Proteomics in drug hypersensitivity

21 p.-4 fig.-1 tab.Drug hypersensitivity reactions result from the activation of the immune system by drugs or their metabolites. The clinical presentations of drug hypersensitivity can range from relatively mild local manifestations to severe systemic syndromes that can be life-threatening. As in other allergic reactions, the causes are multifactorial as genetic, metabolic and concomitant factors may influence the occurrence of drug hypersensitivity. Formation of drug protein adducts is considered a key step in drug adverse reactions, and in particular in the immunological recognition in drug hypersensitivity reactions. Nevertheless, non-covalent interactions of drugs with receptors in immune cells or with MHC clefts and/or exposed peptides can also play an important role. In recent years, development of proteomic approaches has allowed the identification and characterization of the protein targets for modification by drugs in vivo and in vitro, the nature of peptides exposed on MHC molecules, the changes in protein levels induced by drug treatment, and the concomitant modifications induced by danger signals, thus providing insight into context factors. Nevertheless, given the complexity and multifactorial nature of drug hypersensitivity reactions, understanding the underlying mechanisms also requires the integration of knowledge from genomic, metabolomic and clinical studies.This work has been supported by grants SAF2012-36519 and SAF2015-68590R from MINECO/FEDER and RETIC RD12/0013/0008 from ISCIII to D.P.-S., and by RETIC RD12/0013/0001 and CP15/00103 from ISCIII, and PI-0699-2011 and PI-0179-2014 from Junta de Andalucía to M.I.M.Peer reviewe

Anti-adhesive activity of cranberry phenolic compounds and their microbial-derived metabolites against uropathogenic Escherichia coli in bladder epithelial cell cultures

This is an open access article distributed under the Creative Commons Attribution License.-- This article belongs to the Special Issue Phenolics and Polyphenolics 2015.Cranberry consumption has shown prophylactic effects against urinary tract infections (UTI), although the mechanisms involved are not completely understood. In this paper, cranberry phenolic compounds and their potential microbial-derived metabolites (such as simple phenols and benzoic, phenylacetic and phenylpropionic acids) were tested for their capacity to inhibit the adherence of uropathogenic Escherichia coli (UPEC) ATCC®53503™ to T24 epithelial bladder cells. Catechol, benzoic acid, vanillic acid, phenylacetic acid and 3,4-dihydroxyphenylacetic acid showed anti-adhesive activity against UPEC in a concentration-dependent manner from 100-500 µM, whereas procyanidin A2, widely reported as an inhibitor of UPEC adherence on uroepithelium, was only statistically significant (p < 0.05) at 500 µM (51.3% inhibition). The results proved for the first time the anti-adhesive activity of some cranberry-derived phenolic metabolites against UPEC in vitro, suggesting that their presence in the urine could reduce bacterial colonization and progression of UTI.This work was funded by the Ministry of Economy and Competitiveness (MINECO) (Projects AGL-2010-17499 and AGL2012-40172-C02-01) and the Comunidad Autónoma de Madrid (Project ALIBIRD S2013/ABI-2728), Spain. Adelaida Esteban-Fernández would like to thank the MINECO-FPI program for her research contract.We acknowledge the support of the publication fee by the CSIC Open Access Publication Support Initiative through its Unit of Information Resources for Research (URICI).Peer Reviewe

Metal mobility and bioaccessibility from cyanide leaching heaps in a historical mine site

