Nanostructured coatings for intraocular devices with drug delivery function

Despite numerous scientific research efforts, ocular drug delivery remains a challenge for scientists due to the problems related to the current methods that are 90% based on eye drops administration. This therapeutics has some limitations such as rapid drug loss, toxic effects on ocular surfaces and poor patient compliance with the drug regimen. Due to these limitations the current research is focused on the development of newer systems for delivery of the ophthalmic drugs. Nanotechnology-based drug delivery can improve viable solutions giving multiple functionalities to the devices that are inserted in the eye. For example, glaucoma is one of the most troubling chronic diseases, globally considered the second leading cause of blindness by the World Health Organization, whose treatment requires drug administration during years or even during all life. It is therefore imperative to develop alternative therapeutics to administer the drugs into the eye. We are developing a new strategy to deliver the drugs for the glaucoma treatment using biocompatible and nanostructured surfaces that can be used as a coating in an intraocular device. The design of these drug delivery biocompatible surfaces involves the control of its molecular structure and functionality. We have been using Scanning Tunneling Microscopy (STM) at the solid/liquid interface[1-3] to add the components of the monolayers, step-by-step, controlling their adsorption in real time. We used this method to built nanostructured coatings composed of glycosaminoglycans adsorbed on Highly Oriented Pyrolitc Graphite (HOPG). Molecular resolution images were obtained during the formation of the monolayer that revealed a well-packed and organized surface. Presently, we are using these monolayers to adsorb a drug for glaucoma treatment encapsulated in a nanocarrier. Drug release kinetic studies monitored by UV-spectroscopy are underway and preliminary results suggest that this monolayer is very stable and that it is possible to control the drug release as a function of time.info:eu-repo/semantics/publishedVersio

a dynamic model of firms strategic location choice

This paper analyzes the optimal location choice of a firm in a dynamic Cournot framework, in which firms' absorptive capacities may depend on their knowledge stock. The firm decides whether to locate irreversibly in a cluster or in isolation. In the cluster the firm benefits from inward spillovers from its competitors, but also generates outward spillovers. If the firm chooses to locate in isolation no knowledge flows occur. All firms' production costs are determined by their knowledge stocks, which evolve over time due to own R&D investments and potentially inward spillovers. It is shown that, if absorptive capacity is constant, the incentive to locate in the cluster decreases with respect to the firm's knowledge stock. Conversely, if absorptive capacity depends positively on knowledge stock, the firm's incentive to join the cluster is larger the more knowledge it has. It is also shown that qualitative properties of the equilibrium paths of R&D investments and knowledge stocks differ substantially depending on whether absorptive capacities are constant or knowledge dependent

Glucocorticoid receptor antagonism overcomes resistance to BRAF inhibition in BRAFV600E-mutated metastatic melanoma

Clinical applications of glucocorticoids (GC) in Oncology are dependent on their pro-apoptotic action to treat lymphoproliferative cancers, and to alleviate side effects induced by chemotherapy and/or radiotherapy. However, the mechanism(s) by which GC may also promote tumor progression remains unclear. GC receptor (GR) knockdown decreases the antioxidant protection of highly metastatic B16-F10 melanoma cells. We hypothesize that a GR antagonist (RU486, mifepristone) could increase the efficacy of BRAF-related therapy in BRAFV600E-mutated metastatic melanoma. In vivo formed spontaneous skin tumors were reinoculated into nude mice to expand the metastases of different human BRAFV600E melanoma cells. The GR content of melanoma cell lines was measured by [3H]-labeled ligand binding assay. Nuclear Nrf2 and its transcription activity was investigated by RT-PCR, western blotting, and by measuring Nrf2- and redox state-related enzyme activities and metabolites. GR knockdown was achieved using lentivirus, and GR overexpression by transfection with the NR3C1 plasmid. shRNA-induced selective Bcl-xL, Mcl-1, AKT1 or NF-κB/p65 depletion was used to test the efficacy of vemurafenib (VMF) and RU486 against BRAFV600E-mutated metastatic melanoma. During early progression of skin melanoma metastases, RU486 and VMF induced a drastic metastases regression. However, treatment at an advanced stage of growth demonstrated the development of resistance to RU486 and VMF. This resistance was mechanistically linked to overexpression of specific proteins of the Bcl-2 family (Bcl-xL and Mcl-1 in our experimental models). We found that melanoma resistance is decreased if AKT and NF-κB signaling pathways are blocked. Our results highlight mechanisms by which metastatic melanoma cells adapt to survive

Impacto de un programa de recuperación intensificada en cistectomía radical. Estudio comparativo de cohortes

Objetivo: Evaluar los resultados de la instauración de un programa de recuperación intensificada (ERAS) para cistectomía radical en abordaje abierto con respecto a la cohorte histórica de un mismo hospital. Material y métodos: Estudio de análisis retrospectivo de 138 pacientes sometidos a cistectomía radical con derivación ileal tipo Bricker o Studer de forma consecutiva (97 históricos vs. 41 ERAS). Se compararon tasa de complicaciones a 30 días, complicaciones estadio Clavien-Dindo > 2, mortalidad, estancia y tasa de readmisión en el hospital y en cuidados críticos, reintervención y necesidad de sondaje nasogástrico, trasfusión o nutrición parenteral. Resultados: No se hallaron diferencias estadísticamente significativas en cuanto a la tasa de complicaciones globales tras 30 días de alta (73,171 vs. 77.32%; OR 1,25, IC 95% 0,54-2,981; p = 0,601) ni en Clavien-Dindo > 2 (41,463 vs. 42.268%; OR 1.033, IC 95% 0,492-2,167; p = 0,93), así como en mortalidad, estancias o tasas de readmisión y reintervención. La necesidad de sondaje nasogástrico fue menor en el grupo ERAS (43,902 vs. 78,351%; OR 4,624, IC 95% 2,112-10,123; p < 0,0001), así como la necesidad de nutrición parenteral total (26,829 vs. 34,021%; OR 12,234, IC 95% 5,165-28,92; p < 0,0001) y el tiempo bajo intubación orotraqueal desde la inducción anestésica (mediana [RIC] = 325 (285-355) vs. 540 (360-600) min; p < 0,0001). Conclusión: Los programas de recuperación intensificada en cistectomía radical disminuyen el intervencionismo sobre el paciente sin aumentar la morbimortalidad

