Methylthioadenosine phosphorylase gene expression is impaired in human liver cirrhosis and hepatocarcinoma

Methylthioadenosine phosphorylase (MTAP) is a key enzyme in the methionine and adenine salvage pathways. In mammals, the liver plays a central role in methionine metabolism, and this essential function is lost in the progression from liver cirrhosis to hepatocarcinoma. Deficient MTAP gene expression has been recognized in many transformed cell lines and tissues. In the present work, we have studied the expression of MTAP in human and experimental liver cirrhosis and hepatocarcinoma. We observe that MTAP gene expression is significantly reduced in human hepatocarcinoma tissues and cell lines. Interestingly, MTAP gene expression was also impaired in the liver of CCl4-cirrhotic rats and cirrhotic patients. We provide evidence indicating that epigenetic mechanisms, involving DNA methylation and histone deacetylation, may play a role in the silencing of MTAP gene expression in hepatocarcinoma. Given the recently proposed tumor suppressor activity of MTAP, our observations can be relevant to the elucidation of the molecular mechanisms of multistep hepatocarcinogenesis

5'-methylthioadenosine modulates the inflammatory response to endotoxin in mice and in rat hepatocytes

5'-methylthioadenosine (MTA) is a nucleoside generated from S-adenosylmethionine (AdoMet) during polyamine synthesis. Recent evidence indicates that AdoMet modulates in vivo the production of inflammatory mediators. We have evaluated the anti-inflammatory properties of MTA in bacterial lipopolysaccharide (LPS) challenged mice, murine macrophage RAW 264.7 cells, and isolated rat hepatocytes treated with pro-inflammatory cytokines. MTA administration completely prevented LPS-induced lethality. The life-sparing effect of MTA was accompanied by the suppression of circulating tumor necrosis factor-alpha (TNF-alpha), inducible NO synthase (iNOS) expression, and by the stimulation of IL-10 synthesis. These responses to MTA were also observed in LPS-treated RAW 264.7 cells. MTA prevented the transcriptional activation of iNOS by pro-inflammatory cytokines in isolated hepatocytes, and the induction of cyclooxygenase 2 (COX2) in RAW 264.7 cells. MTA inhibited the activation of p38 mitogen-activated protein kinase (MAPK), c-jun phosphorylation, inhibitor kappa B alpha (IkappaBalpha) degradation, and nuclear factor kappaB (NFkappaB) activation, all of which are signaling pathways related to the generation of inflammatory mediators. These effects were independent of the metabolic conversion of MTA into AdoMet and the potential interaction of MTA with the cAMP signaling pathway, central to the anti-inflammatory actions of its structural analog adenosine. In conclusion, these observations demonstrate novel immunomodulatory properties for MTA that may be of value in the management of inflammatory diseases

Methylthioadenosine reverses brain autoimmune disease

OBJECTIVE: To assess the immunomodulatory activity of methylthioadenosine (MTA) in rodent experimental autoimmune encephalomyelitis (EAE) and in patients with multiple sclerosis. METHODS: We studied the effect of intraperitoneal MTA in the acute and chronic EAE model by quantifying clinical and histological scores and by performing immunohistochemistry stains of the brain. We studied the immunomodulatory effect of MTA in lymphocytes from EAE animals and in peripheral blood mononuclear cells from healthy control subjects and multiple sclerosis patients by assessing cell proliferation and cytokine gene expression, by real-time polymerase chain reaction, and by nuclear factor-kappaB modulation by Western blot. RESULTS: We found that MTA prevents acute EAE and, more importantly, reverses chronic-relapsing EAE. MTA treatment markedly inhibited brain inflammation and reduced brain damage. Administration of MTA suppressed T-cell activation in vivo and in vitro, likely through a blockade in T-cell signaling resulting in the prevention of inhibitor of kappa B (IkappaB-alpha) degradation and in the impaired activation transcription factor nuclear factor-kappaB. Indeed, MTA suppressed the production of proinflammatory genes and cytokines (interferon-gamma, tumor necrosis factor-alpha, and inducible nitric oxide synthase) and increased the production of antiinflammatory cytokines (interleukin-10). INTERPRETATION: MTA has a remarkable immunomodulatory activity and may be beneficial for multiple sclerosis and other autoimmune diseases

