treatment of psoriasis and AD. Furthermore, they may serve as an additional monitoring tool for various diseases, in which skin dysfunction is involved. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

  1. IL-21 and other serum proinflammatory cytokine levels in patients with multiple myeloma at diagnosis.

    PubMed

    Mehtap, O; Atesoglu, E B; Tarkun, P; Hacihanefioglu, A; Dolasik, I; Musul, M M

    2014-01-01

    IL-6, IL1-β, TNF-α and IL-21 have been identified in the growth, progression and dissemination of multiple myeloma. To dte, there is no published data about serum levels of IL-21 in patients with multiple myeloma. In the present study we have investigated circulating levels of cytokines, such as IL-6, IL-1β, TNF-α, IL-21 and the association of these levels with the disease stage in newly diagnosed multiple myeloma patients. Twenty healthy controls and 44 newly diagnosed multiple myeloma patients were evaluated. Patients were classified according to Durie-Salmon criteria, international staging system (ISS) and bone disease. Quantification of cytokine levels in serum were performed by using ELISA. The levels of cytokines in patients' serum are found elevated than healthy controls. However, only the serum levels of IL-1β and TNF-α were found statistically significant. TNF-α levels of patients with ISS stage 3 were significantly higher than patients with ISS stage 1 and 2 (P 0.000). IL-1β was significantly elevated in advanced stage patients (stage II-III) (P 0.040). There was no correlation between IL-1β, TNF-α, IL-21 levels and bone lesions. IL-6 levels were significantly elevated who have at least three visible lytic bone lesions and/or bone fracture in comparison to patients who have one or two visible or no visible lytic bone lesions (P 0.048). It appears that there is no association of serum IL-21 level with multiple myeloma in contrast to the other cytokines such as IL-6, IL-1β, TNF-α.

  2. Consensus definitions and application guidelines for control groups in cerebrospinal fluid biomarker studies in multiple sclerosis.

    PubMed

    Teunissen, Charlotte; Menge, Til; Altintas, Ayse; Álvarez-Cermeño, José C; Bertolotto, Antonio; Berven, Frode S; Brundin, Lou; Comabella, Manuel; Degn, Matilde; Deisenhammer, Florian; Fazekas, Franz; Franciotta, Diego; Frederiksen, Jette L; Galimberti, Daniela; Gnanapavan, Sharmilee; Hegen, Harald; Hemmer, Bernhard; Hintzen, Rogier; Hughes, Steve; Iacobaeus, Ellen; Kroksveen, Ann C; Kuhle, Jens; Richert, John; Tumani, Hayrettin; Villar, Luisa M; Drulovic, Jelena; Dujmovic, Irena; Khalil, Michael; Bartos, Ales

    2013-11-01

    The choice of appropriate control group(s) is critical in cerebrospinal fluid (CSF) biomarker research in multiple sclerosis (MS). There is a lack of definitions and nomenclature of different control groups and a rationalized application of different control groups. We here propose consensus definitions and nomenclature for the following groups: healthy controls (HCs), spinal anesthesia subjects (SASs), inflammatory neurological disease controls (INDCs), peripheral inflammatory neurological disease controls (PINDCs), non-inflammatory neurological controls (NINDCs), symptomatic controls (SCs). Furthermore, we discuss the application of these control groups in specific study designs, such as for diagnostic biomarker studies, prognostic biomarker studies and therapeutic response studies. Application of these uniform definitions will lead to better comparability of biomarker studies and optimal use of available resources. This will lead to improved quality of CSF biomarker research in MS and related disorders.

  3. Reproducibility of urinary biomarkers in multiple 24-h urine samples.

    PubMed

    Sun, Qi; Bertrand, Kimberly A; Franke, Adrian A; Rosner, Bernard; Curhan, Gary C; Willett, Walter C

    2017-01-01

    Limited knowledge regarding the reproducibility of biomarkers in 24-h urine samples has hindered the collection and use of the samples in epidemiologic studies. We aimed to evaluate the reproducibility of various markers in repeat 24-h urine samples. We calculated intraclass correlation coefficients (ICCs) of biomarkers measured in 24-h urine samples that were collected in 3168 participants in the NHS (Nurses' Health Study), NHSII (Nurses' Health Study II), and Health Professionals Follow-Up Study. In 742 women with 4 samples each collected over the course of 1 y, ICCs for sodium were 0.32 in the NHS and 0.34 in the NHSII. In 2439 men and women with 2 samples each collected over 1 wk to ≥1 mo, the ICCs ranged from 0.33 to 0.68 for sodium at various intervals between collections. The urinary excretion of potassium, calcium, magnesium, phosphate, sulfate, and other urinary markers showed generally higher reproducibility (ICCs >0.4). In 47 women with two 24-h urine samples, ICCs ranged from 0.15 (catechin) to 0.75 (enterolactone) for polyphenol metabolites. For phthalates, ICCs were generally ≤0.26 except for monobenzyl phthalate (ICC: 0.55), whereas the ICC was 0.39 for bisphenol A (BPA). We further estimated that, for the large majority of the biomarkers, the mean of three 24-h urine samples could provide a correlation of ≥0.8 with true long-term urinary excretion. These data suggest that the urinary excretion of various biomarkers, such as minerals, electrolytes, most polyphenols, and BPA, is reasonably reproducible in 24-h urine samples that are collected within a few days or ≤1 y. Our findings show that three 24-h samples are sufficient for the measurement of long-term exposure status in epidemiologic studies. © 2017 American Society for Nutrition.

  4. Regulation of the syncytin-1 promoter in human astrocytes by multiple sclerosis-related cytokines

    SciTech Connect

    Mameli, Giuseppe . E-mail: viross@uniss.it; Astone, Vito; Khalili, Kamel; Serra, Caterina; Sawaya, Bassel E.; Dolei, Antonina

    2007-05-25

    Syncytin-1 has a physiological role during early pregnancy, as mediator of trophoblast fusion into the syncytiotrophoblast layer, hence allowing embryo implantation. In addition, its expression in nerve tissue has been proposed to contribute to the pathogenesis of multiple sclerosis (MS). Syncytin-1 is the env glycoprotein of the ERVWE1 component of the W family of human endogenous retroviruses (HERV), located on chromosome 7q21-22, in a candidate region for genetic susceptibility to MS. The mechanisms of ERVWE1 regulation in nerve tissue remain to be identified. Since there are correlations between some cytokines and MS outcome, we examined the regulation of the syncytin-1 promoter by MS-related cytokines in human U-87MG astrocytic cells. Using transient transfection assays, we observed that the MS-detrimental cytokines TNF{alpha}, interferon-{gamma}, interleukin-6, and interleukin-1 activate the ERVWE1 promoter, while the MS-protective interferon-{beta} is inhibitory. The effects of cytokines are reduced by the deletion of the cellular enhancer domain of the promoter that contains binding sites for several transcription factors. In particular, we found that TNF{alpha} had the ability to activate the ERVWE1 promoter through an NF-{kappa}B-responsive element located within the enhancer domain of the promoter. Electrophoretic mobility shift and ChIP assays showed that TNF{alpha} enhances the binding of the p65 subunit of NF-{kappa}B, to its cognate site within the promoter. The effect of TNF{alpha} is abolished by siRNA directed against p65. Taken together, these results illustrate a role for p65 in regulating the ERVWE1 promoter and in TNF{alpha}-mediated induction of syncytin-1 in multiple sclerosis.

  5. Universal disease biomarker: can a fixed set of blood microRNAs diagnose multiple diseases?

    PubMed

    Taguchi, Y-h; Murakami, Yoshiki

    2014-08-30

    The selection of disease biomarkers is often difficult because of their unstable identification, i.e., the selection of biomarkers is heavily dependent upon the set of samples analyzed and the use of independent sets of samples often results in a completely different set of biomarkers being identified. However, if a fixed set of disease biomarkers could be identified for the diagnosis of multiple diseases, the difficulties of biomarker selection could be reduced. In this study, the previously identified universal disease biomarker (UDB) consisting of blood miRNAs that could discriminate between patients with multiple diseases and healthy controls was extended to the recently reported independent measurements of blood microRNAs (miRNAs). The performance achieved by UDB in an independent set of samples was competitive with performances achieved with biomarkers selected using lasso, a standard, heavily sample-dependent procedure. Furthermore, the development of stable feature extraction was suggested to be a key factor in constructing more efficient and stable (i.e., sample- and disease-independent) UDBs. The previously proposed UDB was successfully extended to an additional seven diseases and is expected to be useful for the diagnosis of other diseases.

  6. [Impact of gender and age on multiple organ dysfunction syndrome and inflammatory cytokines after multiple injuries].

    PubMed

    Wen, Qiang; Su, Lei

    2009-02-01

    To investigate the impact of age and gender on multiple organ dysfunction syndrome (MODS) after multiple injuries and the possible mechanism. The clinical data of 78 patients with multiple injuries admitted in the ICU in our hospital from Jan. 2004 to Jan. 2007 were reviewed for age, gender, ISS, incidence of MODS, sepsis and mortality, days in ICU, and duration of ventilation. The plasma levels of TNF-alpha and IL-6 were examined by ELISA in the first two weeks after the injury, and the results were analyzed in relation to the demographic and clinical data. With similar ISS scores, the male patients were more likely to develop into MODS than the female patients (P<0.05), and age produced a marginal effect on the incidence of MODS (P=0.06). Compared with patients without MODS, those with MODS had a significantly different pattern of plasma TNF-alpha and IL-6 alterations. In the initial week following the injury, the male patients showed significantly higher plasma IL-6 levels than the female patients with the same ISS scores (P=0.04), but the level alteration in the initial two weeks showed no significant difference between the male and female patients (P=0.14). Gender plays an important role in the occurrence of MODS following multiple injuries, but the effect of age on MODS seems only marginal and need to be further investigated.

  7. Extracellular Vesicles in Multiple Sclerosis as Possible Biomarkers: Dream or Reality?

    PubMed

    Barreca, Maria Magdalena; Aliotta, Emanuele; Geraci, Fabiana

    2017-01-01

    Extracellular vesicles are recently described as specialized structures for intercellular communication. Their role in the central nervous system was diffusely studied in both physiological and pathological condition. In particular, an increased extracellular vesicle number was detected in several autoimmune diseases, including multiple sclerosis, a chronic autoimmune, inflammatory, demyelinating and neurodegenerative disease. This chapter summarizes the available information on the involvement of the extracellular vesicles in multiple sclerosis pathogenesis and their possible use as biomarker of therapy efficacy.

  8. Cognitive impairment effects of early life stress in adolescents can be predicted with early biomarkers: Impacts of sex, experience, and cytokines.

    PubMed

    Grassi-Oliveira, Rodrigo; Honeycutt, Jennifer A; Holland, Freedom H; Ganguly, Prabarna; Brenhouse, Heather C

    2016-09-01

    Childhood adversity increases vulnerability to psychiatric disorders that emerge in adolescence, in a sex-dependent manner. Early adversity modeled in rodents with maternal separation (MS) affects cognition and medial prefrontal cortex (mPFC) circuitry. Humans and animals exposed to early life adversity also display heightened circulating inflammatory cytokines, however the predictive relationship of these early measures with later behavioral deficits is unknown. Here, male and female rats were exposed to MS or control rearing during the postnatal period (P2-21). Blood samples were taken at distinct developmental time points for analysis of the pro-inflammatory cytokine IL-1β and the anti-inflammatory cytokines IL-4, and IL-10, followed by win-shift cognitive testing and analysis of mPFC parvalbumin (PVB) immunofluorescent interneurons in adolescence. Regression analyses were conducted to explore the relationship between early cytokines and adolescent behavioral measures. We observed sex- and age-dependent effects of MS on circulating cytokines. MS also yielded adolescent decreases in mPFC PVB and cognitive deficits, which were predicted by early cytokine expression in a sex- and experience-dependent manner. Taken together, the present data reveals that circulating cytokines and PVB levels are predictive of adolescent cognitive deficits, and therefore provide compelling evidence for a putative role of early biomarkers in mediating MS-induced behavioral dysfunction. Importantly, predictive relationships often depended on sex and on MS history, suggesting that early life experiences may yield individualistic mechanisms of vulnerability compared to the general population. Copyright © 2016 Elsevier Ltd. All rights reserved.

  9. Multiple biomarkers in molecular oncology. I. Molecular diagnostics applications in cervical cancer detection.

    PubMed

    Malinowski, Douglas P

    2007-03-01

    The screening for cervical carcinoma and its malignant precursors (cervical neoplasia) currently employs morphology-based detection methods (Papanicolaou [Pap] smear) in addition to the detection of high-risk human papillomavirus. The combination of the Pap smear with human papillomavirus testing has achieved significant improvements in sensitivity for the detection of cervical disease. Diagnosis of cervical neoplasia is dependent upon histology assessment of cervical biopsy specimens. Attempts to improve the specificity of cervical disease screening have focused on the investigation of molecular biomarkers for adjunctive use in combination with the Pap smear. Active research into the genomic and proteomic alterations that occur during human papillomavirus-induced neoplastic transformation have begun to characterize some of the basic mechanisms inherent to the disease process of cervical cancer development. This research continues to demonstrate the complexity of multiple genomic and proteomic alterations that accumulate during the tumorigenesis process. Despite this diversity, basic patterns of uncontrolled signal transduction, cell cycle deregulation, activation of DNA replication and altered extracellular matrix interactions are beginning to emerge as common features inherent to cervical cancer development. Some of these gene or protein expression alterations have been investigated as potential biomarkers for screening and diagnostics applications. The contribution of multiple gene alterations in the development of cervical cancer suggests that the application of multiple biomarker panels has the potential to develop clinically useful molecular diagnostics. In this review, the application of biomarkers for the improvement of sensitivity and specificity of the detection of cervical neoplasia within cytology specimens will be discussed.

  10. Data integration and systems biology approaches for biomarker discovery: challenges and opportunities for multiple sclerosis.

    PubMed

    Villoslada, Pablo; Baranzini, Sergio

    2012-07-15

    New "omic" technologies and their application to systems biology approaches offer new opportunities for biomarker discovery in complex disorders, including multiple sclerosis (MS). Recent studies using massive genotyping, DNA arrays, antibody arrays, proteomics, glycomics, and metabolomics from different tissues (blood, cerebrospinal fluid, brain) have identified many molecules associated with MS, defining both susceptibility and functional targets (e.g., biomarkers). Such discoveries involve many different levels in the complex organizational hierarchy of humans (DNA, RNA, protein, etc.), and integrating these datasets into a coherent model with regard to MS pathogenesis would be a significant step forward. Given the dynamic and heterogeneous nature of MS, validating biomarkers is mandatory. To develop accurate markers of disease prognosis or therapeutic response that are clinically useful, combining molecular, clinical, and imaging data is necessary. Such an integrative approach would pave the way towards better patient care and more effective clinical trials that test new therapies, thus bringing the paradigm of personalized medicine in MS one step closer.

  11. NCCN Work Group Report: Designing Clinical Trials in the Era of Multiple Biomarkers and Targeted Therapies

    PubMed Central

    Venook, Alan P.; Arcila, Maria E.; Benson, Al B.; Berry, Donald A.; Camidge, David Ross; Carlson, Robert W.; Choueiri, Toni K.; Guild, Valerie; Kalemkerian, Gregory P.; Kurzrock, Razelle; Lovly, Christine M.; McKee, Amy E.; Morgan, Robert J.; Olszanski, Anthony J.; Redman, Mary W.; Stearns, Vered; McClure, Joan; Birkeland, Marian L.

    2016-01-01

    Defining treatment susceptible or resistant populations of cancer patients through the use of genetically defined biomarkers has revolutionized cancer care in recent years for some disease/patient groups. Research continues to show that histologically defined diseases are diverse in their expression of unique mutations or other genetic alterations, however, which presents both opportunities for the development of personalized cancer treatments, but increased difficulty in testing these therapies because potential patient populations are divided into ever-smaller numbers. To address some of the growing challenges in biomarker development and clinical trial design, NCCN assembled a group of experts across specialties and solid tumor disease types to begin to define the problems and to consider alternate ways of designing clinical trials in the era of multiple biomarkers and targeted therapies. Results from that discussion are presented, focusing on issues of clinical trial design from the perspective of statisticians, clinical researchers, regulators, pathologists and information developers. PMID:25361808

  12. Development of biomarkers for screening hepatocellular carcinoma using global data mining and multiple reaction monitoring.

    PubMed

    Kim, Hyunsoo; Kim, Kyunggon; Yu, Su Jong; Jang, Eun Sun; Yu, Jiyoung; Cho, Geunhee; Yoon, Jung-Hwan; Kim, Youngsoo

    2013-01-01

    Hepatocellular carcinoma (HCC) is one of the most common and aggressive cancers and is associated with a poor survival rate. Clinically, the level of alpha-fetoprotein (AFP) has been used as a biomarker for the diagnosis of HCC. The discovery of useful biomarkers for HCC, focused solely on the proteome, has been difficult; thus, wide-ranging global data mining of genomic and proteomic databases from previous reports would be valuable in screening biomarker candidates. Further, multiple reaction monitoring (MRM), based on triple quadrupole mass spectrometry, has been effective with regard to high-throughput verification, complementing antibody-based verification pipelines. In this study, global data mining was performed using 5 types of HCC data to screen for candidate biomarker proteins: cDNA microarray, copy number variation, somatic mutation, epigenetic, and quantitative proteomics data. Next, we applied MRM to verify HCC candidate biomarkers in individual serum samples from 3 groups: a healthy control group, patients who have been diagnosed with HCC (Before HCC treatment group), and HCC patients who underwent locoregional therapy (After HCC treatment group). After determining the relative quantities of the candidate proteins by MRM, we compared their expression levels between the 3 groups, identifying 4 potential biomarkers: the actin-binding protein anillin (ANLN), filamin-B (FLNB), complementary C4-A (C4A), and AFP. The combination of 2 markers (ANLN, FLNB) improved the discrimination of the before HCC treatment group from the healthy control group compared with AFP. We conclude that the combination of global data mining and MRM verification enhances the screening and verification of potential HCC biomarkers. This efficacious integrative strategy is applicable to the development of markers for cancer and other diseases.

  13. Development of Biomarkers for Screening Hepatocellular Carcinoma Using Global Data Mining and Multiple Reaction Monitoring

    PubMed Central

    Yu, Su Jong; Jang, Eun Sun; Yu, Jiyoung; Cho, Geunhee; Yoon, Jung-Hwan; Kim, Youngsoo

    2013-01-01

    Hepatocellular carcinoma (HCC) is one of the most common and aggressive cancers and is associated with a poor survival rate. Clinically, the level of alpha-fetoprotein (AFP) has been used as a biomarker for the diagnosis of HCC. The discovery of useful biomarkers for HCC, focused solely on the proteome, has been difficult; thus, wide-ranging global data mining of genomic and proteomic databases from previous reports would be valuable in screening biomarker candidates. Further, multiple reaction monitoring (MRM), based on triple quadrupole mass spectrometry, has been effective with regard to high-throughput verification, complementing antibody-based verification pipelines. In this study, global data mining was performed using 5 types of HCC data to screen for candidate biomarker proteins: cDNA microarray, copy number variation, somatic mutation, epigenetic, and quantitative proteomics data. Next, we applied MRM to verify HCC candidate biomarkers in individual serum samples from 3 groups: a healthy control group, patients who have been diagnosed with HCC (Before HCC treatment group), and HCC patients who underwent locoregional therapy (After HCC treatment group). After determining the relative quantities of the candidate proteins by MRM, we compared their expression levels between the 3 groups, identifying 4 potential biomarkers: the actin-binding protein anillin (ANLN), filamin-B (FLNB), complementary C4-A (C4A), and AFP. The combination of 2 markers (ANLN, FLNB) improved the discrimination of the before HCC treatment group from the healthy control group compared with AFP. We conclude that the combination of global data mining and MRM verification enhances the screening and verification of potential HCC biomarkers. This efficacious integrative strategy is applicable to the development of markers for cancer and other diseases. PMID:23717429

  14. Label-free capacitive biosensor for sensitive detection of multiple biomarkers using gold interdigitated capacitor arrays.

    PubMed

    Qureshi, Anjum; Niazi, Javed H; Kallempudi, Saravan; Gurbuz, Yasar

    2010-06-15

    In this study, a highly sensitive and label-free multianalyte capacitive immunosensor was developed based on gold interdigitated electrodes (GID) capacitor arrays to detect a panel of disease biomarkers. C-reactive protein (CRP), TNFalpha, and IL6 have strong and consistent relationships between markers of inflammation and future cardiovascular risk (CVR) events. Early detection of a panel of biomarkers for a disease could enable accurate prediction of a disease risk. The detection of protein biomarkers was based on relative change in capacitive/dielectric properties. Two different lab-on-a-chip formats were employed for multiple biomarker detection on GID-capacitors. In format I, capacitor arrays were immobilized with pure forms of anti-CRP, -TNFalpha, and -IL6 antibodies in which each capacitor array contained a different immobilized antibody. Here, the CRP and IL6 were detected in the range 25 pg/ml to 25 ng/ml and 25 pg/ml to 1 ng/ml for TNFalpha in format I. Sensitive detection was achieved with chips co-immobilized (diluted) with equimolar mixtures of anti-CRP, -IL6, and -TNFalpha antibodies (format II) in which all capacitors in an array were identical and tested for biomarkers with sequential incubation. The resulting response to CRP, IL6, and TNFalpha in format II for all biomarkers was found to be within 25 pg/ml to 25 ng/ml range. The capacitive biosensor for panels of inflammation and CVR markers show significant clinical value and provide great potential for detection of biomarker panel in suspected subjects for early diagnosis.

  15. Rapid verification of candidate serological biomarkers using gel-based, label-free multiple reaction monitoring.

    PubMed

    Tang, Hsin-Yao; Beer, Lynn A; Barnhart, Kurt T; Speicher, David W

    2011-09-02

    Stable isotope dilution-multiple reaction monitoring-mass spectrometry (SID-MRM-MS) has emerged as a promising platform for verification of serological candidate biomarkers. However, cost and time needed to synthesize and evaluate stable isotope peptides, optimize spike-in assays, and generate standard curves quickly becomes unattractive when testing many candidate biomarkers. In this study, we demonstrate that label-free multiplexed MRM-MS coupled with major protein depletion and 1D gel separation is a time-efficient, cost-effective initial biomarker verification strategy requiring less than 100 μL of serum. Furthermore, SDS gel fractionation can resolve different molecular weight forms of targeted proteins with potential diagnostic value. Because fractionation is at the protein level, consistency of peptide quantitation profiles across fractions permits rapid detection of quantitation problems for specific peptides from a given protein. Despite the lack of internal standards, the entire workflow can be highly reproducible, and long-term reproducibility of relative protein abundance can be obtained using different mass spectrometers and LC methods with external reference standards. Quantitation down to ~200 pg/mL could be achieved using this workflow. Hence, the label-free GeLC-MRM workflow enables rapid, sensitive, and economical initial screening of large numbers of candidate biomarkers prior to setting up SID-MRM assays or immunoassays for the most promising candidate biomarkers.

  16. A Multiplexed Device Based on Tunable Nanoshearing for Specific Detection of Multiple Protein Biomarkers in Serum

    PubMed Central

    Vaidyanathan, Ramanathan; van Leeuwen, Lara Michelle; Rauf, Sakandar; Shiddiky, Muhammad J. A.; Trau, Matt

    2015-01-01

    Microfluidic flow based multiplexed devices have gained significant promise in detecting biomarkers in complex biological samples. However, to fully exploit their use in bioanalysis, issues such as (i) low sensitivity and (ii) high levels of nonspecific adsorption of non-target species have to be overcome. Herein, we describe a new multiplexed device for the sensitive detection of multiple protein biomarkers in serum by using an alternating current (ac) electrohydrodynamics (ac-EHD) induced surface shear forces based phenomenon referred to as nanoshearing. The tunable nature (via manipulation of ac field) of these nanoshearing forces can alter the capture performance of the device (e.g., improved fluid transport enhances number of sensor-target collisions). This can also selectively displace weakly (nonspecifically) bound molecules from the electrode surface (i.e., fluid shear forces can be tuned to shear away nonspecific species present in biological samples). Using this approach, we achieved sensitive (100 fg mL−1) naked eye detection of multiple protein targets spiked in human serum and a 1000-fold enhancement in comparison to hydrodynamic flow based devices for biomarker detection. We believe that this approach could potentially represent a clinical diagnostic tool that can be integrated into resource-limited settings for sensitive detection of target biomarkers using naked eye. PMID:25978807

  17. Inflammatory cytokine biomarkers to identify women with asymptomatic sexually transmitted infections and bacterial vaginosis who are at high risk of HIV infection.

    PubMed

    Masson, Lindi; Arnold, Kelly B; Little, Francesca; Mlisana, Koleka; Lewis, David A; Mkhize, Nonhlanhla; Gamieldien, Hoyam; Ngcapu, Sinaye; Johnson, Leigh; Lauffenburger, Douglas A; Abdool Karim, Quarraisha; Abdool Karim, Salim S; Passmore, Jo-Ann S

    2016-05-01

    Untreated sexually transmitted infections (STIs) and bacterial vaginosis (BV) cause genital inflammation and increase the risk of HIV infection. WHO-recommended syndromic STI and BV management is severely limited as many women with asymptomatic infections go untreated. The purpose of this cross-sectional study was to evaluate genital cytokine profiles as a biomarker of STIs and BV to identify women with asymptomatic, treatable infections. Concentrations of 42 cytokines in cervicovaginal lavages from 227 HIV-uninfected women were measured using Luminex. All women were screened for BV by microscopy and STIs using molecular assays. Multivariate analyses were used to identify cytokine profiles associated with STIs/BV. A multivariate profile of seven cytokines (interleukin (IL)-1α, IL-1β, tumour necrosis factor-β, IL-4, fractalkine, macrophage-derived chemokine, and interferon-γ) most accurately predicted the presence of a treatable genital condition, with 77% classification accuracy and 75% cross-validation accuracy (sensitivity 72%; specificity 81%, positive predictive value (PPV) 86%, negative predictive value (NPV) 64%). Concomitant increased IL-1β and decreased IP-10 concentrations predicted the presence of a treatable genital condition without a substantial reduction in predictive value (sensitivity 77%, specificity 72%, PPV 82% and NPV 65%), correctly classifying 75% of the women. This approach performed substantially better than clinical signs (sensitivity 19%, specificity 92%, PPV 79% and NPV 40%). Supplementing syndromic management with an assessment of IL-1β and IP-10 as biomarkers of genital inflammation may improve STI/BV management for women, enabling more effective treatment of asymptomatic infections and potentially reducing their risk of HIV infection. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  18. Multiple nutrient stresses at intersecting Pacific Ocean biomes detected by protein biomarkers.

    PubMed

    Saito, Mak A; McIlvin, Matthew R; Moran, Dawn M; Goepfert, Tyler J; DiTullio, Giacomo R; Post, Anton F; Lamborg, Carl H

    2014-09-05

    Marine primary productivity is strongly influenced by the scarcity of required nutrients, yet our understanding of these nutrient limitations is informed by experimental observations with sparse geographical coverage and methodological limitations. We developed a quantitative proteomic method to directly assess nutrient stress in high-light ecotypes of the abundant cyanobacterium Prochlorococcus across a meridional transect in the central Pacific Ocean. Multiple peptide biomarkers detected widespread and overlapping regions of nutritional stress for nitrogen and phosphorus in the North Pacific Subtropical Gyre and iron in the equatorial Pacific. Quantitative protein analyses demonstrated simultaneous stress for these nutrients at biome interfaces. This application of proteomic biomarkers to diagnose ocean metabolism demonstrated Prochlorococcus actively and simultaneously deploying multiple biochemical strategies for low-nutrient conditions in the oceans.

  19. Cytokine Biomarkers and Chronic Pain: Association of Genes, Transcription, and Circulating Proteins with Temporomandibular Disorders and Widespread Palpation Tenderness

    PubMed Central

    Slade, Gary D; Conrad, Mathew; Diatchenko, Luda; Rashid, Naim; Zhong, Sheng; Smith, Shad; Rhodes, Jesse; Medvedev, Alex; Makarov, Sergei; Maixner, William; Nackley, Andrea G

    2011-01-01

    For reasons unknown, temporomandibular disorder (TMD) can manifest as localized pain or in conjunction with widespread pain. We evaluated relationships between cytokines and TMD without or with widespread palpation tenderness (TMD−WPT or TMD+WPT, respectively), at protein, transcription factory activity, and gene levels. Additionally, we evaluated the relationship between cytokines and intermediate phenotypes characteristic of TMD and WPT. In a case-control study of 344 females, blood samples were analyzed for levels of 22 cytokines and activity of 48 transcription factors. Intermediate phenotypes were measured by quantitative sensory testing and questionnaires asking about pain, health, and psychological status. Single nucleotide polymorphisms (SNPs) coding cytokines and transcription factors were genotyped. TMD−WPT cases had elevated protein levels of pro-inflammatory cytokine MCP-1 and anti-inflammatory cytokine IL-1ra, whereas TMD+WPT cases had elevated levels of pro-inflammatory cytokine IL-8. MCP-1, IL-1ra, and IL-8 were differentially associated with experimental pain, self-rated pain, self-rated health, and psychological phenotypes. TMD−WPT and TMD+WPT cases had inhibited transcription activity of the anti-inflammatory cytokine TGFβ1. Interactions were observed between TGFβ1 and IL-8 SNPs: an additional copy of the TGFβ1 rs2241719 minor T allele was associated with twice the odds of TMD+WPT among individuals homozygous for the IL-8 rs4073 major A allele and half the odds of TMD+WPT among individuals heterozygous for rs4073. These results demonstrate how pro- and anti-inflammatory cytokines contribute to the pathophysiology of TMD and WPT in genetically-susceptible people. Furthermore, they identify MCP-1, IL-1ra, IL-8, and TGFβ1 as potential diagnostic markers and therapeutic targets for pain in patients with TMD. PMID:22000099

  20. Biomarker detection in the integration of multiple multi-class genomic studies

    PubMed Central

    Lu, Shuya; Li, Jia; Song, Chi; Shen, Kui; Tseng, George C.

    2010-01-01

    Motivation: Systematic information integration of multiple-related microarray studies has become an important issue as the technology becomes mature and prevalent in the past decade. The aggregated information provides more robust and accurate biomarker detection. So far, published meta-analysis methods for this purpose mostly consider two-class comparison. Methods for combining multi-class studies and considering expression pattern concordance are rarely explored. Results: In this article, we develop three integration methods for biomarker detection in multiple multi-class microarray studies: ANOVA-maxP, min-MCC and OW-min-MCC. We first consider a natural extension of combining P-values from the traditional ANOVA model. Since P-values from ANOVA do not guarantee to reflect the concordant expression pattern information across studies, we propose a multi-class correlation (MCC) measure to specifically seek for biomarkers of concordant inter-class patterns across a pair of studies. For both ANOVA and MCC approaches, we use extreme order statistics to identify biomarkers differentially expressed (DE) in all studies (i.e. ANOVA-maxP and min-MCC). The min-MCC method is further extended to identify biomarkers DE in partial studies by incorporating a recently developed optimally weighted (OW) technique (OW-min-MCC). All methods are evaluated by simulation studies and by three meta-analysis applications to multi-tissue mouse metabolism datasets, multi-condition mouse trauma datasets and multi-malignant-condition human prostate cancer datasets. The results show complementary strength of the three methods for different biological purposes. Availability: http://www.biostat.pitt.edu/bioinfo/ Contact: ctseng@pitt.edu Supplementary information: Supplementary data is available at Bioinformatics online. PMID:19965884

  1. Cytokines and chemokines as biomarkers of ethanol-induced neuroinflammation and anxiety-related behavior: role of TLR4 and TLR2.

    PubMed

    Pascual, María; Baliño, Pablo; Aragón, Carlos M G; Guerri, Consuelo

    2015-02-01

    Recent evidence supports the influence of neuroimmune system activation on behavior. We have demonstrated that ethanol activates the innate immune system by stimulating toll-like receptor 4 (TLR4) signaling in glial cells, which triggers the release of inflammatory mediators and causes neuroinflammation. The present study aimed to evaluate whether the ethanol-induced up-regulation of cytokines and chemokines is associated with anxiety-related behavior, 24 h after ethanol removal, and if TLR4 or TLR2 is involved in these effects. We used WT, TLR4-KO and TLR2-KO mice treated with alcohol for 5 months to show that chronic ethanol consumption increases the levels of cytokines (IL-1β, IL-17, TNF-α) and chemokines (MCP-1, MIP-1α, CX3CL1) in the striatum and serum (MCP-1, MIP-1α, CX3CL1) of WT mice. Alcohol deprivation for 24 h induces IFN-γ levels in the striatum and maintains high levels of some cytokines (IL-1β, IL-17) and chemokines (MIP-1α, CX3CL1) in this brain region. The latter events were associated with an increase in anxiogenic-related behavior, as evaluated by the dark and light box and the elevated plus maze tests. Notably, mice lacking TLR4 or TLR2 receptors are largely protected against ethanol-induced cytokine and chemokine release, and behavioral associated effects during alcohol abstinence. These data support the role of TLR4 and TLR2 responses in neuroinflammation and in anxiogenic-related behavior effects during ethanol deprivation, and also provide evidence that chemokines and cytokines can be biomarkers of ethanol-induced neuroimmune response.

  2. Hematopoietic cytokines.

    PubMed

    Metcalf, Donald

    2008-01-15

    The production of hematopoietic cells is under the tight control of a group of hematopoietic cytokines. Each cytokine has multiple actions mediated by receptors whose cytoplasmic domains contain specialized regions initiating the various responses-survival, proliferation, differentiation commitment, maturation, and functional activation. Individual cytokines can be lineage specific or can regulate cells in multiple lineages, and for some cell types, such as stem cells or megakaryocyte progenitors, the simultaneous action of multiple cytokines is required for proliferative responses. The same cytokines control basal and emergency hematopoietic cell proliferation. Three cytokines, erythropoietin, granulocyte colony-stimulating factor, and granulocyte-macrophage colony-stimulating factor, have now been in routine clinical use to stimulate cell production and in total have been used in the management of many millions of patients. In this little review, discussion will be restricted to those cytokines well established as influencing the production of hematopoietic cells and will exclude newer candidate regulators and those active on lymphoid cells. As requested, this account will describe the cytokines in a historical manner, using a sequential format of discovery, understanding, validation, and puzzlement, a sequence that reflects the evolving views on these cytokines over the past 50 years.

  3. Simultaneous detection of multiple biomarkers by means of SERS on polymer nanopillar gold arrays

    NASA Astrophysics Data System (ADS)

    Morasso, Carlo; Picciolini, Silvia; Mehn, Dora; Pellacani, Paola; Frangolho, Ana; Marchesini, Gerardo; Vanna, Renzo; Gualerzi, Alice; Bedoni, Marzia; Marabelli, Franco; Gramatica, Furio

    2016-03-01

    The detection of biomarkers by means of Surface Enhanced Raman Spectroscopy (SERS) is foreseen to became a very important tool in the clinical practice because of its excellent sensitivity and potential for the simultaneous detection of multiple biomarkers. In the present paper we describe how it was possible to build a sensor for the detection of genetic biomarkers involved in acute myeloid leukemia. The assay is based on the use of a specifically designed SERS substrate made of a 2D crystal structure of polymeric pillars embedded in a gold layer. This substrate is characterized by good enhancing properties coupled with an excellent homogeneity. The SERS substrate was conjugated with DNA probes complementary to a target sequence and used in a sandwich assay with gold nanoparticles labeled with a second DNA probe and a Raman reporter. The so developed assay allowed the detection of a leukemia biomarker (WT1 gene) and an housekeeping gene with low picomolar sensitivity. At last, we optimized the assay in order to tackle one of the main limitations of SERS based assay: the loss of signal that is observed when the Raman spectra are collected in liquid. Combining a preferential functionalization on the polymeric pillars with a different height of the polymer pillars from the gold layer the assay demonstrated its effectiveness even when measured in buffer.

  4. Multiple biomarkers biosensor with just-in-time functionalization: Application to prostate cancer detection.

    PubMed

    Parra-Cabrera, C; Samitier, J; Homs-Corbera, A

    2016-03-15

    We present a novel lab-on-a-chip (LOC) device for the simultaneous detection of multiple biomarkers using simple voltage measurements. The biosensor functionalization is performed in-situ, immediately before its use, facilitating reagents storage and massive devices fabrication. Sensitivity, limit of detection (LOD) and limit of quantification (LOQ) are tunable depending on the in-chip flown sample volumes. As a proof-of-concept, the system has been tested and adjusted to quantify two proteins found in blood that are susceptible to be used combined, as a screening tool, to diagnose prostate cancer (PCa): prostate-specific antigen (PSA) and spondin-2 (SPON2). This combination of biomarkers has been reported to be more specific for PCa diagnostics than the currently accepted but rather controversial PSA indicator. The range of detection for PSA and SPON2 could be adjusted to the clinically relevant range of 1 to 10 ng/ml. The system was tested for specificity to the evaluated biomarkers. This multiplex system can be modified and adapted to detect a larger quantity of biomarkers, or different ones, of relevance to other specific diseases.

  5. Quality assurance of intracellular cytokine staining assays: analysis of multiple rounds of proficiency testing.

    PubMed

    Jaimes, Maria C; Maecker, Holden T; Yan, Ming; Maino, Vernon C; Hanley, Mary Beth; Greer, Angela; Darden, Janice M; D'Souza, M Patricia

    2011-01-05

    When evaluating candidate prophylactic HIV and cancer vaccines, intracellular cytokine staining (ICS) assays that measure the frequency and magnitude of antigen-specific T-cell subsets are one tool to monitor immunogen performance and make product advancement decisions. To assess the inter-laboratory assay variation among multiple laboratories testing vaccine candidates, the NIH/NIAID/DAIDS in collaboration with BD Biosciences implemented an ICS Quality Assurance Program (QAP). Seven rounds of testing have been conducted in which 16 laboratories worldwide participated. In each round, IFN-γ, IL-2 and/or TNF-α responses in CD4+ and CD8+ T-cells to CEF or CMV pp65 peptide mixes were tested using cryopreserved peripheral blood mononuclear cells (PBMC) from CMV seropositive donors. We found that for responses measured above 0.2%, inter-laboratory %CVs were, on average, 35%. No differences in inter-laboratory variation were observed if a 4-color antibody cocktail or a 7-color combination was used. Moreover, the data allowed identification of important sources of variability for flow cytometry-based assays, including: number of collected events, gating strategy and instrument setup and performance. As a consequence, in this multi-site study we were able to define pass and fail criteria for ICS assays, which will be adopted in the subsequent rounds of testing and could be easily extrapolated to QAP for other flow cytometry-based assays.

  6. Post-Traumatic Hypoxia Is Associated with Prolonged Cerebral Cytokine Production, Higher Serum Biomarker Levels, and Poor Outcome in Patients with Severe Traumatic Brain Injury

    PubMed Central

    Yan, Edwin B.; Satgunaseelan, Laveniya; Paul, Eldho; Bye, Nicole; Nguyen, Phuong; Agyapomaa, Doreen; Kossmann, Thomas; Rosenfeld, Jeffrey V.

    2014-01-01

    Abstract Secondary hypoxia is a known contributor to adverse outcomes in patients with traumatic brain injury (TBI). Based on the evidence that hypoxia and TBI in isolation induce neuroinflammation, we investigated whether TBI combined with hypoxia enhances cerebral cytokine production. We also explored whether increased concentrations of injury biomarkers discriminate between hypoxic (Hx) and normoxic (Nx) patients, correlate to worse outcome, and depend on blood–brain barrier (BBB) dysfunction. Forty-two TBI patients with Glasgow Coma Scale ≤8 were recruited. Cerebrospinal fluid (CSF) and serum were collected over 6 days. Patients were divided into Hx (n=22) and Nx (n=20) groups. Eight cytokines were measured in the CSF; albumin, S100, myelin basic protein (MBP) and neuronal specific enolase (NSE) were quantified in serum. CSF/serum albumin quotient was calculated for BBB function. Glasgow Outcome Scale Extended (GOSE) was assessed at 6 months post-TBI. Production of granulocye macrophage-colony stimulating factor (GM-CSF) was higher, and profiles of GM-CSF, interferon (IFN)-γ and, to a lesser extent, tumor necrosis factor (TNF), were prolonged in the CSF of Hx but not Nx patients at 4–5 days post-TBI. Interleukin (IL)-2, IL-4, IL-6, and IL-10 increased similarly in both Hx and Nx groups. S100, MBP, and NSE were significantly higher in Hx patients with unfavorable outcome. Among these three biomarkers, S100 showed the strongest correlations to GOSE after TBI-Hx. Elevated CSF/serum albumin quotients lasted for 5 days post-TBI and displayed similar profiles in Hx and Nx patients. We demonstrate for the first time that post-TBI hypoxia is associated with prolonged neuroinflammation, amplified extravasation of biomarkers, and poor outcome. S100 and MBP could be implemented to track the occurrence of post-TBI hypoxia, and prompt adequate treatment. PMID:24279428

  7. Post-traumatic hypoxia is associated with prolonged cerebral cytokine production, higher serum biomarker levels, and poor outcome in patients with severe traumatic brain injury.

    PubMed

    Yan, Edwin B; Satgunaseelan, Laveniya; Paul, Eldho; Bye, Nicole; Nguyen, Phuong; Agyapomaa, Doreen; Kossmann, Thomas; Rosenfeld, Jeffrey V; Morganti-Kossmann, Maria Cristina

    2014-04-01

    Secondary hypoxia is a known contributor to adverse outcomes in patients with traumatic brain injury (TBI). Based on the evidence that hypoxia and TBI in isolation induce neuroinflammation, we investigated whether TBI combined with hypoxia enhances cerebral cytokine production. We also explored whether increased concentrations of injury biomarkers discriminate between hypoxic (Hx) and normoxic (Nx) patients, correlate to worse outcome, and depend on blood-brain barrier (BBB) dysfunction. Forty-two TBI patients with Glasgow Coma Scale ≤8 were recruited. Cerebrospinal fluid (CSF) and serum were collected over 6 days. Patients were divided into Hx (n=22) and Nx (n=20) groups. Eight cytokines were measured in the CSF; albumin, S100, myelin basic protein (MBP) and neuronal specific enolase (NSE) were quantified in serum. CSF/serum albumin quotient was calculated for BBB function. Glasgow Outcome Scale Extended (GOSE) was assessed at 6 months post-TBI. Production of granulocye macrophage-colony stimulating factor (GM-CSF) was higher, and profiles of GM-CSF, interferon (IFN)-γ and, to a lesser extent, tumor necrosis factor (TNF), were prolonged in the CSF of Hx but not Nx patients at 4-5 days post-TBI. Interleukin (IL)-2, IL-4, IL-6, and IL-10 increased similarly in both Hx and Nx groups. S100, MBP, and NSE were significantly higher in Hx patients with unfavorable outcome. Among these three biomarkers, S100 showed the strongest correlations to GOSE after TBI-Hx. Elevated CSF/serum albumin quotients lasted for 5 days post-TBI and displayed similar profiles in Hx and Nx patients. We demonstrate for the first time that post-TBI hypoxia is associated with prolonged neuroinflammation, amplified extravasation of biomarkers, and poor outcome. S100 and MBP could be implemented to track the occurrence of post-TBI hypoxia, and prompt adequate treatment.

  8. Vaccination induced changes in pro-inflammatory cytokine levels as an early putative biomarker for cognitive improvement in a transgenic mouse model for Alzheimer disease.

    PubMed

    Lin, Xiaoyang; Bai, Ge; Lin, Linda; Wu, Hengyi; Cai, Jianfeng; Ugen, Kenneth E; Cao, Chuanhai

    2014-01-01

    Several pieces of experimental evidence suggest that administration of anti-β amyloid (Aβ) vaccines, passive anti-Aβ antibodies or anti-inflammatory drugs can reduce Aβ deposition as well as associated cognitive/behavioral deficits in an Alzheimer disease (AD) transgenic (Tg) mouse model and, as such, may have some efficacy in human AD patients as well. In the investigation reported here an Aβ 1-42 peptide vaccine was administered to 16-month old APP+PS1 transgenic (Tg) mice in which Aβ deposition, cognitive memory deficits as well as levels of several pro-inflammatory cytokines were measured in response to the vaccination regimen. After vaccination, the anti-Aβ 1-42 antibody-producing mice demonstrated a significant reduction in the sera levels of 4 pro-inflammatory cytokines (TNF-α, IL-6, IL-1 α, and IL-12). Importantly, reductions in the cytokine levels of TNF-α and IL-6 were correlated with cognitive/behavioral improvement in the Tg mice. However, no differences in cerebral Aβ deposition in these mice were noted among the different control and experimental groups, i.e., Aβ 1-42 peptide vaccinated, control peptide vaccinated, or non-vaccinated mice. However, decreased levels of pro-inflammatory cytokines as well as improved cognitive performance were noted in mice vaccinated with the control peptide as well as those immunized with the Aβ 1-42 peptide. These findings suggest that reduction in pro-inflammatory cytokine levels in these mice may be utilized as an early biomarker for vaccination/treatment induced amelioration of cognitive deficits and are independent of Aβ deposition and, interestingly, antigen specific Aβ 1-42 vaccination. Since cytokine changes are typically related to T cell activation, the results imply that T cell regulation may have an important role in vaccination or other immunotherapeutic strategies in an AD mouse model and potentially in AD patients. Overall, these cytokine changes may serve as a predictive marker for AD

  9. Inflammatory Cytokines Interleukin-1β and Tumour Necrosis Factor-α - Novel Biomarkers for the Detection of Periodontal Diseases: a Literature Review.

    PubMed

    Gomes, Francisco Isaac Fernandes; Aragão, Maria Gerusa Brito; Barbosa, Francisco Cesar Barroso; Bezerra, Mirna Marques; de Paulo Teixeira Pinto, Vicente; Chaves, Hellíada Vasconcelos

    2016-01-01

    The article aims to discuss the IL-1β and TNF-α potential use as salivary biomarkers of periodontal diseases pathogenesis and progression. This literature review has been registered in PROSPERO database with following number: CRD42016035729. Data investigation was performed on PubMed database as the main source of studies. The following search terms were used: "salivary biomarkers", "periodontal diseases", "TNF-alpha", "Interleukin-1 beta". Clinical trials and animal experimental models of periodontal disease were included in the discussion. In regards to inclusive dates, published studies from January 2006 to December 2015 were considered in this review along with the mentioned inclusion criteria. IL-1β and TNF-α salivary levels increased in diseased groups, they were associated with onset and disease severity, and their levels reduced in response to periodontal therapy. IL-1β and TNF-α could be promising biomarkers in the detection of periodontal diseases. The use of a salivary cytokine-based diagnosis appears to be a screening method capable of diagnosing periodontal diseases in an early fashion, establishing an era of individualized clinical decisions.

  10. Search for Specific Biomarkers of IFNβ Bioactivity in Patients with Multiple Sclerosis

    PubMed Central

    Malhotra, Sunny; Bustamante, Marta F.; Pérez-Miralles, Francisco; Rio, Jordi; Ruiz de Villa, Mari Carmen; Vegas, Esteban; Nonell, Lara; Deisenhammer, Florian; Fissolo, Nicolás; Nurtdinov, Ramil N.; Montalban, Xavier; Comabella, Manuel

    2011-01-01

    Myxovirus A (MxA), a protein encoded by the MX1 gene with antiviral activity, has proven to be a sensitive measure of IFNβ bioactivity in multiple sclerosis (MS). However, the use of MxA as a biomarker of IFNβ bioactivity has been criticized for the lack of evidence of its role on disease pathogenesis and the clinical response to IFNβ. Here, we aimed to identify specific biomarkers of IFNβ bioactivity in order to compare their gene expression induction by type I IFNs with the MxA, and to investigate their potential role in MS pathogenesis. Gene expression microarrays were performed in PBMC from MS patients who developed neutralizing antibodies (NAB) to IFNβ at 12 and/or 24 months of treatment and patients who remained NAB negative. Nine genes followed patterns in gene expression over time similar to the MX1, which was considered the gold standard gene, and were selected for further experiments: IFI6, IFI27, IFI44L, IFIT1, HERC5, LY6E, RSAD2, SIGLEC1, and USP18. In vitro experiments in PBMC from healthy controls revealed specific induction of selected biomarkers by IFNβ but not IFNγ, and several markers, in particular USP18 and HERC5, were shown to be significantly induced at lower IFNβ concentrations and more selective than the MX1 as biomarkers of IFNβ bioactivity. In addition, USP18 expression was deficient in MS patients compared with healthy controls (p = 0.0004). We propose specific biomarkers that may be considered in addition to the MxA to evaluate IFNβ bioactivity, and to further explore their implication in MS pathogenesis. PMID:21886806

  11. Buccal Cell Cytokeratin 14 Correlates with Multiple Blood Biomarkers of Alzheimer's Disease Risk.

    PubMed

    Leifert, Wayne R; Nguyen, Tori; Rembach, Alan; Martins, Ralph; Rainey-Smith, Stephanie; Masters, Colin L; Ames, David; Rowe, Christopher C; Macaulay, S Lance; François, Maxime; Fenech, Michael F

    2015-01-01

    Mild cognitive impairment (MCI) may reflect early stages of neurodegenerative disorders such as Alzheimer's disease (AD). Our hypothesis was that cytokeratin 14 (CK14) expression could be used with blood-based biomarkers such as homocysteine, vitamin B12, and folate to identify individuals with MCI or AD from the Australian Imaging, Biomarkers and Lifestyle (AIBL) flagship study of aging. Buccal cells from 54 individuals were analyzed by a newly developed method that is rapid, automated, and quantitative for buccal cell CK14 expression levels. CK14 was negatively correlated with plasma Mg²⁺ and LDL, while positively correlated with vitamin B12, red cell hematocrit/volume, and basophils in the MCI group and positively correlated with insulin and vitamin B12 in the AD group. The combined biomarker panel (CK14 expression, plasma vitamin B12, and homocysteine) was significantly lower in the MCI (p = 0.003) and AD (p = 0.0001) groups compared with controls. Receiver-operating characteristic curves yielded area under the curve (AUC) values of 0.829 for the MCI (p = 0.002) group and 0.856 for the AD (p = 0.0003) group. These complex associations of multiple related parameters highlight the differences between the MCI and AD cohorts and possibly an underlying metabolic pathology associated with the development of early memory impairment. The changes in buccal cell CK14 expression observed in this pilot study supports previous results suggesting the peripheral biomarkers and metabolic changes are not restricted to brain pathology alone in MCI and AD and could prove useful as a potential biomarker in identifying individuals with an increased risk of developing MCI and eventually AD.

  12. Identification of potential biomarkers from microarray experiments using multiple criteria optimization.

    PubMed

    Sánchez-Peña, Matilde L; Isaza, Clara E; Pérez-Morales, Jaileene; Rodríguez-Padilla, Cristina; Castro, José M; Cabrera-Ríos, Mauricio

    2013-04-01

    Microarray experiments are capable of determining the relative expression of tens of thousands of genes simultaneously, thus resulting in very large databases. The analysis of these databases and the extraction of biologically relevant knowledge from them are challenging tasks. The identification of potential cancer biomarker genes is one of the most important aims for microarray analysis and, as such, has been widely targeted in the literature. However, identifying a set of these genes consistently across different experiments, researches, microarray platforms, or cancer types is still an elusive endeavor. Besides the inherent difficulty of the large and nonconstant variability in these experiments and the incommensurability between different microarray technologies, there is the issue of the users having to adjust a series of parameters that significantly affect the outcome of the analyses and that do not have a biological or medical meaning. In this study, the identification of potential cancer biomarkers from microarray data is casted as a multiple criteria optimization (MCO) problem. The efficient solutions to this problem, found here through data envelopment analysis (DEA), are associated to genes that are proposed as potential cancer biomarkers. The method does not require any parameter adjustment by the user, and thus fosters repeatability. The approach also allows the analysis of different microarray experiments, microarray platforms, and cancer types simultaneously. The results include the analysis of three publicly available microarray databases related to cervix cancer. This study points to the feasibility of modeling the selection of potential cancer biomarkers from microarray data as an MCO problem and solve it using DEA. Using MCO entails a new optic to the identification of potential cancer biomarkers as it does not require the definition of a threshold value to establish significance for a particular gene and the selection of a normalization

  13. Genetic Diversity in Cytokines Associated with Immune Variation and Resistance to Multiple Pathogens in a Natural Rodent Population

    PubMed Central

    Turner, Andrew K.; Begon, Mike; Jackson, Joseph A.; Bradley, Janette E.; Paterson, Steve

    2011-01-01

    Pathogens are believed to drive genetic diversity at host loci involved in immunity to infectious disease. To date, studies exploring the genetic basis of pathogen resistance in the wild have focussed almost exclusively on genes of the Major Histocompatibility Complex (MHC); the role of genetic variation elsewhere in the genome as a basis for variation in pathogen resistance has rarely been explored in natural populations. Cytokines are signalling molecules with a role in many immunological and physiological processes. Here we use a natural population of field voles (Microtus agrestis) to examine how genetic diversity at a suite of cytokine and other immune loci impacts the immune response phenotype and resistance to several endemic pathogen species. By using linear models to first control for a range of non-genetic factors, we demonstrate strong effects of genetic variation at cytokine loci both on host immunological parameters and on resistance to multiple pathogens. These effects were primarily localized to three cytokine genes (Interleukin 1 beta (Il1b), Il2, and Il12b), rather than to other cytokines tested, or to membrane-bound, non-cytokine immune loci. The observed genetic effects were as great as for other intrinsic factors such as sex and body weight. Our results demonstrate that genetic diversity at cytokine loci is a novel and important source of individual variation in immune function and pathogen resistance in natural populations. The products of these loci are therefore likely to affect interactions between pathogens and help determine survival and reproductive success in natural populations. Our study also highlights the utility of wild rodents as a model of ecological immunology, to better understand the causes and consequences of variation in immune function in natural populations including humans. PMID:22039363

  14. Bone marrow megakaryocytes, soluble P-selectin and thrombopoietic cytokines in multiple myeloma patients.

    PubMed

    Lemancewicz, Dorota; Bolkun, Lukasz; Mantur, Maria; Semeniuk, Janusz; Kloczko, Janusz; Dzieciol, Janusz

    2014-01-01

    The expression of adhesion molecules and other cell-surface molecules is substantial in the communication between plasma cells and bone marrow microenvironment, and may lead to increased proliferation of myeloma cells. Many of the cytokines involved in multiple myeloma (MM) pathogenesis, e.g. thrombopoietin (TPO) and interleukin-6 (IL-6), play a pivotal role in different developmental stages of megakaryocytopoiesis and thrombopoiesis. The principal aim of our study was to explore the relationship between thrombopoietic cytokines, megakaryocytes (MKs) and soluble P-selectin (sP-selectin) levels in MM patients before and after anti-angiogenic treatment. Forty-four patients (20 female and 24 male) with a newly diagnosed MM were examined in three groups, following a division based on the International Staging System, ISS. Plasma levels of TPO, IL-6 and soluble P-selectin (human sP-selectin) were measured by means of ELISA. Bone marrow specimens were studied to determine the number of MKs and the so-called "naked nuclei" (NN), as well as the expression of platelet-derived growth factor (PDGF). The comparison revealed a significantly higher concentration of cytokines and sP-selectin in newly diagnosed MM patients compared to healthy volunteers: for TPO, p=0.01, IL-6, p=0.0005 and sP-selectin, p=0.00008, respectively. Marked differences were observed in the concentration of sP-selectin, expression of PDGF and MKs counts between patients with MM stage I and MM stage III. Statistically meaningful correspondences were also found between MKs versus TPO, NN versus TPO, as well as MKs versus MPV, p=0.009, p=0.004 and p=0.0005, respectively. Furthermore, the analysis exhibited some statistically meaningful divergences between initial concentrations of sP-selectin in subgroups with different response after chemotherapy. The initial concentration of sP-selectin in the group of MM patients with complete or partial remission stood at 31.86 ± 6.13 ng/ml. In the remaining patients

  15. A Novel Electrochemical Microfluidic Chip Combined with Multiple Biomarkers for Early Diagnosis of Gastric Cancer

    NASA Astrophysics Data System (ADS)

    Xie, Yao; Zhi, Xiao; Su, Haichuan; Wang, Kan; Yan, Zhen; He, Nongyue; Zhang, Jingpu; Chen, Di; Cui, Daxiang

    2015-12-01

    Early diagnosis is very important to improve the survival rate of patients with gastric cancer and to understand the biology of cancer. In order to meet the clinical demands for early diagnosis of gastric cancer, we developed a disposable easy-to-use electrochemical microfluidic chip combined with multiple antibodies against six kinds of biomarkers (carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), Helicobacter pylori CagA protein (H.P.), P53oncoprotein (P53), pepsinogen I (PG I), and PG-II). The six kinds of biomarkers related to gastric cancer can be detected sensitively and synchronously in a short time. The specially designed three electrodes system enables cross-contamination to be avoided effectively. The linear ranges of detection of the electrochemical microfluidic chip were as follows: 0.37-90 ng mL-1 for CEA, 10.75-172 U mL-1 for CA19-9, 10-160 U L-1 for H.P., 35-560 ng mL-1 for P53, 37.5-600 ng mL-1 for PG I, and 2.5-80 ng mL-1for PG II. This method owns better sensitivity compared with enzyme-linked immunosorbent assay (ELISA) results of 394 specimens of gastric cancer sera. Furthermore, we established a multi-index prediction model based on the six kinds of biomarkers for predicting risk of gastric cancer. In conclusion, the electrochemical microfluidic chip for detecting multiple biomarkers has great potential in applications such as early screening of gastric cancer patients, and therapeutic evaluation, and real-time dynamic monitoring the progress of gastric cancer in near future.

  16. A Novel Electrochemical Microfluidic Chip Combined with Multiple Biomarkers for Early Diagnosis of Gastric Cancer.

    PubMed

    Xie, Yao; Zhi, Xiao; Su, Haichuan; Wang, Kan; Yan, Zhen; He, Nongyue; Zhang, Jingpu; Chen, Di; Cui, Daxiang

    2015-12-01

    Early diagnosis is very important to improve the survival rate of patients with gastric cancer and to understand the biology of cancer. In order to meet the clinical demands for early diagnosis of gastric cancer, we developed a disposable easy-to-use electrochemical microfluidic chip combined with multiple antibodies against six kinds of biomarkers (carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), Helicobacter pylori CagA protein (H.P.), P53oncoprotein (P53), pepsinogen I (PG I), and PG-II). The six kinds of biomarkers related to gastric cancer can be detected sensitively and synchronously in a short time. The specially designed three electrodes system enables cross-contamination to be avoided effectively. The linear ranges of detection of the electrochemical microfluidic chip were as follows: 0.37-90 ng mL(-1) for CEA, 10.75-172 U mL(-1) for CA19-9, 10-160 U L(-1) for H.P., 35-560 ng mL(-1) for P53, 37.5-600 ng mL(-1) for PG I, and 2.5-80 ng mL(-1)for PG II. This method owns better sensitivity compared with enzyme-linked immunosorbent assay (ELISA) results of 394 specimens of gastric cancer sera. Furthermore, we established a multi-index prediction model based on the six kinds of biomarkers for predicting risk of gastric cancer. In conclusion, the electrochemical microfluidic chip for detecting multiple biomarkers has great potential in applications such as early screening of gastric cancer patients, and therapeutic evaluation, and real-time dynamic monitoring the progress of gastric cancer in near future.

  17. Mycobacterium tuberculosis PPD-induced immune biomarkers measurable in vitro following BCG vaccination of UK adolescents by multiplex bead array and intracellular cytokine staining.

    PubMed

    Smith, Steven G; Lalor, Maeve K; Gorak-Stolinska, Patricia; Blitz, Rose; Beveridge, Natalie E R; Worth, Andrew; McShane, Helen; Dockrell, Hazel M

    2010-07-07

    The vaccine efficacy reported following Mycobacterium bovis Bacillus Calmette Guerin (BCG) administration to UK adolescents is 77% and defining the cellular immune response in this group can inform us as to the nature of effective immunity against tuberculosis. The aim of this study was to identify which cytokines and lymphocyte populations characterise the peripheral blood cellular immune response following BCG vaccination. Diluted blood from before and after vaccination was stimulated with Mycobacterium tuberculosis purified protein derivative for 6 days, after which soluble biomarkers in supernatants were assayed by multiplex bead array. Ten out of twenty biomarkers measured were significantly increased (p < 0.0025) 1 month after BCG vaccination when compared to paired samples (n = 12) taken prior to vaccination (IFNgamma, TNFalpha, IL-1alpha, IL-2, IL-6, IL-10, IL-17, GM-CSF, MIP1alpha, IP-10). All of these remained detectable by multiplex bead array in samples taken 12 months after BCG vaccination of a partially overlapping adolescent group (n = 12). Intracellular cytokine staining after 24 hour Mycobacterium tuberculosis purified protein derivative stimulation of PBMC samples from the 12 month group revealed that IFNgamma expression was detectable in CD4 and CD8 T-cells and natural killer cells. Polyfunctional flow cytometry analysis demonstrated that cells expressing IFNgamma alone formed the majority in each subpopulation of cells. Only in CD4 T-cells and NK cells were there a notable proportion of responding cells of a different phenotype and these were single positive, TNFalpha producers. No significant expression of the cytokines IL-2, IL-17 or IL-10 was seen in any population of cells. The broad array of biomarker responses detected by multiplex bead array suggests that BCG vaccination is capable, in this setting, of inducing a complex immune phenotype. Although polyfunctional T-cells have been proposed to play a role in protective immunity, they were

  18. Mycobacterium tuberculosis PPD-induced immune biomarkers measurable in vitro following BCG vaccination of UK adolescents by multiplex bead array and intracellular cytokine staining

    PubMed Central

    2010-01-01

    Background The vaccine efficacy reported following Mycobacterium bovis Bacillus Calmette Guerin (BCG) administration to UK adolescents is 77% and defining the cellular immune response in this group can inform us as to the nature of effective immunity against tuberculosis. The aim of this study was to identify which cytokines and lymphocyte populations characterise the peripheral blood cellular immune response following BCG vaccination. Results Diluted blood from before and after vaccination was stimulated with Mycobacterium tuberculosis purified protein derivative for 6 days, after which soluble biomarkers in supernatants were assayed by multiplex bead array. Ten out of twenty biomarkers measured were significantly increased (p < 0.0025) 1 month after BCG vaccination when compared to paired samples (n = 12) taken prior to vaccination (IFNγ, TNFα, IL-1α, IL-2, IL-6, IL-10, IL-17, GM-CSF, MIP1α, IP-10). All of these remained detectable by multiplex bead array in samples taken 12 months after BCG vaccination of a partially overlapping adolescent group (n = 12). Intracellular cytokine staining after 24 hour Mycobacterium tuberculosis purified protein derivative stimulation of PBMC samples from the 12 month group revealed that IFNγ expression was detectable in CD4 and CD8 T-cells and natural killer cells. Polyfunctional flow cytometry analysis demonstrated that cells expressing IFNγ alone formed the majority in each subpopulation of cells. Only in CD4 T-cells and NK cells were there a notable proportion of responding cells of a different phenotype and these were single positive, TNFα producers. No significant expression of the cytokines IL-2, IL-17 or IL-10 was seen in any population of cells. Conclusions The broad array of biomarker responses detected by multiplex bead array suggests that BCG vaccination is capable, in this setting, of inducing a complex immune phenotype. Although polyfunctional T-cells have been proposed to play a role in protective immunity

  19. Exploring the human tear fluid: discovery of new biomarkers in multiple sclerosis.

    PubMed

    Salvisberg, Cindy; Tajouri, Nadja; Hainard, Alexandre; Burkhard, Pierre R; Lalive, Patrice H; Turck, Natacha

    2014-04-01

    Multiple sclerosis is the first cause of progressive neurological disability among young adults living in Western countries. Its diagnosis is mostly based on clinical evaluation, neuroimaging, and in some cases cerebrospinal fluid (CSF) analysis, but no definitive diagnostic test exists. We proposed here that the exploration of tears from multiple sclerosis patients could lead to the discovery of new biomarkers. Thirty multiple sclerosis patients (20% men) recruited to the Geneva University Hospitals were included in our study (mean age ± SD [years]: 42.4 ± 15.9). Twenty-five control patients (32% men) were also enrolled (mean age ± SD [years]: 42.7±15.1). Tears, CSF or blood was collected for each patient. Three independent quantitative (tandem mass tag) experiments were carried out between tears from multiple sclerosis and control patients. Protein verification was performed by Western blot on tears and CSF and by ELISA on serum samples. Combined proteomics analyses provided 185 identified tear proteins. Among the differential proteins, alpha-1 antichymotrypsin was the only one to be significantly increased in the three experiments with similar ratios (ratios 1.6 to 2.5, p < 0.05). Its tear, CSF and serum elevation were further confirmed by Western blot and ELISA, respectively. This study supports the concept that modifications of the tear proteome can reflect biological abnormalities associated with multiple sclerosis and perhaps other inflammatory conditions affecting the CNS. In addition, alpha-1 antichymotrypsin elevation in tear fluid emerges as a promising biomarker for the diagnosis of multiple sclerosis. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  20. Anthocyanin-rich extracts inhibit multiple biomarkers of colon cancer in rats.

    PubMed

    Lala, Geeta; Malik, Minnie; Zhao, Cuiwei; He, Jian; Kwon, Youngjoo; Giusti, M Monica; Magnuson, Bernadene A

    2006-01-01

    The aim of the present study was to investigate the chemoprotective activity of anthocyanin-rich extracts (AREs) from bilberry (Vaccinium myrtillus L.), chokeberry (Aronia meloncarpa E.), and grape (Vitis vinifera) by assessing multiple biomarkers of colon cancer in male rats treated with a colon carcinogen, azoxymethane. Fischer 344 male rats were fed the AIN-93 diet (control) or AIN-93 diet supplemented with AREs for 14 wk. Biomarkers that were evaluated included the number and multiplicity of colonic aberrant crypt foci (ACF), colonic cell proliferation, urinary levels of oxidative DNA damage, and expression of cyclooxygenase (COX) genes. To assess the bioavailability, levels of anthocyanins in serum, urine, and feces were evaluated. Total ACF were reduced (P<0.05) in bilberry, chokeberry, and grape diet groups compared with the control group. The number of large ACF was also reduced (P<0.05) in bilberry and chokeberry ARE-fed rats. Colonic cellular proliferation was decreased in rats fed bilberry ARE and chokeberry ARE diets. Rats fed bilberry and grape ARE diets had lower COX-2 mRNA expression of gene. High levels of fecal anthocyanins and increased fecal mass and fecal moisture occurred in ARE-fed rats. There was also a significant reduction (P<0.05) in fecal bile acids in ARE-fed rats. The levels of urinary 8-hydroxyguanosine were similar among rats fed different diets. These results support our previous in vitro studies suggesting a protective role of AREs in colon carcinogenesis and indicate multiple mechanisms of action.

