Modular magnetite-filled nanomicelles for multimodal imaging-guided development of effective anticancer vaccines

188 p.Tanto las células cancerosas como muchos de los patógenos que causan enfermedades crónicas han desarrollado mecanismos para evadir al sistema inmune. Por lo tanto, es necesario desarrollar nuevas tecnologías que nos permitan conseguir vacunas novedosas, seguras y efectivas contra este tipo de enfermedades.En esta tesis se propone un sistema de trasporte capaz de dirigir antígenos tumorales y/o adyuvantes hasta los órganos secundarios linfoides (bazo y nódulos linfáticos) con el propósito de generar una respuesta inmune potente y específica contra el cáncer. Este tipo de sistema de transporte se basa en nanopartículas de óxido de hierro recubiertas con un polímero bio-compatible, lo cual permite conferir propiedades únicas a estas vacunas `sub-unitarias¿.Gracias al tamaño nanométrico, estas vacunas son capaces de transportar ambos tipos de moléculas inmunogénicas a las mismas poblaciones de células presentes en los nódulos linfáticos y, del mismo modo, permiten la interacción con receptores/compartimentos celulares específicos. Este transporte dirigido implica una mejora considerable de la eficacia de la inmunización, incluso a dosis bajas, permitiendo una respuesta inmune humoral y celular específica contra el tumor.Mediante el marcaje de estas nano-vacunas con un fluoróforo (rodamina B) y el radioisótopo 67Ga, es posible estudiar su interacción con las células, su comportamiento en medios fisiológicos y su biodistribución in vivo, mediante técnicas de imagen no-invasivas.Estas nano-vacunas han demostrado ser materiales muy prometedores para el desarrollo de nuevas vacunas contra el cáncer.CIC BiomaGUN

Modular magnetite-filled nanomicelles for multimodal imaging-guided development of effective anticancer vaccines

188 p.Tanto las células cancerosas como muchos de los patógenos que causan enfermedades crónicas han desarrollado mecanismos para evadir al sistema inmune. Por lo tanto, es necesario desarrollar nuevas tecnologías que nos permitan conseguir vacunas novedosas, seguras y efectivas contra este tipo de enfermedades.En esta tesis se propone un sistema de trasporte capaz de dirigir antígenos tumorales y/o adyuvantes hasta los órganos secundarios linfoides (bazo y nódulos linfáticos) con el propósito de generar una respuesta inmune potente y específica contra el cáncer. Este tipo de sistema de transporte se basa en nanopartículas de óxido de hierro recubiertas con un polímero bio-compatible, lo cual permite conferir propiedades únicas a estas vacunas `sub-unitarias¿.Gracias al tamaño nanométrico, estas vacunas son capaces de transportar ambos tipos de moléculas inmunogénicas a las mismas poblaciones de células presentes en los nódulos linfáticos y, del mismo modo, permiten la interacción con receptores/compartimentos celulares específicos. Este transporte dirigido implica una mejora considerable de la eficacia de la inmunización, incluso a dosis bajas, permitiendo una respuesta inmune humoral y celular específica contra el tumor.Mediante el marcaje de estas nano-vacunas con un fluoróforo (rodamina B) y el radioisótopo 67Ga, es posible estudiar su interacción con las células, su comportamiento en medios fisiológicos y su biodistribución in vivo, mediante técnicas de imagen no-invasivas.Estas nano-vacunas han demostrado ser materiales muy prometedores para el desarrollo de nuevas vacunas contra el cáncer.CIC BiomaGUN

Adherence to the Western, Prudent and Mediterranean Dietary Patterns and Colorectal Cancer Risk: Findings from the Spanish Cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Spain)