Unlike acidic sulfide mine wastes, where metal/loid mobility and bioaccessibility has been widely studied, less attention has been paid to alkaline cyanide heap leaching wastes. Thus, the main goal of this study is to evaluate the mobility and bioaccessibility of metal/loids in Fe-rich (up to 55%) mine wastes resulting from historical cyanide leaching activities. Wastes are mainly composed of oxides/oxyhydroxides (i.e. goethite and hematite), oxyhydroxisulfates (i.e. jarosite), sulfates (i.e., gypsum, evaporitic sulfate salts), carbonates (i.e., calcite, siderite) and quartz, with noticeable concentrations of metal/loids (e.g., 1453–6943 mg/kg of As, 5216–15,672 mg/kg; of Pb, 308–1094 mg/kg of Sb, 181–1174 mg/kg of Cu, or 97–1517 mg/kg of Zn). The wastes displayed a high reactivity upon rainfall contact associated to the dissolution of secondary minerals such as carbonates, gypsum, and other sulfates, exceeding the threshold values for hazardous wastes in some heap levels for Se, Cu, Zn, As, and sulfate leading to potential significant risks for aquatic life. High concentrations of Fe, Pb, and Al were released during the simulation of digestive ingestion of waste particles, with average values of 4825 mg/kg of Fe, 1672 mg/kg of Pb, and 807 mg/kg of Al. Mineralogy may control the mobility and bioaccessibility of metal/loids under rainfall events. However, in the case of the bioaccessible fractions different associations may be observed: i) the dissolution of gypsum, jarosite and hematite would mainly release Fe, As, Pb, Cu, Se, Sb and Tl; ii) the dissolution of an un-identified mineral (e.g., aluminosilicate or Mn oxide) would lead to the release of Ni, Co, Al and Mn and iii) the acid attack of silicate materials and goethite would enhance the bioaccessibility of V and Cr. This study highlights the hazardousness of wastes from cyanide heap leaching, and the need to adopt restoration measures in historical mine sites.This work was supported by the Spanish Ministry of Economic and Competitiveness through the projects TRAMPA (PID2020–119196RBC21) and by H2020 European Institute of Innovation and Technology (EIT RawMaterials) through the project Modular recovery process services for hydrometallurgy and water treatment (MORECOVERY). This work was partially supported by FCT (Portugal) through contract UID/ Multi/04349/2019. C.R C´anovas thanks the Spanish Ministry of Science and Innovation for the Postdoctoral Fellowship granted under application reference RYC2019–027949-I. M.D. Basallote thanks the Spanish Ministry of Science and Innovation for the Postdoctoral Fellowship granted under application reference IJC 2018–035056-I. The authors would also like to thank to Prof. Edward D. Burton, Ph.D (Editor) and three anonymous reviewers for the support and comments that notably improved the quality of the original paper

Cranberry-derived phenolic metabolites and urinary tract infections

Resumen del póster presentado a la 7th International Conference on Polyphenols and Health, celebrada en Tours (Francia) del 27 al 30 de octubre de 2015.The beneficial effects of cranbeny products against urinary tract infections (UTIs) have been attributed, at least partly, to their A-type proanthocyanidin (PAC) content. A-type PACs have shown uropathogenic Escherichia coli (UPEC)-anti-adhesive activity, although they are unlikely to appear in urine at relevant concentrations as they are poorly absorbed. One leading hypothesis is that PAC-derived metabolites present in urine would operate in the phase of UPEC adyherence to uroepithelial cells, preventing bacterial colonization. In addition to this, and as it is becoming evident that the intestine is a reservoir for uropathogenic bacteria, other hypothesis is that. A-type proanthocyanidins specifically decrease the transient intestinal colonisation b UPEC, consequently reducing the risk of UTI incidence. In any case, gut microbiota (and its inter-individual variability) seems to be an important factor to be considered. In this communication, we summarize our results from different approaches aimed to look into the mechanisms that are behind the protedive action of cranberry polyphenols against ITUs: 1)in vitro fermentations of cranbeny polyphenols with colonic microbiota, that were performed to access the microbial-derived metabolic profile of cranbeny polyphenols as well as their effect on gut microbiota survival, 2) an in vivo trial with model mouse intraurethral-inoculated wilh UPEC, that evaluated the effectiveness of cranbeny supplementation in bacterial infection as well as its impact on faecal phenolic metabolism and faecal microbiota, 3) testing the UPEC-antiadhesive capacity of cranbeny phenolic compounds and their metabolites in bladder epithelial cell culíures, and 4) ex vivo studies of UPEC-antiadhesive capacity of mice mines collected after cranbeny supplementation.Ministry of Economy and Competitiveness (MiNECO) (Projects AGL-2010-17499 and AGL2012-40172-C02-01) and the Comunidad Autónoma de Madrid (Project ALIBIRD S2013/ABI-2728), Spain.Peer Reviewe

Circulating DNA and survival in solid tumors

[Background]: The ability to undertake molecular analysis to inform on prognosis and predictors of response to therapy is limited by accessibility of tissue. Measurement of total circulating free DNA (cfDNA) or circulating tumor DNA (ctDNA) in peripheral blood may allow easier access to tumor material and help to predict clinical outcomes. [Methods]: A systematic review of electronic databases identified publications exploring the association between cfDNA or ctDNA and overall survival (OS) in solid tumors. HRs for OS were extracted from multivariable analyses and included in a meta-analysis. Pooled HRs were computed and weighted using generic inverse variance and random-effect modeling. For studies not reporting multivariable analyses, univariable ORs were estimated from Kaplan-Meier curves for OS at 1 and 3 years. [Results]: Thirty-nine studies comprising 4,052 patients were included in the analysis. Detection of ctDNA was associated with a significantly worse OS in multivariable analyses [HR, 2.70; 95% confidence interval (CI), 2.02-3.61; P < 0.001). Similar results were observed in the univariable analyses at 3 and 1 year (OR, 4.83; 95% CI, 3.20-7.28; P < 0.001).There was also a statistically significant association between high total cfDNA and worse OS for studies reporting multivariable and univariate data at 3 years (HR, 1.91; 95% CI, 1.59-2.29; P < 0.001 and OR, 2.82; 95% CI, 1.93-4.13; P < 0.001, respectively). [Conclusions]: High levels of total cfDNA and presence of ctDNA are associated with worse survival in solid tumors. [Impact]: Circulating DNA is associated with worse outcome in solid tumors.This work was supported by grants from CRIS cancer foundation (to A. Ocaña and A. Pandiella).Peer Reviewe

