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Graphical abstract, JUP, a homologue of β-catenin, is a cell-cell junction protein involved in adhesion junction and desmosome composition. JUP may have a controversial role in different malignancies dependence of its competence with or collaboration with β-catenin as a transcription factor. In this study, we reveal that the function of JUP is related to its cellular location in GC development process from epithelium-like, low malignant GC to advanced EMT-phenotypic GC. Gradual loss of membrane and/or cytoplasm JUP is closely correlated with GC malignancy and poor prognostics. Knockdown of JUP in epithelium-like GC cells causes EMT and promotes GC cell migration and invasion. Ectopic expression of wild JUP in malignant GC cells leads to an attenuated malignant phenotype such as reduced cell invasive potential. In mechanism, loss of membrane and/or cytoplasm JUP abolishes the restrain of JUP to EGFR at cell membrane and results in increased p-AKT levels and AKT/GSK3β/β-catenin signaling activity. In addition, nuclear JUP interacts with nuclear β-catenin and TCF4 and plays a synergistic role with β-catenin in promoting TCF4 transcription and its downstream target MMP7 expression to fuel GC cell invasion.

Long QT syndrome (LQTS), which is caused by an ion channel–related gene mutation, is a malignant heart disease with a clinical course of a high incidence of ventricular fibrillation and sudden cardiac death in the young. Mutations in KCNH2 (which encodes potassium voltage-gated channel subfamily H member 2) are responsible for LQTS in many patients. Here we report the novel mutation c.1898A>C in KCNH2 in a Chinese family with LQTS through whole-exome sequencing. The c.916dupA mutation in JUP (which encodes junction plakoglobin) is also discovered. Mutations in JUP were found to be associated with arrhythmogenic right ventricular cardiomyopathy. The double mutation in the proband may help explain his severe clinical manifestations, such as sudden cardiac death at an early age. Sequencing for the proband’s family members revealed that the KCNH2 mutation descends from his paternal line, while the mutation in JUP came from his maternal line. The data provided in this study may help expand the spectrum of LQTS-related KCNH2 mutations and add support to the genetic diagnosis and counseling of families affected by malignant arrhythmias.

Breast cancer is the most common malignancy in women worldwide. At the molecular level, breast cancer is a heterogeneous disease. For example, the claudin low subtype of breast cancer is characterised by epithelial-mesenchymal transition (EMT). EMT is a process by which epithelial cells lose cell-cell adhesion and their cell polarity, and gain migratory and invasive properties to become mesenchymal cells. The claudin-low subtype is also driven by specific oncogenes, such as MYC or KRAS. Both EMT and oncogene-driven tumorigenesis have been associated with the unfolded protein response (UPR). The UPR is a cellular stress response pathway which activates an adaptive mechanisms to overcome stress and restore endoplasmic reticulum (ER) homeostasis. The UPR comprises three signalling pathways which are activated by three transmembrane sensors of the ER: inositol requiring enzyme 1 (IRE1), protein kinase RNA‐activated (PKR)‐like ER kinase (PERK) and activating transcription factor 6 (ATF6). In breast cancer, IRE1, PERK and ATF6 contribute to cancer cell proliferation, drug resistance and EMT. Chapter III shows that the pharmacological block of IRE1 has no effect on EMT in breast cancer. The knockout of XBP1 was also not sufficient to induce an epithelial phenotype in the MDA-MB-231 claudin low breast cancer cell line. However, Chapter IV shows that plakoglobin, a component of the cell cell contacts, was down regulated by IRE1 in MDA-MB-231 cell line thus affecting cell migration and adhesion in an EMT independent manner. In Chapter V, the relationship between UPR and oncogenes in the regulation of apoptosis was also investigated by overexpressing the oncogenes MYC and KRASG12V in the MCF10A non-tumorigenic mammary epithelial cell line. We observed that the UPR was not activated by MYC and KRASG12V although these oncoproteins decreased cell viability and induced the activation of caspase-3. Finally, in Chapter VI, a cell free drug screening for IRE1 identified compound NUIG10 as a promising inhibitor of IRE1. Altogether, this thesis has evaluated and broadened our knowledge of the role that the UPR and more specifically IRE1 plays in breast cancer. 2024-12-15

