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排序方式: 共有162条查询结果,搜索用时 15 毫秒
51.
Izaskun Villar-Menéndez Marta Blanch Shiraz Tyebji Thais Pereira-Veiga José Luis Albasanz Mairena Martín Isidre Ferrer Esther Pérez-Navarro Marta Barrachina 《Neuromolecular medicine》2013,15(2):295-309
Adenosine A2A receptor (A2AR) is a G-protein-coupled receptor highly expressed in basal ganglia. Its expression levels are severely reduced in Huntington’s disease (HD), and several pharmacological therapies have shown its implication in this neurodegenerative disorder. The main goal of this study was to gain insight into the molecular mechanisms that regulate A2AR gene (ADORA2A) expression in HD. Based on previous data reported by our group, we measured the methylcytosine (5mC) and hydroxymethylcytosine (5hmC) content in the 5′UTR region of ADORA2A in the putamen of HD patients and in the striatum of R6/1 and R6/2 mice at late stages of the disease. In this genomic region, 5mC and 5hmC remained unchanged in both mice strains, although low striatal A2AR levels were associated with reduced 5mC levels in 30-week-old R6/1 mice and reduced 5hmC levels in 12-week-old R6/2 mice in exon m2. In order to analyze when this mechanism appears during the progression of the disease, a time course for A2AR protein levels was carried out in R6/1 mice striatum (8, 12, and 20 weeks of age). A2AR levels were reduced from 12 weeks of age onwards, and this downregulation was concomitant with reduced 5hmC levels in the 5′UTR region of ADORA2A. Interestingly, increased 5mC levels and reduced 5hmC were found in the 5′UTR region of ADORA2A in the putamen of HD patients with respect to age-matched controls. Therefore, an altered DNA methylation pattern in ADORA2A seems to play a role in the pathologically decreased A2AR expression levels found in HD. 相似文献
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Maria A Dosil Raúl Navaridas Cristina Mirantes Jordi Tarragona Núria Eritja Isidre Felip Izaskun Urdanibia Cristina Megino Mónica Domingo Maria Santacana Sònia Gatius Carme Piñol Carla Barceló Oscar Maiques Anna Macià Ana Velasco Marta Vaquero Xavier Matias-Guiu Xavier Dolcet 《The Journal of pathology》2019,247(1):72-85
54.
Beltran E Fresquet V Martinez-Useros J Richter-Larrea JA Sagardoy A Sesma I Almada LL Montes-Moreno S Siebert R Gesk S Calasanz MJ Malumbres R Rieger M Prosper F Lossos IS Piris MA Fernandez-Zapico ME Martinez-Climent JA 《Proceedings of the National Academy of Sciences of the United States of America》2011,108(30):12461-12466
The chromosomal translocation t(11;14)(q13;q32) leading to cyclin-D1 overexpression plays an essential role in the development of mantle cell lymphoma (MCL), an aggressive tumor that remains incurable with current treatment strategies. Cyclin-D1 has been postulated as an effective therapeutic target, but the evaluation of this target has been hampered by our incomplete understanding of its oncogenic functions and by the lack of valid MCL murine models. To address these issues, we generated a cyclin-D1-driven mouse model in which cyclin-D1 expression can be regulated externally. These mice developed cyclin-D1-expressing lymphomas capable of recapitulating features of human MCL. We found that cyclin-D1 inactivation was not sufficient to induce lymphoma regression in vivo; however, using a combination of in vitro and in vivo assays, we identified a novel prosurvival cyclin-D1 function in MCL cells. Specifically, we found that cyclin-D1, besides increasing cell proliferation through deregulation of the cell cycle at the G(1)-S transition, sequestrates the proapoptotic protein BAX in the cytoplasm, thereby favoring BCL2's antiapoptotic function. Accordingly, cyclin-D1 inhibition sensitized the lymphoma cells to apoptosis through BAX release. Thus, genetic or pharmacologic targeting of cyclin-D1 combined with a proapoptotic BH3 mimetic synergistically killed the cyclin-D1-expressing murine lymphomas, human MCL cell lines, and primary lymphoma cells. Our study identifies a role of cyclin-D1 in deregulating apoptosis in MCL cells, and highlights the potential benefit of simultaneously targeting cyclin-D1 and survival pathways in patients with MCL. This effective combination therapy also might be exploited in other cyclin-D1-expressing tumors. 相似文献
