79 research outputs found

    Clinical and Genomic Characterization of Pancreatic Ductal Adenocarcinoma with Signet-Ring / Poorly Cohesive Cells

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    : Signet-ring cell/poorly cohesive cell (SRC) carcinoma is an aggressive variant of pancreatic ductal adenocarcinoma (PDAC). This study aimed to clarify its clinicopathological and molecular profiles based on a multi-institutional cohort of 20 cases. The molecular profiles were investigated using DNA and RNA sequencing. The clinicopathological parameters and molecular alterations were analyzed based on survival indices and using a validation/comparative cohort of 480 conventional PDAC patients. The primary findings were as follows: 1) clinicopathological features: SRC carcinomas are highly aggressive neoplasms with poor prognosis and the lungs are elective metastatic sites; 2) survival analysis: a higher SRC component was indicative of poorer prognosis. In particular, the most clinically significant threshold of SRC was 80%, showing statistically significant differences in both disease-specific and disease-free survival; 3) genomic profiles: SRC carcinomas are similar to conventional PDAC with the most common alterations affecting the classic PDAC drivers KRAS (70% of cases), TP53 (55%), SMAD4 (25%), and CDKN2A (20%). EGFR alterations, RET-CCDC6 fusion gene, and microsatellite instability (3 different cases, one alteration per case) represent novel targets for precision oncology. The occurrence of SMAD4 mutations was associated with poorer prognosis; 4) pancreatic SRC carcinomas are genetically different from gastric SRC carcinomas: CDH1, the classic driver gene of gastric SRC carcinoma, is not altered in pancreatic SRC carcinoma; 5) transcriptome analysis: the cases clustered into two groups, one classical/exocrine-like and the other squamous-like; 6) SRC carcinoma-derived organoids can be successfully generated, and their cultures preserve the histological and molecular features of parental SRC carcinoma. Although pancreatic SRC carcinoma shares similarities with conventional PDAC regarding the most important genetic drivers, it also exhibits important differences. A personalized approach for patients with this tumor type should consider the clinical relevance of histological determination of the SRC component and the presence of potentially actionable molecular targets

    Partial correction of immunodeficiency by lentiviral vector gene therapy in mouse models carrying Rag1 hypomorphic mutations

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    IntroductionRecombination activating genes (RAG) 1 and 2 defects are the most frequent form of severe combined immunodeficiency (SCID). Patients with residual RAG activity have a spectrum of clinical manifestations ranging from Omenn syndrome to delayed-onset combined immunodeficiency, often associated with granulomas and/or autoimmunity (CID-G/AI). Lentiviral vector (LV) gene therapy (GT) has been proposed as an alternative treatment to the standard hematopoietic stem cell transplant and a clinical trial for RAG1 SCID patients recently started. However, GT in patients with hypomorphic RAG mutations poses additional risks, because of the residual endogenous RAG1 expression and the general state of immune dysregulation and associated inflammation.MethodsIn this study, we assessed the efficacy of GT in 2 hypomorphic Rag1 murine models (Rag1F971L/F971L and Rag1R972Q/R972Q), exploiting the same LV used in the clinical trial encoding RAG1 under control of the MND promoter.Results and discussionStarting 6 weeks after transplant, GT-treated mice showed a decrease in proportion of myeloid cells and a concomitant increase of B, T and total white blood cells. However, counts remained lower than in mice transplanted with WT Lin- cells. At euthanasia, we observed a general redistribution of immune subsets in tissues, with the appearance of mature recirculating B cells in the bone marrow. In the thymus, we demonstrated correction of the block at double negative stage, with a modest improvement in the cortical/medullary ratio. Analysis of antigenspecific IgM and IgG serum levels after in vivo challenge showed an amelioration of antibody responses, suggesting that the partial immune correction could confer a clinical benefit. Notably, no overt signs of autoimmunity were detected, with B-cell activating factor decreasing to normal levels and autoantibodies remaining stable after GT. On the other hand, thymic enlargement was frequently observed, although not due to vector integration and insertional mutagenesis. In conclusion, our work shows that GT could partially alleviate the combined immunodeficiency of hypomorphic RAG1 patients and that extensive efficacy and safety studies with alternative models are required before commencing RAG gene therapy in thesehighly complex patients

    Frege's Theorem and Mathematical Cognition

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    Frege’s theorem states that Peano Arithmetic can be interpreted in Frege Arithmetic, a second-order system with one extra-logical axiom, Hume’s Principle. The epistemological implications of this result have been controversial. Starting from Heck’s epistemological analysis of the conceptual relations between cardinality, counting, and equinumerosity and expanding on his discussion of empirical results on numerical cognition, I assess the relative importance of equinumerosity and the successor relation in empirical results on numerical cognition in developmental psychology and linguistic anthropology. I conclude that both concepts independently play a role in the development of number concepts. However, the cognitive explanations of the acquisition of numerical concepts arguably do not lead to a full understanding of numerical concepts and are in various ways problematic from a methodological point of view. I conclude that for the analysis of numerical concepts in mathematical practice, a modest provisional apsychologism is commendable