Metastatic, drug resistant disease poses the greatest threat to the survival of breast cancer patients. Thus, elucidating and targeting mechanisms which govern this phenotype is a primary goal of the breast cancer field. Breast cancers manipulate cellular stress pathways to gain a survival advantage and fuel their growth. The unfolded protein response (UPR) is a major cell stress pathway responsible for the genesis and growth of many breast cancers. The most evolutionarily conserved transducer of the unfolded protein response is a protein called inositol-requiring enzyme 1 (IRE1), which is an important player in both luminal and basal-like breast cancers. Pro-tumour roles of IRE1 are mediated through its endoribonuclease (RNase) domain which has two functions, X-box binding protein 1 (XBP1) splicing and regulated IRE1-dependent decay (RIDD). In this thesis we have determined that the IRE1 RNase is particularly active in triple negative breast cancer (TNBC), a subtype with a poor prognosis and limited treatment options. We have discovered novel targets of the IRE1 RNase domain, namely C-X-C motif chemokine ligand 1 (CXCL1) which we have shown to govern a drug-resistant and stem cell-like phenotype. We also identified the first RIDD substrate in breast cancer (junction plakoglobin (JUP)) and found that its degradation by IRE1 may promote migration of TNBC cells. We employed MKC8866, a small molecule with clinical potential, to show that both of these processes can be blocked. This work highlights the promise of targeting IRE1 in the clinic to prolong and improve the lives of breast cancer patients. 2022-12-17

Dissertaça o apresentada para cumprimento dos requisitos necessa rios a obtença o do grau de Mestre em Ciências Empresariais- Ramo Gestão Logística Este estudo tem como propósito avaliar a importância das suas características dos sistemas comunitários portuários (PCS – Port Community Systems) para o desempenho dos portos e das economias, ou seja, determinar em que medida as características específicas dos sistemas comunitários portuários influenciam o seu desempenho. Em termos concretos, visa determinar em que medida as características específicas da Janela Única Portuária portuguesa influenciam o seu desempenho, com impacto no desempenho dos portos portugueses. Foi utilizada a metodologia de análise estatística com o SPSS, correlação entre variáveis e do caso de estudo. A amostra inclui 15 observações, recolhidas em outubro de 2017, em Portugal, com recurso a inquérito sobre a importância dos fatores (escala Likert5), para o caso geral dos PCS e para o caso de estudo da JUP. Conclui-se que as variáveis obtidas a partir da literatura definem as características importantes dos sistemas comunitários portuários e das suas medidas de desempenho e que as características dos sistemas comunitários portuários determinam o seu desempenho. The purpose of this study is to evaluate the importance of Port Community Systems (PCS) and their characteristics for the performance of ports and economies, that means, determine in what measure the specific characteristics of Port Community Systems determine their performance. In concrete terms, aims to determine in what measure the specific characteristics of Port Single Window Portuguese influence their performance, with an impact on the performance of Portuguese ports. A methodology of statistical analysis was used with the SPSS, correlation between variables and of the case study. The sample includes 15 observations, collected in October of 2017, in Portugal, with recourse to a survey about the importance of the factors (Likert5 scale) for the general case of PCS and for the JUP case study. Concludes that the variables obtained from the literature define the important characteristics of Port Community Systems and its performance measures, and that the characteristics of the Port Community Systems determine their performance.

