Fundacion Jimenez Diaz University Hospital

Madrid, Spain

Fundacion Jimenez Diaz University Hospital

Madrid, Spain
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Riaza Bermudo-Soriano C.,Ramon jal University Hospital | Perez-Rodriguez M.M.,Mount Sinai School of Medicine | Vaquero-Lorenzo C.,Autonomous University of Madrid | Baca-Garcia E.,Fundacion Jimenez Diaz University Hospital | And 2 more authors.
Pharmacology Biochemistry and Behavior | Year: 2012

Anxiety and stress-related disorders, namely posttraumatic stress disorder (PTSD), generalized anxiety disorder (GAD), obsessive-compulsive disorder (ODC), social and specific phobias, and panic disorder, are a major public health issue. A growing body of evidence suggests that glutamatergic neurotransmission may be involved in the biological mechanisms underlying stress response and anxiety-related disorders. The glutamatergic system mediates the acquisition and extinction of fear-conditioning. Thus, new drugs targeting glutamatergic neurotransmission may be promising candidates for new pharmacological treatments. In particular, N-methyl-d-aspartate receptors (NMDAR) antagonists (AP5, AP7, CGP37849, CGP39551, LY235959, NPC17742, and MK-801), NMDAR partial agonists (DCS, ACPC), α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptors (AMPARs) antagonists (topiramate), and several allosteric modulators targeting metabotropic glutamate receptors (mGluRs) mGluR1, mGluR2/3, and mGluR5, have shown anxiolytic-like effects in several animal and human studies. Several studies have suggested that polyamines (agmatine, putrescine, spermidine, and spermine) may be involved in the neurobiological mechanisms underlying stress-response and anxiety-related disorders. This could mainly be attributed to their ability to modulate ionotropic glutamate receptors, especially NR2B subunits. The aim of this review is to establish that glutamate neurotransmission and polyaminergic system play a fundamental role in the onset of anxiety-related disorders. This may open the way for new drugs that may help to treat these conditions. © 2011 Elsevier Inc. All rights reserved.

Garcia-Arranz M.,Autonomous University of Madrid | Garcia-Arranz M.,Health Research Institute | Guadalajara H.,Fundacion Jimenez Diaz University Hospital | De La Quintana P.,Hospital Universitario La Paz | And 3 more authors.
Stem Cells Translational Medicine | Year: 2015

The aim of this study was to determine whether treatment with adipose-derivedstem cells (ASCs)had any influence on fertility, course of pregnancy, newborn weight, or physical condition of newborns. We performed a retrospective study of patients with a desire to become pregnant after having received intralesional injection of autologous ASCs for the treatment of perianal or rectovaginal fistula associated with Crohn’s disease. We collected data on the resulting pregnancies, deliveries, and new-bornsofthese patients. ASCs were expanded in vitro and characterized according to the international guidelines for cell surface markers (clusters of differentiation) and differentiated to adipocytes, chon-drocytes, and osteocytes prior to implantation (except first implant in 2002). We analyzed five young women with Crohn’s disease treated with ASCs: one for rectovaginal and perianal fistula, two for rec-tovaginal fistula only, and two for perianal fistula only. All patients received 2 doses of 20 million and 40 million cells at an interval of 3–4months. Another patient received 2 doses of 6.6 million and 20 million ASCs with 9 months between each dose. Fertility and pregnancy outcomes were not affected by cell therapy treatment. No signs of treatment-related malformations were observed in the neonates by their respective pediatricians. In the patients studied, cell therapy with ASCs did not affect the course of pregnancy or newborn development. ©AlphaMed Press 2015

PubMed | Parc Tauli Health Corporation, Reina Sofia Hospital Complex, University of Barcelona, Valencian Institute of Oncology and 13 more.
Type: Journal Article | Journal: The oncologist | Year: 2016