  1. Patients with Alzheimer disease with multiple microbleeds: relation with cerebrospinal fluid biomarkers and cognition.

    PubMed

    Goos, Jeroen D C; Kester, M I; Barkhof, Frederik; Klein, Martin; Blankenstein, Marinus A; Scheltens, Philip; van der Flier, Wiesje M

    2009-11-01

    Microbleeds (MBs) are commonly observed in Alzheimer disease. A minority of patients has multiple MBs. We aimed to investigate associations of multiple MBs in Alzheimer disease with clinical and MRI characteristics and cerebrospinal fluid biomarkers. Patients with Alzheimer disease with multiple (>or=8) MBs on T2*-weighted MRI were matched for age, sex, and field strength with patients with Alzheimer disease without MBs on a 1:2 basis. We included 21 patients with multiple MBs (73+/-7 years, 33% female) and 42 patients without MBs (72+/-7 years, 38% female). Mini-Mental State Examination was used to assess dementia severity. Cognitive functions were assessed using neuropsychological tests. Medial temporal lobe atrophy (0 to 4), global cortical atrophy (0 to 3), and white matter hyperintensities (0 to 30) were assessed using visual rating scales. In a subset, apolipoprotein E genotype and cerebrospinal fluid amyloid beta 1-42, total tau and tau phosphorylated at threonine 181 were determined. Patients with multiple MBs performed worse on Mini-Mental State Examination (multiple MB: 17+/-7; no MB: 22+/-4, P<0.05) despite similar disease duration. Atrophy was not related to presence of MBs, but patients with multiple MBs had more white matter hyperintensities (multiple MB: 8.8+/-4.8; no MB: 3.2+/-3.6, P<0.05). Adjusted for age, sex, white matter hyperintensities, and medial temporal lobe atrophy, the multiple MB group additionally performed worse on Visual Association Test object naming and animal fluency. Patients with multiple MBs had lower cerebrospinal fluid amyloid beta 1-42 levels (307+/-61) than patients without MBs (505+/-201, P<0.05). Adjusted for the same covariates, total tau, and tau phosphorylated at threonine 181 were higher in the multiple MB group. Microbleeds are associated with the clinical manifestation and biochemical hallmarks of Alzheimer disease, suggesting possible involvement of MBs in the pathogenesis of Alzheimer disease.

  2. Effect of multiple cytokines plus bacterial endotoxin on glucose and nitric oxide production by cultured hepatocytes.

    PubMed

    Ceppi, E D; Smith, F S; Titheradge, M A

    1996-07-15

    Treatment of cultured hepatocytes with a combination of cytokines, including tumour necrosis factor-alpha, interferon-gamma and interleukin-1 beta, plus lipopolysaccharide resulted in a time-dependent induction of nitric oxide (NO) synthase (as measured by NO2- (+) NO3- production) and inhibition of hepatic gluconeogenesis and glycogen breakdown. The inhibition of glucose release was comparable with the observed following treatment of rats with lipopolysaccharide or treatment of isolated hepatocytes with artificial NO donors. In addition, this effect was also evident with all substrates tested that enter the gluconeogenic pathway below the level of phosphoenolpyruvate carboxykinase, suggesting that this combination of cytokines may underlie the inhibition of gluconeogenesis observed in endotoxic shock. The maximal inhibition of glucose output required the presence of all the cytokines plus lipopolysaccharide, whereas the induction of NO synthase was independent of the lipopolysaccharide when the cytokines were employed. Inclusion of interferon-gamma was essential to obtain a maximal response for either parameter. Inclusion of 1 mM N(G)-monomethyl-L-arginine in the incubation abolished the increase in NO2- (+) NO3- observed with the complete cytokine mixture and various combinations; however, it failed to prevent the inhibition in glucose output, indicating that mechanisms other than NO underlie the cytokine-induced inhibition of glucose release.

  3. Pro-inflammatory cytokines and structural biomarkers are effective to categorize osteoarthritis phenotype and progression in Standardbred racehorses over five years of racing career.

    PubMed

    Bertuglia, Andrea; Pagliara, Eleonora; Grego, Elena; Ricci, Alessandro; Brkljaca-Bottegaro, Nika

    2016-11-08

    Joint impact injuries initiate a progressive articular damage finally leading to post-traumatic osteoarthritis (PTOA). Racehorses represent an ideal, naturally available, animal model of the disease. Standardbred racehorses developing traumatic osteoarthritis of the fetlock joint during the first year of their career were enrolled in our study. Age-matched controls were contemporarily included. Biomarker levels of equine osteoarthritis were measured in serum and synovial fluid (SF) at baseline, and repeated yearly over the next 4 years of training (from T1 to T4). The effect of time and disease on the biomarker concentrations were analysed, and their relationship with clinical and radiographic parameters were assessed. We hypothesized that the kinetics of pro-inflammatory cytokines and structural biomarkers of joint disease would demonstrate progression of degenerative joint status during post-traumatic osteoarthritis and clarify the effect of early joint trauma. The concentrations of IL1-ß, IL-6, TNF-α in the SF of PTOA group peaked at T0, decreased at T1, and then progressively increased with time, reaching levels higher than those observed at baseline starting from T3. CTXII and COMP levels were similar in PTOA and control horses at baseline, and increased in serum and synovial fluid of PTOA horses starting from T2 (serum and synovial CTXII, and serum COMP) or T3 (synovial COMP). The percentual change of TNF-α in the SF of the affected joints independently contributed to explaining the radiological changes at T3 vs T2 and T4 vs T3. Temporal changes of selected biomarkers in STBRs with an acute episode of traumatic fetlock OA demonstrated that long-term increased concentrations of inflammatory cytokines, type II collagen fragments and COMP, in the SF and serum, are related to PTOA. Based on the observed decrease in inflammatory merkers at T1, we hypothesize that the progression of PTOA could be effectively modulated by proper treatment strategies. Annual

  4. Tumor necrosis factor and its targets in the inflammatory cytokine pathway are identified as putative transcriptomic biomarkers for escitalopram response.

    PubMed

    Powell, Timothy R; Schalkwyk, Leonard C; Heffernan, Andrew L; Breen, Gerome; Lawrence, Timothy; Price, Tom; Farmer, Anne E; Aitchison, Katherine J; Craig, Ian W; Danese, Andrea; Lewis, Cathryn; McGuffin, Peter; Uher, Rudolf; Tansey, Katherine E; D'Souza, Ursula M

    2013-09-01

    Converging evidence suggests that the activation of the inflammatory cytokine pathway is important in the pathophysiology of unipolar depression. Antidepressants have anti-inflammatory properties and evidence suggests that inter-individual variability in response to antidepressants may reflect genetic differences in the inflammatory cytokine pathway. In particular, protein levels of Tumor Necrosis Factor (TNF) and the SNPs rs1126757 in interleukin-11 (IL11), and rs7801617 in interleukin-6 (IL6), have previously been implicated in the clinical response to the selective serotonin reuptake inhibitor (SSRI) antidepressant escitalopram. This study investigated the transcription of TNF, IL11 and IL6 as well as genes in the wider inflammatory cytokine pathway both at baseline and after escitalopram treatment in depressed patients who were either clinical "responders" (n=25) or "non-responders" (n=21). Samples were obtained as a subset of the Genome-Based Therapeutic Drugs for Depression (GENDEP) project and response status is based on changes in the Montgomery-Asberg Depression Rating Scores over a 12 wk treatment period. Binary logistic regressions revealed significant expression differences at baseline between responders and non-responders in TNF, and after escitalopram treatment in TNF and IL11. Differences in IL11 after treatment were found to be driven by drug-induced allele-specific expression differences relating to rs1126757. Top hits in the wider inflammatory cytokine pathway at both baseline and after escitalopram treatment were found to be targets of TNF. The current study adds substantial support for the role of the inflammatory cytokine pathway in mediating response to the SSRI escitalopram, and is the first to identify TNF and its targets as putative transcriptomic predictors of clinical response.

  5. Covalently deposited dyes: a new chromogen paradigm that facilitates analysis of multiple biomarkers in situ.

    PubMed

    Day, William A; Lefever, Mark R; Ochs, Robert L; Pedata, Anne; Behman, Lauren J; Ashworth-Sharpe, Julia; Johnson, Donald D; May, Eric J; Grille, James G; Roberts, Esteban A; Kosmeder, Jerry W; Morrison, Larry E

    2017-01-01

    Multiplexed analysis of multiple biomarkers in a tissue sample requires use of reporter dyes with specific spectral properties that enable discrimination of signals. Conventional chromogens with broad absorbance spectra, widely used in immunohistochemistry (IHC), offer limited utility for multiplexed detection. Many dyes with narrow absorbance spectra, eg rhodamines, fluoresceins, and cyanines, potentially useful for multiplexed detection are well-characterized; however, generation of a chromogenic reagent useful for IHC analysis has not been demonstrated. Studies reported herein demonstrate utility of tyramine-chemistry for synthesis of a wide variety of new chromogenic dye conjugates useful for multiplexed in situ analysis using conventional light microscopes. The dyes, useful individually or in blends to generate new colors, provide signal sensitivity and dynamic range similar to conventional DAB chromogen, while enabling analysis of co-localized biomarkers. It is anticipated that this new paradigm will enable generation of a wide variety of new chromogens, useful for both research and clinical biomarker analysis that will benefit clinicians and patients.

  6. Cerebrospinal fluid fetuin-A is a biomarker of active multiple sclerosis.

    PubMed

    Harris, Violaine K; Donelan, Nicola; Yan, Qi Jiang; Clark, Kristi; Touray, Amir; Rammal, Mustapha; Sadiq, Saud A

    2013-10-01

    There is an urgent need for biomarkers in multiple sclerosis (MS) that can reliably measure ongoing disease activity relative to inflammation, neurodegeneration, and demyelination/remyelination. Fetuin-A was recently identified as a potential biomarker in MS cerebrospinal fluid (CSF). Fetuin-A has diverse functions, including a role in immune pathways. The objective of this research is to investigate whether fetuin-A is a direct indicator of disease activity. We measured fetuin-A in CSF and plasma of patients with MS and correlated these findings to clinical disease activity and natalizumab response. Fetuin-A expression was characterized in MS brain tissue and in experimental autoimmune encephalomyelitis (EAE) mice. We also examined the pathogenic role of fetuin-A in EAE using fetuin-A-deficient mice. Elevated CSF fetuin-A correlated with disease activity in MS. In natalizumab-treated patients, CSF fetuin-A levels were reduced one year post-treatment, correlating with therapeutic response. Fetuin-A was markedly elevated in demyelinated lesions and in gray matter within MS brain tissue. Similarly, fetuin-A was elevated in degenerating neurons around demyelinated lesions in EAE. Fetuin-A-deficient mice demonstrated delayed onset and reduced severity of EAE symptoms. Our results show that CSF fetuin-A is a biomarker of disease activity and natalizumab response in MS. Neuronal expression of fetuin-A suggests that fetuin-A may play a pathological role in the disease process.

  7. Biological frontiers in multiple myeloma: From biomarker identification to clinical practice

    PubMed Central

    Landgren, Ola; Morgan, Gareth J.

    2017-01-01

    Since the mid-1990s, the multiple myeloma (MM) treatment landscape has evolved considerably, which has led to improved patient outcomes and prolonged survival. In addition to discovering new, targeted agents or treatment regimens, the identification and validation of biomarkers has the potential to further improve patient outcomes. The International Staging System (ISS) relies on a number of biochemical parameters to stratify patients into risk categories. Other biologically relevant markers that are indicative of inherited genetic variation (e.g., single nucleotide polymorphisms) or tumor acquired genetic events (e.g., chromosomal translocations or mutations) have been studied for their prognostic potential. In patients with high-risk (HR) cytogenetics, plasma cells (PCs) undergo genetic shifts over time, which may partially explain why HR patients relapse and are so difficult to treat. Although novel agents have improved treatment outcomes, identification of markers that will enable clinicians to determine which treatment is most appropriate for HR patients following initial diagnosis represents an exciting frontier in the clinical management of MM. Biomarkers based on quantitating PCs or factors that are secreted from them (e.g., serum free light chain) may also help to risk-stratify patients with asymptomatic MM. Eventually, identification of novel biomarkers may lead to the creation of personalized treatment regimens that are optimized to target clonal PCs that express a specific oncogenomic profile. Although the future is exciting, validation will be necessary before these biologic and molecular beacons can inform decision-making processes in a routine clinical setting. PMID:24270684

  8. A Minimally-invasive Blood-derived Biomarker of Oligodendrocyte Cell-loss in Multiple Sclerosis.

    PubMed

    Olsen, John A; Kenna, Lauren A; Tipon, Regine C; Spelios, Michael G; Stecker, Mark M; Akirav, Eitan M

    2016-08-01

    Multiple sclerosis (MS) is a neurodegenerative disease of the central nervous system (CNS). Minimally invasive biomarkers of MS are required for disease diagnosis and treatment. Differentially methylated circulating-free DNA (cfDNA) is a useful biomarker for disease diagnosis and prognosis, and may offer to be a viable approach for understanding MS. Here, methylation-specific primers and quantitative real-time PCR were used to study methylation patterns of the myelin oligodendrocyte glycoprotein (MOG) gene, which is expressed primarily in myelin-producing oligodendrocytes (ODCs). MOG-DNA was demethylated in O4(+) ODCs in mice and in DNA from human oligodendrocyte precursor cells (OPCs) when compared with other cell types. In the cuprizone-fed mouse model of demyelination, ODC derived demethylated MOG cfDNA was increased in serum and was associated with tissue-wide demyelination, demonstrating the utility of demethylated MOG cfDNA as a biomarker of ODC death. Collected sera from patients with active (symptomatic) relapsing-remitting MS (RRMS) demonstrated a higher signature of demethylated MOG cfDNA when compared with patients with inactive disease and healthy controls. Taken together, these results offer a minimally invasive approach to measuring ODC death in the blood of MS patients that may be used to monitor disease progression. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  9. Biomarkers of sepsis.

    PubMed

    Faix, James D

    2013-01-01

    Sepsis is an unusual systemic reaction to what is sometimes an otherwise ordinary infection, and it probably represents a pattern of response by the immune system to injury. A hyper-inflammatory response is followed by an immunosuppressive phase during which multiple organ dysfunction is present and the patient is susceptible to nosocomial infection. Biomarkers to diagnose sepsis may allow early intervention which, although primarily supportive, can reduce the risk of death. Although lactate is currently the most commonly used biomarker to identify sepsis, other biomarkers may help to enhance lactate's effectiveness; these include markers of the hyper-inflammatory phase of sepsis, such as pro-inflammatory cytokines and chemokines; proteins such as C-reactive protein and procalcitonin which are synthesized in response to infection and inflammation; and markers of neutrophil and monocyte activation. Recently, markers of the immunosuppressive phase of sepsis, such as anti-inflammatory cytokines, and alterations of the cell surface markers of monocytes and lymphocytes have been examined. Combinations of pro- and anti-inflammatory biomarkers in a multi-marker panel may help identify patients who are developing severe sepsis before organ dysfunction has advanced too far. Combined with innovative approaches to treatment that target the immunosuppressive phase, these biomarkers may help to reduce the mortality rate associated with severe sepsis which, despite advances in supportive measures, remains high.

  10. Biomarkers of sepsis

    PubMed Central

    2013-01-01

    Sepsis is an unusual systemic reaction to what is sometimes an otherwise ordinary infection, and it probably represents a pattern of response by the immune system to injury. A hyper-inflammatory response is followed by an immunosuppressive phase during which multiple organ dysfunction is present and the patient is susceptible to nosocomial infection. Biomarkers to diagnose sepsis may allow early intervention which, although primarily supportive, can reduce the risk of death. Although lactate is currently the most commonly used biomarker to identify sepsis, other biomarkers may help to enhance lactate’s effectiveness; these include markers of the hyper-inflammatory phase of sepsis, such as pro-inflammatory cytokines and chemokines; proteins such as C-reactive protein and procalcitonin which are synthesized in response to infection and inflammation; and markers of neutrophil and monocyte activation. Recently, markers of the immunosuppressive phase of sepsis, such as anti-inflammatory cytokines, and alterations of the cell surface markers of monocytes and lymphocytes have been examined. Combinations of pro- and anti-inflammatory biomarkers in a multi-marker panel may help identify patients who are developing severe sepsis before organ dysfunction has advanced too far. Combined with innovative approaches to treatment that target the immunosuppressive phase, these biomarkers may help to reduce the mortality rate associated with severe sepsis which, despite advances in supportive measures, remains high. PMID:23480440

  11. MicroRNAs in Cerebrospinal Fluid as Potential Biomarkers for Parkinson's Disease and Multiple System Atrophy.

    PubMed

    Marques, Tainá M; Kuiperij, H Bea; Bruinsma, Ilona B; van Rumund, Anouke; Aerts, Marjolein B; Esselink, Rianne A J; Bloem, Bas R; Verbeek, Marcel M

    2016-11-14

    Parkinson's disease (PD) and multiple system atrophy (MSA) are both part of the spectrum of neurodegenerative movement disorders and α-synucleinopathies with overlap of symptoms especially at early stages of the disease but with distinct disease progression and responses to dopaminergic treatment. Therefore, having biomarkers that specifically classify patients, which could discriminate PD from MSA, would be very useful. MicroRNAs (miRNAs) regulate protein translation and are observed in biological fluids, including cerebrospinal fluid (CSF), and may therefore have potential as biomarkers of disease. The aim of our study was to determine if miRNAs in CSF could be used as biomarkers for either PD or MSA. Using quantitative PCR (qPCR), we evaluated expression levels of 10 miRNAs in CSF patient samples from PD (n = 28), MSA (n = 17), and non-neurological controls (n = 28). We identified two miRNAs (miR-24 and miR-205) that distinguished PD from controls and four miRNAs that differentiated MSA from controls (miR-19a, miR-19b, miR-24, and miR-34c). Combinations of miRNAs accurately discriminated either PD (area under the curve (AUC) = 0.96) or MSA (AUC = 0.86) from controls. In MSA, we also observed that miR-24 and miR-148b correlated with cerebellar ataxia symptoms, suggesting that these miRNAs are involved in cerebellar degeneration in MSA. Our findings support the potential of miRNA panels as biomarkers for movement disorders and may provide more insights into the pathological mechanisms related to these disorders.

  12. Multiple Inflammatory Biomarkers in Relation to Cardiovascular Events and Mortality in the Community

    PubMed Central

    Schnabel, Renate B.; Yin, Xiaoyan; Larson, Martin G.; Yamamoto, Jennifer F.; Fontes, João D.; Kathiresan, Sekar; Rong, Jian; Levy, Daniel; Keaney, John F.; Wang, Thomas J.; Murabito, Joanne M.; Vasan, Ramachandran S.; Benjamin, Emelia J.

    2013-01-01

    Objective Evidence suggests that chronic low-grade inflammation and oxidative stress are related to cardiovascular disease (CVD) and mortality. Approach and Results We examined 11 established and novel biomarkers representing inflammation and oxidative stress (C-reactive protein [CRP], fibrinogen, interleukin-6, intercellular adhesion molecule-1 [ICAM-1], lipoprotein-associated phospholipase A2 (mass and activity), monocyte chemoattractant protein-1, myeloperoxidase, CD40 ligand, P-selectin, tumor necrosis factor receptor II [TNFRII]) in relation to incident major CVD and mortality in the community. We studied 3035 participants (mean age 61±9 years, 53% women). During follow-up (median 8.9 years), 253 participants experienced a CVD event and 343 died. CRP (hazard ratios [HR] reported per standard deviation ln-transformed biomarker, 1.18, 95% confidence interval [CI] 1.02-1.35; nominal P=0.02) and TNFRII (HR 1.15, 95% CI; 1.01-1.32; nominal P=0.04) were retained in multivariable-adjusted models for major CVD, but were not significant after adjustment for multiple testing. The biomarkers related to mortality were TNFRII (HR 1.33, 95% CI: 1.19-1.49; P<0.0001); ICAM-1 (HR 1.24, 95% CI: 1.12-1.37; P<0.0001), and interleukin-6 (HR 1.25, 95% CI: 1.12-1.39; P<0.0001). The addition of these markers to the model including traditional risk factors increased discrimination and reclassification for risk of death (P<0.0001), but not for CVD. Conclusions Of 11 biomarkers, TNFRII was associated nominally with incident major CVD, and significantly with all-cause mortality, which renders it an interesting target for future research. The combination of TNFRII with CRP in relation to CVD and with interleukin-6 to mortality increased the predictive ability in addition to CVD risk factors for total mortality but not for incident CVD. PMID:23640499

  13. Circulating miR-150 in CSF is a novel candidate biomarker for multiple sclerosis

    PubMed Central

    Bergman, Petra; Piket, Eliane; Khademi, Mohsen; James, Tojo; Brundin, Lou; Olsson, Tomas; Piehl, Fredrik

    2016-01-01

    Objective: To explore circulating microRNAs (miRNAs) in cell-free CSF as novel biomarkers for multiple sclerosis (MS). Methods: Profiling of miRNAs in CSF of pooled patients with clinically isolated syndrome (CIS), patients with relapsing-remitting MS, and inflammatory and noninflammatory neurologic disease controls was performed using TaqMan miRNA arrays. Two independent patient cohorts (n = 142 and n = 430) were used for validation with real-time PCR. Results: We reliably detected 88 CSF miRNAs in the exploratory cohort. Subsequent validation in 2 cohorts demonstrated significantly higher levels of miR-150 in patients with MS. Higher miR-150 levels were also observed in patients with CIS who converted to MS compared to nonconverters, and in patients initiating natalizumab treatment. Levels of miR-150 correlated with immunologic parameters including CSF cell count, immunoglobulin G index, and presence of oligoclonal bands, and with candidate protein biomarkers C-X-C motif chemokine 13, matrix metallopeptidase 9, and osteopontin. Correlation with neurofilament light chain (NFL) was observed only when NFL was adjusted for age using a method that requires further validation. Additionally, miR-150 discriminated MS from controls and CIS converters from nonconverters equally well as the most informative protein biomarkers. Following treatment with natalizumab, but not fingolimod, CSF levels of miR-150 decreased, while plasma levels increased with natalizumab and decreased with fingolimod, suggesting immune cells as a source of miR-150. Conclusions: Our findings demonstrate miR-150 as a putative novel biomarker of inflammatory active disease with the potential to be used for early diagnosis of MS. Classification of evidence: This study provides Class II evidence that CSF miR-150 distinguishes patients with MS from patients with other neurologic conditions. PMID:27144214

  14. Multiple biomarkers responses in Prochilodus lineatus allowed assessing changes in the water quality of Salado River basin (Santa Fe, Argentina).

    PubMed

    Cazenave, Jimena; Bacchetta, Carla; Parma, María J; Scarabotti, Pablo A; Wunderlin, Daniel A

    2009-11-01

    This field study assessed water quality of Salado River basin by using a set of biomarkers in the fish Prochilodus lineatus. Multiple biomarkers were measured, including morphological indexes (condition factor, liver somatic index), hematological (red and white blood cells) and biochemical (glucose, total protein and cholinesterase activity) parameters. Besides, detoxication and oxidative stress markers (antioxidant enzymes, lipid peroxidation) were measured in liver, gills and kidney. Despite water quality assessment did not show marked differences among sites, biomarkers responses indicate that fish are living under stressful environmental conditions. According to multivariate analysis glucose, glutathione S-transferase activity, lipid peroxidation levels and the count of white blood cells are key biomarkers to contribute to discrimination of sites. So, we suggest use those biomarkers in future monitoring of freshwater aquatic systems.

  15. Serum B-cell maturation antigen: a novel biomarker to predict outcomes for multiple myeloma patients.

    PubMed

    Ghermezi, Michael; Li, Mingjie; Vardanyan, Suzie; Harutyunyan, Nika Manik; Gottlieb, Jillian; Berenson, Ariana; Spektor, Tanya M; Andreu-Vieyra, Claudia; Petraki, Sophia; Sanchez, Eric; Udd, Kyle; Wang, Cathy S; Swift, Regina A; Chen, Haiming; Berenson, James R

    2017-04-01

    B-cell maturation antigen is expressed on plasma cells. In this study, we have identified serum B-cell maturation antigen as a novel biomarker that can monitor and predict outcomes for multiple myeloma patients. Compared to healthy donors, patients with multiple myeloma showed elevated serum B-cell maturation antigen levels (P<0.0001). Serum B-cell maturation antigen levels correlated with the proportion of plasma cells in bone marrow biopsies (Spearman's rho = 0.710; P<0.001), clinical status (complete response vs partial response, P=0.0374; complete response vs progressive disease, P<0.0001), and tracked with changes in M-protein levels. Among patients with non-secretory disease, serum B-cell maturation antigen levels correlated with bone marrow plasma cell levels and findings from positron emission tomography scans. Kaplan-Meier analysis demonstrated that serum B-cell maturation antigen levels above the median levels were predictive of a shorter progression-free survival (P=0.0006) and overall survival (P=0.0108) among multiple myeloma patients (n=243). Specifically, patients with serum B-cell maturation antigen levels above the median level at the time of starting front-line (P=0.0043) or a new salvage therapy (P=0.0044) were found to have shorter progression-free survival. Importantly, serum B-cell maturation antigen levels did not show any dependence on renal function and maintained independent significance when tested against other known prognostic markers for multiple myeloma such as age, serum β2 microglobulin, hemoglobin, and bone disease. These data identify serum B-cell maturation antigen as a new biomarker to manage multiple myeloma patients. Copyright© Ferrata Storti Foundation.

  16. Correlation between TH1 response standard cytokines as biomarkers in patients with the delta virus in the western Brazilian Amazon

    PubMed Central

    Nicolete, Larissa Deadame de Figueiredo; Borzacov, Lourdes Maria Pinheiro; Vieira, Deusilene Souza; Nicolete, Roberto; Salcedo, Juan Miguel Villalobos

    2016-01-01

    Hepatitis D virus (HDV) is endemic in the Amazon Region and its pathophysiology is the most severe among viral hepatitis. Treatment is performed with pegylated interferon and the immune response appears to be important for infection control. HDV patients were studied: untreated and polymerase chain reaction (PCR) positive (n = 9), anti-HDV positive and PCR negative (n = 8), and responders to treatment (n = 12). The cytokines, interleukin (IL)-2 (p = 0.0008) and IL-12 (p = 0.02) were differentially expressed among the groups and were also correlated (p = 0.0143). Future studies will be conducted with patients at different stages of treatment, associating the viral load with serum cytokines produced, thereby attempting to establish a prognostic indicator of the infection. PMID:27074258

  17. Association of Th1 and Th2 cytokines with transient inflammatory reaction during lenalidomide plus dexamethasone therapy in multiple myeloma.

    PubMed

    Harada, Takeshi; Ozaki, Shuji; Oda, Asuka; Fujii, Shiro; Nakamura, Shingen; Miki, Hirokazu; Kagawa, Kumiko; Takeuchi, Kyoko; Matsumoto, Toshio; Abe, Masahiro

    2013-06-01

    Transient inflammatory reactions have been reported in a subpopulation of patients with multiple myeloma (MM) during lenalidomide (Len) plus dexamethasone (DEX) therapy. Here, we examined serum levels of Th1 (IL-2 and IFN-γ) and Th2 cytokines (IL-6 and TNF-α) in nine refractory or relapsed MM patients treated with Len plus low-dose DEX. Six patients showed elevation of C-reactive protein (CRP) after the initiation of therapy. In these patients, IFN-γ and IL-6 were also elevated in two and three patients, respectively. The remaining three patients showed no appreciable changes in CRP or these cytokines. Furthermore, Len enhanced the production of both Th1 and Th2 cytokines in normal peripheral blood mononuclear cells and in patient bone marrow mononuclear cells containing primary myeloma cells and lymphocytes. These results suggest that the modulation of the Th1 and Th2 cytokine production by Len may contribute to transient inflammatory reaction in MM patients.

  18. Multivariate and integrative approach to analyze multiple biomarkers in ecotoxicology: A field study in Neotropical region.

    PubMed

    Ghisi, Nédia C; Oliveira, Elton C; Guiloski, Izonete C; de Lima, Sonia Barbosa; Silva de Assis, Helena C; Longhi, Solon Jonas; Prioli, Alberto J

    2017-12-31

    Aquatic pollution has dramatically worsened in developing countries, due to the discharge of a mixture of pollutants into water bodies, to the lack of stringent laws, and the inadequate treatment of effluents. In this study, the Neotropical fish Astyanax aff. paranae was sampled from three sites with different pollution levels: 1) a Biological Reserve (Rebio), protected by the Brazilian government; 2) an agricultural area in one of the most productive regions of Brazil, upstream of an urban zone; and 3) a site downstream from urban zone, characterized by the influx of different effluents, including wastes from industry, a sewer treatment plant, and agricultural areas. We assess biomarkers at multiple levels, such as the comet assay, hepatic histopathological analysis, brain and muscle acetylcholinesterase (AChE) and the hepatic enzymes glutathione-S-transferase (GST), catalase (CAT), and lipoperoxidation (LPO), during winter and summer. The interpretation of field results is always a very complex operation, since many factors can influence the variables analyzed in uncontrollable conditions. For this reason, we apply an integrative multivariate analysis. The results showed that the environmental risk of the three sites was significantly different. We can see a gradient in data distribution in discriminant analysis: separating, from one side, the fish of Rebio; in the middle are the fish from agricultural area and, in the other side are the animals from downstream site. Overall, the biomarkers responses were more greatly altered in the downstream site, whereas fish from the agricultural area showed an intermediate level of damage. The greatest changes were likely caused by agriculture, industrial chemical effluents and ineffective sewage treatments, in a synergic interaction in downstream site. In conclusion, the use of multiple biomarkers at different response levels to assess the toxic effects of mixed pollutants in a natural aquatic environment is an important

  19. The KISS1 Receptor as an In Vivo Microenvironment Imaging Biomarker of Multiple Myeloma Bone Disease

    PubMed Central

    Brandl, Andreas; Müller, Marc; Hofbauer, Lorenz C.; Beilhack, Andreas; Ebert, Regina; Glüer, Claus C.; Tiwari, Sanjay; Schütze, Norbert; Jakob, Franz

    2016-01-01

    Multiple myeloma is one of the most common hematological diseases and is characterized by an aberrant proliferation of plasma cells within the bone marrow. As a result of crosstalk between cancer cells and the bone microenvironment, bone homeostasis is disrupted leading to osteolytic lesions and poor prognosis. Current diagnostic strategies for myeloma typically rely on detection of excess monoclonal immunoglobulins or light chains in the urine or serum. However, these strategies fail to localize the sites of malignancies. In this study we sought to identify novel biomarkers of myeloma bone disease which could target the malignant cells and/or the surrounding cells of the tumor microenvironment. From these studies, the KISS1 receptor (KISS1R), a G-protein-coupled receptor known to play a role in the regulation of endocrine functions, was identified as a target gene that was upregulated on mesenchymal stem cells (MSCs) and osteoprogenitor cells (OPCs) when co-cultured with myeloma cells. To determine the potential of this receptor as a biomarker, in vitro and in vivo studies were performed with the KISS1R ligand, kisspeptin, conjugated with a fluorescent dye. In vitro microscopy showed binding of fluorescently-labeled kisspeptin to both myeloma cells as well as MSCs under direct co-culture conditions. Next, conjugated kisspeptin was injected into immune-competent mice containing myeloma bone lesions. Tumor-burdened limbs showed increased peak fluorescence compared to contralateral controls. These data suggest the utility of the KISS1R as a novel biomarker for multiple myeloma, capable of targeting both tumor cells and host cells of the tumor microenvironment. PMID:27158817

  20. Hexavalent chromium-induced multiple biomarker responses in liver and kidney of goldfish, Carassius auratus.

    PubMed

    Velma, Venkatramreddy; Tchounwou, Paul B

    2011-11-01

    Hexavalent chromium [Cr (VI)] is a constituent of chromite ore. Although it is known to have several industrial and technological applications, its release into the aquatic environment as a result of chemical spill or inadequate waste discharge may hamper the health of aquatic organisms. In this study, we have investigated the effects of Cr (VI) on multiple biomarkers responses in goldfish under subchronic exposure conditions. Laboratory-acclimatized fish were exposed to 4.25 ppm and 8.57 ppm Cr (VI) for four weeks using a continuous flow-through system. During exposure, fish samples were collected on a weekly basis and analyzed for multiple biomarkers including catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), metallothionein (MT), and total protein in liver and kidney. Study results indicated that the CAT activity and total protein levels in Cr (VI) - treated goldfish did not significantly differ (P > 0.05) from their respective controls during experimentation. However, highly significant up-regulations (P < 0.05) of SOD, GPx, and MT expression in Cr (VI) - treated goldfish were recorded at different exposure times depending on Cr (VI) concentration, test organ, and/or biomarker of interest. For example, significantly higher liver GPx levels were found at weeks 2 and 3 in the 4.25 ppm concentration, and at weeks 3 and 4 in the 8.57 ppm, while kidney GPx levels were significantly higher at weeks 1, 2 and 3 in the 4.25 ppm concentration, and at weeks 2, 3 and 4 in the 8.57 ppm concentration. In summary, Cr (VI)-induced oxidative stress was characterized by statistically significant increases in SOD, GPx, and MT expression in goldfish tissues; with the kidney showing a relatively higher sensitivity to Cr (VI) toxicity compared with the liver.

  1. Hexavalent Chromium-Induced Multiple Biomarker Responses in Liver and Kidney of Goldfish, Carassius auratus

    PubMed Central

    Velma, Venkatramreddy; Tchounwou, Paul B.

    2010-01-01

    Hexavalent chromium [Cr (VI)] is a constituent of chromite ore. Although it is known to have several industrial and technological applications, its release into the aquatic environment as a result of chemical spill or inadequate waste discharge may hamper the health of aquatic organisms. In this study, we have investigated the effects of Cr (VI) on multiple biomarkers responses in goldfish under sub-chronic exposure conditions. Laboratory-acclimatized fish were exposed to 4.25 ppm and 8.57 ppm Cr (VI) for four weeks using a continuous flow-through system. During exposure, fish samples were collected on a weekly basis and analyzed for multiple biomarkers including catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), metallothionein (MT), and total protein in liver and kidney. Study results indicated that the CAT activity and total protein levels in Cr (VI) – treated goldfish did not significantly differ (p>0.05) from their respective controls during experimentation. However, highly significant up-regulations (p<0.05) of SOD, GPx, and MT expression in Cr (VI) – treated goldfish were recorded at different exposure times depending on Cr (VI) concentration, test organ, and/or biomarker of interest. For example, significantly higher liver GPx levels were found at weeks 2 and 3 in the 4.25 ppm concentration, and at weeks 3 and 4 in the 8.57 ppm, while kidney GPx levels were significantly higher at weeks 1, 2 and 3 in the 4.25 ppm concentration, and at weeks 2, 3 and 4 in the 8.57 ppm concentration. In summary, Cr (VI)-induced oxidative stress was characterized by statistically significant increases in SOD, GPx, and MT expression in goldfish tissues; with the kidney showing a relatively higher sensitivity to Cr (VI) toxicity compared to the liver. PMID:20549632

  2. Cerebrospinal fluid chitinase-3-like 2 and chitotriosidase are potential prognostic biomarkers in early multiple sclerosis.

    PubMed

    Møllgaard, M; Degn, M; Sellebjerg, F; Frederiksen, J L; Modvig, S

    2016-05-01

    The role of chitinases and chitinase-like proteins in multiple sclerosis (MS) is currently unknown; however, cerebrospinal fluid (CSF) levels of chitinase 3-like 1 (CHI3L1) predict prognosis in early MS. Whether this applies to other chitinases and chitinase-like proteins is yet to be established. Our objective was to investigate the potential of chitinase 3-like 2 (CHI3L2) and chitotriosidase as prognostic biomarkers in optic neuritis (ON) as the first demyelinating episode and to evaluate the ability of CHI3L2 to predict long-term MS risk and disability. In a prospective cohort of 73 patients with ON as a first demyelinating episode and 26 age-matched healthy controls levels of CHI3L2 and chitotriosidase in CSF were explored by enzyme-linked immunosorbent assay. Associations with magnetic resonance imaging white matter lesions, CSF oligoclonal bands, immunoglobulin G index and leukocyte count were investigated. Long-term MS risk and disability (Expanded Disability Status Scale, Multiple Sclerosis Functional Composite components) were examined in a retrospective cohort of 78 patients with ON as the first demyelinating episode (mean follow-up 14 years). The predictive ability of CHI3L2 was compared with CHI3L1. Cerebrospinal fluid levels of CHI3L2 and chitotriosidase were significantly elevated in patients with ON and were associated with MS risk measures. CHI3L2 levels predicted MS development after ON (hazard ratio 1.95, P = 0.00039, Cox regression) and cognitive impairment by the Paced Auditory Serial Addition Test (P = 0.0357, linear regression) at follow-up. In a multivariate analysis of MS risk, CHI3L2 performed better than CHI3L1. CHI3L2 and chitotriosidase are promising biomarkers in patients with a first demyelinating episode. Our findings thus support a role for these proteins as biomarkers in early MS. © 2016 EAN.

  3. Biomarkers of respiratory syncytial virus (RSV) infection: specific neutrophil and cytokine levels provide increased accuracy in predicting disease severity.

    PubMed

    Brown, Paul M; Schneeberger, Dana L; Piedimonte, Giovanni

    2015-09-01

    Despite fundamental advances in the research on respiratory syncytial virus (RSV) since its initial identification almost 60 years ago, recurring failures in developing vaccines and pharmacologic strategies effective in controlling the infection have allowed RSV to become a leading cause of global infant morbidity and mortality. Indeed, the burden of this infection on families and health care organizations worldwide continues to escalate and its financial costs are growing. Furthermore, strong epidemiologic evidence indicates that early-life lower respiratory tract infections caused by RSV lead to the development of recurrent wheezing and childhood asthma. While some progress has been made in the identification of reliable biomarkers for RSV bronchiolitis, a "one size fits all" biomarker capable of accurately and consistently predicting disease severity and post-acute outcomes has yet to be discovered. Therefore, it is of great importance on a global scale to identify useful biomarkers for this infection that will allow pediatricians to cost-effectively predict the clinical course of the disease, as well as monitor the efficacy of new therapeutic strategies.

  4. Ultrasensitive photoelectrochemical biosensing of multiple biomarkers on a single electrode by a light addressing strategy.

    PubMed

    Wang, Juan; Liu, Zhihong; Hu, Chengguo; Hu, Shengshui

    2015-09-15

    Ultrasensitive multiplexed detection of biomarkers on a single electrode is usually a great challenge for electrochemical sensors. Here, a light addressable photoelectrochemical sensor (LAPECS) for the sensitive detection of multiple DNA biomarkers on a single electrode was reported. The sensor was constructed through four steps: (1) immobilization of capture DNA (C-DNA) of different targets on different areas of a single large-sized gold film electrode, (2) recognition of each target DNA (T-DNA) and the corresponding biotin-labeled probe DNA (P-DNA) through hybridization, (3) reaction of the biotin-labeled probe DNA with a streptavidin-labeled all-carbon PEC bioprobe, and (4) PEC detection of multiple DNA targets one by one via a light addressing strategy. Through this principle, the LAPECS can achieve ultrasensitive detection of three DNA sequences related to hepatitis B (HBV), hepatitis C (HCV) and human immunodeficiency (HIV) viruses with a similar wide calibration range of 1.0 pM ∼ 0.01 μM and a low detection limit of 0.7 pM by using one kind of PEC bioprobe. Moreover, the detection throughput of LAPECS may be conveniently expanded by simply enlarging the size of the substrate electrode or reducing the size of the sensing arrays and the light beam. The present work thus demonstrates the promising applications of LAPECS in developing portable, sensitive, high-throughput, and cost-effective biosensing systems.

  5. A Meta-Regression Method for Studying Etiological Heterogeneity Across Disease Subtypes Classified by Multiple Biomarkers

    PubMed Central

    Wang, Molin; Kuchiba, Aya; Ogino, Shuji

    2015-01-01

    In interdisciplinary biomedical, epidemiologic, and population research, it is increasingly necessary to consider pathogenesis and inherent heterogeneity of any given health condition and outcome. As the unique disease principle implies, no single biomarker can perfectly define disease subtypes. The complex nature of molecular pathology and biology necessitates biostatistical methodologies to simultaneously analyze multiple biomarkers and subtypes. To analyze and test for heterogeneity hypotheses across subtypes defined by multiple categorical and/or ordinal markers, we developed a meta-regression method that can utilize existing statistical software for mixed-model analysis. This method can be used to assess whether the exposure-subtype associations are different across subtypes defined by 1 marker while controlling for other markers and to evaluate whether the difference in exposure-subtype association across subtypes defined by 1 marker depends on any other markers. To illustrate this method in molecular pathological epidemiology research, we examined the associations between smoking status and colorectal cancer subtypes defined by 3 correlated tumor molecular characteristics (CpG island methylator phenotype, microsatellite instability, and the B-Raf protooncogene, serine/threonine kinase (BRAF), mutation) in the Nurses' Health Study (1980–2010) and the Health Professionals Follow-up Study (1986–2010). This method can be widely useful as molecular diagnostics and genomic technologies become routine in clinical medicine and public health. PMID:26116215

  6. Cytokine Kinetics in Febrile Neutropenic Children: Insights on the Usefulness as Sepsis Biomarkers, Influence of Filgrastim, and Behavior of the IL-23/IL-17 Pathway

    PubMed Central

    Salomão, Reinaldo; Brunialti, Milena Karina Coló; da Silva, Dafne Cardoso Bourguignon; Senerchia, Andreza Almeida; de Moraes Costa Carlesse, Fabianne Altruda; Petrilli, Antonio Sergio

    2017-01-01

    Background The study aimed to describe the kinetics of various cytokines from day 1 to day 14 of the onset of fever in neutropenic children and to evaluate their performances as discriminators of sepsis in the first 24 hours of fever, the possible influence of filgrastim, and the functioning of the IL-23/IL-17 axis. Methods IL-1β, TNF-α, IL-10, IL-12/23p40, IL-21, IL-6, IL-8, IL-17, G-CSF, and GM-CSF were measured in plasma on days 1, 2, 3, 5, and 14 from the onset of fever in 35 patients. Results Thirteen patients (37.1%) developed sepsis. In mixed models, IL-6, IL-8, IL-10, and G-CSF showed higher estimated means in septic patients (P < 0.005), and IL-12/23p40 and IL-17 in nonseptic patients (P < 0.05). On day 1, IL-6, IL-8, and IL-10 appeared upregulated in patients who received filgrastim. Only IL-6, IL-8, IL-10, and procalcitonin were useful as discriminators of sepsis. Associating the markers with each other or to a risk assessment model improved performance. Conclusions Cytokines kinetics showed proinflammatory and anti-inflammatory responses similar to what is described in nonneutropenic patients. IL-8, IL-6, IL-10, and procalcitonin are useful as early biomarkers of sepsis. Filgrastim upregulates expression of these markers, and we observed deficiency in the IL-23-IL-17 axis accompanying sepsis. PMID:28769538

  7. Serum levels of cytokines and biomarkers for inflammation and immune activation, and HIV-associated non-Hodgkin B-cell lymphoma risk.

    PubMed

    Vendrame, Elena; Hussain, Shehnaz K; Breen, Elizabeth Crabb; Magpantay, Larry I; Widney, Daniel P; Jacobson, Lisa P; Variakojis, Daina; Knowlton, Emilee R; Bream, Jay H; Ambinder, Richard F; Detels, Roger; Martínez-Maza, Otoniel

    2014-02-01

    HIV infection is associated with a marked increase in risk for non-Hodgkin lymphoma (AIDS-NHL). However, the mechanisms that promote the development of AIDS-NHL are not fully understood. In this study, serum levels of several cytokines and other molecules associated with immune activation were measured in specimens collected longitudinally during 1 to 5 years preceding AIDS-NHL diagnosis, in 176 AIDS-NHL cases and 176 HIV(+) controls from the Multicenter AIDS Cohort Study (MACS). Multivariate analyses revealed that serum levels of immunoglobulin free light chains (FLC), interleukin (IL)-6, IL-10, IP-10/CXCL10, neopterin, and TNF-α were elevated in those HIV(+) individuals who went on to develop AIDS-NHL. In addition, the fraction of specimens with detectable IL-2 was increased and the fraction with detectable IL-4 was decreased in these subjects. These results suggest that long-term, chronic immune activation, possibly driven by macrophage-produced cytokines, precedes development of NHL in HIV(+) individuals. FLC, IL-6, IL-10, IP-10/CXCL10, neopterin, and TNF-α may serve as biomarkers for AIDS-NHL. .

  8. Serum Levels of Cytokines, and Biomarkers for Inflammation and Immune Activation, and HIV-Associated Non-Hodgkin B cell Lymphoma Risk

    PubMed Central

    Vendrame, Elena; Hussain, Shehnaz K.; Breen, Elizabeth Crabb; Magpantay, Larry; Widney, Daniel P.; Jacobson, Lisa P.; Variakojis, Daina; Knowlton, Emilee R.; Bream, Jay H.; Ambinder, Richard F.; Detels, Roger; Martínez-Maza, Otoniel

    2013-01-01

    Background: HIV infection is associated with a marked increase in risk for non-Hodgkin lymphoma (AIDS-NHL). However, the mechanisms that promote the development of AIDS-NHL are not fully understood. Methods: In this study serum levels of several cytokines and other molecules associated with immune activation were measured in specimens collected longitudinally during 1-to-5 years preceding AIDS-NHL diagnosis, in 176 AIDS-NHL cases and 176 HIV+ controls from the Multicenter AIDS Cohort Study (MACS). Results: Multivariate analyses revealed that serum levels of immunoglobulin free light chains (FLC), IL-6, IL-10, IP-10/CXCL10, neopterin, and TNFα were elevated in those HIV+ individuals who went on to develop AIDS-NHL. Additionally, the fraction of specimens with detectable IL-2 was increased, and the fraction with detectable IL-4 was decreased, in these subjects. Conclusions: These results suggest that long term, chronic immune activation, possibly driven by macrophage-produced cytokines, precedes development of NHL in HIV+ individuals. Impact: FLC, IL-6, IL-10, IP-10/CXCL10, neopterin, and TNFα may serve as biomarkers for AIDS-NHL. PMID:24220912

  9. Inflammatory Cytokines Interleukin-1β and Tumour Necrosis Factor-α - Novel Biomarkers for the Detection of Periodontal Diseases: a Literature Review

    PubMed Central

    Gomes, Francisco Isaac Fernandes; Aragão, Maria Gerusa Brito; Barbosa, Francisco Cesar Barroso; Bezerra, Mirna Marques; de Paulo Teixeira Pinto, Vicente

    2016-01-01

    ABSTRACT Objectives The article aims to discuss the IL-1β and TNF-α potential use as salivary biomarkers of periodontal diseases pathogenesis and progression. Material and Methods This literature review has been registered in PROSPERO database with following number: CRD42016035729. Data investigation was performed on PubMed database as the main source of studies. The following search terms were used: “salivary biomarkers”, “periodontal diseases”, “TNF-alpha”, “Interleukin-1 beta”. Clinical trials and animal experimental models of periodontal disease were included in the discussion. In regards to inclusive dates, published studies from January 2006 to December 2015 were considered in this review along with the mentioned inclusion criteria. Results IL-1β and TNF-α salivary levels increased in diseased groups, they were associated with onset and disease severity, and their levels reduced in response to periodontal therapy. IL-1β and TNF-α could be promising biomarkers in the detection of periodontal diseases. Conclusions The use of a salivary cytokine-based diagnosis appears to be a screening method capable of diagnosing periodontal diseases in an early fashion, establishing an era of individualized clinical decisions. PMID:27489606

  10. A cytokine immunosensor for Multiple Sclerosis detection based upon label-free electrochemical impedance spectroscopy using electroplated printed circuit board electrodes.

    PubMed

    Bhavsar, Kinjal; Fairchild, Aaron; Alonas, Eric; Bishop, Daniel K; La Belle, Jeffrey T; Sweeney, James; Alford, T L; Joshi, Lokesh

    2009-10-15

    A biosensor for the serum cytokine, Interleukin-12 (IL-12), based upon a label-free electrochemical impedance spectroscopy (EIS) monitoring approach is described. Overexpression of IL-12 has been correlated to the diagnosis of Multiple Sclerosis (MS). An immunosensor has been fabricated by electroplating gold onto a disposable printed circuit board (PCB) electrode and immobilizing anti-IL-12 monoclonal antibodies (MAb) onto the surface of the electrode. This approach yields a robust sensor that facilitates reproducible mass fabrication and easy alteration of the electrode shape. Results indicate that this novel PCB sensor can detect IL-12 at physiological levels, <100 fM with f-values of 0.05 (typically <0.0001) in a label-free and rapid manner. A linear (with respect to log concentration) detectable range was achieved. Detection in a complex biological solution is also explored; however, significant loss of dynamic range is noted in the 100% complex solution. The cost effective approach described here can be used potentially for diagnosis of diseases (like MS) with known biomarkers in body fluids and for monitoring physiological levels of biomolecules with healthcare, food, and environmental relevance.

  11. Abnormal cytokine production by bone marrow stromal cells of multiple myeloma patients in response to RPMI8226 myeloma cells.

    PubMed

    Zdzisińska, Barbara; Bojarska-Junak, Agnieszka; Dmoszyńska, Anna; Kandefer-Szerszeń, Martyna

    2008-01-01

    Recent studies indicate that bone marrow stromal cells (BMSCs) derived from patients with multiple myeloma (MM) differ from those of healthy donors in their expression of extracellular matrix compounds and in cytokine production. It is not known whether these abnormalities are primary or are acquired by BMSCs on contact with MM cells. Interleukin (IL)-6, IL-11, IL-10, and tumor necrosis factor (TNF)-alpha production by CD166+ mesenchymal BMSCs and the CD38+/CD138+ RPMI8226 myeloma cell line cultivated in vitro in monocultures or co-cultivated under cell-to-cell contact or non-contact conditions in the presence of a tissue culture insert were measured. Intracellular cytokines were measured by flow cytometry analysis as the percentage of cytokine-producing cells or by mean fluorescence intensity as the level of cytokine expression in cells. Additionally, ELISA was used to measure IL-6, soluble IL-6 receptor (sIL-6R), IL-11, IL-10, TNF-alpha, B-cell-activating factor of the TNF family (BAFF), hepatocyte growth factor (HGF), and osteopontin (OPN) production in the supernatants of the cultures and co-cultures. A higher ability of the BMSCs of MM patients than in controls was detected to produce IL-6, IL-10, TNF-alpha, OPN, and especially HGF and BAFF in response to the RPMI8226 cells. Moreover, the BMSCs of the MM patients significantly enhanced the production of sIL-6R by the RPMI8226 cells. Cytokines over-expressed by BMSCs of MM patients can function as growth factors for myeloma cells (IL-6, IL-10, HGF), migration stimulatory factors for tumor plasma cells (TNF-alpha, HGF), adhesion stimulatory factors (HGF, BAFF and OPN), stimulators of osteoclastogenesis (IL-6, TNF-alpha), and angiogenic factors (TNF-alpha). The results of this experiment strongly suggest that the BMSCs from MM patients differed in spontaneous and myeloma cell-induced production of cytokines, especially of HGF and BAFF, and these abnormalities were both primary and acquired by the BMSCs on contact

  12. The fornix provides multiple biomarkers to characterize circuit disruption in a mouse model of Alzheimer's disease.

    PubMed

    Badea, Alexandra; Kane, Lauren; Anderson, Robert J; Qi, Yi; Foster, Mark; Cofer, Gary P; Medvitz, Neil; Buckley, Anne F; Badea, Andreas K; Wetsel, William C; Colton, Carol A

    2016-11-15

    Multivariate biomarkers are needed for detecting Alzheimer's disease (AD), understanding its etiology, and quantifying the effect of therapies. Mouse models provide opportunities to study characteristics of AD in well-controlled environments that can help facilitate development of early interventions. The CVN-AD mouse model replicates multiple AD hallmark pathologies, and we identified multivariate biomarkers characterizing a brain circuit disruption predictive of cognitive decline. In vivo and ex vivo magnetic resonance imaging (MRI) revealed that CVN-AD mice replicate the hippocampal atrophy (6%), characteristic of humans with AD, and also present changes in subcortical areas. The largest effect was in the fornix (23% smaller), which connects the septum, hippocampus, and hypothalamus. In characterizing the fornix with diffusion tensor imaging, fractional anisotropy was most sensitive (20% reduction), followed by radial (15%) and axial diffusivity (2%), in detecting pathological changes. These findings were strengthened by optical microscopy and ultrastructural analyses. Ultrastructual analysis provided estimates of axonal density, diameters, and myelination-through the g-ratio, defined as the ratio between the axonal diameter, and the diameter of the axon plus the myelin sheath. The fornix had reduced axonal density (47% fewer), axonal degeneration (13% larger axons), and abnormal myelination (1.5% smaller g-ratios). CD68 staining showed that white matter pathology could be secondary to neuronal degeneration, or due to direct microglial attack. In conclusion, these findings strengthen the hypothesis that the fornix plays a role in AD, and can be used as a disease biomarker and as a target for therapy. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. SIRT1 as a potential biomarker of response to treatment with glatiramer acetate in multiple sclerosis.

    PubMed

    Hewes, Daniel; Tatomir, Alexandru; Kruszewski, Adam M; Rao, Gautam; Tegla, Cosmin A; Ciriello, Jonathan; Nguyen, Vingh; Royal, Walter; Bever, Christopher; Rus, Violeta; Rus, Horea

    2017-04-01

    SIRT1, a NAD dependent histone and protein deacetylase, is a member of the histone deacetylase class III family. We previously showed that SIRT1 mRNA expression is significantly lower in peripheral blood mononuclear cells (PBMCs) of multiple sclerosis (MS) patients during relapses than in stable patients. We have now investigated SIRT1 as a possible biomarker to predict relapse as well as responsiveness to glatiramer acetate (GA) treatment in relapsing-remitting MS (RRMS) patients. Over the course of 2years, a cohort of 15 GA-treated RRMS patients were clinically monitored using the Expanded Disability Status Scale and assessed for MS relapses. Blood samples collected from MS patients were analyzed for levels of SIRT1 and histone H3 lysine 9 (H3K9) acetylation and dimethylation. During relapses, MS patients had a lower expression of SIRT1 mRNA than did stable MS patients. In addition, there was a significant decrease in H3K9 dimethylation (H3K9me2) during relapses in MS patients when compared to stable patients (p=0.01). Responders to GA treatment had significantly higher SIRT1 mRNA (p=0.01) and H3K9me2 levels than did non-responders (p=0.018). Receiver operating characteristic analysis was used to assess the predictive power of SIRT1 and H3K9me2 as putative biomarkers: for SIRT1 mRNA, the predictive value for responsiveness to GA treatment was 70% (p=0.04) and for H3K9me2 was 71% (p=0.03). Our data suggest that SIRT1 and H3K9me2 could serve as potential biomarkers for evaluating patients' responsiveness to GA therapy in order to help guide treatment decisions in MS. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. Selected Cytokines Serve as Potential Biomarkers for Predicting Liver Inflammation and Fibrosis in Chronic Hepatitis B Patients With Normal to Mildly Elevated Aminotransferases.

    PubMed

    Deng, Yong-Qiong; Zhao, Hong; Ma, An-Lin; Zhou, Ji-Yuan; Xie, Shi-Bin; Zhang, Xu-Qing; Zhang, Da-Zhi; Xie, Qing; Zhang, Guo; Shang, Jia; Cheng, Jun; Zhao, Wei-Feng; Zou, Zhi-Qiang; Zhang, Ming-Xiang; Wang, Gui-Qiang

    2015-11-01

    Previous studies of small cohorts have implicated several circulating cytokines with progression of chronic hepatitis B (CHB). However, to date there have been no reliable biomarkers for assessing histological liver damage in CHB patients with normal or mildly elevated alanine aminotransferase (ALT). The aim of the present study was to investigate the association between circulating cytokines and histological liver damage in a large cohort. Also, this study was designed to assess the utility of circulating cytokines in diagnosing liver inflammation and fibrosis in CHB patients with ALT less than 2 times the upper limit of normal range (ULN). A total of 227 CHB patients were prospectively enrolled. All patients underwent liver biopsy and staging by Ishak system. Patients with at least moderate inflammation showed significantly higher levels of CXCL-11, CXCL-10, and interleukin (IL)-2 receptor (R) than patients with less than moderate inflammation (P < 0.001). Patients with significant fibrosis had higher levels of IL-8 (P = 0.027), transforming growth factor alpha (TGF-α) (P = 0.011), IL-2R (P = 0.002), and CXCL-11 (P = 0.032) than the group without significant fibrosis. In addition, 31.8% and 29.1% of 151 patients with ALT < 2 × ULN had at least moderate inflammation and significant fibrosis, respectively. Multivariate analysis demonstrated that CXCL-11 was independently associated with at least moderate inflammation, and TGF-α and IL-2R independently correlated with significant fibrosis in patients with ALT < 2 × ULN. Based on certain cytokines and clinical parameters, an inflammation-index and fib-index were developed, which showed areas under the receiver operating characteristics curve (AUROC) of 0.75 (95% CI 0.66-0.84) for at least moderate inflammation and 0.82 (95% CI 0.75-0.90) for significant fibrosis, correspondingly. Compared to existing scores, fib-index was significantly superior to aspartate aminotransferase

  15. Selected Cytokines Serve as Potential Biomarkers for Predicting Liver Inflammation and Fibrosis in Chronic Hepatitis B Patients With Normal to Mildly Elevated Aminotransferases

    PubMed Central

    Deng, Yong-Qiong; Zhao, Hong; Ma, An-Lin; Zhou, Ji-Yuan; Xie, Shi-Bin; Zhang, Xu-Qing; Zhang, Da-Zhi; Xie, Qing; Zhang, Guo; Shang, Jia; Cheng, Jun; Zhao, Wei-Feng; Zou, Zhi-Qiang; Zhang, Ming-Xiang; Wang, Gui-Qiang

    2015-01-01

    Abstract Previous studies of small cohorts have implicated several circulating cytokines with progression of chronic hepatitis B (CHB). However, to date there have been no reliable biomarkers for assessing histological liver damage in CHB patients with normal or mildly elevated alanine aminotransferase (ALT). The aim of the present study was to investigate the association between circulating cytokines and histological liver damage in a large cohort. Also, this study was designed to assess the utility of circulating cytokines in diagnosing liver inflammation and fibrosis in CHB patients with ALT less than 2 times the upper limit of normal range (ULN). A total of 227 CHB patients were prospectively enrolled. All patients underwent liver biopsy and staging by Ishak system. Patients with at least moderate inflammation showed significantly higher levels of CXCL-11, CXCL-10, and interleukin (IL)-2 receptor (R) than patients with less than moderate inflammation (P < 0.001). Patients with significant fibrosis had higher levels of IL-8 (P = 0.027), transforming growth factor alpha (TGF-α) (P = 0.011), IL-2R (P = 0.002), and CXCL-11 (P = 0.032) than the group without significant fibrosis. In addition, 31.8% and 29.1% of 151 patients with ALT < 2 × ULN had at least moderate inflammation and significant fibrosis, respectively. Multivariate analysis demonstrated that CXCL-11 was independently associated with at least moderate inflammation, and TGF-α and IL-2R independently correlated with significant fibrosis in patients with ALT < 2 × ULN. Based on certain cytokines and clinical parameters, an inflammation-index and fib-index were developed, which showed areas under the receiver operating characteristics curve (AUROC) of 0.75 (95% CI 0.66–0.84) for at least moderate inflammation and 0.82 (95% CI 0.75–0.90) for significant fibrosis, correspondingly. Compared to existing scores, fib-index was significantly superior to aspartate

  16. Systemic complement profiling in multiple sclerosis as a biomarker of disease state

    PubMed Central

    Ingram, G; Hakobyan, S; Hirst, CL; Harris, CL; Loveless, S; Mitchell, JP; Pickersgill, TP; Robertson, NP

    2012-01-01

    Background: There is increasing evidence of significant and dynamic systemic activation and upregulation of complement in multiple sclerosis (MS), which may contribute to disease pathogenesis. Objective: We aimed to investigate the pathological role of complement in MS and the potential role for complement profiling as a biomarker of MS disease state. Methods: Key components of the classical, alternative and terminal pathways of complement were measured in plasma and cerebrospinal fluid (CSF) of patients with MS in different clinical phases of disease and in matched controls. Results: Increased plasma levels of C3 (p<0.003), C4 (p<0.001), C4a (p<0.001), C1 inhibitor (p<0.001), and factor H (p<0.001), and reduced levels of C9 (p<0.001) were observed in MS patients compared with controls. Combined profiling of these analytes produced a statistical model with a predictive value of 97% for MS and 73% for clinical relapse when combined with selected demographic data. CSF-plasma correlations suggested that source of synthesis of these components was both systemic and central. Conclusion: These data provide further evidence of alterations in both local and systemic expression and activation of complement in MS and suggest that complement profiling may be informative as a biomarker of MS disease, although further work is needed to determine its use in distinguishing MS from its differential. PMID:22354735

  17. The Search for Reliable Biomarkers of Disease in Multiple Chemical Sensitivity and Other Environmental Intolerances

    PubMed Central

    De Luca, Chiara; Raskovic, Desanka; Pacifico, Valeria; Thai, Jeffrey Chung Sheun; Korkina, Liudmila

    2011-01-01

    Whilst facing a worldwide fast increase of food and environmental allergies, the medical community is also confronted with another inhomogeneous group of environment-associated disabling conditions, including multiple chemical sensitivity (MCS), fibromyalgia, chronic fatigue syndrome, electric hypersensitivity, amalgam disease and others. These share the features of poly-symptomatic multi-organ cutaneous and systemic manifestations, with postulated inherited/acquired impaired metabolism of chemical/physical/nutritional xenobiotics, triggering adverse reactions at exposure levels far below toxicologically-relevant values, often in the absence of clear-cut allergologic and/or immunologic involvement. Due to the lack of proven pathogenic mechanisms generating measurable disease biomarkers, these environmental hypersensitivities are generally ignored by sanitary and social systems, as psychogenic or “medically unexplained symptoms”. The uncontrolled application of diagnostic and treatment protocols not corresponding to acceptable levels of validation, safety, and clinical efficacy, to a steadily increasing number of patients demanding assistance, occurs in many countries in the absence of evidence-based guidelines. Here we revise available information supporting the organic nature of these clinical conditions. Following intense research on gene polymorphisms of phase I/II detoxification enzyme genes, so far statistically inconclusive, epigenetic and metabolic factors are under investigation, in particular free radical/antioxidant homeostasis disturbances. The finding of relevant alterations of catalase, glutathione-transferase and peroxidase detoxifying activities significantly correlating with clinical manifestations of MCS, has recently registered some progress towards the identification of reliable biomarkers of disease onset, progression, and treatment outcomes. PMID:21845158

  18. Lymphocytosis as a response biomarker of natalizumab therapeutic efficacy in multiple sclerosis.

    PubMed

    Signoriello, E; Lanzillo, R; Brescia Morra, V; Di Iorio, G; Fratta, M; Carotenuto, A; Lus, G

    2016-06-01

    Natalizumab is an effective therapy in relapsing-remitting multiple sclerosis (RRMS), as it reduces lymphocyte transmigration through the blood-brain barrier (BBB) and induces lymphocytosis. To analyse natalizumab-induced lymphocytosis (NIL) as a biomarker of drug efficacy. We enrolled 50 relapsing-remitting (RR) and progressive-relapsing (PR) natalizumab-treated patients who had received at least 16 infusions and had been tested for lymphocyte count 24 hours before each administration. Clinical, MRI and hematological data were collected. Patients were divided into responders and sub-optimal responders according to the experience of at least one clinical and/or instrumental relapse during the treatment. In 15 (30%) patients, an instrumental/clinical (14) or only instrumental (one) relapse occurred. We found a statistically significant difference in the mean percentage of the lymphocytes between the two groups over the first ten administrations (p=0.04). The comparison between the time-to-relapse in the groups with high and low levels of lymphocytes showed that the group with a low NIL had a greater risk of relapse (p=0.03). We suggest that NIL could be a biomarker of therapeutic efficacy in patients with RRMS treated with natalizumab, and that the risk of relapse may be higher in patients with a lower-than-expected NIL. © The Author(s), 2015.

  19. Echinococcus granulosus: different cytokine profiles are induced by single versus multiple experimental infections in dogs.

    PubMed

    Rossi, Andrea; Marqués, Juan M; Gavidia, Cesar M; Gonzalez, Armando E; Carmona, Carlos; García, Hector H; Chabalgoity, José A

    2012-02-01

    Modulation of host responses is an important strategy by which parasites ensure successful establishment and persistence. Host counteraction against this modulation may be required for the host to develop resistance to infection. In this pilot study, experimental infection of dogs with Echinococcus granulosus induced a strong polarization of the cytokine response towards a Th2 phenotype. Consecutive rounds of infection and cure induced resistance to infection resulting in a dramatically lower parasite burden. Repeatedly-infected resistant dogs also lost immune polarization and developed a balanced Th1/Th2 response. No major differences were observed in the production of regulatory cytokines (IL-10, TGF-β) between dogs with high parasite load and dogs with only few intestinal parasites. These results suggest that E. granulosus-driven immunomodulation contributes to successful infection in the definitive host. This information might be relevant for the development of more effective vaccines against this stage of the parasite. Copyright © 2011. Published by Elsevier Inc.

  20. Effect of angiogenesis-related cytokines on rotator cuff disease: the search for sensitive biomarkers of early tendon degeneration.