La relación entre el peronismo y la universidad fue estudiada a partir de un conjunto de prejuicios que afirmaban su total antagonismo. Con el fin de poner en tela de juicio a los mismos, analizaremos el discurso sobre la universidad de la revista 4161; la misma se autodenominada órgano de la Juventud Universitaria Peronista y sus dos números aparecieron entre 1963 y 1964. A nuestro juicio, la relevancia de la revista radica en que fueuna aparición temprana de un conjunto de universitarios dados a la tarea de construir una identidad universitaria peronista. La idea que guía nuestra pesquisaes que la revista ensaya un sincretismo que, partiendo del peronismo, busca converger con diversas corrientes como el reformismo o el marxismo. Este proceso es de vital importancia para dar cuenta de la posterior masividad que adquiere el peronismo en las universidades en la década del 70 y, hacia 1973 y cómo aquellas concepciones influyeron en los proyectos de reforma institucional de las universidades argentinas. Por este sendero, podemos pensar que 4161 fue el inicio de una cultura política universitaria del peronismo., The relationship between Peronism and University has been studied on the basis of the prejudice that upheldtheir mutual antagonism. With de purpose of challenging this prejudice, we shall analyse the discourse about university in 4161 magazine. 4161 designated itself as the news media of the University Peronist Youth (JUP for its acronym in Spanish), andits two issues were released between 1963 and 1964. From our point of view, the relevance of this magazine is based on the fact that it meant the early appearance of a group of university students aiming at building a peronist university identity. The leading idea of our research is that the magazine attempts at a syncretism that, based on peronism, looks at converging with other identities, such as reformism or marxism. This process is crucial to understand the subsequent popularity that peronism gains inthe university world in the seventies and towards 1973, as well as its influence in the projects of institutional reform during this period. Along the same lines, we might affirm that 4161 meant the beginning of the university political culture of peronism., Facultad de Periodismo y Comunicación Social

Recorremos aquí las memorias de la militancia estudiantil reformista y marxista de la UBA acerca de la Juventud Universitaria Peronista entre 1973 y 1976. Analizamos 15 testimonios orales de activistas de diversas organizaciones, en los que encontramos cuatro tópicos centrales: la JUP era una fuerza de formación reciente, con escasa trayectoria y conocimiento del medio universitario; esta agrupación carecía de un proyecto universitario consistente; tenía relaciones conflictivas con sus aliados y, con el pasaje de Montoneros a la clandestinidad, se agudizaron las tensiones con las otras agrupaciones de la UBA. In this paper we visit the memories of the reformist and marxist student activism of the UBA about the Juventud Universitaria Peronista between 1973 and 1976. We analyzed 15 oral testimonies of activists from various organizations and found four main topics: the JUP was a organization of recent formation, with little experience and knowledge of the university environment; this group lacked a consistent university project; the JUP had conflictive relations with its allies and, with the passage of Montoneros to clandestinity, the tensions with the other militant groupings of the UBA were exacerbated. Fil: Millán, Mariano Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Saavedra 15. Instituto de Historia Argentina y Americana "Dr. Emilio Ravignani". Universidad de Buenos Aires. Facultad de Filosofía y Letras. Instituto de Historia Argentina y Americana "Dr. Emilio Ravignani"; Argentina

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a hereditary cardiomyopathy characterized by fibrofatty replacement of cardiomyocytes, ventricular tachyarrhythmias and sudden death. ARVD/C is mainly caused by mutations in genes encoding desmosomal proteins. However, the pathogenicity of variants is not always clear. Therefore, we created an online database (www.arvcdatabase.info), providing information on variants in ARVD/C-associated genes. We searched the literature using ARVD/C and its underlying genes as search terms. From the selected papers and our unpublished data, we collected details on the type of mutation and information provided at the protein level. A "details page" contains clinical data and references. To aid the interpretation of missense mutations, we provide data from in silico prediction methods. In May 2009 the database contained 481 variants in eight genes. A total of 144 variants are considered pathogenic, 73 are unknown/unclassified, and 264 have no known pathogenicity. The database was converted into the Leiden Open Variation Database (LOVD) format, a gene-centered collection of DNA variations. The ARVD/C database will be useful for both researchers and clinicians. It can be searched to determine if variants have been published and whether they are considered pathogenic. External users are invited to add information to improve the quantity and quality of the data entered. Hum Mutat 30:1278-1283, 2009. (C) 2009 Wiley-Liss, Inc.

