Implantable hydrogel embedded dark-gold nanoswitch as a theranostic probe to sense and overcome cancer multidrug resistance

Multidrug resistance (MDR) in cancer cells is a substantial limitation to the success of chemotherapy. Here, we describe facile means to overcome resistance by silencing the multidrug resistance protein 1 (MRP1), before chemotherapeutic drug delivery in vivo with a single local application. Our platform contains hydrogel embedded with dark-gold nanoparticles modified with 5-fluorouracil (5-FU)-intercalated nanobeacons that serve as an ON/OFF molecular nanoswitch triggered by the increased MRP1 expression within the tumor tissue microenvironment. This nanoswitch can sense and overcome MDR prior to local drug release. The nanobeacons comprise a 5-FU intercalated DNA hairpin, which is labeled with a near-infrared (NIR) dye and a dark-quencher. The nanobeacons are designed to open and release the intercalated drug only upon hybridization of the DNA hairpin to a complementary target, an event that restores fluorescence emission due to nanobeacons conformational reorganization. Despite the cross-resistance to 5-FU, more than 90% tumor reduction is achieved in vivo in a triple-negative breast cancer model following 80% MRP1 silencing compared with the continuous tumor growth following only drug or nanobeacon administration. Our approach can be applied to reverse cross-resistance to other chemotherapeutic drugs and restore treatment efficacy. As a universal nanotheranostic probe, this platform can pave the way to early cancer detection and treatment.National Cancer Institute (U.S.) (Cancer Center Support (Core) Grant P30-CA14051)Marie Curie International Fellowship (FP7-PEOPLE-2013-IOF, Project 626386

Estudio del proceso de precipitación de Etringita para la eliminación de sulfatos en los efluentes generados en Industrias Químicas del Ebro

En el trabajo de fin de máster se estudia el proceso de precipitación de etringita para la reducción de la concentración de sulfatos que se generan en los efluentes de vertido de la empresa Industrias Químicas del Ebro. Dicho efluentes proceden, por un lado, de los procesos de tratamiento del agua de origen, agua bruta, y que se empleará en los distintos procesos de fabricación de la planta de IQE y, por otro lado, proceden de los efluentes generados en los procesos de fabricación, aguas post-tratamiento. Estos vertidos contienen concentraciones altas de sulfato, junto con otros iones en concentraciones menores. Cuando estos vertidos se eliminan conjuntamente, pueden dar lugar a la precipitación de carbonato cálcico y sulfato cálcico, lo que genera problemas de en las infraestructuras de la red de alcantarillado, en las instalaciones del sistema de depuración y problemas medioambientales. Para evitar esto, se provoca la precipitación de dichas sustancias dentro de la planta de IQE, teniendo el control en todo momento de los sólidos generados y las concentraciones resultantes de los vertidos tratados. El objetivo de este trabajo es el aumento del porcentaje de sulfatos que se eliminan actualmente con los procesos de precipitación de sulfato cálcico, mediante el proceso de precipitación de etringita. La etringita es un compuesto que contiene calcio, sulfato y aluminio en su estructura. Para la realización de este estudio se han analizado los distintos efluentes que se generan y que se van a emplear como materias primas en la precipitación de etringita. Además se estudian las condiciones de reacción, tiempo y consumo de reactivos, y los sólidos obtenidos en los distintos experimentos realizados en laboratorio y en planta piloto

Regulation of dendrimer/dextran material performance by altered tissue microenvironment in inflammation and neoplasia

available in PMC 2015 October 30A “one material fits all” mindset ignores profound differences in target tissues that affect their responses and reactivity. Yet little attention has been paid to the role of diseased tissue on material performance, biocompatibility, and healing capacity. We assessed material-tissue interactions with a prototypical adhesive material based on dendrimer/dextran and colon as a model tissue platform. Adhesive materials have high sensitivity to changes in their environment and can be exploited to probe and quantify the influence of even subtle modifications in tissue architecture and biology. We studied inflammatory colitis and colon cancer and found not only a difference in adhesion related to surface chemical interactions but also the existence of a complex interplay that determined the overall dendrimer/dextran biomaterial compatibility. Compatibility was contextual, not simply a constitutive property of the material, and was related to the extent and nature of immune cells in the diseased environment present before material implantation. We then showed how to use information about local alterations of the tissue microenvironment to assess disease severity. This in turn guided us to an optimal dendrimer/dextran formulation choice using a predictive model based on clinically relevant conditions.National Institutes of Health (U.S.) (NIH grant R01 GM-49039)Deshpande Center for Technological Innovatio

Dataplane Measurements on a Fronthaul and Backhaul integrated network

Future transport networks serving next generation accesses are expected to carry both fronthaul (FH) and backhaul (BH) traffic simultaneously. This new concept of network which integrates the FH and BH traffic over the same transport substrate is called Crosshaul. A Crosshaul network will use heterogeneous technologies, such as fiber, mmWave, or microwave, and selects the most appropriates ones depending on the use case. Moreover, the softwarization/virtualization trend on the networking industry indicates that Virtual Network Functions (VNFs) will process and exchange both BH and FH data plane traffic. This paper presents performance measurements on promising technologies for the implementation of a Crosshaul network. We investigate to which extent the requirements to carry FH traffic are satisfied by mmWave links, software and multi-layer hardware switches

