Modulation of the Serum Cytokine Expression Pattern in Hymenoptera Allergic Patients Treated with Specific Venom Immunotherapy

[EN] Venom immunotherapy (VIT) is an adequate model to explore the immune mechanisms underlying this type of treatment. We have investigated the use of protein arrays to detect variations in the levels of cytokines in patients receiving VIT. In the present study we selected 11 non-atopic patients with systemic reactions after Hymenoptera sting that received VIT during at least three years. In order to evaluate the success of VIT all of them should have tolerated a sting field after VIT. Serum samples were obtained before initiating VIT and after at least three years of successful VIT. We analyzed 42 serum proteins corresponding to a Th1/Th2 panel using protein array methodology. We observed a significant increase of Interleukin 10, Myeloid Macrophage Colony Stimulation Factor, Macrophage Derived Chemokine, Interleukin 1-α, Vascular Endothelial Growing Factor and Stem Cell Factor serum levels after successful VIT. We discuss the usefulness and normalization of this array method to analyze cytokines and other serum proteins. Monitoring these serum cytokines could help to predict the response and to elucidate the mechanisms underlying immunotherapy.Fundación para la Investigación de la Sociedad Española de Alergología e Inmunología Clínic

A new PTGDR promoter polymorphism in a population of children with asthma.

[EN] Recently, functional genetic variants of the PTGDR gene have been associated with asthma. The objective of this work was to study polymorphisms of the promoter region of PTGDR and their haplotype and diplotype combinations in a Spanish population of children with asthma. In this study, 200 Caucasian individuals were included. Asthma was specialist-physician diagnosed according to the ATS criteria. The polymorphisms were analyzed by direct sequencing. In the study, the new polymorphism (-613C > T) in the promoter region of PTGDR was analyzed. The CT genotype was more common in controls (17%) than in patients with asthma (1%) (p-value = 0.0003; OR, 0.057; 95% CI, 0.007-0.441). The CCCT CCCC diplotype (promoter positions -613, -549, -441, and -197) was more frequent in the group of patients with asthma [Fisher's p-value = 0.012; OR, 10.24; 95% CI (1.25-83.68)]; this diplotype is unambiguous. To our knowledge, this is the first study of -613C > T PTGDR polymorphism in patients. This analysis provides more complete information on influence of diplotype combinations of PTGDR polymorphisms in asthma.Fundación para la Investigación de la Sociedad Española de Alergología e Inmunología Clínica

Genome-wide expression profiling of B lymphocytes reveals IL4R increase in allergic asthma

[EN] Allergic asthma is a multifactorial disorder in which activation and differentiation of B lymphocytes toward the production of IgE play an essential role. In these B cells, molecular mechanisms to generate IgE antibodies from IgM depend on a complex network of molecules that trigger class-switch recombination specifically at the Sε region of the IgH locus. Several trans-membrane receptors and activating signaling cascades are known to physiologically participate in these processes, including the IL4R signaling pathway. In this regard, our group has studied in the past genetic polymorphisms in the IL4/IL4R pathway that might hold clinical correlations with atopy and asthma.Spanish Ministry of Health (FIS - Fondo de Investigación Sanitaria); Instituto de Salud Carlos III; FEDER - Fondo Europeo de Desarrollo Regional funds; Spanish Society of Allergology and Clinical Immunolog

YRNAs overexpression and potential implications in allergy

[EN] Background Small non-coding RNAs (snRNAs) develop important functions related to epigenetic regulation. YRNAs are snRNAs involved in the initiation of DNA replication and RNA stability that regulate gene expression. They have been related to autoimmune, cancer and inflammatory diseases but never before to allergy. In this work we described for the first time in allergic patients the differential expression profile of YRNAs, their regulatory mechanisms and their potential as new diagnostic and therapeutic targets. Methods From a previous whole RNAseq study in B cells of allergic patients, differential expression profiles of coding and non-coding transcripts were obtained. To select the most differentially expressed non coding transcripts, fold change and p-values were analyzed. A validation of the expression differences detected was developed in an independent cohort of 304 individuals, 208 allergic patients and 96 controls by using qPCR. Potential binding and retrotransponibility capacity were characterized by in silico structural analysis. Using a novel bioinformatics approach, RNA targets identification, functional enrichment and network analyses were performed. Results We found that almost 70% of overexpressed non-coding transcripts in allergic patients corresponded to YRNAs. From the three more differentially overexpressed candidates, increased expression was independently confirmed in the peripheral blood of allergic patients. Structural analysis suggested a protein binding capacity decrease and an increase in retrotransponibility. Studies of RNA targets allowed the identification of sequences related to the immune mechanisms underlying allergy. Conclusions Overexpression of YRNAs is observed for the first time in allergic patients. Structural and functional information points to their implication on regulatory mechanisms of the disease.Instituto de Salud Carlos III; European Regional Development Fund; Junta de Castilla y León; Consolidated Research Unit of Castilla y León; Ramón y Cajal program; FEDER/Ministerio de Ciencia, Innovación y Universidades - Agencia Estatal de Investigació