Enumeration and Characterization of Circulating Tumor Cells in Patients with Hepatocellular Carcinoma Undergoing Transarterial Chemoembolization

Circulating tumor cells (CTCs), and particularly circulating cancer stem cells (cCSC), are prognostic biomarkers for different malignancies and may be detected using liquid biopsies. The ex vivo culture of cCSCs would provide valuable information regarding biological aggressiveness and would allow monitoring the adaptive changes acquired by the tumor in real time. In this prospective pilot study, we analyzed the presence of EpCAM+ CTCs using the IsoFlux system in the peripheral blood of 37 patients with hepatocellular carcinoma undergoing transarterial chemoembolization (TACE). The average patient age was 63.5 ± 7.9 years and 91.9% of the patients were men. All patients had detectable CTCs at baseline and 20 patients (54.1%) showed CTC aggregates or clusters in their peripheral blood. The increased total tumor diameter (OR: 2.5 (95% CI: 1.3–4.8), p = 0.006) and the absence of clusters of CTCs at baseline (OR: 0.2 (95% CI: 0.0–1.0), p = 0.049) were independent predictors of a diminished response to TACE. Culture of cCSC was successful in five out of thirty-three patients, mostly using negative enrichment of CD45− cells, ultra-low adherence, high glucose, and a short period of hypoxia followed by normoxia. In conclusion, the identification of clusters of CTCs before TACE and the implementation of standardized approaches for cCSC culture could aid to predict outcomes and to define the optimal adjuvant therapeutic strategy for a true personalized medicine in hepatocellular carcinoma

Comparative effects of A- and B-type proanthocyanidins in the prevention of urinary tract infection in mice

Resumen del póster presentado a la VI International Conference on Polyphenols and Health celebrada en Buenos Aires (Argentina) del 16 al 19 de octubre de 2013.Consumption of cranberry (Vaccinium macrocarpum) is widely recommended forprophylaxis against urinary tract infections (UTI) in women. Among cranberry components, A-type proanthocyanins would be implicated in these preventive effects against UTI. However, proanthocyanidins are poorly absorbed in the small intestine, but subjected to extensive biotransformation in the colon, although studies are almost restricted to B-type proanthocyanidins. Therefore, the hypothesis of this study is that urinary metabolome from of A-type and B-type proanthocyanidins-mainly derived from their colonic catabolism-differ,and only metabolites from the A-type procyanidins have protective effects against UTI. To test this hypothesis, JAXc3H/OuJ female mice previously fed with specific diet (control, 1% cranberry extract and 1% grape seed extract) for 2 weeks, were inoculated with the uropathogenic E. coli (ATCC 53503™) to provoke infection, and maintained 2 weeks more before being sacrificed. Urine samples were collected at different times and subjected to E.coli counting, leukocytary esterase and nitrites analyses, and mieloperoxidase task. Samples of kidney and bladder tissues were also collected for E. coli counting and histopathologic analysis. Additionally, the capacity of the urine samples to inhibit bacterial adherence was tested in the T24 bladder cell line (ATCC HTB4 ™).Peer reviewe

