Terapias avanzadas basadas en nanopartículas: transporte eficiente de fármacos y edición génica mediada por CRISPR/Cas

Tesis inédita de la Universidad Complutense de Madrid, Facultad de Ciencias Químicas, leída el 28/01/2021Nanotechnology is an area of research that studies and uses materials between approximately 1 and 100 nm in size. At this scale, new properties appear allowing novel applications. In this sense, one of the most studied applications of nanotechnology in recent years is focused on the use of nanoparticles in medicine to diagnose and treat diseases such as cancer. In this thesis, different nanostructures have been used to transport various therapeutic agents for the treatment of cancer. In particular, albumin-based nanostructures were selected for the transport of antitumor drugs and CRISPR/Cas gene-editing proteins. Specifically, albumin stabilized gold nanoclusters (BSA-AuNCs) were used for the transportation of the drug AZD8055 for the treatment of uveal melanoma, and doxorubicin and SN38 in the same nanostructure to treat breast cancer. These drugs were covalently conjugated with stimuli-responsive linkers that allow for better control of the release of the drugs into the cancer sites, minimizing the exposure of healthy tissues to cytotoxic agents. The systems developed in this work presented remarkable antitumoral activity in in vitro and in vivo models...La nanotecnología es una rama de la ciencia que estudia y usa materiales de entre aproximadamente 1 y 100 nm de tamaño. A esta escala, aparecen nuevas propiedades que permiten aplicaciones novedosas. En este sentido, una de las aplicaciones más estudiadas de la nanotecnología en los últimos años se centra en el uso de nanopartículas en medicina para diagnosticar y tratar enfermedades como el cáncer. En esta tesis, se han utilizado diferentes tipos de nanoestructuras para el transporte de agentes terapéuticos para el tratamiento del cáncer. Específicamente, se emplearon nanoestructuras basadas en albúmina para el transporte de fármacos antitumorales y proteínas del sistema de edición génica CRISPR/Cas. En concreto, se utilizaron nanoclusters de oro estabilizados con albúmina (BSA-AuNCs) para el transporte del fármaco AZD8055 para el tratamiento del melanoma de úvea, y doxorrubicina y SN38 en la misma nanoestructura para el tratamiento del cáncer de mama. Estos fármacos se conjugaron covalentemente con conectores sensibles a estímulos que liberan los fármacos específicamente en el tumor, minimizando el daño en los tejidos sanos. Los resultados obtenidos en este trabajo revelaron una disminución de la viabilidad celular en modelos in vitro e in vivo de los tumores seleccionados. Además del trasporte de agentes quimioterapéuticos, la BSA también fue utilizada como vehículo de la proteína de edición de génica Cpf1. En este caso, la BSA fue conjugada covalentemente con la Cpf1 para protegerla de la degradación prematura en los sistemas biológicos y favorecer su transporte a las células tumorales. Los resultados preliminares de este estudio mostraron la formación eficiente de un nanocomplejo de BSA-Cpf1 capaz de realizar el corte in vitro del gen EGFP...Fac. de Ciencias QuímicasTRUEunpu

Multifunctional albumin-stabilized gold nanoclusters for the reduction of cancer stem cells

Controlled delivery of multiple chemotherapeutics can improve the effectiveness of treatments and reduce side effects and relapses. Here in, we used albumin-stabilized gold nanoclusters modified with doxorubicin and SN38 (AuNCs-DS) as combined therapy for cancer. The chemotherapeutics are conjugated to the nanostructures using linkers that release them when exposed to different internal stimuli (Glutathione and pH). This system has shown potent antitumor activity against breast and pancreatic cancer cells. Our studies indicate that the antineoplastic activity observed may be related to the reinforced DNA damage generated by the combination of the drugs. Moreover, this system presented antineoplastic activity against mammospheres, a culturing model for cancer stem cells, leading to an efficient reduction of the number of oncospheres and their size. In summary, the nanostructures reported here are promising carriers for combination therapy against cancer and particularly to cancer stem cells.This research was funded by the Spanish Ministry of Economy and Competitiveness (CTQ2016-78454-C2-2-R, SAF2014-56763-R, and SAF2017-87305-R), Comunidad de Madrid (S2013/MIT-2850), Asociación Española Contra el Cáncer, and IMDEA Nanociencia IMDEA Nanociencia acknowledges support from the ‘Severo Ochoa’ Programme for Centres of Excellence in R&D (MINECO, Grant SEV-2016-0686

Selective ablation of glucocorticoid receptor in mouse keratinocytes increases susceptibility to skin tumorigenesis.

