Patogenia de la inflamación: discurso para los ejercicios del grado de Doctor de Santiago Ramón y Cajal

Tesis de doctorado leída en la Universidad Central el 26 de junio de 1877También disponible la reproducción digitalManuscrito firmadoTesis Doctorales históricasTesis Complutenses históricasmanuscritoFacultad de MedicinaFacultad de Medicinatruepu

Interplay Between ncRNAs and Cellular Communication: A Proposal for Understanding Cell-Specific Signaling Pathways

Intercellular communication is essential for the development of specialized cells, tissues, and organs and is critical in a variety of diseases including cancer. Current knowledge states that different cell types communicate by ligand–receptor interactions: hormones, growth factors, and cytokines are released into the extracellular space and act on receptors, which are often expressed in a cell-type-specific manner. Non-coding RNAs (ncRNAs) are emerging as newly identified communicating factors in both physiological and pathological states. This class of RNA encompasses microRNAs (miRNAs, well-studied post-transcriptional regulators of gene expression), long non-coding RNAs (lncRNAs) and other ncRNAs. lncRNAs are diverse in length, sequence, and structure (linear or circular), and their functions are described as transcriptional regulation, induction of epigenetic changes and even direct regulation of protein activity. They have also been reported to act as miRNA sponges, interacting with miRNA and modulating its availability to endogenous mRNA targets. Importantly, lncRNAs may have a cell-type-specific expression pattern. In this paper, we propose that lncRNA–miRNA interactions, analogous to receptor–ligand interactions, are responsible for cell-type-specific outcomes. Specific binding of miRNAs to lncRNAs may drive cell-type-specific signaling cascades and modulate biochemical feedback loops that ultimately determine cell identity and response to stress factors

Inducciones fisiológicas de la morfología y conexiones de las neuronas

Se recordará que Golgi, en sus trabajos sobre la fina anatomia de los centros, habia defendido la idea de que la conducción nerviosa a través de la sustancia gris, se efectúa exclusivamente por los cilindros-ejes, las colaterales nerviosas y la red nerviosa intersticial; las expansiones protoplasmáticas desempeñarían un oficio meramente nutritivo y, para mejor satisfacerlo, pensaba el sabio italiano que todas ellas se dirigen hacia las células de neuroglia perivasculares ó hacia los vasos mismos, con los cuales entrarian algunas veces en contacto. Lo que indujo a Goigi a sostener estos asertos, fue una observación incompleta, a saber: que las expansiones dendriticas se reúnen precisamente donde faltan las fibrillas nerviosas (capas moleculares del cerebro, cerebelo y hasta de Ammon), concentrándose de preferencia, en las zonas limitantes de sustancia gris ricas en corpúsculos de araña.Facultad de Ciencias Jurídicas y Sociale

La Psicología de Don Quijote de la Mancha y el Quijotismo

«Universalmente admirada es la soberbia figura moral del hidalgo manchego. D. Alonso Quijano el bueno, convertido en andante caballero por la sugestión de los disparatados libros de caballería, representa, según se ha dicho mil veces, el más perfecto símbolo del honor y del altruismo. Jamás el genio anglo-sajón, tan dado á imaginar caracteres enérgicos y originales, creó personificación mas exquisita del individualismo indómito y de la abnegación sublime. Pero puntualicemos brevemente los rasgos psicológicos sobresalientes del protagonista de la novela inmortal.

