Papers actancials i papers temàtics en la novel·la negra de Manuel de Pedrolo

El present estudi ofereix una anàlisi de la recepció crítica de l’obra Crim de Germania, de l’escriptor valencià Josep Lozano, publicada per primera vegada a l’abril de 1980 per l’editorial Tres i Quatre, que permet fixar els elements a l’entorn dels quals s’ha anat elaborant la lectura de la novel·la i la seua evolució temporal. Durant més de trenta anys, Crim de Germania ha sigut objecte de nombroses valoracions crítiques a la premsa i en publicacions periòdiques de diversa índole a tot arreu dels territoris de parla catalana. L’estudi s’ha dividit en tres etapes: la primera s’inicia amb la publicació del llibre i conclou l’any 1981; la segona comprén el período des de 1982 fins al 2004, i, la tercera, des de 2005 —any en què la novel·la s’amplia i es reedita per Bromera— fins l’actualitat.This study analyses the critical reception of the work Crim de Germania of the Valencian writer Josep Lozano, first published in April 1980 by Tres i Quatre Editorial. This analysis allows us to set the elements to the environment, and the reading of the novel and its evolution in time have evolved through such elements. For more than 30 years, Crim de Germania has widely been criticized in the press and/or periodical publications of various kinds in all the Catalan-speaking territories. The study is divided into three stages: the first one, which started with the publication of the book and finished in 1981; the second stage, from 1982 to 2004; and the third stage, from 2005 —the year in which this novel is extended and republished by Bromera— to present

Papel de las calpaínas en la remodelación tisular de la glándula mamaria tras el ciclo embarazo/lactancia

En el presente proyecto de tesis se ha contribuido a elucidar el papel de las calpaínas en la muerte celular programada y la remodelación tisular de la glándula mamaria tras el ciclo embarazo/lactancia. La involución de la glándula mamaria se caracteriza por la muerte celular programada (MCP) del epitelio secretor y por la proliferación e invasión de los adipocitos, con el fin de conseguir el estado glandular pre-gestacional. Estudios previos demuestran que las calpaínas, proteasas calcio-dependientes, están activas a lo largo de esta regresión post-lactancia. Estas enzimas, participan en la escisión de numerosas proteínas ubicadas la mayoría en membranas celulares, al poseer las calpaínas un dominio de unión a fosfolípidos que facilita su activación. El incremento del calcio intracelular que acontece durante el destete como consecuencia de la falta de succión por parte de las crías, también incrementa su actividad. Durante la involución de la glándula mamaria, la translocación lisosomal, mitocondrial y nuclear de las calpaínas está involucrada en la desestabilización progresiva de estos orgánulos durante la muerte celular programada de las células epiteliales secretoras. La liberación del contenido lisosomal al citosol constituye el primer paso en la ejecución de esta muerte celular programada. Al translocarse al lisosoma, las calpaínas participan en la degradación de proteínas asociadas a la membrana lisosomal como LAMP2a y VATB2, identificadas por primera vez como dianas lisosomales de estas proteasas. La translocación mitocondrial de las calpaínas induce una desestabilización de la membrana mitocondrial, con la consiguiente liberación de citocromo c al citosol. En el núcleo de células epiteliales, las calpaínas degradan nucleoporinas ubicadas en posiciones periféricas del complejo del poro nuclear. De hecho, nucleoporinas localizadas en partes centrales del poro, no son