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Guinea J.,Complutense University of Madrid | Guinea J.,Institute Investigacion Sanitaria del Hospital Gregorio Maranon | Guinea J.,CIBER ISCIII | Zaragoza O.,Institute Salud Carlos III | And 9 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2014

We report the molecular identifications and antifungal susceptibilities of the isolates causing fungemia collected in the CANDIPOP population-based study conducted in 29 Spanish hospitals. A total of 781 isolates (from 767 patients, 14 of them having mixed fungemia) were collected. The species found most frequently were Candida albicans (44.6%), Candida parapsilosis (24.5%), Candida glabrata (13.2%), Candida tropicalis (7.6%), Candida krusei (1.9%), Candida guilliermondii (1.7%), and Candida lusitaniae (1.3%). Other Candida and non-Candida species accounted for approximately 5% of the isolates. The presence of cryptic species was low. Compared to findings of previous studies conducted in Spain, the frequency of C. glabrata has increased. Antifungal susceptibility testing was performed by using EUCAST and CLSI M27-A3 reference procedures; the two methods were comparable. The rate of fluconazole-susceptible isolates was 80%, which appears to be a decrease compared to findings of previous studies, explained mainly by the higher frequency of C. glabrata. Using the species-specific breakpoints and epidemiological cutoff values, the rate of voriconazole and posaconazole in vitro resistance was low (<2%). In the case of C. tropicalis, using the EUCAST procedure, the rate of azole resistance was around 20%. There was a correlation between the previous use of azoles and the presence of fluconazole-resistant isolates. Resistance to echinocandins was very rare (2%), and resistance to amphotericin B also was very uncommon. The sequencing of the hot spot (HS) regions from FKS1 or FKS2 genes in echi-nocandin-resistant isolates revealed previously described point mutations. The decrease in the susceptibility to fluconazole in Spanish isolates should be closely monitored in future studies. Copyright © 2014, American Society for Microbiology. All Rights Reserved.


Venero J.L.,University of Seville | Venero J.L.,Institute Biomedicina Of Seville Ibis | Burguillos M.A.,Karolinska Institutet | Burguillos M.A.,Neuronal Survival Unit | And 2 more authors.
Cell Death and Differentiation | Year: 2011

Activation of microglia and inflammation-mediated neurotoxicity are suggested to have key roles in the pathogenesis of several neurodegenerative disorders. We recently published an article in Nature revealing an unexpected role for executioner caspases in the microglia activation process. We showed that caspases 8 and 3/7, commonly known to have executioner roles for apoptosis, can promote microglia activation in the absence of death. We found these caspases to be activated in microglia of PD and AD subjects. Inhibition of this signaling pathway hindered microglia activation and importantly reduced neurotoxicity in cell and animal models of disease. Here we review evidence suggesting that microglia can have a key role in the pathology of neurodegenerative disorders. We discuss possible underlying mechanisms regulating their activation and neurotoxic effect. We focus on the provocative hypothesis that caspase inhibition can be neuroprotective by targeting the microglia rather than the neurons themselves. © 2011 Macmillan Publishers Limited All rights reserved.


Munoz-Hernandez R.,University of Seville | Munoz-Hernandez R.,Boston Childrens Hospital | Miranda M.L.,University of Seville | Stiefel P.,University of Seville | And 12 more authors.
Hypertension | Year: 2014

Preeclampsia is a pregnancy-related disorder associated with increased cardiovascular risk for the offspring. Endothelial colony-forming cells (ECFCs) are a subset of circulating endothelial progenitor cells that participate in the formation of vasculature during development. However, the effect of preeclampsia on fetal levels of ECFCs is largely unknown. In this study, we sought to determine whether cord blood ECFC abundance and function are altered in preeclampsia. We conducted a prospective cohort study that included women with normal (n=35) and preeclamptic (n=15) pregnancies. We measured ECFC levels in the umbilical cord blood of neonates and characterized ECFC phenotype, cloning-forming ability, proliferation, and migration toward vascular endothelial growth factor-A and fibroblast growth factor-2, in vitro formation of capillary-like structures, and in vivo vasculogenic ability in immunodeficient mice. We found that the level of cord blood ECFCs was statistically lower in preeclampsia than in control pregnancies (P=0.04), a reduction that was independent of other obstetric factors. In addition, cord blood ECFCs from preeclamptic pregnancies required more time to emerge in culture than control ECFCs. However, once derived in culture, ECFC function was deemed normal and highly similar between preeclampsia and control, including the ability to form vascular networks in vivo. This study demonstrates that preeclampsia affects ECFC abundance in neonates. A reduced level of ECFCs during preeclamptic pregnancies may contribute to an increased risk of developing future cardiovascular events. © 2014 American Heart Association, Inc.


