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Ramos-Sevillano E.,CSIC - Biological Research Center | Ramos-Sevillano E.,CIBER ISCIII | Ramos-Sevillano E.,Institute Salud Carlos III ISCIII | Ramos-Sevillano E.,University of Oxford | And 16 more authors.
Infection and Immunity | Year: 2015

The complement system is a key component of the host immune response for the recognition and clearance of Streptococcus pneumoniae. In this study, we demonstrate that the amidase LytA, the main pneumococcal autolysin, inhibits complement-mediated immunity independently of effects on pneumolysin by a complex process of impaired complement activation, increased binding of complement regulators, and direct degradation of complement C3. The use of human sera depleted of either C1q or factor B confirmed that LytA prevented activation of both the classical and alternative pathways, whereas pneumolysin inhibited only the classical pathway. LytA prevented binding of C1q and the acute-phase protein C-reactive protein to S. pneumoniae, thereby reducing activation of the classical pathway on the bacterial surface. In addition, LytA increased recruitment of the complement downregulators C4BP and factor H to the pneumococcal cell wall and directly cleaved C3b and iC3b to generate degradation products. As a consequence, C3b deposition and phagocytosis increased in the absence of LytA and were markedly enhanced for the lytA ply double mutant, confirming that a combination of LytA and Ply is essential for the establishment of pneumococcal pneumonia and sepsis in a murine model of infection. These data demonstrate that LytA has pleiotropic effects on complement activation, a finding which, in combination with the effects of pneumolysin on complement to assist with pneumococcal complement evasion, confirms a major role of both proteins for the full virulence of the microorganism during septicemia. © 2015, American Society for Microbiology.

Casal Rubio J.,Complexo Hospitalario Universitario Of Vigo Chuvi | Casal Rubio J.,Complexo Hospitalario Universitario Of Vigo | Firvida-Perez J.L.,Complexo Hospitalario de Ourense CHOU | Lazaro-Quintela M.,Complexo Hospitalario Universitario Of Vigo Chuvi | And 9 more authors.
Cancer Chemotherapy and Pharmacology | Year: 2014

Purpose: This single arm, phase II study aims to evaluate the role of epidermal growth factor receptor-tyrosine-kinase inhibitor erlotinib as maintenance therapy following concurrent chemoradiotherapy (cCRT) in unresectable locally advanced non-small-cell lung cancer (NSCLC). Methods: Patients with unresectable stage IIIA o dry IIIB NSCLC with no evidence of tumor progression after receiving a standard cCRT regimen with curative intent were included. Oral erlotinib 150 mg/day was administered within 4-6 weeks after the end of the cCRT for a maximum of 6 months if no disease progression or intolerable toxicity occurred. Primary end point was the progression-free rate (PFR) at 6 months. Secondary end points included time to progression (TTP) and overall survival (OS). Results: Sixty-six patients were enrolled and received maintenance treatment with erlotinib [average: 4.5 months (95 % CI 4.0-5.0)]. PFR at 6 months was 63.5 % (41/66). With a median follow-up of 22.7 months (95 % CI 13.5-37.1), the median TTP was 9.9 months (95 % CI 6.2-12.1), and the median OS was 24.0 months (95 % CI 17.3-48.6). Most common adverse events (AEs) related to erlotinib were rash (78.8 %; 16.7 % grade 3), diarrhea (28.8 %; 1.5 % grade 3), fatigue (15.2 %; 1.5 % grade 3), anorexia (7.6 %; 1.5 % grade 3) and vomiting (4.6 %; none grade 3). Five patients (7.6 %) were withdrawn due to AEs. Conclusions: Erlotinib as maintenance therapy is an active treatment after cCRT in unselected patients with stage III NSCLC, reaching a 6-month PFR of 63.5 % and a median OS of 24 months. The safety profile of maintenance erlotinib was as expected and manageable. © 2013 Springer-Verlag.

Monyarch G.,Autonomous University of Barcelona | De Castro Reis F.,Autonomous University of Barcelona | Zock J.-P.,Institute Of Recerca Hospital Del Mar Imim | Zock J.-P.,CIBER ISCIII | And 17 more authors.
PLoS ONE | Year: 2013