degradadas por su inaccesible localización. Sin embargo, también se ha detectado la presencia de calpaína-1 en núcleos de células adipocíticas a las 48 horas de destete. En estas células, se observa que dicha proteasa presenta una función diferente a la presente en células epiteliales. Experimentos realizados in vivo e in vitro demuestran que la calpaina-1 escinde el extremo amino de la Histona H3 en células estromales de ratones destetados. Ensayos de ChIP señalan la presencia de calpaína-1 en los promotores de genes involucrados en la diferenciación y adquisición del fenotipo de adipocito, como CEBPalfa y leptina, sugiriendo la idea de una participación de la calpaína-1 en la diferenciación y proliferación de los adipocitos, a través de la remodelación de la estructura de la cromatina. Nuestras observaciones revelan que, durante la involución de la glándula mamaria, la calpaína-1 estaría involucrada en la retirada masiva del epitelio secretor, además de presentar un posible papel en la adipogénesis. La desregulación de la actividad de estas proteasas se ha correlacionado con un gran número de enfermedades, como distrofias musculares, neurodegeneración y cáncer, entre otras. De hecho, un reciente estudio determinó que un incremento de la actividad de calpaína-2 desemboca en un peor pronóstico y menor supervivencia específica de pacientes con tumores de mama triple negativos. De ahí que, conocer en profundidad el mecanismo de acción, las dianas proteolíticas, y en general, el funcionamiento de las calpaínas en el contexto de la glándula mamaria, pueda contribuir a avanzar en el conocimiento de estas proteasas con potencial implicación en el cáncer de mama.Mammary gland involution is characterized by programmed cell death of the secretory epithelium, followed by differentiation/proliferation of adipocytes, in order to leave the gland in its pre-gestational state. Prior studies demonstrate that calpains, calcium-dependent proteases, increase their activity during weaning. We observed that lysosomal, mitochondrial, and nuclear calpain translocation is involved in the subsequent organelle membrane destabilization, leading to epithelial cell death. Calpains translocate to lysosomal membranes, where they proteolyze lysosome-associated membrane proteins such as VATB2 and LAMP2a, identified for the first time as calpain targets within the lysosomal membrane. Mitochondrial calpain translocation is involved in the destabilization of mitochondrial membrane, triggering cytochrome c release. Calpains are also able to translocate to nuclear membrane of epithelial cells, degrading nucleoporins localized in peripheral positions of the nuclear pore complex. However, CAPN1 has also been found in the nuclei of adipose cells. This protease is involved in the differentiation process of adipocytes during mammary gland post-lactational remodeling, playing a different role that the one observed in epithelial cells. Histone H3, was first identified as a nuclear target of CAPN1 in adipocytes. The proteolysis occurs in the aminoterminal domain of the protein, around lysine in position 9 and serine in position 10. The removal of this aminoterminal domain favours the activation of adipogenic-related genes through chromatin remodeling. Herein, we have reviewed the major role that calpains play in the involution of the mammary gland after the pregnancy/lactation cycle. CAPN’s targets within the lysosomal, mitochondrial and nuclear membranes, induce membrane leakiness and favors cell death. Whilst in adipose cells, CAPN1 is involved in the modulation of pre-adipocytes differentiation to mature adipocytes through chromatin remodeling