The aim of this study was to explore the association between three previously identified dietary patterns (Western, Prudent, and Mediterranean) and colorectal cancer (CRC) risk by sex and cancer subtype. The Spanish cohort of the European Prospective Investigation into Cancer and Nutrition study provided dietary and epidemiological information from 15,629 men and 25,808 women recruited between 1992 and 1996. Among them, 568 CRC cases and 3289 deaths were identified during a median follow-up of 16.98 years. The associations between adherence to the three dietary patterns and CRC risk (overall, by sex, and by tumour location: proximal and distal colon and rectum) were investigated by fitting multivariate Cox proportional hazards regression models stratified by study centre and age. Possible heterogeneity of the effects by sex and follow-up time (1-10 vs. >= 10 years) was also explored. While no clear effect of the Prudent dietary pattern on CRC risk was found, a suggestive detrimental effect of the Western dietary pattern was observed, especially during the first 10 years of follow-up (HR1SD-increase (95% CI): 1.17 (0.99-1.37)), among females (HR1SD-increase (95% CI): 1.31 (1.06-1.61)), and for rectal cancer (HR1SD-increase (95% CI): 1.38 (1.03-1.84)). In addition, high adherence to the Mediterranean pattern seemed to protect against CRC, especially when restricting the analyses to the first 10 years of follow-up (HR1SD-increase (95% CI): 0.84 (0.73-0.98)), among males (HR1SD-increase (95% CI): 0.80 (0.65-0.98)), and specifically against distal colon cancer (HR1SD-increase (95% CI): 0.81 (0.63-1.03)). In conclusion, low adherence to the Western diet and high adherence to the Mediterranean dietary pattern could prevent CRC, especially distal colon and rectal cancer

Consumption of aspartame and other artificial sweeteners and risk of cancer in the Spanish multicase‐control study (MCC‐Spain)

Use of artificial sweeteners (AS) such as aspartame, cyclamate, saccharin and sucralose is widespread. We evaluated the association of use of aspartame and other AS with cancer. In total 1881 colorectal, 1510 breast, 972 prostate and 351 stomach cancer and 109 chronic lymphocytic leukaemia (CLL) cases and 3629 population controls from the Spanish Multicase-Control (MCC-Spain) study were recruited (2008-2013). The consumption of AS, from table-top sweeteners and artificially sweetened beverages, was assessed through a self-administered and validated food frequency questionnaire (FFQ). Sex-specific quartiles among controls were determined to compare moderate consumers ( third quartile) vs non consumers (reference category), distinguishing aspartame-containing products and other AS. Unconditional logistic regression models were used to estimate adjusted OR and 95%CI, and results were stratified by diabetes status. Overall, we found no associations between the consumption of aspartame or other AS and cancer. Among participants with diabetes, high consumption of other AS was associated with colorectal cancer (OR=1.58, 95% CI 1.05-2.41, P trend=.03) and stomach cancer (OR=2.27 [0.99-5.44], P trend=.06). High consumption of aspartame, was associated with stomach cancer (OR=2.04 [0.7-5.4], P trend=.05), while a lower risk was observed for breast cancer (OR=0.28 [0.08-0.83], P trend=.03). In some cancers, the number of cases in participants with diabetes were small and results should be interpreted cautiously. We did not find associations between use of AS and cancer, but found associations between high consumption of aspartame and other AS and different cancer types among participants with diabetes

Egileen eta arazleen sintaxia jite adjektiboen argitan

Lan honetan -garri eta -kor atzizkien bitartez eraikitzen diren jite adjektiboak arakatu ditugu. Adjektibo horiek mendeko aditzak adierazten duen gertaerarekin edo egoerarekin lotutako irakurketa potentziala, ebaluatiboa edo joerazkoa dute, eta, adjektiboaren arabera, balio aktiboa, pasiboa ala jasaileduna izan dezakete. Lan honetan proposatuko dugu jite adjektiboen interpretazioa adjektiboak mendean hartzen duen egitura morfosintaktikoaren ondorioa dela; zehazki, Boz buruaren, aditz txikiaren eta buru horiei lotutako argumentuen araberakoa (Alexiadou, 2018; Oltra-Massuet, 2013). Azterketa honetatik abiatuta, proposatuko dugu egile eta arazle argumentuak gune desberdinetan sartzen direla sintaxian.