9 páginas, 5 figuras. En material suplementario 5 figuras.We recently demonstrated that mice lacking the epidermal glucocorticoid (GC) receptor (GR) (GR epidermal knockout (GR(EKO)) mice) have developmental defects and sensitivity to epidermal challenge in adulthood. We examined the susceptibility of GR(EKO) mice to skin chemical carcinogenesis. GR(EKO) mice treated with a low dose of 12-dimethylbenz(a) anthracene (DMBA) followed by phorbol 12-myristate 13-acetate (PMA) promotion exhibited earlier papilloma formation with higher incidence and multiplicity relative to control littermates (CO). Augmented proliferation and inflammation and defective differentiation of GR(EKO) keratinocytes contributed to the phenotype, likely through increased AKT and STAT3 (signal transducer and activator of transcription 3) activities. GR(EKO) tumors exhibited signs of early malignization, including delocalized expression of laminin A, dermal invasion of keratin 5 (K5)-positive cells, K13 expression, and focal loss of E-cadherin. Cultured GR(EKO) keratinocytes were spindle like, with loss of E-cadherin and upregulation of smooth muscle actin (SMA) and Snail, suggesting partial epithelial-mesenchymal transition. A high DMBA dose followed by PMA promotion generated sebaceous adenomas and melanocytic foci in GR(EKO) and CO. Importantly, the number, growth kinetics, and extent of both tumor types increased in GR(EKO) mice, suggesting that in addition to regulating tumorigenesis from epidermal lineages, GR in keratinocytes is important for cross-talk with other skin cells. Altogether, our data reinforce the importance of GR in the pathogenesis of skin cancer.This work was supported by grant SAF2011-28115 of the Ministerio de Economía y Competitividad from the Spanish government. VL holds a fellowship from the MICINN (BES-2009-021944).Peer reviewe

Sistema OXPHOS: integración funcional de dos genomas

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímica. Fecha de lectura: 26/06/2014El DNA mitocondrial (mtDNA) es peculiar por muchos aspectos: es circular, extranuclear y poliploide, no tiene intrones, es transmitido uniparentalmente (no cumple las reglas mendelianas), no sufre recombinación y tiene su propio código genético. Si se valora la transcendencia del mtDNA por el tamaño genómico, podría ser considerado casi irrelevante: tan solo 16.569 pb que codifican para 13 proteínas mitocondriales, frente a más de los 3,3 billones de pb del genoma nuclear (nDNA) que codifican para más de 1000 proteínas mitocondriales. Pero, de su relevancia da idea el esfuerzo energético de la célula en su mantenimiento, ya que en términos de masa, el mtDNA representa en torno al 1-3% del DNA celular total, encontrándose en el rango de cualquier otro cromosoma, y alcanza hasta un 35% del DNA total de un oocito. El mtDNA concentra un número estable de polimorfismos en regiones codificantes que definen los llamados haplogrupos mitocondriales. Aunque durante mucho tiempo esta diversidad genética fue considerada funcionalmente irrelevante, en los último años la neutralidad funcional de las variantes de mtDNA se encuentra en constante debate. En este trabajo se ha abordado el estudio de las implicaciones funcionales de la variabilidad poblacional del mtDNA, teniendo en cuenta el doble origen genético de la cadena de transporte de electrones (mETC), en modelos murinos. El sistema de fosforilación oxidativa (OXPHOS) es el único proceso de las células animales cuyos componentes están codificados en dos genomas (mtDNA y nDNA). Por ello proponemos que se pueden generar diferentes grados de ajuste estructural entre los productos génicos nucleares y mitocondriales, concepto que, para distinguirlo del desajuste patológico, denominamos “mismatch intrínseco del nDNA/mtDNA”. Esta hipótesis predice que para un determinado haplotipo de mtDNA, su combinación con diferentes componentes nucleares puede generar un rendimiento variable de la mETC (no patológico) que puede ser detectado a nivel celular desencadenando cascadas de señalización y adaptación específicas. Para evaluar este fenómeno se han usado ratones conplásticos (idéntico nDNA y distinto mtDNA) y heteroplásmicos (contienen dos variantes de mtDNA en la misma célula). De este modo se ha puesto de manifiesto la relevancia del “mismatch nDNA/mtDNA”, y por tanto las implicaciones funcionales de las variantes de mtDNA, en tres puntos claves de la vida de un individuo: (i) durante el desarrollo embrionario, donde un nuevo contexto nuclear se enfrenta a una variante de mtDNA, (ii) en un individuo formado, donde diferentes contextos nucleares y funcionales conviven en los diferentes tipos celulares, (iii) y durante el proceso de envejecimiento, cuando se produce un declive en la capacidad homeostática celularMitochondrial DNA (mtDNA) is peculiar in many aspects: it is circular, extranuclear, polyploid, lacks introns, is uniparentally transmitted (and therefore does not follow mendelian inheritance patterns), does not undergo recombination, and has its own genetic code. In terms of genome size, mitochondrial DNA (mtDNA) could be considered almost irrelevant: 16,569 bp in the mtDNA, encoding only 13 proteins, compared with more than 3.3 billion bp in the nuclear genome, including genes codifying more than 1000 mitochondrial proteins. However, all cells invest a considerable effort in maintaining this small and odd genome. Thus, around 1-3% of the total DNA is mtDNA in a regular cell, and this figure can rise to an incredible 35% in the oocyte. The peculiarity of mtDNA genetics generates a high level of sequence diversity between individuals and human populations, known as mtDNA haplogroups. This diversity was long considered to functionally irrelevant, but this view has now been challenged for more than a decade. Using mice as a model, we have taken into account the double genetic origin of the electron transport chain (mETC) to investigate the possible functional consequences of different mtDNA variants. The OXPHOS system is genetically unique in being the only process in animal cells that requires components encoded in two genomes, mtDNA and nuclear DNA (nDNA). We hypothesize that functional OXPHOS can be generated at high frequency with different degrees of mismatch between mtDNA and nDNA OXPHOS genes; we refer to this as “intrinsic mismatch” to fully distinguish it from pathological mismatch. This proposal predicts that combination of a given non-pathological mtDNA haplotype with different nDNA components would generate distinguishable (yet non-pathological) performance of mtETC. Thus, within certain limits of mismatch, the activity of the OXPHOS system is sensed by the cell, which reacts to optimize its performance to match its specific requirements. We have investigated this concept using conplastic mice (with identical nuclei but interchanged mtDNA) and heteroplasmic mice (containing two mtDNA variants in the same cell). These approaches have revealed the importance of intrinsic mismatch, and therefore the functional implications of mtDNA variants, at three key levels: (i) during embryo development, when a mtDNA variant is confronted with a new nuclear context; (ii) in different cellular and functional contexts within individuals; and (iii) during aging, when there is a decline in homeostatic capacit

