Improving anti-cancer therapies through a better identification and characterization of non-canonical MHC-I associated peptides

Increasing evidence of non-canonical protein translation has sparked interest in their identification and characterization for use in immunotherapy. In addition, recent studies on the repertoire of major histocompatibility complex class I (MHC-I) associated peptides (MAPs or immunopeptidome), have suggested that MAPs derived from these translations are potential targets for cancer immunotherapy. Therefore, the aim of this study was to assess the impact of these MAPs in cancer by developing methods to facilitate their identification and their validation as potential targets for immunotherapy. To facilitate the identification of non-canonical proteins, we developed Ribo-db, a proteogenomic approach that combines RNA sequencing, ribosome profiling and mass spectrometry. This approach enables the generation of specific databases aimed at including protein diversity. The use of Ribo-db to analyze diffuse large B-cell lymphoma (DLBCL) samples revealed that approximately 10% of MAPs were derived from non-canonical proteins. These proteins had distinct properties compared to those derived from canonical proteins. They had shorter lengths and lower stability, but greater efficiency in generating MAPs. Importantly, we found limited overlap between the non-canonical proteins detected in the immunopeptidome and those detected in the whole proteome suggesting the existence of two distinct non-canonical protein repertoires. Knowing that non-canonical MAPs can be effective targets for cancer immunotherapy, we developed BamQuery, a tool to assess their expression in tissues to determine whether they can be used in a vaccine. BamQuery aims to predict the probability of MHC-I presentation of each peptide in different tissues based on its RNA expression. Using BamQuery, we found that previously identified tumor antigens (TA) would be highly expressed in healthy tissues, making them poor candidates for immunotherapy. In addition, we also identified highly potential immunotherapeutic targets in DLBCL that were derived from non-canonical translations. These targets showed promising as they were poorly expressed in normal tissues but highly expressed and shared in tumor samples. Thus, BamQuery proved to be a useful tool for identifying and prioritizing potential immunotherapeutic targets. Overall, our research indicated that non-canonical regions of the genome increase the diversity of MAPs that can be recognized by T cells. Furthermore, the expression of MAPs in tissues can be used as a predictor of their presentation to MHC I to identify reliable targets for immunotherapy, for which BamQuery is an effective tool.Les preuves de plus en plus nombreuses de la traduction des protéines non canonique ont suscité l'intérêt pour leur identification et leur caractérisation en vue de leur utilisation dans les immunothérapies. En outre, des études récentes sur le répertoire des peptides associés au complexe majeur d'histocompatibilité de classe I (CMH-I, connus sous le nom de MAPs ou immunopeptidome), ont suggéré que les MAPs dérivés de ces traductions sont des cibles potentielles pour l'immunothérapie du cancer. L'objectif de cette étude était donc d'évaluer l'impact de ces MAP dans le cancer en développant des méthodes pour faciliter leur identification et leur validation en tant que cibles potentielles pour l'immunothérapie. Afin de faciliter l'identification des protéines non canoniques, nous avons développé Ribodb, une approche protéogénomique qui combine le séquençage de l'ARN, le profilage ribosomal et la spectrométrie de masse. Cette approche permet de générer des bases de données spécifiques visant à inclure la diversité des protéines. Notre analyse avec Ribo-db d'échantillons de lymphome diffus à grandes cellules B (DLBCL) a révélé qu'environ 10% des MAP étaient dérivés de protéines non canoniques. Ces protéines avaient des propriétés distinctes par rapport à celles dérivées de protéines canoniques. Elles étaient plus courtes et avaient une stabilité plus faible, mais une plus grande efficacité dans la génération de MAPs. Fait important, nous avons constaté un chevauchement limité entre les protéines non canoniques détectées dans l'immunopeptidome et celles détectées dans le proteome entier, ce qui suggère l'existence de deux répertoires distincts de protéines non canoniques. Sachant que les MAP non canoniques peuvent être des cibles efficaces pour l'immunothérapie du cancer, nous avons développé BamQuery, un outil permettant d'évaluer leur expression dans les tissus afin de déterminer s'ils peuvent être utilisés dans un vaccin. BamQuery vise à prédire la probabilité de présentation au CMH-I de chaque MAP dans différents tissus sur la base de son expression ARN. En utilisant BamQuery, nous avons découvert que des antigènes tumoraux (TA) précédemment identifiés seraient fortement exprimés dans les tissus sains, ce qui en fait de mauvais candidats pour l'immunothérapie. En outre, nous avons également ii identifié des cibles immunothérapeutiques très potentielles dans DLBCL qui étaient dérivées de traductions non canoniques. Ces cibles se sont révélées prometteuses car elles étaient peu exprimées dans les tissus normaux mais fortement exprimées et partagées dans les échantillons tumoraux. Ainsi, BamQuery s'est avéré être un outil utile pour identifier et hiérarchiser les cibles immunothérapeutiques potentielles. Dans l'ensemble, nos recherches ont indiqué que les régions non canonique du génome augmentent la diversité des MAPs qui peuvent être reconnues par les cellules T. De plus, l'expression des MAPs dans les tissus peut être utilisée comme un prédicteur de leur présentation au CMH I afin d'identifier des cibles fiables pour l'immunothérapie, ce pour quoi BamQuery est un outil efficace