Prevalence of Symptomatic Osteoarthritis in Spain: EPISER2016 Study

[Resumen] Introducción. La Sociedad Española de Reumatología elaboró en el año 2000 el estudio EPISER2000 para conocer la prevalencia de la artrosis y otras enfermedades reumáticas en España. Los cambios sociodemográficos y en los hábitos de vida ocurridos en los últimos años en España justifican actualizar los datos de las enfermedades reumáticas (EPISER2016). Objetivo. Estimar la prevalencia de artrosis sintomática de columna cervical, columna lumbar, cadera, rodilla y mano, en población adulta en España. Material y métodos. Estudio transversal de base poblacional. Se realizó un muestreo aleatorizado polietápico estratificado y por conglomerados. Los participantes fueron contactados por teléfono para cumplimentar un cuestionario de cribado de artrosis. El reumatólogo confirmaba o descartaba el diagnóstico. Se utilizaron los criterios-clínicos-ACR para diagnosticar artrosis de manos y los criterios clínico-radiológicos-ACR para diagnosticar la artrosis de rodilla y cadera. Resultados. La prevalencia de artrosis en España en una o más de las localizaciones estudiadas fue de 29,35%. La prevalencia de artrosis-cervical fue del 10,10% y de artrosis-lumbar del 15,52%. Ambas son más frecuentes en mujeres y a mayor edad, así como en personas con niveles de estudios bajos y obesidad. La prevalencia de artrosis de cadera fue del 5,13% y la de artrosis de rodilla del 13,83%; estas se asocian con el sexo femenino, sobrepeso y obesidad, menor frecuencia en nivel de estudios alto y con la edad. La prevalencia de la artrosis de mano fue del 7,73%. Es más frecuente en mujeres, obesas, con bajo nivel de estudios y mayor edad. Conclusiones. El estudio EPISER2016 es el primero que analiza la prevalencia de artrosis sintomática en 5 localizaciones (columna cervical, lumbar, rodilla, cadera y manos) en España. La artrosis de la columna lumbar es la más prevalente.[Abstract] Introduction. The Spanish Society of Rheumatology carried out the EPISER2000 study in 2000 to determine the prevalence of osteoarthritis and other rheumatic diseases in the Spanish population. Recent sociodemographic changes and lifestyle habits in Spain justified updating the epidemiological data on osteoarthritis and other rheumatic diseases (EPISER2016-study). Objective. To estimate the prevalence of symptomatic osteoarthritis of the cervical spine, lumbar spine, hip, knee and hand in the adult population in Spain. Material and methods. Cross-sectional population-based study. A multistage and stratified random cluster sampling was carried out. The participants were contacted by telephone to complete an osteoarthritis screening questionnaire. A rheumatologist confirmed or discarded the diagnosis. The ACR-clinical-criteria were used to diagnose hand-osteoarthritis and the ACR-clinical-radiological criteria to diagnose knee- and hip-osteoarthritis. To estimate the prevalence and its 95% confidence interval, weights were calculated according to the probability of selection in each of the sampling stages. Results. The prevalence of osteoarthritis in Spain in one or more of the locations studied was 29.35%. The prevalence of cervical-osteoarthritis was 10.10% and of lumbar-osteoarthritis 15.52%. Both are more frequent in women and at older ages, as well as in people with low levels of education and obesity. The prevalence of hip-osteoarthritis was 5.13%, that of knee-osteoarthritis 13.83%, these are associated with female sex, overweight and obesity. The prevalence of hand osteoarthritis was 7.73%. It is more frequent in women, who are obese, with a low educational level and who are older. Conclusion. The EPISER2016 study is the first to analyse the prevalence of symptomatic osteoarthritis in 5 locations (cervical, lumbar, knee, hip and hands) in Spain. Lumbar spine osteoarthritis is the most prevalent.EPISER2016 ha sido financiado por Celgene, Laboratorios, Gebro Pharma, Merck Sharp and Dohme de España, Pfizer y Sanofi-Aventis. Los financiadores no han intervenido en el diseño del estudio, recogida ni análisis de datos, ni en la redacción de este artículo. IRP yMS fueron financiados con programas Miguel Servet II y Contrato Río Hortega-Fondo de Investigación Sanitaria (CPII17/00026 y CM17/00101), respectivamente. El Fondo de Investigación Sanitaria, integrado en el Plan Nacional de Programa Científico, Desarrollo e Innovación Tecnológica 2013-2016, es financiado por el ISCIII-Subdirección General de Evaluación y Promoción de la Investigación-Fondo Europeo de Desarrollo Regional (FEDER) «Una forma de hacer Europa

Waist circumference percentiles for Hispanic-American children and comparison with other international references

Introduction Waist circumference (WC) constitutes an indirect measurement of central obesity in children and adolescents. Objective To provide percentiles of WC for Hispanic-American children and adolescents, and compare them with other international references. Materials and methods The sample comprised 13 289 healthy children between 6 and 18 years coming from public schools of middle and low socioeconomic levels in different parts of Argentina, Cuba, Spain, Mexico, and Venezuela. The LMS method to calculate WC percentiles was applied. Sex and age differences were assessed using Student'sttest and ANOVA (SPSS v.21.0). Comparisons were established with references from the United States, Colombia, India, China, Australia, Kuwait, Germany, Tunisia, Greece, and Portugal. Results WC increases with age in both sexes. Boys show higher WC in P3, P50, and P97. Comparison of 50th and 90th percentiles among populations from diverse sociocultural and geographical contexts shows high variability, not all justified by the measurement method. Discussion and conclusions Specific WC percentiles for sex and age, and P90 cut-off points are provided; these values are potentially useful to assess central obesity in Hispanic-American adolescent children