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Fermín Fernández-Calderón PhD Óscar Lozano-Rojas PhD Antonio Rojas-Tejada PhD Izaskun Bilbao-Acedos BD Claudio Vidal-Giné BD Esperanza Vergara-Moragues PhD 《Substance Abuse》2013,34(1):45-50
ABSTRACT. Background: Raves may be considered recreational settings in which drug use and health risks related to polydrug use are higher than in others. Harm reduction behaviors implemented by ravers are of particular relevance in reducing such risks. This study analyzes harm reduction behaviors and their relationship to raver polysubstance use patterns. Methods: Cross-sectional study of 248 ravers recruited at underground raves in Andalusia (Spain). A questionnaire was developed to collect information about their sociodemographics, drug use, and harm reduction behaviors. Results: The results show that ravers employ harm reduction behaviors for minimizing drug-related harm. Nevertheless, only a small minority of the participants frequently employed harm reduction behavior for polysubstance use as well. Ravers identified as high polysubstance users protected themselves significantly less than those identified as low polysubstance users. Conclusions: This study provides empirical information that may be useful for harm reduction intervention in a hidden and hard-to-reach population like rave attendees. The results point to the need to inform and increase harm reduction behavior specifically aimed at polysubstance use by ravers, especially among more frequent users. Future directions for research are also suggested. 相似文献
58.
Lucía López-Granados Montserrat Torrent Ana Sastre Marta Gonzalez-Vicent Cristina Díaz de Heredia Bienvenida Argilés Antonia Pascual José M. Pérez-Hurtado Luisa Sisinni Miguel Ángel Diaz Izaskun Elorza M. Angeles Dasí Isabel Badell 《Anales de pediatría (Barcelona, Spain : 2003)》2018,88(4):196-203
Introduction
Haematopoietic stem cell transplantation (HSCT) involves implanting cellular elements capable of generating a new and healthy haematopoietic system. Reduced intensity conditioning (RIC) consists of an immunosuppressive treatment to facilitate a progressive implant with lower morbidity. This type of conditioning can also lead to myelosuppression, which is potentially reversible over time.Reduced intensity conditioning enables HSCT to be performed on patients with genetic diseases for whom added comorbidity is undesirable due to the high doses of chemotherapy that accompanies conventional myeloablative regimens.Patients and methods
An analysis was performed on the outcomes of 68 paediatric patients with genetic diseases who underwent HSCT with RIC between 2005 and 2013 in the of Paediatric Haematopoietic Stem Cell Transplantation Units that are part of the Spanish Working Group for Bone Marrow Transplantation in Children.A multicentre study was conducted including 68 patients, of whom 43 had Primary Immunodeficiency, 21 with congenital haematological diseases, and 4 with metabolic diseases.Results
Fifty (73.5%) of the 68 patients were still alive. The Overall Survival (OS) at nine years was 0.74. Twenty-three (33.8%) had some event during the course of the HSCT, with an event-free survival rate of 0.66. The OS in patients with haematological diseases was 0.81, being 0.7 in primary immunodeficiencies, and 0.4 in metabolic diseases. No significant difference was observed between the 3 groups of diseases. As regards the source of haematopoietic progenitors, there was an OS rate of 0.74 in patients transplanted with peripheral blood, 0.70 with bone marrow, and 0.70 and with cord blood, with no statistically significant differences.Conclusions
Favourable results have been obtained in HSCT with reduced intensity conditioning in genetic diseases. It should be noted that the risks and benefits of the RIC in patients with metabolic diseases need to be assessed on an individual basis. 相似文献59.