How effective and cost-effective are behaviour change interventions in improving the prescription and use of antibiotics in low-income and middle-income countries? A protocol for a systematic review.

INTRODUCTION: Antibiotic resistance endangers effective prevention and treatment of infections, and places significant burden on patients, families, communities and healthcare systems. Low-income and middle-income countries (LMICs) are especially vulnerable to antibiotic resistance, owing to high infectious disease burden, and limited resources for treatment. High prevalence of antibiotic prescription and use due to lack of provider's knowledge, prescriber's habits and perceived patient needs further exacerbate the situation. Interventions implemented to address the inappropriate prescription and use of antibiotics in LMICs must address different determinants of antibiotic resistance through sustainable and scalable interventions. The aim of this protocol is to provide a comprehensive overview of the methods that will be used to identify and appraise evidence on the effectiveness and cost-effectiveness of behaviour change interventions implemented in LMICs to improve the prescription and use of antibiotics. METHODS AND ANALYSIS: Two databases (Web of Science and PubMed) will be searched based on a strategy developed in consultation with an essential medicines and health systems researcher. Additional studies will be identified using the same search strategy in Google Scholar. To be included, a study must describe a behaviour change intervention and use an experimental design to estimate effectiveness and/or cost-effectiveness in an LMIC. Following systematic screening of titles, abstracts and keywords, and full-text appraisal, data will be extracted using a customised extraction form. Studies will be categorised by type of behaviour change intervention and experimental design. A meta-analysis or narrative synthesis will be conducted as appropriate, along with an appraisal of quality of studies using the Grading of Recommendation, Assessment, Development and Evaluation (GRADE) checklist. ETHICS AND DISSEMINATION: No individual patient data are used, so ethical approval is not required. The systematic review will be disseminated in a peer-reviewed journal and presented at a relevant international conference. PROSPERO REGISTRATION NUMBER: CRD42017075596

Humanización en cuidado paliativo : escuchar, acompañar y respetar al otro

El Cuidado Paliativo (CP) es un escenario reconocido en el mundo actual, es una necesidad que se fundamenta en el aumento de la esperanza de vida, con el consecuente incremento del envejecimiento poblacional, y mayor prevalencia de las enfermedades crónicas y terminales. Este CP, está dirigido hacia una población que presenta enfermedades de tipo terminal, entidades que promueven un estado de vulnerabilidad en términos físicos, sociales y psicológicos a quienes las padecen. Pese a la importancia de este tipo de cuidado, la evidencia señala que la asistencia de personas con enfermedades terminales es inadecuada, y que hay factores causantes determinantes de esta situación. Uno de estos elementos es la futilidad terapéutica, la cual se presenta cuando el médico no reconoce que la vida tiene límites, y que ciertos manejos terapéuticos atentan contra la autonomía y la dignidad de las personas. Más allá de evitar la muerte, las medidas útiles se encaminan a proveer calidad de vida a los que sobreviven, y calidad de muerte a los que mueren. Lo que se propone en este trabajo es humanizar el cuidado paliativo a través de una interacción entre el médico y el paciente que promueva el acto de escucharse y respetarse el uno al otro, y donde el médico en un rol solidario pueda entregarse al servicio de quien lo necesita. Siempre se deben respetar la dignidad y la autonomía humanas. Finalmente, el CP debe consolidarse como un acompañamiento constante en la búsqueda del cuidado y del bienestar integral del enfermo.At present, Palliative Care (PC) is a worldwide-recognized stage; it is a necessity based on the increase in life expectancy, with the consequent rise in the population aging, and a higher prevalence of chronic and terminal illnesses. This CP is directed toward a population with terminal diseases, entities that promote a vulnerability state in physical, social and psychological terms. Despite the importance of this type of care, the evidence shows that the assistance of people with terminal illnesses is unsuitable, and that exist determining factors causing this. One of these elements is the therapeutic futility, which occurs when a medical doctor does not recognize that life has limits, and that certain therapeutic approaches put in risk the autonomy and dignity of human beings. Actually, beyond avoiding death, the useful measures must aim to provide quality of life to those who survive, and quality of death to those who die. The purpose of this paper is to humanize palliative care through an interaction between the physician and the patient that promotes the act of listening and respect between each other, in which the doctor in a supportive role devotes himself to the service who need him. Always, must be respected human dignity and autonomy. Finally, PC has to consolidate itself as a constant support in the looking for care and comprehensive well-being of the patient.Magíster en BioéticaMaestrí