Epidermal inactivation of the glucocorticoid receptor triggers skin barrier defects and cutaneous inflammation.

9 páginas, 5 figuras. En material suplementario 7 figuras, 2 tablas.The glucocorticoid (GC) receptor (GR) mediates the effects of physiological and pharmacological GC ligands and has a major role in cutaneous pathophysiology. To dissect the epithelial versus mesenchymal contribution of GR in developing and adult skin, we generated mice with keratinocyte-restricted GR inactivation (GR epidermal knockout or GR(EKO) mice). Developing and early postnatal GR(EKO) mice exhibited impaired epidermal barrier formation, abnormal keratinocyte differentiation, hyperproliferation, and stratum corneum (SC) fragility. At birth, GR(EKO) epidermis showed altered levels of epidermal differentiation complex genes, proteases and protease inhibitors which participate in SC maintenance, and innate immunity genes. Many upregulated genes, including S100a8/a9 and Tslp, also have increased expression in inflammatory skin diseases. Infiltration of macrophages and degranulating mast cells were observed in newborn GR(EKO) skin, hallmarks of atopic dermatitis. In addition to increased extracellular signal-regulated kinase activation, GR(EKO) newborn and adult epidermis had increased levels of phosphorylated signal transducer and activator of transcription 3, a feature of psoriasis. Although adult GR(EKO) epidermis had a mild phenotype of increased proliferation, perturbation of skin homeostasis with detergent or phorbol ester triggered an exaggerated proliferative and hyperkeratotic response relative to wild type. Together, our results show that epidermal loss of GR provokes skin barrier defects and cutaneous inflammation.This work was supported by grant SAF2008-00540 and SAF2011-28115 of the Ministerio de Ciencia e Innovación/Economía y Competitividad from the Spanish Government and ACOMP2011/127 from Generalitat Valenciana. LMS holds a JAE-DOC contract partly supported by the EC and VL is a recipient of an FPI fellowship of MICINN (BES-2009-021944).Peer reviewe

The church of San Pablo (Valladolid, Spain). The selection of the recording techniques: appropriateness, suitability and effectiveness for the documentation of a cultural heritage project

After almost five years of studies and works carried out to restore the façade of San Pablo in Valladolid (Spain), this paper aims at promoting a critical evaluation of these works in order to analyze the selection of the recording techniques used before, during and immediately after the development of the preliminary studies and the conservation works. During the restoration process the survey was continuously implemented, collecting new data and using different techniques in order to provide the kind of information requested by a multidisciplinary team of professionals with completely different needs. At the same time this project has had the exceptional feature of exposing to the public the development of the conservation works in real time through a lift platform which entailed the obligation of informing everyday through effective and understandable means about how and where the works were being carried out at the façade. In these terms, this paper will try to bring the attention to the difficulties found in choosing the most suitable, effective and appropriate recording technique for different and specific conservation and communication purposes, searching for a good relation between accuracy, cost, time and efficiency within the whole cultural project

Induction of pro-inflammatory response of the placental trophoblast by Plasmodium falciparum infected erythrocytes and TNF.

