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Vilas-Zornoza A.,University of Navarra | Agirre X.,University of Navarra | Abizanda G.,University of Navarra | Moreno C.,University of Navarra | And 16 more authors.
Leukemia | Year: 2012

Histone deacetylases (HDACs) have been identified as therapeutic targets due to their regulatory function in chromatin structure and organization. Here, we analyzed the therapeutic effect of LBH589, a class I-II HDAC inhibitor, in acute lymphoblastic leukemia (ALL). In vitro, LBH589 induced dose-dependent antiproliferative and apoptotic effects, which were associated with increased H3 and H4 histone acetylation. Intravenous administration of LBH589 in immunodeficient BALB/c-RAG2/γc/mice in which human-derived T and B-ALL cell lines were injected induced a significant reduction in tumor growth. Using primary ALL cells, a xenograft model of human leukemia in BALB/c-RAG2/γc/ mice was established, allowing continuous passages of transplanted cells to several mouse generations. Treatment of mice engrafted with T or B-ALL cells with LBH589 induced an in vivo increase in the acetylation of H3 and H4, which was accompanied with prolonged survival of LBH589-treated mice in comparison with those receiving vincristine and dexamethasone. Notably, the therapeutic efficacy of LBH589 was significantly enhanced in combination with vincristine and dexamethasone. Our results show the therapeutic activity of LBH589 in combination with standard chemotherapy in pre-clinical models of ALL and suggest that this combination may be of clinical value in the treatment of patients with ALL. © 2012 Macmillan Publishers Limited. Source

Ortiz-Espejo M.,University of Cordoba, Spain | Perez-Navero J.L.,University of Cordoba, Spain | Olza J.,University of Granada | Munoz-Villanueva M.C.,Maimonides Institute for Biomedical Research | And 2 more authors.
Nutrition | Year: 2013

Objective: Because nutritional support in perinatal life has been associated with metabolic programming, children with a history of extrauterine growth restriction (EUGR) might display alterations in the adipocyte and in the secretion of adipokines. The aim of this study was to assess adiponectin, resistin, and leptin concentrations in prepubertal children with a history of EUGR, and to determine the potential correlation between these adipokines and metabolic parameters. Methods: This case-control study sample included 38 prepubertal children with a history of EUGR and a control group of 123 healthy children of similar age and sex. Anthropometric measures and blood pressure were assessed. Biochemical markers and blood adipokine concentrations (adiponectin, resistin, and leptin) were evaluated. Results: Adiponectin concentration was significantly lower in the EUGR group compared with controls (EUGR: 11.49 ± 6.07 versus control: 25.72 ± 10.13 μg/mL), and resistin concentration was higher (EUGR: 20332.95 ± 6401.25 versus control: 8056.31 ± 3823.63 pg/mL), even after adjustment for gestational age, weight, and size at birth. Systolic blood pressure was associated with adipokines concentrations in the EUGR group (P < 0.001). In EUGR children adiponectin was associated with high-density lipoprotein cholesterol (P = 0.042), whereas resistin was associated with carbohydrate metabolism parameters (P < 0.001). Conclusions: Early postnatal malnutrition in EUGR children could program adipose tissue. Plasma adipokines can be measured in childhood to identify precocious changes that may be associated with a higher risk for metabolic syndrome or cardiovascular disease later in life. © 2013 Elsevier Inc. Source

Richter-Larrea J.A.,University of Navarra | Robles E.F.,University of Navarra | Fresquet V.,University of Navarra | Beltran E.,University of Navarra | And 9 more authors.
Blood | Year: 2010

In Burkitt lymphoma/leukemia (BL), achievement of complete remission with first-line chemotherapy remains a challenging issue, as most patients who respond remain disease-free, whereas those refractory have few options of being rescued with salvage therapies. The mechanisms underlying BL chemoresistance and how it can be circumvented remain undetermined. We previously reported the frequent inactivation of the proapoptotic BIM gene in B-cell lymphomas. Here we show that BIM epigenetic silencing by concurrent promoter hypermethylation and deacetylation occurs frequently in primary BL samples and BL-derived cell lines. Remarkably, patients with BL with hypermethylated BIM presented lower complete remission rate (24% vs 79%; P = .002) and shorter overall survival (P = .007) than those with BIM-expressing lymphomas, indicating that BIM transcriptional repression may mediate tumor chemoresistance. Accordingly, by combining in vitro and in vivo studies of human BL-xenografts grown in immunodeficient RAG2 -/-γc-/- mice and of murine B220+IgM + B-cell lymphomas generated in Eμ-MYC and Eμ-MYC-BIM +/- transgenes, we demonstrate that lymphoma chemoresistance is dictated by BIM gene dosage and is reversible on BIM reactivation by genetic manipulation or after treatment with histone-deacetylase inhibitors. We suggest that the combination of histone-deacetylase inhibitors and high-dose chemotherapy may overcome chemoresistance, achieve durable remission, and improve survival of patients with BL. © 2010 by The American Society of Hematology. Source