Demetri G.D.,Dana-Farber Cancer Institute | Garrett C.R.,H. Lee Moffitt Cancer Center and Research Institute | Schoffski P.,Catholic University of Leuven | Shah M.H.,Ohio State University | And 16 more authors.
Clinical Cancer Research | Year: 2012

Purpose: To analyze final long-term survival and clinical outcomes from the randomized phase III study of sunitinib in gastrointestinal stromal tumor patients after imatinib failure; to assess correlative angiogenesis biomarkers with patient outcomes. Experimental Design: Blinded sunitinib or placebo was given daily on a 4-week-on/2-week-off treatment schedule. Placebo-assigned patients could cross over to sunitinib at disease progression/study unblinding. Overall survival (OS) was analyzed using conventional statistical methods and the rank-preserving structural failure time (RPSFT) method to explore cross-over impact. Circulating levels of angiogenesis biomarkers were analyzed. Results: In total, 243 patients were randomized to receive sunitinib and 118 to placebo, 103 of whom crossed over to open-label sunitinib. Conventional statistical analysis showed that OS converged in the sunitinib and placebo arms (median 72.7 vs. 64.9 weeks; HR, 0.876; P=0.306) as expected, given the cross-over design. RPSFT analysis estimated median OS for placebo of 39.0 weeks (HR, 0.505, 95% CI, 0.262-1.134; P = 0.306). No new safety concerns emerged with extended sunitinib treatment. No consistent associations were found between the pharmacodynamics of angiogenesis-related plasma proteins during sunitinib treatment and clinical outcome. Conclusions: The cross-over design provided evidence of sunitinib clinical benefit based on prolonged time to tumor progression during the double-blind phase of this trial. As expected, following cross-over, there was no statistical difference in OS. RPSFT analysis modeled the absence of cross-over, estimating a substantial sunitinib OS benefit relative to placebo. Long-term sunitinib treatment was tolerated without new adverse events. ©2012 AACR.


PubMed | Hospital Universitario La Paz, University of Barcelona, Autonomous University of Barcelona, Hospital Infantil Universitario Nino Jesus and 8 more.
Type: | Journal: Cancer letters | Year: 2016

Epigenetic modifications have been shown to be important in developmental tumors as Ewing sarcoma. We profiled the DNA methylation status of 15 primary tumors, 7 cell lines, 10 healthy tissues and 4 human mesenchymal stem cells lines samples using the Infinium Human Methylation 450K. Differential methylation analysis between Ewing sarcoma and reference samples revealed 1166 hypermethylated and 864 hypomethylated CpG sites (Bonferroni p<0.05, --value with absolute difference of >0.20) corresponding to 392 and 470 genes respectively. Gene Ontology analysis of genes differentially methylated in Ewing sarcoma samples showed a significant enrichment of developmental genes. Membrane and cell signal genes were also enriched, among those, 11 were related to caveola formation. We identified differential hypermethylation of CpGs located in the body and S-Shore of the PTRF gene in Ewing sarcoma that correlated with its repressed transcriptional state. Reintroduction of PTRF/Cavin-1 in Ewing sarcoma cells revealed a role of this protein as a tumor suppressor. Restoration of caveolae in the membrane of Ewing sarcoma cells, by exogenously reintroducing PTRF, disrupts the MDM2/p53 complex, which consequently results in the activation of p53 and the induction of apoptosis.


Romero O.A.,Genes and Cancer Group | Torres-Diz M.,Genes and Cancer Group | Pros E.,Genes and Cancer Group | Savola S.,MRC Holland | And 10 more authors.
Cancer Discovery | Year: 2014

Our knowledge of small cell lung cancer (SCLC) genetics is still very limited, ampli-fication of L-MYC, N-MYC, and C-MYC being some of the well-established gene alterations. Here, we report our discovery of tumor-specific inactivation of the MYC-associated factor X gene, MAX, in SCLC. MAX inactivation is mutually exclusive with alterations of MYC and BRG1, the latter coding for an ATPase of the switch/sucrose nonfermentable (SWI/SNF) complex. We demonstrate that BRG1 regulates the expression of MAX through direct recruitment to the MAX promoter, and that depletion of BRG1 strongly hinders cell growth, specifically in MAX-deficient cells, heralding a synthetic lethal interaction. Furthermore, MAX requires BRG1 to activate neuroendocrine transcriptional programs and to upregulate MYC targets, such as glycolysis-related genes. Finally, inactivation of the MAX dimerization protein, MGA, was also observed in both non-small cell lung cancer and SCLC. Our results provide evidence that an aberrant SWI/SNF-MYC network is essential for lung cancer development. SIGNIFICANCE: We discovered that the MYC-associated factor X gene, MAX, is inactivated in SCLCs. Furthermore, we revealed a preferential toxicity of the inactivation of the chromatin remodeler BRG1 in MAX-deficient lung cancer cells, which opens novel therapeutic possibilities for the treatment of patients with SCLC with MAX-deficient tumors. © 2013 American Association for Cancer Research.