In the neoadjuvant setting, changes in the proliferation marker Ki67 are associated with primary endocrine treatment efficacy, but its value as a predictor of response to chemotherapy is still controversial.We analyzed 262 patients with centralized basal Ki67 immunohistochemical evaluation derived from 4 GEICAM (Spanish Breast Cancer Group) clinical trials of neoadjuvant chemotherapy for breast cancer. The objective was to identify the optimal threshold for Ki67 using the receiver-operating characteristic curve method to maximize its predictive value for chemotherapy benefit. We also evaluated the predictive role of the defined Ki67 cutoffs for molecular subtypes defined by estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2).A basal Ki67 cutpoint of 50% predicted pathological complete response (pCR). Patients with Ki67 >50% achieved a pCR rate of 40% (36 of 91) versus a pCR rate of 19% in patients with Ki67 50% (33 of 171) (p = .0004). Ki67 predictive value was especially relevant in ER-HER2- and ER-HER2+ patients (pCR rates of 42% and 64%, respectively, in patients with Ki67 >50% versus 15% and 45%, respectively, in patients with Ki67 50%; p = .0337 and .3238, respectively). Both multivariate analyses confirmed the independent predictive value of the Ki67 cutpoint of 50%.Basal Ki67 proliferation index >50% should be considered an independent predictive factor for pCR reached after neoadjuvant chemotherapy, suggesting that cell proliferation is a phenomenon closely related to chemosensitivity. These findings could help to identify a group of patients with a potentially favorable long-term prognosis.The use of basal Ki67 status as a predictive factor of chemotherapy benefit could facilitate the identification of a patient subpopulation with high probability of achieving pathological complete response when treated with primary chemotherapy, and thus with a potentially favorable long-term prognosis.

PubMed | Hospital Provincial Of Castellon, Son Espases University Hospital, Fuenlabrada University Hospital, University of Murcia and 19 more.
Type: | Journal: Scientific reports | Year: 2017

Sunitinib is the currently standard treatment for metastatic renal cell carcinoma (mRCC). Multiple candidate predictive biomarkers for sunitinib response have been evaluated but none of them has been implemented in the clinic yet. The aim of this study was to analyze single nucleotide polymorphisms (SNPs) in genes linked to mode of action of sunitinib and immune response as biomarkers for mRCC. This is a multicenter, prospective and observational study involving 20 hospitals. Seventy-five mRCC patients treated with sunitinib as first line were used to assess the impact of 63 SNPs in 31 candidate genes on clinical outcome. rs2243250 (IL4) and rs5275 (PTGS2) were found to be significantly associated with shorter cancer-specific survival (CSS). Moreover, allele C (rs5275) was associated with higher PTGS2 expression level confirming its functional role. Combination of rs5275 and rs7651265 or rs2243250 for progression free survival (PFS) or CSS, respectively, was a more valuable predictive biomarker remaining significant after correction for multiple testing. It is the first time that association of rs5275 with survival in mRCC patients is described. Two-SNP models containing this functional variant may serve as more predictive biomarkers for sunitinib and could suppose a clinically relevant tool to improve the mRCC patient management.

PubMed | Autonomous University of Madrid, University of Valladolid, Rey Juan Carlos University, Institute Investigacion Sanitaria Hospital 12 Of Octubre I12 and Fundacion Jimenez Diaz University Hospital
Type: Journal Article | Journal: PloS one | Year: 2016

The presence of more than one non-severe pathogenic mutation in the same mitochondrial DNA (mtDNA) molecule is very rare. Moreover, it is unclear whether their co-occurrence results in an additive impact on mitochondrial function relative to single mutation effects. Here we describe the first example of a mtDNA molecule harboring three Lebers hereditary optic neuropathy (LHON)-associated mutations (m.11778G>A, m.14484T>C, m.11253T>C) and the analysis of its genetic, biochemical and molecular characterization in transmitochondrial cells (cybrids). Extensive characterization of cybrid cell lines harboring either the 3 mutations or the single classic m.11778G>A and m.14484T>C mutations revealed no differences in mitochondrial function, demonstrating the absence of a synergistic effect in this model system. These molecular results are in agreement with the ophthalmological characteristics found in the triple mutant patient, which were similar to those carrying single mtDNA LHON mutations.