β-Cyclodextrins as affordable antivirals to treat coronavirus infection

The SARS-CoV-2 pandemic made evident that there are only a few drugs against coronavirus. Here we aimed to identify a cost-effective antiviral with broad spectrum activity and high safety profile. Starting from a list of 116 drug candidates, we used molecular modelling tools to rank the 44 most promising inhibitors. Next, we tested their efficacy as antivirals against α and β coronaviruses, such as the HCoV-229E and SARS-CoV-2 variants. Four drugs, OSW-1, U18666A, hydroxypropyl-β-cyclodextrin (HβCD) and phytol, showed in vitro antiviral activity against HCoV-229E and SARS-CoV-2. The mechanism of action of these compounds was studied by transmission electron microscopy and by fusion assays measuring SARS-CoV-2 pseudoviral entry into target cells. Entry was inhibited by HβCD and U18666A, yet only HβCD inhibited SARS-CoV-2 replication in the pulmonary Calu-3 cells. Compared to the other cyclodextrins, β-cyclodextrins were the most potent inhibitors, which interfered with viral fusion via cholesterol depletion. β-cyclodextrins also prevented infection in a human nasal epithelium model ex vivo and had a prophylactic effect in the nasal epithelium of hamsters in vivo. All accumulated data point to β-cyclodextrins as promising broad-spectrum antivirals against different SARS-CoV-2 variants and distant alphacoronaviruses. Given the wide use of β-cyclodextrins for drug encapsulation and their high safety profile in humans, our results support their clinical testing as prophylactic antivirals

β-Cyclodextrins as affordable antivirals to treat coronavirus infection

The SARS-CoV-2 pandemic made evident that there are only a few drugs against coronavirus. Here we aimed to identify a cost-effective antiviral with broad spectrum activity and high safety profile. Starting from a list of 116 drug candidates, we used molecular modelling tools to rank the 44 most promising inhibitors. Next, we tested their efficacy as antivirals against α and β coronaviruses, such as the HCoV-229E and SARS-CoV-2 variants. Four drugs, OSW-1, U18666A, hydroxypropyl-β-cyclodextrin (HβCD) and phytol, showed in vitro antiviral activity against HCoV-229E and SARS-CoV-2. The mechanism of action of these compounds was studied by transmission electron microscopy and by fusion assays measuring SARS-CoV-2 pseudoviral entry into target cells. Entry was inhibited by HβCD and U18666A, yet only HβCD inhibited SARS-CoV-2 replication in the pulmonary Calu-3 cells. Compared to the other cyclodextrins, β-cyclodextrins were the most potent inhibitors, which interfered with viral fusion via cholesterol depletion. β-cyclodextrins also prevented infection in a human nasal epithelium model ex vivo and had a prophylactic effect in the nasal epithelium of hamsters in vivo. All accumulated data point to β-cyclodextrins as promising broad-spectrum antivirals against different SARS-CoV-2 variants and distant alphacoronaviruses. Given the wide use of β-cyclodextrins for drug encapsulation and their high safety profile in humans, our results support their clinical testing as prophylactic antivirals.This work has been funded by grant RTI2018-094445-B100 (MCIU/AEI/FEDER, UE) from the Ministry of Science and Innovation of Spain (C.R.), by Palex Medical S.A., Sika S.A.U. and 7 more companies, and by Ms. Raquel Casaus Alvarez, Mr. Miguel Pardo Gil, Mr. Jacques Noguès and a total of 2916 citizens through the Precipita crowdfunding platform of Fecyt (Fundación Española para la Ciencia y la Tecnología). NI-U is supported by the Spanish Ministry of Science and Innovation (grant PID2020-117145RB-I00), EU HORIZON-HLTH-2021-CORONA-01 (grant 101046118) and by institutional funding of Grifols, Pharma Mar, HIPRA, Amassence and Palobiofarma. This work used the computational resources of the Centro de Supercomputación de Galicia (CESGA) supported by the Partnership for Advanced Computing in Europe (PRACE) COVID-19 Fast Track Call for Proposals – Allocation Decision – Proposal COVID19-85.info:eu-repo/semantics/publishedVersio

Precariedad, exclusión social y diversidad funcional (discapacidad): lógicas y efectos subjetivos del sufrimiento social contemporáneo (II). Innovación docente en Filosofía

