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Hauer J.,Heinrich Heine University Dusseldorf | Borkhardt A.,Heinrich Heine University Dusseldorf | Sanchez-Garcia I.,University of Salamanca | Sanchez-Garcia I.,Institute of Biomedical Research of Salamanca IBSAL | Cobaleda C.,Autonomous University of Madrid
Cell Cycle | Year: 2014

B-cell precursor acute lymphoblastic leukemias (pB-ALLs) are the most frequent type of malignancies of the childhood, and also affect an important proportion of adult patients. In spite of their apparent homogeneity, pB-ALL comprises a group of diseases very different both clinically and pathologically, and with very diverse outcomes as a consequence of their biology, and underlying molecular alterations. Their understanding (as a prerequisite for their cure) will require a sustained multidisciplinary effort from professionals coming from many different fields. Among all the available tools for pB-ALL research, the use of animal models stands, as of today, as the most powerful approach, not only for the understanding of the origin and evolution of the disease, but also for the development of new therapies. In this review we go over the most relevant (historically, technically or biologically) genetically engineered mouse models (GEMMs) of human pB-ALLs that have been generated over the last 20 years. Our final aim is to outline the most relevant guidelines that should be followed to generate an "ideal" animal model that could become a standard for the study of human pB-ALL leukemia, and which could be shared among research groups and drug development companies in order to unify criteria for studies like drug testing, analysis of the influence of environmental risk factors, or studying the role of both low-penetrance mutations and cancer susceptibility alterations. © Julia Hauer, Arndt Borkhardt, Isidro Sáanchez-García, and Cáesar Cobaleda.

Brown G.,University of Birmingham | Sanchez-Garcia I.,University of Salamanca | Sanchez-Garcia I.,Institute of Biomedical Research of Salamanca IBSAL
Oncotarget | Year: 2015

Within the past years there have been substantial changes to our understanding of haematopoiesis and cells that initiate and sustain leukemia. Recent studies have revealed that developing haematopoietic stem and progenitor cells are much more heterogeneous and versatile than has been previously thought. This versatility includes cells using more than one route to a fate and cells having progressed some way towards a cell type retaining other lineage options as clandestine. These notions impact substantially on our understanding of the origin and nature of leukemia. An important question is whether leukemia stem cells are as versatile as their cell of origin as an abundance of cells belonging to a lineage is often a feature of overt leukemia. In this regard, we examine the coming of age of the "leukemia stem cell" theory and the notion that leukemia, like normal haematopoiesis, is a hierarchically organized tissue. We examine evidence to support the notion that whilst cells that initiate leukemia have multi-lineage potential, leukemia stem cells are reprogrammed by further oncogenic insults to restrict their lineage decision-making. Accordingly, evolution of a sub-clone of lineage-restricted malignant cells is a key feature of overt leukemia.

Saldana E.,University of Salamanca | Saldana E.,Institute of Biomedical Research of Salamanca IBSAL
Cerebellum | Year: 2015

Enrico Mugnaini has devoted part of his long and fruitful neuroscientific career to investigating the structural similarities between the cerebellar cortex and one of the first relay stations of the mammalian auditory pathway: the dorsal cochlear nucleus. The hypothesis of the cerebellar-like nature of the superficial layers of the dorsal cochlear nucleus received definitive support with the discovery and extensive characterization in his laboratory of unipolar brush cells, a neuron type unique to certain regions of the cerebellar cortex and to the granule cell domains of the cochlear nuclei. Paradoxically, a different line of research carried out in his laboratory revealed that, unlike the mammalian cerebellar cortex, the dorsal cochlear nucleus receives direct projections from the cerebral cortex, a fact that constitutes one of the main differences between the cerebellum and the dorsal cochlear nucleus. In an article published in 1995, Mugnaini’s group described in detail the novel direct projections from the rat auditory neocortex to various subcollicular auditory centers, including the nucleus sagulum, the paralemniscal regions, the superior olivary complex, and the cochlear nuclei (Feliciano et al., Auditory Neuroscience 1995; 1:287–308). This review gives Enrico Mugnaini credit for his seminal contribution to the knowledge of auditory corticosubcollicular projections and summarizes how this growing field has evolved in the last 20 years. © 2015, Springer Science+Business Media New York.

Ocio E.M.,University of Salamanca | Mateos M.-V.,University of Salamanca | San-Miguel J.F.,Institute of Biomedical Research of Salamanca IBSAL
Expert Opinion on Investigational Drugs | Year: 2012

Introduction: Several novel proteasome inhibitors (PIs) and immunomodulatory agents (IMIDs) with similar, but not exactly the same, mechanisms of action than their predecessors have been developed in the last years with three different aims: to increase the efficacy; to overcome the resistance and to exhibit a better toxicity profile. Areas covered: This review summarizes the mechanism of action of novel PIs (carfilzomib, ONX-0912, MLN-9708, marizomib and CEP-18770) and IMIDs (pomalidomide), stressing the similarities and differences with their parental drugs. It also reviews their most updated clinical results. A search of the recent literature in published papers and abstracts from the most important oncology scientific meetings (ASCO and ASH) has been performed. Expert opinion: Novel PIs and IMIDs show clinical activity as single agents and in combination with dexamethasone, with similar or even higher efficacy than their predecessors; moreover, they may even overcome resistance to their parental drugs, indicating that there are some differences in their mechanisms of action and resistance. The investigation of these mechanisms of resistance and ways to overcome it would allow the optimization of the sequential use of these agents, and the design of novel therapeutic strategies and more appropriate scientifically based combinations. © Informa UK, Ltd.

Calvo L.,Institute Neurociencias Of Castilla Y Leon Incyl | Calvo L.,Institute of Biomedical Research of Salamanca IBSAL | Anta B.,Institute Neurociencias Of Castilla Y Leon Incyl | Anta B.,Institute of Biomedical Research of Salamanca IBSAL | And 9 more authors.
Journal of Neuroscience | Year: 2015

The development of the nervous system is a temporally and spatially coordinated process that relies on the proper regulation of the genes involved. Neurotrophins and their receptors are directly responsible for the survival and differentiation of sensory and sympathetic neurons; however, it is not fully understood how genes encoding Trk neurotrophin receptors are regulated. Here, we show that rat Bex3 protein specifically regulates TrkA expression by acting at the trkA gene promoter level. Bex3 dimerization and shuttling to the nucleus regulate the transcription of the trkA promoter under basal conditions and also enhance nerve growth factor (NGF)-mediated trkA promoter activation. Moreover, qChIP assays indicate that Bex3 associates with the trkA promoter within a 150 bp sequence, immediately upstream from the transcription start site, which is sufficient to mediate the effects of Bex3. Consequently, the downregulation of Bex3 using shRNA increases neuronal apoptosis in NGF-dependent sensory neurons deprived of NGF and compromises PC12 cell differentiation in response to NGF. Our results support an important role for Bex3 in the regulation of TrkA expression and in NGF-mediated functions through modulation of the trkA promoter. © 2015 the authors.

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