    PubMed

    Savitskaya, Yulia A; Izaguirre, Aldo; Sierra, Luis; Perez, Francisco; Cruz, Francisco; Villalobos, Enrique; Almazan, Arturo; Ibarra, Clemente

    2011-01-01

    Hallmarks of the pathogenesis of rotator cuff disease (RCD) include an abnormal immune response, angiogenesis, and altered variables of vascularity. Degenerative changes enhance production of pro-inflammatory, anti-inflammatory, and vascular angiogenesis-related cytokines (ARC) that play a pivotal role in the immune response to arthroscopic surgery and participate in the pathogenesis of RCD. The purpose of this study was to evaluate the ARC profile, ie, interleukin (IL): IL-1β, IL-6, IL-8, IL-10, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and angiogenin (ANG), in human peripheral blood serum and correlate this with early degenerative changes in patients with RCD. Blood specimens were obtained from 200 patients with RCD and 200 patients seen in the orthopedic clinic for nonrotator cuff disorders. Angiogenesis imaging assays was performed using power Doppler ultrasound to evaluate variables of vascularity in the rotator cuff tendons. Expression of ARC was measured by commercial Bio-Plex Precision Pro Human Cytokine Assays. Baseline concentrations of IL-1β, IL-8, and VEGF was significantly higher in RCD patients than in controls. Significantly higher serum VEGF levels were found in 85% of patients with RCD, and correlated with advanced stage of disease (r = 0.75; P < 0.0005), average microvascular density (r = 0.68, P < 0.005), and visual analog score (r = 0.75, P < 0.0002) in RCD patients. ANG and IL-10 levels were significantly lower in RCD patients versus controls. IL-1β and ANG levels were significantly correlated with degenerative tendon grade in RCD patients. No difference in IL-6 and bFGF levels was observed between RCD patients and controls. Patients with degenerative changes had markedly lower ANG levels compared with controls. Power Doppler ultrasound showed high blood vessel density in patients with tendon rupture. The pathogenesis of RCD is associated with an imbalance between pro-inflammatory, anti

  1. Stimulated Whole Blood Cytokine Release as a Biomarker of Immunosuppression in the Critically Ill: The Need for a Standardized Methodology

    PubMed Central

    Segre, Elisabetta; Fullerton, James N.

    2016-01-01

    ABSTRACT Objective: Reduced ex vivo lipopolysaccharide (LPS) stimulated whole blood pro-inflammatory cytokine release is a hallmark of immunosuppression in the critically ill and predicts adverse clinical outcomes. No standard technique for performing the assay currently exists. The impact of methodological heterogeneity was determined. Design, Setting, Subjects, and Interventions: Clinical experimental study set in a research laboratory. Venous blood from 5 to 10 healthy volunteers/experiment (total participant group: 18 subjects, 72% men, mean age 32) was stimulated ex vivo to evaluate the effect of variables identified via literature review on tumor necrosis factor-α (TNFα) release. These included sample handling, stimulation technique, and incubation conditions. Reporting convention was additionally assessed. Main Results: Measured TNFα release was significantly altered by source of LPS, concentration of LPS employed, duration and temperature of incubation prior to supernatant aspiration, and predilution of blood (repeated measures ANOVA, all P < 0.01). Sample handling prior to stimulation (anticoagulant employed, time to LPS addition, and storage temperature) also caused significant alterations in TNFα release. Considerable interindividual variation was observed (range 1,024–4,649 pg/mL, mean 2,339 pg/mL). Normalization by monocyte count and pretreatment with a cyclooxygenase inhibitor (indomethacin 10 μM) reduced the coefficient of variation from 47.17% to 32.09%. Conclusions: Inconsistency in interlaboratory methodology and reporting impairs interpretation, comparability, and reproducibility of the ex vivo LPS-stimulated whole blood cytokine release assay. A standardized validated technique is required. The advent of trials of immunoadjuvant agents renders this a clinical imperative. PMID:27089173

  2. Paper-based upconversion fluorescence resonance energy transfer biosensor for sensitive detection of multiple cancer biomarkers.

    PubMed

    Xu, Sai; Dong, Biao; Zhou, Donglei; Yin, Ze; Cui, Shaobo; Xu, Wen; Chen, Baojiu; Song, Hongwei

    2016-03-22

    A paper-based upconversion fluorescence resonance energy transfer assay device is proposed for sensitive detection of CEA. The device is fabricated on a normal filter paper with simple nano-printing method. Upconversion nanoparticles tagged with specific antibodies are printed to the test zones on the test paper, followed by the introduction of assay antigen. Upconversion fluorescence measurements are directly conducted on the test zones after the antigen-to-antibody reactions. Furthermore, a multi-channel test paper for simultaneous detection of multiple cancer biomarkers was established by the same method and obtained positive results. The device showed high anti-interfere, stability, reproducible and low detection limit (0.89 ng/mL), moreover it is very easy to fabricate and operate, which is a promising prospect for a clinical point-of-care test.

  3. Paper-based upconversion fluorescence resonance energy transfer biosensor for sensitive detection of multiple cancer biomarkers

    PubMed Central

    Xu, Sai; Dong, Biao; Zhou, Donglei; Yin, Ze; Cui, Shaobo; Xu, Wen; Chen, Baojiu; Song, Hongwei

    2016-01-01

    A paper-based upconversion fluorescence resonance energy transfer assay device is proposed for sensitive detection of CEA. The device is fabricated on a normal filter paper with simple nano-printing method. Upconversion nanoparticles tagged with specific antibodies are printed to the test zones on the test paper, followed by the introduction of assay antigen. Upconversion fluorescence measurements are directly conducted on the test zones after the antigen-to-antibody reactions. Furthermore, a multi-channel test paper for simultaneous detection of multiple cancer biomarkers was established by the same method and obtained positive results. The device showed high anti-interfere, stability, reproducible and low detection limit (0.89 ng/mL), moreover it is very easy to fabricate and operate, which is a promising prospect for a clinical point-of-care test. PMID:27001460

  4. TH1/TH2 Cytokine profile in relapsing-remitting multiple sclerosis patients treated with Glatiramer acetate or Natalizumab

    PubMed Central

    2012-01-01

    Background The balance between T helper cells Th2- and Th1-related cytokines plays a key role in multiple sclerosis (MS). A shift from a Th1 towards a Th2 cytokine profile could have a beneficial effect on the clinical course of the disease. The objective of this study was to assess Th2/Th1 cytokine profile in relapsing-remitting MS (RRMS) patients receiving an immunosuppressive treatment with natalizumab (NAT), or an immunomodulatory treatment with glatiramer acetate (GA) after one year of treatment. Methods This was an observational cross-sectional study. All consecutive patients diagnosed with RRMS who had received GA or NAT for 12 months were included in the study. We determined serum levels of Th1 and Th2 cytokines (interleukin [IL]-1a, IL-1b, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-13, monocyte chemotactic protein [MCP]-1, tumor-necrosis factor [TNF]-α, interferon [IFN]-γ and granulocyte macrophage colony stimulating factor [GM-CSF]) by flow cytometry. Th2/Th1 bias was defined based on the ratio of IL-4, IL-5, IL-6 or IL-10 Th2 cytokines and proinflammatory INF-γ or TNF-α Th1 cytokines. Results Eleven patients under treatment with NAT and 12 patients treated with GA were evaluated. RRMS patients treated with NAT showed significantly higher levels of IL-6 (p < 0.05), MCP-1 (p < 0.01), and GM-CSF (p < 0.05) compared to GA patients after one year of treatment. A trend for increasing of IL-12p70, IL-1b, TNF- α and IFN- γ levels was also found in patients receiving NAT compared to GA patients. IL-4/IFN-γ, IFN-γ/TNF-α and IL-10/IFN-γ ratios as markers of Th2/Th1 ratio were significantly elevated in GA patients compared to those receiving NAT (p < 0.05). Conclusion In conclusion, our findings suggest that GA promotes a superior Th2-biased anti-inflammatory response as compared with NAT in the systemic circulation of RRMS patients. Future studies with larger cohorts will determine whether this immune Th2 shift in GA patients is

  5. Predictive value of cytokines and immune activation biomarkers in AIDS-related non-Hodgkin lymphoma treated with rituximab plus infusional EPOCH (AMC-034 trial)

    PubMed Central

    Epeldegui, Marta; Lee, Jeannette Y.; Martínez, Anna C.; Widney, Daniel P.; Magpantay, Larry I.; Regidor, Deborah; Mitsuyasu, Ronald; Sparano, Joseph A.; Ambinder, Richard F.; Martínez-Maza, Otoniel

    2015-01-01

    Purpose The aims of this study were to determine if pre-treatment plasma levels of cytokines and immune activation-associated molecules changed following treatment for AIDS-NHL with rituximab plus infusional EPOCH, and to determine if pre-treatment levels of these molecules were associated with response to treatment and/or survival. Experimental design We quantified plasma levels of B cell activation-associated molecules (sCD27, sCD30, sCD23) and cytokines (IL-6, IL-10, CXCL13) prior to and after the initiation of treatment in persons with AIDS-NHL (n=69) in the AIDS Malignancies Consortium (AMC) 034 study, which evaluated treatment of AIDS-NHL with EPOCH chemotherapy and rituximab. Results Treatment resulted in decreased plasma levels of some of these molecules (CXCL13, sCD27, sCD30), with decreased levels persisting for one year following the completion of treatment. Lower levels of CXCL13 before treatment were associated with complete responses following lymphoma therapy. Elevated levels of IL-6 pre-treatment were associated with decreased overall survival, while higher IL-10 levels were associated with shorter progression-free survival, in multivariate analyses. Furthermore, patients with CXCL13 or IL-6 levels higher than the median levels for the NHL group, as well as those who had detectable IL-10, had lower overall survival and PFS, in Kaplan Meier analyses. Conclusions These results indicate that CXCL13, IL-6 and IL-10 have significant potential as prognostic biomarkers for AIDS-NHL. PMID:26384320

  6. Effect of Angiogenesis-Related Cytokines on Rotator Cuff Disease: The Search for Sensitive Biomarkers of Early Tendon Degeneration

    PubMed Central

    Savitskaya, Yulia A.; Izaguirre, Aldo; Sierra, Luis; Perez, Francisco; Cruz, Francisco; Villalobos, Enrique; Almazan, Arturo; Ibarra, Clemente

    2011-01-01

    Background: Hallmarks of the pathogenesis of rotator cuff disease (RCD) include an abnormal immune response, angiogenesis, and altered variables of vascularity. Degenerative changes enhance production of pro-inflammatory, anti-inflammatory, and vascular angiogenesis-related cytokines (ARC) that play a pivotal role in the immune response to arthroscopic surgery and participate in the pathogenesis of RCD. The purpose of this study was to evaluate the ARC profile, ie, interleukin (IL): IL-1β, IL-6, IL-8, IL-10, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and angiogenin (ANG), in human peripheral blood serum and correlate this with early degenerative changes in patients with RCD. Methods: Blood specimens were obtained from 200 patients with RCD and 200 patients seen in the orthopedic clinic for nonrotator cuff disorders. Angiogenesis imaging assays was performed using power Doppler ultrasound to evaluate variables of vascularity in the rotator cuff tendons. Expression of ARC was measured by commercial Bio-Plex Precision Pro Human Cytokine Assays. Results: Baseline concentrations of IL-1β, IL-8, and VEGF was significantly higher in RCD patients than in controls. Significantly higher serum VEGF levels were found in 85% of patients with RCD, and correlated with advanced stage of disease (r = 0.75; P < 0.0005), average microvascular density (r = 0.68, P < 0.005), and visual analog score (r = 0.75, P < 0.0002) in RCD patients. ANG and IL-10 levels were significantly lower in RCD patients versus controls. IL-1β and ANG levels were significantly correlated with degenerative tendon grade in RCD patients. No difference in IL-6 and bFGF levels was observed between RCD patients and controls. Patients with degenerative changes had markedly lower ANG levels compared with controls. Power Doppler ultrasound showed high blood vessel density in patients with tendon rupture. Conclusion: The pathogenesis of RCD is associated with an imbalance

  7. The proinflammatory cytokine interleukin-18 alters multiple signaling pathways to inhibit natural killer cell death

    USGS Publications Warehouse

    Hodge, D.L.; Subleski, J.J.; Reynolds, D.A.; Buschman, M.D.; Schill, W.B.; Burkett, M.W.; Malyguine, A.M.; Young, H.A.

    2006-01-01

    The proinflammatory cytokine, interleukin-18 (IL-18), is a natural killer (NK) cell activator that induces NK cell cytotoxicity and interferon-?? (IFN-??) expression. In this report, we define a novel role for IL-18 as an NK cell protective agent. Specifically, IL-18 prevents NK cell death initiated by different and distinct stress mechanisms. IL-18 reduces NK cell self-destruction during NK-targeted cell killing, and in the presence of staurosporin, a potent apoptotic inducer, IL-18 reduces caspase-3 activity. The critical regulatory step in this process is downstream of the mitochondrion and involves reduced cleavage and activation of caspase-9 and caspase-3. The ability of IL-18 to regulate cell survival is not limited to a caspase death pathway in that IL-18 augments tumor necrosis factor (TNF) signaling, resulting in increased and prolonged mRNA expression of c-apoptosis inhibitor 2 (cIAP2), a prosurvival factor and caspase-3 inhibitor, and TNF receptor-associated factor 1 (TRAF1), a prosurvival protein. The cumulative effects of IL-18 define a novel role for this cytokine as a molecular survival switch that functions to both decrease cell death through inhibition of the mitochondrial apoptotic pathway and enhance TNF induction of prosurvival factors. ?? Mary Ann Liebert, Inc.

  8. Multiple Functions of the New Cytokine-Based Antimicrobial Peptide Thymic Stromal Lymphopoietin (TSLP)

    PubMed Central

    Bjerkan, Louise; Sonesson, Andreas; Schenck, Karl

    2016-01-01

    Thymic stromal lymphopoietin (TSLP) is a pleiotropic cytokine, hitherto mostly known to be involved in inflammatory responses and immunoregulation. The human tslp gene gives rise to two transcription and translation variants: a long form (lfTSLP) that is induced by inflammation, and a short, constitutively-expressed form (sfTSLP), that appears to be downregulated by inflammation. The TSLP forms can be produced by a number of cell types, including epithelial and dendritic cells (DCs). lfTSLP can activate mast cells, DCs, and T cells through binding to the lfTSLP receptor (TSLPR) and has a pro-inflammatory function. In contrast, sfTSLP inhibits cytokine secretion of DCs, but the receptor mediating this effect is unknown. Our recent studies have demonstrated that both forms of TSLP display potent antimicrobial activity, exceeding that of many other known antimicrobial peptides (AMPs), with sfTSLP having the strongest effect. The AMP activity is primarily mediated by the C-terminal region of the protein and is localized within a 34-mer peptide (MKK34) that spans the C-terminal α-helical region in TSLP. Fluorescent studies of peptide-treated bacteria, electron microscopy, and liposome leakage models showed that MKK34 exerted membrane-disrupting effects comparable to those of LL-37. Expression of TSLP in skin, oral mucosa, salivary glands, and intestine is part of the defense barrier that aids in the control of both commensal and pathogenic microbes. PMID:27399723

  9. Multiple effects of TRAIL in human carcinoma cells: Induction of apoptosis, senescence, proliferation, and cytokine production

    SciTech Connect

    Levina, Vera; Marrangoni, Adele M.; DeMarco, Richard; Gorelik, Elieser; Lokshin, Anna E.

    2008-04-15

    TRAIL is a death ligand that induces apoptosis in malignant but not normal cells. Recently the ability of TRAIL to induce proliferation in apoptosis-resistant normal and malignant cells was reported. In this study, we analyzed TRAIL effects in apoptosis sensitive MCF7, OVCAR3 and H460 human tumor cell lines. TRAIL at low concentrations preferentially induced cell proliferation. At 100 ng/ml, apoptotic death was readily observed, however surviving cells acquired higher proliferative capacity. TRAIL-stimulated production of several cytokines, IL-8, RANTES, MCP-1 and bFGF, and activation of caspases 1 and 8 was essential for this effect. Antibodies to IL-8, RANTES, and bFGF blocked TRAIL-induced cell proliferation and further stimulated apoptosis. For the first time, we report that high TRAIL concentrations induced cell senescence as determined by the altered morphology and expression of several senescence markers: SA-{beta}-gal, p21{sup Waf1/Cip1}, p16{sup INK4a}, and HMGA. Caspase 9 inhibition protected TRAIL-treated cells from senescence, whereas inhibition of caspases 1 and 8 increased the yield of SLP cells. In conclusion, in cultured human carcinoma cells, TRAIL therapy results in three functional outcomes, apoptosis, proliferation and senescence. TRAIL-induced proapoptotic and prosurvival responses correlate with the strength of signaling. TRAIL-induced cytokine production is responsible for its proliferative and prosurvival effects.

  10. Monocyte/macrophage-derived soluble CD163: a novel biomarker in multiple myeloma.

    PubMed

    Andersen, Morten N; Abildgaard, Niels; Maniecki, Maciej B; Møller, Holger J; Andersen, Niels F

    2014-07-01

    Macrophages play an important role in cancer by suppression of adaptive immunity and promotion of angiogenesis and metastasis. Tumor-associated macrophages strongly express the hemoglobin scavenger receptor CD163, which can also be found as a soluble protein in serum and other body fluids (soluble CD163, sCD163). In this study, we examined serum sCD163 as a biomarker in patients with newly diagnosed multiple myeloma. Peripheral blood (n = 104) and bone marrow (n = 17) levels of sCD163 were measured using an enzyme-linked immunosorbent assay. At diagnosis, high sCD163 was associated with higher stage according to the International Staging System (ISS) and with other known prognostic factors in multiple myeloma (creatinine, C-reactive protein, and beta-2 microglobulin). Soluble CD163 decreased upon high-dose treatment, and in a multivariate survival analysis including the covariates treatment modality and age at diagnosis, higher levels of sCD163 were associated with poor outcome (HR = 1.82; P = 0.010). The prognostic significance of sCD163 was lost when including ISS stage in the model (HR = 1.51; P = 0.085). Soluble CD163 values were significantly higher in bone marrow samples than in the matched blood samples, which indicate a localized production of sCD163 within the bone marrow microenvironment. Soluble CD163 was found to be a prognostic marker in patients with multiple myeloma. This may indicate that macrophages and/or monocytes have an important role in the bone marrow microenvironment of myeloma patients, supporting myeloma cell proliferation and survival. We propose the serum sCD163 value 1.8 mg/L as a cutoff concentration for survival analysis in patients with multiple myeloma, which should be validated in future studies. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  11. Predicting the outcomes for out-of-hospital cardiac arrest patients using multiple biomarkers and suspension microarray assays

    PubMed Central

    Huang, Chien-Hua; Tsai, Min-Shan; Chien, Kuo-Liong; Chang, Wei-Tien; Wang, Tzung-Dau; Chen, Shyr-Chyr; Ma, Matthew Huei-Ming; Hsu, Hsin-Yun; Chen, Wen-Jone

    2016-01-01

    Predicting the prognosis for cardiac arrest is still challenging. Combining biomarkers from diverse pathophysiological pathways may provide reliable indicators for the severity of injury and predictors of long-term outcomes. We investigated the feasibility of using a multimarker strategy with key independent biomarkers to improve the prediction of outcomes in cardiac arrest. Adult out-of-hospital cardiac arrest patients with sustained return of spontaneous circulation were prospectively enrolled in this study. Blood samples were taken at 2 and 24 hours after cardiac arrest. Suspension microarray assays were used to test 21 different biomarkers. A total of 99 patients were enrolled, 45 of whom survived to hospital discharge. We identified 11 biomarkers that, when combined with clinical variables and factors of APACHE II score and history of arrhythmia, were independent determinants for outcome of in-hospital mortality (concordance = 0.9249, standard error = 0.0779). Three biomarkers combined with APACHE II and age were independent determinants for favorable neurological outcome at hospital discharge (area under the receiver-operator characteristic curve, 0.938; 95% confidence interval, 0.854 ~ 1.0). In conclusion, a systemic multiple biomarker approach using suspension microarray assays can identify independent predictors and model the outcomes of cardiac arrest patients during the post-cardiac arrest period. PMID:27256246

  12. Using multiple biomarkers and determinants to obtain a better measurement of oxidative stress: a latent variable structural equation model approach.

    PubMed

    Eldridge, Ronald C; Flanders, W Dana; Bostick, Roberd M; Fedirko, Veronika; Gross, Myron; Thyagarajan, Bharat; Goodman, Michael

    2017-09-01

    Since oxidative stress involves a variety of cellular changes, no single biomarker can serve as a complete measure of this complex biological process. The analytic technique of structural equation modeling (SEM) provides a possible solution to this problem by modelling a latent (unobserved) variable constructed from the covariance of multiple biomarkers. Using three pooled datasets, we modelled a latent oxidative stress variable from five biomarkers related to oxidative stress: F2-isoprostanes (FIP), fluorescent oxidation products, mitochondrial DNA copy number, γ-tocopherol (Gtoc) and C-reactive protein (CRP, an inflammation marker closely linked to oxidative stress). We validated the latent variable by assessing its relation to pro- and anti-oxidant exposures. FIP, Gtoc and CRP characterized the latent oxidative stress variable. Obesity, smoking, aspirin use and β-carotene were statistically significantly associated with oxidative stress in the theorized directions; the same exposures were weakly and inconsistently associated with the individual biomarkers. Our results suggest that using SEM with latent variables decreases the biomarker-specific variability, and may produce a better measure of oxidative stress than do single variables. This methodology can be applied to similar areas of research in which a single biomarker is not sufficient to fully describe a complex biological phenomenon.

  13. Serum free light chain ratio as a biomarker for high-risk smoldering multiple myeloma

    PubMed Central

    Larsen, JT; Kumar, SK; Dispenzieri, A; Kyle, RA; Katzmann, JA; Rajkumar, SV

    2013-01-01

    A markedly elevated serum free light chain (FLC) ratio may serve as a biomarker for malignant transformation in high-risk smoldering multiple myeloma (SMM) and identify patients who are at imminent risk of progression. We retrospectively studied the predictive value of the serum (FLC) assay in 586 patients with SMM diagnosed between 1970 to 2010. A serum involved/uninvolved FLC ratio ≥100 was used to define high-risk SMM, which included 15% (n = 90) of the total cohort. Receiver operating characteristics analysis determined the optimal FLC ratio cut-point to predict progression to symptomatic multiple myeloma (MM) within 2 years of diagnosis, which resulted in a specificity of 97% and sensitivity of 16%. Fifty-six percent of patients developed progressive disease during median follow-up of 52 months, but this increased to 98% in the subgroup of patients with FLC ratio ≥100. The median time to progression in the FLC ratio ≥100 group was 15 months versus 55 months in the FLC <100 group (P<0.0001). The risk of progression to MM within the first 2 years in patients with an FLC ratio ≥100 was 72%; the risk of progression to MM or light chain amyloidosis in 2 years was 79%. We conclude that a high FLC ratio ≥100 is a predictor of imminent progression in SMM, and such patients may be considered candidates for early treatment intervention. PMID:23183428

  14. Serum free light chain ratio as a biomarker for high-risk smoldering multiple myeloma.

    PubMed

    Larsen, J T; Kumar, S K; Dispenzieri, A; Kyle, R A; Katzmann, J A; Rajkumar, S V

    2013-04-01

    A markedly elevated serum free light chain (FLC) ratio may serve as a biomarker for malignant transformation in high-risk smoldering multiple myeloma (SMM) and identify patients who are at imminent risk of progression. We retrospectively studied the predictive value of the serum (FLC) assay in 586 patients with SMM diagnosed between 1970 to 2010. A serum involved/uninvolved FLC ratio ≥ 100 was used to define high-risk SMM, which included 15% (n=90) of the total cohort. Receiver operating characteristics analysis determined the optimal FLC ratio cut-point to predict progression to symptomatic multiple myeloma (MM) within 2 years of diagnosis, which resulted in a specificity of 97% and sensitivity of 16%. Fifty-six percent of patients developed progressive disease during median follow-up of 52 months, but this increased to 98% in the subgroup of patients with FLC ratio ≥ 100. The median time to progression in the FLC ratio ≥ 100 group was 15 months versus 55 months in the FLC <100 group (P<0.0001). The risk of progression to MM within the first 2 years in patients with an FLC ratio ≥ 100 was 72%; the risk of progression to MM or light chain amyloidosis in 2 years was 79%. We conclude that a high FLC ratio ≥ 100 is a predictor of imminent progression in SMM, and such patients may be considered candidates for early treatment intervention.

  15. [Potential relationship and clinical significance of miRNAs and Th17 related cytokines in patients with multiple myeloma].

    PubMed

    Li, Yanjie; Li, Depeng; Yan, Zhiling; Qi, Kunming; Chen, Lili; Zjang, Zhiyao; Fan, Guoqin; Li, Hujun; Xu, Kailin; Li, Zhenyu

    2015-02-01

    To explore the expression and significance of miRNAs and Th17 related cytokines in patients with multiple myeloma (MM). A total of 27 MM patients and 8 health controls were enrolled in this study. The expression of miR-15a/16,miR-34a,miR-194-2-192 cluster and miR-181a/b in bone marrow were detected by real-time quantitative PCR (qRT-PCR). Enzyme-linked immunosorbent assay (ELISA) was used to determine the levels of Th17 related cytokines interleukin-17 (IL-17), IL-21, IL-22, IL-23 and IL-27 in peripheral blood plasma. The role of miRNAs and Th17 related cytokines was analyzed in the development of MM. The expression of miR-15a/16,miR-34a,miR-194-2-192 cluster in MM patients were significantly lower than those of the health controls, while miR-181a/b were exactly the reverse (P<0.05). The levels of IL-17, IL-21 and IL-27 were up-regulated in MM patients compared to health controls while IL-22 was down-regulated (P<0.05). There was no significant difference of IL-23 between the two groups. The levels of miRNAs and Th17 related cytokines had associated with ISS but not with some clinical parameters (such as gender, age, disease classification). Higher expression of IL-17, IL-21, IL-23, IL-27, miR-181a/b and lower expression of miR-15a/16,miR-34a,miR-194 and IL-22 were observed in the end stage than the early stage of MM patients (P<0.05). There was a significant correlation between miRNAs and Th17 related cytokines. Up-regulated IL-17, IL-21 and IL-27 may potentially down-regulate the expression of several miRNAs in MM patients. Establishment of the relationship may be useful for understanding the pathogenesis of MM and for clinical diagnosis of the disease.

  16. Comprehensive evaluation of serum microRNAs as biomarkers in multiple sclerosis

    PubMed Central

    Regev, Keren; Paul, Anu; Healy, Brian; von Glenn, Felipe; Diaz-Cruz, Camilo; Gholipour, Taha; Mazzola, Maria Antonietta; Raheja, Radhika; Nejad, Parham; Glanz, Bonnie I.; Kivisakk, Pia; Chitnis, Tanuja; Weiner, Howard L.

    2016-01-01

    Objective: To identify circulating microRNAs (miRNAs) linked to disease stage and disability in multiple sclerosis (MS). Methods: Sera from 296 participants including patients with MS, other neurologic diseases (Alzheimer disease and amyotrophic lateral sclerosis), and inflammatory diseases (rheumatoid arthritis and asthma) and healthy controls (HCs) were tested. miRNA profiles were determined using LNA (locked nucleic acid)-based quantitative PCR. Patients with MS were categorized according to disease stage and disability. In the discovery phase, 652 miRNAs were measured in sera from 26 patients with MS and 20 HCs. Following this, significant miRNAs (p < 0.05) from the discovery set were validated using quantitative PCR in 58 patients with MS, 30 HCs, and in 74 samples from other disease controls (Alzheimer disease, amyotrophic lateral sclerosis, asthma, and rheumatoid arthritis). Results: We validated 7 miRNAs that differentiate patients with MS from HCs (p < 0.05 in both the discovery and validation phase); miR-320a upregulation was the most significantly changing serum miRNA in patients with MS. We also identified 2 miRNAs linked to disease progression, with miR-27a-3p being the most significant. Ten miRNAs correlated with the Expanded Disability Status Scale of which miR.199a.5p had the strongest correlation with disability. Of the 15 unique miRNAs we identified in the different group comparisons, 12 have previously been reported to be associated with MS but not in serum. Conclusions: Our findings identify circulating serum miRNAs as potential biomarkers to diagnose and monitor disease status in MS. Classification of evidence: This study provides Class III evidence that circulating serum miRNAs can be used as biomarker for MS. PMID:27606352

  17. Limited value of pro-inflammatory oxylipins and cytokines as circulating biomarkers in endometriosis – a targeted ‘omics study

    PubMed Central

    Lee, Yie Hou; Cui, Liang; Fang, Jinling; Chern, Bernard Su Min; Tan, Heng Hao; Chan, Jerry K. Y.

    2016-01-01

    Endometriosis is a common, complex gynecologic disorder characterized by the presence of endometrial-like tissues at extrauterine sites. Elevation in protein and lipid mediators of inflammation including oxylipins and cytokines within the peritoneum characterize the inflamed pelvic region and may contribute to the survival and growth of displaced endometrial tissues. The presence of a clinically silent but molecularly detectable systemic inflammation in endometriosis has been proposed. Thus, we examined serum oxylipin and immunomodulatory protein levels in 103 women undergoing laparoscopy to evaluate systematically any involvement in systemic pathophysiological inflammation in endometriosis. Oxylipin levels were similar between women with and without endometriosis. Stratification by menstrual phase or severity did not offer any difference. Women with ovarian endometriosis had significantly lower 12-HETE relative to peritoneal endometriosis (−50.7%). Serum oxylipin levels were not associated with pre-operative pain symptoms. Changes to immunomodulatory proteins were minimal, with IL-12(p70), IL-13 and VEGF significantly lower in mild endometriotic women compared to non-endometriotic women (−39%, −54% and −76% respectively). Verification using C-reactive protein as a non-specific marker of inflammation further showed similar levels between groups. The implications of our work suggest pro-inflammatory mediators in the classes studied may have potentially limited value as circulating biomarkers for endometriosis, suggesting of potentially tenuous systemic inflammation in endometriosis. PMID:27193963

  18. Protein isoform-specific validation defines multiple chloride intracellular channel and tropomyosin isoforms as serological biomarkers of ovarian cancer.

    PubMed

    Tang, Hsin-Yao; Beer, Lynn A; Tanyi, Janos L; Zhang, Rugang; Liu, Qin; Speicher, David W

    2013-08-26

    New serological biomarkers for early detection and clinical management of ovarian cancer are urgently needed, and many candidates have been reported. A major challenge frequently encountered when validating candidates in patients is establishing quantitative assays that distinguish between highly homologous proteins. The current study tested whether multiple members of two recently discovered ovarian cancer biomarker protein families, chloride intracellular channel (CLIC) proteins and tropomyosins (TPM), were detectable in ovarian cancer patient sera. A multiplexed, label-free multiple reaction monitoring (MRM) assay was established to target peptides specific to all detected CLIC and TPM family members, and their serum levels were quantitated for ovarian cancer patients and non-cancer controls. In addition to CLIC1 and TPM1, which were the proteins initially discovered in a xenograft mouse model, CLIC4, TPM2, TPM3, and TPM4 were present in ovarian cancer patient sera at significantly elevated levels compared with controls. Some of the additional biomarkers identified in this homolog-centric verification and validation approach may be superior to the previously identified biomarkers at discriminating between ovarian cancer and non-cancer patients. This demonstrates the importance of considering all potential protein homologs and using quantitative assays for cancer biomarker validation with well-defined isoform specificity. This manuscript addresses the importance of distinguishing between protein homologs and isoforms when identifying and validating cancer biomarkers in plasma or serum. Specifically, it describes the use of targeted in-depth LC-MS/MS analysis to determine the members of two protein families, chloride intracellular channel (CLIC) and tropomyosin (TPM) proteins that are detectable in sera of ovarian cancer patients. It then establishes a multiplexed isoform- and homology-specific MRM assay to quantify all observed gene products in these two protein

  19. Prediagnosis biomarkers of insulin-like growth factor-1, insulin, and interleukin-6 dysregulation and multiple myeloma risk in the Multiple Myeloma Cohort Consortium

    PubMed Central

    Neuhouser, Marian L.; Rosner, Bernard; Albanes, Demetrius; Buring, Julie E.; Giles, Graham G.; Lan, Qing; Lee, I-Min; Purdue, Mark P.; Rothman, Nathaniel; Severi, Gianluca; Yuan, Jian-Min; Anderson, Kenneth C.; Pollak, Michael; Rifai, Nader; Hartge, Patricia; Landgren, Ola; Lessin, Lawrence; Virtamo, Jarmo; Wallace, Robert B.; Manson, JoAnn E.; Colditz, Graham A.

    2012-01-01

    Insulin-like growth factor-1 (IGF-1), insulin, and IL-6 are dysregulated in multiple myeloma pathogenesis and may also contribute to multiple myeloma etiology. To examine their etiologic role, we prospectively analyzed concentrations of serologic markers in 493 multiple myeloma cases and 978 controls from 8 cohorts in the Multiple Myeloma Cohort Consortium. We computed odds ratios (ORs) and 95% confidence intervals (CIs) for multiple myeloma per 1-SD increase in biomarker concentration using conditional logistic regression. We examined heterogeneity by time since blood collection (≤ 3, 4- ≤ 6, and > 6 years) in stratified models. Fasting IGF binding protein-1 concentration was associated with multiple myeloma risk within 3 years (OR, 95% CI per 1-SD increase: 2.3, 1.4-3.8, P = .001) and soluble IL-6 receptor level was associated within 6 years after blood draw (OR ≤ 3 years, 95% CI, 1.4, 1.1-1.9, P = .01; OR4- ≤ 6 years, 95% CI, 1.4, 1.1-1.7, P = .002). No biomarker was associated with longer-term multiple myeloma risk (ie, > 6 years). Interactions with time were statistically significant (IGF binding protein-1, P-heterogeneity = .0016; sIL6R, P-heterogeneity = .016). The time-restricted associations probably reflect the bioactivity of tumor and microenvironment cells in transformation from monoclonal gammopathy of undetermined significance or smoldering multiple myeloma to clinically manifest multiple myeloma. PMID:23074271

  20. Prediagnosis biomarkers of insulin-like growth factor-1, insulin, and interleukin-6 dysregulation and multiple myeloma risk in the Multiple Myeloma Cohort Consortium.

    PubMed

    Birmann, Brenda M; Neuhouser, Marian L; Rosner, Bernard; Albanes, Demetrius; Buring, Julie E; Giles, Graham G; Lan, Qing; Lee, I-Min; Purdue, Mark P; Rothman, Nathaniel; Severi, Gianluca; Yuan, Jian-Min; Anderson, Kenneth C; Pollak, Michael; Rifai, Nader; Hartge, Patricia; Landgren, Ola; Lessin, Lawrence; Virtamo, Jarmo; Wallace, Robert B; Manson, JoAnn E; Colditz, Graham A

    2012-12-13

    Insulin-like growth factor-1 (IGF-1), insulin, and IL-6 are dysregulated in multiple myeloma pathogenesis and may also contribute to multiple myeloma etiology. To examine their etiologic role, we prospectively analyzed concentrations of serologic markers in 493 multiple myeloma cases and 978 controls from 8 cohorts in the Multiple Myeloma Cohort Consortium. We computed odds ratios (ORs) and 95% confidence intervals (CIs) for multiple myeloma per 1-SD increase in biomarker concentration using conditional logistic regression. We examined heterogeneity by time since blood collection (≤ 3, 4- ≤ 6, and > 6 years) in stratified models. Fasting IGF binding protein-1 concentration was associated with multiple myeloma risk within 3 years (OR, 95% CI per 1-SD increase: 2.3, 1.4-3.8, P = .001) and soluble IL-6 receptor level was associated within 6 years after blood draw (OR (≤ 3 years), 95% CI, 1.4, 1.1-1.9, P = .01; OR(4- ≤ 6 years), 95% CI, 1.4, 1.1-1.7, P = .002). No biomarker was associated with longer-term multiple myeloma risk (ie, > 6 years). Interactions with time were statistically significant (IGF binding protein-1, P-heterogeneity = .0016; sIL6R, P-heterogeneity = .016). The time-restricted associations probably reflect the bioactivity of tumor and microenvironment cells in transformation from monoclonal gammopathy of undetermined significance or smoldering multiple myeloma to clinically manifest multiple myeloma.

  1. Current and future biomarkers in allergic asthma.

    PubMed

    Zissler, U M; Esser-von Bieren, J; Jakwerth, C A; Chaker, A M; Schmidt-Weber, C B

    2016-04-01

    Diagnosis early in life, sensitization, asthma endotypes, monitoring of disease and treatment progression are key motivations for the exploration of biomarkers for allergic rhinitis and allergic asthma. The number of genes related to allergic rhinitis and allergic asthma increases steadily; however, prognostic genes have not yet entered clinical application. We hypothesize that the combination of multiple genes may generate biomarkers with prognostic potential. The current review attempts to group more than 161 different potential biomarkers involved in respiratory inflammation to pave the way for future classifiers. The potential biomarkers are categorized into either epithelial or infiltrate-derived or mixed origin, epithelial biomarkers. Furthermore, surface markers were grouped into cell-type-specific categories. The current literature provides multiple biomarkers for potential asthma endotypes that are related to T-cell phenotypes such as Th1, Th2, Th9, Th17, Th22 and Tregs and their lead cytokines. Eosinophilic and neutrophilic asthma endotypes are also classified by epithelium-derived CCL-26 and osteopontin, respectively. There are currently about 20 epithelium-derived biomarkers exclusively derived from epithelium, which are likely to innovate biomarker panels as they are easy to sample. This article systematically reviews and categorizes genes and collects current evidence that may promote these biomarkers to become part of allergic rhinitis or allergic asthma classifiers with high prognostic value.

  2. Bayesian modeling and inference for diagnostic accuracy and probability of disease based on multiple diagnostic biomarkers with and without a perfect reference standard.

    PubMed

    Jafarzadeh, S Reza; Johnson, Wesley O; Gardner, Ian A

    2016-03-15

    The area under the receiver operating characteristic (ROC) curve (AUC) is used as a performance metric for quantitative tests. Although multiple biomarkers may be available for diagnostic or screening purposes, diagnostic accuracy is often assessed individually rather than in combination. In this paper, we consider the interesting problem of combining multiple biomarkers for use in a single diagnostic criterion with the goal of improving the diagnostic accuracy above that of an individual biomarker. The diagnostic criterion created from multiple biomarkers is based on the predictive probability of disease, conditional on given multiple biomarker outcomes. If the computed predictive probability exceeds a specified cutoff, the corresponding subject is allocated as 'diseased'. This defines a standard diagnostic criterion that has its own ROC curve, namely, the combined ROC (cROC). The AUC metric for cROC, namely, the combined AUC (cAUC), is used to compare the predictive criterion based on multiple biomarkers to one based on fewer biomarkers. A multivariate random-effects model is proposed for modeling multiple normally distributed dependent scores. Bayesian methods for estimating ROC curves and corresponding (marginal) AUCs are developed when a perfect reference standard is not available. In addition, cAUCs are computed to compare the accuracy of different combinations of biomarkers for diagnosis. The methods are evaluated using simulations and are applied to data for Johne's disease (paratuberculosis) in cattle.

  3. Transcriptome Analysis of Recurrently Deregulated Genes across Multiple Cancers Identifies New Pan-Cancer Biomarkers.

    PubMed

    Kaczkowski, Bogumil; Tanaka, Yuji; Kawaji, Hideya; Sandelin, Albin; Andersson, Robin; Itoh, Masayoshi; Lassmann, Timo; Hayashizaki, Yoshihide; Carninci, Piero; Forrest, Alistair R R

    2016-01-15

    Genes that are commonly deregulated in cancer are clinically attractive as candidate pan-diagnostic markers and therapeutic targets. To globally identify such targets, we compared Cap Analysis of Gene Expression profiles from 225 different cancer cell lines and 339 corresponding primary cell samples to identify transcripts that are deregulated recurrently in a broad range of cancer types. Comparing RNA-seq data from 4,055 tumors and 563 normal tissues profiled in the The Cancer Genome Atlas and FANTOM5 datasets, we identified a core transcript set with theranostic potential. Our analyses also revealed enhancer RNAs, which are upregulated in cancer, defining promoters that overlap with repetitive elements (especially SINE/Alu and LTR/ERV1 elements) that are often upregulated in cancer. Lastly, we documented for the first time upregulation of multiple copies of the REP522 interspersed repeat in cancer. Overall, our genome-wide expression profiling approach identified a comprehensive set of candidate biomarkers with pan-cancer potential, and extended the perspective and pathogenic significance of repetitive elements that are frequently activated during cancer progression.

  4. UCHL1 is a biomarker of aggressive multiple myeloma required for disease progression

    PubMed Central

    Hussain, Sajjad; Bedekovics, Tibor; Chesi, Marta; Bergsagel, P. Leif; Galardy, Paul J.

    2015-01-01

    The success of proteasome inhibition in multiple myeloma highlights the critical role for the ubiquitin-proteasome system (UPS) in this disease. However, there has been little progress in finding more specific targets within the UPS involved in myeloma pathogenesis. We previously found the ubiquitin hydrolase UCH-L1 to be frequently over-expressed in B-cell malignancies, including myeloma, and showed it to be a potent oncogene in mice. Here we show that UCH-L1 is a poor prognostic factor that is essential for the progression of myeloma. We found high levels of UCHL1 to predict early progression in newly diagnosed patients; a finding reversed by the inclusion of bortezomib. We also found high UCHL1 levels to be a critical factor in the superiority of bortezomib over high-dose dexamethasone in relapsed patients. High UCHL1 partially overlaps with, but is distinct from, known genetic risks including 4p16 rearrangement and 1q21 amplification. Using an orthotopic mouse model, we found UCH-L1 depletion delays myeloma dissemination and causes regression of established disease. We conclude that UCH-L1 is a biomarker of aggressive myeloma that may be an important marker of bortezomib response, and may itself be an effective target in disseminated disease. PMID:26513019

  5. Multiple biomarkers of biological effects induced by cadmium in clam Ruditapes philippinarum.

    PubMed

    Ji, Chenglong; Wu, Huifeng; Zhou, Mo; Zhao, Jianmin

    2015-06-01

    Cadmium (Cd) is a known heavy metal pollutant in the Bohai Sea. Manila clam Ruditapes philippinarum is an important fishery species along the Bohai coast. In this study, the biological effects induced by two concentrations (20 and 200 μg/L) of Cd were characterized using multiple biochemical indices in the digestive glands of clam R. philippinarum. The total hemocyte counts, reactive oxygen species productions and antioxidant enzyme activities exhibited that Cd induced dose-dependent immune and oxidative stresses in clam digestive glands. Metabolic responses indicated that both Cd exposures caused immune stress marked by the elevated branched chain amino acids (valine, leucine and isoleucine), together with the disturbance in energy metabolism. The differential metabolic biomarkers related to osmotic stress, including homarine, betaine, tyrosine and phenylalanine, suggested the differential responsive mechanisms in clam digestive glands induced by Cd exposures. In addition, both Cd treatments enhanced the anaerobiosis metabolism in clam digestive glands via differential metabolic pathways. Copyright © 2015 Elsevier Ltd. All rights reserved.

  6. Quantitative analysis of the suppressors of cytokine signaling 1 and 3 in peripheral blood leukocytes of patients with multiple sclerosis.

    PubMed

    Sedeño-Monge, Virginia; Arcega-Revilla, Raúl; Rojas-Morales, Emmanuel; Santos-López, Gerardo; Perez-García, Juan Carlos; Sosa-Jurado, Francisca; Vallejo-Ruiz, Verónica; Solis-Morales, Casandra Lucrecia; Aguilar-Rosas, Salvador; Reyes-Leyva, Julio

    2014-08-15

    Multiple sclerosis (MS) is an autoimmune disease characterized by a triad of inflammation, demyelination and gliosis. Because the suppressors of cytokine signaling (Socs) regulate the immune response, we quantified SOCS1 and SOCS3 transcription in peripheral blood leukocytes of patients with MS. SOCS1 transcription decreased significantly in MS patients compared with neurologically healthy persons (0.08±0.02 vs. 1.02±0.23; p=0.0001); while SOCS3 transcription increased in MS patients compared with controls (2.76±0.66 vs. 1.03±0.27; p=0.0008). Our results showed an imbalance of SOCS1 and SOCS3 transcription in MS patients, and a moderated negative correlation between them (Spearman's r=-0.57; p=0.0003).

  7. Identification of four potential predicting miRNA biomarkers for multiple myeloma from published datasets

    PubMed Central

    Sun, Peng; Liu, Gao

    2017-01-01

    Background Multiple myeloma is a cancer which has a high occurrence rate and causes great injury to people worldwide. In recent years, many studies reported the effects of miRNA on the appearance of multiple myeloma. However, due to the differences of samples and sequencing platforms, a large number of inconsistent results have been generated among these studies, which limited the cure of multiple myeloma at the miRNA level. Methods We performed meta-analyses to identify the key miRNA biomarkers which could be applied on the treatment of multiple myeloma. The key miRNAs were determined by overlap comparisons of seven datasets in multiple myeloma. Then, the target genes for key miRNAs were predicted by the software TargetScan. Additionally, functional enrichments and binding TFs were investigated by DAVID database and Tfacts database, respectively. Results Firstly, comparing the normal tissues, 13 miRNAs were differently expressed miRNAs (DEMs) for at least three datasets. They were considered as key miRNAs, with 12 up-regulated (hsa-miR-106b, hsa-miR-125b, hsa-miR-130b, hsa-miR-138, hsa-miR-15b, hsa-miR-181a, hsa-miR-183, hsa-miR-191, hsa-miR-19a, hsa-miR-20a, hsa-miR-221 and hsa-miR-25) and one down-regulated (hsa-miR-223). Secondly, functional enrichment analyses indicated that target genes of the upregulated miRNAs were mainly transcript factors and enriched in transcription regulation. Besides, these genes were enriched in multiple pathways: the cancer signal pathway, insulin signal metabolic pathway, cell binding molecules, melanin generation, long-term regression and P53 signaling pathway. However, no significant enrichment was found for target genes of the down-regulated genes. Due to the distinct regulation function, four miRNAs (hsa-miR-19a has-miR-221 has-miR25 and has-miR223) were ascertained as the potential prognostic and diagnostic markers in MM. Thirdly, transcript factors analysis unveiled that there were 148 TFs and 60 TFs which bind target genes

  8. A Promising Approach to Integrally Evaluate the Disease Outcome of Cerebral Ischemic Rats Based on Multiple-Biomarker Crosstalk

    PubMed Central

    Wang, Yixuan; Wei, Chunxiang; Zhu, Tao; Wang, Haidong; He, Hua

    2017-01-01

    Purpose The study was designed to evaluate the disease outcome based on multiple biomarkers related to cerebral ischemia. Methods Rats were randomly divided into sham, permanent middle cerebral artery occlusion, and edaravone-treated groups. Cerebral ischemia was induced by permanent middle cerebral artery occlusion surgery in rats. To form a simplified crosstalk network, the related multiple biomarkers were chosen as S100β, HIF-1α, IL-1β, PGI2, TXA2, and GSH-Px. The levels or activities of these biomarkers in plasma were detected before and after ischemia. Concurrently, neurological deficit scores and cerebral infarct volumes were assessed. Based on a mathematic model, network balance maps and three integral disruption parameters (k, φ, and u) of the simplified crosstalk network were achieved. Results The levels or activities of the related biomarkers and neurological deficit scores were significantly impacted by cerebral ischemia. The balance maps intuitively displayed the network disruption, and the integral disruption parameters quantitatively depicted the disruption state of the simplified network after cerebral ischemia. The integral disruption parameter u values correlated significantly with neurological deficit scores and infarct volumes. Conclusion Our results indicate that the approach based on crosstalk network may provide a new promising way to integrally evaluate the outcome of cerebral ischemia. PMID:28630527

  9. Multiple biomarkers and risk of clinical and subclinical vascular brain injury: the framingham offspring study

    USDA-ARS?s Scientific Manuscript database

    Several biomarkers have been individually associated with vascular brain injury, but no prior study has explored the simultaneous association of a biologically plausible panel of biomarkers with the incidence of stroke/transient ischemic attack and the prevalence of subclinical brain injury. In 3127...

  10. Multiple growth factors, cytokines, and neurotrophins rescue photoreceptors from the damaging effects of constant light.

    PubMed Central

    LaVail, M M; Unoki, K; Yasumura, D; Matthes, M T; Yancopoulos, G D; Steinberg, R H

    1992-01-01

    Recent demonstrations of survival-promoting activity by neurotrophic agents in diverse neuronal systems have raised the possibility of pharmacological therapy for inherited and degenerative disorders of the central nervous system. We have shown previously that, in the retina, basic fibroblast growth factor delays photoreceptor degeneration in Royal College of Surgeons rats with inherited retinal dystrophy and that the growth factor reduces or prevents the rapid photoreceptor degeneration produced by constant light in the rat. This light-damage model now provides an efficient way to assess quantitatively the survival-promoting activity in vivo of a number of growth factors and other molecules. We report here that photoreceptors can be significantly protected from the damaging effects of light by intravitreal injection of eight different growth factors, cytokines, and neurotrophins that typically act through several distinct receptor families. In addition to basic fibroblast growth factor, those factors providing a high degree of photoreceptor rescue include brain-derived neurotrophic factor, ciliary neurotrophic factor, interleukin 1 beta, and acidic fibroblast growth factor; those with less activity include neurotrophin 3, insulin-like growth factor II, and tumor necrosis factor alpha; those showing little or no protective effect are nerve growth factor, epidermal growth factor, platelet-derived growth factor, insulin, insulin-like growth factor I, heparin, and laminin. Although we used at least one relatively high concentration of each agent (the highest available), it is still possible that other concentrations or factor combinations might be more protective. Injecting heparin along with acidic fibroblast growth factor or basic fibroblast growth factor further enhanced the degree of photoreceptor survival and also suppressed the increased incidence of macrophages produced by either factor, especially basic fibroblast growth factor. These results now provide the

  11. Cytokine assays: an assessment of the preparation and treatment of blood and tissue samples.

    PubMed

    Keustermans, Genoveva C E; Hoeks, Sanne B E; Meerding, Jenny M; Prakken, Berent J; de Jager, Wilco

    2013-05-15

    Cytokines are key components of the innate and adaptive immune system. As pivotal players in the progression or regression of a pathological process, these molecules provide a window through which diseases can be monitored and can thus act as biomarkers. In order to measure cytokine levels, a plethora of protocols can be applied. These methods include bioassays, protein microarrays, high-performance liquid chromatography (HPLC), sandwich enzyme-linked immunosorbent assay (ELISA), Meso Scale Discovery (MSD) electrochemiluminescence and bead based multiplex immunoassays (MIA). Due to the interaction and activity of cytokines, multiplex immunoassays are at the forefront of cytokine analysis by allowing multiple cytokines to be measured in parallel. However, even with optimized protocols, sample standardization needs to occur before these proteins can optimally act as biomarkers. This review describes various factors influencing the levels of cytokines measured in plasma, serum, dried blood spots and tissue biopsies, focusing on sample collection and handling, long term storage and the repetitive use of samples. By analyzing how each of these factors influences protein levels, it is concluded that samples should be stored at low temperatures in order to maintain cytokine stability. In addition, within a study, sample manipulations should be kept the same, with measurement protocols being chosen for their compatibility with the research in question. By having a clear understanding of what factors influence cytokine levels and how to overcome these technical issues, minimally confounded data can be obtained and cytokines can achieve optimal biomarker activity.

  12. Integrating multiple ‘omics’ analyses identifies serological protein biomarkers for preeclampsia

    PubMed Central

    2013-01-01

    Background Preeclampsia (PE) is a pregnancy-related vascular disorder which is the leading cause of maternal morbidity and mortality. We sought to identify novel serological protein markers to diagnose PE with a multi-’omics’ based discovery approach. Methods Seven previous placental expression studies were combined for a multiplex analysis, and in parallel, two-dimensional gel electrophoresis was performed to compare serum proteomes in PE and control subjects. The combined biomarker candidates were validated with available ELISA assays using gestational age-matched PE (n=32) and control (n=32) samples. With the validated biomarkers, a genetic algorithm was then used to construct and optimize biomarker panels in PE assessment. Results In addition to the previously identified biomarkers, the angiogenic and antiangiogenic factors (soluble fms-like tyrosine kinase (sFlt-1) and placental growth factor (PIGF)), we found 3 up-regulated and 6 down-regulated biomakers in PE sera. Two optimal biomarker panels were developed for early and late onset PE assessment, respectively. Conclusions Both early and late onset PE diagnostic panels, constructed with our PE biomarkers, were superior over sFlt-1/PIGF ratio in PE discrimination. The functional significance of these PE biomarkers and their associated pathways were analyzed which may provide new insights into the pathogenesis of PE. PMID:24195779

  13. The relationship of trauma severity and mortality with cardiac enzymes and cytokines at multiple trauma patients.

    PubMed

    Karakuş, Ali; Kekeç, Zeynep; Akçan, Ramazan; Seydaoğlu, Gülşah

    2012-07-01

    In this study, we aimed to determine the effects of trauma severity on cardiac involvement through evaluating the trauma severity score together with diagnostic tests in multiple trauma patients. A trauma score was determined using various trauma severity scales. After obtaining the approval of the ethics committee of the faculty, this prospective study was performed through evaluating 100 multiple trauma patients, aged over 15 years, who applied to our Emergency Department (ED). After determining the trauma severity score using instruments such as the Injury Severity Score (ISS), Glasgow Coma Scale (GCS), and Revised Trauma Score (RTS), the cardiac condition was evaluated using biochemical and radiological diagnostic tests. During the study period, 100 patients were evaluated (78 male, 22 female; mean age: 33.2±15.4; range 15 to 70 years). It was determined that 92 (92%) were blunt trauma cases, and 77 (77%) of them were due to traffic accidents. The majority of cases showed electrocardiogram (ECG) abnormalities (63%) and sinus tachycardia (36%). Abnormal echocardiogram (ECHO) findings, mostly accompanied by ventricular defects (n=24), were determined in 31 of the cases. Nineteen cases with high trauma severity score resulted in death, and 14 of all deaths were secondary to traffic accidents. Trauma scores were found to show a significant difference between the two groups. The ISS trauma scale was determined to be the most effective in terms of indicating heart involvement in patients with multiple traumas. Close follow-up and cardiac monitoring should be applied to patients with high trauma severity scores considering possible cardiac rhythm changes and hemodynamic disturbances due to cardiac involvement.

  14. Slowed Prosaccades and Increased Antisaccade Errors As a Potential Behavioral Biomarker of Multiple System Atrophy

    PubMed Central

    Brooks, Sarah H.; Klier, Eliana M.; Red, Stuart D.; Mehta, Neeti D.; Patel, Saumil S.; Chuang, Alice Z.; Suescun, Jessika; Schiess, Mya C.; Sereno, Anne B.

    2017-01-01

    Current clinical diagnostic tools are limited in their ability to accurately differentiate idiopathic Parkinson’s disease (PD) from multiple system atrophy (MSA) and other parkinsonian disorders early in the disease course, but eye movements may stand as objective and sensitive markers of disease differentiation and progression. To assess the use of eye movement performance for uniquely characterizing PD and MSA, subjects diagnosed with PD (N = 21), MSA (N = 11), and age-matched controls (C, N = 20) were tested on the prosaccade and antisaccade tasks using an infrared eye tracker. Twenty of these subjects were retested ~7 months later. Saccade latencies, error rates, and longitudinal changes in saccade latencies were measured. Both PD and MSA patients had greater antisaccade error rates than C subjects, but MSA patients exhibited longer prosaccade latencies than both PD and C patients. With repeated testing, antisaccade latencies improved over time, with benefits in C and PD but not MSA patients. In the prosaccade task, the normal latencies of the PD group show that basic sensorimotor oculomotor function remain intact in mid-stage PD, whereas the impaired latencies of the MSA group suggest additional degeneration earlier in the disease course. Changes in antisaccade latency appeared most sensitive to differences between MSA and PD across short time intervals. Therefore, in these mid-stage patients, increased antisaccade errors combined with slowed prosaccade latencies might serve as a useful marker for early differentiation between PD and MSA, and, antisaccade performance, a measure of MSA progression. Together, our findings suggest that eye movements are promising biomarkers for early differentiation and progression of parkinsonian disorders. PMID:28676787

  15. Increased effect of IMiDs by addition of cytokine-induced killer cells in multiple myeloma.

    PubMed

    Bullok, Katharina F; Sippel, Christoph; Schmidt-Wolf, Ingo G H

    2016-12-01

    Immunomodulatory drugs (IMiDs), such as thalidomide, lenalidomide and pomalidomide, represent the basic principle of multiple myeloma treatment. However, the development of resistance is a limiting factor. Over the last years, the efficient application of cytokine-induced killer (CIK) cells has been reported as an alternative strategy to treat hematological neoplasms. In this study, we tested for a potential synergistic effect by combining the IMiDs thalidomide, lenalidomide and pomalidomide with CIK cells in different myeloma cell lines in vitro. Myeloma cells tested with CIK cells were significantly reduced. In the combination, myeloma cells were significantly reduced compared with cells only tested with IMiDs but not to the cells tested with CIK cells. Otherwise, the number of CIK cells was significantly reduced when treated with IMiDs. Because IMiDs are active in patients with myeloma, these results lead to the expectation that combination of IMiDs and CIK cells achieve better results in the treatment of multiple myeloma compared with the single use of IMiDs. Therefore, further examinations in an in vivo setting are necessary to have a closer look on the cellular interactions. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

  16. Angiogenic cytokines profile in smoldering multiple myeloma: no difference compared to MGUS but altered compared to symptomatic myeloma.

    PubMed

    Gkotzamanidou, Maria; Christoulas, Dimitrios; Souliotis, Vasillis L; Papatheodorou, Athanasios; Dimopoulos, Meletios A; Terpos, Evangelos

    2013-12-20

    Symptomatic multiple myeloma (MM) evolves from an asymptomatic precursor state termed monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM). Angiogenesis plays a key role in the pathogenesis of MM but there are very limited data for angiogenesis in SMM. We measured the circulating levels of angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), vascular endothelial growth factor (VEGF), and angiogenin in 54 patients with SMM. The results were compared with those of 27 MGUS patients, 55 MM patients, and 22 healthy controls. The expression of VEGF-A gene was also evaluated in 10 patients with SMM, 10 with symptomatic MM, and 10 with MGUS. The ratio of circulating Ang-1/Ang-2 was reduced in MM patients with symptomatic disease due to a dramatic increase of Ang-2 (p<0.001), but not in patients with SMM or MGUS, in whom it did not differ compared to controls. VEGF and angiogenin were increased in all patients compared to controls. However, circulating VEGF was higher in symptomatic MM compared to SMM and MGUS, while angiogenin was reduced. There were no differences in the expression of VEGF-A among the 3 patients categories. SMM has a circulating angiogenic cytokine profile similar to that of MGUS, but has altered profile compared to symptomatic MM. Thus, in the progression of MGUS to SMM, circulating angiogenic cytokines seem to be the same. On the contrary, in symptomatic myeloma, the alterations of angiopoietins along with VEGF contribute to myeloma cell growth, supporting the target of these molecules for the development of novel anti-myeloma agents.

  17. Type D personality and course of health status over 18 months in outpatients with heart failure: multiple mediating inflammatory biomarkers.

    PubMed

    Mommersteeg, Paula M C; Pelle, Aline J; Ramakers, Christian; Szabó, Balázs M; Denollet, Johan; Kupper, Nina

    2012-02-01

    The distressed (Type D) personality is associated with poor health status (HS) and increased inflammatory activation in heart failure (HF). We tested whether multiple inflammatory biomarkers mediated the association between Type D personality and the course of self-reported HS over 18 months. HF outpatients (n=228, 80% male, mean age 67.0±8.7 years), filled out the Type D questionnaire (DS14) at inclusion and the Short Form-12 (SF12) and the Kansas City Cardiomyopathy Questionnaire (KCCQ) at 0, 6, 12, and 18 months. Blood samples at inclusion were analyzed for high sensitive C-reactive protein (hsCRP), interleukin (IL)-6, tumor necrosis factor (TNF)-α, and its soluble receptors (sTNFr1, sTNFr2). A multiple mediation latent growth model was tested using structural equation modeling. Type D personality (prevalence=21%) was associated with poorer HS (all scales p<0.001), deterioration of mental HS (p<0.001), and higher TNF-α and sTNFr2 levels in the full mediation model. A higher inflammatory burden was associated with a poorer baseline level and a deterioration of generic physical, mental and disease-specific HS. No mediating effects were found for the multiple inflammatory biomarkers on the association between Type D and baseline self-reported HS, whereas change in physical HS was significantly mediated by the group of five inflammatory biomarkers (p=0.026). Only the association between Type D personality and change in self-reported physical health status was significantly mediated by inflammatory biomarkers. Future research should investigate whether the association between Type D personality and poor health status may be explained by other biological or behavioral factors. Copyright © 2011 Elsevier Inc. All rights reserved.

  18. A lectin-coupled, targeted proteomic mass spectrometry (MRM MS) platform for identification of multiple liver cancer biomarkers in human plasma.

    PubMed

    Ahn, Yeong Hee; Shin, Park Min; Oh, Na Ree; Park, Gun Wook; Kim, Hoguen; Yoo, Jong Shin

    2012-09-18

    Aberrantly glycosylated proteins related to liver cancer progression were captured with specific lectin and identified from human plasma by multiple reaction monitoring (MRM) mass spectrometry as multiple biomarkers for hepatocellular carcinoma (HCC). The lectin fractionation for fucosylated protein glycoforms in human plasma was conducted with a fucose-specific aleuria aurantia lectin (AAL). Following tryptic digestion of the lectin-captured fraction, plasma samples from 30 control cases (including 10 healthy, 10 hepatitis B virus [HBV], and 10 cirrhosis cases) and 10 HCC cases were quantitatively analyzed by MRM to identify which glycoproteins are viable HCC biomarkers. A1AG1, AACT, A1AT, and CERU were found to be potent biomarkers to differentiate HCC plasma from control plasmas. The AUROC generated independently from these four biomarker candidates ranged from 0.73 to 0.92. However, the lectin-coupled MRM assay with multiple combinations of biomarker candidates is superior statistically to those generated from the individual candidates with AUROC more than 0.95, which can be an alternative to the immunoassay inevitably requiring tedious development of multiple antibodies against biomarker candidates to be verified. Eventually the lectin-coupled, targeted proteomic mass spectrometry (MRM MS) platform was found to be efficient to identify multiple biomarkers from human plasma according to cancer progression. Copyright © 2012 Elsevier B.V. All rights reserved.

  19. Semi-quantitative analysis of multiple cytokines in canine peripheral blood mononuclear cells by [correction of zby] a single tube RT-PCR.

    PubMed

    Chamizo, C; Rubio, J M; Moreno, J; Alvar, J

    2001-12-01

    Cytokines play an important role in the regulation of the immune system, but low circulating levels in plasma make routine measurement a difficult task. A new methodology based on single tube RT-PCR has been developed to determine the expression of multiple canine cytokines (TNF-alpha, IL-2, IFN-gamma, IL-18, IL-4, IL-6 and IL-10) using primers and protocols designed allow specific amplification of the mRNAs. The technique is performed in one tube in two consecutive steps, a specific transcription of the mRNA of a given cytokine and amplification of the corresponding gene by PCR. The technique was used to analyse the mRNA cytokine profile of peripheral blood mononuclear cells (PBMCs) from healthy dogs using two approaches: (i) analysis of PBMC isolated ex vivo; (ii) analysis of PBMC after in vitro cultures with or without the mitogen ConA. The samples were separated in agarose gels and the intensity of ethidium bromide signals quantified using standard video imaging equipment. Results were interpreted as the ratio of cytokine to GAPDH expression. The results obtained show that the method is easy to use and reproducible. Therefore, this method of monitoring the mRNA cytokine expression might be an useful tool for understanding the immune response in dogs.

  20. Semi-automated literature mining to identify putative biomarkers of disease from multiple biofluids

    PubMed Central

    2014-01-01

    Background Computational methods for mining of biomedical literature can be useful in augmenting manual searches of the literature using keywords for disease-specific biomarker discovery from biofluids. In this work, we develop and apply a semi-automated literature mining method to mine abstracts obtained from PubMed to discover putative biomarkers of breast and lung cancers in specific biofluids. Methodology A positive set of abstracts was defined by the terms ‘breast cancer’ and ‘lung cancer’ in conjunction with 14 separate ‘biofluids’ (bile, blood, breastmilk, cerebrospinal fluid, mucus, plasma, saliva, semen, serum, synovial fluid, stool, sweat, tears, and urine), while a negative set of abstracts was defined by the terms ‘(biofluid) NOT breast cancer’ or ‘(biofluid) NOT lung cancer.’ More than 5.3 million total abstracts were obtained from PubMed and examined for biomarker-disease-biofluid associations (34,296 positive and 2,653,396 negative for breast cancer; 28,355 positive and 2,595,034 negative for lung cancer). Biological entities such as genes and proteins were tagged using ABNER, and processed using Python scripts to produce a list of putative biomarkers. Z-scores were calculated, ranked, and used to determine significance of putative biomarkers found. Manual verification of relevant abstracts was performed to assess our method’s performance. Results Biofluid-specific markers were identified from the literature, assigned relevance scores based on frequency of occurrence, and validated using known biomarker lists and/or databases for lung and breast cancer [NCBI’s On-line Mendelian Inheritance in Man (OMIM), Cancer Gene annotation server for cancer genomics (CAGE), NCBI’s Genes & Disease, NCI’s Early Detection Research Network (EDRN), and others]. The specificity of each marker for a given biofluid was calculated, and the performance of our semi-automated literature mining method assessed for breast and lung cancer

  1. The incremental prognostic and clinical value of multiple novel biomarkers in heart failure.

    PubMed

    Jackson, Colette E; Haig, Caroline; Welsh, Paul; Dalzell, Jonathan R; Tsorlalis, Ioannis K; McConnachie, Alex; Preiss, David; Anker, Stefan D; Sattar, Naveed; Petrie, Mark C; Gardner, Roy S; McMurray, John J V

    2016-12-01

    In recent years there has been an increase in the number of biomarkers in heart failure (HF). The clinical role for these novel biomarkers in combination is not clear. The following novel biomarkers were measured from 628 patients recently hospitalized with decompensated HF; mid-regional pro-adrenomedullin (MR-proADM), mid-regional pro-atrial natriuretic peptide (MR-proANP), copeptin, high-sensitivity cardiac troponin T (hs-cTnT), ST2, galectin-3, cystatin C, combined free light chains (cFLC) and high sensitivity C-reactive protein (hsCRP). The incremental prognostic value of these novel biomarkers was evaluated within an extensive model containing established predictors of mortality. During a mean (SD) follow-up of 3.2 (1.5) years, 290 (46%) patients died. Elevated concentrations of all novel biomarkers were associated with an increased unadjusted risk of mortality but only two-thirds were independent predictors following multivariable analysis. Using dichotomized cut-points from receiver operating characteristic analysis, MR-proADM, hs-cTnT, cFLC, hsCRP, and ST2 remained independent predictors of mortality. Further dichotomization into low (0-2 elevated biomarkers) or high (at least three of the five biomarkers elevated) risk groups provided greatest incremental prognostic value (hazard ratio 2.20, 95% confidence interval 1.37-3.54; P = 0.001) and improved the performance of the model (C-statistic 0.730 from 0.721, net reclassification index 32.5%). The novel biomarkers included in this study added little, if any, incremental prognostic value on their own to a model containing established predictors of mortality. However, following dichotomization, five of the novel biomarkers provided incremental prognostic value. There was a clear gradient in the risk of death with increasing numbers of elevated novel biomarkers, with the presence of at least three identifying patients at greatest risk of mortality. © 2016 The Authors. European Journal of Heart Failure

  2. [Response surface methodology for optimizing the technology of induction and isolation of dendritic cells by multiple cytokines].

