Mecanismos moleculares implicados en el modo de acción de alergoides conjugados a manano y tratamientos anti-IgE en células dendríticas humanas

Tesis inédita de la Universidad Complutense de Madrid, Facultad de Ciencias Químicas, Departamento de Bioquímica y Biología Molecular, leída el 21-01-2022Allergy is defined as the unexpected abnormal or exaggerated reaction to an exogenous stimulus (allergen) involving the immune system. Allergic diseases represent a major health problem of increasing prevalence with high socio-economic burden, decreasing the quality of life of many patients. Nowadays, allergen-specific immunotherapy (AIT) is the only treatment with potential long-lasting disease-modifying effects for allergic diseases, and together with biologicals such as monoclonal antibodies (mAbs), represent the most effective therapies for allergic patients when conventional medication is not enough to control the symptoms. However, they still have drawbacks in terms of efficacy, security, long duration or high cost. Therefore, there is an urgent need to develop more effective and safer treatments. Allergoid-mannan conjugates represent next-generation vaccines for AIT targeting dendritic cells (DCs) able to promote the generation of functional regulatory T (Treg) cells. On the other hand, omalizumab, an anti-IgE biological, is approved for the treatment of severe allergic asthma, for chronic spontaneous urticaria (CSU) and for chronic rhinosinusitis with nasal polyps (CRSwNP). Recently, a next-generation anti-IgE mAb (ligelizumab) with significant higher affinity for IgE than omalizumab, has been developed and it is being currently assayed in phase III random clinical trials for CSU...La alergia se define como una reacción exagerada a sustancias externas (alérgenos) mediada por el sistema inmune. Las enfermedades alérgicas constituyen un problema muy importante de salud con una gran carga socioeconómica, disminuyendo la calidad de vida de los pacientes. Actualmente, la inmunoterapia específica de alérgeno (AIT) es el único tratamiento con capacidad potencial para modificar el curso de las enfermedades alérgicas a largo plazo, y junto a los biológicos como los anticuerpos monoclonales (mAbs) dirigidos frente a dianas específicas, representan las terapias más efectivas para los pacientes en los que la medicación convencional no es suficiente para el control de los síntomas. Sin embargo, estos tratamientos aún presentan ciertas limitaciones en cuanto a eficacia, seguridad, larga duración o alto coste, por lo que hay una necesidad urgente de desarrollar tratamientos más efectivos y seguros. Los alergoides conjugados a manano son vacunas de nueva generación para AIT dirigidas frente a células dendríticas (DCs) capaces de inducir células T reguladoras (Treg) funcionales. Por otro lado, omalizumab, un biológico anti-IgE, está aprobado para el tratamiento del asma alérgica grave, de urticaria crónica espontánea (CSU) y de rinosinusitis crónica con pólipos nasales (CRSwNP). Recientemente, se ha desarrollado un nuevo mAb anti-IgE de alta afinidad (ligelizumab) que se encuentra actualmente en fases muy avanzadas para el tratamiento de CSU...Fac. de Ciencias QuímicasTRUEunpu

The adipokine lipocalin-2 in the context of the osteoarthritic osteochondral junction

Corrigendum: The adipokine lipocalin-2 in the context of the osteoarthritic osteochondral junction. Scientific Reports, 6, 30666. https://doi.org/10.1038/srep30666Obesity and osteoarthritis (OA) form a vicious circle in which obesity contributes to cartilage destruction in OA, and OA-associated sedentary behaviour promotes weight gain. Lipocalin-2 (LCN2), a novel adipokine with catabolic activities in OA joints, contributes to the obesity and OA pathologies and is associated with other OA risk factors. LCN2 is highly induced in osteoblasts in the absence of mechanical loading, but its role in osteoblast metabolism is unclear. Therefore, because osteochondral junctions play a major role in OA development, we investigated the expression and role of LCN2 in osteoblasts and chondrocytes in the OA osteochondral junction environment. Our results showed that LCN2 expression in human osteoblasts and chondrocytes decreased throughout osteoblast differentiation and was induced by catabolic and inflammatory factors; however, TGF-beta 1 and IGF-1 reversed this induction. LCN2 reduced osteoblast viability in the presence of iron and enhanced the activity of MMP-9 released by osteoblasts. Moreover, pre-stimulated human osteoblasts induced LCN2 expression in human chondrocytes, but the inverse was not observed. Thus, LCN2 is an important catabolic adipokine in osteoblast and chondrocyte metabolism that is regulated by differentiation, inflammation and catabolic and anabolic stimuli, and LCN2 expression in chondrocytes is regulated in a paracrine manner after osteoblast stimulation.The authors acknowledge Mr. Oliver Shaw for performing the English revision and the support of Dr. Esbrit's. The authors' research is supported by research grants from Fondo de Investigación Sanitaria funded by the Instituto de Salud Carlos III (PI12/00144, PI13/00570, CP15/00007, PI14/00016 and PIE13/00024). R.G. is funded by the Instituto de Salud Carlos III through a Miguel Servet programme. A.V. is the recipient of a fellowship from the Fundación Conchita Rábago. A.G.M. was funded by the Universidad Carlos III de Madrid (Spain). R.L. and O.G. were funded by the Instituto de Salud Carlos III. O.G. is a member of the RETICS Programme, RD12/0009/0008 Instituto de Salud Carlos III (ISCIII). The research is supported by research grant from FEDE

