Distribution of the transcription factor islet-1 in the central nervous system of nonteleost actinopterygian fish: Relationshipwith cholinergic and catecholaminergic systems

Islet-1 (Isl1) is one of the most conserved transcription factors in the evolution of vertebrates, due to its continuing involvement in such important functions as the differentiation of motoneurons, among other essential roles in cell fate in the forebrain. Although its functions are thought to be similar in all vertebrates, the knowledge about the conservation of its expression pattern in the central nervous system goes as far as teleosts, leaving the basal groups of actinopterygian fishes overlooked, despite their important phylogenetic position. In order to assess the extent of its conservation among vertebrates, we studied its expression pattern in the central nervous system of selected nonteleost actinopterygian fishes. By means of immunohistochemical techniques, we analyzed the Isl1 expression in the brain, spinal cord, and sensory ganglia of the cranial nerves of young adult specimens of the cladistian species Polypterus senegalus and Erpetoichthys calabaricus, the chondrostean Acipenser ruthenus, and the holostean Lepisosteus oculatus. We also detected the presence of the transcription factor Orthopedia and the enzymes tyrosine hydroxylase (TH) and choline acetyltransferase (ChAT) to better locate all the immunoreactive structures in the different brain areas and to reveal the possible coexpression with Isl1. Numerous conserved features in the expression pattern of Isl1 were observed in these groups of fishes, such as populations of cells in the subpallial nuclei, preoptic area, subparaventricular and tuberal hypothalamic regions, prethalamus, epiphysis, cranial motor nuclei and sensory ganglia of the cranial nerves, and the ventral horn of the spinal cord. Double labeling of TH and Isl1 was observed in cells of the preoptic area, the subparaventricular and tuberal hypothalamic regions, and the prethalamus, while virtually all motoneurons in the hindbrain and the spinal cord coexpressed ChAT and Isl1. Altogether, these results show the high degree of conservation of the expression pattern of the transcription factor Isl1, not only among fish, but in the subsequent evolution of vertebrates.Depto. de Biología CelularFac. de Ciencias BiológicasTRUEMinisterio de Ciencia e Innovación (MICINN)Universidad Complutense de Madrid (UCM)pu

Factors associated with the clinical outcome of patients with relapsed/refractory CD19+acute lymphoblastic leukemia treated with ARI-0001 CART19-cell therapy

The prognosis of patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) remains poor, particularly for those relapsing after allogeneic hema-topoietic cell transplantation (alloHCT). Novel agents such as inotuzumab ozogamicin or blinatumomab achieve increased response rates, but these are generally transient unless followed by alloHCT. Chimeric antigen receptors (CAR) targeting CD19 have shown promising results in R/R ALL, and one of these products (tisagenlecleucel) has been approved for the treatment of patients with R/R ALL up to 25 years of age

Organización neuroanatómica de los sistemas catecolaminérgicos, serotoninérgico, nitrérgico y orexinérgico en el sistema nervioso central de los peces holósteos

Los peces holósteos forman un pequeño grupo monofilético de peces actinopterigios que es actualmente considerado como el grupo hermano de los teleósteos, junto con los cuales constituyen el grupo de peces neopterigios. Los peces holósteos viven, generalmente, en aguas dulces de América del norte y central, y están formados por ocho especies agrupadas en tres géneros, y éstos a su vez en dos órdenes: Lepisosteiformes (siete especies entre los géneros Lepisosteus y Atractosteus) y Amiiformes (una especie, Amia calva). A diferencia de los teleósteos, el sistema nervioso central (SNC) de los holósteos no ha sido estudiado en profundidad, a pesar de su interesante posición filogenética como el grupo de peces más cercano a los teleósteos. Durante la segunda mitad del siglo XX se realizaron algunos trabajos neuroanatómicos acerca de la organización general del SNC de estos peces, pero sus sistemas de neurotransmisión aún no se conocen lo suficiente. Por ello, se ha estudiado la organización neuroanatómica de los sistemas de neurotransmisión catecolaminérgicos, serotoninérgico, nitrérgico y orexinérgico, realizando además un análisis comparado con el resto de grupos de peces actinopterigios, para tratar de entender los cambios evolutivos en estos grupos de peces, y con el resto de grupos de vertebrados, para establecer posibles homologías y evaluar los caracteres específicos de los peces holósteos y los que se han conservado en la evolución de los vertebrados..

Pax6 expression highlights regional organization in the adult brain of lungfishes, the closest living relatives of land vertebrates

The Pax6 gene encodes a regulatory transcription factor that is key in brain develop-ment. The molecular structure of Pax6, the roles it plays and its patterns of expres-sion in the brain have been highly conserved during vertebrate evolution. Asneurodevelopment proceeds, the Pax6 expression changes from the mitotic germinalzone in the ventricular zone to become distributed in cell groups in the adult brain.Studies in various vertebrates, from fish to mammals, found that the Pax6 expressionis maintained in adults in most regions that express it during development. Specifi-cally, in amphibians, Pax6 is widely expressed in the adult brain and its distributionpattern serves to highlight regional organization of the brain. In the present study, weanalyzed the detailed distribution of Pax6 cells in the adult central nervous systemof lungfishes, the closest living relatives of all tetrapods. Immunohistochemistryperformed using double labeling techniques with several neuronal markers of knowndistribution patterns served to evaluate the actual location of Pax6 cells. Our resultsshow that the Pax6 expression is maintained in the adult brain of lungfishes, in dis-tinct regions of the telencephalon (pallium and subpallium), diencephalon, mesen-cephalon, hindbrain, spinal cord, and retina. The pattern of Pax6 expression is largelyshared with amphibians and helps to understand the primitive condition that wouldhave characterized the common ancestors to all sarcopterygians (lobe-finned fishes and tetrapods), in which Pax6 would be needed to maintain specific entities of sub-populations of neurons

Epithelial-mesenchymal transition can suppress major attributes of human epithelial tumor-initiating cells

Malignant progression in cancer requires populations of tumor-initiating cells (TICs) endowed with unlimited self renewal, survival under stress, and establishment of distant metastases. Additionally, the acquisition of invasive properties driven by epithelial-mesenchymal transition (EMT) is critical for the evolution of neoplastic cells into fully metastatic populations. Here, we characterize 2 human cellular models derived from prostate and bladder cancer cell lines to better understand the relationship between TIC and EMT programs in local invasiveness and distant metastasis. The model tumor subpopulations that expressed a strong epithelial gene program were enriched in highly metastatic TICs, while a second subpopulation with stable mesenchymal traits was impoverished in TICs. Constitutive overexpression of the transcription factor Snai1 in the epithelial/TIC-enriched populations engaged a mesenchymal gene program and suppressed their self renewal and metastatic phenotypes. Conversely, knockdown of EMT factors in the mesenchymal-like prostate cancer cell subpopulation caused a gain in epithelial features and properties of TICs. Both tumor cell subpopulations cooperated so that the nonmetastatic mesenchymal-like prostate cancer subpopulation enhanced the in vitro invasiveness of the metastatic epithelial subpopulation and, in vivo, promoted the escape of the latter from primary implantation sites and accelerated their metastatic colonization. Our models provide new insights into how dynamic interactions among epithelial, self-renewal, and mesenchymal gene programs determine the plasticity of epithelial TICs