Antimicrobial 3D Porous Scaffolds Prepared by Additive Manufacturing and Breath Figures

We describe herein a novel strategy for the fabrication of efficient 3D printed antibacterial scaffolds. For this purpose, both the surface topography as well as the chemical composition of 3D scaffolds fabricated by additive manufacturing were modified. The scaffolds were fabricated by fused deposition modeling (FDM) using high-impact polystyrene (HIPS) filaments. The surface of the objects was then topographically modified providing materials with porous surfaces by means of the Breath Figures approach. The strategy involves the immersion of the scaffold in a polymer solution during a precise period of time. This approach permitted the modification of the pore size varying the immersion time as well as the solution concentration. Moreover, by using polymer blend solutions of polystyrene and polystyrene-b-poly(acrylic acid) (PS-b-PAA) and a quaternized polystyrene-b-poly(dimethylaminoethyl methacrylate) (PS-b-PDMAEMAQ), the scaffolds were simultaneously chemically modified. The surfaces were characterized by scanning electron microscopy and infrared spectroscopy. Finally, the biological response toward bacteria was explored. Porous surfaces prepared using quaternized PDMAEMA as well as those prepared using PAA confer antimicrobial activity to the films, i.e., were able to kill on contact Staphylococcus aureus employed as model bacteria.We gratefully acknowledge support from the Consejo Superior de Investigaciones Cienti ́ fi cas (CSIC). Equally, this work was fi nancially supported by the Ministerio de Economi ́ ay Competitividad (MINECO) through MAT2016-78437-R (AEI/FEDER, UE), BIO2012-34835 and BIO2017-77367-C2- 1R projects. Nelson Vargas Alfredo thanks the support for postdoctoral research from the CONACYT (CN: 274411)Peer Reviewe

Colour and CaCO3 content in the Upper Maastrichtian and the Lower Eocene couplets at Sopelana (Basque Arc): palaeoenvironmental responses

The Sopelana sea-cliff exposes marl-limestone couplets from the Upper Maastrichtian (MS1 and MS2 sections) and the Lower Eocene (EI section), in the deep Basque Arc domain. The high-resolution analysis (% CaCO3) of the MS1 couplets confirms a complex behaviour with strong compositional contrast vs. a more regular MS2 couplets. This may be due to a drastic environmental change (long humid and rainy alternating to drier periods) towards dominant humid and rainy periods, with a minor seasonal nature and high sedimentation rate (72 cm/20 ky). The deep, cold, oxygenated marine water produces a change of coloration (grey to purple) during the sedimentation, in the Upper Maastrichtian couplets before diagenesis activity. It is the beginning of the Cretaceous oceanic red beds (CORB´s

Highly Efficient Antibacterial Surfaces Based on Bacterial/Cell Size Selective Microporous Supports

We report on the fabrication of efficient antibacterial substrates selective for bacteria, i.e., noncytotoxic against mammalian cells. The strategy proposed is based on the different size of bacteria (1-4 μm) in comparison with mammalian cells (above 20 μm) that permit the bacteria to enter in contact with the inner part of micrometer-sized pores where the antimicrobial functionality are placed. On the contrary, mammalian cells, larger in terms of size, remain at the top surface, thus reducing adverse cytotoxic effects and improving the biocompatibility of the substrates. For this purpose, we fabricated well-ordered functional microporous substrates (3-5 μm) using the breath figures approach that enabled the selective functionalization of the pore cavity, whereas the rest of the surface remained unaffected. Microporous surfaces were prepared from polymer blends comprising a homopolymer (i.e., polystyrene) and a block copolymer (either polystyrene-b-poly(dimethylaminoethyl methacrylate) (PDMAEMA) or a quaternized polystyrene-b-poly(dimethylaminoethyl methacrylate)). As a result, porous surfaces with a narrow size distribution and a clear enrichment of the PDMAEMA or the quaternized PDMAEMA block inside the pores were obtained that, in the case of the quaternized PDMAEMA, provided an excellent antimicrobial activity to the films.The authors gratefully acknowledge support from the Consejo Superior de Investigaciones Cientifí cas (CSIC). Equally, this work was financially supported by the Ministerio de Economía y Competitividad (MINECO) through MAT2016-78437-RAEI/ FEDER, UE (J.R.H.), BIO2012-34835, and BIO2016- 77367 (A.L.C).Peer Reviewe

Fabrication of biocompatible and efficient antimicrobial porous polymer surfaces by the Breath Figures approach