Results of an early access treatment protocol of daratumumab monotherapy in spanish patients with relapsed or refractory multiple myeloma

Daratumumab is a human CD38-targeted monoclonal antibody approved as monotherapy for heavily pretreated relapsed and refractory multiple myeloma. We report findings for the Spanish cohort of an open-label treatment protocol that provided early access to daratumumab monotherapy and collected safety and patient-reported outcomes data for patients with relapsed or refractory multiple myeloma. At 15 centers across Spain, intravenous daratumumab (16mg/kg) was administered to 73 patients who had ≥3 prior lines of therapy, including a proteasome inhibitor and an immunomodulatory drug, or who were double refractory to both. The median duration of daratumumab treatment was 3.3 (range: 0.03–13.17) months, with a median number of 12 (range: 1–25) infusions. Grade 3/4 treatment-emergent adverse events were reported in 74% of patients and included lymphopenia (28.8%), thrombocytopenia (27.4%), neutropenia (21.9%), leukopenia (19.2%), and anemia (15.1%). Common (>5%) serious treatmentemergent adverse events included respiratory tract infection (9.6%), general physical health deterioration (6.8%), and back pain (5.5%). Infusion-related reactions occurred in 45% of patients. The median change from baseline in all domains of the EQ-5D-5L and EORTC QLQ-C30 was mostly 0. A total of 18 (24.7%) patients achieved a partial response or better, with 10 (13.7%) patients achieving a very good partial response or better. Median progression-free survival was 3.98 months. The results of this early access treatment protocol are consistent with previously reported trials of daratumumab monotherapy and confirm its safety and antitumoral efficacy in Spanish patients with heavily treated relapsed or refractory multiple myeloma

Escuela en acción infantil : revista de pedagogía de magisterio

Proyecto de integración de niños ciegos en un centro educativo. La base de esta experiencia es que todos aquellos que rodean al niño ciego deben entender sus dificultades y aceptarle. Para ello, muestra una serie de actividades que, por medio de fichas, pueden realizarse en el aula. Finaliza con un apartado dedicado a la ONCE y a su labor educativa.MadridES

Motivación y cambio conceptual : implicaciones para el aprendizaje y la enseñanza de las Ciencias Naturales, la Historia y la Ética en la ESO