    PubMed

    Duan, Xunwei; Xiao, Guiqing; Zhao, Yanlan; Wang, Lixing; Zheng, Chenna; Dong, Le; Wu, Wenlin

    2017-07-01

    Objective To promote the induction and separation efficiency of bone marrow-derived dendritic cells (BMDCs) in vitro through optimizing the inducing and isolating process by multiple cytokines. Methods The factors to be optimized in single factor tests included recombinant mouse granulocyte macrophage-colony stimulating factor (rmGM-CSF), recombinant mouse interleukine 4 (rmIL-4), lipopolysaccharide (LPS), recombinant mouse tumor necrosis factor α (rmTNF-α) and inducing time. The numbers of immature dendritic cells (imDCs) and mature dendritic cells (mDCs) were investigated as the indicators. Box-Behnken experimental design-response surface methodology was used to analyze and verify the data. Morphological changes were observed using the inverted microscopy and the transmission electron microscopy. Surface molecules including CD11c and CD86 were detected using the flow cytometry. Results The optimum inducing conditions for imDCs were obtained as follows: rmGM-CSF was 46 ng/mL, rmIL-4 was 24 ng/mL, inducing time was 6 days, and the number of imDCs was (4.58±0.28)×10(6) cells, and the relative deviation was 4.00%. The optimum inducing conditions for mDCs were as follows: LPS was 1.4 μg/mL, rmTNF-α was 30 ng/mL, inducing time was 1 day, and the number of mDCs was (4.21±0.15)×10(6) cells, and the relative deviation was 3.80%. Sufficient typical imDCs and mDCs were obtained within 5-7 days of induction in vitro. Also, flow cytometry showed that the amplified imDCs had a high expression of CD11c (68.62%±2.3%) and a low expression of CD86 (37.95%±1.8%), and the mDCs had high expressions of both CD86 (90.34%±1.4%) and CD11c (82.05%±1.6%). Conclusion The combination of single factor tests and Box-Behnken design -response surface methodology could optimize the inducing and isolating method for DCs in vitro by multiple cytokines rapidly and efficiently, which provided basic experiment materials for further studies.

  3. Pointwise mutual information quantifies intratumor heterogeneity in tissue sections labeled with multiple fluorescent biomarkers

    PubMed Central

    Spagnolo, Daniel M.; Gyanchandani, Rekha; Al-Kofahi, Yousef; Stern, Andrew M.; Lezon, Timothy R.; Gough, Albert; Meyer, Dan E.; Ginty, Fiona; Sarachan, Brion; Fine, Jeffrey; Lee, Adrian V.; Taylor, D. Lansing; Chennubhotla, S. Chakra

    2016-01-01

    Background: Measures of spatial intratumor heterogeneity are potentially important diagnostic biomarkers for cancer progression, proliferation, and response to therapy. Spatial relationships among cells including cancer and stromal cells in the tumor microenvironment (TME) are key contributors to heterogeneity. Methods: We demonstrate how to quantify spatial heterogeneity from immunofluorescence pathology samples, using a set of 3 basic breast cancer biomarkers as a test case. We learn a set of dominant biomarker intensity patterns and map the spatial distribution of the biomarker patterns with a network. We then describe the pairwise association statistics for each pattern within the network using pointwise mutual information (PMI) and visually represent heterogeneity with a two-dimensional map. Results: We found a salient set of 8 biomarker patterns to describe cellular phenotypes from a tissue microarray cohort containing 4 different breast cancer subtypes. After computing PMI for each pair of biomarker patterns in each patient and tumor replicate, we visualize the interactions that contribute to the resulting association statistics. Then, we demonstrate the potential for using PMI as a diagnostic biomarker, by comparing PMI maps and heterogeneity scores from patients across the 4 different cancer subtypes. Estrogen receptor positive invasive lobular carcinoma patient, AL13-6, exhibited the highest heterogeneity score among those tested, while estrogen receptor negative invasive ductal carcinoma patient, AL13-14, exhibited the lowest heterogeneity score. Conclusions: This paper presents an approach for describing intratumor heterogeneity, in a quantitative fashion (via PMI), which departs from the purely qualitative approaches currently used in the clinic. PMI is generalizable to highly multiplexed/hyperplexed immunofluorescence images, as well as spatial data from complementary in situ methods including FISSEQ and CyTOF, sampling many different components

  4. Multiple Inflammatory Biomarker Detection in a Prospective Cohort Study: A Cross-Validation between Well-Established Single-Biomarker Techniques and an Electrochemiluminescense-Based Multi-Array Platform

    PubMed Central

    van Bussel, Bas C. T.; Ferreira, Isabel; van de Waarenburg, Marjo P. H.; van Greevenbroek, Marleen M. J.; van der Kallen, Carla J. H.; Henry, Ronald M. A.; Feskens, Edith J. M.; Stehouwer, Coen D. A.; Schalkwijk, Casper G.

    2013-01-01

    Background In terms of time, effort and quality, multiplex technology is an attractive alternative for well-established single-biomarker measurements in clinical studies. However, limited data comparing these methods are available. Methods We measured, in a large ongoing cohort study (n = 574), by means of both a 4-plex multi-array biomarker assay developed by MesoScaleDiscovery (MSD) and single-biomarker techniques (ELISA or immunoturbidimetric assay), the following biomarkers of low-grade inflammation: C-reactive protein (CRP), serum amyloid A (SAA), soluble intercellular adhesion molecule 1 (sICAM-1) and soluble vascular cell adhesion molecule 1 (sVCAM-1). These measures were realigned by weighted Deming regression and compared across a wide spectrum of subjects’ cardiovascular risk factors by ANOVA. Results Despite that both methods ranked individuals’ levels of biomarkers very similarly (Pearson’s r all≥0.755) absolute concentrations of all biomarkers differed significantly between methods. Equations retrieved by the Deming regression enabled proper realignment of the data to overcome these differences, such that intra-class correlation coefficients were then 0.996 (CRP), 0.711 (SAA), 0.895 (sICAM-1) and 0.858 (sVCAM-1). Additionally, individual biomarkers differed across categories of glucose metabolism, weight, metabolic syndrome and smoking status to a similar extent by either method. Conclusions Multiple low-grade inflammatory biomarker data obtained by the 4-plex multi-array platform of MSD or by well-established single-biomarker methods are comparable after proper realignment of differences in absolute concentrations, and are equally associated with cardiovascular risk factors, regardless of such differences. Given its greater efficiency, the MSD platform is a potential tool for the quantification of multiple biomarkers of low-grade inflammation in large ongoing and future clinical studies. PMID:23472208

  5. [Clinical validation of multiple biomarkers suspension array technology for ovarian cancer].

    PubMed

    Zhao, B B; Yang, Z J; Wang, Q; Pan, Z M; Zhang, W; Li, L

    2017-01-25

    Objective: To investigates the diagnostic value of combined detection serum CCL18, CXCL1 antigen, C1D, TM4SF1, FXR1, TIZ IgG autoantibody by suspension array for ovarian cancer. Methods: Suspension array was used to detect CCL18, CXCL1 antigen, C1D, TM4SF1, FXR1, TIZ IgG autoantibody in 120 cases of healthy women, 204 cases of patients with benign pelvic tumors, 119 cases of pelvic malignant tumor patients, and 40 cases with breast cancer, lung cancer oroliver cancer, respectively. Constructed diagnosis model of combined detection six biomarkers for diagnosis of ovarian malignant tumor. Constructed diagnosis model of combined detection autoantibodies to diagnose epithelial ovarian cancer. Analysed the value of detecting six biomarkers for diagnosis of ovarian malignant tumor and detecting autoantibodies for diagnosis of epithelial ovarian cancer. Analysed diagnostic value of detecting six biomarkers to diagnose stage Ⅰ and Ⅱepithelial ovarian cancer. Compared diagnostic value of detecting six biomarkers in diagnosis of tissue types and pathologic grading with that of CA(125). Results: Model of combined detecting six biomarkers to diagnose ovarian malignant tumor was logit (P) =-11.151+0.008×C1D+0.011×TM4SF1+0.011×TIZ-0.008×FXR1+0.021×CCL18+0.200×CXCL1. Model of combined detection autoantibodies to diagnose epithelial ovarian cancer was logit (P) =-5.137+0.013×C1D+0.014×TM4SF1+0.060×TIZ-0.060×FXR1. Sensitivity and specificity of detecting six biomarker to diagnose ovarian malignant tumor was 90.6% and 98.7%. Sensitivity and specificity of detecting autoantibodies to diagnose epithelial ovarian cancer was 75.8% and 96.7%. Combined detection for six biomarkers to diagnose serous and mucinous ovarian cancer was statistically no better than those of CA(125) (P=0.196 and P=0.602, respectively); there was significantly difference in diagnosis of ovarian cancer (P=0.023), and there was no significantly difference in diagnosis of different pathological grading

  6. Multiple protein biomarker assessment for recombinant bovine somatotropin (rbST) abuse in cattle.

    PubMed

    Ludwig, Susann K J; Smits, Nathalie G E; van der Veer, Grishja; Bremer, Maria G E G; Nielen, Michel W F

    2012-01-01

    Biomarker profiling, as a rapid screening approach for detection of hormone abuse, requires well selected candidate biomarkers and a thorough in vivo biomarker evaluation as previously done for detection of growth hormone doping in athletes. The bovine equivalent of growth hormone, called recombinant bovine somatotropin (rbST) is (il)legally administered to enhance milk production in dairy cows. In this study, first a generic sample pre-treatment and 4-plex flow cytometric immunoassay (FCIA) were developed for simultaneous measurement of four candidate biomarkers selected from literature: insulin-like growth factor 1 (IGF-1), its binding protein 2 (IGFBP2), osteocalcin and endogenously produced antibodies against rbST. Next, bovine serum samples from two extensive controlled rbST animal treatment studies were used for in vivo validation and biomarker evaluation. Finally, advanced statistic tools were tested for the assessment of biomarker combination quality aiming to correctly identify rbST-treated animals. The statistical prediction tool k-nearest neighbours using a combination of the biomarkers osteocalcin and endogenously produced antibodies against rbST proved to be very reliable and correctly predicted 95% of the treated samples starting from the second rbST injection until the end of the treatment period and even thereafter. With the same biomarker combination, only 12% of untreated animals appeared false-positive. This reliability meets the requirements of Commission Decision 2002/657/EC for screening methods in veterinary control. From the results of this multidisciplinary study, it is concluded that the osteocalcin - anti-rbST-antibodies combination represent fit-for-purpose biomarkers for screening of rbST abuse in dairy cattle and can be reliably measured in both the developed 4-plex FCIA as well as in a cost-effective 2-plex microsphere-based binding assay. This screening method can be incorporated in routine veterinary monitoring programmes: in the

  7. Multiple Protein Biomarker Assessment for Recombinant Bovine Somatotropin (rbST) Abuse in Cattle

    PubMed Central

    Ludwig, Susann K. J.; Smits, Nathalie G. E.; van der Veer, Grishja; Bremer, Maria G. E. G.; Nielen, Michel W. F.

    2012-01-01

    Biomarker profiling, as a rapid screening approach for detection of hormone abuse, requires well selected candidate biomarkers and a thorough in vivo biomarker evaluation as previously done for detection of growth hormone doping in athletes. The bovine equivalent of growth hormone, called recombinant bovine somatotropin (rbST) is (il)legally administered to enhance milk production in dairy cows. In this study, first a generic sample pre-treatment and 4-plex flow cytometric immunoassay (FCIA) were developed for simultaneous measurement of four candidate biomarkers selected from literature: insulin-like growth factor 1 (IGF-1), its binding protein 2 (IGFBP2), osteocalcin and endogenously produced antibodies against rbST. Next, bovine serum samples from two extensive controlled rbST animal treatment studies were used for in vivo validation and biomarker evaluation. Finally, advanced statistic tools were tested for the assessment of biomarker combination quality aiming to correctly identify rbST-treated animals. The statistical prediction tool k-nearest neighbours using a combination of the biomarkers osteocalcin and endogenously produced antibodies against rbST proved to be very reliable and correctly predicted 95% of the treated samples starting from the second rbST injection until the end of the treatment period and even thereafter. With the same biomarker combination, only 12% of untreated animals appeared false-positive. This reliability meets the requirements of Commission Decision 2002/657/EC for screening methods in veterinary control. From the results of this multidisciplinary study, it is concluded that the osteocalcin – anti-rbST-antibodies combination represent fit-for-purpose biomarkers for screening of rbST abuse in dairy cattle and can be reliably measured in both the developed 4-plex FCIA as well as in a cost-effective 2-plex microsphere-based binding assay. This screening method can be incorporated in routine veterinary monitoring programmes: in the

  8. Serum Neurofilament light: A biomarker of neuronal damage in multiple sclerosis

    PubMed Central

    Disanto, Giulio; Barro, Christian; Benkert, Pascal; Naegelin, Yvonne; Schädelin, Sabine; Giardiello, Antonella; Zecca, Chiara; Blennow, Kaj; Zetterberg, Henrik; Leppert, David; Kappos, Ludwig; Gobbi, Claudio; Kuhle, Jens; Lorscheider, Johannes; Yaldizli, Özgür; Derfuss, Tobias; Kappos, Ludwig; Disanto, Giulio; Zecca, Chiara; Gobbi, Claudio; Benkert, Pascal; Achtnichts, Lutz; Nedeltchev, Krassen; Kamm, Christian P; Salmen, Anke; Chan, Andrew; Lalive, Patrice H; Pot, Caroline; Schluep, Myriam; Granziera, Cristina; Du Pasquier, Renaud; Müller, Stefanie; Vehoff, Jochen

    2017-01-01

    Objective Neurofilament light chains (NfL) are unique to neuronal cells, are shed to the cerebrospinal fluid (CSF), and are detectable at low concentrations in peripheral blood. Various diseases causing neuronal damage have resulted in elevated CSF concentrations. We explored the value of an ultrasensitive single‐molecule array (Simoa) serum NfL (sNfL) assay in multiple sclerosis (MS). Methods sNfL levels were measured in healthy controls (HC, n = 254) and two independent MS cohorts: (1) cross‐sectional with paired serum and CSF samples (n = 142), and (2) longitudinal with repeated serum sampling (n = 246, median follow‐up = 3.1 years, interquartile range [IQR] = 2.0–4.0). We assessed their relation to concurrent clinical, imaging, and treatment parameters and to future clinical outcomes. Results sNfL levels were higher in both MS cohorts than in HC (p < 0.001). We found a strong association between CSF NfL and sNfL (β = 0.589, p < 0.001). Patients with either brain or spinal (43.4pg/ml, IQR = 25.2–65.3) or both brain and spinal gadolinium‐enhancing lesions (62.5pg/ml, IQR = 42.7–71.4) had higher sNfL than those without (29.6pg/ml, IQR = 20.9–41.8; β = 1.461, p = 0.005 and β = 1.902, p = 0.002, respectively). sNfL was independently associated with Expanded Disability Status Scale (EDSS) assessments (β = 1.105, p < 0.001) and presence of relapses (β = 1.430, p < 0.001). sNfL levels were lower under disease‐modifying treatment (β = 0.818, p = 0.003). Patients with sNfL levels above the 80th, 90th, 95th, 97.5th, and 99th HC‐based percentiles had higher risk of relapses (97.5th percentile: incidence rate ratio = 1.94, 95% confidence interval [CI] = 1.21–3.10, p = 0.006) and EDSS worsening (97.5th percentile: OR = 2.41, 95% CI = 1.07–5.42, p = 0.034). Interpretation These results support the value of sNfL as a sensitive and clinically meaningful blood biomarker to monitor tissue damage and the effects of therapies in MS. Ann Neurol 2017

  9. STAT2 Is a Pervasive Cytokine Regulator due to Its Inhibition of STAT1 in Multiple Signaling Pathways

    PubMed Central

    Ho, Johnathan; Pelzel, Christin; Begitt, Andreas; Mee, Maureen; Elsheikha, Hany M.; Scott, David J.; Vinkemeier, Uwe

    2016-01-01

    STAT2 is the quintessential transcription factor for type 1 interferons (IFNs), where it functions as a heterodimer with STAT1. However, the human and murine STAT2-deficient phenotypes suggest important additional and currently unidentified type 1 IFN-independent activities. Here, we show that STAT2 constitutively bound to STAT1, but not STAT3, via a conserved interface. While this interaction was irrelevant for type 1 interferon signaling and STAT1 activation, it precluded the nuclear translocation specifically of STAT1 in response to IFN-γ, interleukin-6 (IL-6), and IL-27. This is explained by the dimerization between activated STAT1 and unphosphorylated STAT2, whereby the semiphosphorylated dimers adopted a conformation incapable of importin-α binding. This, in turn, substantially attenuated cardinal IFN-γ responses, including MHC expression, senescence, and antiparasitic immunity, and shifted the transcriptional output of IL-27 from STAT1 to STAT3. Our results uncover STAT2 as a pervasive cytokine regulator due to its inhibition of STAT1 in multiple signaling pathways and provide an understanding of the type 1 interferon-independent activities of this protein. PMID:27780205

  10. Potential relationship and clinical significance of miRNAs and Th17 cytokines in patients with multiple myeloma.

    PubMed

    Li, Yanjie; Li, Depeng; Yan, Zhiling; Qi, Kunming; Chen, Lili; Zhang, Zhiyao; Fan, Guoqin; Li, Hujun; Xu, Kailin; Li, Zhenyu

    2014-09-01

    We evaluated the potential relationship between miRNAs and Th17 cytokines in multiple myeloma (MM) patients. Twenty-seven newly diagnosed myeloma patients and eight normal donors were studied. We determined that the relative expression levels of miR-15a/16, miR-34a, miR-194 in MM patients were significantly lower than those in the healthy controls with exception for miR-181a/b, which showed significantly higher in MM patients (P<0.05). In contrast, the levels of IL-17, IL-21 and IL-27 were up-regulated in MM patients compared to healthy controls while IL-22 was down-regulated (P<0.05). The expression patterns of them were differentially present in various groups according to the International Staging System (ISS) criteria. Up-regulated IL-17, IL-21 and IL-27 may potentially down-regulate the expression of several miRNAs in MM patients. Establishment of the relationship may be useful for understanding the pathogenesis of MM and for clinical diagnosis of the disease. Copyright © 2014 Elsevier Ltd. All rights reserved.

  11. Interpretation of multiple archaeal lipid biomarkers in deep sediments bearing gas hydrate in the East Sea

    NASA Astrophysics Data System (ADS)

    Dong-Hun, Lee; Jong-Gu, Gal; Ji-Hoon, Kim; Jang-Jun, Bahk; Kyung-Hoon, Shin

    2014-05-01

    We investigate the distributions and stable carbon isotope values of arhaeal lipid biomarkers at seismically chimney and non-chimney sites (UBGH 2-3, UBGH 2-1_1) of gas hydrate bearing deep core sediments during the second Ulleung Basin Gas Hydrate Drilling Expedition (UBGH 2). The objective of this study was to identify and compare the metabolic pathway of methane-related archaea between both sites. The increased concentration and δ13C-depleted archaeol and sn-2-hydroxyarcheol at the Sulphate-Methane transition Zone (SMTZ) of UBGH 2-11 could be predominantly methanotrophic activity indicating methane consumption by Anaerobic Oxidation of Methane (AOM). The concentration of methane-related specific biomarkers (PMI, crocetane, archaeol, sn-2-hydroxyarcheol) within deep core sediment bearing gas hydrate of both sites is relatively higher than in other sediment sections, showing lower Cl- concentration. The carbon stable isotopic data (-47.5 o -75.2o to -52.4) for archaeol, sn-2-hydroxyarcheol in the sediment sections (20mbsf, 93 - 100mbsf) at UBGH 2-11 reflect methane production via microbial carbon dioxide reduction in deep core sediment. Archaeal lipid biomarker concentrations are slightly different depending on upward methane diffusion or advection with the seismic characteristics of both sites. Based on the archaeal lipid biomarker ratio (sn-2-hydroxyarchaeol/archaeol) as a tool to demonstrate the different ANME communities, our result suggest that the predominant occurrence of ANMEs is mediated by upward migration of microbial methane. Consequently, geochemical signature of archaeal lipid biomarkers in the East Sea of the western North Paci?c may be a potential indicator reflected by upward transported-methane in methane cycle of deep core sediment. In addition, the distribution of glycerol dialkyl glycerol tetraethers (GDGTs) is discussed with archaeal lipid biomarkers in the gas hydrate bearing deep sediment.

  12. Multiple biomarkers of pollution effects in caged mussels on the Greek coastline.

    PubMed

    Tsangaris, C; Kormas, K; Strogyloudi, E; Hatzianestis, I; Neofitou, C; Andral, B; Galgani, F

    2010-04-01

    A suite of biomarkers was measured in caged mussels at areas impacted by different anthropogenic activities along the Greek coastline to assess biological effects of environmental pollution. Mussels were caged at coastal sites in the vicinity of major cities, in areas influenced by major industries, agricultural practices and in islands away from known sources of pollution. Biomarkers indicative of neurotoxicity (acetylcholinesterase, AchE), oxidative stress (catalase, CAT), phase II biotransformation of xenobiotics (glutathione S-transferase, GST), metal exposure (metallothioneins, MTs) and protein synthesis (RNA:DNA ratio) were measured to assess effects of various types of pollutants. AchE activity proved to be the most responsive biomarker with decreased values at sites influenced by agricultural, urban and industrial activities. Decreased CAT and GST activities and increased MTs levels were recorded at a number of anthropogenic-impacted sites. RNA:DNA ratio showed a biphasic response as both high and low values were found at impacted sites. Principal component analysis clearly distinguished sites receiving pollution inputs from non-polluted sites. The combination of the selected biomarkers used in caged mussels resulted useful in the assessment of the effects of environmental pollution.

  13. Effect of temperature in multiple biomarkers of oxidative stress in coastal shrimp.

    PubMed

    Vinagre, Catarina; Madeira, Diana; Mendonça, Vanessa; Dias, Marta; Roma, Joma; Diniz, Mário S

    2014-04-01

    Various studies in captivity and in the wild have pointed to the effect of season, and temperature in particular, in the levels of the oxidative stress biomarkers currently used for environmental quality assessment. However, knowledge on how temperature affects the oxidative stress response is unavailable for most species. This study investigated the effect of increasing temperature on lipid peroxidation, catalase activity, superoxide dismutase and glutathione-S-transferase in the shrimps, Palaemon elegans and Palaemon serratus. It was concluded that increasing temperatures significantly affect all the biomarkers tested in both species, with the exception of superoxide dismutase in P. serratus which was not affected by temperature. The oxidative stress response was more intense in P. elegans, than in P. serratus, producing higher peaks of all biomarkers at temperatures between 22°C and 26°C, followed by low levels at higher temperatures. It was concluded that monitoring of ecosystems using oxidative stress biomarkers should take into account the species and thermal history of the organisms. Sampling should be avoided during heat waves and immediately after heat waves.

  14. RGC-32 as a potential biomarker of relapse and response to treatment with glatiramer acetate in multiple sclerosis.

    PubMed

    Kruszewski, Adam M; Rao, Gautam; Tatomir, Alexandru; Hewes, Daniel; Tegla, Cosmin A; Cudrici, Cornelia D; Nguyen, Vingh; Royal, Walter; Bever, Christopher T; Rus, Violeta; Rus, Horea

    2015-12-01

    Currently there is critical need for the identification of reliable biomarkers to help guide clinical management of multiple sclerosis (MS) patients. We investigated the combined roles of Response Gene to Complement 32 (RGC-32), FasL, CDC2, AKT, and IL-21 as possible biomarkers of relapse and response to glatiramer acetate (GA) treatment in relapsing-remitting MS (RRMS) patients. Over the course of 2 years, a cohort of 15 GA-treated RRMS patients was clinically monitored and peripheral blood mononuclear cells (PBMCs) were collected at 0, 3, 6, and 12 months. Target gene mRNA expression was measured in patients' isolated PBMCs by real-time qRT-PCR. Compared to stable MS patients, those with acute relapses exhibited decreased expression of RGC-32 (p<0.0001) and FasL (p<0.0001), increased expression of IL-21 (p=0.04), but no change in CDC2 or AKT. Compared to non-responders, responders to GA treatment showed increased expression of RGC-32 (p<0.0001) and FasL (p<0.0001), and decreased expression of IL-21 (p=0.02). Receiver operating characteristic (ROC) analysis was used to assess the predictive accuracy of each putative biomarker. The probability of accurately detecting relapse was 90% for RGC-32, 88% for FasL, and 75% for IL-21. The probability of accurately detecting response to GA was 85% for RGC-32, 90% for FasL, and 85% for IL-21. Our data suggest that RGC-32, FasL, and IL-21 could serve as potential biomarkers for the detection of MS relapse and response to GA therapy. Copyright © 2015 Elsevier Inc. All rights reserved.

  15. Cerebrospinal fluid biomarkers as a measure of disease activity and treatment efficacy in relapsing-remitting multiple sclerosis.

    PubMed

    Novakova, Lenka; Axelsson, Markus; Khademi, Mohsen; Zetterberg, Henrik; Blennow, Kaj; Malmeström, Clas; Piehl, Fredrik; Olsson, Tomas; Lycke, Jan

    2017-04-01

    Cerebrospinal fluid (CSF) biomarkers can reflect different aspects of the pathophysiology of relapsing-remitting multiple sclerosis (RRMS). Understanding the impact of different disease modifying therapies on the CSF biomarker profile may increase their implementation in clinical practice and their appropriateness for monitoring treatment efficacy. This study investigated the influence of first-line (interferon beta) and second-line (natalizumab) therapies on seven CSF biomarkers in RRMS and their correlation with clinical and radiological outcomes. We included 59 RRMS patients and 39 healthy controls. The concentrations of C-X-C motif chemokine 13 (CXCL13), C-C motif chemokine ligand 2 (CCL2), chitinase-3-like protein 1 (CHI3L1), glial fibrillary acidic protein, neurofilament light protein (NFL), and neurogranin were determined by ELISA, and chitotriosidase (CHIT1) was analyzed by spectrofluorometry. RRMS patients had higher levels of NFL, CXCL13, CHI3L1, and CHIT1 than controls (p < 0.001). Subgroup analysis revealed higher NFL, CXCL13 and CHIT1 levels in patients treated with first-line therapy compared to second-line therapy (p = 0.008, p = 0.001 and p = 0.026, respectively). NFL and CHIT1 levels correlated with relapse status, and NFL and CXCL13 levels correlated with the formation of new magnetic resonance imaging lesions. Furthermore, we found an association between inflammatory and degenerative biomarkers. The results indicate that CSF levels of NFL, CXCL13, CHI3L1, and CHIT1 correlate with the clinical and/or radiological disease activity, providing additional dimensions in the assessment of treatment efficacy. © 2016 International Society for Neurochemistry.

  16. Multiple biomarkers of pollution effects in Solea solea fish on the Tunisia coastline.

    PubMed

    Jebali, Jamel; Sabbagh, Marwa; Banni, Mohamed; Kamel, Naouel; Ben-Khedher, Sana; M'hamdi, Naceur; Boussetta, Hamadi

    2013-06-01

    This field study investigates the morphological indices (condition index, hepatosomatic index) and biochemical (catalase (CAT), glutathione S-transferase (GST), acetylcholinesterase (AChE), metallothionein (MT), lipid peroxidation) parameters in liver, gills and kidney of common sole (Solea solea) originating from different sites of the Tunisian coast area impacted by different anthropogenic activities. Differences among sites and tissues for AChE, GST, CAT, MT and TBARS were found and possibly related to known sources of domestic and industrial discharges in the studied sites. Liver, gills and kidney CAT, liver and kidney MT and brain AChE were key biomarkers to discriminate fish of different sites. So, we suggest using these biomarkers in future biomonitoring.

  17. Multiple Biomarker Responses in Corbicula fluminea Exposed to Copper in Laboratory Toxicity Tests.

    PubMed

    Bonnail, Estefanía; Buruaem, Lucas M; Araujo, Giuliana S; Abessa, Denis M S; DelValls, T Ángel

    2016-08-01

    This study evaluated the alteration of the enzymatic system of the freshwater Asian clam exposed to different copper concentrations. Individuals of Corbicula fluminea were exposed to different concentrations of dissolved Cu (0.5, 1, and 2 mg L(-1)) for 7 days, then, biomarkers of oxidative stress (GST, GPx, GR), exposure (MTs), effect (AChE), and damage (LPO, DNA strand breaks) were quantified. Results showed positive correlations between dissolved metal concentrations and GPx, MTs, and DNA damage, and negative correlation with GST and AChE. In contrast, no clear trend was found for GR and LPO. In general, the established mechanisms of protection might have a beneficial effect on the decreasing ROS attack on membrane and the activation of the metallothioneins. Integrated biomarker analysis revealed that the measured alterations are well correlated with the levels of increasing dissolved copper concentrations in water, demonstrating the effectiveness of this organism for biomonitoring approach purposes.

  18. Assessment of a multiple biomarker panel for diagnosis of amyotrophic lateral sclerosis.

    PubMed

    Chen, Xueping; Chen, Yongping; Wei, Qianqian; Ou, Ruwei; Cao, Bei; Zhao, Bi; Shang, Hui-Fang

    2016-09-15

    The aim of the study was to assess a panel of promising biomarkers for their ability to improve diagnosis of sporadic amyotrophic lateral sclerosis (ALS). Forty patients with sporadic ALS and 40 controls with other neurological diseases were evaluated. Levels of phosphorylated neurofilament heavy chain (pNfH), S100-β, cystatin C, and chitotriosidase (CHIT) in cerebrospinal fluid were assayed using two-site solid-phase sandwich ELISA. Patients with sporadic ALS showed higher levels of pNfH and CHIT than controls, but lower levels of cystatin C. Multivariate logistic regression that adjusted for patient age and sex identified significant associations between sporadic ALS and levels of pNfH, CHIT and cystatin C. Levels of pNfH correlated positively with rate of progression and decline based on the Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised. Based on receiver operating curve analysis, a pNfH cut-off of 437 ng/L discriminated patients from controls with a sensitivity of 97.3 % and specificity of 83.8 %. A CHIT cut-off of 1593.779 ng/L discriminated patients from controls with a sensitivity of 83.8 % and specificity of 81.1 %. Combining the two biomarkers gave a sensitivity of 83.8 % and specificity of 91.9 %. Levels of pNfH in cerebrospinal fluid may be a reliable biomarker for diagnosing ALS, and combining this biomarker with levels of CHIT may improve diagnostic accuracy.

  19. Development of a diagnostic test based on multiple continuous biomarkers with an imperfect reference test.

    PubMed

    García Barrado, Leandro; Coart, Els; Burzykowski, Tomasz

    2016-02-20

    Ignoring the fact that the reference test used to establish the discriminative properties of a combination of diagnostic biomarkers is imperfect can lead to a biased estimate of the diagnostic accuracy of the combination. In this paper, we propose a Bayesian latent-class mixture model to select a combination of biomarkers that maximizes the area under the ROC curve (AUC), while taking into account the imperfect nature of the reference test. In particular, a method for specification of the prior for the mixture component parameters is developed that allows controlling the amount of prior information provided for the AUC. The properties of the model are evaluated by using a simulation study and an application to real data from Alzheimer's disease research. In the simulation study, 100 data sets are simulated for sample sizes ranging from 100 to 600 observations, with a varying correlation between biomarkers. The inclusion of an informative as well as a flat prior for the diagnostic accuracy of the reference test is investigated. In the real-data application, the proposed model was compared with the generally used logistic-regression model that ignores the imperfectness of the reference test. Conditional on the selected sample size and prior distributions, the simulation study results indicate satisfactory performance of the model-based estimates. In particular, the obtained average estimates for all parameters are close to the true values. For the real-data application, AUC estimates for the proposed model are substantially higher than those from the 'traditional' logistic-regression model.

  20. Defining Multiple Characteristic Raman Bands of α-Amino Acids as Biomarkers for Planetary Missions Using a Statistical Method

    NASA Astrophysics Data System (ADS)

    Rolfe, S. M.; Patel, M. R.; Gilmour, I.; Olsson-Francis, K.; Ringrose, T. J.

    2016-06-01

    Biomarker molecules, such as amino acids, are key to discovering whether life exists elsewhere in the Solar System. Raman spectroscopy, a technique capable of detecting biomarkers, will be on board future planetary missions including the ExoMars rover. Generally, the position of the strongest band in the spectra of amino acids is reported as the identifying band. However, for an unknown sample, it is desirable to define multiple characteristic bands for molecules to avoid any ambiguous identification. To date, there has been no definition of multiple characteristic bands for amino acids of interest to astrobiology. This study examined l-alanine, l-aspartic acid, l-cysteine, l-glutamine and glycine and defined several Raman bands per molecule for reference as characteristic identifiers. Per amino acid, 240 spectra were recorded and compared using established statistical tests including ANOVA. The number of characteristic bands defined were 10, 12, 12, 14 and 19 for l-alanine (strongest intensity band: 832 cm-1), l-aspartic acid (938 cm-1), l-cysteine (679 cm-1), l-glutamine (1090 cm-1) and glycine (875 cm-1), respectively. The intensity of bands differed by up to six times when several points on the crystal sample were rotated through 360 °; to reduce this effect when defining characteristic bands for other molecules, we find that spectra should be recorded at a statistically significant number of points per sample to remove the effect of sample rotation. It is crucial that sets of characteristic Raman bands are defined for biomarkers that are targets for future planetary missions to ensure a positive identification can be made.

  1. Defining Multiple Characteristic Raman Bands of α-Amino Acids as Biomarkers for Planetary Missions Using a Statistical Method.

    PubMed

    Rolfe, S M; Patel, M R; Gilmour, I; Olsson-Francis, K; Ringrose, T J

    2016-06-01

    Biomarker molecules, such as amino acids, are key to discovering whether life exists elsewhere in the Solar System. Raman spectroscopy, a technique capable of detecting biomarkers, will be on board future planetary missions including the ExoMars rover. Generally, the position of the strongest band in the spectra of amino acids is reported as the identifying band. However, for an unknown sample, it is desirable to define multiple characteristic bands for molecules to avoid any ambiguous identification. To date, there has been no definition of multiple characteristic bands for amino acids of interest to astrobiology. This study examined L-alanine, L-aspartic acid, L-cysteine, L-glutamine and glycine and defined several Raman bands per molecule for reference as characteristic identifiers. Per amino acid, 240 spectra were recorded and compared using established statistical tests including ANOVA. The number of characteristic bands defined were 10, 12, 12, 14 and 19 for L-alanine (strongest intensity band: 832 cm(-1)), L-aspartic acid (938 cm(-1)), L-cysteine (679 cm(-1)), L-glutamine (1090 cm(-1)) and glycine (875 cm(-1)), respectively. The intensity of bands differed by up to six times when several points on the crystal sample were rotated through 360 °; to reduce this effect when defining characteristic bands for other molecules, we find that spectra should be recorded at a statistically significant number of points per sample to remove the effect of sample rotation. It is crucial that sets of characteristic Raman bands are defined for biomarkers that are targets for future planetary missions to ensure a positive identification can be made.

  2. A novel microRNA-132-sirtuin-1 axis underlies aberrant B-cell cytokine regulation in patients with relapsing-remitting multiple sclerosis [corrected].

    PubMed

    Miyazaki, Yusei; Li, Rui; Rezk, Ayman; Misirliyan, Hétoum; Moore, Craig; Farooqi, Nasr; Solis, Mayra; Goiry, Lorna Galleguillos; de Faria Junior, Omar; Dang, Van Duc; Colman, David; Dhaunchak, Ajit Singh; Antel, Jack; Gommerman, Jennifer; Prat, Alexandre; Fillatreau, Simon; Bar-Or, Amit

    2014-01-01

    Clinical trial results demonstrating that B-cell depletion substantially reduces new relapses in patients with multiple sclerosis (MS) have established that B cells play a role in the pathophysiology of MS relapses. The same treatment appears not to impact antibodies directed against the central nervous system, which underscores the contribution of antibody-independent functions of B cells to disease activity. One mechanism by which B cells are now thought to contribute to MS activity is by over-activating T cells, including through aberrant expression of B cell pro-inflammatory cytokines. However, the mechanisms underlying the observed B cell cytokine dysregulation in MS remain unknown. We hypothesized that aberrant expression of particular microRNAs might be involved in the dysregulated pro-inflammatory cytokine responses of B cells of patients with MS. Through screening candidate microRNAs in activated B cells of MS patients and matched healthy subjects, we discovered that abnormally increased secretion of lymphotoxin and tumor necrosis factor α by MS B cells is associated with abnormally increased expression of miR-132. Over-expression of miR-132 in normal B cells significantly enhanced their production of lymphotoxin and tumor necrosis factor α. The over-expression of miR-132 also suppressed the miR-132 target, sirtuin-1. We confirmed that pharmacological inhibition of sirtuin-1 in normal B cells induces exaggerated lymphotoxin and tumor necrosis factor α production, while the abnormal production of these cytokines by MS B cells can be normalized by resveratrol, a sirtuin-1 activator. These results define a novel miR-132-sirtuin-1 axis that controls pro-inflammatory cytokine secretion by human B cells, and demonstrate that a dysregulation of this axis underlies abnormal pro-inflammatory B cell cytokine responses in patients with MS.

  3. Metabolomics Identifies Multiple Candidate Biomarkers to Diagnose and Stage Human African Trypanosomiasis

    PubMed Central

    Vincent, Isabel M.; Daly, Rónán; Courtioux, Bertrand; Cattanach, Amy M.; Biéler, Sylvain; Ndung’u, Joseph M.; Bisser, Sylvie; Barrett, Michael P.

    2016-01-01

    Treatment for human African trypanosomiasis is dependent on the species of trypanosome causing the disease and the stage of the disease (stage 1 defined by parasites being present in blood and lymphatics whilst for stage 2, parasites are found beyond the blood-brain barrier in the cerebrospinal fluid (CSF)). Currently, staging relies upon detecting the very low number of parasites or elevated white blood cell numbers in CSF. Improved staging is desirable, as is the elimination of the need for lumbar puncture. Here we use metabolomics to probe samples of CSF, plasma and urine from 40 Angolan patients infected with Trypanosoma brucei gambiense, at different disease stages. Urine samples provided no robust markers indicative of infection or stage of infection due to inherent variability in urine concentrations. Biomarkers in CSF were able to distinguish patients at stage 1 or advanced stage 2 with absolute specificity. Eleven metabolites clearly distinguished the stage in most patients and two of these (neopterin and 5-hydroxytryptophan) showed 100% specificity and sensitivity between our stage 1 and advanced stage 2 samples. Neopterin is an inflammatory biomarker previously shown in CSF of stage 2 but not stage 1 patients. 5-hydroxytryptophan is an important metabolite in the serotonin synthetic pathway, the key pathway in determining somnolence, thus offering a possible link to the eponymous symptoms of “sleeping sickness”. Plasma also yielded several biomarkers clearly indicative of the presence (87% sensitivity and 95% specificity) and stage of disease (92% sensitivity and 81% specificity). A logistic regression model including these metabolites showed clear separation of patients being either at stage 1 or advanced stage 2 or indeed diseased (both stages) versus control. PMID:27941966

  4. St. John's wort extract and hyperforin inhibit multiple phosphorylation steps of cytokine signaling and prevent inflammatory and apoptotic gene induction in pancreatic β cells.

    PubMed

    Novelli, Michela; Menegazzi, Marta; Beffy, Pascale; Porozov, Svetlana; Gregorelli, Alex; Giacopelli, Daniela; De Tata, Vincenzo; Masiello, Pellegrino

    2016-12-01

    The extract of the herbaceous plant St. John's wort (SJW) and its phloroglucinol component hyperforin (HPF) were previously shown to inhibit cytokine-induced STAT-1 and NF-κB activation and prevent damage in pancreatic β cells. To further clarify the mechanisms underlying their protective effects, we evaluated the phosphorylation state of various factors of cytokine signaling pathways and the expression of target genes involved in β-cell function, inflammatory response and apoptosis induction. In the INS-1E β-cell line, exposed to a cytokine mixture with/without SJW extract (2-5μg/ml) or HPF (1-5μM), protein phosphorylation was assessed by western blotting and expression of target genes by real-time quantitative PCR. SJW and HPF markedly inhibited, in a dose-dependent manner (from 60 to 100%), cytokine-induced activating phosphorylations of STAT-1, NF-κB p65 subunit and IKK (NF-κB inhibitory subunit IκBα kinase). MAPK and Akt pathways were also modulated by the vegetal compounds through hindrance of p38 MAPK, ERK1/2, JNK and Akt phosphorylations, each reduced by at least 65% up to 100% at the higher dose. Consistently, SJW and HPF a) abolished cytokine-induced mRNA expression of pro-inflammatory genes; b) avoided down-regulation of relevant β-cell functional/differentiation genes; c) corrected cytokine-driven imbalance between pro- and anti-apoptotic factors, by fully preventing up-regulation of pro-apoptotic genes and preserving expression or function of anti-apoptotic Bcl-2 family members; d) protected INS-1E cells against cytokine-induced apoptosis. In conclusion, SJW extract and HPF exert their protective effects through simultaneous inhibition of multiple phosphorylation steps along various cytokine signaling pathways and consequent restriction of inflammatory and apoptotic gene expression. Thus, they have a promising therapeutic potential for the prevention or limitation of immune-mediated β-cell dysfunction and damage leading to type 1 diabetes.

  5. ST. JOHN's wort extract and hyperforin inhibit multiple phosphorylation steps of cytokine signaling and prevent inflammatory and apoptotic gene induction in pancreatic β cells.

    PubMed

    Novelli, Michela; Menegazzi, Marta; Beffy, Pascale; Porozov, Svetlana; Gregorelli, Alex; Giacopelli, Daniela; Tata, Vincenzo De; Masiello, Pellegrino

    2016-10-22

    The extract of the herbaceous plant St. John's wort (SJW) and its phloroglucinol component hyperforin (HPF) were previously shown to inhibit cytokine-induced STAT-1 and NF-κB activation and prevent damage in pancreatic β cells. To further clarify the mechanisms underlying their protective effects, we evaluated the phosphorylation state of various factors of cytokine signaling pathways and the expression of target genes involved in β-cell function, inflammatory response and apoptosis induction. In the INS-1E β-cell line, exposed to a cytokine mixture with/without SJW extract (2-5μg/ml) or HPF (1-5μM), protein phosphorylation was assessed by Western blotting and expression of target genes by real-time quantitative PCR. SJW and HPF markedly inhibited, in a dose-dependent manner (from 60 to 100%), cytokine-induced activating phosphorylations of STAT-1, NF-κB p65 subunit and IKK (NF-κB inhibitory subunit IκBα kinase). MAPK and Akt pathways were also modulated by the vegetal compounds through hindrance of p38 MAPK, ERK1/2, JNK and Akt phosphorylations, each reduced by at least 65% up to 100% at the higher dose. Consistently, SJW and HPF a) abolished cytokine-induced mRNA expression of pro-inflammatory genes; b) avoided down-regulation of relevant β-cell functional/differentiation genes; c) corrected cytokine-driven imbalance between pro- and anti-apoptotic factors, by fully preventing up-regulation of pro-apoptotic genes and preserving expression or function of anti-apoptotic Bcl-2 family members; d) protected INS-1E cells against cytokine-induced apoptosis. In conclusion, SJW extract and HPF exert their protective effects through simultaneous inhibition of multiple phosphorylation steps along various cytokine signaling pathways and consequent restriction of inflammatory and apoptotic gene expression. Thus, they have a promising therapeutic potential for the prevention or limitation of immune-mediated β-cell dysfunction and damage leading to type 1 diabetes.

  6. Combined exercise training reduces fatigue and modulates the cytokine profile of T-cells from multiple sclerosis patients in response to neuromediators.

    PubMed

    Alvarenga-Filho, Helcio; Sacramento, Priscila M; Ferreira, Thais B; Hygino, Joana; Abreu, Jorge Eduardo Canto; Carvalho, Sonia Regina; Wing, Ana Cristina; Alvarenga, Regina Maria Papais; Bento, Cleonice A M

    2016-04-15

    Fatigue is a common and disabling symptom of multiple sclerosis (MS), a classical Th1- and Th17-mediated autoimmune disease. There is no effective pharmacological treatment for fatigue, but some reports point towards beneficial effects of physical activity on management of the fatigue in MS patients. As both MS and fatigue have been associated with dysregulated cytokine network production, the objective of the present study was to evaluate the impact of a physical activity program consisting of a 12-week series of combining Pilates and aerobic exercises on fatigue severity, determined by FSS, and cytokine production, quantified by ELISA, by T cells from MS patients (n=08) with low disability (EDSS≤2). The results showed decrease in FSSs in all patients at the end of physical activity intervention. Regarding the cytokines, a significant reduction of IL-22 release was observed in polyclonally-activated T cells form MS patients post-training follow-up. Interestingly, while the physical activity attenuated the ability of dopamine in up-regulating Th17-related cytokines, it enhanced the anti-inflammatory effects of serotonin, evidenced by high IL-10 production. In summary, all results suggest that programmed physical activity has beneficial effects on management of fatigue in MS patients, and it could be related, at least in part, to its ability in regulating neuroimmune parameters into T cell compartment.

  7. A Magnetic Bead-Based Sensor for the Quantification of Multiple Prostate Cancer Biomarkers

    PubMed Central

    Jokerst, Jesse V.; Chen, Zuxiong; Xu, Lingyun; Nolley, Rosalie; Chang, Edwin; Mitchell, Breeana; Brooks, James D.; Gambhir, Sanjiv S.

    2015-01-01

    Novel biomarker assays and upgraded analytical tools are urgently needed to accurately discriminate benign prostatic hypertrophy (BPH) from prostate cancer (CaP). To address this unmet clinical need, we report a piezeoelectric/magnetic bead-based assay to quantitate prostate specific antigen (PSA; free and total), prostatic acid phosphatase, carbonic anhydrase 1 (CA1), osteonectin, IL-6 soluble receptor (IL-6sr), and spondin-2. We used the sensor to measure these seven proteins in serum samples from 120 benign prostate hypertrophy patients and 100 Gleason score 6 and 7 CaP using serum samples previously collected and banked. The results were analyzed with receiver operator characteristic curve analysis. There were significant differences between BPH and CaP patients in the PSA, CA1, and spondin-2 assays. The highest AUC discrimination was achieved with a spondin-2 OR free/total PSA operation—the area under the curve was 0.84 with a p value below 10−6. Some of these data seem to contradict previous reports and highlight the importance of sample selection and proper assay building in the development of biomarker measurement schemes. This bead-based system offers important advantages in assay building including low cost, high throughput, and rapid identification of an optimal matched antibody pair. PMID:26421725

  8. Rapid assessment of marine pollution using multiple biomarkers and chemical immunoassays.

    PubMed

    Galloway, Tamara S; Sanger, Ross C; Smith, Karen L; Fillmann, Gilberto; Readman, James W; Ford, Timothy E; Depledge, Michael H

    2002-05-15

    To fully assess the impact of pollutant releases into the environment, it is necessary to determine both the concentration of chemicals accumulating in biota and the biological effects they give rise to. Owing to time, expertise, and cost constraints, this is, however, rarely achieved. Here, quick, simple to perform, and inexpensive biomarkers and chemical immunoassays were combined in a rapid assessment approach to measure exposure to and effects of organic and metal pollutants on the ribbed mussel (Geukensia demmissa) from New Bedford Harbor, MA. Significant differences in polychlorinated biphenyl (PCB) and polyaromatic hydrocarbon (PAH) tissue residue concentrations were detected among sites using RaPID immunoassay. Selected analyses were verified using GC/MS. No significant differences were observed in metal concentrations (Cu, Cd, Pb, As, Hg, Ni) throughout the area. While causality cannot be attributed, multivariate canonical correlation analysis indicated that PCB and PAH concentrations were strongly associated with the induction of biomarkers of genotoxicity (micronucleus formation), immunotoxicity (spontaneous cytotoxicity), and physiological impairment (heart rate). It is concluded thatthe incorporation of chemical immunoassays with biological monitoring tools into routine management procedures is clearly viable and valuable as a means of identifying toxic impacts of pollutants on biota in situ.

  9. SERS-based multiple biomarker detection using a gold-patterned microarray chip

    NASA Astrophysics Data System (ADS)

    Kim, Insup; Junejo, Inam-ur-Rehman; Lee, Moonkwon; Lee, Sangyeop; Lee, Eun Kyu; Chang, Soo-Ik; Choo, Jaebum

    2012-09-01

    We report a highly sensitive surface-enhanced Raman scattering (SERS)-based immunoassay platform for the multiplex detection of biomarkers. For this purpose, a gold-patterned microarray chip has been fabricated and used as a SERS detection template. Here, a typical sandwich immunocomplex protocol was adopted. Monoclonal antibodies were immobilized on gold patterned substrates, and then antigen solutions and polyclonal antibody-conjugated hollow gold nanospheres (HGNs) were sequentially added for the formation of sandwich immunocomplexes. Antigen biomarkers can be quantitatively assayed by monitoring the intensity change of a characteristic SERS peak of a reporter molecule adsorbed on the surfaces of HGNs. Under optimized assay conditions, the limits of detections (LODs) were determined to be 10 fg/mL for human IgG and 10-100 fg/mL for rabbit IgG. In addition, the SERS-based immunoassay technique can be applied in a wider dynamic concentration range with a good sensitivity compared to ELISA. The proposed method fulfills the current needs of high sensitivity and selectivity which are essential for the clinical diagnosis of a disease.

  10. Single v. multiple measures of skin carotenoids by resonance Raman spectroscopy as a biomarker of usual carotenoid status.

    PubMed

    Scarmo, Stephanie; Cartmel, Brenda; Lin, Haiqun; Leffell, David J; Ermakov, Igor V; Gellermann, Werner; Bernstein, Paul S; Mayne, Susan T

    2013-09-14

    Resonance Raman spectroscopy (RRS) is a non-invasive method of assessing carotenoid status in the skin, which has been suggested as an objective indicator of fruit/vegetable intake. The present study assessed agreement and identified predictors of single v. multiple RRS measures of skin carotenoid status. A total of seventy-four participants had their skin carotenoid status measured in the palm of the hand by RRS at six time points over 6 months. Questionnaires were administered to collect information on demographic, lifestyle and dietary data. Mean age of the participants was 36.6 years, 62.2% were female, 83.8% Caucasian and 85.1% were non-smoking at baseline. There was a good agreement between a single measure of skin carotenoids by RRS and multiple measures (weighted κ = 0.80; 95% CI 0.72, 0.88). The same variables were significantly associated with carotenoid status based on single or multiple measures, including a positive association with intake of total carotenoids (P< 0.01) and an inverse association with season of measurement (P≤ 0.05). The exception was recent sun exposure, which emerged as a significant predictor of lower carotenoid status only when using multiple RRS measures (P≤ 0.01). A single RRS measure was reasonably accurate at classifying usual skin carotenoid status. Researchers using RRS may want to take into account other factors that are associated with the biomarker, including season of measurement and recent sun exposure.

  11. Single v. multiple measures of skin carotenoids by resonance Raman spectroscopy as a biomarker of usual carotenoid status

    PubMed Central

    Scarmo, Stephanie; Cartmel, Brenda; Lin, Haiqun; Leffell, David J.; Ermakov, Igor V.; Gellermann, Werner; Bernstein, Paul S.; Mayne, Susan T.

    2013-01-01

    Resonance Raman spectroscopy (RRS) is a non-invasive method of assessing carotenoid status in the skin, which has been suggested as an objective indicator of fruit/vegetable intake. The present study assessed agreement and identified predictors of single v. multiple RRS measures of skin carotenoid status. A total of seventy-four participants had their skin carotenoid status measured in the palm of the hand by RRS at six time points over 6 months. Questionnaires were administered to collect information on demographic, lifestyle and dietary data. Mean age of the participants was 36.6 years, 62.2% were female, 83.8% Caucasian and 85.1% were non-smoking at baseline. There was a good agreement between a single measure of skin carotenoids by RRS and multiple measures (weighted κ = 0.80; 95% CI 0.72, 0.88). The same variables were significantly associated with carotenoid status based on single or multiple measures, including a positive association with intake of total carotenoids (P<0.01) and an inverse association with season of measurement (P≤0.05). The exception was recent sun exposure, which emerged as a significant predictor of lower carotenoid status only when using multiple RRS measures (P≤0.01). A single RRS measure was reasonably accurate at classifying usual skin carotenoid status. Researchers using RRS may want to take into account other factors that are associated with the biomarker, including season of measurement and recent sun exposure. PMID:23351238

  12. Assessment of a mussel as a metal bioindicator of coastal contamination: relationships between metal bioaccumulation and multiple biomarker responses.

    PubMed

    Chandurvelan, Rathishri; Marsden, Islay D; Glover, Chris N; Gaw, Sally

    2015-04-01

    This is the first study to use a multiple biomarker approach on the green-lipped mussel, Perna canaliculus to test its feasibility as a bioindicator of coastal metal contamination in New Zealand (NZ). Mussels were collected from six low intertidal sites varying in terms of anthropogenic impacts, within two regions (West Coast and Nelson) of the South Island of NZ. Trace elements, including arsenic (As), cadmium (Cd), copper (Cu), lead (Pb), nickel (Ni), and zinc (Zn), were measured in the gills, digestive gland, foot and mantle, and in the surface sediments from where mussels were collected. Metal levels in the sediment were relatively low and there was only one site (Mapua, Nelson) where a metal (Ni) exceeded the Australian and New Zealand Interim Sediment Quality Guideline values. Metal levels in the digestive gland were generally higher than those from the other tissues. A variety of biomarkers were assessed to ascertain mussel health. Clearance rate, a physiological endpoint, correlated with metal level in the tissues, and along with scope for growth, was reduced in the most contaminated site. Metallothionein-like protein content and catalase activity in the digestive gland, and catalase activity and lipid peroxidation in the gill, were also correlated to metal accumulation. Although there were few regional differences, the sampling sites were clearly distinguishable based on the metal contamination profiles and biomarker responses. P. canaliculus appears to be a useful bioindicator species for coastal habitats subject to metal contamination. In this study tissue and whole organism responses provided insight into the biological stress responses of mussels to metal contaminants, indicating that such measurements could be a useful addition to biomonitoring programmes in NZ.

  13. DNA Subtraction of In Vivo Selected Phage Repertoires for Efficient Peptide Pathology Biomarker Identification in Neuroinflammation Multiple Sclerosis Model

    PubMed Central

    Vargas-Sanchez, Karina; Vekris, Antonios; Petry, Klaus G.

    2016-01-01

    To streamline in vivo biomarker discovery, we developed a suppression subtractive DNA hybridization technique adapted for phage-displayed combinatorial libraries of 12 amino acid peptides (PhiSSH). Physical DNA subtraction is performed in a one-tube-all-reactions format by sequential addition of reagents, producing the enrichment of specific clones of one repertoire. High-complexity phage repertoires produced by in vivo selections in the multiple sclerosis rat model (experimental autoimmune encephalomyelitis, EAE) and matched healthy control rats were used to evaluate the technique. The healthy repertoire served as a physical DNA subtractor from the EAE repertoire to produce the subtraction repertoire. Full next-generation sequencing (NGS) of the three repertoires was performed to evaluate the efficiency of the subtraction technique. More than 96% of the clones common to the EAE and healthy repertoires were absent from the subtraction repertoire, increasing the probability of randomly selecting various specific peptides for EAE pathology to about 70%. Histopathology experiments were performed to confirm the quality of the subtraction repertoire clones, producing distinct labeling of the blood–brain barrier (BBB) affected by inflammation among healthy nervous tissue or the preferential binding to IL1-challenged vs. resting human BBB model. Combining PhiSSH with NGS will be useful for controlled in vivo screening of small peptide combinatorial libraries to discover biomarkers of specific molecular alterations interspersed within healthy tissues. PMID:26917946

  14. Vitamin D Binding Protein Isoforms and Apolipoprotein E in Cerebrospinal Fluid as Prognostic Biomarkers of Multiple Sclerosis

    PubMed Central

    Lis, Katarzyna; Minari, Nicoletta; Falvo, Sara; Marnetto, Fabiana; Caldano, Marzia; Reviglione, Raffaella; Berchialla, Paola; Capobianco, Marco A.; Malentacchi, Maria; Corpillo, Davide; Bertolotto, Antonio

    2015-01-01

    Background Multiple sclerosis (MS) is a multifactorial autoimmune disease of the central nervous system with a heterogeneous and unpredictable course. To date there are no prognostic biomarkers even if they would be extremely useful for early patient intervention with personalized therapies. In this context, the analysis of inter-individual differences in cerebrospinal fluid (CSF) proteome may lead to the discovery of biological markers that are able to distinguish the various clinical forms at diagnosis. Methods To this aim, a two dimensional electrophoresis (2-DE) study was carried out on individual CSF samples from 24 untreated women who underwent lumbar puncture (LP) for suspected MS. The patients were clinically monitored for 5 years and then classified according to the degree of disease aggressiveness and the disease-modifying therapies prescribed during follow up. Results The hierarchical cluster analysis of 2-DE dataset revealed three protein spots which were identified by means of mass spectrometry as Apolipoprotein E (ApoE) and two isoforms of vitamin D binding protein (DBP). These three protein spots enabled us to subdivide the patients into subgroups correlated with clinical classification (MS aggressive forms identification: 80%). In particular, we observed an opposite trend of values for the two protein spots corresponding to different DBP isoforms suggesting a role of a post-translational modification rather than the total protein content in patient categorization. Conclusions These findings proved to be very interesting and innovative and may be developed as new candidate prognostic biomarkers of MS aggressiveness, if confirmed. PMID:26046356

  15. Decreased soluble IFN-β receptor (sIFNAR2) in multiple sclerosis patients: A potential serum diagnostic biomarker.

    PubMed

    Órpez-Zafra, Teresa; Pavía, Jose; Hurtado-Guerrero, Isaac; Pinto-Medel, Maria J; Rodriguez Bada, Jose Luis; Urbaneja, Patricia; Suardíaz, Margarita; Villar, Luisa M; Comabella, Manuel; Montalban, Xavier; Alvarez-Cermeño, Jose C; Leyva, Laura; Fernández, Óscar; Oliver-Martos, Begoña

    2017-06-01

    The soluble isoform of the interferon-β (IFN-β) receptor (sIFNAR2) could modulate the activity of both endogenous and systemically administered IFN-β. Previously, we described lower serum sIFNAR2 levels in untreated multiple sclerosis (MS) than in healthy controls (HCs). To assess sIFNAR2 levels in a new cohort of MS patients and HCs, as well as in patients with clinically isolated syndrome (CIS) and with other inflammatory neurological disorders (OIND) and to assess its ability as a diagnostic biomarker. The cross-sectional study included 148 MS (84 treatment naive and 64 treated), 87 CIS, 42 OIND, and 96 HCs. Longitudinal study included 94 MS pretreatment and after 1 year of therapy with IFN-β, glatiramer acetate (GA), or natalizumab. sIFNAR2 serum levels were measured by a quantitative ELISA developed and validated in our laboratory. Naive MS and CIS patients showed significantly lower sIFNAR2 levels than HCs and OIND patients. The sensitivity and specificity to discriminate between MS and OIND, for a sIFNAR2 cutoff value of 122.02 ng/mL, were 70.1%, and 79.4%, respectively. sIFNAR2 increased significantly in IFN-β-treated patients during the first year of therapy in contrast to GA- and natalizumab-treated patients who showed non-significant changes. The results suggest that sIFNAR2 could be a potential diagnostic biomarker for MS.

  16. Role of platelet-derived growth factor-AB in tumour growth and angiogenesis in relation with other angiogenic cytokines in multiple myeloma.

    PubMed

    Tsirakis, George; Pappa, Constantina A; Kanellou, Peggy; Stratinaki, Maria A; Xekalou, Athina; Psarakis, Fotios E; Sakellaris, George; Alegakis, Athanasios; Stathopoulos, Efstathios N; Alexandrakis, Michael G

    2012-09-01

    Angiogenesis is a complex process essential for the growth, invasion, and metastasis of various malignant tumours, including multiple myeloma (MM). Various angiogenic cytokines have been implicated in the angiogenic process. Among them, platelet-derived growth factor-AB (PDGF-AB) has been reported to be a potent stimulator of angiogenesis in many solid tumours and haematological malignancies, including MM. The aim of the study was to investigate the relationship between PDGF-AB, microvascular density (MVD), and various angiogenic cytokines, such as basic fibroblast growth factor (b-FGF), angiogenin (ANG), and interleukin-6 (IL-6), in MM patients. Forty-seven MM patients before treatment, 22 of whom were in plateau phase, were studied. We determined the serum levels of the aforementioned cytokines and MVD in bone marrow biopsies before and after treatment. Mean serum values of PDGF-AB, b-FGF, ANG, and MVD were significantly higher in patients compared with controls and with increasing disease stage. Significant positive correlations were observed between serum PDGF-AB, ANG, and IL-6 levels and MVD. Furthermore, we found significant positive correlations between PDGF-AB and b-FGF, IL-6, ANG, and β2 microglobulin. We also found that patients with high MVD had statistically significantly higher serum levels of PDGF-AB when a median MVD value of 7.7 was used as the cutoff point. Furthermore, a significant difference was found in serum levels of PDGF-AB between pre- and post-treatment patients. Finally, survival time was significantly higher in the low MVD group versus the high MVD group (76 vs 51 months). Our results showed that there is a strong positive correlation between PDGF-AB and the studied angiogenic cytokines and MVD. It seems that PDGF-AB plays a role in the complex network of cytokines inducing bone marrow neovascularization in patients with MM. Copyright © 2011 John Wiley & Sons, Ltd.

  17. Biomarker Discovery After Occupational Exposure To Volatile Organic Compounds And Aerosols In F-15 and C-130 Flight Line Crews: Examination of ProInflammatory Cytokines in Serum

    DTIC Science & Technology

    2014-08-29

    Summary of Mann-Whitney U- Tests ............................................................................47 vi Distribution A. Approved for... tested or run before and after flight. Since little is known concerning levels of exposure and the corresponding response biomarkers associated with...irritation and defatting, neurotoxicity, nephrotoxicity, and renal carcinogenicity (in male rats). Animal studies support previous findings involving

  18. A Comparison of Multiple Esterases as Biomarkers of Organophosphate Exposure and Effect in Two Earthworm Species

    PubMed Central

    Schneider, Ashley; Stoskopf, Michael K.

    2011-01-01

    Two different earthworm species, Eisenia fetida and Lumbricus terrestris, were exposed to 5 μg/cm2 of malathion to evaluate their usefulness as sentinels of organophosphate exposure and to assess three different esterases, as biomarkers of malathion exposure and effect. Tissue xenobiotic burdens and esterase activity were determined for each species and each esterase in order to assess variability. E. fetida exhibited 4-fold less variability in tissue burdens than did L. terrestris and had less variable basal esterase activities. An attempt was made to correlate malathion and malaoxon tissue burdens with esterase activity post-exposure. There was no malaoxon present in the earthworm tissues. No significant correlations were determined by comparing acetylcholinesterase, butyrylcholinesterase, nor carboxylesterase activities with malathion burdens. PMID:21404045

  19. Mouse oncostatin M: an immediate early gene induced by multiple cytokines through the JAK-STAT5 pathway.

    PubMed Central

    Yoshimura, A; Ichihara, M; Kinjyo, I; Moriyama, M; Copeland, N G; Gilbert, D J; Jenkins, N A; Hara, T; Miyajima, A

    1996-01-01

    Oncostatin M (OSM) is a member of the interleukin-6 (IL6)-related cytokine subfamily that includes IL6, IL11, leukemia inhibitory factor (LIF), ciliary neurotrophic factor and cardiotrophin-1. While human OSM has been characterized and the bovine OSM gene was recently cloned, the murine counterpart had not been identified. Here we describe molecular cloning of murine OSM as an immediate early gene induced by a subset of cytokines including IL2, IL3 and erythropoietin (EPO) in myeloid and lymphoid cell lines. The induction kinetics of OSM are rapid and transient, reaching a maximal level within 30-60 min and decreasing thereafter. Induction of OSM depends on the signals generated by the membrane-proximal region of the EPO receptor as well as that of the beta chain of the IL3/GM-CSF receptor, which activate JAK2 and STAT5. About 100 bases upstream of the transcription initiation site of the OSM gene contains a possible STAT5 binding site which is essential for IL2, IL3 and EPO-dependent promoter activity of the OSM gene. Expression of STAT5 and the EPO receptor in COS cells conferred EPO-dependent activation of the OSM promoter. Moreover, the mutant IL2 receptor lacking the ability to activate STAT5 induced c-myc but failed to induce OSM. Thus OSM is one of the common targets of a subset of cytokines that activate STAT5. The murine OSM gene is located near to the LIF gene, expressed at high levels in bone marrow and possesses similar biological activity to human OSM. Identification of murine OSM as a cytokine-inducible immediate early gene provides a new insight into the physiological function of this unique cytokine. Images PMID:8605875

  20. Comparative investigations on the biological effects of As (III) and As (V) in clam Ruditapes philippinarum using multiple biomarkers.

    PubMed

    Ji, Chenglong; Xu, Hai'e; Wang, Qing; Zhao, Jianmin; Wu, Huifeng

    2015-11-01

    Inorganic arsenic is a known pollutant with two chemical forms, arsenite (As (III)) and arsenate (As (V)), in marine environment. Clam Ruditapes philippinarum is an important fishery species along the Bohai coast. In this study, the biological effects induced by the two arsenic chemical forms (arsenite and arsenate) were compared using multiple biochemical indices in the digestive glands of clam R. philippinarum. The production of reactive oxygen species, antioxidant enzyme activities and metabolic responses exhibited that both As (III) and As (V) induced immune, oxidative and osmotic stresses in clam digestive glands. The differential metabolic biomarkers, histidine and taurine, indicated the differential responsive mechanisms in osmotic regulation in clam digestive glands. In addition, both arsenic treatments enhanced the anaerobiosis metabolism in clam digestive glands. Overall, this work illustrated that arsenite and arsenate induced similar biological effects in clams, which might be accounted for the biological transformation of arsenate to arsenite in clams. Copyright © 2015 Elsevier Ltd. All rights reserved.