Sanchez-Pernaute O.,University of Zürich | Sanchez-Pernaute O.,Fundacion Jimenez Diaz University Hospital | Filkova M.,University of Zürich | Gabucio A.,Fundacion Jimenez Diaz University Hospital | And 10 more authors.
Annals of the Rheumatic Diseases | Year: 2013

Objective Fibrin deposits are characteristic of the synovial tissues in rheumatoid arthritis (RA). Once citrullinated, fibrin becomes an autoantigen and is thought to contribute in this way to perpetuate the disease. Our study aimed to analyse the responses of RA synovial fibroblasts (RASF) to native and citrullinated fibrin. Methods The transcriptome induced by fibrin in RASF was approached with whole-genome-based gene expression arrays. The upregulation of selected proinflammatory genes by fibrin was confirmed in additional primary cell cultures using quantitative PCR and ELISA. Citrullination reactions were carried out with recombinant human peptidylarginine deiminases (PAD) 2 and 4. Results In the whole-genome array native fibrin was found to modulate the gene expression profile of RASF, particularly upregulating mRNA levels of several proinflammatory cytokines. The induction of interleukin (IL)-6 and IL-8 by fibrin was confirmed in additional samples at both the mRNA and the protein level. Blocking and knockdown experiments showed the participation of tolllike receptor (TLR)4 in the induction of both cytokines. As compared with the native macromolecule, PAD2- citrullinated fibrin induced significantly higher expression of the pro-inflammatory cytokines in these cells. Conclusions Our results suggest that fibrin mediates inflammatory responses in RASF via a TLR4 pathway. In this way, fibrin and particularly its citrullinated form may contribute to sustain the cytokine burst in RA.

Cortes J.,University of Barcelona | Saura C.,University of Barcelona | Bellet M.,University of Barcelona | Munoz-Couselo E.,University of Barcelona | And 4 more authors.
Nature Reviews Clinical Oncology | Year: 2011

HER2-positive tumors have a worse prognosis than HER2-negative cancers. Although the standard treatment for HER2-positive metastatic breast cancer is chemotherapy and trastuzumab, the combination of aromatase inhibitors with anti-HER2 therapies has become an available strategy in patients with HER2-positive and hormone receptor-positive tumors. However, although this new treatment option is more effective than hormone therapy alone, it has not been compared with the standard chemotherapy and trastuzumab-based regimens. In fact, the activity observed in randomized clinical trials with chemotherapy and anti-HER2 therapies seems to be higher than that observed with aromatase inhibitors and trastuzumab-based or lapatinib-based therapies. In this article, we highlight the importance of considering chemotherapy and anti-HER2 therapy as the standard of care in HER2-positive and hormone receptor-positive tumors. © 2011 Macmillan Publishers Limited. All rights reserved.

Martin-Reyes R.,Fundacion Jimenez Diaz University Hospital | Moreno R.,Hospital Universitario La Paz | Sanchez-Recalde A.,Hospital Universitario La Paz | Navarro F.,Fundacion Jimenez Diaz University Hospital | And 3 more authors.
International Journal of Cardiology | Year: 2012

Background/Objective Despite the effectiveness of first generation drug eluting stent, DES-1 (Taxus and Cypher) in avoiding restenosis and the need for new revascularizations, a slightly increase in stent thrombosis, ST have been published. Second generation drug eluting stent, DES-2 has been developed to optimize the results of percutaneous coronary intervention in terms of efficacy and safety, for avoiding early and late ST. Our objective was to compare the risk of ST between DES-1 and DES-2. Methods We performed a meta-analysis of 19 randomized trials. Overall 16,924 patients; 7294 were allocated to DES-1 and 9630 were allocated to DES-2. The primary endpoint was to compare the risk of overall ST during the first year. Other clinical outcomes of interest were to compare the incidence of early (< 1 month) and late ST (> 1 month-< 1 year). Results The incidence of overall ST was not increased in patients receiving DES-1 (1.13% DES-1 vs 0.75% DES-2, OR 0.79, 95% CI:0.45-1.40, p 0.43). There were no significant differences in the incidence of; early ST (0.85% DES-1 vs 0.53% DES-2, OR 0.68, 95% CI:0.31-1.51, p 0.35) and late ST (0.40% DES-1 vs 0.25% DES-2, OR 0.69, 95% CI:0.39-1.24, p 0.22). Conclusions During the first year after stent implantation, we didn't found differences in ST between DES-1 and DES-2. Most of ST was produced under appropriate anti-platelet therapy so it is possible that many other factors such as; clopidogrel resistance, procedural complications or stent malapposition were implicated. Safety after longer follow-up (> 1 year) remains unclear. © 2011 Elsevier Ireland Ltd. All rights reserved.

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