Evaluar la influencia del contenido de la tarea en el proceso de cambio conceptual, utilizándose como estrategia la presentación de datos anómalos o conflictivos; evaluar la influencia que el estilo epistémico de los alumnos, concretamente su grado de relativismo, evaluado a través de su capacidad para reconocer y reconciliar posturas diferentes, tiene en diferentes dominios de conocimiento en el proceos de cambio conceptual; estudiar la influencia variables motivacionales en el proceso de cambio conceptual; obtener las implicaciones instruccionales para el aprendizaje y la enseñanza de las Ciencias Sociales y Naturales que se derivan de los estudios llevados a cabo. Se plantearon las siguientes hipótesis: se logrará menor nivel de cambio en la tarea en la que las creencias-explicaciones de los sujetos estén más arraigadas, esto es, en las que los sujetos muestren un posicionamiento más fuerte hacia una u otra versión, independientemente del contenido de la tarea (cotidiano, ético, histórico o científico); no habrá diferencias significativas en el grado de cambio alcanzado en las tareas cotidianas y éticas frente a las históricas o frente a las científicas. 669 estudiantes de ESO, siendo 302 alumnos procedentes de diversos colegios e institutos públicos de Madrid de primero de ESO y un grupo de cuarto de ESO compuesto por 367 estudiantes. Se han realizado tres estudios. En el primero, se ha estudiado la influencia del contenido de la tarea y del grado de arraigo de las creencias de los alumnos en el grado de cambio que han logrado los estudiantes. Se estudiaron cuatro dominios: historia, ciencias naturales, ética y vida cotidiana. En el segundo estudio se ha evaluado el grado de relativismo cognitivo de los sujetos participantes en el estudio, teniendo en cuenta: reconocimiento de la contradicción en conflicto entre dos versiones alternativas, identificación de versiones y capacidad de reconciliación de versiones contrapuestas. En el tercer estudio se evaluó el patrón motivacional. Se tuvieron en cuenta variables motivacionales (interés por la tarea, interés en la materia y patrón motivacional). Tablas, gráficos. Los resultados obtenidos indican que el posicionamiento inicial de los sujetos en las tareas determina en buena medida el grado de cambio. Si suposicionamiento es claro, el porcentaje de cambio es inferior. Las tareas en las que el posicionamiento de los sujetos ha sido mayor y por tanto, mayor también el grado de arraigo de sus creencias han sido las dos de Etica, seguida de las de Historia. El porcentaje medio de cambio entre la respuesta inicial y la final fue de un 19,32 por cien , lo que sugiere que la presentación de versiones contradictorias puede ser una estrategia didáctica que trabajada en el aula permitiría identificar el posicionamiento inicial de los estudiantes y promover los primeros pasos del proceso de cambio conceptual, a la vez que mejorar su nivel de relativismo cognitivo. En cuanto a la evaluación del grado de relativismo de los participantes, los resultados indican que los estudiantes, en general, son capaces de reconocer la contradicción e identificar las versiones, pero tienen más dificultades para reconciliar posiciones. Parece haber una mejora del nivel del relativismo en los alumnos de cuarto de ESO respecto a los de primero. Los estudiantes con menos nivel de relativismo logran un porcentaje medio de cambio entre sus respuestas iniciales y finales superior a la media, lo que parece indicar que son estos estudiantes los que parecen obtener mayor beneficio de esta estrategia didáctica consistente en presentar versiones alternativas. El patrón motivacional de los alumnos participantes y el nivel de interés en la tarea, al menos con los instrumentos que hemos utilizado, no parecen influir en el grado de cambio logrado por los sujetos. Es necesario realizar nuevas investigaciones que contribuyan a precisar el papel de las variables motivacionales en el proceso de cambio conceptual.Ministerio Educación CIDEBiblioteca de Educación del Ministerio de Educación, Cultura y Deporte; Calle San Agustín, 5 - 3 Planta; 28014 Madrid; Tel. +34917748000; Fax +34917748026; [email protected]

5'-methylthioadenosine modulates the inflammatory response to endotoxin in mice and in rat hepatocytes

5'-methylthioadenosine (MTA) is a nucleoside generated from S-adenosylmethionine (AdoMet) during polyamine synthesis. Recent evidence indicates that AdoMet modulates in vivo the production of inflammatory mediators. We have evaluated the anti-inflammatory properties of MTA in bacterial lipopolysaccharide (LPS) challenged mice, murine macrophage RAW 264.7 cells, and isolated rat hepatocytes treated with pro-inflammatory cytokines. MTA administration completely prevented LPS-induced lethality. The life-sparing effect of MTA was accompanied by the suppression of circulating tumor necrosis factor-alpha (TNF-alpha), inducible NO synthase (iNOS) expression, and by the stimulation of IL-10 synthesis. These responses to MTA were also observed in LPS-treated RAW 264.7 cells. MTA prevented the transcriptional activation of iNOS by pro-inflammatory cytokines in isolated hepatocytes, and the induction of cyclooxygenase 2 (COX2) in RAW 264.7 cells. MTA inhibited the activation of p38 mitogen-activated protein kinase (MAPK), c-jun phosphorylation, inhibitor kappa B alpha (IkappaBalpha) degradation, and nuclear factor kappaB (NFkappaB) activation, all of which are signaling pathways related to the generation of inflammatory mediators. These effects were independent of the metabolic conversion of MTA into AdoMet and the potential interaction of MTA with the cAMP signaling pathway, central to the anti-inflammatory actions of its structural analog adenosine. In conclusion, these observations demonstrate novel immunomodulatory properties for MTA that may be of value in the management of inflammatory diseases