  1. Circulating serum microRNAs as novel diagnostic and prognostic biomarkers for multiple myeloma and monoclonal gammopathy of undetermined significance.

    PubMed

    Kubiczkova, Lenka; Kryukov, Fedor; Slaby, Ondrej; Dementyeva, Elena; Jarkovsky, Jiri; Nekvindova, Jana; Radova, Lenka; Greslikova, Henrieta; Kuglik, Petr; Vetesnikova, Eva; Pour, Ludek; Adam, Zdenek; Sevcikova, Sabina; Hajek, Roman

    2014-03-01

    Multiple myeloma still remains incurable in the majority of cases prompting a further search for new and better prognostic markers. Emerging evidence has suggested that circulating microRNAs can serve as minimally invasive biomarkers for multiple myeloma and monoclonal gammopathy of undetermined significance. In this study, a global analysis of serum microRNAs by TaqMan Low Density Arrays was performed, followed by quantitative real-time PCR. The analyses revealed five deregulated microRNAs: miR-744, miR-130a, miR-34a, let-7d and let-7e in monoclonal gammopathy of undetermined significance, newly diagnosed and relapsed multiple myeloma when compared to healthy donors. Multivariate logistical regression analysis showed that a combination of miR-34a and let-7e can distinguish multiple myeloma from healthy donors with a sensitivity of 80.6% and a specificity of 86.7%, and monoclonal gammopathy of undetermined significance from healthy donors with a sensitivity of 91.1% and a specificity of 96.7%. Furthermore, lower levels of miR-744 and let-7e were associated with shorter overall survival and remission of myeloma patients. One-year mortality rates for miR-744 and let-7e were 41.9% and 34.6% for the 'low' expression and 3.3% and 3.9% for the 'high' expression groups, respectively. Median time of remission for both miR-744 and let-7e was approximately 11 months for the 'low' expression and approximately 47 months for the 'high' expression groups of myeloma patients These data demonstrate that expression patterns of circulating microRNAs are altered in multiple myeloma and monoclonal gammopathy of undetermined significance and miR-744 with let-7e are associated with survival of myeloma patients.

  2. Metabolic profile biomarkers of metal contamination in a sentinel terrestrial species are applicable across multiple sites.

    PubMed

    Bundy, Jacob G; Keun, Hector C; Sidhu, Jasmin K; Spurgeon, David J; Svendsen, Claus; Kille, Peter; Morgan, A John

    2007-06-15

    In this study, we addressed the question of whether an omic approach could genuinely be useful for biomarker profile analysis across different field sites with different physicochemical characteristics. We collected earthworms (Lumbricus rubellus) from seven sites with very different levels of metal contamination and prevailing soil type and analyzed tissue extracts by 1H nuclear magnetic resonance spectroscopy. Pattern recognition analysis of the data showed that both site- and contaminant-specific effects on the metabolic profiles could be discerned. Zinc was identified as the probable major contaminant causing a metabolic change in the earthworms. Individual sites could be resolved on the basis of NMR spectral profiles by principal component analysis; these site differences may also have been caused by additional abiotic factors such as soil pH. Despite an inevitable degree of confounding between site and contaminant concentrations, it was possible to identify metabolites which were correlated with zinc across all different sites. This study therefore acts as a proof of principle for the use of NMR-based metabolic profiling as a diagnostic tool for ecotoxicological research in polluted field soils.

  3. Baseline serum levels of multiple cytokines and adhesion molecules in patients with acute myeloid leukemia: results of a pivotal trial.

    PubMed

    Kupsa, T; Vasatova, M; Karesova, I; Zak, P; Horacek, J M

    2014-12-01

    Evaluation of serum levels of 17 cytokines and 5 adhesion molecules in patients with newly diagnosed acute myeloid leukemia (AML) using biochip array technology. We searched for links between baseline levels and age, hyperleukocytosis, secondary origin of AML, resistance to induction therapy with cytarabine and daunorubicin and standard risk stratification according to cytogenetics and molecular genetics. We evaluated the sera of 51 consecutive patients. Serum samples were analyzed by biochip based immunoassays on the Evidence Investigator analyzer. T-tests were used for statistical analysis. We found that higher age is associated with lower levels of interleukin (IL)-12. Patients with secondary disease were older, had higher levels of EGF and IL-7, and lower levels of E-selectin, IL-12 and IL-13. In hyperleukocytosis, the levels of IL-1β, IL-2, TNF-α, VCAM-1, ICAM-1, -E-selectin and L-selectin were increased, whereas levels of IFN-γ and MCP-1 were decreased. In patients who failed to achieve complete remission after induction therapy, we found lower E-selectin and P-selectin levels. High risk patients had lower levels of IFN-γ. Some leukemic cell subpopulations have the ability to produce cytokines that modulate the microenvironment by inducing inflammation. This causes endothelial cells to be activated and overexpress adhesion molecules. Hyperleukocytosis and secondary origin of the disease are the major factors influencing the cytokine and adhesion molecule profile in newly diagnosed AML patients.

  4. Mercury exposure and neurochemical biomarkers in multiple brain regions of Wisconsin river otters (Lontra canadensis).

    PubMed

    Dornbos, Peter; Strom, Sean; Basu, Niladri

    2013-04-01

    River otters are fish-eating wildlife that bioaccumulate high levels of mercury (Hg). Mercury is a proven neurotoxicant to mammalian wildlife, but little is known about the underlying, sub-clinical effects. Here, the overall goal was to increase understanding of Hg's neurological risk to otters. First, Hg values across several brain regions and tissues were characterized. Second, in three brain regions with known sensitivity to Hg (brainstem, cerebellum, and occipital cortex), potential associations among Hg levels and neurochemical biomarkers [N-methyl-D-aspartic acid (NMDA) and gamma-aminobutyric acid (GABAA) receptor] were explored. There were no significant differences in Hg levels across eight brain regions (rank order, highest to lowest: frontal cortex, cerebellum, temporal cortex, occipital cortex, parietal cortex, basal ganglia, brainstem, and thalamus), with mean values ranging from 0.7 to 1.3 ug/g dry weight. These brain levels were significantly lower than mean values in the muscle (2.1 ± 1.4 ug/g), liver (4.7 ± 4.3 ug/g), and fur (8.8 ± 4.8 ug/g). While a significant association was found between Hg and NMDA receptor levels in the brain stem (P = 0.028, rp = -0.293), no relationships were found in the cerebellum and occipital cortex. For the GABA receptor, no relationships were found. The lack of consistent Hg-associated neurochemical changes is likely due to low brain Hg levels in these river otters, which are amongst the lowest reported.

  5. Genetic, Immune-Inflammatory, and Oxidative Stress Biomarkers as Predictors for Disability and Disease Progression in Multiple Sclerosis.

    PubMed

    Kallaur, Ana Paula; Reiche, Edna Maria Vissoci; Oliveira, Sayonara Rangel; Simão, Andrea Name Colado; Pereira, Wildea Lice de Carvalho Jennings; Alfieri, Daniela Frizon; Flauzino, Tamires; Proença, Caio de Meleck; Lozovoy, Marcell Alysson Batisti; Kaimen-Maciel, Damacio Ramón; Maes, Michael

    2017-01-01

    The aim of this study was to evaluate the TNFβ NcoI polymorphism (rs909253) and immune-inflammatory, oxidative, and nitrosative stress (IO&NS) biomarkers as predictors of disease progression in multiple sclerosis (MS). We included 212 MS patients (150 female, 62 male, mean (±standard deviation (SD)) age = 42.7 ± 13.8 years) and 249 healthy controls (177 female, 72 male, 36.8 ± 11 years). The disability was measured the Expanded Disability Status Scale (EDSS) in 2006 and 2011. We determined the TNFβ NcoI polymorphism and serum levels of interleukin (IL)-6, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, IL-4, IL-10, and IL-17, albumin, ferritin, and plasma levels of lipid hydroperoxides (CL-LOOH), carbonyl protein, advanced oxidation protein products (AOPPs), nitric oxide metabolites (NOx), and total radical-trapping antioxidant parameter (TRAP). The mean EDSS (±SD) in 2006 was 1.62 ± 2.01 and in 2011 3.16 ± 2.29, and disease duration was 7.34 ± 7.0 years. IL-10, TNF-α, IFN-γ, AOPP, and NOx levels were significantly higher and IL-4 lower in MS patients with a higher 2011 EDSS scores (≥3) as compared with those with EDSS < 3. The actual increases in EDSS from 2006 to 2011 were positively associated with TNF-α and IFN-γ. Increased IFN-γ values were associated with higher pyramidal symptoms and increased IL-6 with sensitive symptoms. Increased carbonyl protein and IL-10 but lowered albumin levels predicted cerebellar symptoms. The TNFB1/B2 genotype decreased risk towards progression of pyramidal symptoms. Treatments with IFN-β and glatiramer acetate significantly reduced TNF-α but did not affect the other IO&NS biomarkers or disease progression. Taken together, IO&NS biomarkers and NcoI TNFβ genotypes predict high disability in MS and are associated with different aspects of disease progression. New drugs to treat MS should also target oxidative stress pathways.

  6. Intense Inflammation and Nerve Damage in Early Multiple Sclerosis Subsides at Older Age: A Reflection by Cerebrospinal Fluid Biomarkers

    PubMed Central

    Khademi, Mohsen; Dring, Ann M.; Gilthorpe, Jonathan D.; Wuolikainen, Anna; Al Nimer, Faiez; Harris, Robert A.; Andersson, Magnus; Brundin, Lou; Piehl, Fredrik; Olsson, Tomas; Svenningsson, Anders

    2013-01-01

    Inflammatory mediators have crucial roles in leukocyte recruitment and subsequent central nervous system (CNS) neuroinflammation. The extent of neuronal injury and axonal loss are associated with the degree of CNS inflammation and determine physical disability in multiple sclerosis (MS). The aim of this study was to explore possible associations between a panel of selected cerebrospinal fluid biomarkers and robust clinical and demographic parameters in a large cohort of patients with MS and controls (n = 1066) using data-driven multivariate analysis. Levels of matrix metalloproteinase 9 (MMP9), chemokine (C–X–C motif) ligand 13 (CXCL13), osteopontin (OPN) and neurofilament-light chain (NFL) were measured by ELISA in 548 subjects comprising different MS subtypes (relapsing-remitting, secondary progressive and primary progressive), clinically isolated syndrome and persons with other neurological diseases with or without signs of inflammation/infection. Principal component analyses and orthogonal partial least squares methods were used for unsupervised and supervised interrogation of the data. Models were validated using data from a further 518 subjects in which one or more of the four selected markers were measured. There was a significant association between increased patient age and lower levels of CXCL13, MMP9 and NFL. CXCL13 levels correlated well with MMP9 in the younger age groups, but less so in older patients, and after approximately 54 years of age the levels of CXCL13 and MMP9 were consistently low. CXCL13 and MMP9 levels also correlated well with both NFL and OPN in younger patients. We demonstrate a strong effect of age on both inflammatory and neurodegenerative biomarkers in a large cohort of MS patients. The findings support an early use of adequate immunomodulatory disease modifying drugs, especially in younger patients, and may provide a biological explanation for the relative inefficacy of such treatments in older patients at later disease

  7. Iron Is a Sensitive Biomarker for Inflammation in Multiple Sclerosis Lesions

    PubMed Central

    Mehta, Veela; Pei, Wei; Yang, Grant; Li, Suyang; Swamy, Eashwar; Boster, Aaron; Schmalbrock, Petra; Pitt, David

    2013-01-01

    MRI phase imaging in multiple sclerosis (MS) patients and in autopsy tissue have demonstrated the presence of iron depositions in white matter lesions. The accumulation of iron in some but not all lesions suggests a specific, potentially disease-relevant process, however; its pathophysiological significance remains unknown. Here, we explore the role of lesional iron in multiple sclerosis using multiple approaches: immunohistochemical examination of autoptic MS tissue, an in vitro model of iron-uptake in human cultured macrophages and ultra-highfield phase imaging of highly active and of secondary progressive MS patients. Using Perls' stain and immunohistochemistry, iron was detected in MS tissue sections predominantly in non-phagocytosing macrophages/microglia at the edge of established, demyelinated lesions. Moreover, iron-containing macrophages but not myelin-laden macrophages expressed markers of proinflammatory (M1) polarization. Similarly, in human macrophage cultures, iron was preferentially taken up by non-phagocytosing, M1-polarized macrophages and induced M1 (super) polarization. Iron uptake was minimal in myelin-laden macrophages and active myelin phagocytosis led to depletion of intracellular iron. Finally, we demonstrated in MS patients using GRE phase imaging with ultra-highfield MRI that phase hypointense lesions were significantly more prevalent in patients with active relapsing than with secondary progressive MS. Taken together, our data provide a basis to interpret iron-sensitive GRE phase imaging in MS patients: iron is present in non-phagocytosing, M1-polarized microglia/macrophages at the rim of chronic active white matter demyelinating lesions. Phase imaging may therefore visualize specific, chronic proinflammatory activity in established MS lesions and thus provide important clinical information on disease status and treatment efficacy in MS patients. PMID:23516409

  8. CD28 ligation in the absence of TCR stimulation up-regulates IL-17A and pro-inflammatory cytokines in relapsing-remitting multiple sclerosis T lymphocytes.

    PubMed

    Camperio, Cristina; Muscolini, Michela; Volpe, Elisabetta; Di Mitri, Diletta; Mechelli, Rosella; Buscarinu, Maria C; Ruggieri, Serena; Piccolella, Enza; Salvetti, Marco; Gasperini, Claudio; Battistini, Luca; Tuosto, Loretta

    2014-01-01

    CD28 is a crucial costimulatory receptor necessary full T cell activation. The role of CD28 in multiple sclerosis (MS) has been evaluated as the source of costimulatory signals integrating those delivered by TCR. However, CD28 is also able to act as a unique signaling receptor and to deliver TCR-independent autonomous signals, which regulate the expression and production of pro-inflammatory cytokines and chemokines. By comparing the cytokine/chemokine profiles of CD4(+) T cells from relapsing-remitting multiple sclerosis (RRMS) patients and healthy donors (HD), we found that CD28 engagement without TCR strongly up-regulates IL-8 and IL-6 expression in RRMS compared to HD. More interestingly, in RRMS but not in HD, CD28 stimulation selectively induces the expression of IL-17A by cooperating with IL-6-mediated signals. By using specific inhibitory drugs, we also identify the phosphatidylinositol 3 kinase (PI3K) as the critical regulator of CD28 proinflammatory functions in MS. Copyright © 2014 Elsevier B.V. All rights reserved.

  9. Development of multiple necrotizing enteritis induced by a tumor necrosis factor-like cytokine from lipopolysaccharide-stimulated peritoneal macrophages in rats.

    PubMed Central

    Torimoto, K.; Sato, N.; Okubo, M.; Yagihashi, A.; Wada, Y.; Hara, I.; Hayasaka, H.; Kikuchi, K.

    1990-01-01

    We report the development of an animal model of multiple necrotizing enteritis (MNE) in rats. When rats were injected directly with a culture supernatant of lipopolysaccharide (LPS)-stimulated rat peritoneal macrophages into the abdominal aorta, the overt pathologic lesions of MNE developed within 30 minutes after injection. The rats showed an elevated level of blood fibrinogen degradation product content even 30 minutes after injection. Furthermore the rats that were pretreated intravenously with heparin sulfate did not develop MNE, indicating the acute disturbances of blood microcirculation in the intestine. Multiple necrotizing enteritis was developed also by the injection with recombinant tumor necrosis factor (rTNF) but rarely was observed with even a high dose of recombinant interleukin-1 (rIL-1) or platelet-activating factor (PAF). The supernatant was cytotoxic in vitro to TNF-susceptible LM and many other cells but was less cytotoxic to the TNF-resistant LR line. Partial purification of the supernatant suggested that the supernatant contained a cytokine that has biochemical features of TNF. Furthermore polyclonal anti-TNF antibody could inhibit not only the cytotoxicity in vitro but also MNE development in vivo by this factor. These data strongly indicate that MNE possibly could be caused by a TNF-like cytokine produced by macrophages that are stimulated by the endotoxin. Images Figure 1 PMID:2240161

  10. Interleukin 3-dependent and -independent mast cells stimulated with IgE and antigen express multiple cytokines

    PubMed Central

    1989-01-01

    In response to IgE and specific multivalent antigen, mast cell lines (both growth factor-dependent and -independent) induce the transcription and/or secretion of a number of cytokines having a wide spectrum of activities. We have identified IL-1, IL-3, IL-5, IL-6, IFN- gamma, GM-CSF, JE, MIP1 alpha, MIP1 beta, and TCA3 RNA in at least two of four mast cell clones. The production of these products (except JE) is activation-associated and can be induced by IgE plus antigen. In selected instances cytokine expression can also be induced by activation with Con A or phorbol ester plus ionophore, albeit to levels less than those observed with IgE plus antigen. In addition, long-term mast cell clones and primary cultures of bone marrow-derived mast cells specifically release IL-1, IL-4, and/or IL-6 bioactivity after activation. These findings suggest that in addition to their inflammatory effector function mast cells may serve as a source of growth and regulatory factors. The relationship of mast cells to cells of the T lymphocyte lineage is discussed. PMID:2473161

  11. Multiple reaction monitoring (MRM)-profiling for biomarker discovery applied to human polycystic ovarian syndrome.

    PubMed

    Cordeiro, Fernanda B; Ferreira, Christina R; Sobreira, Tiago Jose P; Yannell, Karen E; Jarmusch, Alan K; Cedenho, Agnaldo P; Lo Turco, Edson G; Cooks, R Graham

    2017-09-15

    We describe multiple reaction monitoring (MRM)-profiling, which provides accelerated discovery of discriminating molecular features, and its application to human polycystic ovary syndrome (PCOS) diagnosis. The discovery phase of the MRM-profiling seeks molecular features based on some prior knowledge of the chemical functional groups likely to be present in the sample. It does this through use of a limited number of pre-chosen and chemically specific neutral loss and/or precursor ion MS/MS scans. The output of the discovery phase is a set of precursor/product transitions. In the screening phase these MRM transitions are used to interrogate multiple samples (hence the name MRM-profiling). MRM-profiling was applied to follicular fluid samples of 22 controls and 29 clinically diagnosed PCOS patients. Representative samples were delivered by flow injection to a triple quadrupole mass spectrometer set to perform a number of pre-chosen and chemically specific neutral loss and/or precursor ion MS/MS scans. The output of this discovery phase was a set of 1012 precursor/product transitions. In the screening phase each individual sample was interrogated for these MRM transitions. Principal component analysis (PCA) and receiver operating characteristic (ROC) curves were used for statistical analysis. To evaluate the method's performance, half the samples were used to build a classification model (testing set) and half were blinded (validation set). Twenty transitions were used for the classification of the blind samples, most of them (N = 19) showed lower abundances in the PCOS group and corresponded to phosphatidylethanolamine (PE) and phosphatidylserine (PS) lipids. Agreement of 73% with clinical diagnosis was found when classifying the 26 blind samples. MRM-profiling is a supervised method characterized by its simplicity, speed and the absence of chromatographic separation. It can be used to rapidly isolate discriminating molecules in healthy/disease conditions by

  12. Proteomic Profiling in Multiple Sclerosis Clinical Courses Reveals Potential Biomarkers of Neurodegeneration

    PubMed Central

    Liguori, Maria; Qualtieri, Antonio; Tortorella, Carla; Direnzo, Vita; Bagalà, Angelo; Mastrapasqua, Mariangela; Spadafora, Patrizia; Trojano, Maria

    2014-01-01

    The aim of our project was to perform an exploratory analysis of the cerebrospinal fluid (CSF) proteomic profiles of Multiple Sclerosis (MS) patients, collected in different phases of their clinical course, in order to investigate the existence of peculiar profiles characterizing the different MS phenotypes. The study was carried out on 24 Clinically Isolated Syndrome (CIS), 16 Relapsing Remitting (RR) MS, 11 Progressive (Pr) MS patients. The CSF samples were analysed using the Matrix Assisted Laser Desorption Ionisation Time Of Flight (MALDI-TOF) mass spectrometer in linear mode geometry and in delayed extraction mode (m/z range: 1000–25000 Da). Peak lists were imported for normalization and statistical analysis. CSF data were correlated with demographic, clinical and MRI parameters. The evaluation of MALDI-TOF spectra revealed 348 peak signals with relative intensity ≥1% in the study range. The peak intensity of the signals corresponding to Secretogranin II and Protein 7B2 were significantly upregulated in RRMS patients compared to PrMS (p<0.05), whereas the signals of Fibrinogen and Fibrinopeptide A were significantly downregulated in CIS compared to PrMS patients (p<0.04). Additionally, the intensity of the Tymosin β4 peak was the only signal to be significantly discriminated between the CIS and RRMS patients (p = 0.013). Although with caution due to the relatively small size of the study populations, and considering that not all the findings remained significant after adjustment for multiple comparisons, in our opinion this mass spectrometry evaluation confirms that this technique may provide useful and important information to improve our understanding of the complex pathogenesis of MS. PMID:25098164

  13. Proteomic profiling in multiple sclerosis clinical courses reveals potential biomarkers of neurodegeneration.

    PubMed

    Liguori, Maria; Qualtieri, Antonio; Tortorella, Carla; Direnzo, Vita; Bagalà, Angelo; Mastrapasqua, Mariangela; Spadafora, Patrizia; Trojano, Maria

    2014-01-01

    The aim of our project was to perform an exploratory analysis of the cerebrospinal fluid (CSF) proteomic profiles of Multiple Sclerosis (MS) patients, collected in different phases of their clinical course, in order to investigate the existence of peculiar profiles characterizing the different MS phenotypes. The study was carried out on 24 Clinically Isolated Syndrome (CIS), 16 Relapsing Remitting (RR) MS, 11 Progressive (Pr) MS patients. The CSF samples were analysed using the Matrix Assisted Laser Desorption Ionisation Time Of Flight (MALDI-TOF) mass spectrometer in linear mode geometry and in delayed extraction mode (m/z range: 1000-25000 Da). Peak lists were imported for normalization and statistical analysis. CSF data were correlated with demographic, clinical and MRI parameters. The evaluation of MALDI-TOF spectra revealed 348 peak signals with relative intensity ≥ 1% in the study range. The peak intensity of the signals corresponding to Secretogranin II and Protein 7B2 were significantly upregulated in RRMS patients compared to PrMS (p<0.05), whereas the signals of Fibrinogen and Fibrinopeptide A were significantly downregulated in CIS compared to PrMS patients (p<0.04). Additionally, the intensity of the Tymosin β4 peak was the only signal to be significantly discriminated between the CIS and RRMS patients (p = 0.013). Although with caution due to the relatively small size of the study populations, and considering that not all the findings remained significant after adjustment for multiple comparisons, in our opinion this mass spectrometry evaluation confirms that this technique may provide useful and important information to improve our understanding of the complex pathogenesis of MS.

  14. Adverse events during the titration phase of interferon-beta in remitting-relapsing multiple sclerosis are not predicted by body mass index nor by pharmacodynamic biomarkers

    PubMed Central

    2013-01-01

    Background This study aimed to correlate body mass index or biomarkers with the frequency of common adverse events (AEs) with subcutaneous IFN β-1a during treatment titration in patients with relapsing-remitting multiple sclerosis previously naïve to IFN β. Methods Eighty-four patients (66.3% females) were followed up during 8 weeks, 25.3% were overweight and 14.5% were obese. Results Biomarkers steadily increased during all study period by 45.3% for β2-microglobulin, 262.8% for olygoadenylate synthetase-1, and 92.8% for neopterin. Overall AE reporting did not vary with the dose or treatment duration. Conclusions BMI was not predictive of increased risk for AEs. Biomarkers did not discriminate on the frequency of any AE either. PMID:23845043

  15. mRNA of cytokines in bone marrow and bone biomarkers in response to propranolol in a nutritional growth retardation model.

    PubMed

    Tasat, Deborah R; Lezón, Christian E; Astort, Francisco; Pintos, Patricia M; Macri, Elisa V; Friedman, Silvia M; Boyer, Patricia M

    2014-10-01

    The aim of this study was to assess mRNA of IL-6, TNFα and IL-10 cytokines in bone marrow, possible mediators involved in altered bone remodeling with detrimental consequences on bone quality in NGR (Nutritional growth retardation) rats. Weanling male Wistar rats were assigned either to control (C) or experimental group (NGR) (n=20 each). C and NGR groups were assigned to 2 groups according to receiving saline solution (SS) or propranolol hydrochloride (P): C, C+P (CP), NGR or NGR+P (NGRP). For 4 weeks, NGR and NGRP rats received 80% of the amount of food consumed by C and CP, respectively, the previous day, corrected by body weight. P (7 mg/kg/day) was injected ip 5 days/week, for 4 weeks in CP and NGRP rats. Body weight and length were recorded. After 4 weeks, blood was drawn. Femurs were dissected for RNA isolation from bone marrow and mRNA of cytokines assays. Food restriction induced a significant negative effect on body growth in NGR and NGRP rats (p<0.001). P had no effects on zoometric parameters (p>0.05). CTX-I increased in NGR rats vs. C (p<0.001), but diminished in NGRP (p<0.01). Serum osteocalcin, PTH, calcium and phosphate levels remained unchanged between groups (p>0.05). In NGR, bone marrow IL-6 mRNA and IL-10 mRNA levels were low as compared to other groups (p<0.05). In contrast, bone marrow TNF-α mRNA levels were significantly high (p<0.05). This study provides evidences that NGR outcomes in a bone marrow proinflammatory microenvironment leading to unbalanced bone remodeling by enhancement of bone resorption reverted by propranolol. Copyright © 2014. Published by Elsevier Urban & Partner Sp. z o.o.

  16. Ultraviolet light and osmotic stress: Activation of the JNK cascade through multiple growth factor and cytokine receptors

    SciTech Connect

    Rosette, C.; Karin, M.

    1996-11-15

    Exposure of mammalian cells to ultraviolet (UV) light or high osmolarity strongly activated the c-Jun amino-terminal protein kinase (JNK) cascade, causing induction of many target genes. Exposure to UV light or osmotic shock induced clustering and internalization of cell surface receptors for epidermal growth factor (EGF), tumor necrosis factor (TNF), and interleukin-1 (IL-1). Activation of the EGF and TNF receptors was also detected biochemically. Whereas activation of each receptor alone resulted in modest activation of JNK, coadministration of EGF, IL-1, and TNF resulted in a strong synergistic response equal to that caused by exposure to osmotic shock or UV light. Inhibition of clustering or receptor down-regulation attenuated both the osmotic shock and UV responses. Physical stresses may perturb the cell surface or alter receptor conformation, thereby subverting signaling pathways normally used by growth factors and cytokines. 24 refs., 5 figs.

  17. Search for cellular stress biomarkers in lymphocytes from patients with multiple sclerosis: a pilot study.

    PubMed

    Grecchi, Sabrina; Mazzini, Giuliano; Lisa, Antonella; Armentero, Marie-Therese; Bergamaschi, Roberto; Romani, Alfredo; Blandini, Fabio; Di Perri, Carol; Scovassi, Anna Ivana

    2012-01-01

    Multiple Sclerosis (MS) is a chronic disease of the central nervous system, the etiology of which, although not completely known, involves inflammation and autoimmunity. In the present study we aimed at identifying molecular markers of apoptosis, cellular stress and DNA damage in isolated peripheral blood mononuclear cells (PBMCs) of MS patients. The analysis was carried on 19 relapsing-remitting untreated MS patients and 13 healthy individuals. We investigated the emergency-driven synthesis of poly(ADP-ribose) (PAR), the expression level of the constitutive enzyme poly(ADP-ribose) polymerase-1 (PARP-1) and the DNA damage-induced phosphorylation of histone H2AX. PAR accumulation, PARP-1 and phosphorylated H2AX (γH2AX) were detected by immunofluorescence experiments on PBMCs isolated from 19 patients and 13 healthy volunteers. Our results show for the first time a net increased amount in PAR and γH2AX in MS patients compared to healthy individuals. Patients were further subdivided in three groups, according to the neuroimaging (MRI)-based classification of disease phase. Remarkably, we found a positive correlation between the level of γH2AX and MS aggressiveness. In addition, apoptosis in PBMCs was monitored by flow cytometry of both phosphatidylserine exposure (revealed by Annexin V-FITC labeling) and membrane permeability to propidium iodide. Our observations provide the evidence that the number of apoptotic cells was significantly higher in patients compared to healthy individuals, thus suggesting that apoptosis could affect MS lymphocyte function.

  18. Search for Cellular Stress Biomarkers in Lymphocytes from Patients with Multiple Sclerosis: A Pilot Study

    PubMed Central

    Grecchi, Sabrina; Mazzini, Giuliano; Lisa, Antonella; Armentero, Marie-Therese; Bergamaschi, Roberto; Romani, Alfredo; Blandini, Fabio; Di Perri, Carol; Scovassi, Anna Ivana

    2012-01-01

    Multiple Sclerosis (MS) is a chronic disease of the central nervous system, the etiology of which, although not completely known, involves inflammation and autoimmunity. In the present study we aimed at identifying molecular markers of apoptosis, cellular stress and DNA damage in isolated peripheral blood mononuclear cells (PBMCs) of MS patients. The analysis was carried on 19 relapsing-remitting untreated MS patients and 13 healthy individuals. We investigated the emergency-driven synthesis of poly(ADP-ribose) (PAR), the expression level of the constitutive enzyme poly(ADP-ribose) polymerase-1 (PARP-1) and the DNA damage-induced phosphorylation of histone H2AX. PAR accumulation, PARP-1 and phosphorylated H2AX (γH2AX) were detected by immunofluorescence experiments on PBMCs isolated from 19 patients and 13 healthy volunteers. Our results show for the first time a net increased amount in PAR and γH2AX in MS patients compared to healthy individuals. Patients were further subdivided in three groups, according to the neuroimaging (MRI)-based classification of disease phase. Remarkably, we found a positive correlation between the level of γH2AX and MS aggressiveness. In addition, apoptosis in PBMCs was monitored by flow cytometry of both phosphatidylserine exposure (revealed by Annexin V-FITC labeling) and membrane permeability to propidium iodide. Our observations provide the evidence that the number of apoptotic cells was significantly higher in patients compared to healthy individuals, thus suggesting that apoptosis could affect MS lymphocyte function. PMID:23028690

  19. Multiple biomarkers in molecular oncology. II. Molecular diagnostics applications in breast cancer management.

    PubMed

    Malinowski, Douglas P

    2007-05-01

    In recent years, the application of genomic and proteomic technologies to the problem of breast cancer prognosis and the prediction of therapy response have begun to yield encouraging results. Independent studies employing transcriptional profiling of primary breast cancer specimens using DNA microarrays have identified gene expression profiles that correlate with clinical outcome in primary breast biopsy specimens. Recent advances in microarray technology have demonstrated reproducibility, making clinical applications more achievable. In this regard, one such DNA microarray device based upon a 70-gene expression signature was recently cleared by the US FDA for application to breast cancer prognosis. These DNA microarrays often employ at least 70 gene targets for transcriptional profiling and prognostic assessment in breast cancer. The use of PCR-based methods utilizing a small subset of genes has recently demonstrated the ability to predict the clinical outcome in early-stage breast cancer. Furthermore, protein-based immunohistochemistry methods have progressed from using gene clusters and gene expression profiling to smaller subsets of expressed proteins to predict prognosis in early-stage breast cancer. Beyond prognostic applications, DNA microarray-based transcriptional profiling has demonstrated the ability to predict response to chemotherapy in early-stage breast cancer patients. In this review, recent advances in the use of multiple markers for prognosis of disease recurrence in early-stage breast cancer and the prediction of therapy response will be discussed.

  20. A paper/polymer hybrid microfluidic microplate for rapid quantitative detection of multiple disease biomarkers

    NASA Astrophysics Data System (ADS)

    Sanjay, Sharma T.; Dou, Maowei; Sun, Jianjun; Li, Xiujun

    2016-07-01

    Enzyme linked immunosorbent assay (ELISA) is one of the most widely used laboratory disease diagnosis methods. However, performing ELISA in low-resource settings is limited by long incubation time, large volumes of precious reagents, and well-equipped laboratories. Herein, we developed a simple, miniaturized paper/PMMA (poly(methyl methacrylate)) hybrid microfluidic microplate for low-cost, high throughput, and point-of-care (POC) infectious disease diagnosis. The novel use of porous paper in flow-through microwells facilitates rapid antibody/antigen immobilization and efficient washing, avoiding complicated surface modifications. The top reagent delivery channels can simply transfer reagents to multiple microwells thus avoiding repeated manual pipetting and costly robots. Results of colorimetric ELISA can be observed within an hour by the naked eye. Quantitative analysis was achieved by calculating the brightness of images scanned by an office scanner. Immunoglobulin G (IgG) and Hepatitis B surface Antigen (HBsAg) were quantitatively analyzed with good reliability in human serum samples. Without using any specialized equipment, the limits of detection of 1.6 ng/mL for IgG and 1.3 ng/mL for HBsAg were achieved, which were comparable to commercial ELISA kits using specialized equipment. We envisage that this simple POC hybrid microplate can have broad applications in various bioassays, especially in resource-limited settings.

  1. A paper/polymer hybrid microfluidic microplate for rapid quantitative detection of multiple disease biomarkers

    PubMed Central

    Sanjay, Sharma T.; Dou, Maowei; Sun, Jianjun; Li, XiuJun

    2016-01-01

    Enzyme linked immunosorbent assay (ELISA) is one of the most widely used laboratory disease diagnosis methods. However, performing ELISA in low-resource settings is limited by long incubation time, large volumes of precious reagents, and well-equipped laboratories. Herein, we developed a simple, miniaturized paper/PMMA (poly(methyl methacrylate)) hybrid microfluidic microplate for low-cost, high throughput, and point-of-care (POC) infectious disease diagnosis. The novel use of porous paper in flow-through microwells facilitates rapid antibody/antigen immobilization and efficient washing, avoiding complicated surface modifications. The top reagent delivery channels can simply transfer reagents to multiple microwells thus avoiding repeated manual pipetting and costly robots. Results of colorimetric ELISA can be observed within an hour by the naked eye. Quantitative analysis was achieved by calculating the brightness of images scanned by an office scanner. Immunoglobulin G (IgG) and Hepatitis B surface Antigen (HBsAg) were quantitatively analyzed with good reliability in human serum samples. Without using any specialized equipment, the limits of detection of 1.6 ng/mL for IgG and 1.3 ng/mL for HBsAg were achieved, which were comparable to commercial ELISA kits using specialized equipment. We envisage that this simple POC hybrid microplate can have broad applications in various bioassays, especially in resource-limited settings. PMID:27456979

  2. Comparative proteomic profiling of refractory/relapsed multiple myeloma reveals biomarkers involved in resistance to bortezomib-based therapy

    PubMed Central

    Wrobel, Tomasz; Usnarska-Zubkiewicz, Lidia; Brzezniakiewicz, Katarzyna; Jamroziak, Krzysztof; Giannopoulos, Krzysztof; Przybylowicz-Chalecka, Anna; Ratajczak, Blazej; Czerwinska-Rybak, Joanna; Nowicki, Adam; Joks, Monika; Czechowska, Elzbieta; Zawartko, Magdalena; Szczepaniak, Tomasz; Grzasko, Norbert; Morawska, Marta; Bochenek, Maciej; Kubicki, Tadeusz; Morawska, Michalina; Tusznio, Katarzyna; Jakubowiak, Andrzej; Komarnicki, Mieczysław

    2016-01-01

    Identifying biomarkers of the resistance in multiple myeloma (MM) is a key research challenge. We aimed to identify proteins that differentiate plasma cells in patients with refractory/relapsed MM (RRMM) who achieved at least very good partial response (VGPR) and in those with reduced response to PAD chemotherapy (bortezomib, doxorubicin and dexamethasone). Comparative proteomic analysis was conducted on pretreatment plasma cells from 77 proteasome inhibitor naïve patients treated subsequently with PAD due to RRMM. To increase data confidence we used two independent proteomic platforms: isobaric Tags for Relative and Absolute Quantitation (iTRAQ) and label free (LF). Proteins were considered as differentially expressed when their accumulation between groups differed by at least 50% in iTRAQ and LF. The proteomic signature revealed 118 proteins (35 up-regulated and 83 down-regulated in ≥ VGPR group). Proteins were classified into four classes: (1) involved in proteasome function; (2) involved in the response to oxidative stress; (3) related to defense response; and (4) regulating the apoptotic process. We confirmed the differential expression of proteasome activator complex subunit 1 (PSME1) by enzyme-linked immunosorbent assay. Increased expression of proteasomes and proteins involved in protection from oxidative stress (eg., TXN, TXNDC5) plays a major role in bortezomib resistance. PMID:27527861

  3. Free kappa light chains in cerebrospinal fluid as a biomarker to assess risk conversion to multiple sclerosis

    PubMed Central

    Menéndez-Valladares, P; García-Sánchez, MI; Cuadri Benítez, P; Lucas, M; Adorna Martínez, M; Carranco Galán, V; García De Veas Silva, JL; Bermudo Guitarte, C

    2015-01-01

    Background Multiple sclerosis (MS) initiates with a first attack or clinically isolated syndrome (CIS). The importance of an early treatment in MS leads to the search, as soon as possible, for novel biomarkers which can predict conversion from CIS to MS. Objective The purpose of this study was to assess the predictive value of the kappa index (κ index), using kappa free light light chains (κFLCs) in cerebrospinal fluid (CSF), for the conversion of CIS patients to MS, and compare its accuracy with other parameters used in clinical practice. Methods FLC levels were analysed in CSF from 176 patients: 70 as control group, 77 CIS, and 29 relapsing–remitting MS. FLC levels were quantified by nephelometry. Results κ Index sensitivity and specificity (93.1%; 95.7%) was higher than those from the immunoglobulin G (IgG) index (75.9%; 94.3%), and lower than those from oligoclonal IgG bands (OCGBs) (96.5%; 98.6%). The optimal cut-off for κ index was 10.62. Most of the CIS patients with κ index >10.62 presented OCGBs, IgG index >0.56 and fulfilled magnetic resonance imaging (MRI) criteria. Conclusion CIS patients above κ index cut-off of 10.62 present 7.34-fold risk of conversion to MS than CIS below this value. The κ index correlated with positive OCGBs, IgG index above 0.56 and MRI criteria. PMID:28607709

  4. Soluble PD-L1: A biomarker to predict progression of autologous transplantation in patients with multiple myeloma

    PubMed Central

    Lin, Chung-Wu; Li, Chi-Cheng; Yao, Ming; Tang, Jih-Luh; Hou, Hsin-An; Tsay, Woei; Chou, Sheng-Je; Cheng, Chieh-Lung; Tien, Hwei-Fang

    2016-01-01

    Autologous hematopoietic stem cell transplantation (AuHSCT) is standard in treating eligible multiple myeloma (MM) patients. However, the outcome after treatment is highly variable. We used ELISA to analyze the levels of soluble PD-L1 (suPD-L1) in bone marrow (BM) plasma from 61 patients with MM at 100 days after AuHSCT. Patients were classified into high (H) and normal-to-low (NL) groups depending on their suPD-L1 levels. Among patients who had a very good partial response (VGPR) or better after AuHSCT, those in the H-group had a shorter response period (RpSCT) as well as shorter overall survival (OS) than those in the NL-group. Multivariate analyses confirmed that a high suPD-L1 level and high-risk cytogenetic abnormalities are independent factors for RpSCT. Our data suggest that suPD-L1 in the BM plasma of MM patients who have VGPR or better after AuHSCT could be used as a biomarker to predict outcome. PMID:27566569

  5. [MicroRNAs and their neuroimmunoregulator mechanisms in multiple sclerosis. Development of biomarkers for diagnosis].

    PubMed

    Sánchez-Chaparro, M Marisela; Rodríguez-Sánchez, Iram P; Barrera-Saldaña, Hugo A; Martínez-Villarreal, Laura E; Resendez-Pérez, Diana; Gámez-Escobedo, Idalia A

    2015-06-16

    Introduccion. Los microARN (miARN) son moleculas que han generado gran atencion como reguladores de procesos de silenciamiento genico en diferentes organismos. La desregulacion de los mecanismos efectuados por estas moleculas se vincula al desarrollo y progresion de los trastornos relacionados con el sistema inmune. Diferentes estudios exponen que los miARN desempeñan un papel fundamental en procesos neuronales e inmunes, y se relacionan con los mecanismos de las enfermedades que afectan ambos sistemas. La esclerosis multiple (EM) es una enfermedad neurodegenerativa debida a la desmielinizacion axonal causada por procesos autoinmunes. Objetivo. Mostrar la estrecha relacion de las funciones regulatorias de los miARN en vias de señalizacion neuroinmunologicas en el desarrollo de la EM, asi como su estudio como biomarcadores diagnosticos para su uso en pacientes. Desarrollo. En la literatura cientifica se ha estudiado y establecido el papel de los miARN como moduladores de los procesos celulares. Sin embargo, poco se ha abordado sobre su funcionalidad en las celulas gliales dentro de los procesos de plasticidad neuronal, regulacion de la desmielinizacion y reconstitucion axonal, por lo que su revision constituye el proposito de este escrito. Ademas, algunos miARN previamente evaluados se describen para su enfoque diagnostico para la deteccion, curso y tratamiento de la EM, y se encuentran en investigacion o implementacion. Conclusiones. Existe una fuerte evidencia del papel que realizan los miARN en los mecanismos homeostaticos axonales durante la evolucion de la EM. Esto representa un area de estudio para explorar el uso de estas moleculas para la comprension de esta enfermedad, su diagnostico oportuno y la evolucion en los pacientes.

  6. Evolving changes in disease biomarkers and risk of early progression in smoldering multiple myeloma

    PubMed Central

    Ravi, P; Kumar, S; Larsen, J T; Gonsalves, W; Buadi, F; Lacy, M Q; Go, R; Dispenzieri, A; Kapoor, P; Lust, J A; Dingli, D; Lin, Y; Russell, S J; Leung, N; Gertz, M A; Kyle, R A; Bergsagel, P L; Rajkumar, S V

    2016-01-01

    We studied 190 patients with smoldering multiple myeloma (SMM) at our institution between 1973 and 2014. Evolving change in monoclonal protein level (eMP) was defined as ⩾10% increase in serum monoclonal protein (M) and/or immunoglobulin (Ig) (M/Ig) within the first 6 months of diagnosis (only if M-protein ⩾3 g/dl) and/or ⩾25% increase in M/Ig within the first 12 months, with a minimum required increase of 0.5 g/dl in M-protein and/or 500 mg/dl in Ig. Evolving change in hemoglobin (eHb) was defined as ⩾0.5 g/dl decrease within 12 months of diagnosis. A total of 134 patients (70.5%) progressed to MM over a median follow-up of 10.4 years. On multivariable analysis adjusting for factors known to predict for progression to MM, bone marrow plasma cells ⩾20% (odds ratio (OR)=3.37 (1.30–8.77), P=0.013), eMP (OR=8.20 (3.19–21.05), P<0.001) and eHb (OR=5.86 (2.12–16.21), P=0.001) were independent predictors of progression within 2 years of SMM diagnosis. A risk model comprising these variables was constructed, with median time to progression of 12.3, 5.1, 2.0 and 1.0 years among patients with 0–3 risk factors respectively. The 2-year progression risk was 81.5% in individuals who demonstrated both eMP and eHb, and 90.5% in those with all three risk factors. PMID:27471870

  7. The critical role of antigen-presentation-induced cytokine crosstalk in the central nervous system in multiple sclerosis and experimental autoimmune encephalomyelitis.

    PubMed

    Sosa, Rebecca A; Forsthuber, Thomas G

    2011-10-01

    Multiple sclerosis (MS) is a debilitating disease of the central nervous system (CNS) that has been extensively studied using the animal model experimental autoimmune encephalomyelitis (EAE). It is believed that CD4(+) T lymphocytes play an important role in the pathogenesis of this disease by mediating the demyelination of neuronal axons via secretion of proinflammatory cytokines resulting in the clinical manifestations. Although a great deal of information has been gained in the last several decades about the cells involved in the inflammatory and disease mediating process, important questions have remained unanswered. It has long been held that initial neuroantigen presentation and T cell activation events occur in the immune periphery and then translocate to the CNS. However, an increasing body of evidence suggests that antigen (Ag) presentation might initiate within the CNS itself. Importantly, it has remained unresolved which antigen presenting cells (APCs) in the CNS are the first to acquire and present neuroantigens during EAE/MS to T cells, and what the conditions are under which this takes place, ie, whether this occurs in the healthy CNS or only during inflammatory conditions and what the related cytokine microenvironment is comprised of. In particular, the central role of interferon-γ as a primary mediator of CNS pathology during EAE has been challenged by the emergence of Th17 cells producing interleukin-17. This review describes our current understanding of potential APCs in the CNS and the contribution of these and other CNS-resident cells to disease pathology. Additionally, we discuss the question of where Ag presentation is initiated and under what conditions neuroantigens are made available to APCs with special emphasis on which cytokines may be important in this process.

  8. Biological definition of multiple chemical sensitivity from redox state and cytokine profiling and not from polymorphisms of xenobiotic-metabolizing enzymes

    SciTech Connect

    De Luca, Chiara; Scordo, Maria G.; Cesareo, Eleonora; Pastore, Saveria; Mariani, Serena; Maiani, Gianluca; Stancato, Andrea; Loreti, Beatrice; Valacchi, Giuseppe; Lubrano, Carla; Raskovic, Desanka; De Padova, Luigia; Genovesi, Giuseppe; Korkina, Liudmila G.

    2010-11-01

    Background: Multiple chemical sensitivity (MCS) is a poorly clinically and biologically defined environment-associated syndrome. Although dysfunctions of phase I/phase II metabolizing enzymes and redox imbalance have been hypothesized, corresponding genetic and metabolic parameters in MCS have not been systematically examined. Objectives: We sought for genetic, immunological, and metabolic markers in MCS. Methods: We genotyped patients with diagnosis of MCS, suspected MCS and Italian healthy controls for allelic variants of cytochrome P450 isoforms (CYP2C9, CYP2C19, CYP2D6, and CYP3A5), UDP-glucuronosyl transferase (UGT1A1), and glutathione S-transferases (GSTP1, GSTM1, and GSTT1). Erythrocyte membrane fatty acids, antioxidant (catalase, superoxide dismutase (SOD)) and glutathione metabolizing (GST, glutathione peroxidase (Gpx)) enzymes, whole blood chemiluminescence, total antioxidant capacity, levels of nitrites/nitrates, glutathione, HNE-protein adducts, and a wide spectrum of cytokines in the plasma were determined. Results: Allele and genotype frequencies of CYPs, UGT, GSTM, GSTT, and GSTP were similar in the Italian MCS patients and in the control populations. The activities of erythrocyte catalase and GST were lower, whereas Gpx was higher than normal. Both reduced and oxidised glutathione were decreased, whereas nitrites/nitrates were increased in the MCS groups. The MCS fatty acid profile was shifted to saturated compartment and IFNgamma, IL-8, IL-10, MCP-1, PDGFbb, and VEGF were increased. Conclusions: Altered redox and cytokine patterns suggest inhibition of expression/activity of metabolizing and antioxidant enzymes in MCS. Metabolic parameters indicating accelerated lipid oxidation, increased nitric oxide production and glutathione depletion in combination with increased plasma inflammatory cytokines should be considered in biological definition and diagnosis of MCS.

  9. The Critical Role of Antigen-Presentation-Induced Cytokine Crosstalk in the Central Nervous System in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis

    PubMed Central

    Sosa, Rebecca A.

    2011-01-01

    Multiple sclerosis (MS) is a debilitating disease of the central nervous system (CNS) that has been extensively studied using the animal model experimental autoimmune encephalomyelitis (EAE). It is believed that CD4+ T lymphocytes play an important role in the pathogenesis of this disease by mediating the demyelination of neuronal axons via secretion of proinflammatory cytokines resulting in the clinical manifestations. Although a great deal of information has been gained in the last several decades about the cells involved in the inflammatory and disease mediating process, important questions have remained unanswered. It has long been held that initial neuroantigen presentation and T cell activation events occur in the immune periphery and then translocate to the CNS. However, an increasing body of evidence suggests that antigen (Ag) presentation might initiate within the CNS itself. Importantly, it has remained unresolved which antigen presenting cells (APCs) in the CNS are the first to acquire and present neuroantigens during EAE/MS to T cells, and what the conditions are under which this takes place, ie, whether this occurs in the healthy CNS or only during inflammatory conditions and what the related cytokine microenvironment is comprised of. In particular, the central role of interferon-γ as a primary mediator of CNS pathology during EAE has been challenged by the emergence of Th17 cells producing interleukin-17. This review describes our current understanding of potential APCs in the CNS and the contribution of these and other CNS-resident cells to disease pathology. Additionally, we discuss the question of where Ag presentation is initiated and under what conditions neuroantigens are made available to APCs with special emphasis on which cytokines may be important in this process. PMID:21919736

  10. Serum Biomarker gMS-Classifier2: Predicting Conversion to Clinically Definite Multiple Sclerosis

    PubMed Central

    Yarden, Jennifer; Fire, Ella; Spector, Larissa; Dotan, Nir; Dukler, Avinoam; Rovira, Alex; Montalban, Xavier; Tintore, Mar

    2013-01-01

    Background Anti-glycan antibodies can be found in autoimmune diseases. IgM against glycan P63 was identified in clinically isolated syndromes (CIS) and included in gMS-Classifier2, an algorithm designed with the aim of identifying patients at risk of a second demyelinating attack. Objective To determine the value of gMS-Classifier2 as an early and independent predictor of conversion to clinically definite multiple sclerosis (CDMS). Methods Data were prospectively acquired from a CIS cohort. gMS-Classifier2 was determined in patients first seen between 1995 and 2007 with ≥ two 200 µL serum aliquots (N = 249). The primary endpoint was time to conversion to CDMS at two years, the factor tested was gMS-Classifier2 status (positive/negative) or units; other exploratory time points were 5 years and total time of follow-up. Results Seventy-five patients (30.1%) were gMS-Classifier2 positive. Conversion to CDMS occurred in 31/75 (41.3%) of positive and 45/174 (25.9%) of negative patients (p = 0.017) at two years. Median time to CDMS was 37.8 months (95% CI 10.4–65.3) for positive and 83.9 months (95% CI 57.5–110.5) for negative patients. gMS-Classifier2 status predicted conversion to CDMS within two years of follow-up (HR = 1.8, 95% CI 1.1–2.8; p = 0.014). gMS-Classifier2 units were also independent predictors when tested with either Barkhof criteria and OCB (HR = 1.2, CI 1.0–1.5, p = 0.020) or with T2 lesions and OCB (HR = 1.3, CI 1.1–1.5, p = 0.008). Similar results were obtained at 5 years of follow-up. Discrimination measures showed a significant change in the area under the curve (ΔAUC) when adding gMS-Classifier2 to a model with either Barkhof criteria (ΔAUC 0.0415, p = 0.012) or number of T2 lesions (ΔAUC 0.0467, p = 0.009), but not when OCB were added to these models. Conclusions gMS-Classifier2 is an independent predictor of early conversion to CDMS and could be of clinical relevance, particularly in cases in

  11. Osteolytic lesions, cytogenetic features and bone marrow levels of cytokines and chemokines in multiple myeloma patients: Role of chemokine (C-C motif) ligand 20.

    PubMed

    Palma, B Dalla; Guasco, D; Pedrazzoni, M; Bolzoni, M; Accardi, F; Costa, F; Sammarelli, G; Craviotto, L; De Filippo, M; Ruffini, L; Omedè, P; Ria, R; Aversa, F; Giuliani, N

    2016-02-01

    The relationship between bone marrow (BM) cytokine and chemokine levels, cytogenetic profiles and skeletal involvement in multiple myeloma (MM) patients is not yet defined. This study investigated a cohort of 455 patients including monoclonal gammopathy of uncertain significance (MGUS), smoldering MM and symptomatic MM patients. Skeletal surveys, positron emission tomography (PET)/computerized tomography (CT) and magnetic resonance imaging (MRI) were used to identify myeloma bone disease. Significantly higher median BM levels of both C-C motif Ligand (CCL)3 and CCL20 were found in MM patients with radiographic evidence of osteolytic lesions as compared with those without, and in all MM patients with positive PET/CT scans. BM levels of CCL3, CCL20, Activin-A and Dickkopf-1 (DKK-1) were significantly higher in patients with high bone disease as compared with patients with low bone disease. Moreover, CCL20 BM levels were significant predictors of osteolysis on X-rays by multivariate logistic analysis. On the other hand, DKK-1 levels were related to the presence of MRI lesions independently of the osteolysis at the X-rays. Our data define the relationship between bone disease and the BM cytokine and chemokine patterns highlighting the tight relationship between CCL20 BM levels and osteolysis in MM.

  12. Biomarkers of Inflammation and Axonal Degeneration/Damage in Patients with Newly Diagnosed Multiple Sclerosis: Contributions of the Soluble CD163 CSF/Serum Ratio to a Biomarker Panel

    PubMed Central

    Stilund, Morten; Gjelstrup, Mikkel Carstensen; Petersen, Thor; Møller, Holger Jon; Rasmussen, Peter Vestergaard; Christensen, Tove

    2015-01-01

    Background Expression of soluble CD163 (sCD163), a macrophage/microglia biomarker, is increased in inflammatory conditions, and sCD163 levels in the cerebrospinal fluid (CSF) have recently been shown to be elevated in patients with multiple sclerosis (MS): the sCD163 CSF/serum ratio was elevated in patients with relapsing-remitting MS (RRMS), primary progressive MS (PPMS), and clinically isolated syndrome (CIS) compared with symptomatic controls. Objective To investigate the contributions of the sCD163 CSF/serum ratio to a biomarker panel focusing on inflammation and axonal degeneration in newly diagnosed MS; thus optimising a diagnostic biomarker panel for MS. Methods After a full MS diagnostic work-up, including collection of paired samples of CSF and serum, 125 patients were included in this study. Patients were divided into groups based on their diagnosis, and patients with normal clinical and paraclinical findings were defined as symptomatic controls. Serum and CSF levels, ratios, and indices of sCD163, CXCL13, osteopontin, neopterin, and CSF levels of neurofilament light polypeptide were determined by enzyme-linked immunosorbent assays (ELISAs). For sCD163 the results constitute a post-hoc analysis of already published data. Results All tested biomarkers, notably the sCD163 ratio, the CXCL13 ratio, the NEO ratio, the CSF level of NfL, the IgG index, and the serum level of OPN, were significantly correlated to RRMS, PPMS, and/or CIS. The individual biomarkers in single tests had a lower performance than the IgG index, however, their combined receiver operating characteristic (ROC) curve demonstrated excellent diagnostic discriminatory power. Conclusion The biomarker panel showed distinct profiles for each patient group and could be a valuable tool for clinical differentiation of MS subgroups. The combined ROC analysis showed that sCD163 contributes positively as a diagnostic marker to a panel of established MS biomarkers. Patients with PPMS were demonstrated

  13. Interplay between pro-inflammatory cytokines and brain oxidative stress biomarkers: evidence of parallels between butyl paraben intoxication and the valproic acid brain physiopathology in autism rat model.

    PubMed

    Hegazy, Hoda G; Ali, Elham H A; Elgoly, Amany H Mahmoud

    2015-02-01

    Butyl paraben is a preservative used in food, drugs and cosmetics. Neurotoxic effect was reported recently beside the potential estrogenic activity of parabens. There is controversy as to the potential harmful effects of butyl parabens, which are suspected to contribute to autism and learning disabilities. The purpose of this study was to examine the similarities between paraben intoxication signs in the rat brain and brain markers in an autistic like rat model. This study provides evidence of many parallels between the two, including (1) oxidative stress, (2) decreased reduced glutathione levels and elevated oxidised glutathione, (3) mitochondrial dysfunction, and (4) neuroinflammation and increased pro-inflammatory cytokine levels in the brain (tumour necrosis factor-alpha, interleukin-1-beta, and interleukin-6). (5) Increased protein oxidation reported by a significant increase in 3-nitrotyrosine (3-NT)/tyrosine ratio. (6) A marked disturbance was found in the production of energy carriers (AMP, ATP and AMP/ATP ratio) in comparison with the control. The evidence suggests that paraben may, to some extent, either cause or contribute to the brain physiopathology in ASDs or pathogens that produce the brain pathology observed in the diagnosed rat model of ASD.

  14. Pattern of cytokine (IL-6 and IL-10) level as inflammation and anti-inflammation mediator of multiple organ dysfunction syndrome (MODS) in polytrauma.

    PubMed

    Sapan, Heber Bombang; Paturusi, Idrus; Jusuf, Irawan; Patellongi, Ilhamjaya; Massi, Muh Nasrum; Pusponegoro, Aryono Djuned; Arief, Syafrie Kamsul; Labeda, Ibrahim; Islam, Andi Asadul; Rendy, Leo; Hatta, Mochammad

    2016-01-01

    Massive injury remains the most common cause of death for productive age group globally. The current immune, inflammatory paradigm, based on an incomplete understanding of the functional integration of the complex host response, remains a major impediment to the development of effective innovative diagnostic and therapeutic effort. This study attempt to investigate the pattern of inflammatory and anti-inflammatory cytokines such as interleukin-6 and 10 (IL-6 and IL-10) and their interaction in severe injury condition with its major complication as multiple organ dysfunction syndrome (MODS) and failure (MOF) after polytrauma. This is multicenter study held at 4 academic Level-1 Trauma center included 54 polytrauma participants. Inclusion criteria were age between 16-60 years old, had new acute episode of polytrauma which defined as injury in ≥2 body region with Injury Severity Score (ISS) ≥16, and the presence of Systemic Inflammation Response Syndrome (SIRS). Serum level of IL-6 and IL-10 were taken on day 2, 3, and 5 after trauma. During hospitalization, samples were observed for the occurrence of MODS or MOF using Sequential Organ Failure Assessment (SOFA) and mortality rate were also noted. Participant were mostly male with mean of age of 35, 9 years old, endured polytrauma caused by traffic accident. Elevation of cytokines (IL-6, IL-10, and IL-6/IL-10 ratio) had directly proportional with MODS and mortality. Threshold level of compensation for severe trauma is IL-6 of 50 pg/mL and trauma load of ISS ≥30. Inflammation reaction greater than this threshold level would result in downhill level of IL-6, IL-10, or IL-6/IL-10 ratio which associated with poor outcome (MODS and death). The elevation of these cytokines level were represent as compensation/adaptive immune system and its fall represent decompensating/failure of immune system after severe trauma. The pattern of IL-6 and IL-10 after polytrauma represent immune system effort to restore homeostasis

  15. Pattern of cytokine (IL-6 and IL-10) level as inflammation and anti-inflammation mediator of multiple organ dysfunction syndrome (MODS) in polytrauma

    PubMed Central

    Sapan, Heber Bombang; Paturusi, Idrus; Jusuf, Irawan; Patellongi, Ilhamjaya; Massi, Muh Nasrum; Pusponegoro, Aryono Djuned; Arief, Syafrie Kamsul; Labeda, Ibrahim; Islam, Andi Asadul; Rendy, Leo; Hatta, Mochammad

    2016-01-01

    Massive injury remains the most common cause of death for productive age group globally. The current immune, inflammatory paradigm, based on an incomplete understanding of the functional integration of the complex host response, remains a major impediment to the development of effective innovative diagnostic and therapeutic effort. This study attempt to investigate the pattern of inflammatory and anti-inflammatory cytokines such as interleukin-6 and 10 (IL-6 and IL-10) and their interaction in severe injury condition with its major complication as multiple organ dysfunction syndrome (MODS) and failure (MOF) after polytrauma. This is multicenter study held at 4 academic Level-1 Trauma center included 54 polytrauma participants. Inclusion criteria were age between 16-60 years old, had new acute episode of polytrauma which defined as injury in ≥2 body region with Injury Severity Score (ISS) ≥16, and the presence of Systemic Inflammation Response Syndrome (SIRS). Serum level of IL-6 and IL-10 were taken on day 2, 3, and 5 after trauma. During hospitalization, samples were observed for the occurrence of MODS or MOF using Sequential Organ Failure Assessment (SOFA) and mortality rate were also noted. Participant were mostly male with mean of age of 35, 9 years old, endured polytrauma caused by traffic accident. Elevation of cytokines (IL-6, IL-10, and IL-6/IL-10 ratio) had directly proportional with MODS and mortality. Threshold level of compensation for severe trauma is IL-6 of 50 pg/mL and trauma load of ISS ≥30. Inflammation reaction greater than this threshold level would result in downhill level of IL-6, IL-10, or IL-6/IL-10 ratio which associated with poor outcome (MODS and death). The elevation of these cytokines level were represent as compensation/adaptive immune system and its fall represent decompensating/failure of immune system after severe trauma. The pattern of IL-6 and IL-10 after polytrauma represent immune system effort to restore homeostasis

  16. Macrophage Inhibitory Cytokine 1 Biomarker Serum Immunoassay in Combination with PSA Is a More Specific Diagnostic Tool for Detection of Prostate Cancer

    PubMed Central

    Li, Ji; Veltri, Robert W.; Yuan, Zhen; Christudass, Christhunesa S.; Mandecki, Wlodek

    2015-01-01

    Background Prostate cancer (PCa) is the most common malignancy among men in the United States. Though highly sensitive, the often-used prostate-specific antigen (PSA) test has low specificity which leads to overdiagnosis and overtreatment of PCa. This paper presents results of a retrospective study that indicates that testing for macrophage inhibitory cytokine 1 (MIC-1) concentration along with the PSA assay could provide much improved specificity to the assay. Methods The MIC-1 serum level was determined by a novel p-Chip-based immunoassay run on 70 retrospective samples. The assay was configured on p-Chips, small integrated circuits (IC) capable of storing in their electronic memories a serial number to identify the molecular probe immobilized on its surface. The distribution of MIC-1 and pre-determined PSA concentrations were displayed in a 2D plot and the predictive power of the dual MIC-1/PSA assay was analyzed. Results MIC-1 concentration in serum was elevated in PCa patients (1.44 ng/ml) compared to normal and biopsy-negative individuals (0.93 ng/ml and 0.88 ng/ml, respectively). In addition, the MIC-1 level was correlated with the progression of PCa. The area under the receiver operator curve (AUC-ROC) was 0.81 providing an assay sensitivity of 83.3% and specificity of 60.7% by using a cutoff of 0.494 for the logistic regression value of MIC-1 and PSA. Another approach, by defining high-frequency PCa zones in a two-dimensional plot, resulted in assay sensitivity of 78.6% and specificity of 89.3%. Conclusions The analysis based on correlation of MIC-1 and PSA concentrations in serum with the patient PCa status improved the specificity of PCa diagnosis without compromising the high sensitivity of the PSA test alone and has potential for PCa prognosis for patient therapy strategies. PMID:25853582

  17. [Relation between cytokine IL-6 levels and the occurrence of systemic complications in patients with multiple injuries and blunt abdominal trauma].

    PubMed

    Gregorić, Pavle D; Bajec, Djordje D; Sijacki, Ana D; Karadzić, Borivoje A

    2003-01-01

    Severe trauma is the third cause of death and the first one in the most vital and young population. In USA more children die of trauma then of all other causes. Blunt abdominal trauma takes 56% cases of multiple traumas of all etiologies. Among multiple injured patients, near to 50% have some system-complications, more of 60% in the group of critically injured (ISS > 35). Cytokines play the main role in the inflammatory reaction during the early phase response on trauma. Their secretion predicts system-complications as ARDS, SIRS, even MODS. Hypothetically, level of concentration of Interleukin-6 (IL 6) can improve methods of early diagnostic procedures for detecting SIRS and MODS, when scores are still low (preclinical level), at which stages therapy is more powerful and also cheaper. This prospective study includes 35 multiple injured persons with blunt abdominal trauma (75 > ISS > 18). We have used standard diagnostic procedures. Concentration of IL 6 was detected with ELISA-test. Levels of IL 6 were significantly higher in correlation with SIRS score groups. Correlation with MODS score was not significant for the lowest scores, but IL 6 showed significant higher levels in the second and the third MODS score group.

  18. Melatonin exacerbates acute experimental autoimmune encephalomyelitis by enhancing the serum levels of lactate: A potential biomarker of multiple sclerosis progression.

    PubMed

    Ghareghani, Majid; Dokoohaki, Shima; Ghanbari, Amir; Farhadi, Naser; Zibara, Kazem; Khodadoust, Saeid; Parishani, Mohammad; Ghavamizadeh, Mehdi; Sadeghi, Heibatollah

    2017-01-01

    Melatonin has a beneficial role in adult rat models of multiple sclerosis (MS). In this study, melatonin treatment (10 mg/kg/d) was investigated in young age (5-6 weeks old) Lewis rat model of acute experimental autoimmune encephalomyelitis (EAE) followed by assessing serum levels of lactate and melatonin. Results showed that clinical outcomes were exacerbated in melatonin- (neurological score = 6) vs PBS-treated EAE rats (score = 5). Melatonin caused a significant increase in serum IFN-γ, in comparison to PBS-treated EAE rats whereas no considerable change in IL-4 levels were found, although they were significantly lower than those of controls. The ratio of IFN-γ/IL-4, an indicator of Th-1/Th-2, was significantly higher in PBS- and melatonin- treated EAE rats, in comparison to controls. Moreover, results showed increased lymphocyte infiltration, activated astrocytes (GFAP+ cells) but also higher demyelinated plaques (MBP-deficient areas) in the lumbar spinal cord of melatonin-treated EAE rats. Finally, serum levels of lactate, but not melatonin, significantly increased in the melatonin group, compared to untreated EAE and normal rats. In conclusion, our results indicated a relationship between age and the development of EAE since a negative impact was found for melatonin on EAE recovery of young rats by enhancing IFN-γ, the ratio of Th1/Th2 cells, and astrocyte activation, which seems to delay the remyelination process. While melatonin levels decline in MS patients, lactate might be a potential diagnostic biomarker for prediction of disease progression. Early administration of melatonin in the acute phase of MS might be harmful and needs further investigations. © 2016 John Wiley & Sons Australia, Ltd.