VIOLETA PARRA: UMA VIDA DEDICADA AO RESGATE E À RECOPILAÇÃO DA CULTURA POPULAR CHILENA

This article is part of the doctoral research aims to analyze, in  the work of  Violeta Parra, how this Chilean multi-artist reworks elements of popular culture of  his country, whose attitude demonstrates the political commitment to decolonization and the emancipation of popular knowledge. This position opens cracks in the ways of conceiving religious and spiritual values ​​of Western culture, which were brought to Latin America. It is noted that Violeta understood the rescue of the popular memory as a way to rebuild the historical past of his people. Thus, his work enables an understanding of the future built on cultural and epistemological self-awareness, dominated by symbolic forms of modernity / coloniality. This article presents testimonial texts of their children and people from the artistic scope , who knew and knew their emancipatory project allowing cover their work under the cloak of chilenidad which is the core of all his artistic production.The research is based on theoretical assumptions of postcolonial studies such as Fanon (1961 ) , Spivak (2010 ) , Bhabha (1998 ) , Mignolo (2003 : 2007) , Quijano (2000 ) , Colombres (2007 ) Martin- Barbero (1991 ) and Lienhard (2011 ), among others, proponents break the colonialist fixidez and binarisms  cultural identity.    Este artículo hace parte de una investigación científica doctoral que tiene como objetivo analizar, en la obra de Violeta Parra, el modo como esta multi-artista chilena reelabora elementos de la cultura popular de su país, demostrando compromiso político con la descolonización y la emancipación del saber popular.  Tal posicionamiento le abre grietas a los modos como se conciben valores religiosos, espirituales y culturales occidentales que fueron introducidos en América Latina. Se observa que Violeta Parra comprendía, el rescate de la tradición popular, como una forma de reconstruir el  pasado histórico de su pueblo. De esta manera, su obra posibilita la comprensión del futuro  de su país, pautada sobre la autoconsciencia cultural y epistemológica, dominada hasta entonces por las formas simbólicas de la modernidad/ colonialidad. En este artículo, se presentan textos testimoniales de sus hijos y personas del ámbito artístico, que la conocieron y sabían de su proyecto emancipador, lo que permitió, que su obra se cubriera de un espíritu de chilenidade, que es el cerne de toda su producción artística. La investigación se fundamenta en los presupuestos teóricos de los estudios poscoloniales de: Franz Fanón (1961), Spivak (2010), Homi Bhabha (1998),Walter Mignolo (2003:2007), Aníbal Quijano (2000), Adolfo Colombres (2007) Jesús Martin-Barbero(1991) y Martín  Lienhard (2011), entre otros, los cuales proponen  romper con la fixidez colonialista y los binarismos culturales identitário.Este artigo faz parte da pesquisa doutoral que tem como objetivo analisar, na obra de Violeta Parra, o modo como esta multiartista chilena reelabora elementos da cultura popular de seu país, cuja atitude demonstra o compromisso político com a decolonização e a emancipação do saber popular.  Tal posicionamento abre fissuras nos modos de conceber valores religiosos, espirituais e culturais Ocidentais que foram trazidos para América Latina. Observa-se que Violeta Parra compreendia no resgate da tradição popular uma forma de reconstruir o passado histórico do seu povo. Desta forma, sua obra possibilita uma compreensão de futuro construída na autoconsciência cultural e epistemológica, dominada pelas formas simbólicas da modernidade/ colonialidade. Neste artigo, se apresentam textos testemunhais de seus filhos e pessoas do âmbito artístico, que a conheceram e sabiam do seu projeto emancipatório, o que permitiu, que sua obra se cobrisse de um espírito de chilenidade que é o cerne de toda sua produção artística. A pesquisa se sustenta nos pressupostos teóricos dos estudos pós-coloniais de: Frantz Fanon (1961), Spivak (2010), Homi Bhabha (1998),Walter Mignolo (2003:2007), Anibal Quijano (2000), Adolfo Colombres (2007) Jesús Martin-Barbero(1991) e Martín  Lienhard (2011), entre outros, os quais propõem romper com a fixidez colonialista e com binarismos culturais identitários