Singular Temperatures Connected to Charge Transport Mechanism Transitions in Perylene Bisimides from Steady-State Photocurrent Measurements

Perylene bisimides (PBIs) are n-type semiconducting and photogenerating materials widely used in a variety of optoelectronic devices. Particularly interesting are PBIs that are simultaneously water-soluble and liquid-crystalline (PBI-W+LC) and, thus, attractive for the development of high-performing easily processable applications in biology and “green” organic electronics. In this work, singular temperatures connected to charge transport mechanism transitions in a PBI-W+LC derivative are determined with high accuracy by means of temperature-dependent photocurrent studies. These singular temperatures include not only the ones observed at 60 and 110 °C, corresponding to phase transition temperatures from crystalline to liquid-crystalline (LC) and from LC to the isotropic phase, respectively, as confirmed by differential scanning calorimetry (DSC), but also a transition at 45 °C, not observed by DSC. By analyzing the photocurrent dependence simultaneously on temperature and on light intensity, this transition is interpreted as a change from monomolecular to bimolecular recombination. These results might be useful for other semiconducting photogenerating materials, not necessarily PBIs or even organic semiconductors, which also show transport behavior changes at singular temperatures not connected with structural or phase transitions.We appreciate support from the Spanish government (MINECO) and the European Community (FEDER) through Grant MAT-2011-28167-C02-01, as well as the University of Alicante. We gratefully acknowledge financial support from MINECO (MAT2014-52305-P) and the UCM-BSCH joint project (GR3/14-910759). A. de la Peña thanks Universidad Complutense for a predoctoral fellowship

Resultados de la ventriculocisternostomía endoscópica en pacientes con hidrocefalia obstructiva

Introducción: La Ventriculocisternostomía endoscópica (VCE) es una técnica neuroquirúrgica que consiste en realizar un orificio en el piso del III ventrículo con el objetivo de restablecer la hidrodinámica del líquido cefalorraquídeo. Constituye el tratamiento de elección en pacientes con Hidrocefalia obstructiva.Objetivo: Describir los resultados de la ventriculocisternostomía endoscópica en pacientes con Hidrocefalia obstructiva.Diseño Metodológico: Estudio observacional, descriptivo y transversal a 47 pacientes portadores de Hidrocefalia obstructiva, a los que se les realizó la VCE, desde el año 2008 al 2018 en el HMC “Dr. Carlos J. Finlay”.Resultados: La causa más frecuente de Hidrocefalia obstructiva fue la tumoral, representando el 78.72%. La modalidad electiva se realizó en el 72.34% de los casos y la VCE se realizó como único proceder en mayor frecuencia. La principal complicación fue el cierre del estroma, que se presentó en 4 pacientes. El éxito de la VCE fue de un 97.87%.Conclusiones: La VCE resultó un proceder mínimamente invasivo, cuya aplicación ofreció buenos resultados en los pacientes hidrocefálicos. La técnica fue realizada de forma urgente o electiva y combinada a otros procederes endoscópicos. Su implementación mostró un porciento bajo de morbimortalidad y excelente éxito terapéutico

Distributed feedback lasers based on dichromated poly(vinyl alcohol) reusable surface-relief gratings