Kawasaki Disease Patient Stratification and Pathway Analysis Based on Host Transcriptomic and Proteomic Profiles

The aetiology of Kawasaki disease (KD), an acute inflammatory disorder of childhood, remains unknown despite various triggers of KD having been proposed. Host ‘omic profiles offer insights into the host response to infection and inflammation, with the interrogation of multiple ‘omic levels in parallel providing a more comprehensive picture. We used differential abundance analysis, pathway analysis, clustering, and classification techniques to explore whether the host response in KD is more similar to the response to bacterial or viral infections at the transcriptomic and proteomic levels through comparison of ‘omic profiles from children with KD to those with bacterial and viral infections. Pathways activated in patients with KD included those involved in anti-viral and anti-bacterial responses. Unsupervised clustering showed that the majority of KD patients clustered with bacterial patients on both ‘omic levels, whilst application of diagnostic signatures specific for bacterial and viral infections revealed that many transcriptomic KD samples had low probabilities of having bacterial or viral infections, suggesting that KD may be triggered by a different process not typical of either common bacterial or viral infections. Clustering based on the transcriptomic and proteomic responses during KD revealed three clusters of KD patients on both ‘omic levels, suggesting heterogeneity within the inflammatory response during KD. The observed heterogeneity may reflect differences in the host response to a common trigger, or variation dependent on different triggers of the condition

Reverse logistics, stakeholders' influence, organizational slack, and managers' posture

Reverse logistics (RL) has strategic importance. However, little is known concerning what motivates firms to adopt RL systems. Drawing on stakeholder theory formulations, organizational slack, and the manager's strategic stance concept, this article develops a model that proposes external, internal, and individual factors that affect the implementation of RL programs. Our framework considers three major explicative variables: the attributes of the stakeholder (power, legitimacy and urgency), organizational slack for RL programs, and the manager's strategic posture. The study draws on a sample of 118 Spanish companies and uses a probit model to determine the influence of these factors on the probability of firms to implement RL systems. The study finds that customers, employees, and the government salience in terms of RL activities and manager's progressive posture have a significant influence on the final decision of implanting RL programs. Conversely, the study finds that shareholder salience negatively impacts the decision.Fundación BBVA and the project “Estrategias en las empresas europeas internacionales y medioambiente: análisis de recursos humanos, producción y negocio” for supporting this research. They also acknowledge the help of Prof. Dr. Carlos Larrinaga in providing access to financial statements. They are indebted as well to the Spanish Minister of Education and Science and the Comunidad Autónoma de Madrid which have provided financial support under the research projects entitled “Diseño e implantación de las estrategias medioambientales de aprovisionamiento, fabricación y comercialización: relación con el rendimiento organizativo” (sec2001-1578-c02- 01), “La dirección de operaciones y las teorías de stakeholders y de recursos y capacidades. Implicaciones estratégicas en la gestión del ciclo de vida de los equipos informáticos” (SEJ04- 07877-C02-02),. “Efectos de los distintos tipos de relaciones entre las empresas y sus mercados: prácticas de marketing, orientación al mercado y resultados económicos”, and “ Innovación versus imitacón: un test de la capacidad innovadora de las empresas de la Comunidad de Madrid “.Publicad

A multi-platform approach to identify a blood-based host protein signature for distinguishing between bacterial and viral infections in febrile children (PERFORM): a multi-cohort machine learning study.