Changing perspectives on the internationalization of R&D and innovation by multinational enterprises: a review of the literature

Internationalization of R&D and innovation by Multinational Enterprises (MNEs) has undergone a gradual and comprehensive change in perspective over the past 50 years. From sporadic works in the late 1950s and in the 1960s, it became a systematically analysed topic in the 1970s, starting with pioneering reports and “foundation texts”. Our review unfolds the theoretical and empirical evolution of the literature from dyadic interpretations of centralization versus decentralization of R&D by MNEs to more comprehensive frameworks, wherein established MNEs from Advanced Economies still play a pivotal role, but new players and places also emerge in the global generation and diffusion of knowledge. Hence views of R&D internationalization increasingly rely on concepts, ideas and methods from IB and other related disciplines such as industrial organization, international economics and economic geography. Two main findings are highlighted. First, scholarly research pays an increasing attention to the network-like characteristics of international R&D activities. Second, different streams of literature have emphasized the role of location- specific factors in R&D internationalization. The increasing emphasis on these aspects has created new research opportunities in some key areas, including inter alia: cross-border knowledge sourcing strategies, changes in the geography of R&D and innovation, and the international fragmentation of production and R&D activities

Bottom-Up Self-Assembled Supramolecular Structures Built by STM at the Solid/Liquid Interface

One of the lines of research on organic devices is focused on their miniaturization to obtain denser and faster electronic circuits. The challenge is to build devices adding atom by atom or molecule by molecule until the desired structures are achieved. To do this job, techniques able to see and manipulate matter at this scale are needed. Scanning tunneling microscopy (STM) has been the selected technique by scientists to develop smart and functional unimolecular devices. This review article compiles the latest developments in this field giving examples of supramolecular systems monitored and fabricated at the molecular scale by bottom-up approaches using STM at the solid/liquid interface

Glucocorticoid receptor knockdown decreases the antioxidant protection of B16 melanoma cells: an endocrine system-related mechanism that compromises metastatic cell resistance to vascular endothelium-induced tumor cytotoxicity.

We previously reported an interorgan system in which stress-related hormones (corticosterone and noradrenaline), interleukin-6, and glutathione (GSH) coordinately regulate metastatic growth of highly aggressive B16-F10 melanoma cells. Corticosterone, at levels measured in tumor-bearing mice, also induces apoptotic cell death in metastatic cells with low GSH content. In the present study we explored the potential role of glucocorticoids in the regulation of metastatic cell death/survival during the early stages of organ invasion. Glucocorticoid receptor (GCR) knockdown decreased the expression and activity of γ-glutamylcysteine synthetase (γ-GCS), the rate-limiting step in GSH synthesis, in metastatic cells in vivo independent of the tumor location (liver, lung, or subcutaneous). The decrease in γ-GCS activity was associated with lower intracellular GSH levels. Nrf2- and p53-dependent down-regulation of γ-GCS was associated with a decrease in the activities of superoxide dismutase 1 and 2, catalase, glutathione peroxidase, and glutathione reductase, but not of the O2--generating NADPH oxidase. The GCR knockdown-induced decrease in antioxidant protection caused a drastic decrease in the survival of metastatic cells during their interaction with endothelial cells, both in vitro and in vivo; only 10% of cancer cells attached to the endothelium survived compared to 90% survival observed in the controls. This very low rate of metastatic cell survival was partially increased (up to 52%) in vivo by inoculating B16-F10 cells preloaded with GSH ester, which enters the cell and delivers free GSH. Taken together, our results indicate that glucocorticoid signaling influences the survival of metastatic cells during their interaction with the vascular endothelium

Triplet-State and Singlet Oxygen Formation in Fluorene-Based Alternating Copolymers

Data are reported on the triplet states of a series of fluorene-based A-alt-B type alternating copolymers based on pulse radiolysis-energy transfer and flash photolysis experiments. From the pulse radiolysis experiments, spectra are given for eight copolymers involving phenylene, thiophene, benzothiadiazole, and oligothienylenevinylene groups. Quantum yields for triplet-state formation (ΦT) have been obtained by flash photolysis following laser excitation and in one case by photoacoustic calorimetry. In addition, yields of sensitized formation of singlet oxygen have been determined by time-resolved phosphorescence and are, in general, in excellent agreement with the ΦT values. In all cases, the presence of thiophene units is seen to increase intersystem-crossing quantum yields, probably because of the presence of the heavy sulfur atom. However, with the poly[2,7-(9,9-bis(2‘-ethylhexyl)fluorene)-alt-1,4-phenylene] (PFP), thiophene S,S-dioxide (PFTSO2) and benzothiadiazole (F8BT) copolymers, low yields of triplet formation are observed. With three of the copolymers, the energies of the triplet states have been determined. With PFP, the triplet energy is virtually identical to that of poly[2,7-(9,9-bis(2‘-ethylhexyl)fluorene)]. In contrast, with fluorene−thiophene copolymers PFaT and PF3T, the triplet energies are closer to those of thiophene oligomers, indicating that there is significant conjugation between fluorene and thiophene units but also that there is a more localized triplet state than with the homopolymers