En este artículo analizamos el conflicto estudiantil y universitario en la UBA durante el rectorado de Rodolfo Puiggrós, entre junio y principios de octubre de 1973. Realizamos una periodización de los enfrentamientos distinguiendo centralmente los grupos que chocaron y los complejos procesos para la formación de alianzas. Mostramos los bríos y las dificultades para la composición de fuerzas en la izquierda, así como la emergencia de articulaciones de centro y de derechas de creciente importancia. Nuestra periodización tiene tres grandes cortes, signados por el avance de estos sectores: la llamada Masacre de Ezeiza, el día 20 de junio de 1973; el final del gobierno de Héctor Cámpora, el 13 de julio y la renuncia de Rodolfo Puiggrós, el 1 de octubre del mismo año. In this article we analyze student’s and university conflicts in UBA during the rectory of Rodolfo Puiggrós between June and early October 1973. We make a periodization of the struggles, marking the groups that clashed and the complex process of forming alliances. We show the vigor and the difficulties for the composition of forces on the left wing, and the emergence of increasingly important political forces from center and right wing. Our periodization has three major sections, marked by strengthening of conservative forces: the so calledEzeiza massacre, on June 20th, 1973; the end of the government of Hector Cámpora, on July 13th and Rodolfo Puiggrós´s resignation on October 1st of that year. Fil: Millán, Mariano Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Saavedra 15. Instituto de Historia Argentina y Americana ; Argentina