    Integrative characterization of intraductal tubulopapillary neoplasm (ITPN) of the pancreas and associated invasive adenocarcinoma

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    Pancreatic intraductal tubulopapillary neoplasm (ITPN) is a recently recognized intraductal neoplasm. This study aimed to clarify the clinicopathologic and molecular features of this entity, based on a multi-institutional cohort of 16 pancreatic ITPNs and associated adenocarcinomas. The genomic profiles were analyzed using histology-driven multi-regional sequencing to provide insight on tumor heterogeneity and evolution. Furthermore, an exploratory transcriptomic characterization was performed on eight invasive adenocarcinomas. The clinicopathologic parameters and molecular alterations were further analyzed based on survival indices. The main findings were as follows: 1) the concomitant adenocarcinomas, present in 75% of cases, were always molecularly associated with the intraductal components. These data definitively establish ITPN as origin of invasive pancreatic adenocarcinoma; 2) alterations restricted to infiltrative components included mutations in chromatin remodeling genes ARID2, ASXL1, and PBRM1, and ERBB2-P3H4 fusion; 3) pancreatic ITPN can arise in the context of genetic syndromes, such as BRCA-germline and Peutz-Jeghers syndrome; 4) mutational profile: mutations in the classical PDAC drivers are present, but less frequently, in pancreatic ITPN; 5) novel genomic alterations were observed, including amplification of the Cyclin and NOTCH family genes and ERBB2, fusions involving RET and ERBB2, and RB1 disruptive variation; 6) chromosomal alterations: the most common was 1q gain (75% of cases); 7) by transcriptome analysis, ITPN-associated adenocarcinomas clustered into three subtypes that correlate with the activation of signaling mechanism pathways and tumor microenvironment, displaying squamous features in their majority; and 8) TP53 mutational status is a marker for adverse prognosis. ITPNs are precursor lesions of pancreatic cancer with a high malignant transformation risk. A personalized approach for patients with ITPN should recognize that such neoplasms could arise in the context of genetic syndromes. BRCA alterations, ERBB2 and RET fusions, and ERBB2 amplification are novel targets in precision oncology. The TP53 mutation status can be used as a prognostic biomarker

    Peano's Philosophical Views between Structuralism and Logicism

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    El nomos digital y el nuevo orden mundial: hacia una crítica teológica de Silicon Valley

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    Entre las narrativas dominantes que forman el sustrato ideol√≥gico de los procesos globales, podemos identificar poderosas mitolog√≠as de la tecnolog√≠a de corte determinista y sustantivista. La m√°s influyente es la cosmovisi√≥n de Silicon Valley como productora y exportadora de una teolog√≠a pol√≠tica que plantea que la inminente crisis civilizatoria encontrar√° una soluci√≥n t√©cnica. Esta cosmovisi√≥n ha colonizado la vida cotidiana del mundo. Diversas corrientes cr√≠ticas han situado la narrativa sustantivista-determinista en el contexto de una historia intelectual ligada a la teolog√≠a pol√≠tica como marco conceptual que otorga sentido a varios aspectos de esta narrativa, cuya funci√≥n principal es la legitimaci√≥n. Por lo tanto, la sociolog√≠a de los conceptos propuesta por Carl Schmitt permite identificar las contradicciones presentes dentro de dichas narrativas contempor√°neas. La teolog√≠a pol√≠tica vista como el estudio de las estructuras y las fuentes de la legitimidad pol√≠tica abre las puertas para dilucidar el poder de dominaci√≥n que ejerce la cosmovisi√≥n siliconiana y entenderla como una teolog√≠a pol√≠tica cuya caracter√≠stica fundamental es su invisibilidad, que es proporcional a su poder de dominaci√≥n y sienta las bases de un nuevo nomos digital.Among the dominant narratives that form the ideological substrate of global processes, we can identify powerful deterministic and substantivist mythologies about technology. The most influential of these is the worldview of Silicon Valley, as a producer and exporter of a political theology that holds that the impending civilizational crisis will find a technical solution. This worldview has colonized the daily life of the world, providing a new spatial ordering for our present temporality. Various critical currents have placed the substantivist-deterministic narrative in the context of an intellectual history linked to political theology, a conceptual framework that illuminates several functions of this narrative ‚Äď chief among these, the function of legitimation. Therefore, the sociology of concepts proposed by Carl Schmitt allows us to identify the contradictions present within these contemporary narratives. Political theology, seen as the study of the structures and sources of political legitimacy, helps us elucidate the power that the Siliconian worldview exerts. Among other aspects, the framework of political theology highlights the fundamental invisibility of these mythologies, which is proportional to their power of domination, and sets the basis for a new digital nomos of the earth.Entre as narrativas dominantes que formam o substrato ideol√≥gico dos processos globais, podemos identificar mitologias poderosas da tecnologia determin√≠stica e substantiva. Um exemplo √© a vis√£o de mundo do Silicon Valley como produtor e exportador de uma teologia pol√≠tica que afirma que a iminente crise civilizat√≥ria encontrar√° uma solu√ß√£o t√©cnica. Essa vis√£o colonizou a vida cotidiana do mundo. V√°rias correntes cr√≠ticas colocaram a narrativa substantivista-determinista no contexto de uma hist√≥ria intelectual ligada √† teologia pol√≠tica como uma estrutura conceitual que d√° sentido a v√°rios aspectos dessa narrativa, cuja principal fun√ß√£o √© a legitima√ß√£o. Essa √© tamb√©m a principal fun√ß√£o da teologia pol√≠tica. Portanto, a sociologia dos conceitos propostos por Carl Schmitt nos permite identificar as contradi√ß√Ķes presentes nessas narrativas contempor√Ęneas. A teologia pol√≠tica vista como o estudo das estruturas e fontes de legitimidade pol√≠tica abre as portas para elucidar o poder de domina√ß√£o exercido pela cosmovis√£o siliconiana e entend√™-la como uma teologia pol√≠tica cuja caracter√≠stica fundamental √© a sua invisibilidade, que √© proporcional ao seu poder de domina√ß√£o e lan√ßa as bases de um novo nomos digital.Fil: Sereni, Cristina Andrea. Consejo Nacional de Investigaciones Cient√≠ficas y T√©cnicas. Centro Cient√≠fico Tecnol√≥gico Conicet - Patagonia Norte; Argentina. Universidad Nacional de R√≠o Negro. Sede Andina. Centro de Estudios en Ciencia, Tecnolog√≠a, Cultura y Desarrollo; Argentin