El PIMCD "Precariedad, exclusión social y diversidad funcional (discapacidad): lógicas y efectos subjetivos del sufrimiento social contemporáneo (II). Innovación docente en Filosofía" se ocupa de conceptos generalmente eludidos por la tradición teórica (contando como núcleos aglutinantes los de la precariedad laboral, la exclusión social y diversidad funcional o discapacidad), cuyo análisis propicia nuevas prácticas en la enseñanza universitaria de filosofía, adoptando como meta principal el aprendizaje centrado en el estudiantado, el diseño de nuevas herramientas de enseñanza y el fomento de una universidad inclusiva. El proyecto cuenta con 26 docentes de la UCM y otros 28 docentes de otras 17 universidades españolas (UV, UNED, UGR, UNIZAR, UAH, UC3M, UCA, UNIOVI, ULL, EHU/UPV, UA, UAM, Deusto, IFS/CSIC, UCJC, URJC y Univ. Pontificia de Comillas), que permitirán dotar a las actividades programadas de un alcance idóneo para consolidar la adquisición de competencias argumentativas y dialécticas por parte de lxs estudiantes implicados en el marco de los seminarios previstos. Se integrarán en el PIMCD, aparte de PDI, al menos 26 estudiantes de máster y doctorado de la Facultad de Filosofía, a lxs que acompañarán durante el desarrollo del PIMCD 4 Alumni de la Facultad de Filosofía de la UCM, actualmente investigadores post-doc y profesorxs de IES, cuya experiencia será beneficiosa para su introducción en la investigación. Asimismo, el equipo cuenta con el apoyo de varixs profesorxs asociadxs, que en algunos casos son también profesores de IES. Varixs docentes externos a la UCM participantes en el PIMCD poseen una dilatada experiencia en la coordinación de proyectos de innovación de otras universidades, lo que redundará en beneficio de las actividades a desarrollar. La coordinadora y otrxs miembros del PIMCD pertenecen a la Red de Innovación Docente en Filosofia (RIEF), puesta en marcha desde la Universitat de València (http://rief.blogs.uv.es/encuentros-de-la-rief/), a la que mantendremos informada de las actividades realizadas en el proyecto. Asimismo, lxs 6 miembros del PAS permitirán difundir debidamente las actividades realizadas en el PIMCD entre lxs estudiantes Erasmus IN del curso 2019/20 en la Facultad de Filosofía, de la misma manera que orientar en las tareas de maquetación y edición que puedan ser necesarias de cara a la publicación de lxs resultados del PIMCD y en las tareas de pesquisa bibliográfica necesarias para el desarrollo de los objetivos propuestos. Han manifestado su interés en los resultados derivados del PIMCD editoriales especializadas en la difusión de investigaciones predoctorales como Ápeiron y CTK E-Books

Localized and disease-selective drug delivery using adhesive hydrogels for treatment of locally advanced TNBC

Thesis: Ph. D., Harvard-MIT Program in Health Sciences and Technology, 2016.Cataloged from PDF version of thesis.Includes bibliographical references (pages 111-117).Triple negative breast cancer (TNBC) is an aggressive form of cancer that represents 20% of invasive breast cancers, and about 15% are locally advanced at time of presentation. TNBC is negative for estrogen and progesterone receptor, as well as for HER2, and hence it is not treatable with common endocrine treatment such as tamoxifen or Herceptin. Systemic neoadjuvant therapy has been established as the preferred therapeutic approach for locally advanced breast cancer, downstaging the disease and preventing mastectomy. However, complications of systemic chemotherapy are devastating. Local therapy would prevent high concentrations of circulating drug and reduce off-target tissue retention. Yet, the means to attain ideal release kinetics and selective uptake remain elusive. I developed a novel class of biocompatible and biodegradable adhesive materials based on dendrimer and dextran that can coat the tumor and locally release doxorubicin in a controlled manner. Doxorubicin was conjugated to the dendritic component of the adhesive hydrogel to form a pro-drug capable of being released over time as the hydrogel degrades at a pre-programmed rate. The pro-drug was further modified with a ligand capable of sensing and discerning between healthy and cancer cells and facilitating uptake through receptor-mediated endocytosis (RME). The platform developed herein provides a paradigm shift in the way we treat cancer, in a local, selective and targeted manner, to impart optimal clinical outcome.by Nuria Oliva Jorge.Ph. D

Polyplex-Loaded Hydrogels for Local Gene Delivery to Human Dermal Fibroblasts

Impaired cutaneous healing, leading to chronic wounds, affects between 2 and 6% of the total population in most developed countries and it places a substantial burden on healthcare budgets. Current treatments involving antibiotic dressings and mechanical debridement are often not effective, causing severe pain, emotional distress and social isolation in patients for years or even decades, ultimately resulting in limb amputation. Alternatively, gene therapy (such as mRNA therapies) emerges as a viable option to promote wound healing through modulation of gene expression. However, protecting the genetic cargo from degradation and efficient transfection into primary cells remain significant challenges in the push to clinical translation. Another limiting aspect of current therapies is the lack of sustained release of drugs to match the therapeutic window. Herein, we have developed an injectable, biodegradable and biocompatible hydrogel-based wound dressing that delivers pBAE nanoparticles in a sustained manner over a range of therapeutic windows. We also demonstrate that pBAE nanoparticles, successfully used in previous in vivo studies, protect the mRNA load and efficiently transfect human dermal fibroblasts upon sustained release from the hydrogel wound dressing. This prototype wound dressing technology can enable the development of novel gene therapies for the treatment of chronic wounds