  19. Evaluation of Multiple Biomarkers of Cardiovascular Stress for Risk Prediction and Guiding Medical Therapy in Patients with Stable Coronary Disease

    PubMed Central

    Sabatine, Marc S.; Morrow, David A.; de Lemos, James A.; Omland, Torbjorn; Sloan, Sarah; Jarolim, Petr; Solomon, Scott D.; Pfeffer, Marc A.; Braunwald, Eugene

    2012-01-01

    Background Circulating biomarkers can offer insight into subclinical cardiovascular stress and thus have the potential to aid in risk stratification and tailoring of therapy. Methods & Results We measured plasma levels of 4 cardiovascular biomarkers, midregional pro-atrial natriuretic peptide (MR-proANP), midregional pro-adrenomedullin (MR-proADM), C-terminal pro-endothelin-1 (CT-proET-1) and copeptin, in 3717 patients with stable CAD and preserved left ventricular ejection fraction (LVEF) who were randomized to trandolapril or placebo as part of the Prevention of Events with Angiotensin Converting Enzyme (PEACE) trial. After adjustment for clinical cardiovascular risk predictors and LVEF, elevated levels of MR-proANP, MR-proADM, and CT-proET-1 were independently associated with the risk of cardiovascular death or heart failure (HRs per 1-SD of log-transformed biomarker levels of 1.97, 1.48, and 1.47, respectively; P≤0.002 for each biomarker). These three biomarkers also significantly improved metrics of discrimination when added to a clinical model. Trandolapril significantly reduced the risk of cardiovascular death or heart failure in patients who had elevated levels of 2 or more these biomarkers (HR 0.53, 95% CI 0.36–0.80), whereas there was no benefit in patients with elevated levels of 0 or 1 biomarkers (HR 1.09, 95% CI 0.74–1.59) (Pinteraction=0.012). Conclusions In patients with stable CAD and preserved LVEF, our results suggest elevated levels of novel biomarkers of cardiovascular stress may help identify patients who are at higher risk of cardiovascular death and heart failure and may be useful to select patients who derive significant benefit from ACE inhibitor therapy. PMID:22179538

  20. The Glycan Role in the Glycopeptide Immunogenicity Revealed by Atomistic Simulations and Spectroscopic Experiments on the Multiple Sclerosis Biomarker CSF114(Glc)

    NASA Astrophysics Data System (ADS)

    Bruno, Agostino; Scrima, Mario; Novellino, Ettore; D'Errico, Gerardino; D'Ursi, Anna Maria; Limongelli, Vittorio

    2015-03-01

    Glycoproteins are often recognized as not-self molecules by antibodies triggering the onset of severe autoimmune diseases such as Multiple Sclerosis (MS). Thus, the development of antigen-mimicking biomarkers represents an attractive strategy for an early diagnosis of the disease. An example is the synthetic glycopeptide CSF114(Glc), which was designed and tested as MS biomarker and whose clinical application was limited by its reduced ability to detect autoantibodies in MS patients. In the attempt to improve the efficacy of CSF114(Glc), we have characterized all the events leading to the final binding of the biomarker to the autoantibody using atomistic simulations, ESR and NMR experiments. The glycosydic moiety plays a primary role in the whole process. In particular, in an environment mimicking that used in the clinical tests the glycopeptide assumes a α-helix structure that is functional for the interaction with the antibody. In this conformation CSF114(Glc) binds the monoclonal antibody mAb8-18C5 similarly to the myelin oligodendrocyte glycoprotein MOG, which is a known MS auto-antigen, thus explaining its diagnostic activity. Our study offers new molecular bases to design more effective biomarkers and provides a most valid protocol to investigate other systems where the environment effect is determinant for the biological activity.

  1. The Glycan Role in the Glycopeptide Immunogenicity Revealed by Atomistic Simulations and Spectroscopic Experiments on the Multiple Sclerosis Biomarker CSF114(Glc)

    PubMed Central

    Bruno, Agostino; Scrima, Mario; Novellino, Ettore; D'Errico, Gerardino; D'Ursi, Anna Maria; Limongelli, Vittorio

    2015-01-01

    Glycoproteins are often recognized as not-self molecules by antibodies triggering the onset of severe autoimmune diseases such as Multiple Sclerosis (MS). Thus, the development of antigen-mimicking biomarkers represents an attractive strategy for an early diagnosis of the disease. An example is the synthetic glycopeptide CSF114(Glc), which was designed and tested as MS biomarker and whose clinical application was limited by its reduced ability to detect autoantibodies in MS patients. In the attempt to improve the efficacy of CSF114(Glc), we have characterized all the events leading to the final binding of the biomarker to the autoantibody using atomistic simulations, ESR and NMR experiments. The glycosydic moiety plays a primary role in the whole process. In particular, in an environment mimicking that used in the clinical tests the glycopeptide assumes a α-helix structure that is functional for the interaction with the antibody. In this conformation CSF114(Glc) binds the monoclonal antibody mAb8-18C5 similarly to the myelin oligodendrocyte glycoprotein MOG, which is a known MS auto-antigen, thus explaining its diagnostic activity. Our study offers new molecular bases to design more effective biomarkers and provides a most valid protocol to investigate other systems where the environment effect is determinant for the biological activity. PMID:25776265

  2. Cytokines and autoimmunity.

    PubMed Central

    Cavallo, M G; Pozzilli, P; Thorpe, R

    1994-01-01

    Although the immunopathology of most autoimmune diseases has been well defined, the mechanisms responsible for the breakdown of self-tolerance and which lead to the development of systemic and organ-specific autoaggression are still unclear. Evidence has accumulated which supports a role for a disregulated production of cytokines by leucocytes and possibly other cells in the pathogenesis of some autoimmune diseases. However, due to the complexity and heterogeneity of cytokine effects in the regulation of the immune response, it is difficult to determine whether abnormalities in the patterns of cytokine production are primary or secondary to the pathological process. Confusion is also caused by the fact that the biological activities of cytokines are multiple and often overlapping, and consequently it is difficult to focus on a unique effect of any one cytokine. Characterization of the potential and actual involvement of cytokines is important not only for a better understanding of the pathogenesis of autoimmune conditions, but particularly because of the implications for the development of immunotherapeutic strategies for the prevention and treatment of the diseases. PMID:8149655

  3. CENTRAL AUDTIORY DEVELOPMENT IN CHILDREN WITH HEARING LOSS: CLINICAL RELEVANCE OF THE P1 CAEP BIOMARKER IN HEARING-IMPAIRED CHILDREN WITH MULTIPLE DISABILITIES*

    PubMed Central

    Sharma, Anu; Glick, Hannah; Campbell, Julia; Biever, Allison

    2013-01-01

    Objective First, we review the development and plasticity of the central auditory pathways in infants and children with hearing loss who are fitted with cochlear implants (CIs). Second, we describe case studies demonstrating the clinical utility of the P1 central auditory evoked potential (CAEP) for evaluating cortical auditory maturation in the rapidly increasing number of cochlear-implanted children who have multiple disabilities. Study Design Children who receive CIs provide a platform to examine the trajectories of deprivation-induced and experience-dependent plasticity in the central auditory system. We review the evidence for, and time limits of sensitive periods for cortical auditory maturation framing an optimal period for cochlear implantation. Finally, we evaluate the use of the P1 biomarker as an objective assessment tool in the special case of children with multiple disabilities. Results The P1 response was useful in assessing central auditory maturation in patients with CHARGE association, ANSD, and Pallister-Killian Syndrome concomitant with hearing loss. Conclusion The presence of co-existing disabilities in addition to hearing loss poses unique challenges regarding both pre-intervention evaluation and post-intervention rehabilitation for children with multiple disabilities. When combined with a standard audiological test battery, the P1 CAEP biomarker has a useful role in objectively evaluating the maturation of central auditory pathways to determine the effectiveness of various intervention strategies in hearing-impaired children with multiple disabilities. PMID:24273704

  4. Mining potential biomarkers associated with space flight in Caenorhabditis elegans experienced Shenzhou-8 mission with multiple feature selection techniques.

    PubMed

    Zhao, Lei; Gao, Ying; Mi, Dong; Sun, Yeqing

    To identify the potential biomarkers associated with space flight, a combined algorithm, which integrates the feature selection techniques, was used to deal with the microarray datasets of Caenorhabditis elegans obtained in the Shenzhou-8 mission. Compared with the ground control treatment, a total of 86 differentially expressed (DE) genes in responses to space synthetic environment or space radiation environment were identified by two filter methods. And then the top 30 ranking genes were selected by the random forest algorithm. Gene Ontology annotation and functional enrichment analyses showed that these genes were mainly associated with metabolism process. Furthermore, clustering analysis showed that 17 genes among these are positive, including 9 for space synthetic environment and 8 for space radiation environment only. These genes could be used as the biomarkers to reflect the space environment stresses. In addition, we also found that microgravity is the main stress factor to change the expression patterns of biomarkers for the short-duration spaceflight.

  5. A multiplex cytokine score for the prediction of disease severity in pediatric hematology/oncology patients with septic shock.

    PubMed

    Xu, Xiao-Jun; Tang, Yong-Min; Song, Hua; Yang, Shi-Long; Xu, Wei-Qun; Shi, Shu-Wen; Zhao, Ning; Liao, Chan

    2013-11-01

    Although many inflammatory cytokines are prognostic in sepsis, the utility of cytokines in evaluating disease severity in pediatric hematology/oncology patients with septic shock was rarely studied. On the other hand, a single particular cytokine is far from ideal in guiding therapeutic intervention, but combination of multiple biomarkers improves the accuracy. In this prospective observational study, 111 episodes of septic shock in pediatric hematology/oncology patients were enrolled from 2006 through 2012. Blood samples were taken for inflammatory cytokine measurement by cytometric bead array (CBA) technology at the initial onset of septic shock. Interleukin (IL)-6 and IL-10 were significantly elevated in majority of patients, while tumor necrosis factor (TNF)-α and interferon (IFN)-γ were markedly increased in patients with high pediatric index of mortality 2 (PIM2) score and non-survivors. All the four cytokines paralleled the PIM2 score and differentially correlated with hemodynamic disorder and fatal outcomes. The pediatric multiplex cytokine score (PMCS), which integrated the four cytokines into one score system, was related to hemodynamic disorder and mortality as well, but showed more powerful prediction ability than each of the four cytokines. PMCS was an independent predictive factor for fatal outcome, presenting similar discriminative power with PIM2, with accuracy of 0.83 (95% CI, 0.71-0.94). In conclusion, this study develops a cytokine scoring system based on CBA technique, which performs well in disease severity and fatality prediction in pediatric hematology/oncology patients with septic shock.

  6. Evolution of cytokines and inflammatory biomarkers during infliximab induction therapy and the impact of inflammatory burden on primary response in patients with Crohn's disease.

    PubMed

    Billiet, Thomas; Cleynen, Isabelle; Ballet, Vera; Claes, Karolien; Princen, Fred; Singh, Sharat; Ferrante, Marc; Van Assche, Gert; Gils, Ann; Vermeire, Severine

    2017-10-01

    Primary non-response to infliximab in Crohn's disease is still incompletely understood. Our aim was to further characterize the role of inflammatory burden during infliximab induction therapy. We studied a well-characterized cohort of 201 anti-TNF naive Crohn's disease patients treated with infliximab 5mg/kg at week 0, 2, 6 and 14 who had serum samples drawn just before every infusion. All serum samples were analyzed for CRP, albumin, TNF, IFN-γ, IL-6, IL-8, IL-10, infliximab trough concentrations (in-house-developed ELISA) and antibodies to infliximab (HMSA, Prometheus Laboratories Inc., San Diego, CA). Primary non-response was defined as the absence of clinical improvement at week 14. The incidence of primary non-response to infliximab was 8% (n = 16). IL-8 concentrations at baseline were higher (p = .01) and albumin at week 6 was lower in primary non-responders (p = .01) compared to responders. During induction, IFN-γ and IL-6 concentrations decreased significantly at week 2 and week 6 in responders compared to primary non-responders (p < .05). Serum TNF increased significantly after each infliximab infusion and this increase from week 0 to week 14 was more pronounced in responders (p = .03). Multiple logistic regression identified TNF/CRP ratio at baseline as predictive for primary non-response to infliximab at week 14 (OR 2.8 (95% CI 1.4-5.5; p = .003)). In this intensively sampled cohort of Crohn's disease patients, we demonstrate that inflammatory burden is more determining for primary non-response than drug exposure or immunogenicity. Our findings furthermore suggest that the contribution of TNF in inflammation might be higher in primary non-response, contradicting the non-TNF-driven concept.

  7. New serological biomarkers of inflammatory bowel disease

    PubMed Central

    Li, Xuhang; Conklin, Laurie; Alex, Philip

    2008-01-01

    Serological biomarkers in inflammatory bowel disease (IBD) are a rapidly expanding list of non-invasive tests for objective assessments of disease activity, early diagnosis, prognosis evaluation and surveillance. This review summarizes both old and new biomarkers in IBD, but focuses on the development and characterization of new serological biomarkers (identified since 2007). These include five new anti-glycan antibodies, anti-chitobioside IgA (ACCA), anti-laminaribioside IgG (ALCA), anti-manobioside IgG (AMCA), and antibodies against chemically synthesized (Σ) two major oligomannose epitopes, Man α-1,3 Man α-1,2 Man (ΣMan3) and Man α-1,3 Man α-1,2 Man α-1,2 Man (ΣMan4). These new biomarkers serve as valuable complementary tools to existing biomarkers not only in differentiating Crohn’s disease (CD), ulcerative colitis (UC), normal and other non-IBD gut diseases, but also in predicting disease involvement (ileum vs colon), IBD risk (as subclinical biomarkers), and disease course (risk of complication and surgery). Interestingly, the prevalence of the antiglycan antibodies, including anti-Saccharomyces cerevisiae antibodies (ASCA), ALCA and AMCA, was found to be associated with single nucleotide polymorphisms (SNPs) of IBD susceptible genes such as NOD2/CARD15, NOD1/CARD4, toll-like receptors (TLR) 2 and 4, and β-defensin-1. Furthermore, a gene dosage effect was observed: anti-glycan positivity became more frequent as the number of NOD2/CARD15 SNPS increased. Other new serum/plasma IBD biomarkers reviewed include ubiquitination factor E4A (UBE4A), CXCL16 (a chemokine), resistin, and apolipoprotein A-IV. This review also discusses the most recent studies in IBD biomarker discovery by the application of new technologies such as proteomics, fourier transform near-infrared spectroscopy, and multiplex enzyme-linked immunosorbent assay (ELISA)’s (with an emphasis on cytokine/chemokine profiling). Finally, the prospects of developing more clinically useful

  8. New serological biomarkers of inflammatory bowel disease.

    PubMed

    Li, Xuhang; Conklin, Laurie; Alex, Philip

    2008-09-07

    Serological biomarkers in inflammatory bowel disease (IBD) are a rapidly expanding list of non-invasive tests for objective assessments of disease activity, early diagnosis, prognosis evaluation and surveillance. This review summarizes both old and new biomarkers in IBD, but focuses on the development and characterization of new serological biomarkers (identified since 2007). These include five new anti-glycan antibodies, anti-chitobioside IgA (ACCA), anti-laminaribioside IgG (ALCA), anti-manobioside IgG (AMCA), and antibodies against chemically synthesized (Sigma) two major oligomannose epitopes, Man alpha-1,3 Man alpha-1,2 Man (SigmaMan3) and Man alpha-1,3 Man alpha-1,2 Man alpha-1,2 Man (SigmaMan4). These new biomarkers serve as valuable complementary tools to existing biomarkers not only in differentiating Crohn's disease (CD), ulcerative colitis (UC), normal and other non-IBD gut diseases, but also in predicting disease involvement (ileum vs colon), IBD risk (as subclinical biomarkers), and disease course (risk of complication and surgery). Interestingly, the prevalence of the antiglycan antibodies, including anti-Saccharomyces cerevisiae antibodies (ASCA), ALCA and AMCA, was found to be associated with single nucleotide polymorphisms (SNPs) of IBD susceptible genes such as NOD2/CARD15, NOD1/CARD4, toll-like receptors (TLR) 2 and 4, and beta-defensin-1. Furthermore, a gene dosage effect was observed: anti-glycan positivity became more frequent as the number of NOD2/CARD15 SNPS increased. Other new serum/plasma IBD biomarkers reviewed include ubiquitination factor E4A (UBE4A), CXCL16 (a chemokine), resistin, and apolipoprotein A-IV. This review also discusses the most recent studies in IBD biomarker discovery by the application of new technologies such as proteomics, fourier transform near-infrared spectroscopy, and multiplex enzyme-linked immunosorbent assay (ELISA)'s (with an emphasis on cytokine/chemokine profiling). Finally, the prospects of developing more

  9. Novel ageing-biomarker discovery using data-intensive technologies.

    PubMed

    Griffiths, H R; Augustyniak, E M; Bennett, S J; Debacq-Chainiaux, F; Dunston, C R; Kristensen, P; Melchjorsen, C J; Navarrete, Santos A; Simm, A; Toussaint, O

    2015-11-01

    Ageing is accompanied by many visible characteristics. Other biological and physiological markers are also well-described e.g. loss of circulating sex hormones and increased inflammatory cytokines. Biomarkers for healthy ageing studies are presently predicated on existing knowledge of ageing traits. The increasing availability of data-intensive methods enables deep-analysis of biological samples for novel biomarkers. We have adopted two discrete approaches in MARK-AGE Work Package 7 for biomarker discovery; (1) microarray analyses and/or proteomics in cell systems e.g. endothelial progenitor cells or T cell ageing including a stress model; and (2) investigation of cellular material and plasma directly from tightly-defined proband subsets of different ages using proteomic, transcriptomic and miR array. The first approach provided longitudinal insight into endothelial progenitor and T cell ageing. This review describes the strategy and use of hypothesis-free, data-intensive approaches to explore cellular proteins, miR, mRNA and plasma proteins as healthy ageing biomarkers, using ageing models and directly within samples from adults of different ages. It considers the challenges associated with integrating multiple models and pilot studies as rational biomarkers for a large cohort study. From this approach, a number of high-throughput methods were developed to evaluate novel, putative biomarkers of ageing in the MARK-AGE cohort. Crown Copyright © 2015. Published by Elsevier Ireland Ltd. All rights reserved.

  10. Biomarkers in bipolar disorder: a positional paper from the International Society for Bipolar Disorders Biomarkers Task Force.

    PubMed

    Frey, Benicio N; Andreazza, Ana C; Houenou, Josselin; Jamain, Stéphane; Goldstein, Benjamin I; Frye, Mark A; Leboyer, Marion; Berk, Michael; Malhi, Gin S; Lopez-Jaramillo, Carlos; Taylor, Valerie H; Dodd, Seetal; Frangou, Sophia; Hall, Geoffrey B; Fernandes, Brisa S; Kauer-Sant'Anna, Marcia; Yatham, Lakshmi N; Kapczinski, Flavio; Young, L Trevor

    2013-04-01

    Although the etiology of bipolar disorder remains uncertain, multiple studies examining neuroimaging, peripheral markers and genetics have provided important insights into the pathophysiologic processes underlying bipolar disorder. Neuroimaging studies have consistently demonstrated loss of gray matter, as well as altered activation of subcortical, anterior temporal and ventral prefrontal regions in response to emotional stimuli in bipolar disorder. Genetics studies have identified several potential candidate genes associated with increased risk for developing bipolar disorder that involve circadian rhythm, neuronal development and calcium metabolism. Notably, several groups have found decreased levels of neurotrophic factors and increased pro-inflammatory cytokines and oxidative stress markers. Together these findings provide the background for the identification of potential biomarkers for vulnerability, disease expression and to help understand the course of illness and treatment response. In other areas of medicine, validated biomarkers now inform clinical decision-making. Although the findings reviewed herein hold promise, further research involving large collaborative studies is needed to validate these potential biomarkers prior to employing them for clinical purposes. Therefore, in this positional paper from the ISBD-BIONET (biomarkers network from the International Society for Bipolar Disorders), we will discuss our view of biomarkers for these three areas: neuroimaging, peripheral measurements and genetics; and conclude the paper with our position for the next steps in the search for biomarkers for bipolar disorder.

  11. Biomarkers that discriminate multiple myeloma patients with or without skeletal involvement detected using SELDI-TOF mass spectrometry and statistical and machine learning tools.

    PubMed

    Bhattacharyya, Sudeepa; Epstein, Joshua; Suva, Larry J

    2006-01-01

    Multiple Myeloma (MM) is a severely debilitating neoplastic disease of B cell origin, with the primary source of morbidity and mortality associated with unrestrained bone destruction. Surface enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) was used to screen for potential biomarkers indicative of skeletal involvement in patients with MM. Serum samples from 48 MM patients, 24 with more than three bone lesions and 24 with no evidence of bone lesions were fractionated and analyzed in duplicate using copper ion loaded immobilized metal affinity SELDI chip arrays. The spectra obtained were compiled, normalized, and mass peaks with mass-to-charge ratios (m/z) between 2000 and 20,000 Da identified. Peak information from all fractions was combined together and analyzed using univariate statistics, as well as a linear, partial least squares discriminant analysis (PLS-DA), and a non-linear, random forest (RF), classification algorithm. The PLS-DA model resulted in prediction accuracy between 96-100%, while the RF model was able to achieve a specificity and sensitivity of 87.5% each. Both models as well as multiple comparison adjusted univariate analysis identified a set of four peaks that were the most discriminating between the two groups of patients and hold promise as potential biomarkers for future diagnostic and/or therapeutic purposes.

  12. Bioanalytical Chemistry of Cytokines-A Review

    PubMed Central

    Stenken, Julie A.; Poschenrieder, Andreas J.

    2014-01-01

    Cytokines are bioactive proteins produced by many different cells of the immune system. Due to their role in different inflammatory disease states and maintaining homeostasis, there is enormous clinical interest in the quantitation of cytokines. The typical standard methods for quantitation of cytokines are immunoassay-based techniques including enzyme-linked immusorbent assays (ELISA) and bead-based immunoassays read by either standard or modified flow cytometers. A review of recent developments in analytical methods for measurements of cytokine proteins is provided. This review briefly covers cytokine biology and the analysis challenges associated with measurement of these biomarker proteins for understanding both health and disease. New techniques applied to immunoassay-based assays are presented along with the uses of aptamers, electrochemistry, mass spectrometry, optical resonator-based methods. Methods used for elucidating the release of cytokines from single cells as well as in vivo collection methods are described. PMID:25467452

  13. Bioanalytical chemistry of cytokines--a review.

    PubMed

    Stenken, Julie A; Poschenrieder, Andreas J

    2015-01-01

    Cytokines are bioactive proteins produced by many different cells of the immune system. Due to their role in different inflammatory disease states and maintaining homeostasis, there is enormous clinical interest in the quantitation of cytokines. The typical standard methods for quantitation of cytokines are immunoassay-based techniques including enzyme-linked immusorbent assays (ELISA) and bead-based immunoassays read by either standard or modified flow cytometers. A review of recent developments in analytical methods for measurements of cytokine proteins is provided. This review briefly covers cytokine biology and the analysis challenges associated with measurement of these biomarker proteins for understanding both health and disease. New techniques applied to immunoassay-based assays are presented along with the uses of aptamers, electrochemistry, mass spectrometry, optical resonator-based methods. Methods used for elucidating the release of cytokines from single cells as well as in vivo collection methods are described.

  14. Neuropsychiatric aspects of cytokines research: an overview.

    PubMed

    Malek-Ahmadi, P

    1996-01-01

    Cytokines are a group of proteins primarily synthesized by various immune cells. They have multiple functions within the immune system and have been implicated in a number of disease states. There is growing evidence that some cytokines are also synthesized in the central nervous system. Taking into consideration that some cytokines are also capable of inducing behavioral effects, it has been suggested that cytokines may play a role in some psychiatric and neurologic disorders.

  15. Enhancing the 'real world' prediction of cardiovascular events and major bleeding with the CHA2DS2-VASc and HAS-BLED scores using multiple biomarkers.

    PubMed

    Roldán, Vanessa; Rivera-Caravaca, José Miguel; Shantsila, Alena; García-Fernández, Amaya; Esteve-Pastor, María Asunción; Vilchez, Juan Antonio; Romera, Marta; Valdés, Mariano; Vicente, Vicente; Marín, Francisco; Lip, Gregory Y H

    2017-09-18

    value of CHA2DS2-VASc for cardiovascular events, but not the predictive value of HAS-BLED for major bleeding. Reclassification analyses did not show improvement adding multiple biomarkers. Despite the improvement observed, the added predictive advantage is marginal and the clinical usefulness and net benefit over current clinical scores is lower.

  16. Autoantibodies to myelin basic protein (MBP) in healthy individuals and in patients with multiple sclerosis: a role in regulating cytokine responses to MBP.

    PubMed

    Hedegaard, Chris J; Chen, Ning; Sellebjerg, Finn; Sørensen, Per Soelberg; Leslie, R Graham Q; Bendtzen, Klaus; Nielsen, Claus H

    2009-09-01

    Anti-myelin basic protein (-MBP) autoantibodies have generally been considered to be absent from sera from healthy individuals, but to be detectable in sera from some patients with multiple sclerosis (MS). However, their pathogenic role is uncertain. We demonstrate the presence of MBP-reactive autoantibodies in sera from 17 healthy individuals and 17 MS patients. The addition of MBP to the sera caused a dose-dependent deposition of MBP and co-deposition of immunoglobulin M (IgM) and fragments of complement component 3 (C3) on allogeneic monocytes. Calcium chelation abrogated the immunoglobulin deposition, indicating that formation of complement-activating immune complexes played a role in the binding process. Furthermore, MBP elicited tumour necrosis factor (TNF)-alpha and interleukin (IL)-10 production by normal mononuclear cells in the presence of serum from both patients and controls. Mononuclear cells from MS patients responded to MBP with the production of interferon (IFN)-gamma, IL-4 and IL-5, in addition to TNF-alpha and IL-10. The production of IFN-gamma and IL-5 was increased when MS serum was added rather than normal serum. Denaturation of MBP strongly inhibited MBP deposition and the MBP-induced IgM deposition and cytokine production, indicating that these events were facilitated by autoantibodies recognizing conformational epitopes on MBP. We infer that MBP-elicited TNF-alpha and IL-10 responses are promoted to equal extents by naturally occurring MBP autoantibodies and autoantibodies contained in MS sera. However, the latter seem to be more efficient in facilitating the production of IFN-gamma and IL-5.

  17. Can biomarkers help us hit targets in difficult-to-treat asthma?

    PubMed

    Fricker, Michael; Heaney, Liam G; Upham, John W

    2017-04-01

    Biomarkers may be a key foundation for the precision medicine of the future. In this article, we review current knowledge regarding biomarkers in difficult-to-treat asthma and their ability to guide the use of both conventional asthma therapies and novel (targeted) therapies. Biomarkers (as measured by tests including prednisolone and cortisol assays and the fractional exhaled nitric oxide (NO) suppression test) show promise in the assessment and management of non-adherence to inhaled and oral corticosteroids. Multiple markers of type 2 inflammation have been developed, including eosinophils in sputum and blood, exhaled NO, serum IgE and periostin. Although these show potential in guiding the selection of novel interventions for refractory type 2 inflammation in asthma, and in determining if the desired response is being achieved, it is becoming clear that different biomarkers reflect distinct components of the complex type 2 inflammatory pathways. Less progress has been made in identifying biomarkers for use in difficult-to-treat asthma that is not associated with type 2 inflammation. The future is likely to see further biomarker discovery, direct measurements of individual cytokines rather than surrogates of their activity and the increasing use of biomarkers in combination. If the promise of biomarkers is to be fulfilled, they will need to provide useful information that aids clinical decision-making, rather than being 'just another test' for clinicians to order.

  18. Encapsulated Solid-Liquid Phase Change Nanoparticles as Thermal Barcodes for Highly Sensitive Detections of Multiple Lung Cancer Biomarkers

    DTIC Science & Technology

    2012-10-01

    lead alloy , indium, and bismuth). Figure 5A shows the DSC curves of indium nanoparticles attached onto aluminum plates after detecting rabbit IgG in...transduction mechanism based on solid- liquid phase change nanoparticles works for the detection of multiple proteins. A series of metal and alloy ...for the detection of multiple proteins. A series of metal and alloy nanoparticles have been made and used for the detection of multiple proteins

  19. Z-Scan Analysis: a New Method to Determine the Oxidative State of Low-Density Lipoprotein and Its Association with Multiple Cardiometabolic Biomarkers

    NASA Astrophysics Data System (ADS)

    de Freitas, Maria Camila Pruper; Figueiredo Neto, Antonio Martins; Giampaoli, Viviane; da Conceição Quintaneiro Aubin, Elisete; de Araújo Lima Barbosa, Milena Maria; Damasceno, Nágila Raquel Teixeira

    2016-04-01

    The great atherogenic potential of oxidized low-density lipoprotein has been widely described in the literature. The objective of this study was to investigate whether the state of oxidized low-density lipoprotein in human plasma measured by the Z-scan technique has an association with different cardiometabolic biomarkers. Total cholesterol, high-density lipoprotein cholesterol, triacylglycerols, apolipoprotein A-I and apolipoprotein B, paraoxonase-1, and glucose were analyzed using standard commercial kits, and low-density lipoprotein cholesterol was estimated using the Friedewald equation. A sandwich enzyme-linked immunosorbent assay was used to detect electronegative low-density lipoprotein. Low-density lipoprotein and high-density lipoprotein sizes were determined by Lipoprint® system. The Z-scan technique was used to measure the non-linear optical response of low-density lipoprotein solution. Principal component analysis and correlations were used respectively to resize the data from the sample and test association between the θ parameter, measured with the Z-scan technique, and the principal component. A total of 63 individuals, from both sexes, with mean age 52 years (±11), being overweight and having high levels of total cholesterol and low levels of high-density lipoprotein cholesterol, were enrolled in this study. A positive correlation between the θ parameter and more anti-atherogenic pattern for cardiometabolic biomarkers together with a negative correlation for an atherogenic pattern was found. Regarding the parameters related with an atherogenic low-density lipoprotein profile, the θ parameter was negatively correlated with a more atherogenic pattern. By using Z-scan measurements, we were able to find an association between oxidized low-density lipoprotein state and multiple cardiometabolic biomarkers in samples from individuals with different cardiovascular risk factors.

  20. Association of cytokine and matrix metalloproteinase profiles with disease activity and function in ankylosing spondylitis

    PubMed Central

    2012-01-01

    Introduction The pathology of ankylosing spondylitis (AS) suggests that certain cytokines and matrix metalloproteinases (MMPs) might provide useful markers of disease activity. Serum levels of some cytokines and MMPs have been found to be elevated in active disease, but there is a general lack of information about biomarker profiles in AS and how these are related to disease activity and function. The purpose of this study was to investigate whether clinical measures of disease activity and function in AS are associated with particular profiles of circulating cytokines and MMPs. Methods Measurement of 30 cytokines, five MMPs and four tissue inhibitors of metalloproteinases was carried out using Luminex® technology on a well-characterised population of AS patients (n = 157). The relationship between biomarker levels and measures of disease activity (Bath ankylosing spondylitis disease activity index (BASDAI)), function (Bath ankylosing spondylitis functional index) and global health (Bath ankylosing spondylitis global health) was investigated. Principal component analysis was used to reduce the large number of biomarkers to a smaller set of independent components, which were investigated for their association with clinical measures. Further analyses were carried out using hierarchical clustering, multiple regression or multivariate logistic regression. Results Principal component analysis identified eight clusters consisting of various combinations of cytokines and MMPs. The strongest association with the BASDAI was found with a component consisting of MMP-8, MMP-9, hepatocyte growth factor and CXCL8, and was independent of C-reactive protein levels. This component was also associated with current smoking. Hierarchical clustering revealed two distinct patient clusters that could be separated on the basis of MMP levels. The high MMP cluster was associated with increased C-reactive protein, the BASDAI and the Bath ankylosing spondylitis functional index. Conclusions

  1. Inflammatory cytokines.

    PubMed

    Cerami, A

    1992-01-01

    The immune system produces cytokines and other humoral factors to protect the host when threatened by inflammatory agents, microbial invasion, or injury. In some cases this complex defense network successfully restores normal homeostasis, but at other times the overproduction of immunoregulatory mediators may actually prove deleterious to the host. Some examples of immune system-mediated injury have been extensively investigated including anaphylactic shock, autoimmune disease, and immune complex disorders. More recently it has become clear that the cytokine cachectin/tumor necrosis factor (TNF) occupies a key role in the pathophysiology associated with diverse inflammatory states and other serious illnesses including septic shock and cachexia. For example, when cachectin/TNF is produced by resident macrophages during early microbial infection, it mediates an inflammatory response that may alienate and repel the attacking organisms. If the infection spreads, however, the subsequent release of large quantities of cachectin/TNF into the circulation may be catastrophic and trigger a state of lethal shock. These toxic effects occur by direct action of TNF on host cells and by the interaction with a cascade of other endogenous mediators including interleukin-1 and interferon-gamma. The biology of cachectin/TNF will be reviewed, along with the potential for modulating the effects of this pluripotent molecule in a variety of pathologic states.

  2. [Cytokines in bone diseases. What is cytokine?].

    PubMed

    Murakami, Yousuke; Kohsaka, Hitoshi

    2010-10-01

    Cytokines have an essential role for cell-cell communication. They can regulate cell proliferation, differentiation, survival, and function. Interaction of cell surface receptor with cytokines is necessary for control of physiological responses. Activation of cytokine receptors transduces specific signal in the receptor-expressing cells, resulting that cytokines can regulate specific cell population. Thus, cytokines contribute directly or indirectly to morphogenesis, host defense and immune response, play critical roles for homeostasis and development.

  3. Biological hypotheses and biomarkers of bipolar disorder.

    PubMed

    Sigitova, Ekaterina; Fišar, Zdeněk; Hroudová, Jana; Cikánková, Tereza; Raboch, Jiří

    2017-02-01

    The most common mood disorders are major depressive disorders and bipolar disorders (BD). The pathophysiology of BD is complex, multifactorial, and not fully understood. Creation of new hypotheses in the field gives impetus for studies and for finding new biomarkers for BD. Conversely, new biomarkers facilitate not only diagnosis of a disorder and monitoring of biological effects of treatment, but also formulation of new hypotheses about the causes and pathophysiology of the BD. BD is characterized by multiple associations between disturbed brain development, neuroplasticity, and chronobiology, caused by: genetic and environmental factors; defects in apoptotic, immune-inflammatory, neurotransmitter, neurotrophin, and calcium-signaling pathways; oxidative and nitrosative stress; cellular bioenergetics; and membrane or vesicular transport. Current biological hypotheses of BD are summarized, including related pathophysiological processes and key biomarkers, which have been associated with changes in genetics, systems of neurotransmitter and neurotrophic factors, neuroinflammation, autoimmunity, cytokines, stress axis activity, chronobiology, oxidative stress, and mitochondrial dysfunctions. Here we also discuss the therapeutic hypotheses and mechanisms of the switch between depressive and manic state. © 2016 The Authors. Psychiatry and Clinical Neurosciences © 2016 Japanese Society of Psychiatry and Neurology.

  4. High multi-cytokine levels are not a predictive marker of alloimmunization in transfused sickle cell disease patients.

    PubMed

    Tatari-Calderone, Zohreh; Fasano, Ross M; Miles, Megan R; Pinto, Ligia A; Luban, Naomi L C; Vukmanovic, Stanislav

    2014-07-01

    Patients with sickle cell disease (SCD) receive multiple red blood cell (RBC) transfusions for both prevention of and therapy for disease-related complications. In some patients, transfusion results in development of both allo- and auto-antibodies to RBC antigens. What precipitates the antibody formation is currently unclear. It has been hypothesized that a pro-inflammatory state preceding the therapeutic transfusion may be a predisposing factor. Plasma levels of ten cytokines were evaluated upon recruitment to the study of 83 children with SCD undergoing therapeutic RBC transfusions. The levels of cytokines were correlated with development of anti-RBC antibodies prior, or during seven years post recruitment. Twelve subjects displayed significantly higher levels of all cytokines examined, with pro-, as well as anti-inflammatory properties. Surprisingly, the elevated levels of cytokines were preferentially found in patients without anti-RBC allo- and/or auto-antibodies. Further, presence of high cytokine levels was not predictive of anti-RBC antibody development during the subsequent seven year follow up. These data suggest that the increased concentration of multiple cytokines is not a biomarker of either the presence of or susceptibility to the development of RBC alloimmunization.

  5. Biomarkers present in asphaltenes

    SciTech Connect

    Philp, R.P.

    1985-01-01

    The significance and distribution of biomarkers in sediments, source rocks and crude oils are well documented in the literature. Little attention has been directed towards the biomarkers that are present in the asphaltene fractions of crude oils and source rock extracts. Asphaltene fractions by definition are insoluble in certain solvents and consist of high molecular components which makes them difficult to analyze by techniques commonly used to characterize the soluble extracts. Asphaltenes are ideally suited for analysis by microscale pyrolysis techniques (py) combined with gas chromatography (GC) and gas chromatography-mass spectrometry (GC-MS). Utilization of the multiple ion detection technique in conjunction with the py-GC-MS analyses permits the distribution of the steranes, triterpanes and other biomarker produced by pyrolysis of the asphaltenes to be easily determined. It is proposed in this paper to discuss the pyrolysis of asphaltene from a variety of source rocks and analysis of the biomarkers, released by the pyrolysis. These biomarkers distributions can be used to obtain information on source and maturity of the organic matter in a similar manner to using the soluble biomarkers. It is proposed to discuss the asphaltene biomarker distributions and also to speculate as to why certain biomarkers are present only in the extracts and asphaltenes and not produced by pyrolysis of the kerogens.

  6. HMGB1 promotes the secretion of multiple cytokines and potentiates the osteogenic differentiation of mesenchymal stem cells through the Ras/MAPK signaling pathway

    PubMed Central

    Feng, Lin; Xue, Deting; Chen, Erman; Zhang, Wei; Gao, Xiang; Yu, Jiawei; Feng, Yadong; Pan, Zhijun

    2016-01-01

    High mobility group box 1 (HMGB1) protein has been previously been detected in the inflammatory microenvironment of bone fractures. It is well known that HMGB1 acts as a chemoattractant to mesenchymal stem cells (MSCs). In the present study, the effects of HMGB1 on cytokine secretion from MSCs were determined, and the molecular mechanisms underlying these effects of HMGB1 on osteogenic differentiation were elucidated. To detect cytokine secretion, antibody array assays were performed, which demonstrated that HGMB1 induced the differential secretion of cytokines that are predominantly associated with cell development, regulation of growth and cell migration, stress responses, and immune system functions. Moreover, the secretion of epidermal growth factor receptor (EGFR) was significantly upregulated by HMGB1. The EGFR-activated Ras/MAPK pathway regulates the osteogenic differentiation of MSCs. These results suggested that HMGB1 enhances the secretion of various cytokines by MSCs and promotes osteogenic differentiation via the Ras/MAPK signaling pathway. The present study may provide a theoretical basis for the development of novel techniques for the treatment of bone fractures in the future. PMID:28105126

  7. Macrophage migration inhibitory factor (MIF): a promising biomarker

    PubMed Central

    Grieb, Gerrit; Merk, Melanie; Bernhagen, Jürgen; Bucala, Richard

    2011-01-01

    Macrophage migration inhibitory (MIF) factor is an immunoregulatory cytokine whose effect on arresting random immune cell movement was recognized several decades ago. Despite its historic name, MIF also has a direct chemokine-like function and promotes cell recruitment. Multiple clinical studies have pointed to the utility of MIF as a biomarker for different diseases that have an inflammatory component; these include systemic infections and sepsis, autoimmune diseases, cancer, and metabolic disorders such as type 2 diabetes and obesity. The identification of functional promoter polymorphisms in the MIF gene (MIF) and their association with the susceptibility or severity of different diseases has served not only to validate MIF’s role in disease development but opened the possibility of using MIF genotype information to better predict risk and outcome. In this article, we review the clinical data of MIF and discuss its potential as a biomarker for different disease applications. PMID:20520854

  8. Wolfberry Water Soluble Phytochemicals Down-Regulate ER Stress Biomarkers and Modulate Multiple Signaling Pathways Leading To Inhibition of Proliferation and Induction of Apoptosis in Jurkat Cells

    PubMed Central

    Jiang, Yu; Zhang, Yunong; Wark, Logan; Ortiz, Edlin; Lim, Soyoung; He, Hui; Wang, Weiqun; Medeiros, Denis; Lin, Dingbo

    2012-01-01

    Phytochemicals have received much recent attention in cancer prevention through simultaneous targeting multiple pathways in the disease progression. Here we determined that wolfberry phytochemicals was chemopreventive on the leukemic Jurkat cell. The water soluble wolfberry fractions (i.e., wolfberry phytochemicals) were enriched in carbohydrates (73.4 ± 4.5 % (w/w)), polyphenolics (1555 ± 112 mg quercetin equivalent/100 g freeze dry powder, including 213 mg rutin/100 g freeze dry powder), and had enhanced antioxidant activity (7771 ± 207 μM Trolox equivalent/100 g freeze dry powder). Wolfberry phytochemicals, but not purified wolfberry polysaccharide fractions, inhibited Jurkat cell proliferation, induced cycle arrest at the G2/M phase in a dose dependent manner starting at 1 mg/ml for 48 h. Wolfberry phytochemicals eliminated cellular reactive oxygen species, declined expression of endoplasmic reticulum (ER) stress biomarkers, including glucose regulated protein 78, inositol-requiring protein 1(IRE1), activating transcription factor 6 (ATF6), protein kinase RNA-like ER kinase (PERK), and c/EBP-homologous protein, and induced activation of AMP activated protein kinase, stabilization of β-catenin, and inhibition of NFκB, and AKT activity. Simultaneous siRNA knockdown of ATF6, IRE1 and PERK caused inhibition of cell proliferation and induction of apoptosis. Data suggested that ER stress and multiple survival/apoptosis signaling pathways were modulated by wolfberry phytochemicals during the apoptotic progression. Consumption of wolfberry could be an efficacious dietary strategy for preventing leukemia. PMID:22685690

  9. Using 'swallow-tail' sign and putaminal hypointensity as biomarkers to distinguish multiple system atrophy from idiopathic Parkinson's disease: A susceptibility-weighted imaging study.

    PubMed

    Wang, Na; Yang, HuaGuang; Li, ChengBo; Fan, GuoGuang; Luo, XiaoGuang

    2017-08-01

    To investigate the value of 'swallow-tail' sign and putaminal hypointensity on 3 T susceptibility-weighted imaging (SWI) for distinguishing multiple system atrophy (MSA) from idiopathic Parkinson's disease (IPD). Three groups - 39 MSA patients, 18 IPD patients,and 31 healthy controls (HCs) - were administered a 3 T SWI sequence to evaluate 'swallow-tail' sign and putaminal hypointensity using visual scales from 0 to 2 and 0 to 3 scores, respectively. The diagnostic accuracy of the two signs separately and combined was calculated using a receiver operating characteristic curve, with clinical diagnosis as the gold standard. The scores of 'swallow-tail' sign were lower in IPD than in MSA or in HCs, as well as for putaminal hypointensity in IPD or HCs than in MSA (p < 0.05). The sensitivity and specificity of 'swallow-tail' sign and putaminal hypointensity were 87.9% and 83.3%, and 35.9% and 100%, respectively, in the respective patient groups. The area under the curve of combined signs was increased from 0.85 ('swallow tail') or 0.68 (putaminal hypointensity) to 0.93. The combination of 'swallow-tail' sign and putaminal hypointensity can increase the accuracy of discriminating between MSA and IPD. • Differential diagnosis of MSA and IPD is still challenging in clinical practice. • Absence of 'swallow-tail' sign is a valuable biomarker for IPD on SWI. • Putaminal hypointensity is a valuable biomarker for MSA on SWI. • Combined 'swallow- tail' sign and putaminal hypointensity increase diagnostic accuracy.

  10. The Association of Multiple Biomarkers of Iron Metabolism and Type 2 Diabetes - the EPIC-InterAct Study

    PubMed Central

    Podmore, Clara; Meidtner, Karina; Schulze, Matthias B; Scott, Robert A; Ramond, Anna; Butterworth, Adam S; Di Angelantonio, Emanuele; Danesh, John; Arriola, Larraitz; Barricarte, Aurelio; Boeing, Heiner; Clavel-Chapelon, Françoise; Cross, Amanda J; Dahm, Christina C; Fagherazzi, Guy; Franks, Paul W; Gavrila, Diana; Grioni, Sara; Gunter, Marc J; Gusto, Gaelle; Jakszyn, Paula; Katzke, Verena; Key, Timothy J; Kühn, Tilman; Mattiello, Amalia; Nilsson, Peter M; Olsen, Anja; Overvad, Kim; Palli, Domenico; Quirós, J. Ramón; Rolandsson, Olov; Sacerdote, Carlotta; Sánchez-Cantalejo, Emilio; Slimani, Nadia; Sluijs, Ivonne; Spijkerman, Annemieke MW; Tjonneland, Anne; Tumino, Rosario; van der A, Daphne L; van der Schouw, Yvonne T; Feskens, Edith JM; Forouhi, Nita G; Sharp, Stephen J; Riboli, Elio; Langenberg, Claudia; Wareham, Nicholas J

    2016-01-01

    Objective Observational studies show an association between ferritin and type 2 diabetes (T2D), suggesting a role of high iron stores for T2D development. However, ferritin is influenced by factors other than iron stores, which is less the case for other biomarkers of iron metabolism. We investigate associations of ferritin, transferrin saturation (TSAT), serum iron and transferrin with T2D incidence, to clarify the role of iron in the pathogenesis of T2D. Research and Design Methods The EPIC-InterAct study includes 12,403 incident T2D cases and a representative sub-cohort of 16,154 individuals from a European cohort with 3.99 million person-years of follow-up. We studied the prospective association of ferritin, TSAT, serum iron and transferrin with incident T2D in 11,052 cases and a random sub-cohort of 15,182 individuals and assessed whether these associations differed by subgroups of the population. Results Higher levels of ferritin and transferrin were associated with a higher risk of T2D [HR in men and women, respectively: 1.07 (95% CI: 1.01; 1.12) and 1.12 (1.05; 1.19) per 100 μg/L higher ferritin level; 1.11 (1.00; 1.24) and 1.22 (1.12; 1.33) per 0.5 g/L higher transferrin level] after adjustment for age, centre, BMI, physical activity, smoking status, education, hsCRP, ALT and GGT. Elevated TSAT (≥45% versus <45%) was associated with a lower risk of T2D in women [0.68 (0.54; 0.86)] but was not statistically significantly associated in men [0.90 (0.75; 1.08)]. Serum iron was not associated with T2D. The association of ferritin with T2D was stronger among leaner individuals (pinteraction<0.01). Conclusions The pattern of association of TSAT and transferrin with T2D suggests that the underlying relationship between iron stores and T2D is more complex than the simple link suggested by the association of ferritin with T2D. PMID:26861925

  11. Association of Multiple Biomarkers of Iron Metabolism and Type 2 Diabetes: The EPIC-InterAct Study.

    PubMed

    Podmore, Clara; Meidtner, Karina; Schulze, Matthias B; Scott, Robert A; Ramond, Anna; Butterworth, Adam S; Di Angelantonio, Emanuele; Danesh, John; Arriola, Larraitz; Barricarte, Aurelio; Boeing, Heiner; Clavel-Chapelon, Françoise; Cross, Amanda J; Dahm, Christina C; Fagherazzi, Guy; Franks, Paul W; Gavrila, Diana; Grioni, Sara; Gunter, Marc J; Gusto, Gaelle; Jakszyn, Paula; Katzke, Verena; Key, Timothy J; Kühn, Tilman; Mattiello, Amalia; Nilsson, Peter M; Olsen, Anja; Overvad, Kim; Palli, Domenico; Quirós, J Ramón; Rolandsson, Olov; Sacerdote, Carlotta; Sánchez-Cantalejo, Emilio; Slimani, Nadia; Sluijs, Ivonne; Spijkerman, Annemieke M W; Tjonneland, Anne; Tumino, Rosario; van der A, Daphne L; van der Schouw, Yvonne T; Feskens, Edith J M; Forouhi, Nita G; Sharp, Stephen J; Riboli, Elio; Langenberg, Claudia; Wareham, Nicholas J

    2016-04-01

    Observational studies show an association between ferritin and type 2 diabetes (T2D), suggesting a role of high iron stores in T2D development. However, ferritin is influenced by factors other than iron stores, which is less the case for other biomarkers of iron metabolism. We investigated associations of ferritin, transferrin saturation (TSAT), serum iron, and transferrin with T2D incidence to clarify the role of iron in the pathogenesis of T2D. The European Prospective Investigation into Cancer and Nutrition-InterAct study includes 12,403 incident T2D cases and a representative subcohort of 16,154 individuals from a European cohort with 3.99 million person-years of follow-up. We studied the prospective association of ferritin, TSAT, serum iron, and transferrin with incident T2D in 11,052 cases and a random subcohort of 15,182 individuals and assessed whether these associations differed by subgroups of the population. Higher levels of ferritin and transferrin were associated with a higher risk of T2D (hazard ratio [HR] [95% CI] in men and women, respectively: 1.07 [1.01-1.12] and 1.12 [1.05-1.19] per 100 μg/L higher ferritin level; 1.11 [1.00-1.24] and 1.22 [1.12-1.33] per 0.5 g/L higher transferrin level) after adjustment for age, center, BMI, physical activity, smoking status, education, hs-CRP, alanine aminotransferase, and γ-glutamyl transferase. Elevated TSAT (≥45% vs. <45%) was associated with a lower risk of T2D in women (0.68 [0.54-0.86]) but was not statistically significantly associated in men (0.90 [0.75-1.08]). Serum iron was not associated with T2D. The association of ferritin with T2D was stronger among leaner individuals (Pinteraction < 0.01). The pattern of association of TSAT and transferrin with T2D suggests that the underlying relationship between iron stores and T2D is more complex than the simple link suggested by the association of ferritin with T2D. © 2016 by the American Diabetes Association. Readers may use this article as long as the

  12. High-Resolution Diffusion Tensor Spinal Cord MRI Measures as Biomarkers of Disability Progression in a Rodent Model of Progressive Multiple Sclerosis

    PubMed Central

    Gilli, Francesca; Chen, Xi; Pachner, Andrew R.; Gimi, Barjor

    2016-01-01

    Disease in the spinal cord is a major component of disability in multiple sclerosis, yet current techniques of imaging spinal cord injury are insensitive and nonspecific. This study seeks to remove this major impediment to research in multiple sclerosis and other spinal cord diseases by identifying reliable biomarkers of disability progression using diffusion tensor imaging (DTI), a magnetic resonance imaging technique, to evaluate the spinal cord in a model of multiple sclerosis, i.e. the Theiler’s Murine Encephalitis Virus-Induced Demyelinating Disease (TMEV-IDD). Mice with TMEV-IDD with varying levels of clinical disease were imaged using a 9.4T small animal MRI scanner. Axial diffusivity, radial diffusivity, and fractional anisotropy were calculated. Disability was assessed periodically using Rotarod assay and data were expressed as a neurological function index. Correlation was performed between DTI measurements and disability scores. TMEV-IDD mice displayed significant increased neurological deficits over time when compared with controls (p<0.0001). Concurrently, the values of fractional anisotropy and axial diffusivity were both decreased compared to controls (both p<0.0001), while radial diffusivity was increased (p<0.0001). Overall, fractional anisotropy changes were larger in white matter than in grey matter and differences were more pronounced in the ventral region. Lower disability scores were associated with decreased fractional anisotropy values measured in the ventral (r = 0.68; p<0.0001) and ventral-lateral (r = 0.70; p<0.0001) regions of the white matter. These data demonstrate that DTI measures of the spinal cord contribute to strengthening the association between neuroradiological markers and clinical disability, and support the use of DTI measures in spinal cord imaging in MS patients. PMID:27467829

  13. A regulation probability model-based meta-analysis of multiple transcriptomics data sets for cancer biomarker identification.

    PubMed

    Xie, Xin-Ping; Xie, Yu-Feng; Wang, Hong-Qiang

    2017-08-23

    Large-scale accumulation of omics data poses a pressing challenge of integrative analysis of multiple data sets in bioinformatics. An open question of such integrative analysis is how to pinpoint consistent but subtle gene activity patterns across studies. Study heterogeneity needs to be addressed carefully for this goal. This paper proposes a regulation probability model-based meta-analysis, jGRP, for identifying differentially expressed genes (DEGs). The method integrates multiple transcriptomics data sets in a gene regulatory space instead of in a gene expression space, which makes it easy to capture and manage data heterogeneity across studies from different laboratories or platforms. Specifically, we transform gene expression profiles into a united gene regulation profile across studies by mathematically defining two gene regulation events between two conditions and estimating their occurring probabilities in a sample. Finally, a novel differential expression statistic is established based on the gene regulation profiles, realizing accurate and flexible identification of DEGs in gene regulation space. We evaluated the proposed method on simulation data and real-world cancer datasets and showed the effectiveness and efficiency of jGRP in identifying DEGs identification in the context of meta-analysis. Data heterogeneity largely influences the performance of meta-analysis of DEGs identification. Existing different meta-analysis methods were revealed to exhibit very different degrees of sensitivity to study heterogeneity. The proposed method, jGRP, can be a standalone tool due to its united framework and controllable way to deal with study heterogeneity.

  14. Novel Approaches to Detect Serum Biomarkers for Clinical Response to Interferon-β Treatment in Multiple Sclerosis

    PubMed Central

    Gandhi, Kaushal S.; McKay, Fiona C.; Diefenbach, Eve; Crossett, Ben; Schibeci, Stephen D.; Heard, Robert N.; Stewart, Graeme J.; Booth, David R.; Arthur, Jonathan W.

    2010-01-01

    Interferon beta (IFNβ) is the most common immunomodulatory treatment for relapsing-remitting multiple sclerosis (RRMS). However, some patients fail to respond to treatment. In this study, we identified putative clinical response markers in the serum and plasma of people with multiple sclerosis (MS) treated with IFNβ. In a discovery-driven approach, we use 2D-difference gel electrophoresis (DIGE) to identify putative clinical response markers and apply power calculations to identify the sample size required to further validate those markers. In the process we have optimized a DIGE protocol for plasma to obtain cost effective and high resolution gels for effective spot comparison. APOA1, A2M, and FIBB were identified as putative clinical response markers. Power calculations showed that the current DIGE experiment requires a minimum of 10 samples from each group to be confident of 1.5 fold difference at the p<0.05 significance level. In a complementary targeted approach, Cytometric Beadarray (CBA) analysis showed no significant difference in the serum concentration of IL-6, IL-8, MIG, Eotaxin, IP-10, MCP-1, and MIP-1α, between clinical responders and non-responders, despite the association of these proteins with IFNβ treatment in MS. PMID:20463963

  15. Novel approaches to detect serum biomarkers for clinical response to interferon-beta treatment in multiple sclerosis.

    PubMed

    Gandhi, Kaushal S; McKay, Fiona C; Diefenbach, Eve; Crossett, Ben; Schibeci, Stephen D; Heard, Robert N; Stewart, Graeme J; Booth, David R; Arthur, Jonathan W

    2010-05-05

    Interferon beta (IFNbeta) is the most common immunomodulatory treatment for relapsing-remitting multiple sclerosis (RRMS). However, some patients fail to respond to treatment. In this study, we identified putative clinical response markers in the serum and plasma of people with multiple sclerosis (MS) treated with IFNbeta. In a discovery-driven approach, we use 2D-difference gel electrophoresis (DIGE) to identify putative clinical response markers and apply power calculations to identify the sample size required to further validate those markers. In the process we have optimized a DIGE protocol for plasma to obtain cost effective and high resolution gels for effective spot comparison. APOA1, A2M, and FIBB were identified as putative clinical response markers. Power calculations showed that the current DIGE experiment requires a minimum of 10 samples from each group to be confident of 1.5 fold difference at the p<0.05 significance level. In a complementary targeted approach, Cytometric Beadarray (CBA) analysis showed no significant difference in the serum concentration of IL-6, IL-8, MIG, Eotaxin, IP-10, MCP-1, and MIP-1alpha, between clinical responders and non-responders, despite the association of these proteins with IFNbeta treatment in MS.

  16. Cytokines for monitoring anti-tuberculous therapy: A systematic review.

    PubMed

    Clifford, Vanessa; Zufferey, Christel; Street, Alan; Denholm, Justin; Tebruegge, Marc; Curtis, Nigel

    2015-05-01

    The ability to monitor response to therapy for tuberculosis (TB) and confirm adequate treatment would be a major advance. The low reversion rate of interferon-gamma based assays means that they are unlikely to be useful for monitoring therapy. Several exploratory studies have evaluated the diagnostic potential of cytokine biomarkers other than interferon-gamma for monitoring anti-tuberculous therapy. A systematic review of these studies was performed to identify the most promising candidate biomarkers. TNF-α, IL-2, IL-6, IL-10 and IL-12 were the most extensively investigated cytokines. There was significant heterogeneity between studies in relation to study design and laboratory methodology, complicating direct comparisons. There was marked variation between studies in the observed changes during treatment for many of the biomarkers. Further longitudinal studies in sufficiently large patient cohorts with rigorous methodology are needed to determine the true potential of individual cytokine biomarkers, or combinations, for monitoring TB treatment.

  17. Biomarkers for Heart Failure in Asia.

    PubMed

    Richards, Arthur Mark

    2015-10-01

    Contributions from the Asian biomedical community to knowledge of biomarkers in heart failure have grown rapidly since 2000. Japan has made world-leading contributions in the discovery and application of cardiac natriuretic peptides as biomarkers in heart failure, but there has been rapid growth in reports from China. Contributions also come from Taiwan, South Korea, Singapore, and Hong Kong. Centers in Asia have established clinical cohorts providing powerful platforms for the discovery and validation of biomarkers in heart failure. This century, Asian enquiry into biomarkers in heart failure will include peptides, cytokines, metabolites, nucleic acids, and other analytes. Copyright © 2015 Elsevier Inc. All rights reserved.

  18. Posttranscriptional regulation of cytokine expression.

    PubMed

    Kovarik, Pavel; Ebner, Florian; Sedlyarov, Vitaly

    2017-01-01

    Expression of cytokines and chemokines is regulated at multiple steps during the transfer of the genetic information from DNA sequence to the functional protein. The multilayered control of cytokine expression reflects the need of the immune system to precisely and rapidly adjust the magnitude and duration of immune responses to external cues. Common features of the regulation of cytokine expression are temporal and highly dynamic changes in cytokine mRNA stability. Failures in the timing and extent of mRNA decay can result in disease. Recent advances in transcriptome-wide approaches began to shed light into the complex network of cis-acting sequence elements and trans-acting factors controlling mRNA stability. These approaches led to the discovery of novel unexpected paradigms but they also revealed new questions. This review will discuss the control of cytokine mRNA stability both in the context of high content approaches as well as focused mechanistic studies and animal models. The article highlights the need for systems biology approaches as important means to understand how cytokine mRNA decay helps maintain the immune and tissue homeostasis, and to explore options for therapeutical exploitation of mRNA stability regulation. Copyright © 2015 Elsevier Ltd. All rights reserved.

  19. Genetic biomarkers of depression

    PubMed Central

    Tamatam, Anand; Khanum, Farhath; Bawa, Amarinder Singh

    2012-01-01

    Depression is a term that has been used to describe a variety of ailments, ranging from minor to incapacitating. Clinically significant depression, termed as major depression, is a serious condition characterized not only by depressed mood but also by a cluster of somatic, cognitive, and motivational symptoms. Significant research efforts are aimed to understand the neurobiological as well as psychiatric disorders, and the evaluation of treatment of these disorders is still based solely on the assessment of symptoms. In order to identify the biological markers for depression, we have focused on gathering information on different factors responsible for depression including stress, genetic variations, neurotransmitters, and cytokines and chemokines previously suggested to be involved in the pathophysiology of depression. The present review illustrates the potential of biomarker profiling for psychiatric disorders, when conducted in large collections. The review highlighted the biomarker signatures for depression, warranting further investigation. PMID:22754217

  20. Plasma Biomarker Profiles Differ Depending on Breast Cancer Subtype but RANTES is Consistently Increased

    SciTech Connect

    Gonzales, Rachel M.; Daly, Don S.; Tan, Ruimin; Marks, Jeffrey R.; Zangar, Richard C.

    2011-07-01

    Background: Current biomarkers for breast cancer have little potential for detection. We determined if breast cancer subtypes influence circulating protein biomarkers. Methods: A sandwich-ELISA microarray platform was used to evaluate 23 candidate biomarkers in plasma samples that were obtained from subjects with either benign breast disease or invasive breast cancer. All plasma samples were collected at the time of biopsy, after a referral due to a suspicious screen (e.g., mammography). Cancer samples were evaluated based on breast cancer subtypes, as defined by the HER2 and estrogen receptor statuses. Results: Ten proteins were statistically altered in at least one breast cancer subtype, including four epidermal growth factor receptor ligands, two matrix metalloproteases, two cytokines, and two angiogenic factors. Only one cytokine, RANTES, was significantly increased (P<0.01 for each analysis) in all four subtypes, with areas under receiver operating characteristic curves (AUC) that ranged from 0.76 to 0.82, depending on cancer subtype. The best AUC values were observed for analyses that combined data from multiple biomarkers, with values ranging from 0.70 to 0.99, depending on the cancer subtype. Although the results for RANTES are consistent with previous publications, the multi-assay results need to be validated in independent sample sets. Conclusions: Different breast cancer subtypes produce distinct biomarker profiles, and circulating protein biomarkers have potential to differentiate between true and false positive screens for breast cancer. Impact: Subtype-specific biomarker panels may be useful for detecting breast cancer or as an adjunct assay to improve the accuracy of current screening methods.

  1. Assessment of intracellular cytokines and regulatory cells in patients with autoimmune diseases and primary immunodeficiencies - novel tool for diagnostics and patient follow-up.

    PubMed

    Osnes, Liv T; Nakken, Britt; Bodolay, Edit; Szodoray, Peter

    2013-08-01

    Serum and intracytoplasmic cytokines are mandatory in host defense against microbes, but also play a pivotal role in the pathogenesis of autoimmune diseases by initiating and perpetuating various cellular and humoral autoimmune processes. The intricate interplay and fine balance of pro- and anti-inflammatory processes drive, whether inflammation and eventually organ damage will occur, or the inflammatory cascade quenches. In the early and late, as well as inactive and active stages of autoimmune diseases, different cellular and molecular patterns can dominate in these patients. However, the simultaneous assessment of pro- and anti-inflammatory biomarkers aids to define the immunological state of a patient. A group of the most useful inflammatory biomarkers are cytokines, and with increasing knowledge during the last decade their role have been well-defined in patients with autoimmune diseases and immunodeficiencies. Multiple pathological processes drive the development of autoimmunity and immunodeficiencies, most of which involve quantitative and qualitative disturbances in regulatory cells, cytokine synthesis and signaling pathways. The assessment of these biomarkers does not aid only in the mechanistic description of autoimmune diseases and immunodeficiencies, but further helps to subcategorize diseases and to evaluate therapy responses. Here, we provide an overview, how monitoring of cytokines and regulatory cells aid in the diagnosis and follow-up of patients with autoimmune diseases and immunodeficiencies furthermore, we pinpoint novel cellular and molecular diagnostic possibilities in these diseases.

  2. An in vivo assay performed using multiple biomarkers related to testosterone synthesis and conversion for assessing the androgenic potency of refuse leachate.

    PubMed

    Gong, Yufeng; Tian, Hua; Dong, Yifei; Zhang, Xiaona; Wang, Wei; Ru, Shaoguo

    2017-01-01

    Refuse leachate is likely an important source of androgens. However, common in vitro bioassays underestimate the potential androgenic activity of leachate, owing to non-receptor-mediated mechanisms that modify the balance of sex hormones and promote the accumulation of endogenous androgens. This study aimed to develop an in vivo assay by using multiple biomarkers related to testosterone synthesis and conversion for assessing the potential androgenic activity of refuse leachate sampled from a municipal solid waste treatment plant in Qingdao, China. The results indicated that exposure to leachate increased the levels of testosterone and luteinizing hormone, but decreased those of 17β-estradiol in both male and female goldfish (Carassius auratus), suggesting a potential androgenic activity. Further, Leydig cell hyperplasia and decreased gonadal P450 aromatase mRNA levels were observed; these alterations might promote the biosynthesis of testosterone and hinder the conversion of testosterone to 17β-estradiol, which in turn enhance testosterone accumulation. Exposure to leachate also resulted in reproductive impairments, including decreased gonadosomatic index and plasma vitellogenin levels of female goldfish, as well as decreased testicular enzyme activities in male goldfish. The integrated use of biochemical, molecular, and histological markers not only improved our understanding of the androgenic effects of leachate but also verified the reliability and validity of the results. Therefore, the in vivo bioassay described in this study might allow the investigation of the androgenic effects of other complex contaminant mixtures in the future.

  3. Autophagy-related gene16L2, a potential serum biomarker of multiple sclerosis evaluated by bead-based proteomic technology.

    PubMed

    Yin, Linlin; Liu, Jianghong; Dong, Huiqing; Xu, Erhe; Qiao, Yuchen; Wang, Lin; Zhang, Lan; Jia, Jianping; Li, Lin; Geng, Xingchao

    2014-03-06

    Multiple sclerosis (MS) is an autoimmune disease characterized by neuroinflammation and demyelination that are mediated by T cells. The prolonged survival of autoreactive T cells acts as a primary event to trigger an inflammatory cascade that mediates myelin loss and clinical relapse in MS. Recently, T cell survival has been shown to be modulated by the autophagy-related gene (Atg). In the present study, we performed bead fractionation/matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry analyses using serum from 54 MS patients and 55 healthy controls. Eleven peptides were significantly different between the two groups with one being identified as a fragment of Atg16L2. Then the decreased levels of Atg16L2 peptides in MS patients were validated by immunoblotting and real-time PCR. As the Atg12-Atg5·Atg16 multimeric complex plays an essential role in autophagy, our results suggest that Atg16L2 may play an important role in autophagy of T cells and serve as a potential biomarker to predict clinical relapse of MS.