La leucémie aiguë myéloïde est une hémopathie maligne génétiquement hétérogène caractérisée par de fréquents réarrangements impliquant la bande chromosomique 21q22 et le gène RUNX1. Dans ce groupe d’anomalies, les translocations t(8;21)(q22;q22) et t(3;21)(q26;q22), associées respectivement à un pronostic favorable et défavorable, sont les mieux étudiées. Or, plus de la moitié des réarrangements ciblant RUNX1 ne sont toujours pas caractérisés au niveau clinique et moléculaire. Les principaux objectifs de cette thèse sont de caractériser quatre nouvelles translocations ciblant RUNX1 et d’étudier la dérégulation transcriptionnelle associée à ces anomalies au niveau de cibles plus spécifiques ayant un rôle dans l’auto-renouvellement ou dans la différenciation hématopoïétique. À l’aide des techniques de cytogénétique et de biologie moléculaire, deux nouveaux partenaires de RUNX1, soit CLCA2 et SV2B, ont été identifiés au sein des t(1;21)(p22.3;q22) et t(15;21)(q26.1;q22) et la récurrence des partenaires USP42 et TRPS1 a été démontrée suite à l’étude des t(7;21)(p22.1;q22) et t(8;21)(q23.3;q22). Ce travail a permis de confirmer l’existence de divers modes de dérégulation de RUNX1 dans les leucémies aiguës. L’expression présumée de protéines chimériques et/ou d’isoformes tronquées de RUNX1, un dosage aberrant des transcrits de RUNX1 et la surexpression des gènes partenaires sont des conséquences révélées par l’étude de ces fusions. Le séquençage et l’analyse des jonctions génomiques des fusions récurrentes RUNX1-USP42/USP42-RUNX1 et RUNX1-TRPS1/TRPS1-RUNX1 ont démontré la présence de signatures moléculaires caractéristiques du mode de recombinaison non-homologue de type NHEJ. En raison de la structure et de la composition différente des jonctions, l’implication de composantes distinctes du mécanisme NHEJ a été proposée. Enfin, des analyses par PCR quantitative en temps réel nous ont permis de démontrer l’existence de cibles de dérégulation partagées par les fusions récurrentes et plus rares de RUNX1. Nous avons démontré que CEBPA est moins exprimé dans la majorité des spécimens étudiés présentant une fusion de RUNX1 par rapport aux spécimens avec un caryotype normal alors que JUP, une composante effectrice de la voie Wnt, est plutôt surexprimé. Malgré l’activation transcriptionnelle de JUP dans l’ensemble de ces spécimens, certaines cibles de la voie Wnt telles que CCND1 et MYC sont différemment exprimées dans ces cellules, appuyant l’hétérogénéité décrite dans ce groupe de leucémies. Malgré l’implication de partenaires variés, nos données d’expression démontrent que les chimères et les protéines tronquées de RUNX1 partagent des cibles communes d’activation et de répression transcriptionnelle et établissent, pour la première fois, des évidences moléculaires suggérant l’existence de similitudes entre la fusion récurrente RUNX1-RUNX1T1 et quatre fusions plus rares de RUNX1. Puisque des rechutes surviennent fréquemment dans ce groupe génétique, l’inhibition de JUP pourrait être une option thérapeutique intéressante et ceci est appuyé par les bénéfices observés lors de l’inhibition de la voie Wnt dans d’autres groupes génétiques de leucémies aiguës., Acute myeloid leukemia (AML) is a genetically heterogeneous disease characterized by frequent rearrangements of the RUNX1 gene located at chromosomal band 21q22. In this subtype of leukemias, t(8;21)(q22;q22) and t(3;21)(q26;q22) translocations are among the most studied rearrangements, being respectively associated with a favourable and poor prognosis. However, approximately half of RUNX1 translocations remain uncharacterized at the clinical and molecular levels at the present time. The main objectives of this thesis are to characterize four novel RUNX1 translocations in adult patients with acute leukemias and to study the expression profiles of specific transcriptional targets of RUNX1 fusions involved in self-renewal or differentiation of hematopoietic cells. Using molecular techniques, we identified CLCA2 and SV2B genes as novel fusion partners of RUNX1 in t(1;21)(p22;q22) and t(15;21)(q26;q22) translocations. We also described the recurrence of the USP42 and TRPS1 genes involved in t(7;21)(p22;q22) and t(8;21)(q23.3;q22) translocations. Chimeric fusion proteins, truncated isoforms of RUNX1, alteration of RUNX1 transcripts expression and overexpression of the fusion partner were possible outcomes of these various fusions, thus demonstrating the diversity of RUNX1 alterations in acute leukemias. Genomic breakpoints of the recurrent RUNX1-UPS42/USP42-RUNX1 and RUNX1-TRPS1/TRPS1-RUNX1 fusions were cloned and analyzed revealing typical signatures of the non-homologous end joining recombination mechanism at fusion junctions. Since variation in the structure and composition of these junctions was observed, we proposed that distinct cellular machineries would be involved in the genesis of these abnormalities. Quantitative real-time PCR was performed on primary leukemic cells expressing these rare RUNX1 fusions. We demonstrated, for the first time, that similar downregulation of CEBPA and upregulation of JUP, an effector of the Wnt pathway, are detected in most samples studied presenting either recurrent or rare RUNX1 fusions. Despite an overexpression of JUP detected in each RUNX1 positive sample studied, other targets of the Wnt pathway like CCND1 and MYC genes were differently expressed in these cells, thus confirming the heterogeneity of this group of leukemias. Our expression data show that similar transcriptional targets, activated or repressed, are detected in cells expressing either chimeric or truncated RUNX1 proteins and establish the first molecular evidences suggesting that the recurrent RUNX1-RUNX1T1 and four rare RUNX1 fusions share common molecular deregulations. As relapse frequently occurs in RUNX1 positive leukemias, JUP overexpression could be of particular interest with regard to targeted-therapy, as demonstrated by previous work showing potential benefits of inhibiting the Wnt pathway in other genetic groups of acute leukemias.