BACKGROUND Differentiating between self-resolving viral infections and bacterial infections in children who are febrile is a common challenge, causing difficulties in identifying which individuals require antibiotics. Studying the host response to infection can provide useful insights and can lead to the identification of biomarkers of infection with diagnostic potential. This study aimed to identify host protein biomarkers for future development into an accurate, rapid point-of-care test that can distinguish between bacterial and viral infections, by recruiting children presenting to health-care settings with fever or a history of fever in the previous 72 h. METHODS In this multi-cohort machine learning study, patient data were taken from EUCLIDS, the Swiss Pediatric Sepsis study, the GENDRES study, and the PERFORM study, which were all based in Europe. We generated three high-dimensional proteomic datasets (SomaScan and two via liquid chromatography tandem mass spectrometry, referred to as MS-A and MS-B) using targeted and untargeted platforms (SomaScan and liquid chromatography mass spectrometry). Protein biomarkers were then shortlisted using differential abundance analysis, feature selection using forward selection-partial least squares (FS-PLS; 100 iterations), along with a literature search. Identified proteins were tested with Luminex and ELISA and iterative FS-PLS was done again (25 iterations) on the Luminex results alone, and the Luminex and ELISA results together. A sparse protein signature for distinguishing between bacterial and viral infections was identified from the selected proteins. The performance of this signature was finally tested using Luminex assays and by calculating disease risk scores. FINDINGS 376 children provided serum or plasma samples for use in the discovery of protein biomarkers. 79 serum samples were collected for the generation of the SomaScan dataset, 147 plasma samples for the MS-A dataset, and 150 plasma samples for the MS-B dataset. Differential abundance analysis, and the first round of feature selection using FS-PLS identified 35 protein biomarker candidates, of which 13 had commercial ELISA or Luminex tests available. 16 proteins with ELISA or Luminex tests available were identified by literature review. Further evaluation via Luminex and ELISA and the second round of feature selection using FS-PLS revealed a six-protein signature: three of the included proteins are elevated in bacterial infections (SELE, NGAL, and IFN-γ), and three are elevated in viral infections (IL18, NCAM1, and LG3BP). Performance testing of the signature using Luminex assays revealed area under the receiver operating characteristic curve values between 89·4% and 93·6%. INTERPRETATION This study has led to the identification of a protein signature that could be ultimately developed into a blood-based point-of-care diagnostic test for rapidly diagnosing bacterial and viral infections in febrile children. Such a test has the potential to greatly improve care of children who are febrile, ensuring that the correct individuals receive antibiotics. FUNDING European Union's Horizon 2020 research and innovation programme, the European Union's Seventh Framework Programme (EUCLIDS), Imperial Biomedical Research Centre of the National Institute for Health Research, the Wellcome Trust and Medical Research Foundation, Instituto de Salud Carlos III, Consorcio Centro de Investigación Biomédica en Red de Enfermedades Respiratorias, Grupos de Refeencia Competitiva, Swiss State Secretariat for Education, Research and Innovation

Aberrant DNA methylation profile of chronic and transformed classic Philadelphia-negative myeloproliferative neoplasms

Most DNA methylation studies in classic Philadelphia-negative myeloproliferative neoplasms have been performed on a gene-by-gene basis. Therefore, a more comprehensive methylation profiling is needed to study the implications of this epigenetic marker in myeloproliferative neoplasms. Here, we have analyzed 71 chronic (24 polycythemia vera, 23 essential thrombocythemia and 24 primary myelofibrosis) and 13 transformed myeloproliferative neoplasms using genome-wide DNA methylation arrays. The three types of chronic Philadelphia-negative myeloproliferative neoplasms showed a similar aberrant DNA methylation pattern when compared to control samples. Differentially methylated regions were enriched in a gene network centered on the NF-κB pathway, indicating that they may be involved in the pathogenesis of these diseases. In the case of transformed myeloproliferative neoplasms, we detected an increased number of differentially methylated regions with respect to chronic myeloproliferative neoplasms. Interestingly, these genes were enriched in a list of differentially methylated regions in primary acute myeloid leukemia and in a gene network centered around the IFN pathway. Our results suggest that alterations in the DNA methylation landscape play an important role in the pathogenesis and leukemic transformation of myeloproliferative neoplasms. The therapeutic modulation of epigenetically-deregulated pathways may allow us to design targeted therapies for these patients

Whole-epigenome analysis in multiple myeloma reveals DNA hypermethylation of B cell-specific enhancers

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