Activación de las calpaínas en la glándula mamaria tras el destete: identificación mediante Proteómica de nuevas dianas

Comunicaciones a congreso

Loss of E-cadherin provides tolerance to centrosome amplification in epithelial cancer cells

Centrosome amplification is a common feature of human tumors. To survive, cancer cells cluster extra centrosomes during mitosis, avoiding the detrimental effects of multipolar divisions. However, it is unclear whether clustering requires adaptation or is inherent to all cells. Here, we show that cells have varied abilities to cluster extra centrosomes. Epithelial cells are innately inefficient at clustering even in the presence of HSET/KIFC1, which is essential but not sufficient to promote clustering. The presence of E-cadherin decreases cortical contractility during mitosis through a signaling cascade leading to multipolar divisions, and its knockout promotes clustering and survival of cells with multiple centrosomes. Cortical contractility restricts centrosome movement at a minimal distance required for HSET/KIFC1 to exert its function, highlighting a biphasic model for centrosome clustering. In breast cancer cell lines, increased levels of centrosome amplification are accompanied by efficient clustering and loss of E-cadherin, indicating that this is an important adaptation mechanism to centrosome amplification in cancer

Current papers and thematic papers in the black novel by Manuel de Pedrolo

El present estudi ofereix una anàlisi de la recepció crítica de l’obra Crim de Germania, de l’escriptor valencià Josep Lozano, publicada per primera vegada a l’abril de 1980 per l’editorial Tres i Quatre, que permet fixar els elements a l’entorn dels quals s’ha anat elaborant la lectura de la novel·la i la seua evolució temporal. Durant més de trenta anys, Crim de Germania ha sigut objecte de nombroses valoracions crítiques a la premsa i en publicacions periòdiques de diversa índole a tot arreu dels territoris de parla catalana. L’estudi s’ha dividit en tres etapes: la primera s’inicia amb la publicació del llibre i conclou l’any 1981; la segona comprén el período des de 1982 fins al 2004, i, la tercera, des de 2005 —any en què la novel·la s’amplia i es reedita per Bromera— fins l’actualitat.This study analyses the critical reception of the work Crim de Germania of the Valencian writer Josep Lozano, first published in April 1980 by Tres i Quatre Editorial. This analysis allows us to set the elements to the environment, and the reading of the novel and its evolution in time have evolved through such elements. For more than 30 years, Crim de Germania has widely been criticized in the press and/or periodical publications of various kinds in all the Catalan-speaking territories. The study is divided into three stages: the first one, which started with the publication of the book and finished in 1981; the second stage, from 1982 to 2004; and the third stage, from 2005 —the year in which this novel is extended and republished by Bromera— to present

Centrosome amplification mediates small extracellular vesicles secretion via lysosome disruption

SummaryBidirectional communication between cells and their surrounding environment is critical in both normal and pathological settings. Extracellular vesicles (EVs), which facilitate the horizontal transfer of molecules between cells, are recognized as an important constituent of cell-cell communication. In cancer, alterations in EV secretion contribute to the growth and metastasis of tumor cells. However, the mechanisms underlying these changes remain largely unknown. Here, we show that centrosome amplification is associated with and sufficient to promote small extracellular vesicle (SEV) secretion in pancreatic cancer cells. This is a direct result due of lysosomal dysfunction, caused by increased reactive oxygen species (ROS) downstream of extra centrosomes. Defects in lysosome function promotes multivesicular body fusion with the plasma membrane, thereby enhancingSEV secretion. Furthermore, we find thatSEVs secreted in response to amplified centrosomes are functionally distinct and activate pancreatic stellate cells (PSCs). These activated PSCs promote the invasion of pancreatic cancer cells in heterotypic 3-D cultures. We propose thatSEVs secreted by cancer cells with amplified centrosomes influence the bidirectional communication between the tumor cells and the surrounding stroma to promote malignancy.</jats:p

Loss of E-cadherin provides tolerance to centrosome amplification in epithelial cancer cells

Centrosome amplification is a common feature of human tumors. To survive, cancer cells cluster extra centrosomes during mitosis, avoiding the detrimental effects of multipolar divisions. However, it is unclear whether clustering requires adaptation or is inherent to all cells. Here, we show that cells have varied abilities to cluster extra centrosomes. Epithelial cells are innately inefficient at clustering even in the presence of HSET/KIFC1, which is essential but not sufficient to promote clustering. The presence of E-cadherin decreases cortical contractility during mitosis through a signaling cascade leading to multipolar divisions, and its knockout promotes clustering and survival of cells with multiple centrosomes. Cortical contractility restricts centrosome movement at a minimal distance required for HSET/KIFC1 to exert its function, highlighting a biphasic model for centrosome clustering. In breast cancer cell lines, increased levels of centrosome amplification are accompanied by efficient clustering and loss of E-cadherin, indicating that this is an important adaptation mechanism to centrosome amplification in cancer

Oxidative stress in cells with extra centrosomes drives non-cell-autonomous invasion

Centrosomal abnormalities, in particular centrosome amplification, are recurrent features of human tumors. Enforced centrosome amplification in vivo plays a role in tumor initiation and progression. However, centrosome amplification occurs only in a subset of cancer cells, and thus, partly due to this heterogeneity, the contribution of centrosome amplification to tumors is unknown. Here, we show that supernumerary centrosomes induce a paracrine-signaling axis via the secretion of proteins, including interleukin-8 (IL-8), which leads to non-cell-autonomous invasion in 3D mammary organoids and zebrafish models. This extra centrosomes-associated secretory phenotype (ECASP) promotes invasion of human mammary cells via HER2 signaling activation. Further, we demonstrate that centrosome amplification induces an early oxidative stress response via increased NOX-generated reactive oxygen species (ROS), which in turn mediates secretion of pro-invasive factors. The discovery that cells with extra centrosomes can manipulate the surrounding cells highlights unexpected and far-reaching consequences of these abnormalities in cancer