Clinical and histopathological effects of heart failure drug therapy in advanced heart failure patients on chronic mechanical circulatory support 下载免费PDF全文
Anna B. Catino Peter Ferrin James Wever‐Pinzon Benjamin D. Horne Omar Wever‐Pinzon Abdallah G. Kfoury Lauren McCreath Nikolaos A. Diakos Stephen McKellar Antigone Koliopoulou Michael J. Bonios Mohammad Al‐Sarie Iosif Taleb Elizabeth Dranow James C. Fang Stavros G. Drakos 《European journal of heart failure》2018,20(1):164-174
Aims
Adjuvant heart failure (HF) drug therapy in patients undergoing chronic mechanical circulatory support (MCS) is often used in conjunction with a continuous‐flow left ventricular assist device (LVAD), but its potential impact is not well defined. The objective of the present study was to examine the effects of conventional HF drug therapy on myocardial structure and function, peripheral organ function and the incidence of adverse events in the setting of MCS.Methods and results
Patients with chronic HF requiring LVAD support were prospectively enrolled. Paired myocardial tissue samples were obtained prior to LVAD implantation and at transplantation for histopathology. The Meds group comprised patients treated with neurohormonal blocking therapy (concurrent beta‐blocker, angiotensin‐converting enzyme inhibitor/angiotensin receptor blocker, and aldosterone antagonist), and the No Meds group comprised patients on none of these. Both the Meds (n = 37) and No Meds (n = 44) groups experienced significant improvements in cardiac structure and function over the 6 months following LVAD implantation. The degree of improvement was greater in the Meds group, including after adjustment for baseline differences. There were no differences between the two groups in arrhythmias, end‐organ injury, or neurological events. In patients with high baseline pre‐LVAD myocardial fibrosis, treatment with HF drug therapy was associated with a reduction in fibrosis.Conclusions
Clinical and histopathological evidence showed that adjuvant HF drug therapy was associated with additional favourable effects on the structure and function of the unloaded myocardium that extended beyond the beneficial effects attributed to LVAD‐induced unloading alone. Adjuvant HF drug therapy did not influence the incidence of major post‐LVAD adverse events during the follow‐up period. 相似文献60.
Rodríguez-Navarro JA Gómez A Rodal I Perucho J Martinez A Furió V Ampuero I Casarejos MJ Solano RM de Yébenes JG Mena MA 《Human molecular genetics》2008,17(20):3128-3143
Deposition of proteins leading to amyloid takes place in some neurodegenerative diseases such as Alzheimer's disease and Huntington's disease. Mutations of tau and parkin proteins produce neurofibrillary abnormalities without deposition of amyloid. Here we report that mature, parkin null, over-expressing human mutated tau (PK(-/-)/Tau(VLW)) mice have altered behaviour and dopamine neurotransmission, tau pathology in brain and amyloid deposition in brain and peripheral organs. PK(-/-)/Tau(VLW) mice have abnormal behaviour and severe drop out of dopamine neurons in the ventral midbrain, up to 70%, at 12 months and abundant phosphorylated tau positive neuritic plaques, neuro-fibrillary tangles, astrogliosis, microgliosis and plaques of murine beta-amyloid in the hippocampus. PK(-/-)/Tau(VLW) mice have organomegaly of the liver, spleen and kidneys. The electron microscopy of the liver confirmed the presence of a fibrillary protein deposits with amyloid characteristics. There is also accumulation of mouse tau in hepatocytes. These mice have lower levels of CHIP-HSP70, involved in the proteosomal degradation of tau, increased oxidative stress, measured as depletion of glutathione which, added to lack of parkin, could trigger tau accumulation and amyloidogenesis. This model is the first that demonstrates beta-amyloid deposits caused by over-expression of tau and without modification of the amyloid precursor protein, presenilins or secretases. PK(-/-)/Tau(VLW) mice provide a link between the two proteins more important for the pathogenesis of Alzheimer disease. 相似文献