A simple, low-cost and versatile holographic method to produce reusable surface-relief gratings on dichromated poly(vinyl alcohol) (DCPVA) films, with periods Λ ≥ 270 nm and modulation depths up to 300 nm, is reported. DCPVA presents processing advantages with respect to other photoresists, such as dichromated gelatine, i.e. higher light sensitivity, simpler fabrication process and better batch to batch reproducibility. The successful use of these DCPVA relief gratings as distributed feedback (DFB) laser resonators is demonstrated. Second-order DFB devices emitting in the wavelength range 577-614 nm have been easily prepared by coating a dye-doped polymer film on top of the resonators.We thank the Spanish Government (MINECO) and the European Union (FEDER) for grant no. MAT2011-28167-C02

Sub-400 nm film thickness determination from transmission spectra in organic distributed feedback lasers fabrication

The design and fabrication of thin-film based organic optoelectronic devices require knowledge of the film optical properties. A low-cost and non-destructive method often used for optical characterization of films is the well-established spectrophotometric envelope method. However, this method is typically limited to thickness above 400 nm, a value often higher than that of the films involved in these devices. This paper studies a procedure to obtain the thickness of sub-400 nm active films from their spectrophotometric trace when the refractive index is previously known. The proposed procedure is based on comparing the experimental transmission spectrum in the transparent spectral window with that obtained by simulation. The capabilities of the proposed method are demonstrated here by its application in the fabrication of organic distributed feedback lasers, for which a fine control of film thickness is important to obtain an optimized and reproducible response. Results are verified with other techniques, such as ellipsometry and profilometry. Thus, with the proposed method, film thickness can be easily determined down to 40 nm maintaining an accuracy of about 5 nm even for films with low refractive index (1.5–1.7). Different methods to determine refractive index of these films are also discussed.Spanish Ministry of Economy and Competitivity (MINECO) and European Community (FEDER) through grant no. MAT2015-66586-R

Perylenediimide-based distributed feedback lasers with holographic relief gratings on dichromated gelatine

One dimensional second-order distributed feedback (DFB) lasers consisting of polystyrene (PS) films doped with a perylenediimide laser dye, deposited over dichromated gelatine (DCG) photoresist layers with solvent resistant relief gratings recorded by holographic lithography, are reported. The advantage of using the grating on DCG in the final device is that the fabrication process is simplified and the grating pattern better preserved, since no etching methods to transfer the grating to another substrate are needed. A very simple model, proposed to explain the experimental waveguide properties, has allowed identifying the waveguide mode at which DFB emission appears, which was the key to optimize the device performance. In the frame of this model, the thickness of the PS and DCG films could be adjusted in order to minimize the laser threshold and to control its wavelength tuneability. The performance of these lasers is comparable to that of recently reported devices based on the same active material, but deposited over high-quality DFB gratings engraved on SiO2 by nanoimprint lithography.We thank support from the Spanish Government (MINECO) and the European Community (FEDER) through Grant Nos. MAT2008-06648-C02 and MAT-2011-28167-C02, as well as to the University of Alicante. M.G.R. was supported by a CSIC fellowship within the program JAE

Distributed feedback lasers based on perylenediimide dyes for label-free refractive index sensing

The refractive index sensing capabilitity of distributed feedback (DFB) lasers based on highly photostable (under ambient conditions) perylenediimide-based active films, are reported. The sensor bulk sensitivity is determined from changes in the laser emission wavelength upon exposure to different liquids. The role of the active film thickness (hf) on the sensor sensitivity and on the laser parameters is studied. Sensors based on very thin films (hf = 160 nm) show the highest sensitivities, but their laser thresholds are relatively high and their operational durabilities moderate. The use of thicker films (hf = 850 nm) allows reducing the laser threshold and increasing the durability by two orders of magnitude. In this case, a higher sensitivity is achieved when the sensor operates at the wavelength corresponding to the first-order TE1 mode, instead of at the TE0 one. Finally, it is also shown that the inclusion of a high refractive index TiO2 layer on top of the sensor structure improves the sensitivity by around two times.This work was supported by the Spanish Government (MINECO) and the European Community (FEDER) through grant no. MAT-2011–28167-C02. This work was partially funded by the Basque Government within the framework of the Etortek Program (Grant No. IE13-360). M. Morales-Vidal has been partly supported by a MINECO FPI fellowship (no. BES-2009-020747)