A Mulher no Romance Don Quijote De La Mancha

Este artigo pretende refletir sobre a idealização do papel feminino na personagem Dulcinea del Toboso da obra El Ingenioso hidalgo Don Quijote de la Mancha (1605-1616) em oposição à lavradora Aldonza Lorenzo, uma camponesa rude e de pouco trato, representante da mulher trabalhadora rural do século XVII. No capítulo X da segunda parte, Miguel de Cervantes, (1547-1616) configura o modelo feminino criado pela tradição do amor cortês, da qual as novelas de cavalaria do século XI e XII são exemplos, e Dulcinea del Toboso, coroamento. Um senhor que, como Don Quijote, tivesse partido às batalhas pensando em restabelecer a justiça social e os valores cristãos no mundo, precisava ter a quem oferecer suas vitórias, uma bela donzela que o esperasse cheia de amor e saudade, seguindo, assim, o modelo proposto por aquela tradição. A mestria de Cervantes consiste em fazer sua obra mergulhar no imaginário popular criado em torno a uma atitude fictícia frente à vida. Os cavaleiros andantes ocupam um papel relevante nesse imaginário: eles juravam vassalagem à mulher e sofriam qualquer tipo de provação pelo seu amor. Dessa situação, derivam todos os parâmetros de avaliação de Don Quijote. A temática deste capítulo se articula nos códigos de cavalaria. Normas e ditames morais são obedecidos cegamente pela personagem para modificar seus atos ou conduta. Observa-se que tal aspecto é decisivo para a constituição da subjetividade moderna e a compreensão da forma de construir a realidade na obra

Mapping The Research Evolution Of Immigrant Minors Legislation And Its Relationship To Physical Education And Mental Health (In The Period 2001-2022)

Background: Migration is one of the major challenges Europe is facing, primarily due to the proliferation of the massive arrival of unaccompanied minors. This difficulty also affects the rest of the world and is considered one of the most prominent social issues of this new era (2) Methods: Hence, we conducted a bibliometric study of research published on immigrant minors in the period 2001-2022 to gain insights into and analyze the scientific perspectives on this topic. (3) Findings and (4) Conclusions: Our conclusion reveals that the United States and Spain are the countries with the highest production of research in this field, mainly because they have the largest number of immigrant minors in their countries, predominantly from Mexico and Morocco, respectively

Cervantes – precursor da contemporaneidade

RESUMO: As transformações, que vêm ocorrendo nas narrativas latino-americanas a partir de Cervantes, permitem fazer relações entre a sua obra e a Nova Novela Histórica Latino-Americana (NNHLA) e considerá-lo o antecessor do novo gênero narrativo. Nas narrativas novelística e contista, levam a acreditar que houve um processo de maturidade que afetou os escritores latino-americanos e suas produções literárias. Tal processo se desata na procura por explicar a realidade por meio da invenção deliberada de elementos ficcionais que os sentidos não percebem e representam o esforço individual da genial imaginação de Cervantes, fazendo com que essa narrativa adquirisse características especiais, as quais foram analisadas por Ainsa (1991) neste novo gênero narrativo. O primeiro romance moderno – Dom Quixote de la Mancha, (1605-1615) de Miguel de Cervantes – induziu a uma nova visão do fazer literário, caracterizado pelo desejo imperioso de seu autor de “fazer-de-outro-modo” e guiado por um certo ideal ascético que percorre toda a obra de Cervantes. Esse novo modo de fazer literatura acaba por contagiar os escritores latino-americanos que buscavam ansiosamente romper com a tradição literária. Cabe, aqui, destacar que o termo “fazer-de-outro-modo” está sendo usado, neste estudo, no sentido empregado por Nietzsche (1987), em Genealogia da Moral. O novo fazer narrativo dos escritores latino-americanos revela não apenas uma transformação no fazer literário, mas também uma reação contrária à centralização do foco temático das obras na problemática social, que banalizada as obras, elevando-as, desta forma, ao nível dos mais conceituados romances polifônicos

Presença do canto e da poesia mapuche nas composições de Violeta Parra. Entrevista com Paula Miranda

O texto apresenta parte de entrevista realizada com a pesquisadora Paula Miranda Herrera, do curso de Letras, Graduação e Pós-graduação da PUC-Chile e investigadora do Centro de Estudos Interculturais e Indígenas (CIIR). A entrevista objetiva dar visibilidade aos estudos latinoamericanos que se voltam à obra artística de Violeta Parra, sobretudo, aqueles que aproximam as composições musicais e poéticas da multiartista chilena com a poesia e o canto do povo mapuche. Trabalho que se visualiza nas reflexões de Elicura Chihuailaf, Paula Miranda, Elisa Loncon. Allison Ramay, Adriana Paredes, Pindal, dentre outros