  4. EPILEPSY BIOMARKERS

    PubMed Central

    Engel, Jerome; Pitkänen, Asla; Loeb, Jeffrey A.; Dudek, F. Edward; Bertram, Edward H.; Cole, Andrew J.; Moshé, Solomon L.; Wiebe, Samuel; Fureman, Brandy E.; Jensen, Frances E.; Mody, Istvan; Nehlig, Astrid; Vezzani, Annamaria

    2013-01-01

    Summary A biomarker is defined as an objectively measured characteristic of a normal or pathological biological process. Identification and proper validation of biomarkers of epileptogenesis, the development of epilepsy, and ictogenesis, the propensity to generate spontaneous seizures, might predict the development of an epilepsy condition; identify the presence and severity of tissue capable of generating spontaneous seizures; measure progression after the condition is established; and determine pharmacoresistance. Such biomarkers could be used to create animal models for more cost-effective screening of potential antiepileptogenic and antiseizure drugs and devices, and to reduce the cost of clinical trials by enriching the trial population, and acting as surrogate markers to shorten trial duration. The objectives of the biomarker subgroup for the London Workshop were to define approaches for identifying possible biomarkers for these purposes. Research to identify reliable biomarkers may also reveal underlying mechanisms that could serve as therapeutic targets for the development of new antiepileptogenic and antiseizure compounds. PMID:23909854

  5. Peripheral blood cytokine and chemokine profiles in juvenile localized scleroderma

    PubMed Central

    Torok, Kathryn S.; Kurzinski, Katherine; Kelsey, Christina; Yabes, Jonathan; Magee, Kelsey; Vallejo, Abbe N.; Medsger, Thomas; Feghali-Bostwick, Carol A.

    2015-01-01

    Objective To evaluate peripheral blood T-helper (TH) cell associated cytokine and chemokine profiles in localized scleroderma (LS), and correlate them with clinical disease features, including disease activity parameters. Methods A 29-plex Luminex platform was used to analyze the humoral profile of plasma samples from 69 pediatric LS patients and 71 healthy pediatric controls. Cytokine/chemokine levels were compared between these two groups and within LS patients, focusing on validated clinical outcome measures of disease activity and damage in LS. Results Plasma levels of IP-10, MCP-1, IL-17a, IL-12p70, GM-CSF, PDGF-bb, IFN-α2, and IFN-γ were significantly higher in LS compared to healthy controls. Analysis within the LS group demonstrated IP-10, TNF-α and GM-CSF correlated with clinical measures of disease activity. Several cytokines/chemokines correlated with anti-histone antibody, while only a few correlated with positive ANA and single-stranded DNA antibody. Conclusion This is the first time that multiple cytokines and chemokines have been examined simultaneously LS. In general, a TH-1 (IFN-γ) and TH-17 (IL-17a) predominance was demonstrated in LS compared to healthy controls. There is also an IFN–γ signature with elevated IP-10, MCP-1 and IFN-γ, which has been previously demonstrated in systemic sclerosis, suggesting a shared pathophysiology. Within the LS patients, those with active disease demonstrated IP-10, TNF-α and GM-CSF, which may potentially serve as biomarkers of disease activity in the clinical setting. PMID:26254121

  6. Serum cytokines correlated with the disease severity of generalized pustular psoriasis.

    PubMed

    Yamamoto, Masaaki; Imai, Yasutomo; Sakaguchi, Yoshiko; Haneda, Takashi; Yamanishi, Kiyofumi

    2013-01-01

    To characterize serum biomarkers reflecting the severity of generalized pustular psoriasis (GPP), we measured multiple cytokine/chemokine levels in 39 serum samples from 6 cases with GPP during the course of the disease. Serum levels of IL-4, IL-8, CXCL1 and CCL3 were positively correlated with the severity scores of GPP, white blood cell counts and serum C-reactive protein levels. Serum levels of IL-1β, IL-1ra, IL-6, IL-10, IL-12p70, IL-18, IL-22, IFN-γ and VEGF showed strong positive correlations (r>0.4, p<0.01) with all those 3 clinical markers. Of those, IL-10 and IL-22 were significantly decreased after treatment in parallel with the GPP score and therefore those two serum cytokines might be useful to evaluate the efficacy of treatment for GPP.

  7. Serum Cytokines Correlated with The Disease Severity of Generalized Pustular Psoriasis

    PubMed Central

    Yamamoto, Masaaki; Imai, Yasutomo; Sakaguchi, Yoshiko; Haneda, Takashi; Yamanishi, Kiyofumi

    2013-01-01

    To characterize serum biomarkers reflecting the severity of generalized pustular psoriasis (GPP), we measured multiple cytokine/chemokine levels in 39 serum samples from 6 cases with GPP during the course of the disease. Serum levels of IL-4, IL-8, CXCL1 and CCL3 were positively correlated with the severity scores of GPP, white blood cell counts and serum C-reactive protein levels. Serum levels of IL-1β, IL-1ra, IL-6, IL-10, IL-12p70, IL-18, IL-22, IFN-γ and VEGF showed strong positive correlations (r > 0.4, p < 0.01) with all those 3 clinical markers. Of those, IL-10 and IL-22 were significantly decreased after treatment in parallel with the GPP score and therefore those two serum cytokines might be useful to evaluate the efficacy of treatment for GPP. PMID:23334651

  8. Th1 cytokine-based immunotherapy for cancer.

    PubMed

    Xu, Hong-Mei

    2014-10-01

    Cytokine-based immunotherapy is executed by harnessing cytokines to activate the immune system to suppress tumors. Th1-type cytokines including IL-1, IL-2, IL-12 and granulocyte-macrophage colony-stimulating factor are potent stimulators of Th1 differentiation and Th1-based antitumor response. Many preclinical studies demonstrated the antitumor effects of Th1 cytokines but their clinical efficacy is limited. Multiple factors influence the efficacy of immunotherapy for tumors. For instance immunosuppressive cells in the tumor microenvironment can produce inhibitory cytokines which suppress antitumor immune response. Most studies on cytokine immunotherapy focused on how to boost Th1 response; many studies combined cytokine-based therapy with other treatments to reverse immunosuppression in tumor microenvironment. In addition, cytokines have pleiotropic functions and some cytokines show paradoxical activities under different settings. Better understanding the physiological and pathological functions of cytokines helps clinicians to design Th1-based cancer therapy in clinical practice.

  9. IKAROS expression in distinct bone marrow cell populations as a candidate biomarker for outcome with lenalidomide-dexamethasone therapy in multiple myeloma.

    PubMed

    Bolomsky, Arnold; Hübl, Wolfgang; Spada, Stefano; Müldür, Ercan; Schlangen, Karin; Heintel, Daniel; Rocci, Alberto; Weißmann, Adalbert; Fritz, Veronique; Willheim, Martin; Zojer, Niklas; Palumbo, Antonio; Ludwig, Heinz

    2017-03-01

    Immunomodulatory drugs (IMiDs) are a cornerstone in the treatment of multiple myeloma (MM), but specific markers to predict outcome are still missing. Recent work pointed to a prognostic role for IMiD target genes (e.g. CRBN). Moreover, indirect activity of IMiDs on immune cells correlated with outcome, raising the possibility that cell populations in the bone marrow (BM) microenvironment could serve as biomarkers. We therefore analysed gene expression levels of six IMiD target genes in whole BM samples of 44 myeloma patients treated with lenalidomide-dexamethasone. Expression of CRBN (R = 0.30, P = .05), IKZF1 (R = 0.31, P = .04), IRF4 (R = 0.38, P = .01), MCT-1 (R = 0.30, P = .05), and CD147 (R = 0.38, P = .01), but not IKZF3 (R = -0.15, P = .34), was significantly associated with response. Interestingly, IKZF1 expression was elevated in BM environmental cells and thus selected for further investigation by multicolor flow cytometry. High IKAROS protein levels in total BM mononuclear cells (median OS 83.4 vs. 32.2 months, P = .02), CD19(+) B cells (median OS 71.1 vs. 32.2 months, P = .05), CD3(+) CD8(+) T cells (median OS 83.4 vs 19.0 months, P = .008) as well as monocytes (median OS 53.9 vs 18.0 months, P = .009) were associated with superior overall survival (OS). In contrast, IKAROS protein expression in MM cells was not predictive for OS. Our data therefore corroborate the central role of immune cells for the clinical activity of IMiDs and built the groundwork for prospective analysis of IKAROS protein levels in distinct cell populations as a potential biomarker for IMiD based therapies.

  10. Systems biomarkers as acute diagnostics and chronic monitoring tools for traumatic brain injury

    NASA Astrophysics Data System (ADS)

    Wang, Kevin K. W.; Moghieb, Ahmed; Yang, Zhihui; Zhang, Zhiqun

    2013-05-01

    Traumatic brain injury (TBI) is a significant biomedical problem among military personnel and civilians. There exists an urgent need to develop and refine biological measures of acute brain injury and chronic recovery after brain injury. Such measures "biomarkers" can assist clinicians in helping to define and refine the recovery process and developing treatment paradigms for the acutely injured to reduce secondary injury processes. Recent biomarker studies in the acute phase of TBI have highlighted the importance and feasibilities of identifying clinically useful biomarkers. However, much less is known about the subacute and chronic phases of TBI. We propose here that for a complex biological problem such as TBI, multiple biomarker types might be needed to harness the wide range of pathological and systemic perturbations following injuries, including acute neuronal death, neuroinflammation, neurodegeneration and neuroregeneration to systemic responses. In terms of biomarker types, they range from brain-specific proteins, microRNA, genetic polymorphism, inflammatory cytokines and autoimmune markers and neuro-endocrine hormones. Furthermore, systems biology-driven biomarkers integration can help present a holistic approach to understanding scenarios and complexity pathways involved in brain injury.

  11. Peripheral blood cytokine and chemokine profiles in juvenile localized scleroderma: T-helper cell-associated cytokine profiles.

    PubMed

    Torok, Kathryn S; Kurzinski, Katherine; Kelsey, Christina; Yabes, Jonathan; Magee, Kelsey; Vallejo, Abbe N; Medsger, Thomas; Feghali-Bostwick, Carol A

    2015-12-01

    To evaluate peripheral blood T-helper (TH) cell-associated cytokine and chemokine profiles in localized scleroderma (LS), and correlate them with clinical disease features, including disease activity parameters. A 29-plex Luminex platform was used to analyze the humoral profile of plasma samples from 69 pediatric LS patients and 71 healthy pediatric controls. Cytokine/chemokine levels were compared between these two groups and within LS patients, focusing on validated clinical outcome measures of disease activity and damage in LS. Plasma levels of IP-10, MCP-1, IL-17a, IL-12p70, GM-CSF, PDGF-bb, IFN-α2, and IFN-γ were significantly higher in LS subjects compared to healthy controls. Analysis within the LS group demonstrated IP-10, TNF-α, and GM-CSF correlated with clinical measures of disease activity. Several cytokines/chemokines correlated with anti-histone antibody, while only a few correlated with positive ANA and single-stranded DNA antibody. This is the first time that multiple cytokines and chemokines have been examined simultaneously in LS. In general, a TH1 (IFN-γ) and TH17 (IL-17a) predominance was demonstrated in LS compared to healthy controls. There is also an IFN-γ signature with elevated IP-10, MCP-1, and IFN-γ, which has been previously demonstrated in systemic sclerosis, suggesting a shared pathophysiology. Within the LS patients, those with active disease demonstrated IP-10, TNF-α, and GM-CSF, which may potentially serve as biomarkers of disease activity in the clinical setting. Copyright © 2015 Elsevier Inc. All rights reserved.

  12. Analysis of multiple cytokine polymorphisms in individuals with untreated deep carious lesions reveals IL1B (rs1143643) as a susceptibility factor for periapical lesion development.

    PubMed

    Dill, Alisa; Letra, Ariadne; Chaves de Souza, Letícia; Yadlapati, Mamatha; Biguetti, Claudia Cristina; Garlet, Gustavo Pompermaier; Vieira, Alexandre R; Silva, Renato Menezes

    2015-02-01

    It has been proposed that individual genetic predisposition may contribute to persistent apical periodontitis. Cytokines are associated with levels of inflammation and are involved in caries, pulpal, and periapical tissue destruction. We hypothesized that polymorphisms in cytokine genes may contribute to an individual's increased susceptibility to apical tissue destruction in response to deep carious lesions. Subjects with deep carious lesions with or without periapical lesions (≥3 mm) were recruited at the University of Pittsburgh, Pittsburgh, PA, and the University of Texas at Houston, Houston, TX. Genomic DNA samples of 316 patients were sorted into 2 groups: 136 cases with deep carious lesions and periapical lesions (cases) and 180 cases with deep carious lesions but no periapical lesions (controls). Nine single-nucleotide polymorphisms in IL1B, IL6, TNF, RANK, RANKL, and OPG genes were selected for genotyping. Genotypes were generated by end point analysis using TaqMan chemistry (Invitrogen, Carlsbad, CA) in a real-time polymerase chain reaction instrument. Allele and genotype frequencies were compared among cases and controls using the PLINK program (http://pngu.mgh.harvard.edu/purcell/plink/). Ninety-three human periapical granulomas and 24 healthy periodontal ligament tissues collected postoperatively were used for messenger RNA expression analyses of IL1B. A single-nucleotide polymorphism in IL1B (rs1143643) showed allelic (P = .02) and genotypic (P = .004) association with cases of deep caries and periapical lesions. We also observed altered transmission of IL1B marker haplotypes (P = .02) in these individuals. IL1B was highly expressed in granulomas (P < .001). Variations in IL1B may be associated with periapical lesion formation in individuals with untreated deep carious lesions. Future studies could help predict host susceptibility to developing periapical lesions. Copyright © 2015 American Association of Endodontists. Published by Elsevier Inc. All

  13. Serum cytokine profiling and enrichment analysis reveal the involvement of immunological and inflammatory pathways in stable patients with chronic obstructive pulmonary disease.

    PubMed

    Bade, Geetanjali; Khan, Meraj Alam; Srivastava, Akhilesh Kumar; Khare, Parul; Solaiappan, Krishna Kumar; Guleria, Randeep; Palaniyar, Nades; Talwar, Anjana

    2014-01-01

    Chronic obstructive pulmonary disease (COPD) is a major global health problem. It results from chronic inflammation and causes irreversible airway damage. Levels of different serum cytokines could be surrogate biomarkers for inflammation and lung function in COPD. We aimed to determine the serum levels of different biomarkers in COPD patients, the association between cytokine levels and various prognostic parameters, and the key pathways/networks involved in stable COPD. In this study, serum levels of 48 cytokines were examined by multiplex assays in 30 subjects (control, n=9; COPD, n=21). Relationships between serum biomarkers and forced expiratory volume in 1 second, peak oxygen uptake, body mass index, dyspnea score, and smoking were assessed. Enrichment pathways and network analyses were implemented, using a list of cytokines showing differential expression between healthy controls and patients with COPD by Cytoscape and GeneGo Metacore™ software (Thomson-Reuters Corporation, New York, NY, USA). Concentrations of cutaneous T-cell attracting chemokine, eotaxin, hepatocyte growth factor, interleukin 6 (IL-6), IL-16, and stem cell factor are significantly higher in COPD patients compared with in control patients. Notably, this study identifies stem cell factor as a biomarker for COPD. Multiple regression analysis predicts that cutaneous T-cell-attracting chemokine, eotaxin, IL-6, and stem cell factor are inversely associated with forced expiratory volume in 1 second and peak oxygen uptake change, whereas smoking is related to eotaxin and hepatocyte growth factor changes. Enrichment pathways and network analyses reveal the potential involvement of specific inflammatory and immune process pathways in COPD. Identified network interaction and regulation of different cytokines would pave the way for deeper insight into mechanisms of the disease process.

  14. Identification of Novel Inflammatory Cytokines and Contribution of Keratinocyte-Derived Chemokine to Inflammation in Response to Vibrio vulnificus Infection in Mice.

    PubMed

    Liu, Xiao-Fei; Wu, Jing; Wang, Ming-Yi; Chen, Ying-Jian; Cao, Yuan; Hu, Cheng-Jin

    2015-10-01

    Currently, only tumor necrosis factor alpha (TNF-α) and interleukin family cytokines have been found to be elicited in Vibrio vulnificus (V. vulnificus)-infected animal models and humans. However, multiple other cytokines are also involved in the immune and inflammatory responses to foreign microorganism infection. Antibody array technology, unlike traditional enzyme-linked immunosorbent assay (ELISA), is able to detect multiple cytokines at one time. Therefore, in this study, we examined the proinflammatory cytokine profile in the serum and liver homogenate samples of bacterial-infected mice using antibody array technology. We identified nine novel cytokines in response to V. vulnificus infection in mice. We found that keratinocyte-derived chemokine (KC) was the most elevated cytokine and demonstrated that KC played a very important role in the V. vulnificus infection-elicited inflammatory response in mice, as evidenced by the fact that the blocking of KC by anti-KC antibody reduced hepatic injury in vivo and that KC induced by V. vulnificus infection in AML-12 cells chemoattracted neutrophils. Our findings implicate that KC may serve as a novel diagnostic biomarker and a possible therapeutic target for V. vulnificus infection.

  15. Proteomic-Based Approaches for the Study of Cytokines in Lung Cancer.

    PubMed

    Marrugal, Ángela; Ojeda, Laura; Paz-Ares, Luis; Molina-Pinelo, Sonia; Ferrer, Irene

    2016-01-01

    Proteomic techniques are currently used to understand the biology of different human diseases, including studies of the cell signaling pathways implicated in cancer progression, which is important in knowing the roles of different proteins in tumor development. Due to its poor prognosis, proteomic approaches are focused on the identification of new biomarkers for the early diagnosis, prognosis, and targeted treatment of lung cancer. Cytokines are proteins involved in inflammatory processes and have been proposed as lung cancer biomarkers and therapeutic targets because it has been reported that some cytokines play important roles in tumor development, invasion, and metastasis. In this review, we aim to summarize the different proteomic techniques used to discover new lung cancer biomarkers and therapeutic targets. Several cytokines have been identified as important players in lung cancer using these techniques. We underline the most important cytokines that are useful as biomarkers and therapeutic targets. We also summarize some of the therapeutic strategies targeted for these cytokines in lung cancer.

  16. PML control of cytokine signaling.

    PubMed

    Maarifi, Ghizlane; Chelbi-Alix, Mounira K; Nisole, Sébastien

    2014-10-01

    The promyelocytic leukemia (PML) protein is a tumor suppressor acting as the organizer of nuclear matrix-associated structures named nuclear bodies (NBs). The involvement of PML in various cell processes, including cell death, senescence or antiviral defense underlines the multiple functions of PML due to its ability to interact with various partners either in the cytoplasm or in the nucleus. The importance of paracrine signaling in the regulation of PML expression is well established. More recently, a growing body of evidence also supports PML as a key regulator of cytokine signaling. These findings shed light on unsuspected biological functions of PML such as immune response, inflammation and cytokine-induced apoptosis. Here we review the current understanding of the pleiotropic activities of PML on cytokine-induced signaling. Copyright © 2014 Elsevier Ltd. All rights reserved.

  17. [Protein biomarker measurement and simple/rapid diagnostics with supersensitive and multiplex assay, MUSTag technology].

    PubMed

    Shibasaki, Futoshi; Morizane, Yoshihito; Makisaka, Noriko

    2009-11-01

    Recently, we face the rapid progression of an aging population, and so the importance of preventive medicine is growing. We would all like to pursue a healthy life during old age through effective treatment on the basis of the early detection of diseases. In this situation, we have developed MUSTag (Multiple Simultaneous Tag) assay technology through an innovative modification of the immuno-PCR method for the super-sensitive and multiplex detection of target biomarkers. In MUSTag technology, each different oligo-tag simultaneously detects multiplex protein targets with extremely high-level sensitivity (more than 10 fg(10(-15) g)/ml) in a dose-dependent manner by qRT-PCR (maximum: 3 plexes). Herein we report our recent results of multiple cytokine assays or disease-specific biomarker assays using MUSTag technology, and, further, clinical results from patients with cancer, ischemic brain, or heart attack, who need a prompt and predictive diagnosis for adequate treatment.

  18. Biological effects of the interferons and other cytokines.

    PubMed

    Friedman, R M; Grimley, P; Baron, S

    1996-01-01

    There were seven workshops that primarily concerned the biological effects of the interferons and the other cytokines. These were: Workshop 6, The refractory state in the response to interferons (IFNs) and antibodies in treated patients; Workshop 7, IFNs, multiple sclerosis, and the nervous system; Workshop 9, Viral inhibition of the response to IFNs and other cytokines; Workshop 10, Cell growth inhibition by IFNs and other cytokines; Workshop 12, Cytokines and cell death; Workshop 13, Interactions between cytokines; and, Workshop 14, Cytokine gene therapy. Summaries of each of these sessions follow.

  19. Polyamine Metabolites Profiling for Characterization of Lung and Liver Cancer Using an LC-Tandem MS Method with Multiple Statistical Data Mining Strategies: Discovering Potential Cancer Biomarkers in Human Plasma and Urine.

    PubMed

    Xu, Huarong; Liu, Ran; He, Bosai; Bi, Cathy Wenchuan; Bi, Kaishun; Li, Qing

    2016-08-10

    Polyamines, one of the most important kind of biomarkers in cancer research, were investigated in order to characterize different cancer types. An integrative approach which combined ultra-high performance liquid chromatography-tandem mass spectrometry detection and multiple statistical data processing strategies including outlier elimination, binary logistic regression analysis and cluster analysis had been developed to discover the characteristic biomarkers of lung and liver cancer. The concentrations of 14 polyamine metabolites in biosamples from lung (n = 50) and liver cancer patients (n = 50) were detected by a validated UHPLC-MS/MS method. Then the concentrations were converted into independent variables to characterize patients of lung and liver cancer by binary logic regression analysis. Significant independent variables were regarded as the potential biomarkers. Cluster analysis was engaged for further verifying. As a result, two values was discovered to identify lung and liver cancer, which were the product of the plasma concentration of putrescine and spermidine; and the ratio of the urine concentration of S-adenosyl-l-methionine and N-acetylspermidine. Results indicated that the established advanced method could be successfully applied to characterize lung and liver cancer, and may also enable a new way of discovering cancer biomarkers and characterizing other types of cancer.

  20. Role of cytokines in genesis, progression and prognosis of cervical cancer.

    PubMed

    Paradkar, Prajakta Hemant; Joshi, Jayashree Vinay; Mertia, Priyanka Nirmalsingh; Agashe, Shubhada Vidyadhar; Vaidya, Rama Ashok

    2014-01-01

    Cytokine research is currently at the forefront in cancer research. Deciphering the functions of these multiple small molecules, discovered within the cell and in intercellular spaces, with their abundance and pleotrophism, was initially a great challenge. Advances in analytical chemistry and molecular biology have made it possible to unravel the pathophysiological functions of these polypeptides/proteins which are called interleukins, chemokines, monokines, lymphokines and growth factors. With more than 5 million women contracting cervical cancer every year this cancer is a major cause of mortality and morbidity the world over, particularly in the developing countries. In more than 95% of cases it is associated with human papilloma virus (HPV) infection which is persistent, particularly in those with a defective immune system. Although preventable, the mere magnitude of prevalence of HPV in the world population makes it a dominating current health hazard. The discovery of cytokine dysregulation in cervical cancer has spurted investigation into the possibility of using them as biomarkers in the early diagnosis of cases at high risk of developing cancer. Their critical role in carcinogenesis and progression of cervical cancer is now being revealed to a great extent. From diagnostics to prognosis, and now with a possible role in therapeutics and prevention of cervical cancer, the cytokines are being evaluated in all anticancer approaches. This review endeavours to capture the essence of the astonishing journey of cytokine research in cervical neoplasia.

  1. Direct Write Protein Patterns for Multiplexed Cytokine Detection From Live Cells Using Electron Beam Lithography

    PubMed Central

    Lau, Uland Y.; Saxer, Sina S.; Lee, Juneyoung; Bat, Erhan; Maynard, Heather D.

    2016-01-01

    Simultaneous detection of multiple biomarkers, such as extracellular signaling molecules, is a critical aspect in disease profiling and diagnostics. Precise positioning of antibodies on surfaces, especially at the micro- and nano- scale, is important for the improvement of assays, biosensors, and diagnostics on the molecular level, and therefore, the pursuit of device miniaturization for parallel, fast, low-volume assays is a continuing challenge. Here, we describe a multiplexed cytokine immunoassay utilizing electron beam lithography and a trehalose glycopolymer as a resist for the direct writing of antibodies on silicon substrates allowing for micro- and nano-scale precision of protein immobilization. Specifically, anti-interleukin 6 (IL-6) and anti-tumor necrosis factor alpha (TNFα) antibodies were directly patterned. Retention of the specific binding properties of the patterned antibodies was shown by the capture of secreted cytokines from stimulated RAW 264.7 macrophages. A sandwich immunoassay was employed using gold nanoparticles and enhancement with silver for the detection and visualization of bound cytokines to the patterns by localized surface plasmon resonance detected with dark field microscopy. Multiplexing with both IL-6 and TNFα on a single chip was also successfully demonstrated with high specificity and in relevant cell culture conditions and at different times after cell stimulation. The direct fabrication of capture antibody patterns for cytokine detection described here could be useful for biosensing applications. PMID:26679368

  2. Direct Write Protein Patterns for Multiplexed Cytokine Detection from Live Cells Using Electron Beam Lithography.

    PubMed

    Lau, Uland Y; Saxer, Sina S; Lee, Juneyoung; Bat, Erhan; Maynard, Heather D

    2016-01-26

    Simultaneous detection of multiple biomarkers, such as extracellular signaling molecules, is a critical aspect in disease profiling and diagnostics. Precise positioning of antibodies on surfaces, especially at the micro- and nanoscale, is important for the improvement of assays, biosensors, and diagnostics on the molecular level, and therefore, the pursuit of device miniaturization for parallel, fast, low-volume assays is a continuing challenge. Here, we describe a multiplexed cytokine immunoassay utilizing electron beam lithography and a trehalose glycopolymer as a resist for the direct writing of antibodies on silicon substrates, allowing for micro- and nanoscale precision of protein immobilization. Specifically, anti-interleukin 6 (IL-6) and antitumor necrosis factor alpha (TNFα) antibodies were directly patterned. Retention of the specific binding properties of the patterned antibodies was shown by the capture of secreted cytokines from stimulated RAW 264.7 macrophages. A sandwich immunoassay was employed using gold nanoparticles and enhancement with silver for the detection and visualization of bound cytokines to the patterns by localized surface plasmon resonance detected with dark-field microscopy. Multiplexing with both IL-6 and TNFα on a single chip was also successfully demonstrated with high specificity and in relevant cell culture conditions and at different times after cell stimulation. The direct fabrication of capture antibody patterns for cytokine detection described here could be useful for biosensing applications.

  3. Cytokines in Drosophila immunity.

    PubMed

    Vanha-Aho, Leena-Maija; Valanne, Susanna; Rämet, Mika

    2016-02-01

    Cytokines are a large and diverse group of small proteins that can affect many biological processes, but most commonly cytokines are known as mediators of the immune response. In the event of an infection, cytokines are produced in response to an immune stimulus, and they function as key regulators of the immune response. Cytokines come in many shapes and sizes, and although they vary greatly in structure, their functions have been well conserved in evolution. The immune signaling pathways that respond to cytokines are remarkably conserved from fly to man. Therefore, Drosophila melanogaster, provides an excellent platform for studying the biology and function of cytokines. In this review, we will describe the cytokines and cytokine-like molecules found in the fly and discuss their roles in host immunity. Copyright © 2015 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

  4. Current status and challenges of cytokine pharmacology

    PubMed Central

    Zídek, Z; Anzenbacher, P; Kmoníčková, E

    2009-01-01

    The major concern of pharmacology about cytokines has originated from plentiful data showing association between gross changes in their production and pathophysiological processes. Despite the enigmatic role of cytokines in diseases, a number of them have become a subject of cytokine and anti-cytokine immunotherapies. Production of cytokines can be influenced by many endogenous and exogenous stimuli including drugs. Cells of the immune system, such as macrophages and lymphocytes, are richly endowed with receptors for the mediators of physiological functions, such as biogenic amines, adenosine, prostanoids, steroids, etc. Drugs, agonists or antagonists of these receptors can directly or indirectly up- and down-regulate secretion of cytokines and expression of cytokine receptors. Vice versa, cytokines interfere with drug pharmacokinetics and pharmacodynamics through the interactions with cytochrome P450 and multiple drug resistance proteins. The aim of the review is to encourage more intensive studies in these fields of cytokine pharmacology. It also outlines major areas of searching promising candidates for immunotherapeutic interventions. PMID:19371342

  5. Cytokine/anti-cytokine therapy - novel treatments for asthma?

    PubMed

    Hansbro, Philip M; Kaiko, Gerard E; Foster, Paul S

    2011-05-01

    Asthma is a chronic inflammatory disease of the airways and there are no preventions or cures. Inflammatory cells through the secretion of cytokines and pro-inflammatory molecules are thought to play a critical role in pathogenesis. Type 2 CD4(+) lymphocytes (Th2 cells) and their cytokines predominate in mild to moderate allergic asthma, whereas severe steroid-resistant asthma has more of a mixed Th2/Th1 phenotype with a Th17 component. Other immune cells, particularly neutrophils, macrophages and dendritic cells, as well structural cells such as epithelial and airway smooth muscle cells also produce disease-associated cytokines in asthma. Increased levels of these immune cells and cytokines have been identified in clinical samples and their potential role in disease demonstrated in studies using mouse models of asthma. Clinical trials with inhibitors of cytokines such as interleukin (IL)-4, -5 and tumour necrosis factor-α have had success in some studies but not others. This may reflect the design of the clinical trials, including treatments regimes and the patient population included in these studies. IL-13, -9 and granulocyte-macrophage colony-stimulating factor are currently being evaluated in clinical trials or preclinically and the outcome of these studies is eagerly awaited. Roles for IL-25, -33, thymic stromal lymphopoietin, interferon-γ, IL-17 and -27 in the regulation of asthma are just emerging, identifying new ways to treat inflammation. Careful interpretation of results from mouse studies will inform the development and application of therapeutic approaches for asthma. The most effective approaches may be combination therapies that suppress multiple cytokines and a range of redundant and disconnected pathways that separately contribute to asthma pathogenesis. Astute application of these approaches may eventually lead to the development of effective asthma therapeutics. Here we review the current state of knowledge in the field. © 2011 The Authors

  6. Suppression of Canine Dendritic Cell Activation/Maturation and Inflammatory Cytokine Release by Mesenchymal Stem Cells Occurs Through Multiple Distinct Biochemical Pathways.

    PubMed

    Wheat, William H; Chow, Lyndah; Kurihara, Jade N; Regan, Daniel P; Coy, Jonathan W; Webb, Tracy L; Dow, Steven W

    2017-02-15

    Mesenchymal stem cells (MSC) represent a readily accessible source of cells with potent immune modulatory activity. MSC can suppress ongoing inflammatory responses by suppressing T cell function, while fewer studies have examined the impact of MSC on dendritic cell (DC) function. The dog spontaneous disease model represents an important animal model with which to evaluate the safety and effectiveness of cellular therapy with MSC. This study evaluated the effects of canine MSC on the activation and maturation of canine monocyte-derived DC, as well as mechanisms underlying these effects. Adipose-derived canine MSC were cocultured with canine DC, and the MSC effects on DC maturation and activation were assessed by flow cytometry, cytokine ELISA, and confocal microscopy. We found that canine MSC significantly suppressed lipopolysaccharide (LPS)-stimulated upregulation of DC activation markers such as major histocompatibility class II (MHCII), CD86, and CD40. Furthermore, pretreatment of MSC with interferon gamma (IFNγ) augmented this suppressive activity. IFNγ-activated MSC also significantly reduced LPS-elicited DC secretion of tumor necrosis factor alpha without reducing secretion of interleukin-10. The suppressive effect of IFNγ-treated MSC on LPS-induced DC activation was mediated by soluble factors secreted by both MSC and DC. Pathways of DC functional suppression included programmed death ligand-1 expression and secretion of nitrous oxide, prostaglandin E2, and adenosine by activated MSC. Coculture of DC with IFNγ-treated MSC maintained DC in an immature state and prolonged DC antigen uptake during LPS maturation stimulus. Taken together, canine MSC are capable of potently suppressing DC function in a potentially inflammatory microenvironment through several separate immunological pathways and confirm the potential for immune therapy with MSC in canine immune-mediated disease models.

  7. Cytokines and skeletal physiology.

    PubMed

    Goldring, S R; Goldring, M B

    1996-03-01

    Cytokines are soluble factors that play a critical role in mediating cell to cell interactions within skeletal tissues. These effects are mediated by paracrine, autocrine, and juxtacrine mechanisms. There are also examples in which the cytokines can function in an endocrine fashion. The regulatory functions of the cytokines are performed throughout life, beginning with bone growth and development and continuing in the mature organism, in which bone remodeling is regulated. The cytokines can be grouped into distinct families based on their principal biologic activity and cell target. However, the activities of the cytokines are pleiotropic, and they exhibit considerable overlap and redundancy in their actions. The molecular cloning of the cytokines and their receptors and elucidation of their common structural features have aided in the understanding of the molecular basis for the redundancy and pleiotropy of cytokine effects. Examination of most physiologic processes in which cytokines play an important regulatory role reveals that cytokines rarely exert their biologic activities in isolation. Instead, these soluble factors usually are produced locally in concert with many other cytokines. The interaction of these structurally and functionally distinct factors in a highly ordered temporal and spatial sequence creates a cytokine network that ultimately determines a given tissue's response. Continued investigation into the molecular and biologic mechanisms by which cytokines regulate bone cell function will provide additional insights into normal bone physiology and permit more effective and specific use of these factors in the treatment of skeletal disorders.

  8. [Interleukins network in rheumatoid arthritis pathophysiology: beyond proinflammatory cytokines].

    PubMed

    Sánchez-Ramón, Silvia; López-Longo, Francisco Javier; Carreño, Luis

    2011-03-01

    Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by synovitis and progressive destruction of the joint cartilage and underlying bone, together with diverse extra-articular manifestations. Cytokines act as soluble effector mediators of the inflammatory process. Therapeutic neutralization with monoclonal antibodies against the pro-inflammatory cytokines TNF-alpha and interleukin 1 (IL-1) has shown a clear efficacy on inflammation and clinical manifestations of RA, although a percentage of patients do not respond. This review covers new relevant cytokines in the RA physiopathology and potential biomarkers of inflammation. The current challenge is to develop biomarkers that enable an earlier diagnosis, as well as prognostic markers and new therapeutic candidates. Combined administration of several of these cytokines could eventually address a personalized treatment approach for each patient.

  9. Cytokines as biochemical markers for knee osteoarthritis

    PubMed Central

    Mabey, Thomas; Honsawek, Sittisak

    2015-01-01

    Osteoarthritis (OA) is a debilitating degenerative joint disease particularly affecting weightbearing joints within the body, principally the hips and knees. Current radiographic techniques are insufficient to show biochemical changes within joint tissue which can occur many years before symptoms become apparent. The need for better diagnostic and prognostic tools is heightened with the prevalence of OA set to increase in aging and obese populations. As inflammation is increasingly being considered an important part of OAs pathophysiology, cytokines are being assessed as possible candidates for biochemical markers. Cytokines, both pro- and anti-inflammatory, as well as angiogenic and chemotactic, have in recent years been studied for relevant characteristics. Biochemical markers show promise in determination of the severity of disease in addition to monitoring of the efficacy and safety of disease-modifying OA drugs, with the potential to act as diagnostic and prognostic tools. Currently, the diagnostic power of interleukin (IL)-6 and the relationship to disease burden of IL-1β, IL-15, tumor necrosis factor-α, and vascular endothelial growth factor make these the best candidates for assessment. Grouping appropriate cytokine markers together and assessing them collectively alongside other bone and cartilage degradation products will yield a more statistically powerful tool in research and clinical applications, and additionally aid in distinguishing between OA and a number of other diseases in which cytokines are known to have an involvement. Further large scale studies are needed to assess the validity and efficacy of current biomarkers, and to discover other potential biomarker candidates. PMID:25621214

  10. Intracellular Cytokine Staining and Flow Cytometry: Considerations for Application in Clinical Trials of Novel Tuberculosis Vaccines.

    PubMed

    Smith, Steven G; Smits, Kaatje; Joosten, Simone A; van Meijgaarden, Krista E; Satti, Iman; Fletcher, Helen A; Caccamo, Nadia; Dieli, Francesco; Mascart, Francoise; McShane, Helen; Dockrell, Hazel M; Ottenhoff, Tom H M

    2015-01-01

    Intracellular cytokine staining combined with flow cytometry is one of a number of assays designed to assess T-cell immune responses. It has the specific advantage of enabling the simultaneous assessment of multiple phenotypic, differentiation and functional parameters pertaining to responding T-cells, most notably, the expression of multiple effector cytokines. These attributes make the technique particularly suitable for the assessment of T-cell immune responses induced by novel tuberculosis vaccines in clinical trials. However, depending upon the particular nature of a given vaccine and trial setting, there are approaches that may be taken at different stages of the assay that are more suitable than other alternatives. In this paper, the Tuberculosis Vaccine Initiative (TBVI) TB Biomarker Working group reports on efforts to assess the conditions that will determine when particular assay approaches should be employed. We have found that choices relating to the use of fresh whole blood or peripheral blood mononuclear cells (PBMC) and frozen PBMC; use of serum-containing or serum-free medium; length of stimulation period and use of co-stimulatory antibodies can all affect the sensitivity of intracellular cytokine assays. In the case of sample material, frozen PBMC, despite some loss of sensitivity, may be more advantageous for batch analysis. We also recommend that for multi-site studies, common antibody panels, gating strategies and analysis approaches should be employed for better comparability.

  11. Cytokines in sleep regulation.

    PubMed

    Krueger, J M; Takahashi, S; Kapás, L; Bredow, S; Roky, R; Fang, J; Floyd, R; Renegar, K B; Guha-Thakurta, N; Novitsky, S

    1995-01-01

    The central thesis of this essay is that the cytokine network in brain is a key element in the humoral regulation of sleep responses to infection and in the physiological regulation of sleep. We hypothesize that many cytokines, their cellular receptors, soluble receptors, and endogenous antagonists are involved in physiological sleep regulation. The expressions of some cytokines are greatly amplified by microbial challenge. This excess cytokine production during infection induces sleep responses. The excessive sleep and wakefulness that occur at different times during the course of the infectious process results from dynamic changes in various cytokines that occur during the host's response to infectious challenge. Removal of any one somnogenic cytokine inhibits normal sleep, alters the cytokine network by changing the cytokine mix, but does not completely disrupt sleep due to the redundant nature of the cytokine network. The cytokine network operates in a paracrine/autocrine fashion and is responsive to neuronal use. Finally, cytokines elicit their somnogenic actions via endocrine and neurotransmitter systems as well as having direct effects neurons and glia. Evidence in support of these postulates is reviewed in this essay.

  12. Cytokines and feeding.

    PubMed

    Plata-Salamán, C R

    2001-12-01

    Various categories of cytokines participate in the control of feeding, including interleukin-1 and -6 and other activators of gp 130, leptin (ob protein), interleukin-8 and other chemokines, tumor necrosis factor-alpha, and interferon-alpha. These feeding-inhibitory cytokines may play a role in the regulation of food intake during physiological (eg a role proposed for leptin) and pathophysiological (eg proinflammatory cytokines) conditions. Data show that various cytokines participate in acute and chronic disease-associated anorexia such as during infection, inflammation or malignancy. Food intake suppression (reported as anorexia) is also a common central manifestation observed during cytokine immunotherapy in humans. The concept of local production of various cytokines within specific brain regions in response to peripheral challenges and pathophysiological processes has broad implications for the interpretation of brain cytokines as mediators or participants in CNS modulation of feeding and anorexia.

  13. Temporal Trends in the Inflammatory Cytokine Profile of Human Breastmilk

    PubMed Central

    Chollet-Hinton, Lynn S.; Stuebe, Alison M.; Casbas-Hernandez, Patricia; Chetwynd, Ellen

    2014-01-01

    Abstract A longer lifetime duration of breastfeeding may decrease the risk of breast cancer by reducing breast inflammation and mitigating inflammatory cytokine expression during postlactational involution. However, little is known about how the inflammatory cytokine profile in human breastmilk changes over time. To study temporal trends in breastmilk cytokine expression, we measured 80 human cytokines in the whey fraction of breastmilk samples from 15 mothers at 1, 4, 8, and 12 weeks postpartum. We used mixed models to identify temporal changes in cytokine expression and investigated parity status (multiparous vs. primiparous) as a potential confounder. Nine cytokines (monocyte chemoattractant protein-1, epithelial-derived neutrophil-activating protein-78, hepatocyte growth factor, insulin-like growth factor-binding protein-1, interleukin-16, interleukin-8, macrophage colony-stimulating factor, osteoprotegerin, and tissue inhibitor of metallopeptidase-2) had significantly decreased expression with increasing breastfeeding duration; all nine have known roles in breast involution, inflammation, and cancer and may serve as biomarkers of changing breast microenvironment. No cytokine significantly increased in level over the study period. Total protein concentration significantly decreased over time (p<0.0001), which may mediate the association between length of breastfeeding and inflammatory cytokine expression. Parity status did not confound temporal trends, but levels of several cytokines were significantly higher among multiparous versus primiparous women. Our results suggest that inflammatory cytokine expression during lactation is dynamic, and expressed milk may provide a noninvasive window into the extensive biological changes that occur in the postpartum breast. PMID:25380323

  14. Temporal trends in the inflammatory cytokine profile of human breastmilk.

    PubMed

    Chollet-Hinton, Lynn S; Stuebe, Alison M; Casbas-Hernandez, Patricia; Chetwynd, Ellen; Troester, Melissa A

    2014-12-01

    A longer lifetime duration of breastfeeding may decrease the risk of breast cancer by reducing breast inflammation and mitigating inflammatory cytokine expression during postlactational involution. However, little is known about how the inflammatory cytokine profile in human breastmilk changes over time. To study temporal trends in breastmilk cytokine expression, we measured 80 human cytokines in the whey fraction of breastmilk samples from 15 mothers at 1, 4, 8, and 12 weeks postpartum. We used mixed models to identify temporal changes in cytokine expression and investigated parity status (multiparous vs. primiparous) as a potential confounder. Nine cytokines (monocyte chemoattractant protein-1, epithelial-derived neutrophil-activating protein-78, hepatocyte growth factor, insulin-like growth factor-binding protein-1, interleukin-16, interleukin-8, macrophage colony-stimulating factor, osteoprotegerin, and tissue inhibitor of metallopeptidase-2) had significantly decreased expression with increasing breastfeeding duration; all nine have known roles in breast involution, inflammation, and cancer and may serve as biomarkers of changing breast microenvironment. No cytokine significantly increased in level over the study period. Total protein concentration significantly decreased over time (p<0.0001), which may mediate the association between length of breastfeeding and inflammatory cytokine expression. Parity status did not confound temporal trends, but levels of several cytokines were significantly higher among multiparous versus primiparous women. Our results suggest that inflammatory cytokine expression during lactation is dynamic, and expressed milk may provide a noninvasive window into the extensive biological changes that occur in the postpartum breast.

  15. Biomarkers in patients treated with BCG: an update.

    PubMed

    Klap, Julia; Schmid, Marianne; Loughlin, Kevin R

    2014-08-01

    Bacillus Calmette-Guerin (BCG) instillations are the recommended treatment for non-muscle invasive bladder cancer but high recurrence and progression rates remain after treatment. Despite patients risk stratification, BCG effectiveness remains unpredictable. A close, invasive and expensive follow up is mandatory. To improve or even replace this heavy surveillance in this high risk population, validated biomarkers were developed. To identify the useful tools for the urologist in monitoring bladder cancer patients, we reviewed the literature focusing on plasma and urinary biomarkers of BCG-therapy outcome. Articles dated from 1988 to 2013 including specific keywords (urinary bladder neoplasm, biological markers, intravesical administration, recurrence) were examined and relevant papers were selected. Before treatment initiation, genetic polymorphisms of multiple agents (cytokines, matrix-metalloproteinases) were found to become very useful to tailor therapy and monitoring. Those biomarkers belong to personalized medicine which is a topic of great interest today, but still need to be validated in cohorts from different ethnicities. During instillations, cytokines (IL-2, IL-8, IL-6/IL-10) were reported to be reliable to determine treatment response and efficacy. Further studies are needed to confirm results and standardize thresholds. After treatment, UroVysion, the FDA-approved fluorescence in situ hybridization (FISH), appeared to be the most robust marker of all the clinical parameters reviewed; but is not yet validated for BCG-treated patients. No recommendations for everyday practice can be established today, but a combination of several markers and clinicopathological characteristics may be the future. As bladder cancer diagnosis and management are evolving, practicing urologists should be aware of and utilize bladder cancer markers in clinical practice.

  16. Drug targets in the cytokine universe for autoimmune disease.

    PubMed

    Liu, Xuebin; Fang, Lei; Guo, Taylor B; Mei, Hongkang; Zhang, Jingwu Z

    2013-03-01

    In autoimmune disease, a network of diverse cytokines is produced in association with disease susceptibility to constitute the 'cytokine milieu' that drives chronic inflammation. It remains elusive how cytokines interact in such a complex network to sustain inflammation in autoimmune disease. This has presented huge challenges for successful drug discovery because it has been difficult to predict how individual cytokine-targeted therapy would work. Here, we combine the principles of Chinese Taoism philosophy and modern bioinformatics tools to dissect multiple layers of arbitrary cytokine interactions into discernible interfaces and connectivity maps to predict movements in the cytokine network. The key principles presented here have important implications in our understanding of cytokine interactions and development of effective cytokine-targeted therapies for autoimmune disorders. Copyright © 2012 Elsevier Ltd. All rights reserved.

  17. Multiplicity

    DTIC Science & Technology

    1991-04-01

    practice as a "[descent] into that inner circle of the Inferno where the damned endlessly degate multiplicity for sentencing." United States v. Barnard...select the charges to be brought in a particular case"). 19 Brown v. Ohio, 432 U.S. 161, 165 (1977). 20 Whalen v. United States, 445 U.S. at 689. 21...parte Lange, 8-5 U.S. (19 Wall.) 163 (1874). Cf. Brown v. Ohio, 432 U.S. at 165 ("once the legislature has acted courts may not impose more than one

  18. Capparis ovata treatment suppresses inflammatory cytokine expression and ameliorates experimental allergic encephalomyelitis model of multiple sclerosis in C57BL/6 mice.

    PubMed

    Ozgun-Acar, Ozden; Celik-Turgut, Gurbet; Gazioglu, Isil; Kolak, Ufuk; Ozbal, Seda; Ergur, Bekir U; Arslan, Sevki; Sen, Alaattin; Topcu, Gulacti

    2016-09-15

    Since ancient times, Capparis species have been widely used in traditional medicine to treat various diseases. Our recent investigations have suggested Capparis ovata's potential anti-neuroinflammatory application for the treatment of multiple sclerosis (MS). The present study was designed to precisely determine the underlying mechanism of its anti-neuroinflammatory effect in a mouse model of MS. C. ovata water extract (COWE) was prepared using the plant's fruit, buds, and flower parts (Turkish Patent Institute, PT 2012/04,093). We immunized female C57BL/6J mice with MOG35-55/CFA. COWE was administered at a daily dose of 500mg/kg by oral gavage either from the day of immunization (T1) or at disease onset (T2) for 21days. Gene expression analysis was performed using a Mouse Multiple Sclerosis RT² Profiler PCR Array, and further determinations and validations of the identified genes were performed using qPCR. Whole-genome transcriptome profiling was analyzed using Agilent SurePrint G3 Mouse GE 8X60K microarrays. Immunohistochemical staining was applied to brain sections of the control and treated mice to examine the degree of degeneration. COWE was further fractionated and analyzed phytochemically using the Zivak Tandem Gold Triple Quadrupole LC/MS-MS system. COWE remarkably suppressed the development of EAE in T1, and the disease activity was completely inhibited. In the T2 group, the maximal score was significantly reduced compared with that of the parallel EAE group. The COWE suppression of EAE was associated with a significantly decreased expression of genes that are important in inflammatory signaling, such as TNFα, IL6, NF-κB, CCL5, CXCL9, and CXCK10. On the other hand, the expression of genes involved in myelination/remyelination was significantly increased. Immunohistochemical analysis further supported these effects, showing that the number of infiltrating immune cells was decreased in the brains of COWE-treated animals. In addition, differential

  19. Inflammatory biomarkers for AMD.

    PubMed

    Stanton, Chloe M; Wright, Alan F

    2014-01-01

    Age-related macular degeneration (AMD) is the leading cause of blindness worldwide, affecting an estimated 50 million individuals aged over 65 years.Environmental and genetic risk-factors implicate chronic inflammation in the etiology of AMD, contributing to the formation of drusen, retinal pigment epithelial cell dysfunction and photoreceptor cell death. Consistent with a role for chronic inflammation in AMD pathogenesis, several inflammatory mediators, including complement components, chemokines and cytokines, are elevated at both the local and systemic levels in AMD patients. These mediators have diverse roles in the alternative complement pathway, including recruitment of inflammatory cells, activation of the inflammasome, promotion of neovascularisation and in the resolution of inflammation. The utility of inflammatory biomarkers in assessing individual risk and progression of the disease is controversial. However, understanding the role of these inflammatory mediators in AMD onset, progression and response to treatment may increase our knowledge of disease pathogenesis and provide novel therapeutic options in the future.

  20. Collection of aerosolized human cytokines using Teflon® filters.

    PubMed

    McKenzie, Jennifer H; McDevitt, James J; Fabian, M Patricia; Hwang, Grace M; Milton, Donald K

    2012-01-01

    Collection of exhaled breath samples for the analysis of inflammatory biomarkers is an important area of research aimed at improving our ability to diagnose, treat and understand the mechanisms of chronic pulmonary disease. Current collection methods based on condensation of water vapor from exhaled breath yield biomarker levels at or near the detection limits of immunoassays contributing to problems with reproducibility and validity of biomarker measurements. In this study, we compare the collection efficiency of two aerosol-to-liquid sampling devices to a filter-based collection method for recovery of dilute laboratory generated aerosols of human cytokines so as to identify potential alternatives to exhaled breath condensate collection. Two aerosol-to-liquid sampling devices, the SKC® Biosampler and Omni 3000™, as well as Teflon® filters were used to collect aerosols of human cytokines generated using a HEART nebulizer and single-pass aerosol chamber setup in order to compare the collection efficiencies of these sampling methods. Additionally, methods for the use of Teflon® filters to collect and measure cytokines recovered from aerosols were developed and evaluated through use of a high-sensitivity multiplex immunoassay. Our results show successful collection of cytokines from pg/m(3) aerosol concentrations using Teflon® filters and measurement of cytokine levels in the sub-picogram/mL concentration range using a multiplex immunoassay with sampling times less than 30 minutes. Significant degradation of cytokines was observed due to storage of cytokines in concentrated filter extract solutions as compared to storage of dry filters. Use of filter collection methods resulted in significantly higher efficiency of collection than the two aerosol-to-liquid samplers evaluated in our study. The results of this study provide the foundation for a potential new technique to evaluate biomarkers of inflammation in exhaled breath samples.

  1. Collection of Aerosolized Human Cytokines Using Teflon® Filters

    PubMed Central

    McKenzie, Jennifer H.; McDevitt, James J.; Fabian, M. Patricia; Hwang, Grace M.; Milton, Donald K.

    2012-01-01

    Background Collection of exhaled breath samples for the analysis of inflammatory biomarkers is an important area of research aimed at improving our ability to diagnose, treat and understand the mechanisms of chronic pulmonary disease. Current collection methods based on condensation of water vapor from exhaled breath yield biomarker levels at or near the detection limits of immunoassays contributing to problems with reproducibility and validity of biomarker measurements. In this study, we compare the collection efficiency of two aerosol-to-liquid sampling devices to a filter-based collection method for recovery of dilute laboratory generated aerosols of human cytokines so as to identify potential alternatives to exhaled breath condensate collection. Methodology/Principal Findings Two aerosol-to-liquid sampling devices, the SKC® Biosampler and Omni 3000™, as well as Teflon® filters were used to collect aerosols of human cytokines generated using a HEART nebulizer and single-pass aerosol chamber setup in order to compare the collection efficiencies of these sampling methods. Additionally, methods for the use of Teflon® filters to collect and measure cytokines recovered from aerosols were developed and evaluated through use of a high-sensitivity multiplex immunoassay. Our results show successful collection of cytokines from pg/m3 aerosol concentrations using Teflon® filters and measurement of cytokine levels in the sub-picogram/mL concentration range using a multiplex immunoassay with sampling times less than 30 minutes. Significant degradation of cytokines was observed due to storage of cytokines in concentrated filter extract solutions as compared to storage of dry filters. Conclusions Use of filter collection methods resulted in significantly higher efficiency of collection than the two aerosol-to-liquid samplers evaluated in our study. The results of this study provide the foundation for a potential new technique to evaluate biomarkers of inflammation in

  2. Genetic toxicity of cytokines.

    PubMed

    Lazutka, J R

    1996-12-12

    Review of the literature shows that such cytokines as human interferons alpha and gamma, tumor necrosis factor alpha, epidermal growth factor and interleukin-2 may exhibit genotoxic properties in human peripheral blood lymphocyte cultures. For all above cytokines, except interleukin-2, parabolic-like relationship between the dose and the frequency of sister chromatid exchanges was found. Although the mechanisms of these genotoxic actions remain largely unknown, generation of free radicals or interaction with enzymes such as DNA topoisomerase II may be suspected. Human interferon alpha also may be considered as an antimutagenic compound in human cells. Human tumor necrosis factor alpha has been reported to enhance cytotoxicity and DNA fragmentation produced by DNA topoisomerase II-targeted anticancer drugs. At the same time, it has some radio- and chemoprotective properties in vitro and in vivo. Despite these facts, the question about genotoxicity of cytokines is not answered. Some problems must be resolved before receiving the final answer. First, much more cytokines must be tested for their genotoxic activity. Second, appropriate test-systems must be designed. Third, genotoxicity studies of cytokines must account for cytokine interaction in the cytokine network as well as for such cytokine-induced effects as cytotoxicity and apoptosis. Fourth, in each case, it is necessary to have experimental evidence that observed genotoxic effects were caused by cytokine under investigation and not by the other factors.

  3. Cytokines in psoriasis.

    PubMed

    Baliwag, Jaymie; Barnes, Drew H; Johnston, Andrew

    2015-06-01

    Psoriasis is a common inflammatory skin disease with an incompletely understood etiology. The disease is characterized by red, scaly and well-demarcated skin lesions formed by the hyperproliferation of epidermal keratinocytes. This hyperproliferation is driven by cytokines secreted by activated resident immune cells, an infiltrate of T cells, dendritic cells and cells of the innate immune system, as well as the keratinocytes themselves. Psoriasis has a strong hereditary character and has a complex genetic background. Genome-wide association studies have identified polymorphisms within or near a number of genes encoding cytokines, cytokine receptors or elements of their signal transduction pathways, further implicating these cytokines in the psoriasis pathomechanism. A considerable number of inflammatory cytokines have been shown to be elevated in lesional psoriasis skin, and the serum concentrations of a subset of these also correlate with psoriasis disease severity. The combined effects of the cytokines found in psoriasis lesions likely explain most of the clinical features of psoriasis, such as the hyperproliferation of keratinocytes, increased neovascularization and skin inflammation. Thus, understanding which cytokines play a pivotal role in the disease process can suggest potential therapeutic targets. A number of cytokines have been therapeutically targeted with success, revolutionizing treatment of this disease. Here we review a number of key cytokines implicated in the pathogenesis of psoriasis.

  4. Cytokines in psoriasis

    PubMed Central

    Baliwag, Jaymie; Barnes, Drew H.; Johnston, Andrew

    2015-01-01

    Psoriasis is a common inflammatory skin disease with an incompletely understood etiology. The disease is characterized by red, scaly and well-demarcated skin lesions formed by the hyperproliferation of epidermal keratinocytes. This hyperproliferation is driven by cytokines secreted by activated resident immune cells, an infiltrate of T cells, dendritic cells and cells of the innate immune system, as well as the keratinocytes themselves. Psoriasis has a strong hereditary character and has a complex genetic background. Genome-wide association studies have identified polymorphisms within or near a number of genes encoding cytokines, cytokine receptors or elements of their signal transduction pathways, further implicating these cytokines in the psoriasis pathomechanism. A considerable number of inflammatory cytokines have been shown to be elevated in lesional psoriasis skin, and the serum concentrations of a subset of these also correlate with psoriasis disease severity. The combined effects of the cytokines found in psoriasis lesions likely explain most of the clinical features of psoriasis, such as the hyperproliferation of keratinocytes, increased neovascularization and skin inflammation. Thus, understanding which cytokines play a pivotal role in the disease process can suggest potential therapeutic targets. A number of cytokines have been therapeutically targeted with success, revolutionizing treatment of this disease. Here we review a number of key cytokines implicated in the pathogenesis of psoriasis. PMID:25585875

  5. Biomarkers in pediatrics: children as biomarker orphans.

    PubMed

    Savage, William J; Everett, Allen D

    2010-12-01

    Biomarkers have enormous potential to improve patient care by establishing tests of diagnosis, prognosis, and treatment effects. Successfully translating a biomarker from discovery to clinical application demands high-quality discovery research and high-quality clinical studies for biomarker validation; however, there are additional challenges that face biomarker research in pediatrics. There are also additional characteristics of pediatric medicine that make biomarker research especially needed. This review focuses on the fundamentals of biomarkers, the additional considerations needed for applying biomarker research to children, and recommendations for advancing pediatric biomarker research.

  6. Cytokine quantitation: technologies and applications.

    PubMed

    Sachdeva, Naresh; Asthana, Deshratn

    2007-05-01

    Assessment of cytokines in body fluids, cells or tissues provides important information in understanding of disease process and designing treatment strategies. Today, wide range of cytokine assays are available, including; measurement of levels of cytokines (direct) or cytokine soluble receptor levels (indirect) in body fluids or cellular supernatants (immunoassays and cytokine bioassays), measurement of cytokines produced by population of cells (multiparametric flow cytometry, magnetic beads based quantitation of cytokine producing cells, mRNA based assays), measurement of cytokines produced by single cells (Enzyme-linked immunospot (ELISPOT), Intra-cytoplasmic cytokine staining (ICC), mRNA based assays) and detection of cytokines in tissues (immunostaining). Improved understanding of cytokine interactions has led to a consensus that simultaneous assessment of many cytokines in a biological sample provides more comprehensive information rather than assessing a single cytokine. Thus, technologies that measure one cytokine at a time are being gradually replaced by multiplex-type formats (DNA and protein microarrays).

  7. Cytokine inhibition in the treatment of COPD

    PubMed Central

    Caramori, Gaetano; Adcock, Ian M; Di Stefano, Antonino; Chung, Kian Fan

    2014-01-01

    Cytokines play an important part in many pathobiological processes of chronic obstructive pulmonary disease (COPD), including the chronic inflammatory process, emphysema, and altered innate immune response. Proinflammatory cytokines of potential importance include tumor necrosis factor (TNF)-α, interferon-γ, interleukin (IL)-1β, IL-6, IL-17, IL-18, IL-32, and thymic stromal lymphopoietin (TSLP), and growth factors such as transforming growth factor-β. The current objectives of COPD treatment are to reduce symptoms, and to prevent and reduce the number of exacerbations. While current treatments achieve these goals to a certain extent, preventing the decline in lung function is not currently achievable. In addition, reversal of corticosteroid insensitivity and control of the fibrotic process while reducing the emphysematous process could also be controlled by specific cytokines. The abnormal pathobiological process of COPD may contribute to these fundamental characteristics of COPD, and therefore targeting cytokines involved may be a fruitful endeavor. Although there has been much work that has implicated various cytokines as potentially playing an important role in COPD, there have been very few studies that have examined the effect of specific cytokine blockade in COPD. The two largest studies that have been reported in the literature involve the use of blocking antibody to TNFα and CXCL8 (IL-8), and neither has provided benefit. Blocking the actions of CXCL8 through its CXCR2 receptor blockade was not successful either. Studies of antibodies against IL-17, IL-18, IL-1β, and TSLP are currently either being undertaken or planned. There is a need to carefully phenotype COPD and discover good biomarkers of drug efficacy for each specific target. Specific groups of COPD patients should be targeted with specific anticytokine therapy if there is evidence of high expression of that cytokine and there are features of the clinical expression of COPD that will respond

  8. Biomarkers in cardiovascular medicine.

    PubMed

    Martín-Ventura, José L; Blanco-Colio, Luis M; Tuñón, José; Muñoz-García, Begoña; Madrigal-Matute, Julio; Moreno, Juan A; Vega de Céniga, Melina; Egido, Jesús

    2009-06-01

    Cardiovascular disease is the principal cause of death in developed countries. The underlying pathological process is arterial wall thickening due to the formation of atherosclerotic plaque, which is frequently complicated by thrombus, thereby giving rise to the possibility of acute coronary syndrome or stroke. One of the major challenges in cardiovascular medicine is to find a way of predicting the risk that an individual will suffer an acute thrombotic event. During the last few decades, there has been considerable interest in finding diagnostic and prognostic biomarkers that can be detected in blood. Of these, C-reactive protein is the best known. Others, such as the soluble CD40 ligand, can be used to predict cardiovascular events. However, to date, no biomarker has been generally accepted for use in clinical practice. At present, there are a number of high-performance techniques, such as proteomics, that have the ability to detect multiple potential biomarkers. In the near future, these approaches may lead to the discovery of new biomarkers that, when used with imaging techniques, could help improve our ability to predict the occurrence of acute vascular events.

  9. Oral Palmitoylethanolamide Treatment Is Associated with Reduced Cutaneous Adverse Effects of Interferon-β1a and Circulating Proinflammatory Cytokines in Relapsing-Remitting Multiple Sclerosis.

    PubMed

    Orefice, Nicola S; Alhouayek, Mireille; Carotenuto, Antonio; Montella, Silvana; Barbato, Franscesco; Comelli, Albert; Calignano, Antonio; Muccioli, Giulio G; Orefice, Giuseppe

    2016-04-01

    Palmitoylethanolamide (PEA) is an endogenous lipid mediator known to reduce pain and inflammation. However, only limited clinical studies have evaluated the effects of PEA in neuroinflammatory and neurodegenerative diseases. Multiple sclerosis (MS) is a chronic autoimmune and inflammatory disease of the central nervous system. Although subcutaneous administration of interferon (IFN)-β1a is approved as first-line therapy for the treatment of relapsing-remitting MS (RR-MS), its commonly reported adverse events (AEs) such as pain, myalgia, and erythema at the injection site, deeply affect the quality of life (QoL) of patients with MS. In this randomized, double-blind, placebo-controlled study, we tested the effect of ultramicronized PEA (um-PEA) added to IFN-β1a in the treatment of clinically defined RR-MS. The primary objectives were to estimate whether, with um-PEA treatment, patients with MS perceived an improvement in pain and a decrease of the erythema width at the IFN-β1a injection site in addition to an improvement in their QoL. The secondary objectives were to evaluate the effects of um-PEA on circulating interferon-γ, tumor necrosis factor-α, and interleukin-17 serum levels, N-acylethanolamine plasma levels, Expanded Disability Status Scale (EDSS) progression, and safety and tolerability after 1 year of treatment. Patients with MS receiving um-PEA perceived an improvement in pain sensation without a reduction of the erythema at the injection site. A significant improvement in QoL was observed. No significant difference was reported in EDSS score, and um-PEA was well tolerated. We found a significant increase of palmitoylethanolamide, anandamide and oleoylethanolamide plasma levels, and a significant reduction of interferon-γ, tumor necrosis factor-α, and interleukin-17 serum profile compared with the placebo group. Our results suggest that um-PEA may be considered as an appropriate add-on therapy for the treatment of IFN-β1a-related adverse effects in

  10. Imaging Biomarkers or Biomarker Imaging?

    PubMed Central

    Mitterhauser, Markus; Wadsak, Wolfgang

    2014-01-01

    Since biomarker imaging is traditionally understood as imaging of molecular probes, we highly recommend to avoid any confusion with the previously defined term “imaging biomarkers” and, therefore, only use “molecular probe imaging (MPI)” in that context. Molecular probes (MPs) comprise all kinds of molecules administered to an organism which inherently carry a signalling moiety. This review highlights the basic concepts and differences of molecular probe imaging using specific biomarkers. In particular, PET radiopharmaceuticals are discussed in more detail. Specific radiochemical and radiopharmacological aspects as well as some legal issues are presented. PMID:24967536

  11. Multiple biomarker responses in Prochilodus lineatus subjected to short-term in situ exposure to streams from agricultural areas in Southern Brazil.

    PubMed

    Vieira, Carlos Eduardo Delfino; Costa, Patrícia Gomes; Lunardelli, Bruna; de Oliveira, Luciana Fernandes; Cabrera, Liziara da Costa; Risso, Wagner Ezequiel; Primel, Ednei Gilberto; Meletti, Paulo César; Fillmann, Gilberto; Martinez, Claudia Bueno dos Reis

    2016-01-15

    In order to assess the quality of streams susceptible to contamination by pesticides we apply biochemical and genotoxic biomarkers in the Neotropical fish Prochilodus lineatus submitted to in situ tests. Fish were caged, for 96 h, in two streams located in areas with intensive use of pesticides, the Apertados (AP) and the Jacutinga (JC), and in a small stream (Godoy stream — GD) found inside a forest fragment adjacent to a State Park. Biochemical parameters, such as biotransformation enzymes 7-ethoxyresorufin-O-deethylase (EROD) and glutathione-S-transferase (GST), non-protein thiols (NPSH), lipoperoxidation (LPO), protein carbonylation (PCO) and acetylcholinesterase (AChE) were evaluated in various fish organs, as well as genotoxic biomarkers (damage to DNA and occurrence of micronuclei and erythrocyte nuclear abnormalities). Samples of water and sediment were collected for analysis of metals (Cu, Cr, Pb, Ni, Mn, Cd and Zn), organochloride pesticides, and triazine and glyphosate herbicides. We observed an increase in liver GST activity in fish at AP and gill GST activity in fish at JC. An increase in liver LPO was also observed in fish exposed to AP and JC. The same animals also exhibited increased DNA damage and erythrocyte nuclear abnormalities (ENAs) compared to the fish kept in GD. A number of compounds showed concentrations higher than the permitted levels, in particular, dichlorodiphenyltrichloroethane (DDT), its metabolites dichlorodiphenyldichloroethylene (DDE) and dichlorodiphenyldichloroethane (DDD), hexachlorocyclohexanes (HCH), heptachloride, diclofluanid and aldrins. These pesticides were detected at higher concentrations in water and sediment samples from AP, followed by JC and GD. The Integrated Biomarker Response Index (IBR) indicated that AP and JC (AP: 21.7 > JC: 18.5 > GD: 12.6) have the worst environmental quality. Integrated biomarker analysis revealed that the alterations observed related well with the levels of environmental contaminants

  12. Meeting Report--NASA Radiation Biomarker Workshop

    SciTech Connect

    Straume, Tore; Amundson, Sally A,; Blakely, William F.; Burns, Frederic J.; Chen, Allen; Dainiak, Nicholas; Franklin, Stephen; Leary, Julie A.; Loftus, David J.; Morgan, William F.; Pellmar, Terry C.; Stolc, Viktor; Turteltaub, Kenneth W.; Vaughan, Andrew T.; Vijayakumar, Srinivasan; Wyrobek, Andrew J.