ABSTARCT: Plasmodium falciparum placental malaria is characterized by the sequestration of infected erythrocytes (IEs) in the placental intervillous space via adherence to chondroitin sulphate A (CSA), production of inflammatory molecules, and leukocytes infiltration. Previous reports suggest that the syncytiotrophoblast (ST) immunologically responds to IEs contact. This study explores the inflammatory response induced in BeWo cells by adherence of IEs and TNFstimulation. METHODS: A non-syncitialized BeWo cells (trophoblast model) were used to evaluate its response to CSA-adherents IEs (FCB1csa, FCB2csa, FCR3csa, 3D7csa) and TNF stimulation. Expression of membrane ICAM-1 (mICAM-1) receptor in BeWo cells was quantified by flow cytometry and the IL-8, IL-6 and soluble ICAM-1 (sICAM-1) concentrations were quantified by enzyme-linked immunosorbentassay (ELISA) in BeWo stimulated supernatants. RESULTS: BeWo cells stimulated with TNF and CSA-adherents IEs of FCB1csa and 3D7csa (strains with higher adhesion) increase the expression of ICAM-1 on the surface of cells and the secretion of immune factors IL-8, IL-6 and sICAM-1. This inflammatory response appears to be related to the level of adherence of IEs because less adherent strains do not induce significant changes. CONCLUSIONS: It was found that BeWo cells responds to CSA-IEs and to TNF favouring a placental pro-inflammatory environment, evidenced by increases in the expression of membrane mICAM-1 and release of soluble ICAM-1, as well as the IL-8 and IL-6 secretion. The expression of ICAM-1 in BeWo cells might be associated to an increase in leukocyte adhesion to the trophoblast barrier, promoting greater inflammation, while the sICAM-1 release could be a protection mechanism activated by trophoblastic cells, in order to regulate the local inflammatory response

Green synthesis of Fe3O4 nanoparticles embedded in a porous carbon matrix and its use as anode material for Li-ion batteries

A scalable and simple process was developed for the preparation of Fe3O4 nanoparticles embedded in carbon using nontoxic and affordable materials. The resulting composite showed a high reversible capacity of 702 mA h g(-1) as anode material in a Li-ion battery after 50 cycles.Latorre Sánchez, M.; Primo Arnau, AM.; García Gómez, H. (2012). Green synthesis of Fe3O4 nanoparticles embedded in a porous carbon matrix and its use as anode material for Li-ion batteries. Journal of Materials Chemistry. 22(40):21373-21375. doi:10.1039/c2jm34978gS21373213752240Aricò, A. S., Bruce, P., Scrosati, B., Tarascon, J.-M., & van Schalkwijk, W. (2005). Nanostructured materials for advanced energy conversion and storage devices. Nature Materials, 4(5), 366-377. doi:10.1038/nmat1368Kang, K. (2006). Electrodes with High Power and High Capacity for Rechargeable Lithium Batteries. Science, 311(5763), 977-980. doi:10.1126/science.1122152Armand, M., & Tarascon, J.-M. (2008). Building better batteries. 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Structure and electrochemical performance of nanostructured Fe3O4/carbon nanotube composites as anodes for lithium ion batteries. Electrochimica Acta, 55(3), 1140-1144. doi:10.1016/j.electacta.2009.10.014Yang, Z., Shen, J., & Archer, L. A. (2011). An in situ method of creating metal oxide–carbon composites and their application as anode materials for lithium-ion batteries. Journal of Materials Chemistry, 21(30), 11092. doi:10.1039/c1jm10902bZhang, W.-M., Wu, X.-L., Hu, J.-S., Guo, Y.-G., & Wan, L.-J. (2008). Carbon Coated Fe3O4Nanospindles as a Superior Anode Material for Lithium-Ion Batteries. Advanced Functional Materials, 18(24), 3941-3946. doi:10.1002/adfm.200801386Piao, Y., Kim, H. S., Sung, Y.-E., & Hyeon, T. (2010). Facile scalable synthesis of magnetitenanocrystals embedded in carbon matrix as superior anode materials for lithium-ion batteries. Chem. Commun., 46(1), 118-120. doi:10.1039/b920037aZhang, M., Lei, D., Yin, X., Chen, L., Li, Q., Wang, Y., & Wang, T. (2010). 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El cuerpo como fundamento de la experiencia estética

