MEIS1, PREP1, and PBX4 Are Differentially Expressed in Acute Lymphoblastic Leukemia: Association of MEIS1 Expression with Higher Proliferation and Chemotherapy Resistance

<p>Abstract</p> <p>Background</p> <p>The Three-amino acid-loop-extension (<it>TALE</it>) superfamily of homeodomain-containing transcription factors have been implicated in normal hematopoiesis and in leukemogenesis and are important survival, differentiation, and apoptosis pathway modulators. In this work, we determined the expression levels of <it>TALE </it>genes in leukemic-derived cell lines, in blood samples of patients with Acute lymphoblastic leukemia (ALL), and in the blood samples of healthy donors.</p> <p>Results</p> <p>Here we show increased expression of <it>MEIS1, MEIS2, </it>and <it>PREP1 </it>genes in leukemia-derived cell lines compared with blood normal cells. High levels of <it>MEIS1 </it>and <it>PREP1</it>, and low levels of <it>PBX4 </it>expression were also founded in samples of patients with ALL. Importantly, silencing of <it>MEIS1 </it>decreases the proliferation of leukemia-derived cells but increases their survival after etoposide treatment. Etoposide-induced apoptosis induces down-regulation of MEIS1 expression or <it>PREP1 </it>up-regulation in chemotherapy-resistant cells.</p> <p>Conclusions</p> <p>Our results indicate that up-regulation of <it>MEIS1 </it>is important for sustaining proliferation of leukemic cells and that down-regulation of <it>MEIS1 </it>or up-regulation of <it>PREP1 </it>and <it>PBX </it>genes could be implicated in the modulation of the cellular response to chemotherapeutic-induced apoptosis.</p

Collaborative blog as a multidisciplinary and interuniversity transversal learning tool

Llevamos décadas usando el blog como herramienta en docencia universitaria, fomentando el trabajo colaborativo en un entorno virtual familiar para el alumnado. Habitualmente, estas experiencias se realizan en asignaturas/ materias concretas de algún Grado. En el campo de la Arquitectura y la Edificación es imprescindible fomentar la transversalidad entre: Proyectos, Estructuras, Construcción e Instalaciones; y la colaboración y diálogo entre profesionales, garantizando la calidad de la obra construida. El Grado en Arquitectura y de Ingeniería de Edificación de la UCAM Universidad Católica de Murcia y el Grado en Fundamentos de la Arquitectura de la Universitat Politècnica de València, pusieron en marcha el curso 21/22 un proyecto de innovación docente, que utiliza el blog con una nueva y amplia perspectiva, implicando al profesorado y alumnado de varias asignaturas/materias de ambos grados y universidades. La participación activa del estudiantado nutrió el blog con 5 publicaciones por participante y semestre. Se ampliaron los conocimientos específicos y se trabajaron competencias básicas y trasnversales: la iniciación a la investigación, el aprendizaje autónomo, etc.; en un entorno colaborativo que despertó su razonamiento crítico y capacidad de gestión de información. Los buenos resultados motivan la continuidad del proyecto en este curso académico, estableciendo sinergias interuniversitarias muy enriquecedoras.It is been a while we have been using the blog as a tool for university teaching, aiming promoting collaborative work, in a daily virtual environment for students. These experiences are carried out in specific subjects/courses of a specific university degree. In the field of Architecture and Building, it is essential to promote transversality between: Project Design, Structures, Construction and Installations; as well as encourage collaboration and dialogue between professionals, guaranteeing the quality of the built work. The Degree in Architecture and the Degree in Building Engineering at UCAM Universidad Católica de Murcia, together with the Degree in the Fundamentals of Architecture of the Universitat Politècnica de València, launched together in the 21/22 academic year, a Teaching Innovation Project, which uses the blog with a new and broad perspective, involving teachers and students of various subjects/courses of both degrees and universities. The students’ active participation provided this blog with five publications per participant and semester. Specific knowledge was expanded and basic and transversal skills were worked on: initiation to research, autonomous learning, etc.; in a collaborative environment that awakened their critical thinking and information management skills

Sensitization of U937 leukemia cells to doxorubicin by the MG132 proteasome inhibitor induces an increase in apoptosis by suppressing NF-kappa B and mitochondrial membrane potential loss

Background: The resistance of cancerous cells to chemotherapy remains the main limitation for cancer treatment at present. Doxorubicin (DOX) is a potent antitumor drug that activates the ubiquitin-proteasome system, but unfortunately it also activates the Nuclear factor kappa B (NF-k{cyrillic}B) pathway leading to the promotion of tumor cell survival. MG132 is a drug that inhibits I kappa B degradation by the proteasome-avoiding activation of NF-k{cyrillic}B. In this work, we studied the sensitizing effect of the MG132 proteasome inhibitor on the antitumor activity of DOX. Methods: U937 human leukemia cells were treated with MG132, DOX, or both drugs. We evaluated proliferation, viability, apoptosis, caspase-3, -8, and -9 activity and cleavage, cytochrome c release, mitochondrial membrane potential, the Bcl-2 and Bcl-XL antiapoptotic proteins, senescence, p65 phosphorylation, and pro- and antiapoptotic genes. Results: The greatest apoptosis percentage in U937 cells was obtained with a combination of MG132 + DOX. Likewise, employing both drugs, we observed a decrease in tumor cell proliferation and important caspase-3 activation, as well as mitochondrial membrane potential loss. Therefore, MG132 decreases senescence, p65 phosphorylation, and the DOX-induced Bcl-2 antiapoptotic protein. The MG132 + DOX treatment induced upregulation of proapoptotic genes BAX, DIABLO, NOXA, DR4, and FAS. It also induced downregulation of the antiapoptotic genes BCL-XL and SURVIVIN. Conclusion: MG132 sensitizes U937 leukemia cells to DOX-induced apoptosis, increasing its anti-leukemic effectiveness. © 2014 Ortiz-Lazareno et al.; licensee BioMed Central Ltd