Background: In a previous study, we showed that individuals who had participated in oil clean-up tasks after the wreckage of the Prestige presented an increase of structural chromosomal alterations two years after the acute exposure had occurred. Other studies have also reported the presence of DNA damage during acute oil exposure, but little is known about the long term persistence of chromosomal alterations, which can be considered as a marker of cancer risk. Objectives: We analyzed whether the breakpoints involved in chromosomal damage can help to assess the risk of cancer as well as to investigate their possible association with DNA repair efficiency. Methods: Cytogenetic analyses were carried out on the same individuals of our previous study and DNA repair errors were assessed in cultures with aphidicolin. Results: Three chromosomal bands, 2q21, 3q27 and 5q31, were most affected by acute oil exposure. The dysfunction in DNA repair mechanisms, expressed as chromosomal damage, was significantly higher in exposed-oil participants than in those not exposed (p= 0.016). Conclusion: The present study shows that breaks in 2q21, 3q27 and 5q31 chromosomal bands, which are commonly involved in hematological cancer, could be considered useful genotoxic oil biomarkers. Moreover, breakages in these bands could induce chromosomal instability, which can explain the increased risk of cancer (leukemia and lymphomas) reported in chronically benzene-exposed individuals. In addition, it has been determined that the individuals who participated in clean-up of the oil spill presented an alteration of their DNA repair mechanisms two years after exposure. © 2013 Fuster et al.

Aranda J.,Autonomous University of Barcelona | Aranda J.,Complexo Hospitalario Universitario a Coruna | Lopez M.,Autonomous University of Barcelona | Leiva E.,Autonomous University of Barcelona | And 4 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2014

The role of Acinetobacter baumannii ATCC 17978 UmuDC homologs A1S-0636-A1S-0637, A1S-1174-A1S-1173, and A1S-1389 (UmuDAb) in antibiotic resistance acquired through UV-induced mutagenesis was evaluated. Neither the growth rate nor the UV-related survival of any of the three mutants was significantly different from that of the wild-type parental strain. However, all mutants, and especially the umuDAb mutant, were less able to acquire resistance to rifampin and streptomycin through the activities of their error-prone DNA polymerases. Furthermore, in the A. baumannii mutant defective in the umuDAb gene, the spectrum of mutations included a dramatic reduction in the frequency of transition mutations, the mutagenic signature of the DNA polymerase V encoded by umuDC. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Rodriguez-Trigo G.,Servicio de Neumologia | Zock J.-P.,Center for Research in Environmental Epidemiology | Gomez F.P.,Servei de Pneumologia | Monyarch G.,Autonomous University of Barcelona | And 6 more authors.
Annals of Internal Medicine | Year: 2010

Background: In 2002, the oil tanker Prestige spilled more than 67 000 tons of bunker oil, heavily contaminating the coast of northwestern Spain. Objective: To assess respiratory effects and chromosomal damage in clean-up workers of the oil spill 2 years after the exposure. Design: Cross-sectional study. Setting: Fishermen cooperatives in coastal villages. Participants: Local fishermen who were highly exposed (n = 501) or not exposed (n = 177) to oil 2 years after the spill. Measurements: Respiratory symptoms; forced spirometry; methacholine challenge; markers of oxidative stress (8-isoprostane), airway inflammation (interleukins, tumor necrosis factor-α, and interferon-γ), and growth factor activity in exhaled breath condensate; and chromosomal lesions and structural alterations in circulating lymphocytes. Results: Compared with nonexposed participants, persons exposed to oil were at increased risk for lower respiratory tract symptoms (risk difference, 8.0 [95% CI, 1.1 to 14.8]). Lung function did not significantly differ between the groups. Among nonsmoking participants, exposed individuals had higher exhaled 8-isoprostane levels than nonexposed individuals (geometric mean ratio, 2.5 [CI, 1.7 to 3.7]), and exposed individuals with lower respiratory tract symptoms had higher 8-isoprostane levels than those of exposed individuals without symptoms. Exposed nonsmoking participants also had higher levels of exhaled vascular endothelial growth factor (risk difference, 44.8 [CI, 27.9 to 61.6]) and basic fibroblast growth factor (risk difference, 16.0 [CI, 3.5 to 28.6]). A higher proportion of exposed participants had structural chromosomal alterations (risk difference, 27.4 [CI, 10.0 to 44.8]), predominantly unbalanced alterations. The risk for elevated levels of exhaled 8-isoprostane, vascular endothelial growth factor, and basic fibroblast growth factor and structural chromosomal alterations seemed to increase with intensity of exposure to clean-up work. Limitations: The clinical significance of exhaled biomarkers and chromosomal findings are uncertain. The association between oil exposure and the observed changes may not be causal. The findings may not apply to spills involving other types of oil or to different populations of oil spill workers. Conclusion: Participation in clean-up of a major oil spill was associated with persistent respiratory symptoms, elevated markers of airway injury in breath condensate, and chromosomal damage. Primary Funding Source: Instituto de Salud Carlos III. © 2010 American College of Physicians.

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