Human Anatomy Unit

Barcelona, Spain

Human Anatomy Unit

Barcelona, Spain
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Castellano J.J.,Human Anatomy Unit | Navarro A.,Human Anatomy Unit | Vinolas N.,Hospital Clinic of Barcelona | Marrades R.M.,Hospital Clinic of Barcelona | And 8 more authors.
Journal of Thoracic Oncology | Year: 2016

Introduction Long intergenic noncoding RNA-p21 (lincRNA-p21) is a long noncoding RNA transcriptionally activated by tumor protein p53 (TP53) and hypoxia inducible factor 1 alpha subunit (HIF1A). It is involved in the regulation of TP53-dependent apoptosis and the Warburg effect. We have investigated the role of lincRNA-p21 in NSCLC. Methods LincRNA-p21 expression was assessed in tumor and normal tissue from 128 patients with NSCLC and correlated with time to relapse and cancer-specific survival (CSS). H23, H1299, and HCC-44 cell lines were cultured in hypoxic conditions after silencing of lincRNA-p21. The TaqMan human angiogenesis array was used to explore angiogenesis-related gene expression. Levels of the protein vascular endothelial growth factor A were measured by enzyme-linked immunosorbent assay in the cell supernatants. Angiogenic capability was measured by human umbilical vein endothelial cell tube formation assay. Microvascular density in tumor samples was analyzed by immunohistochemistry. Results LincRNA-p21 was down-regulated in tumor tissue, but no association was observed with TP53 mutational status. High lincRNA-p21 levels were associated with poor CSS in all patients (p = 0.032). When patients were classified according to histological subtypes, the impact of lincRNA-p21 was confined to patients with adenocarcinoma in both time to relapse (p = 0.006) and CSS (p < 0.001). To explain the poor outcome of patients with high lincRNA-p21 expression, we studied the role of lincRNA-p21 in angiogenesis in vitro and observed a global downregulation in the expression of angiogenesis-related genes when lincRNA-p21 was inhibited. Moreover, supernatants from lincRNA-p21-inhibited cells were significantly less angiogenic and had lower levels of secreted vascular endothelial growth factor A than controls did. Finally, tumor samples with high lincRNA-p21 levels had higher microvascular density. Conclusions Our findings suggest that lincRNA-p21 affects outcome in patients with NSCLC adenocarcinoma through the regulation of angiogenesis. © 2016 International Association for the Study of Lung Cancer.


Artells R.,Human Anatomy Unit | Moreno I.,Hospital Municipal Of Badalona | Diaz T.,Human Anatomy Unit | Martinez F.,Hospital Municipal Of Badalona | And 5 more authors.
European Journal of Cancer | Year: 2010

Background: Human prominin-1 (CD133) is a novel pentaspan membrane protein which was originally classified as a marker of primitive haematopoietic and neural stem cells. Cancer stem cells have been isolated and expanded from leukaemia and several solid tumours, and have been associated with metastasis, chemoresistance and relapse. CD133 is recognised as a stem cell marker and is capable of identifying a tumour-initiating subpopulation in brain, colon, melanoma and other solid tumours. Methods: We assessed CD133 mRNA expression levels by RT-QPCR in tumour and matched normal tissue from 64 stages I-III colorectal cancer (CRC) patients and correlated tumour CD133 levels with clinicopathological characteristics and clinical outcome. Results: In four patients, CD133 mRNA was not expressed in tumour or in normal tissue. In the remaining 60 patients, expression levels were higher in tumour than in normal tissue (p = 0.001). Higher levels of CD133 expression were associated with shorter relapse-free interval (RFI) (p = 0.004) and overall survival (OS) (p < 0.0001). In the multivariate analyses, CD133 levels emerged as a prognostic marker for RFI and OS. Conclusions: We have observed longer RFI and OS in patients with lower levels of CD133, regardless of adjuvant treatment and other clinical characteristics. If these findings are confirmed in larger prospective studies, CD133 assessment may prove useful for new diagnostic and therapeutic procedures for CRC patients. © 2009 Elsevier Ltd. All rights reserved.


Objectives This study sought to evaluate the efficacy of enalapril and carvedilol to prevent chemotherapy-induced left ventricular systolic dysfunction (LVSD) in patients with hematological malignancies. Background Current chemotherapy may induce LVSD. Angiotensin-converting enzyme inhibitors and beta-blockers prevent LVSD in animal models of anthracycline-induced cardiomyopathy. Methods In this randomized, controlled study, 90 patients with recently diagnosed acute leukemia (n = 36) or patients with malignant hemopathies undergoing autologous hematopoietic stem cell transplantation (HSCT) (n = 54) and without LVSD were randomly assigned to a group receiving enalapril and carvedilol (n = 45) or to a control group (n = 45). Echocardiographic and cardiac magnetic resonance (CMR) imaging studies were performed before and at 6 months after randomization. The primary efficacy endpoint was the absolute change from baseline in LV ejection fraction (LVEF). Results The mean age of patients was 50 ± 13 years old, and 43% were women. At 6 months, LVEF did not change in the intervention group but significantly decreased in controls, resulting in a -3.1% absolute difference by echocardiography (p = 0.035) and -3.4% (p = 0.09) in the 59 patients who underwent CMR. The corresponding absolute difference (95% confidence interval [CI]) in LVEF was -6.38% (95% CI: -11.9 to -0.9) in patients with acute leukemia and -1.0% (95% CI: -4.5 to 2.5) in patients undergoing autologous HSCT (p = 0.08 for interaction between treatment effect and disease category). Compared to controls, patients in the intervention group had a lower incidence of the combined event of death or heart failure (6.7% vs. 22%, p = 0.036) and of death, heart failure, or a final LVEF <45% (6.7% vs. 24.4%, p = 0.02). Conclusions Combined treatment with enalapril and carvedilol may prevent LVSD in patients with malignant hemopathies treated with intensive chemotherapy. The clinical relevance of this strategy should be confirmed in larger studies. (Prevention of Left Ventricular Dysfunction During Chemotherapy [OVERCOME]; NCT01110824). © 2013 by the American College of Cardiology Foundation.