We designed and fabricated highly efficient and selective antibacterial substrates, i.e. surface non-cytotoxic against mammalian cells but exhibiting strong antibacterial activity. For that purpose, microporous substrates (pore sizes in the range of 3–5 μm) were fabricated using the Breath Figures approach (BFs). These substrates have additionally a defined chemical composition in the pore cavity (herein either a poly(acrylic acid) or the antimicrobial peptide Nisin) while the composition of the rest of the surface is identical to the polymer matrix. As a result, considering the differences in size of bacteria (1–4 μm) in comparison to mammalian cells (above 10 µm) the bacteria were able to enter in contact with the inner part of the pores where the antimicrobial functionality has been placed. On the opposite, mammalian cells remain in contact with the top surface thus preventing cytotoxic effects and enhancing the biocompatibility of the substrates. The resulting antimicrobial surfaces were exposed to Staphylococcus aureus as a model bacteria and murine endothelial C166-GFP cells. Superior antibacterial performance while maintaining an excellent biocompatibility was obtained by those surfaces prepared using PAA while no evidence of significant antibacterial activity was observed at those surfaces prepared using Nisin.The authors gratefully acknowledge support from the Consejo Superior de Investigaciones Científicas (CSIC). Equally, this work was financially supported by the Ministerio de Economía y Competitividad (MINECO) through MAT2016-78437-R-FEDER-EU (JRH) and BIO2012-34835, BIO2016-77367-C2-1-R (ALC) projects. Nelson Vargas Alfredo thanks the support for postdoctoral research from the CONACYT (CN: 274411).Peer Reviewe

Development of synthetic, self-adjuvanting, and self-assembling anticancer vaccines based on a minimal saponin adjuvant and the tumor- associated MUC1 antigen

The overexpression of aberrantly glycosylated tumor-associated mucin-1 (TA-MUC1) in human cancers makes it a major target for the development of anticancer vaccines derived from synthetic MUC1-(glyco) peptide antigens. However, glycopeptide-based subunit vaccines are weakly immunogenic, requiring adjuvants and/or additional immunopotentiating approaches to generate optimal immune responses. Among these strategies, unimolecular self-adjuvanting vaccine constructs that do not need coadministration of adjuvants or conjugation to carrier proteins emerge as a promising but still underexploited approach. Herein, we report the design, synthesis, immune-evaluation in mice, and NMR studies of new, self-adjuvanting and self-assembling vaccines based on our QS-21-derived minimal adjuvant platform covalently linked to TA-MUC1-(glyco)peptide antigens and a peptide helper T-cell epitope. We have developed a modular, chemoselective strategy that harnesses two distal attachment points on the saponin adjuvant to conjugate the respective components in unprotected form and high yields via orthogonal ligations. In mice, only tri-component candidates but not unconjugated or di- component combinations induced significant TA-MUC1-specific IgG antibodies able to recognize the TA-MUC1 on cancer cells. NMR studies revealed the formation of self-assembled aggregates, in which the more hydrophilic TA-MUC1 moiety gets exposed to the solvent, favoring B-cell recognition. While dilution of the di-component saponin–(Tn)MUC1 constructs resulted in partial aggregate disruption, this was not observed for the more stably-organized tri-component candidates. This higher structural stability in solution correlates with their increased immunogenicity and suggests a longer half-life of the construct in physiological media, which together with the enhanced antigen multivalent presentation enabled by the particulate self-assembly, points to this self-adjuvanting tri-component vaccine as a promising synthetic candidate for further development.Funding from the European Research Council (ERC-2016-STG-716878 to A. F.-T.; ERC-2017-AdG-788143 to J. J. B.) and the Spanish Ministry of Science and Innovation MCIN/AEI (PID2020-117911RB-I00, CTQ2017-87530-R, RYC-2015-17888 to A. F.-T.; RTI2018-096494-B-100 to J. A.; RTI2018-094751-B-C21 to J. J. B) is gratefully acknowledged. We thank Felix Elortza and Ibon Iloro from the CIC bioGUNE Proteomics Platform and Javier Calvo from the CIC biomaGUNE Mass Spectrometry Platform for their support with MALDI and HRMS analyses. A. F. T. thanks Raquel Fernandez for inspiration