En 1907, con las lecciones Cosa y espacio, Husserl da inicio a su fenomenología genética en la cual la preocupación por el cuerpo va más allá de concebirlo como una cosa material. El desarrollo de esta idea se encuentra en su obra no acabada Ideas II, en la que se esboza el papel del cuerpo frente a la naturaleza material, anímica y espiritual. Este artículo muestra la estructura de la propuesta somatológica de Husserl y cómo ésta hace del cuerpo el fundamento para la experiencia estética, base de la vida ética y de la constitución de la cultura y la sociedad.Husserl begins his genetic phenomenology with the lessons of Thing and Space (1907) in which the concern by the body goes beyond of conceiving it as a material thing. The development of this idea is found in his unfinished Ideas II, where it sketches the role of the body with respect of material nature, mental and spirit. This paper shows the structure of the somatological proposal of Husserl and how it makes the body a foundation for the aesthetic experience, ethical basis of life and the constitution of culture and society

Padronização dos prontuarios utilizados por peritos odonto-legistas nos institutos medico-legais em procedimentos de identificação humana

Orientador: Dagmar de Paula QueluzDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Odontologia de PiracicabaResumo: A incumbência de identificar um corpo humano é uma tarefa cujo grau de dificuldade pode variar de uma comprovação em questão de segundos até as raias da impossibilidade, de acordo com a quantidade e qualidade das informações ante e post-mortem adquiridas pela equipe de peritos. Uma linha de ação bem definida e padronizada pode agilizar em muito esta árdua missão, principalmente nas situações em que o cadáver encontrar-se em estado avançado de decomposição, carbonizado, esqueletizado, afogado, fragmentado, ou, ainda, quando houver a necessidade de trocas de informações dentárias entre órgãos de diferentes Estados. Tendo em vista tal necessidade, buscou-se avaliar os procedimentos utilizados em identificações de rotina pelos odonto-Iegistas dos Institutos Médico-legais do Brasil e propor um protocolo padronizado para estas atividades, sendo este inserido em um software para registro e comparação de informações ante e post-mortem de seres humanos. Para tanto, contatou-se os diretores de Institutos Médico-legais dos 26 Estados e Distrito Federal, visando a verificar a presença do perito odonto-Iegista em seus respectivos quadros de pessoal. Apurou-se que destes, apenas 14 responderam positivamente, aos quais solicitaram-se informações sobre suas condutas nas identificações. Dez Institutos Médico-legais retomaram tais informações, e destes, sete formulários vieram com informações úteis à proposta. Constatou-se, pela análise do material recebido, que há diferentes tipos de condutas, havendo, também, carência no detalhamento de informações registradas. Evidenciou-se que uma possível troca de informações entre Estados seria difícil, em virtude de terminologias e odontogramas diferentes, além da falta de informatização por parte de praticamente todos os Institutos Médico-legais. Formulou-se um prontuário de cadáver abrangente e de fácil interpretação, proporcionando eficácia e simplicidade ao processo de identificaçãoAbstract: The levei of complexity in the process to identify a human body can vary from the simplicity of seconds up to almost impossible identification. This degree of difficulty varies according the quality and quantity of information ante and postmortem collected by the forensic experts. A well defined and standardized line of action for this task can help a lot in the execution of the forensic team mission, especially when the body is in an advanced stage of decomposition or it is burned, fragmented or whenever there is a need to exchange dental data with agencies from different States. Based on this necessity, this job has analised the criteria and procedures used in routine identification by the forensic dentists in the Brasilian Forensic Institutes, and suggested a standardized protocol, which data can be introduced in a software that allows the register and comparison of ante and postmortem information. The research started verifying what States in Brazil have the Dental forensic expert, in order to request from them the most number of information on their examination procedures, professional conduct and investigation techniques. 10 of 14 States which confirmed that they have Dental forensic expert sent research material for this study. From these 10 States, 07 had useful information for this research. The comparative study was very useful for the process to analise differences between the many methodologies used by the professionals and to help in determining a stardardized procedure. It was evidenced that an exchange of information and data collection among ali the States would be very difficult due different terminology and odontograms, further on scarcity of data by many of the informants. The study ended with the compilation of ali the collected data in a broad system that can be used in a very easy and simply way in order to organize the application of the new methodology for identification of bodies proposed by this paperMestradoMestre em Odontologia Legal e Deontologi