Corrigendum : Pío del Río-Hortega: A Visionary in the Pathology of Central Nervous System Tumors

Fondo de Investigaciones Sanitarias (11/00185), Redes Temáticas de Investigación Cooperativa en Salud (Ref. RD06/0020/1020

Internal translation of the connexin 43 transcript

Connexin 43 (Cx43), the most widely expressed gap junction protein, is associated with a number of physiological and pathological conditions. Many functions of Cx43 have been shown to be independent of gap junction formation and only require the expression of Cx43 C-terminal fragments. Recent evidence demonstrated that naturally occurring C-terminal isoforms can be generated via internal translation. Here, we confirm that C-terminal domains of Cx43, particularly the major 20-kDa isoform, can be independently generated and regulated by internal translation of the same single GJA1 gene transcript that encodes full-length Cx43. Through direct RNA transfection experiments, we provide evidence that internal translation is not due to a bona fide cap-independent IRES-mediated mechanism, as upstream ribosomal scanning or translation is required. In addition to the mTOR pathway, we show for the first time, using both inhibitors and cells from knockout mice, that the Mnk1/2 pathway regulates the translation of the main 20-kDa isoform. Internal translation of the Cx43 transcript occurs but is not cap-independent and requires translation upstream of the internal start codon. In addition to the PI3K/AKT/mTOR pathway, the major 20-kDa isoform is regulated by the Mnk1/2 pathway. Our results have major implications for past and future studies escribing gap junction-independent functions of Cx43 in cancer and other pathological conditions. This study provides further clues to the signalling pathways that regulate internal mRNA translation, an emerging mechanism that allows for increased protein diversity and functional complexity from a single mRNA transcript

Ovarian Fibrosarcoma: Clinicopathologic Considerations about the Intraoperative and Post-Surgical Procedures

Primary ovarian fibrosarcomas are very uncommon neoplasms. Since the diagnostic criteria were established in 1981, less than one hundred cases have been reported. This diagnosis can be difficult to establish and other similar appearing mesenchymal processes must be ruled out. In every case this diagnosis is under consideration. Multiple sections of the specimen and immunohistochemical stains will be necessary to support this diagnosis. The difficulty of recognition in frozen section in the majority of the situations implies that the diagnosis should be deferred to the definitive study of the permanent sections with immunohistochemical studies. There exists a histological resemblance between a primary ovarian fibrosarcoma and actively mitotic fibroma. In some cases, it can be impossible to separate exactly these two entities. We report a well-differentiated ovarian fibrosarcoma, with less than 1-2 mitosis ×10 HPF and low-grade cytological atypia, similar to active mitotic fibromas, developing liver metastasis one year later. Despite having distant metastasis, some cases with long survival rates have been reported in patients who received chemotherapy after surgery; so that the adjuvant chemotherapy should be considered, especially in young females

Interplay between YB-1 and IL-6 promotes the metastatic phenotype in breast cancer cells

Epithelial to mesenchymal transition (EMT) induces cell plasticity and promotes metastasis. The multifunctional oncoprotein Y-box binding protein-1 (YB-1) and the pleiotropic cytokine interleukin 6 (IL-6) have both been implicated in tumor cell metastasis and EMT, but via distinct pathways. Here, we show that direct interplay between YB-1 and IL-6 regulates breast cancer metastasis. Overexpression of YB-1 in breast cancer cell lines induced IL-6 production while stimulation with IL-6 increased YB-1 expression and YB-1 phosphorylation. Either approach was sufficient to induce EMT features, including increased cell migration and invasion. Silencing of YB-1 partially reverted the EMT and blocked the effect of IL-6 while inhibition of IL-6 signaling blocked the phenotype induced by YB-1 overexpression, demonstrating a clear YB-1/IL-6 interdependence. Our findings describe a novel signaling network in which YB-1 regulates IL-6, and vice versa, creating a positive feed-forward loop driving EMT-like metastatic features during breast cancer progression. Identification of signaling partners or pathways underlying this co-dependence may uncover novel therapeutic opportunitiesThis work was supported by Fondo de Investigaciones Sanitarias (11/00185) and Redes Temáticas de Investigación Cooperativa en Salud (Ref. RD06/0020/1020). SRC acknowledges support from Generalitat de Catalunya (Ref. 2005SGR00144) and Fundación Mutua Madrileña (FMMA/2009/02). TA acknowledges support from Instituto de Salud Carlos III grant PI13/00763 and grant CP10/00624, co-financed by the European Regional Development Fund (ERDF