Santos-Garcia D.,Hospital A Marcide | De La Fuente-Fernandez R.,Hospital A Marcide | Valldeoriola F.,University of Barcelona | Palasi A.,University of Barcelona | And 6 more authors.
Journal of Neurology | Year: 2012

Some reports have emerged describing the occurrence of Guillain- Barré syndrome and polyneuropathy related to vitamin B12 deficiency in some patients with Parkinson's disease (PD) treated with continuous duodenal levodopa infusion. We describe five PD patients who developed axonal polyneuropathy and vitamin B12 deficiency while on treatment with duodenal levodopa infusion, review other cases reported in the literature, discuss potential etiologic factors, and suggest a possible algorithm for the management and prevention of this complication. One case of Guillain-Barré syndrome and at least 12 cases of polyneuropathy related to vitamin B12 deficiency have been reported in PD patients treated with duodenal levodopa infusion. Levodopa gel infusion may induce a decrease in vitamin B12 levels, leading to peripheral neuropathy. Additional pathogenetic mechanisms include alterations related to the metabolism of L-dopa, abnormal L-dopa absorption, and direct neurotoxicity of L-dopa at high doses. Vitamin B12 supplementation may need to be considered in PD patients on duodenal levodopa infusion therapy. Vitamin B12 deficiency in patients on duodenal levodopa infusion therapy may be more frequent than the published data suggest. We must be alert. © Springer-Verlag 2012.


Cubo L.,Autonomous University of Madrid | Hambley T.W.,University of Sydney | Sanz Miguel P.J.,TU Dortmund | Carnero A.,Institute Biomedicina Of Seville Ibis | And 2 more authors.
Dalton Transactions | Year: 2011

The physical and biological properties have been determined for three Pt(iv) complexes with trans amine ligands: trans,trans,trans-[PtCl 2(OH)2(dimethylamine)(isopropylamine)] (1IV), trans,trans,trans-[PtCl2(OH)2(dimethylamine)(methylamine)] (2IV) and trans,trans,trans-[PtCl2(OH) 2(isopropylamine)(methylamine)] (3IV). The crystal structures of 2IV and 3IV reveal substantial strain resulting from repulsion between the amine ligands and the chlorido and hydroxido ligands. All three complexes have reduction potentials in the range -666 to -770 mV, values usually associated with high resistance to reduction and low cytotoxicity. However, the complexes all demonstrate surprisingly high cytotoxicity with values and trends that closely follow those seen for the Pt(ii) congeners of these complexes. These results are consistent with more rapid reduction of the Pt(iv) complexes than would be expected based on the reduction potentials, perhaps associated with the trans arrangement of the chlorido ligands. © 2011 The Royal Society of Chemistry.


Lin R.-Z.,Harvard University | Moreno-Luna R.,Institute Biomedicina Of Seville Ibis | Moreno-Luna R.,Harvard University | Zhou B.,Harvard University | And 3 more authors.
Angiogenesis | Year: 2012

Mesenchymal stem cells (MSCs) can generate multiple end-stage mesenchymal cell types and constitute a promising population of cells for regenerative therapies. Additionally, there is increasing evidence supporting other trophic activities of MSCs, including the ability to enable formation of vasculature in vivo. Although MSCs were originally isolated from the bone marrow, the presence of these cells in the stromal vascular fraction of multiple adult tissues has been recently recognized. However, it is unknown whether the capacity to modulate vasculogenesis is ubiquitous to all MSCs regardless of their tissue of origin. Here, we demonstrated that tissue-resident MSCs isolated from four distinct tissues have equal capacity to modulate endothelial cell function, including formation of vascular networks in vivo. MSCs were isolated from four murine tissues, including bone marrow, white adipose tissue, skeletal muscle, and myocardium. In culture, all four MSC populations secreted a plethora of pro-angiogenic factors that unequivocally induced proliferation, migration, and tube formation of endothelial colony-forming cells (ECFCs). In vivo, co-implantation of MSCs with ECFCs into mice generated an extensive network of blood vessels with ECFCs specifically lining the lumens and MSCs occupying perivascular positions. Importantly, there were no differences among all four MSCs evaluated. Our studies suggest that the capacity to modulate the formation of vasculature is a ubiquitous property of all MSCs, irrespective of their original anatomical location. These results validate multiple tissues as potential sources of MSCs for future cell-based vascular therapies. © 2012 Springer Science+Business Media B.V.


Blanco-Aparicio C.,Spanish National Cancer Research Center | Carnero A.,Institute Biomedicina Of Seville Ibis
Biochemical Pharmacology | Year: 2013

PIM proteins belong to a family of ser/thr kinases composed of 3 members, PIM1, PIM2 and PIM3, with greatly overlapping functions. PIM kinases are mainly responsible for cell cycle regulation, antiapoptotic activity and the homing and migration of receptor tyrosine kinases mediated via the JAK/STAT pathway. PIM kinases have been found to be upregulated in many hematological malignancies and solid tumors. Although these kinases have been described as weak oncogenes, they are heavily targeted for anticancer drug discovery. The present review summarizes the discoveries made to date regarding PIM kinases as driving oncogenes in the process of tumorigenesis and their validation as drug targets. © 2012 Elsevier Inc.

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