    Ablation of Collagen VI leads to the release of platelets with altered function

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    Hemostatic abnormalities and impaired platelet function have been described in patients affected by connective tissue disorders. We observed a moderate bleeding tendency in patients affected by Collagen VI-related disorders and investigated the defects in platelet functionality whose mechanisms are unknown. We demonstrated that megakaryocytes express Collagen VI that is involved in the regulation of functional platelet production. By exploiting a Collagen VI null mouse model (Col6a1-/-), we found that Collagen VI null platelets display significantly increased susceptibility to activation and intracellular calcium signaling. Col6a1-/- megakaryocytes and platelets showed increased expression of STIM1 and ORAI1, the components of Store-Operated Calcium Entry (SOCE), and activation of the mTOR signaling pathway. In vivo mTOR inhibition by rapamycin reduced both STIM1 and ORAI1 expression and calcium flows, resulting in a normalization of platelet susceptibility to activation. These defects were cell-autonomous, as transplantation of lineage-negative bone marrow cells from Col6a1-/- mice into lethally irradiated wild-type animals showed the same alteration in SOCE and platelet activation as compared to Col6a1-/- mice. Peripheral blood platelets of patients affected by Collagen VI-related diseases, Bethlem myopathy and Ullrich congenital muscular dystrophy, displayed increased expression of STIM1 and ORAI1 and were more prone to activation. Altogether, these data demonstrate the importance of Collagen VI in the production of functional platelets by megakaryocytes in mouse models and in Collagen VI-related diseases

    A criticist approach to the question concerning emotionality in high-tech entrepreneurship: Technicist management?

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    Este artículo tiene como propósito indagar de manera crítica sobre el rol de las emociones y la gestión de éstas en el marco del paradigma del emprendedurismo high tech. Este paradigma surgió dentro del sistema neoliberal, entendido aquí como un sistema teológico-político postmoderno. La investigación, interdisciplinaria y bidireccional, pone en diálogo un marco teórico específico con resultados empíricos de trabajo de campo, combinando el campo de la filosofía de la tecnología con el de la antropología. El punto de partida es un caso situado analizado a partir del marco teórico propuesto. Se han identificado las características esenciales del sistema neoliberal como sistema teológico-político para establecer su relación con el horizonte de posibilidad del emprendedurismo high-tech. En segundo lugar, ha sido problematizado un caso etnográfico dentro de este marco teórico, en base a lo cual se han formulado preguntas ancladas en las prácticas de los actores sociales.The purpose of this article is to critically inquire about the role of emotions and their management within the framework of the high tech entrepreneurial paradigm. This paradigm emerged within the neoliberal system, understood here as a postmodern theological-political system. The interdisciplinary and bidirectional research puts into dialogue a specific theoretical framework with empirical results of field work, combining the field of the philosophy of technology with that of anthropology. The starting point is a situated case analyzed within the proposed theoretical framework. The essential characteristics of the neoliberal system as a theological-political system have been identified to establish its relationship with the possibility horizon of high- tech entrepreneurship. Secondly, an ethnographic case has been problematized within this theoretical framework, based on which questions anchored in the practices of social actors have been formulated.Fil: Sereni, Cristina Andrea. Universidad Nacional de Río Negro. Sede Andina. Centro de Estudios en Ciencia, Tecnología, Cultura y Desarrollo; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte; ArgentinaFil: Burton, Bárbara. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte; Argentina. Universidad Nacional de Río Negro. Sede Andina. Centro de Estudios en Ciencia, Tecnología, Cultura y Desarrollo; Argentin
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