Navarro A.,Human Anatomy Unit | Tejero R.,Human Anatomy Unit | Diaz T.,Human Anatomy Unit | Ferrer G.,Human Anatomy Unit | And 2 more authors.
Clinical Cancer Research | Year: 2012

Purpose: A distinctive new group of polymorphisms is constituted by single-nucleotide polymorphism (SNP) in miRNA processing machinery in miRNA precursor molecules and in miRNA-binding sites, known as miRSNPs. The aim of this study was to ascertain the prognostic impact of six miRSNPs in patients with multiple myeloma and analyze the functional consequences. Experimental Design: One hundred and thirty-seven patients with chemosensitive multiple myeloma (73M/64F) intensified with autologous stem cell transplantation (ASCT) were studied. The median follow-up was 4 years. The genes and SNPs evaluated in genomic DNA by allelic discrimination were KRT81 (rs3660), AFF1 (rs17703261), FAM179b (rs1053667), and MIR196A2 (rs11614913) for miRNA target genes and TRBP (rs784567) and XPO5 (rs11077) for miRNA biogenesis pathway. Results: Overall survival (OS) was significantly longer in patients with KRT81 rs3660 C/C variant (P =0.037). Functional analysis showed that the presence of C variant in KRT81 30 untranslated region (UTR) is related with a reduction of the protein levels. Moreover, the reduction of KRT81 protein levels by siRNA in multiple myeloma cell lines is related to a decreased proliferation. On the other hand, OS was significantly longer in patients with C/C or A/C variant in XPO5 rs11077 (P=0.012). There was also a significantly longer progression-free survival (PFS) for this SNP (P=0.013). This SNP retained its prognostic impact on PFS and OS in a multivariate regression analysis (P = 0.028 and P = 0.014, respectively). Conclusion: This is the first report that relates miRSNPs with prognosis in multiple myeloma either in a keratin gene (KRT81), target of diverse miRNA multiple myeloma clusters, or in the miRNA biogenesis pathway-related protein exportin-5. ©2012 AACR.


Navarro A.,Human Anatomy Unit | Diaz T.,Human Anatomy Unit | Cordeiro A.,Human Anatomy Unit | Beya M.D.,Hospital Clinic Barcelona | And 2 more authors.
Leukemia and Lymphoma | Year: 2015

Epigenetic mechanisms are crucial for the inactivation of key genes related to the survival of Hodgkin lymphoma (HL) cells, and methylation is a frequent epigenetic mechanism of microRNA silencing. We have examined the methylation-induced silencing of tumor suppressor microRNAs in HL cell lines and confirmed our results in patient lymph nodes. In addition, we evaluated the in vitro effectiveness of 5-aza-2-deoxycytidine (5-Aza-dC) in HL cell lines. Ten microRNAs containing CpG islands in their promoter region were re-expressed in both the L-428 and L-1236 cell lines. Interestingly, miR-34a and miR-203, both known tumor suppressor microRNAs, were found to be methylated in cell lines and in patient samples. 5-Aza-dC treatment resulted in a dose-dependent antiproliferative effect at 72 h in all the HL cell lines. In summary, 5-Aza-dC treatment of HL cell lines inhibits proliferation at high doses and produces re-expression of the tumor suppressor microRNAs at low-intermediate doses. © 2015 Informa UK, Ltd.


Bosch X.,University of Barcelona | Esteve J.,University of Barcelona | Sitges M.,University of Barcelona | Ortiz J.T.,University of Barcelona | And 4 more authors.
Journal of Cardiac Failure | Year: 2011

Background: The current treatment of hematologic malignancies includes diverse potentially cardiotoxic chemotherapy agents, including high-dose myeloablative regimens used in autologous hematopoietic stem cell transplantation (HSCT). Many of these treatments could induce left ventricular dysfunction (LVD), and limit their efficacy. Angiotensin-converting enzime inhibitors and beta-blockers prevent LVD and prolong survival after infarction, and recent animal and pilot clinical studies suggest that they can prevent the development of chemotherapy-induced cardiac toxicity. Methods: This is a prevention, parallel-assignment, randomized, controlled, clinical efficacy study. Ninety patients recently diagnosed of acute leukemia or undergoing autologous HSCT and with normal LV ejection fraction will be randomized to enalapril and carvedilol or to the control group. Echocardiogram and a cardiac magnetic resonance imaging studies will be performed at baseline and 6-9 months after randomization. The primary efficacy endpoint is the change from baseline in LV ejection fraction. Secondary endpoints include the assessment of LV volumes and diastolic function, and the incidence of death, heart failure, or LVD. Conclusions: The OVERCOME study will be the first clinical trial to test the preventive efficacy on LVD of combined treatment with enalapril and carvedilol administered to patients with hematologic malignancies submitted to current treatment with intensive chemotherapy. © 2011 Elsevier Inc. All rights reserved.

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