    2008-05-01

    A summary is provided of presentations and discussions from the NASA Radiation Biomarker Workshop held September 27-28, 2007, at NASA Ames Research Center in Mountain View, California. Invited speakers were distinguished scientists representing key sectors of the radiation research community. Speakers addressed recent developments in the biomarker and biotechnology fields that may provide new opportunities for health-related assessment of radiation-exposed individuals, including for long-duration space travel. Topics discussed include the space radiation environment, biomarkers of radiation sensitivity and individual susceptibility, molecular signatures of low-dose responses, multivariate analysis of gene expression, biomarkers in biodefense, biomarkers in radiation oncology, biomarkers and triage following large-scale radiological incidents, integrated and multiple biomarker approaches, advances in whole-genome tiling arrays, advances in mass-spectrometry proteomics, radiation biodosimetry for estimation of cancer risk in a rat skin model, and confounding factors. Summary conclusions are provided at the end of the report.

  13. Integrating multiple fish biomarkers and risk assessment as indicators of metal pollution along the Red Sea coast of Hodeida, Yemen Republic.

    PubMed

    Omar, Wael A; Saleh, Yousef S; Marie, Mohamed-Assem S

    2014-12-01

    The marine environment of the Red Sea coast of Yemen Republic is subjected to increasing anthropogenic activities. The present field study assesses the impacts of metal pollutants on two common marine fish species; Pomadasys hasta and Lutjanus russellii collected from a reference site in comparison to two polluted sites along the Red Sea coast of Hodeida, Yemen Republic. Concentrations of heavy metals (Fe, Cu, Zn, Cd and Pb) in fish vital organs, metal pollution index (MPI), indicative biochemical parameters of liver functions (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) and kidney functions (urea and creatinine) as well as histopathological changes in gills, liver and kidney of both fish species are integrated as biomarkers of metal pollution. These biomarkers showed species-specific and/or site-specific response. The hazard index (HI) was used as an indicator of human health risks associated with fish consumption. The detected low HI values in most cases doesn't neglect the fact that the cumulative risk effects for metals together give an alarming sign and that the health of fish consumers is endangered around polluted sites. The levels of ALT, AST and urea in plasma of both fish species collected from the polluted sites showed significant increase in comparison to those of reference site. Histopathological alterations and evident damage were observed in tissues of fish collected from the polluted sites. The investigated set of biomarkers proved to be efficient and reliable in biomonitoring the pollution status along different pollution gradients.

  14. Using exposure biomarkers in children to compare between-child and within-child variance and calculate correlations among siblings for multiple environmental chemicals.

    PubMed

    Sexton, Ken; Ryan, Andrew D

    2012-01-01

    Longitudinal measurements of biomarkers for metals, phthalates, environmental tobacco smoke, organochlorine and organophosphate pesticides, polychlorinated biphenyls, and volatile organic compounds were made in blood and/or urine from a stratified, random sample of more than 100 elementary school-aged children living in an inner-city section of Minneapolis. Repeated measures of 31 exposure biomarkers indicate that between-child variance (B-CV) was greater than within-child variance (W-CV) for 8 compounds, B-CV was a significant proportion of total variance for 9 compounds, and variances were homogeneous for 14 compounds. Among siblings living in the same household, positive correlations were observed for biomarker concentrations of polychlorinated biphenyls, organochlorine pesticides, metals, and volatile organic chemicals in blood, and total cotinine in urine. Biologic markers confirm that children from a low-income, ethnically diverse neighborhood experienced concurrent exposure to a variety of hazardous environmental chemicals during their everyday activities. Future monitoring studies should examine the nature and magnitude of children's cumulative exposure to both chemical and non-chemical stressors, especially in disadvantaged populations.

  15. Elevated specific peripheral cytokines found in major depressive disorder patients with childhood trauma exposure: a cytokine antibody array analysis.

    PubMed

    Lu, Shaojia; Peng, Hongjun; Wang, Lifeng; Vasish, Seewoobudul; Zhang, Yan; Gao, Weijia; Wu, Weiwei; Liao, Mei; Wang, Mi; Tang, Hao; Li, Wenping; Li, Weihui; Li, Zexuan; Zhou, Jiansong; Zhang, Zhijun; Li, Lingjiang

    2013-10-01

    Taking into consideration the previous evidence of revealing the relationship of early life adversity, major depressive disorder (MDD), and stress-linked immunological changes, we recruited 22 MDD patients with childhood trauma exposures (CTE), 21 MDD patients without CTE, and 22 healthy controls without CTE, and then utilized a novel cytokine antibody array methodology to detect potential biomarkers underlying MDD in 120 peripheral cytokines and to evaluate the effect of CTE on cytokine changes in MDD patients. Although 13 cytokines were identified with highly significant differences in expressions between MDD patients and normal controls, this relationship was significantly attenuated and no longer significant after consideration of the effect of CTE in MDD patients. Depressed individuals with CTE (TD patients) were more likely to have higher peripheral levels of those cytokines. Severity of depression was associated with plasma levels of certain increased cytokines; meanwhile, the increased cytokines led to a proper separation of TD patients from normal controls during clustering analyses. Our research outcomes add great strength to the relationship between depression and cytokine changes and suggest that childhood trauma may play a vital role in the co-appearance of cytokine changes and depression.

  16. Cytokine measurement using cytometric bead arrays.

    PubMed

    Castillo, Luis; MacCallum, Donna M

    2012-01-01

    Cytokines can be measured by enzyme-linked immunosorbent assay (ELISA) or multiplex assay. Both techniques are commonly used in immunology to detect the presence of antibody or antigen in a sample. However, multiplex bead array technology provides the means to simultaneously measure multiple analytes in a single reaction, thereby saving time and resources. This method can detect up to 30 proteins at once, using a relatively small sample volume, without losing sensitivity, accuracy, or reproducibility. In this chapter, we describe the cytometric bead array (CBA) approach to simultaneously measure multiple cytokines in biological samples such as spleen, kidney, or serum from mice infected with the human fungal pathogen Candida albicans.

  17. Urine biomarkers in prostate cancer.

    PubMed

    Ploussard, Guillaume; de la Taille, Alexandre

    2010-02-01

    The deficiencies of serum PSA as a prostate-cancer-specific diagnostic test are well recognized. Thus, the development of novel biomarkers for prostate cancer detection remains an important and exciting challenge. Noninvasive urine-based tests are particularly attractive candidates for large-scale screening protocols, and biomarker discovery programs using urine samples have emerged for detecting and predicting aggressiveness of prostate cancer. Some new biomarkers already outperform serum PSA in the diagnosis of this disease. Currently, the PCA3 (prostate cancer antigen 3) urine test is probably the best adjunct to serum PSA for predicting biopsy outcome, and has proven its clinical relevance by surpassing the predictive abilities of traditional serum biomarkers. New research methods are also emerging, and high-throughput technologies will facilitate high-dimensional biomarker discovery. Future approaches will probably integrate proteomic, transcriptomic and multiplex approaches to detect novel biomarkers, and aim to identify combinations of multiple biomarkers to optimize the detection of prostate cancer. In addition, an unmet need remains for markers that differentiate indolent from aggressive cancers, to better inform treatment decisions.

  18. Cytokine/anti-cytokine therapy – novel treatments for asthma?

    PubMed Central

    Hansbro, Philip M; Kaiko, Gerard E; Foster, Paul S

    2011-01-01

    Asthma is a chronic inflammatory disease of the airways and there are no preventions or cures. Inflammatory cells through the secretion of cytokines and pro-inflammatory molecules are thought to play a critical role in pathogenesis. Type 2 CD4+ lymphocytes (Th2 cells) and their cytokines predominate in mild to moderate allergic asthma, whereas severe steroid-resistant asthma has more of a mixed Th2/Th1 phenotype with a Th17 component. Other immune cells, particularly neutrophils, macrophages and dendritic cells, as well structural cells such as epithelial and airway smooth muscle cells also produce disease-associated cytokines in asthma. Increased levels of these immune cells and cytokines have been identified in clinical samples and their potential role in disease demonstrated in studies using mouse models of asthma. Clinical trials with inhibitors of cytokines such as interleukin (IL)-4, -5 and tumour necrosis factor-α have had success in some studies but not others. This may reflect the design of the clinical trials, including treatments regimes and the patient population included in these studies. IL-13, -9 and granulocyte-macrophage colony-stimulating factor are currently being evaluated in clinical trials or preclinically and the outcome of these studies is eagerly awaited. Roles for IL-25, -33, thymic stromal lymphopoietin, interferon-γ, IL-17 and -27 in the regulation of asthma are just emerging, identifying new ways to treat inflammation. Careful interpretation of results from mouse studies will inform the development and application of therapeutic approaches for asthma. The most effective approaches may be combination therapies that suppress multiple cytokines and a range of redundant and disconnected pathways that separately contribute to asthma pathogenesis. Astute application of these approaches may eventually lead to the development of effective asthma therapeutics. Here we review the current state of knowledge in the field. LINKED ARTICLES This

  19. Cytokines and chemokines in neuromyelitis optica: pathogenetic and therapeutic implications.

    PubMed

    Uzawa, Akiyuki; Mori, Masahiro; Masahiro, Mori; Kuwabara, Satoshi

    2014-01-01

    Neuromyelitis optica (NMO) is characterized by severe optic neuritis and longitudinally extensive transverse myelitis. The discovery of an NMO-specific autoantibody to the aquaporin-4 (AQP4) water channel has improved knowledge of NMO pathogenesis. Many studies have focused on inflammatory and pathological biomarkers of NMO, including cytokines and chemokines. Increased concentrations of T helper (Th)17- and Th2-related cytokines and chemokines may be essential factors for developing NMO inflammatory lesions. For example, interleukin-6 could play important roles in NMO pathogenesis, as it is involved in the survival of plasmablasts that produce anti-AQP4 antibody in peripheral circulation and in the enhancement of inflammation in the central nervous system. Therefore, assessment of these useful biomarkers may become a supportive criterion for diagnosing NMO. Significant advances in the understanding of NMO pathogenesis will lead to the development of novel treatment strategies. This review focuses on the current advances in NMO immunological research, particularly that of cytokines and chemokines.

  20. Insights into cytokine-receptor interactions from cytokine engineering.

    PubMed

    Spangler, Jamie B; Moraga, Ignacio; Mendoza, Juan L; Garcia, K Christopher

    2015-01-01

    Cytokines exert a vast array of immunoregulatory actions critical to human biology and disease. However, the desired immunotherapeutic effects of native cytokines are often mitigated by toxicity or lack of efficacy, either of which results from cytokine receptor pleiotropy and/or undesired activation of off-target cells. As our understanding of the structural principles of cytokine-receptor interactions has advanced, mechanism-based manipulation of cytokine signaling through protein engineering has become an increasingly feasible and powerful approach. Modified cytokines, both agonists and antagonists, have been engineered with narrowed target cell specificities, and they have also yielded important mechanistic insights into cytokine biology and signaling. Here we review the theory and practice of cytokine engineering and rationalize the mechanisms of several engineered cytokines in the context of structure. We discuss specific examples of how structure-based cytokine engineering has opened new opportunities for cytokines as drugs, with a focus on the immunotherapeutic cytokines interferon, interleukin-2, and interleukin-4.

  1. Cytokines and mucosal immunity.

    PubMed

    Bamias, Giorgos; Arseneau, Kristen O; Cominelli, Fabio

    2014-11-01

    Cytokines are integral mediators for maintaining intestinal mucosal homeostasis, as well as prominent effector molecules during chronic gut inflammatory diseases. This review focuses on recent studies of the role of specific cytokines in mucosal immunity. Dichotomous, or even opposing, functions have been described for several cytokines involved in intestinal innate immunity (most notably for members of the interleukin-1 family), which depend on the specific inflammatory conditions within the intestinal mucosa. For example, both interleukin-1α and interleukin-33 exhibit 'alarmin'-type properties that can signal tissue or cell damage, which further add to their well described proinflammatory roles. Costimulatory molecules of the tumor necrosis factor/tumor necrosis factor receptor superfamily, such as TNF-like cytokine 1A and LIGHT, are actively involved in mucosal proinflammatory pathways, but also may exert protection against infectious agents to facilitate recovery from acute inflammation. Finally, innate lymphoid cells are increasingly recognized as important cellular sources of pivotal mucosal cytokines, including the interleukin-23/T helper 17 cytokine, interleukin-22. Elucidating the complexity of cytokine signaling within the normal mucosa and during acute and chronic inflammation will be a pivotal step toward understanding the pathogenesis of immune-mediated gut diseases and developing effective therapies to treat them.

  2. Measurement of inflammatory biomarkers in synovial tissue extracts by enzyme-linked immunosorbent assay.

    PubMed

    Rosengren, Sanna; Firestein, Gary S; Boyle, David L

    2003-11-01

    We developed methods for measuring inflammatory biomarkers (cytokines, chemokines, and metalloproteinases) in synovial biopsy specimens from patients with rheumatoid arthritis (RA) and osteoarthritis (OA). Soluble extracts of synovial fragments were prepared with mild detergent and analyzed by enzyme-linked immunosorbent assay (ELISA) for interleukin 1beta (IL-1beta), IL-6, IL-8, tumor necrosis factor alpha (TNF-alpha), and matrix metalloproteinase 3. The optimal detergent was 0.1% Igepal CA-630, which interfered minimally with ELISA detection but extracted 80% of IL-6 from synovial tissue. Upon spiking, 81 to 107% of added biomarkers could be recovered. To determine within-tissue variability, multiple biopsy specimens from each RA synovial extract were analyzed individually. A resulting coefficient of variation of 35 to 62% indicated that six biopsy specimens per synovial extract would result in a sampling error of < or = 25%. Preliminary power analysis suggested that 8 to 15 patients per group would suffice to observe a threefold difference before and after treatment in a serial biopsy clinical study. The previously described significant differences in IL-1beta, IL-6, IL-8, and TNF-alpha levels between RA and OA could be detected, thereby validating the use of synovial extracts for biomarker analysis in arthritis. These methods allow monitoring of biomarker protein levels in synovial tissue and could potentially be applied to early-phase clinical trials to provide a preliminary estimate of drug efficacy.

  3. Recombinant cytokines from plants.

    PubMed

    Sirko, Agnieszka; Vaněk, Tomas; Góra-Sochacka, Anna; Redkiewicz, Patrycja

    2011-01-01

    Plant-based platforms have been successfully applied for the last two decades for the efficient production of pharmaceutical proteins. The number of commercialized products biomanufactured in plants is, however, rather discouraging. Cytokines are small glycosylated polypeptides used in the treatment of cancer, immune disorders and various other related diseases. Because the clinical use of cytokines is limited by high production costs they are good candidates for plant-made pharmaceuticals. Several research groups explored the possibilities of cost-effective production of animal cytokines in plant systems. This review summarizes recent advances in this field.

  4. Cytokines and pulmonary fibrosis.

    PubMed

    Zhang, K; Phan, S H

    1996-01-01

    In the past several years, significant progress in many aspects of pulmonary fibrosis research has been made. Among them, the finding that a variety of cytokines play important roles in the complex process appears most intriguing. These cytokines include at least transforming growth factor-beta (TGF-beta), tumor necrosis factor-alpha (TNF-alpha), platelet-derived growth factor, fibroblast growth factors, (TGF-alpha), interleukin-1, monocyte chemoattractant protein-1 and macrophage inflammatory protein-1 alpha. These cytokines have been demonstrated to be produced at the sites of active fibrosis where they appear to be expressed by activated inflammatory cells, such as macrophages and eosinophils. More interestingly, other noninflammatory lung cells including mesenchymal cells, such as myofibroblasts, and epithelial cells, have been found to be significant sources as well, albeit in most instances at somewhat different time points than those by inflammatory cells. Study of the individual cytokines in vitro has revealed a variety of potential roles for these cytokines in the regulation of the fibrotic process in vivo, including chemoattractant, mitogenic activities for fibroblasts, stimulation of extracellular matrix and alpha-smooth muscle actin gene expression, alteration of the contractile phenotype of fibroblasts and regulation of diverse functions of lung inflammatory and epithelial cells which can further impact on the fibrotic process by autocrine and paracrine mechanisms. Of these cytokines, it appears that TGF-beta is probably the most important cytokine in terms of the direct stimulation of lung matrix expression which typifies fibrosis. Recently however, there is accumulating evidence to indicate that the situation is much more complex than any one single cytokine being solely responsible for the fibrotic response. The concept of complex lung cytokine networks, orchestrated by a few key cytokines, such as TNF-alpha, being responsible for this response has

  5. Tissue-based Alzheimer gene expression markers-comparison of multiple machine learning approaches and investigation of redundancy in small biomarker sets.

    PubMed

    Scheubert, Lena; Luštrek, Mitja; Schmidt, Rainer; Repsilber, Dirk; Fuellen, Georg

    2012-10-15

    Alzheimer's disease has been known for more than 100 years and the underlying molecular mechanisms are not yet completely understood. The identification of genes involved in the processes in Alzheimer affected brain is an important step towards such an understanding. Genes differentially expressed in diseased and healthy brains are promising candidates. Based on microarray data we identify potential biomarkers as well as biomarker combinations using three feature selection methods: information gain, mean decrease accuracy of random forest and a wrapper of genetic algorithm and support vector machine (GA/SVM). Information gain and random forest are two commonly used methods. We compare their output to the results obtained from GA/SVM. GA/SVM is rarely used for the analysis of microarray data, but it is able to identify genes capable of classifying tissues into different classes at least as well as the two reference methods. Compared to the other methods, GA/SVM has the advantage of finding small, less redundant sets of genes that, in combination, show superior classification characteristics. The biological significance of the genes and gene pairs is discussed.

  6. Use of Lithobates catesbeianus tadpoles in a multiple biomarker approach for the assessment of water quality of the Reconquista River (Argentina).

    PubMed

    Ossana, N A; Castañé, P M; Salibián, A

    2013-10-01

    The water quality of the Reconquista River (Argentina) water was monitored between 2009 and 2010 by means of a multiparametric approach. This periurban river is affected by agricultural, urban, and industrial discharges. Water samples were collected at a dam located in the headwaters and at 18 km downstream (M). Physicochemical profile and two water-quality indices (WQIs) were determined. Laboratory bioassays were performed by exposing Lithobates catesbeianus tadpoles to environmental samples for 96 h and determining the following parameters: (1) brain: acetylcholinesterase (AChE) activity; (2) gill: catalase and glutathione-S-transferase (GST) activities and glutathione (GSH) content; (3) liver: CAT and GST activities, superoxide dismutase, lipid peroxidation, and GSH content; (4) condition factor and hepatosomatic index; and (5) genotoxicity [micronucleus (MN) test in erythrocytes]. Physicochemical profile and WQIs corresponded with extensive pollution in M. Important temporal and spatial variability in biomarkers of tadpoles exposed to samples was found. Multivariate analyses showed that AChE in brain, MN frequency, liver and gill GST activities, and GSH content were key biomarkers.

  7. OXIDATIVE STRESS: BIOMARKERS AND NOVEL THERAPEUTIC PATHWAYS

    PubMed Central

    Maiese, Kenneth; Chong, Zhao Zhong; Hou, Jinling; Shang, Yan Chen

    2010-01-01

    Oxidative stress significantly impacts multiple cellular pathways that can lead to the initiation and progression of varied disorders throughout the body. It therefore becomes imperative to elucidate the components and function of novel therapeutic strategies against oxidative stress to further clinical diagnosis and care. In particular, both the growth factor and cytokine erythropoietin (EPO) and members of the mammalian forkhead transcription factors of the O class (FoxOs) may offer the greatest promise for new treatment regimens since these agents and the cellular pathways they oversee cover a range of critical functions that directly influence progenitor cell development, cell survival and degeneration, metabolism, immune function, and cancer cell invasion. Furthermore, both EPO and FoxOs function not only as therapeutic targets, but also as biomarkers of disease onset and progression, since their cellular pathways are closely linked and overlap with several unique signal transduction pathways. However, biological outcome with EPO and FoxOs may sometimes be both unexpected and undesirable that can raise caution for these agents and warrant further investigations. Here we present the exciting as well as complicated role EPO and FoxOs possess to uncover the benefits as well as the risks of these agents for cell biology and clinical care in processes that range from stem cell development to uncontrolled cellular proliferation. PMID:20064603

  8. Oxidative stress: Biomarkers and novel therapeutic pathways.

    PubMed

    Maiese, Kenneth; Chong, Zhao Zhong; Hou, Jinling; Shang, Yan Chen

    2010-03-01

    Oxidative stress significantly impacts multiple cellular pathways that can lead to the initiation and progression of varied disorders throughout the body. It therefore becomes imperative to elucidate the components and function of novel therapeutic strategies against oxidative stress to further clinical diagnosis and care. In particular, both the growth factor and cytokine erythropoietin (EPO) and members of the mammalian forkhead transcription factors of the O class (FoxOs) may offer the greatest promise for new treatment regimens since these agents and the cellular pathways they oversee cover a range of critical functions that directly influence progenitor cell development, cell survival and degeneration, metabolism, immune function, and cancer cell invasion. Furthermore, both EPO and FoxOs function not only as therapeutic targets, but also as biomarkers of disease onset and progression, since their cellular pathways are closely linked and overlap with several unique signal transduction pathways. However, biological outcome with EPO and FoxOs may sometimes be both unexpected and undesirable that can raise caution for these agents and warrant further investigations. Here we present the exciting as well as complicated role EPO and FoxOs possess to uncover the benefits as well as the risks of these agents for cell biology and clinical care in processes that range from stem cell development to uncontrolled cellular proliferation.

  9. Inhibiting inflammatory cytokines.

    PubMed

    Kluth, D C; Rees, A J

    1996-11-01

    Acute glomerulonephritis is a common cause of renal dysfunction and ultimately renal failure. The inflammation involved is a tightly regulated response with pro- and anti-inflammatory cytokines playing key roles. Interleukin-1 (IL-1) and tumor necrosis factor (TNF) are the principal pro-inflammatory cytokines produced by intrinsic cells and infiltrating leukocytes. IL-1 and TNF can be directly antagonized using IL-1 receptor antagonist (IL-1ra) or binding proteins such as soluble receptors or antibodies. Alternatively, cytokines with anti-inflammatory properties can be used to decrease IL-1 and TNF synthesis, increase the production of their natural antagonists and deactivate inflammatory cells such as macrophages. This review will focus on these anti-inflammatory cytokines, principally IL-4, IL-6, IL-10 and IL-13, and highlight recent research of their activities in existing models of renal disease. The results of these experiments offer a promising new avenue of treatment.

  10. Cytokines and thyroid function.

    PubMed

    Ajjan, R A; Watson, P F; Weetman, A P

    1996-01-01

    Cytokines play a crucial role in autoimmune thyroid disease (ATD) through various mechanisms. They are produced in the thyroid by intrathyroidal inflammatory cells, in particular lymphocytes, as well as by the thyroid follicular cells (TFC) themselves and may thus act in a cascade to enhance the autoimmune process (Fig. 1). Cytokines upregulate the inflammatory reaction through stimulation of both T and B cells, resulting in antibody production and tissue injury. In addition, intrathyroidal cytokines induce immunological changes in TFC including enhancement of both major histocompatibility complex (MHC) class I and class II molecule expression, and upregulation of adhesion and complement regulatory molecule expression. Cytokines can also modulate both growth and function of TFC and have a role in extrathyroidal complications of ATD, most importantly thyroid-associated ophthalmopathy (TAO), where they induce fibroblast proliferation and enhance the production of glycosaminoglycans (GAG), resulting in proptosis and the other clinical features of the disease. In addition to these effects, exogenous administration of cytokines has been associated with impairment of thyroid function ranging from the appearance of autoantibodies alone to the development of frank thyroid dysfunction. Cytokines have also been implicated in subacute thyroiditis (SAT) and amiodarone-induced thyroid dysfunction, as well as in thyroid function abnormalities occurring in patients with non-thyroidal illnesses (NTI). Genetic variations in cytokine genes represent potential risk factors for ATD, and disease associations have been described for polymorphisms in IL-1ra and TNF beta genes. Recent experimental evidence suggests the possibility of novel cytokine-based therapeutic approaches for ATD and its complications, in particular TAO.

  11. Using Biomarkers to Inform Cumulative Risk Assessment

    PubMed Central

    Ryan, P. Barry; Burke, Thomas A.; Cohen Hubal, Elaine A.; Cura, Jerome J.; McKone, Thomas E.

    2007-01-01

    Background Biomarkers are considered the method of choice for determining exposure to environmental contaminants and relating such exposures to health outcomes. However, the association between many biomarkers and outcome is not direct because of variability in sensitivity and susceptibility in the individual. Objectives We explore the relationship between environmental exposures and health outcomes as mitigated by differential susceptibility in individuals or populations and address the question “Can biomarkers enable us to understand and quantify better the population burden of disease and health effects attributable to environmental exposures?” Methods We use a case–study approach to develop the thesis that biomarkers offer a pathway to disaggregation of health effects into specific, if multiple, risk factors. We offer the point of view that a series or array of biomarkers, including biomarkers of exposure, biomarkers of susceptibility, and biomarkers of effect, used in concert offer the best means by which to effect this disaggregation. We commence our discussion by developing the characteristics of an ideal biomarker, then give some examples of commonly used biomarkers to show the strengths and weaknesses of current usage. We follow this by more detailed case-study assessment outlining the state-of-the-science in specific cases. We complete our work with recommendations regarding the future use of biomarkers and areas for continued development. Conclusions The case studies provide examples of when and how biomarkers can be used to infer the source and magnitude of exposure among a set of competing sources and pathways. The answer to this question is chemical specific and relates to how well the biomarker matches the characteristics of an “ideal” biomarker–in particular ease of collection and persistence. The use of biomarkers in combination provides a better opportunity to disaggregate both source and pathway contributions. PMID:17520075

  12. Cytokines: The Good, the Bad, and the Deadly.

    PubMed

    Ramani, Thulasi; Auletta, Carol S; Weinstock, Daniel; Mounho-Zamora, Barbara; Ryan, Patricia C; Salcedo, Theodora W; Bannish, Gregory

    2015-01-01

    Over the past 30 years, the world of pharmaceutical toxicology has seen an explosion in the area of cytokines. An overview of the many aspects of cytokine safety evaluation currently in progress and evolving strategies for evaluating these important entities was presented at this symposium. Cytokines play a broad role to help the immune system respond to diseases, and drugs which modulate their effect have led to some amazing therapies. Cytokines may be "good" when stimulating the immune system to fight a foreign pathogen or attack tumors. Other "good" cytokine effects include reduction of an immune response, for example interferon β reduction of neuron inflammation in patients with multiple sclerosis. They may be "bad" when their expression causes inflammatory diseases, such as the role of tumor necrosis factor α in rheumatoid arthritis or asthma and Crohn's disease. Therapeutic modulation of cytokine expression can help the "good" cytokines to generate or quench the immune system and block the "bad" cytokines to prevent damaging inflammatory events. However, care must be exercised, as some antibody therapeutics can cause "ugly" cytokine release which can be deadly. Well-designed toxicology studies should incorporate careful assessment of cytokine modulation that will allow effective therapies to treat unmet needs. This symposium discussed lessons learned in cytokine toxicology using case studies and suggested future directions. © The Author(s) 2015.

  13. Cytokines and Blastocyst Hatching.

    PubMed

    Seshagiri, Polani B; Vani, Venkatappa; Madhulika, Pathak

    2016-03-01

    Blastocyst implantation into the uterine endometrium establishes early pregnancy. This event is regulated by blastocyst- and/or endometrium-derived molecular factors which include hormones, growth factors, cell adhesion molecules, cytokines and proteases. Their coordinated expression and function are critical for a viable pregnancy. A rate-limiting event that immediately precedes implantation is the hatching of blastocyst. Ironically, blastocyst hatching is tacitly linked to peri-implantation events, although it is a distinct developmental phenomenon. The exact molecular network regulating hatching is still unclear. A number of implantation-associated molecular factors are expressed in the pre-implanting blastocyst. Among others, cytokines, expressed by peri-implantation blastocysts, are thought to be important for hatching, making blastocysts implantation competent. Pro-inflammatory (IL-6, LIF, GM-CSF) and anti-inflammatory (IL-11, CSF-1) cytokines improve hatching rates; they modulate proteases (MMPs, tPAs, cathepsins and ISP1). However, functional involvement of cytokines and their specific mediation of hatching-associated proteases are unclear. There is a need to understand mechanistic roles of cytokines and proteases in blastocyst hatching. This review will assess the available knowledge on blastocyst-derived pro-inflammatory and anti-inflammatory cytokines and their role in potentially regulating blastocyst hatching. They have implications in our understanding of early embryonic loss and infertility in mammals, including humans.

  14. Holocene climate changes in the eastern equatorial Pacific from hydrogen isotopes of multiple biomarkers from a Galápagos lake

    NASA Astrophysics Data System (ADS)

    Atwood, A.; Sachs, J. P.

    2012-12-01

    The climate dynamics of the tropical Pacific play a fundamental role in climate variability across the globe. Rainfall patterns in the tropical Pacific are largely governed by the position of the Intertropical Convergence Zone (ITCZ) and the El Niño/Southern Oscillation (ENSO). Robust reconstructions of past changes in these two climate phenomena have been elusive, as few paleoclimate records come from within the core regions of the ITCZ and ENSO but outside the complicating influence of continents. We present a Holocene rainfall record from the Galápagos Islands that is based on paired biomarker records from the sediment of El Junco Lake. Rainfall in this area is highly sensitive to both movements of the ITCZ and ENSO and is little affected by monsoons and other regional climate processes, allowing inference of changes in these large-scale climate phenomena from local rainfall patterns. We distinguish between ITCZ- and ENSO-related rainfall changes through analysis of biomarker distributions and hydrogen isotopes from several types of plants and algae that are thought to grow under differing climate conditions. These biomarker records show significant oscillations between wet and dry conditions throughout the Holocene and no evidence for multi-millennial scale changes in ENSO or the position of the ITCZ. The early Holocene (9 - 7 ka) is characterized by multi-centennial scale fluctuations in the position of the ITCZ and El Niño activity, while the mid-Holocene (6 - 4 ka) is characterized by predominately wetter conditions than modern and intermittent periods of a southward shifted ITCZ and weaker El Niño activity. The largest rainfall changes appear to have occurred over the last millennium even though the primary drivers of Earth's climate, including orbital parameters and continental ice sheet extent, did not change significantly during this time. Changes in the tropical Pacific inferred from our records are concomitant with global-scale changes of the

  15. Multiplex cytokine analysis of Werner syndrome

    PubMed Central

    Goto, Makoto; Hayata, Koichiro; Chiba, Junji; Matsuura, Masaaki; Iwaki-Egawa, Sachiko; Watanabe, Yasuhiro

    2015-01-01

    Summary We reported a minor inflammation-driven ageing (inflammageing) assessed by highly sensitive CRP (hsCRP) in normal individuals and patients with Werner syndrome (WS), followed by an ageing associated Th2-biased cytokine change in normal ageing in the previous papers. To further study the association of hsCRP and 26 cytokines/chemokines in 35 WS patients, a multiple cytokine array system was used in the same serum samples as were examined for hsCRP. The serum levels of Th2 cytokines (IL-4, IL-6, IL-10, and GM-CSF), Th1 products (IL-2, TNFα, IL-12, and IFNγ) and monocyte/macrophage products (MCP-1, basic FGF and G-CSF) in WS were significantly elevated compared with normal ageing. Elevated hsCRP level in WS was significantly correlated with IL-6, IL-12 and VEGF levels, if age and sex were taken into account. A pro-inflammatory cytokine/chemokine circuit-stimulated immunological shift to Th2 in WS was similar to normal ageing. These cytokine/chemokine changes may induce a systemic chronic inflammation monitored by hsCRP, though these immunological changes in WS were more complicated than normal ageing, possibly due to the WS-specific chronic inflammation such as skin ulcer, diabetes mellitus and central obesity with visceral fat deposition. Further study may warrant the pathophysiology of Th2 shift and Th2-biased inflammageing in normal ageing and WS. PMID:26668779

  16. IL-17 family: cytokines, receptors and signaling

    PubMed Central

    Gu, Chunfang; Wu, Ling; Li, Xiaoxia

    2013-01-01

    The interleukin 17 (IL-17) family, a subset of cytokines consisting of IL-17A-F, plays crucial roles in host defense against microbial organisms and in the development of inflammatory diseases. Although IL-17A is the signature cytokine produced by T helper 17 (Th17) cells, IL-17A and other IL-17 family cytokines have multiple sources ranging from immune cells to non-immune cells. The IL-17 family signals via their correspondent receptors and activates downstream pathways that include NFκB, MAPKs and C/EBPs to induce the expression of anti-microbial peptides, cytokines and chemokines. The proximal adaptor Act1 is a common mediator during the signaling of all IL-17 cytokines so far and is thus involved in IL-17 mediated host defense and IL-17-driven autoimmune conditions. This review will give an overview and recent updates on the IL-17family, the activation and regulation of IL-17 signaling as well as diseases associated with this cytokine family PMID:24011563

  17. IL-1β is a key cytokine that induces trypsin upregulation in the influenza virus-cytokine-trypsin cycle.

    PubMed

    Indalao, I L; Sawabuchi, T; Takahashi, E; Kido, H

    2017-01-01

    Severe influenza is characterized by a cytokine storm, and the influenza virus-cytokine-trypsin cycle is one of the important mechanisms of viral multiplication and multiple organ failure. The aim of this study was to define the key cytokine(s) responsible for trypsin upregulation. Mice were infected with influenza virus strain A/Puerto Rico/8/34 (H1N1) or treated individually or with a combination of interleukin-1β, interleukin-6, and tumor necrosis factor α. The levels of these cytokines and trypsin in the lungs were monitored. The neutralizing effects of anti-IL-1β antibodies on cytokine and trypsin expression in human A549 cells and lung inflammation in the infected mice were examined. Infection induced interleukin-1β, interleukin-6, tumor necrosis factor α, and ectopic trypsin in mouse lungs in a dose- and time-dependent manner. Intraperitoneal administration of interleukin-1β combined with other cytokines tended to upregulate trypsin and cytokine expression in the lungs, but the combination without interleukin-1β did not induce trypsin. In contrast, incubation of A549 cells with interleukin-1β alone induced both cytokines and trypsin, and anti-interleukin-1β antibody treatment abrogated these effects. Administration of the antibody in the infected mice reduced lung inflammation area. These findings suggest that IL-1β plays a key role in trypsin upregulation and has a pathological role in multiple organ failure.

  18. Inflammation biomarkers in vaginal fluid and preterm delivery

    PubMed Central

    Taylor, Brandie D.; Holzman, Claudia B.; Fichorova, Raina N.; Tian, Yan; Jones, Nicole M.; Fu, Wenjiang; Senagore, Patricia K.

    2013-01-01

    both PTD subtypes. Results were similar when a combination of IL-6 and bacterial vaginosis (BV) was explored. Thus, the use of multiple biomarkers did not detect PTD subtypes with a greater sensitivity than IL-6 alone, and IL-6 is a specific but non-sensitive marker for the detection of spontaneous PTD. LIMITATIONS, REASONS FOR CAUTION Our ability to find small effect size associations between PTD and inflammation biomarkers (OR <2.0) might have been limited by the modest number of less common PTD subtypes in our population (e.g. spontaneous delivery <35 weeks, PTD accompanied by HCA) and by relatively higher variability for some cytokines, for example tumor necrosis factor-α, IL-12p70, IL-10 and granulocyte-macrophage colony-stimulating factor, that are less stable and commonly undetectable or detectable at low levels in human vaginal secretions. WIDER IMPLICATIONS OF THE FINDINGS Larger studies are needed to further explore a role of inflammation biomarkers in combination with other risk factors, including specific BV-associated organisms, for the prediction of PTD subtypes. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by the National Institute of Child Health and Human Development, National Institute of Nursing, March of Dimes Foundation, Thrasher Research Foundation and Centers for Disease Control and Prevention. The authors have no conflicts of interest. PMID:23416276

  19. An integrated use of multiple biomarkers to investigate the individual and combined effect of copper and cadmium on the marine green mussel (Perna viridis).

    PubMed

    Goswami, Prasun; Hariharan, G; Godhantaraman, Nallamuthu; Munuswamy, Natesan

    2014-01-01

    The present study documents individual and combined sub-lethal effect of one redox active (copper) and one non-redox active (cadmium) metal on green mussel (Perna viridis). The mussels were exposed to 60 μg L(-1) of Cu and 150 μg L(-1) of Cd (individually and in combination) for 21 days. Histopathological and ultrastructural studies revealed significant metal induced alterations such as vacuolization, fusion of gill lamellae, enhance mucous deposition, hyperplasia and necrosis in gills. Antioxidant enzyme assays revealed significant increase in superoxide dismutase (SOD), glutathione S-transferase (GST) and glutathione peroxidase (GPx) activity. Similarly, single exposure to Cd and Cu caused significant induction in Malate dehydrogenase (MDH) activity. However, combined Cu+Cd exposure modulated suppression in MDH activity. Unlike MDH, Cu and Cd individual exposure resulted in a decrease in esterase (EST) activity, but their combined exposure caused an induction. Non-enzymatic biomarkers such as lipid peroxidation (LPO) and metallothionein (MT) levels showed no significant change in response to Cu exposure, whereas, individual Cd exposure or Cd exposure in combination with Cu caused significant changes in their levels. Comet assay revealed a significant increase in DNA damage upon metal exposure. These results indicate that Cu (redox active) and Cd (non-redox active) can induce measurable physiological, biochemical as well as genotoxic perturbations in mussels even at sub-lethal concentrations. A monitoring programme based on the biomarkers discussed here would be useful to study the effect of metal pollutants reaching the coastal waters.

  20. Novel chemiluminescent imaging microtiter plates for high-throughput detection of multiple serum biomarkers related to Down's syndrome via soybean peroxidase as label enzyme.

    PubMed

    Zhao, Fang; Chai, Da; Lu, Jusheng; Yu, Jiachao; Liu, Songqin

    2015-08-01

    Novel chemiluminescent (CL) imaging microtiter plates with high-throughput, low-cost, and simple operation for detection of four biomarkers related to Down's syndrome screening were developed and evaluated. To enhance the sensitivity of CL immunosensing, soybean peroxidase (SBP) was used instead of horseradish peroxide (HRP) as a label enzyme. The microtiter plates were fabricated by simultaneously immobilizing four capture monoclonal antibodies, anti-inhibin-A, anti-unconjugated oestriol (anti-uE3), anti-alpha-fetoprotein (anti-AFP), and beta anti-HCG (anti-β-HCG), on nitrocellulose (NC) membrane to form immunosensing microtiter wells. Under a sandwiched immunoassay, the CL signals on each sensing site of the microtiter plates were collected by a charge-coupled device (CCD), presenting an array-based chemiluminescence imaging method for detection of four target antigens in a well at the same time. The linear response to the analyte concentration ranged from 0.1 to 40 ng/mL for inhibin-A, 0.075 to 40 ng/mL for uE3, 0.2 to 400 ng/mL for AFP, and 0.4 to 220 ng/mL for β-HCG. The proposed microtiter plates possessed high-throughput, good stability, and acceptable accuracy for detection of four antigens in clinical serum samples and demonstrated potential for practical applicability of the proposed method to Down's syndrome screening. Graphical Abstract Schematic evaluation of the microtiter plater for simultaneous detection of the four biomarkers.

  1. Separating ITCZ- and ENSO-related rainfall changes in the Galápagos over the last 3 kyr using D/H ratios of multiple lipid biomarkers

    NASA Astrophysics Data System (ADS)

    Atwood, Alyssa R.; Sachs, Julian P.

    2014-10-01

    We present a 3000-yr rainfall reconstruction from the Galápagos Islands that is based on paired biomarker records from the sediment of El Junco Lake. Located in the eastern equatorial Pacific, the climate of the Galápagos Islands is governed by movements of the Intertropical Convergence Zone (ITCZ) and the El Niño-Southern Oscillation (ENSO). We use a novel method for reconstructing past ENSO- and ITCZ-related rainfall changes through analysis of molecular and isotopic biomarker records representing several types of plants and algae that grow under differing climatic conditions. We propose that δD values of dinosterol, a sterol produced by dinoflagellates, record changes in mean rainfall in El Junco Lake, while δD values of C34 botryococcene, a hydrocarbon unique to the green alga Botryococcus braunii, record changes in rainfall associated with moderate-to-strong El Niño events. We use these proxies to infer changes in mean rainfall and El Niño-related rainfall over the past 3000 yr. During periods in which the inferred change in El Niño-related rainfall opposed the change in mean rainfall, we infer changes in the amount of ITCZ-related rainfall. Simulations with an idealized isotope hydrology model of El Junco Lake help illustrate the interpretation of these proxy reconstructions. Opposing changes in El Niño- and ITCZ-related rainfall appear to account for several of the largest inferred hydrologic changes in El Junco Lake. We propose that these reconstructions can be used to infer changes in frequency and/or intensity of El Niño events and changes in the position of the ITCZ in the eastern equatorial Pacific over the past 3000 yr. Comparison with El Junco Lake sediment grain size records indicates general agreement of inferred rainfall changes over the late Holocene.

  2. Biomarkers of Selenium Status

    PubMed Central

    Combs, Gerald F.

    2015-01-01

    The essential trace element, selenium (Se), has multiple biological activities, which depend on the level of Se intake. Relatively low Se intakes determine the expression of selenoenzymes in which it serves as an essential constituent. Higher intakes have been shown to have anti-tumorigenic potential; and very high Se intakes can produce adverse effects. This hierarchy of biological activities calls for biomarkers informative at different levels of Se exposure. Some Se-biomarkers, such as the selenoproteins and particularly GPX3 and SEPP1, provide information about function directly and are of value in identifying nutritional Se deficiency and tracking responses of deficient individuals to Se-treatment. They are useful under conditions of Se intake within the range of regulated selenoprotein expression, e.g., for humans <55 μg/day and for animals <20 μg/kg diet. Other Se-biomarkers provide information indirectly through inferences based on Se levels of foods, tissues, urine or feces. They can indicate the likelihood of deficiency or adverse effects, but they do not provide direct evidence of either condition. Their value is in providing information about Se status over a wide range of Se intake, particularly from food forms. There is need for additional Se biomarkers particularly for assessing Se status in non-deficient individuals for whom the prospects of cancer risk reduction and adverse effects risk are the primary health considerations. This would include determining whether supranutritional intakes of Se may be required for maximal selenoprotein expression in immune surveillance cells. It would also include developing methods to determine low molecular weight Se-metabolites, i.e., selenoamino acids and methylated Se-metabolites, which to date have not been detectable in biological specimens. Recent analytical advances using tandem liquid chromatography-mass spectrometry suggest prospects for detecting these metabolites. PMID:25835046

  3. Profiling the human immune response to Mycobacterium tuberculosis by human cytokine array.

    PubMed

    Chen, Tao; Li, Zhenyan; Yu, Li; Li, Haicheng; Lin, Jinfei; Guo, Huixin; Wang, Wei; Chen, Liang; Zhang, Xianen; Wang, Yunxia; Chen, Yuhui; Liao, Qinghua; Tan, Yaoju; Shu, Yang; Huang, Wenyan; Cai, Changhui; Zhou, Zhongjing; Yu, Meiling; Li, Guozhou; Zhou, Lin; Zhong, Qiu; Bi, Lijun; Zhao, Meigui; Guo, Lina; Zhou, Jie

    2016-03-01

    Tuberculosis (TB) continues to be one of the most serious infectious diseases in the world, however, no effective biomarkers can be used for rapid screening of latent tuberculosis infection (LTBI) and active TB. In this study, serum cytokines were screened and tested as potential biomarker for TB diagnosis. Cytokine array was used to track the cytokine profile and its dynamic change after TB infection. The different expressions of cytokines were confirmed by ELISA assay. ROC curve analyses were used to evaluate the efficacy of a cytokine or cytokine combination for diagnosis. Eotaxin-2, ICAM-1, MCSF, IL-12p70, and IL-11 were significantly higher in the LTBI individuals. I-309, MIG, Eotaxin-2, IL-8, ICAM-1, IL-6sR, and Eotaxin were significantly higher in active TB patients. ROC curve analyses gave AUCs of 0.843, 0.898, and 0.888 for I-309, MIG, and IL-8, respectively, and 0.894 for the combination panel in active TB diagnosis. IFN-γ/IL-4 and IL-2/TNF-α ratios exhibit dynamic changes in the healthy control and LTBI to different stages of active TB. Serum cytokines, including I-309 and MIG, IL-8, Extoxin-2, ICAM-1 and combinations of cytokines, including IFN-γ/IL-4 and IL-2/TNF-α, can be used as serum biomarkers for LTBI and active TB screening, thus indicating prospective clinical applications. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. T(H)17 cytokines in autoimmune neuro-inflammation.

    PubMed

    Becher, Burkhard; Segal, Benjamin M

    2011-12-01

    It has been firmly established that IL-23 polarized T(H)17 cells are potent effectors in the pathogenesis of experimental autoimmune encephalitomyelitis (EAE). However, the relative importance of these cells in comparison to other encephalitogenic T(H) subsets, and the mechanisms that they employ to effect inflammatory demyelination, are topics of continuing investigation. Interestingly, deletion of individual 'T(H)17 cytokines', such as IL-17A, IL-17F, IL-22 and IL-21, does not phenocopy the complete EAE-resistance of IL-23-deficient mice. The instability of T(H)17 cells in vivo introduces an additional layer of complexity to their role in the context of relapsing or chronic disease. Recent data indicate that IL-23 drives the production of myeloid activating factors, such as GM-CSF, by myelin-reactive T cells and facilitates their accumulation in the CNS. This review discusses the above issues in relation to the use of T(H)17 cells and related factors as potential therapeutic targets and biomarkers in CNS autoimmune diseases such as multiple sclerosis (MS). Copyright © 2011 Elsevier Ltd. All rights reserved.

  5. Profiling of cytokines in human epithelial ovarian cancer ascites

    PubMed Central

    Matte, Isabelle; Lane, Denis; Laplante, Claude; Rancourt, Claudine; Piché, Alain

    2012-01-01

    Background The behavior of tumor cells is influenced by the composition of the surrounding tumor environment. The importance of ascites in ovarian cancer (OC) progression is being increasingly recognized. The characterization of soluble factors in ascites is essential to understand how this environment affects OC progression. The development of cytokine arrays now allows simultaneous measurement of multiple cytokines per ascites using a single array. Methods We applied a multiplex cytokine array technology that simultaneously measures the level of 120 cytokines in ascites from 10 OC patients. The ascites concentration of a subset (n = 5) of cytokines that was elevated based on the multiplex array was validated by commercially available ELISA. The ascites level of these 5 cytokines was further evaluated by ELISA in a cohort of 38 patients. Kaplan-Meier analysis was used to assess the association of cytokine expression with progression-free survival (PFS) in this cohort. Results We observed a wide variability of expression between different cytokines and levels of specific cytokines also varied in the 10 malignant ascites tested. Fifty-three (44%) cytokines were not detected in any of the 10 ascites. The level of several factors including, among others, angiogenin, angiopoietin-2, GRO, ICAM-1, IL-6, IL-6R, IL-8, IL-10, leptin, MCP-1, MIF NAP-2, osteprotegerin (OPG), RANTES, TIMP-2 and UPAR were elevated in most malignant ascites. Higher levels of OPG, IL-10 and leptin in OC ascites were associated with shorter PFS. IL-10 was shown to promote the anti-apoptotic activity of malignant ascites whereas OPG did not. Conclusion Our data demonstrated that there is a complex network of cytokine expression in OC ascites. Characterization of cytokine profiles in malignant ascites may provide information from which to prioritize key functional cytokines and understand the mechanism by which they alter tumor cells behavior. A better understanding of the cytokine network is

  6. Oral application of cytokines.

    PubMed

    Georgiades, J A; Fleischmann, W R

    1996-01-01

    A number of different laboratories reported on studies with orally administered interferons and cytokines. Their observations extend previous observations which showed that orally administered interferons and cytokines can exert both local and systemic effects. As difficult as it may be to understand how orally administered interferons and cytokines may exert both effects, the increasing number of laboratories that demonstrate biological effects with orally administered cytokines suggests that serious consideration be given to the possibility that orally administered interferons and cytokines can indeed exert effects. They also raise the possibility that these effects may have biological relevance for the treatment of human disease. Moreover, they may indicate that the nasal/oral region is a window on the environment. It is most important, however, to assure that these experiments are performed with special care to avoid presenting preliminary data that is not properly controlled. It is essential to carry out these studies with sufficient animals or patients to ascertain their significance; and to plan the studies as double-blind evaluations to avoid misinterpretations when subjective tests are used. Nevertheless, the overall data presented give one the impression of an area that should be pursued.

  7. [Cytokines and asthma].

    PubMed

    Gani, F; Senna, G; Piglia, P; Grosso, B; Mezzelani, P; Pozzi, E

    1998-10-01

    Asthma is a chronic inflammatory lung disease in which eosinophils are one of the most important involved cells. These cells accumulate in the lung because of cytokines, which are able to regulate cellular responses. The role of cytokines is well known in allergic asthma: IL4, IL5, IL3, GMCSF are the principally cytokine involved. IL4 regulate IgE synthesis while IL5, (and IL3) cause the activation and accumulation of eosinophils. In non allergic asthma, whilst only IL5 seemed to be important recent data, shows that also IL4 plays an important role. Therefore nowadays no relevant difference seems to exist between allergic and non allergic asthma; instead the primer is different: the allergen in allergic asthma and often an unknown factor in the non allergic asthma. Recently other cytokines have been proved to play a role in the pathogenesis of asthma. IL8 is chemotactic not only for neutrophils but also for eosinophils and might cause chronic inflammation in severe asthma. IL13 works like IL4, while RANTES seems to be a more important chemotactic agent than IL5. Finally IL10, which immunoregulates T lymphocyte responses, may reduce asthma inflammation. In conclusion cytokine made us to learn more about the pathogenesis of asthma even if we do not yet know when and how asthma inflammation develops.

  8. Immunoreactive cytokines within primates.

    PubMed

    Ahne, W; Mayr, A; Wiesner, H

    1996-12-01

    Peripheral blood mononuclear cells of primates (man, orang utan, gorilla, baboon), rodents (mouse, rat), carnivores (cat, dog), artiodactyls (cattle, goat, pig) and perissodactyls (horse) were isolated and stimulated with mitogens (5 micrograms/ml LPS, 5 micrograms/ml PHA) at 37 degrees C. Cytokines immunoreactive to monoclonal antibodies (mAb) directed to human cytokines (TNF-alpha, IL-1 alpha, IL-2, IL-6, IFN-gamma) could be detected by enzyme-linked immunosorbent assay (ELISA) in the case of primates only. The mAb used did not recognize cytokines of the other mammalian species investigated. The results demonstrate the close relationship within the primates from the immunophysiological point of view.

  9. Insulin resistance, atherogenicity, and iron metabolism in multiple sclerosis with and without depression: Associations with inflammatory and oxidative stress biomarkers and uric acid.

    PubMed

    Oliveira, Sayonara Rangel; Kallaur, Ana Paula; Lopes, Josiane; Colado Simão, Andrea Name; Vissoci Reiche, Edna Maria; de Almeida, Elaine Regina Delicato; Morimoto, Helena Kaminami; de Carvalho Jennings de Pereira, Wildea Lice; Alfieri, Daniela Frizon; Flauzino, Tamires; de Meleck Proença, Caio; Gomes, Anna Maria; Kaimen-Maciel, Damacio Ramón; Maes, Michael

    2017-04-01

    Depression is accompanied by metabolic disorders in iron metabolism, lipoproteins, and insulin resistance. We measured plasma levels of ferritin, iron, lipids, insulin, and glucose and computed the homeostasis model assessment (HOMA2IR) and atherogenic index of plasma (AIP) in MS patients with and without depression and healthy controls. Explanatory variables were serum uric acid, interleukin (IL)-6, lipid hydroperoxides (CL-LOOH), albumin, and C-reactive protein (CRP). Depression was assessed using the Hospital Anxiety and Depression Scale (HADS), neurological disability using the Expanded Disability Status Scale (EDSS), and disease progression using ∆EDSS over five years earlier. HOMA2IR and insulin were predicted by diagnosis (increased in MS), age and body mass index (BMI); AIP by diagnosis, sex, BMI, CRP, and uric acid; triglycerides by diagnosis (higher in MS without depression), age, BMI and uric acid; ferritin by diagnosis (higher in MS), sex, CRP, and albumin; and iron by albumin. The HADS score was significantly predicted by ∆EDSS, gastro-intestinal symptoms, iron (inverse), and age. MS is characterized by significantly increased insulin resistance, which is determined by increased insulin levels; and increased ferritin, a biomarker of inflammation. Depression in MS is not associated with increased insulin resistance and atherogenicity but with lowered iron.

  10. [Cytokine imbalance in critically ill patients: SIRS and CARS].

    PubMed

    Murata, A; Kikuchi, M; Mishima, S; Sakaki, S; Goto, H; Matsuoka, T; Tanaka, H; Yukioka, T; Shimazaki, S

    1999-07-01

    It remains difficult to treat severely ill patients, especially those who have sepsis and subsequent multiple organ dysfunction syndrome. We propose the hypothesis that the pathophysiology in the sequential sepsis and multiple organ dysfunction syndrome may be strongly related to the imbalance between inflammatory cytokines and antiinflammatory cytokines induced for the host defense to active neutrophils and endothelial cells. Thus we attempted to develop cytokine modulation therapy to normalize the cytokine balance in the host defense system. In this review, we elucidate the relationship between cytokine imbalance and SIRS/CARS in patients with severe burn injury. Furthermore, we examine the possible usage of G-CSF to amplify neutrophil function, and clarify the reasons why various innovative therapies against sepsis have failed.

  11. The effects of age and gender on plasma levels of 63 cytokines.

    PubMed

    Larsson, Anders; Carlsson, Lena; Gordh, Torsten; Lind, Anne-Li; Thulin, Måns; Kamali-Moghaddam, Masood

    2015-10-01

    Cytokines play important roles as regulators of cell functions, and over the last decades a number of cytokine assays have been developed. The aim of the present study was to investigate the effects of age and gender on a large number of cytokines. Plasma samples were collected from 33 healthy blood donors. The samples were analyzed using a multiplex proximity extension assay (PEA) allowing simultaneous measurement of 92 cytokines and four technical controls. Biomarkers with less than 80% quantitative results were excluded leaving 63 cytokines that were analyzed for the effects of gender and age. The plasma level of three of the investigated biomarkers (DNER, MCP-4 and MMP-10) were found to be significantly different for the two genders (adjusted p-value<0.05), and 15 of the biomarkers (CCL11, CCL25, CDCP1, CSF-1, CXCL11, CXCL9, FGF-23, Flt3L, HGF, IL-10RB, MCP-3, MCP-4, MMP-10, OPG, VEGF-A) were significantly associated with age. This study reveals the effects of age and gender on a large number of cytokine assays. CXCL5 and TNFB were significantly higher in females, while the other markers with significant gender-dependent differences were higher in males. For the markers that were significantly associated with age, only CXCL6 was found to decrease with age, while the other biomarkers increased with age.

  12. Myelin basic protein-primed T cells of female but not male mice induce nitric-oxide synthase and proinflammatory cytokines in microglia: implications for gender bias in multiple sclerosis.

    PubMed

    Dasgupta, Subhajit; Jana, Malabendu; Liu, Xiaojuan; Pahan, Kalipada

    2005-09-23

    Females are more susceptible than males to multiple sclerosis (MS). However, the underlying mechanism behind this gender difference is poorly understood. Because the presence of neuroantigen-primed T cells within the CNS is necessary for the development of MS, the present study was undertaken to investigate the activation of microglia by myelin basic protein (MBP)-primed T cells of male, female, and castrated male mice. Interestingly, MBP-primed T cells isolated from female and castrated male but not from male mice induced the expression of inducible nitric-oxide synthase (iNOS) and proinflammatory cytokines (interleukin-1beta (IL-1beta), IL-1alpha, IL-6, and tumor necrosis factor-alpha) in microglia by cell-cell contact. Again there was no apparent defect in male microglia, because MBP-primed T cells isolated from female and castrated male but not male mice were capable of inducing the production of NO in male primary microglia. Inhibition of female T cell contact-mediated microglial expression of proinflammatory molecules by dominant-negative mutants of p65 and C/EBPbeta suggest that female MBP-primed T cells induce microglial expression of proinflammatory molecules through the activation of NF-kappaB and C/EBPbeta. Interestingly, MBP-primed T cells of male, female, and castrated male mice were able to induce microglial activation of NF-kappaB. However, MBP-primed T cells of female and castrated male but not male mice induced microglial activation of C/EBPbeta. These studies suggest that microglial activation of C/EBPbeta but not NF-kappaB by T cell:microglial contact is a gender-specific event and that male MBP-primed T cells are not capable of inducing microglial expression of proinflammatory molecules due to their inability to induce the activation of C/EBPbeta in microglia. This novel gender-sensitive activation of microglia by neuroantigen-primed T cell contact could be one of the mechanisms behind the female-loving nature of MS.

  13. Utility of CSF Cytokine/Chemokines as Markers of Active Intrathecal Inflammation: Comparison of Demyelinating, Anti-NMDAR and Enteroviral Encephalitis

    PubMed Central

    Kothur, Kavitha; Wienholt, Louise; Mohammad, Shekeeb S.; Tantsis, Esther M.; Pillai, Sekhar; Britton, Philip N.; Jones, Cheryl A.; Angiti, Rajeshwar R.; Barnes, Elizabeth H.; Schlub, Timothy; Bandodkar, Sushil; Brilot, Fabienne; Dale, Russell C.

    2016-01-01

    Background Despite the discovery of CSF and serum diagnostic autoantibodies in autoimmune encephalitis, there are still very limited CSF biomarkers for diagnostic and monitoring purposes in children with inflammatory or autoimmune brain disease. The cause of encephalitis is unknown in up to a third of encephalitis cohorts, and it is important to differentiate infective from autoimmune encephalitis given the therapeutic implications. Aim To study CSF cytokines and chemokines as diagnostic biomarkers of active neuroinflammation, and assess their role in differentiating demyelinating, autoimmune, and viral encephalitis. Methods We measured and compared 32 cytokine/chemokines using multiplex immunoassay and APRIL and BAFF using ELISA in CSF collected prior to commencing treatment from paediatric patients with confirmed acute disseminated encephalomyelitis (ADEM, n = 16), anti-NMDAR encephalitis (anti-NMDAR E, n = 11), and enteroviral encephalitis (EVE, n = 16). We generated normative data using CSF from 20 non-inflammatory neurological controls. The sensitivity of CSF cytokine/chemokines to diagnose encephalitis cases was calculated using 95th centile of control values as cut off. We correlated CSF cytokine/chemokines with disease severity and follow up outcome based on modified Rankin scale. One-way hierarchical correlational cluster analysis of molecules was performed in different encephalitis and outcome groups. Results In descending order, CSF TNF-α, IL-10, IFN-α, IL-6, CXCL13 and CXCL10 had the best sensitivity (>79.1%) when all encephalitis patients were included. The combination of IL-6 and IFN-α was most predictive of inflammation on multiple logistic regression with area under the ROC curve 0.99 (CI 0.97–1.00). There were no differences in CSF cytokine concentrations between EVE and anti-NMDAR E, whereas ADEM showed more pronounced elevation of Th17 related (IL-17, IL-21) and Th2 (IL-4, CCL17) related cytokine/chemokines. Unlike EVE, heat map analysis

  14. Biomarkers in Diabetic Retinopathy

    PubMed Central

    Jenkins, Alicia J.; Joglekar, Mugdha V.; Hardikar, Anandwardhan A.; Keech, Anthony C.; O'Neal, David N.; Januszewski, Andrzej S.

    2015-01-01

    There is a global diabetes epidemic correlating with an increase in obesity. This coincidence may lead to a rise in the prevalence of type 2 diabetes. There is also an as yet unexplained increase in the incidence of type 1 diabetes, which is not related to adiposity. Whilst improved diabetes care has substantially improved diabetes outcomes, the disease remains a common cause of working age adult-onset blindness. Diabetic retinopathy is the most frequently occurring complication of diabetes; it is greatly feared by many diabetes patients. There are multiple risk factors and markers for the onset and progression of diabetic retinopathy, yet residual risk remains. Screening for diabetic retinopathy is recommended to facilitate early detection and treatment. Common biomarkers of diabetic retinopathy and its risk in clinical practice today relate to the visualization of the retinal vasculature and measures of glycemia, lipids, blood pressure, body weight, smoking, and pregnancy status. Greater knowledge of novel biomarkers and mediators of diabetic retinopathy, such as those related to inflammation and angiogenesis, has contributed to the development of additional therapeutics, in particular for late-stage retinopathy, including intra-ocular corticosteroids and intravitreal vascular endothelial growth factor inhibitors ('anti-VEGFs') agents. Unfortunately, in spite of a range of treatments (including laser photocoagulation, intraocular steroids, and anti-VEGF agents, and more recently oral fenofibrate, a PPAR-alpha agonist lipid-lowering drug), many patients with diabetic retinopathy do not respond well to current therapeutics. Therefore, more effective treatments for diabetic retinopathy are necessary. New analytical techniques, in particular those related to molecular markers, are accelerating progress in diabetic retinopathy research. Given the increasing incidence and prevalence of diabetes, and the limited capacity of healthcare systems to screen and treat

  15. Biomarkers in Diabetic Retinopathy.

    PubMed

    Jenkins, Alicia J; Joglekar, Mugdha V; Hardikar, Anandwardhan A; Keech, Anthony C; O'Neal, David N; Januszewski, Andrzej S

    2015-01-01

    There is a global diabetes epidemic correlating with an increase in obesity. This coincidence may lead to a rise in the prevalence of type 2 diabetes. There is also an as yet unexplained increase in the incidence of type 1 diabetes, which is not related to adiposity. Whilst improved diabetes care has substantially improved diabetes outcomes, the disease remains a common cause of working age adult-onset blindness. Diabetic retinopathy is the most frequently occurring complication of diabetes; it is greatly feared by many diabetes patients. There are multiple risk factors and markers for the onset and progression of diabetic retinopathy, yet residual risk remains. Screening for diabetic retinopathy is recommended to facilitate early detection and treatment. Common biomarkers of diabetic retinopathy and its risk in clinical practice today relate to the visualization of the retinal vasculature and measures of glycemia, lipids, blood pressure, body weight, smoking, and pregnancy status. Greater knowledge of novel biomarkers and mediators of diabetic retinopathy, such as those related to inflammation and angiogenesis, has contributed to the development of additional therapeutics, in particular for late-stage retinopathy, including intra-ocular corticosteroids and intravitreal vascular endothelial growth factor inhibitors ('anti-VEGFs') agents. Unfortunately, in spite of a range of treatments (including laser photocoagulation, intraocular steroids, and anti-VEGF agents, and more recently oral fenofibrate, a PPAR-alpha agonist lipid-lowering drug), many patients with diabetic retinopathy do not respond well to current therapeutics. Therefore, more effective treatments for diabetic retinopathy are necessary. New analytical techniques, in particular those related to molecular markers, are accelerating progress in diabetic retinopathy research. Given the increasing incidence and prevalence of diabetes, and the limited capacity of healthcare systems to screen and treat

  16. Multiplexed Detection of Cytokines Based on Dual Bar-Code Strategy and Single-Molecule Counting.

    PubMed

    Li, Wei; Jiang, Wei; Dai, Shuang; Wang, Lei

    2016-02-02

    Cytokines play important roles in the immune system and have been regarded as biomarkers. While single cytokine is not specific and accurate enough to meet the strict diagnosis in practice, in this work, we constructed a multiplexed detection method for cytokines based on dual bar-code strategy and single-molecule counting. Taking interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) as model analytes, first, the magnetic nanobead was functionalized with the second antibody and primary bar-code strands, forming a magnetic nanoprobe. Then, through the specific reaction of the second antibody and the antigen that fixed by the primary antibody, sandwich-type immunocomplex was formed on the substrate. Next, the primary bar-code strands as amplification units triggered multibranched hybridization chain reaction (mHCR), producing nicked double-stranded polymers with multiple branched arms, which were served as secondary bar-code strands. Finally, the secondary bar-code strands hybridized with the multimolecule labeled fluorescence probes, generating enhanced fluorescence signals. The numbers of fluorescence dots were counted one by one for quantification with epi-fluorescence microscope. By integrating the primary and secondary bar-code-based amplification strategy and the multimolecule labeled fluorescence probes, this method displayed an excellent sensitivity with the detection limits were both 5 fM. Unlike the typical bar-code assay that the bar-code strands should be released and identified on a microarray, this method is more direct. Moreover, because of the selective immune reaction and the dual bar-code mechanism, the resulting method could detect the two targets simultaneously. Multiple analysis in human serum was also performed, suggesting that our strategy was reliable and had a great potential application in early clinical diagnosis.

  17. Circulating Biomarkers in Bladder Cancer

    PubMed Central

    Nandagopal, Lakshminarayanan; Sonpavde, Guru

    2016-01-01

    Bladder cancer is a molecularly heterogeneous disease characterized by multiple unmet needs in the realm of diagnosis, clinical staging, monitoring and therapy. There is an urgent need to develop precision medicine for advanced urothelial carcinoma. Given the difficulty of serial analyses of metastatic tumor tissue to identify resistance and new therapeutic targets, development of non-invasive monitoring using circulating molecular biomarkers is critically important. Although the development of circulating biomarkers for the management of bladder cancer is in its infancy and may currently suffer from lower sensitivity of detection, they have inherent advantages owing to non-invasiveness. Additionally, circulating molecular alterations may capture tumor heterogeneity without the sampling bias of tissue biopsy. This review describes the accumulating data to support further development of circulating biomarkers including circulating tumor cells, cell-free circulating tumor (ct)-DNA, RNA, micro-RNA and proteomics to improve the management of bladder cancer. PMID:28035318

  18. Sepsis and cytokines: current status.

    PubMed

    Blackwell, T S; Christman, J W

    1996-07-01

    Sepsis is a constellation of clinical signs and symptoms resulting from excessive systemic host inflammatory response to infection. This inflammatory response is largely mediated by cytokines, which are released into the systemic circulation. Plasma concentrations of specific cytokines, TNF alpha, IL-1 beta, IL-6 and IL-8 are frequently elevated in human sepsis and cytokine concentrations correlate with severity and outcome of s