Addition of pentoxifylline to pegylated interferon-alpha-2a and ribavirin improves sustained virological response to chronic hepatitis C virus: a randomized clinical trial

Background and aim. The commonly accepted treatment for hepatitis C virus (HCV) infection, pegylated interferon alpha (PEG INF-alpha) and ribavirin, leads to 50–60% of sustained virological response (SVR). On the other hand, pentoxifylline (PTX) possesses antiviral and hepatoprotector properties. Aim. To investigate whether the addition of PTX to conventional hepatitis C treatment increases SVR.Material and methods. Seventy two patients of both genders were studied in a randomized fashion; the diagnosis of chronic HCV infection was made according to clinical and laboratory criteria and histopathologically classified according to METAVIR scoring system criteria. HCV viral load was tested by PCR, baseline, and after 6 months of treatment, as well as anti-HCV, anti-hepatitis B virus, and anti-human immunodeficiency virus antibodies by enzyme-linked immunosorbent assay. During 48 weeks, control group patients were treated with PEG INF-alpha-2a plus ribavirin. PTX was administered to Experimental Group patients prior to the treatment.Results. Demographic data were similar in both groups. Experimental- and control-group subjects were at F2 and F3 states according to the METAVIR classification. The most common HCV genotypes were 1a and 1b (39% in the control group in each case, and 42% in the experimental group in each case). At the end of the study, hepatic enzymes and viral load decreased in both groups to similar values. SVR in the experimental group increased significantly (p < 0.05) when compared with standard therapy alone.Conclusion. Addition of PTX to conventional chronic hepatitis C treatment may increase the percentage of patients with SVR

Cervical Cancer Cell Supernatants Induce a Phenotypic Switch from U937-Derived Macrophage-Activated M1 State into M2-Like Suppressor Phenotype with Change in Toll-Like Receptor Profile

Cervical cancer (CC) is the second most common cancer among women worldwide. Infection with human papillomavirus (HPV) is the main risk factor for developing CC. Macrophages are important immune effector cells; they can be differentiated into two phenotypes, identified as M1 (classically activated) and M2 (alternatively activated). Macrophage polarization exerts profound effects on the Toll-like receptor (TLR) profile. In this study, we evaluated whether the supernatant of human CC cells HeLa, SiHa, and C-33A induces a shift of M1 macrophage toward M2 macrophage in U937-derived macrophages. Results. The results showed that soluble factors secreted by CC cells induce a change in the immunophenotype of macrophages from macrophage M1 into macrophage M2. U937-derived macrophages M1 released proinflammatory cytokines and nitric oxide; however, when these cells were treated with the supernatant of CC cell lines, we observed a turnover of M1 toward M2. These cells increased CD163 and IL-10 expression. The expression of TLR-3, -7, and -9 is increased when the macrophages were treated with the supernatant of CC cells. Conclusions. Our result strongly suggests that CC cells may, through the secretion of soluble factors, induce a change of immunophenotype M1 into M2 macrophages

Spontaneous activity regulates Robo1 transcription to mediate a switch in thalamocortical axon growth

Developing axons must control their growth rate to follow the appropriate pathways and establish specific connections. However, the regulatory mechanisms involved remain elusive. By combining live imaging with transplantation studies in mice, we found that spontaneous calcium activity in the thalamocortical system and the growth rate of thalamocortical axons were developmentally and intrinsically regulated. Indeed, the spontaneous activity of thalamic neurons governed axon growth and extension through the cortex in vivo. This activity-dependent modulation of growth was mediated by transcriptional regulation of Robo1 through an NF-κB binding site. Disruption of either the Robo1 or Slit1 genes accelerated the progression of thalamocortical axons in vivo, and interfering with Robo1 signaling restored normal axon growth in electrically silent neurons. Thus, modifications to spontaneous calcium activity encode a switch in the axon outgrowth program that allows the establishment of specific neuronal connections through the transcriptional regulation of Slit1 and Robo1 signaling. © 2012 Nature America, Inc. All rights reserved.This work was supported by grants from the Spanish Ministerio de Ciencia e Innovación (BFU2006-07138 to J.L. and BFU2009-08261 to G.L.-B.), an Human Frontier Science Program Organization grant (RGP29/2008), the Consolider programme (CSD2007-00023) and an European Research Council grant (ERC-2009-StG_20081210 to G.L.-B.).Peer Reviewe