Ortea I.,Maimonides Institute for Biomedical Research | Rodriguez-Ariza A.,University of Cordoba, Spain | Chicano-Galvez E.,Maimonides Institute for Biomedical Research | Arenas Vacas M.S.,University of Cordoba, Spain | Jurado Gamez B.,University of Cordoba, Spain
Journal of Proteomics | Year: 2016

Lung cancer currently ranks as the neoplasia with the highest global mortality rate. Although some improvements have been introduced in recent years, new advances in diagnosis are required in order to increase survival rates. New mildly invasive endoscopy-based diagnostic techniques include the collection of bronchoalveolar lavage fluid (BALF), which is discarded after using a portion of the fluid for standard pathological procedures. BALF proteomic analysis can contribute to clinical practice with more sensitive biomarkers, and can complement cytohistological studies by aiding in the diagnosis, prognosis, and subtyping of lung cancer, as well as the monitoring of treatment response. The range of quantitative proteomics methodologies used for biomarker discovery is currently being broadened with the introduction of data-independent acquisition (DIA) analysis-related approaches that address the massive quantitation of the components of a proteome. Here we report for the first time a DIA-based quantitative proteomics study using BALF as the source for the discovery of potential lung cancer biomarkers. The results have been encouraging in terms of the number of identified and quantified proteins. A panel of candidate protein biomarkers for adenocarcinoma in BALF is reported; this points to the activation of the complement network as being strongly over-represented and suggests this pathway as a potential target for lung cancer research. In addition, the results reported for haptoglobin, complement C4-A, and glutathione S-transferase pi are consistent with previous studies, which indicates that these proteins deserve further consideration as potential lung cancer biomarkers in BALF. Our study demonstrates that the analysis of BALF proteins by liquid chromatography-tandem mass spectrometry (LC-MS/MS), combining a simple sample pre-treatment and SWATH DIA MS, is a useful method for the discovery of potential lung cancer biomarkers. Significance: Bronchoalveolar lavage fluid (BALF) analysis can contribute to clinical practice with more sensitive biomarkers, thus complementing cytohistological studies in order to aid in the diagnosis, prognosis, and subtyping of lung cancer, as well as the monitoring of treatment response. Here we report a panel of candidate protein biomarkers for adenocarcinoma in BALF. Forty-four proteins showed a fold-change higher than 3.75 among adenocarcinoma patients compared with controls. This report is the first DIA-based quantitative proteomics study to use bronchoalveolar lavage fluid (BALF) as a matrix for discovering potential biomarkers. The results are encouraging in terms of the number of identified and quantified proteins, demonstrating that the analysis of BALF proteins by a SWATH approach is a useful method for the discovery of potential biomarkers of pulmonary diseases. © 2016 Elsevier B.V. Source

Rivero-Juarez A.,Hospital Universitario Reina Sofia | Rivero-Juarez A.,Maimonides Institute for Biomedical Research | Lopez-Cortes L.F.,University of Seville | Camacho A.,Hospital Universitario Reina Sofia | And 11 more authors.
PLoS ONE | Year: 2012

Background: The aim of the study was to analyze the different impact of standard and low-dose Peg-IFN-α2a/RBV therapies on HCV viral decline in HIV/HCV genotype 3 co-infected patients during the first weeks of treatment. Methods: Plasma HCV viral decline was analyzed between baseline and weeks 1, 2 and 4 in two groups of treatment-naïve HCV genotype 3 patients with HIV co-infection. The Standard Dose Group (SDG) included patients who received Peg-IFN at 180 μg/per week with a weight-adjusted dose of ribavirin; Low-Dose Group (LDG) patients received Peg-IFN at 135 μg/per week with 800 mg/day ribavirin. The effect of IL28B genotype on HCV viral decline was evaluated in both groups. HCV viral decline was analyzed using a multivariate linear regression model. Results: One hundred and six patients were included: 48 patients in the SDG and 58 in the LDG. HCV viral decline for patients in the LDG was less than for those in the SDG (week 1:1.72±0.74 log10 IU/mL versus 1.78±0.67 log10 IU/mL, p = 0.827; week 2:2.3±0.89 log10 IU/mL versus 3.01±1.02 log10 IU/mL, p = 0.013; week 4:3.52±1.2 log10 IU/mL versus 4.09±1.1 log10 IU/mL, p = 0.005). The linear regression model identified the Peg-IFN/RBV dose as an independent factor for HCV viral decline at week 4. Conclusions: Our results showed that HCV viral decline was less for patients in the low-dose group compared to those receiving the standard dose. Until a randomized clinical trial is conducted, clinicians should be cautious about using lower doses of Peg-IFN/RBV in HIV/HCV genotype 3 co-infected patients. © 2012 Rivero-Jurez et al. Source

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