PSMA-Targeted Mesoporous Silica Nanoparticles for Selective Intracellular Delivery of Docetaxel in Prostate Cancer Cells

[EN] Although docetaxel is currently broadly used in prostate cancer treatment, poor water solubility and systemic toxicity limit the dose and duration of therapy. In this context, although different nanoplatforms have been proposed to overcome these issues, selective therapy needs developing methodologies to target malignant cells and minimizing the impact on healthy tissue. We here present a novel drug delivery system obtained by covalent conjugation of docetaxel and an anti-prostate specific membrane antigen (PSMA) molecule (anti-FOLH1 monoclonal antibody, clone C803N) over mesoporous silica nanoparticles. This conjugate remains stable in physiological medium and shows high selectivity for LNCaP, a specific cell line that overexpresses PSMA. As a consequence, cell internalization is increased by 25%. Furthermore, cytotoxic activity of the targeted system increases by 2-fold with regard to nontargeted nanoparticles and by 2 orders with regard to the naked drug. Conversely, no targeting effect is observed over PC3, a nonbearing PSMA cell line. We expect that this therapeutic system shows strong potential for treating nonmetastatic prostate cancer, mostly through intraprostatic administration.Financial support from the Spanish Ministry of Economy and Competitiveness (projects MAT2015-66666-C3-2-R, TEC2016-80976-R, and SEV-2016-0683) and the Generalitat Valenciana (project PROMETEO/2017/060) is gratefully acknowledged. We appreciate the assistance of the Electron Microscopy Service of the Universitat Politecnica de Valencia.Rivero-Buceta, EM.; Vidaurre Agut, CM.; Vera Donoso, CD.; Benlloch Baviera, JM.; Moreno Manzano, V.; Botella Asuncion, P. (2019). PSMA-Targeted Mesoporous Silica Nanoparticles for Selective Intracellular Delivery of Docetaxel in Prostate Cancer Cells. ACS Omega. 4(1):1281-1291. https://doi.org/10.1021/acsomega.8b02909S128112914

Mechanism and Consequences of The Impaired Hif-1alfa Response to Hypoxia in Human Proximal Tubular HK-2 Cells Exposed to High Glucose

Renal hypoxia and loss of proximal tubular cells (PTC ) are relevant in diabetic nephropathy. Hypoxia inhibits hypoxia-inducible factor-1? (HIF-1?) degradation, which leads to cellular adaptive responses through HIF-1-dependent activation of gene hypoxia-responsive elements (HRE). However, the diabetic microenvironment represses the HIF-1/HRE response in PTC. Here we studied the mechanism and consequences of impaired HIF-1? regulation in human proximal tubular HK-2 cells incubated in hyperglycemia. Inhibition at different levels of the canonical pathway of HIF-1? degradation did not activate the HIF-1/HRE response under hyperglycemia, except when proteasome was inhibited. Further studies suggested that hyperglycemia disrupts the interaction of HIF-1? with Hsp90, a known cause of proteasomal degradation of HIF-1?. Impaired HIF-1? regulation in cells exposed to hyperglycemic, hypoxic diabetic-like milieu led to diminished production of vascular endothelial growth factor-A and inhibition of cell migration (responses respectively involved in tubular protection and repair). These effects, as well as impaired HIF-1? regulation, were reproduced in normoglycemia in HK-2 cells incubated with microparticles released by HK-2 cells exposed to diabetic-like milieu. In summary, these results highlight the role of proteasome-dependent mechanisms of HIF-1? degradation on diabetes-induced HK-2 cells dysfunction and suggest that cell-derived microparticles may mediate negative effects of the diabetic milieu on PTC.Ministerio de Ciencia e Innovació

Amino modified metal-organic frameworks as pH-responsive nanoplatforms for safe delivery of camptothecin

[EN] MIL-100(Fe) and MIL-101(Fe) metal-organic frameworks (MOFs) are excellent vehicles for drug delivery systems (DDSs) due to their high biocompatibility and stability in physiological fluids, as well as their pore diameter in the mesoporous range. Although they are appropriate for the internal diffusion of 20-(S)-camptothecin (CPT), a strongly cytotoxic molecule with excellent antitumor activity, no stable delivery system has been proposed so far for this drug based in MOFs. We here present novel DDSs based in amine functionalized MIL-100(Fe) and MIL-101(Fe) nanoMOFs with covalently bonded CPT. These CPT nanoplatforms are able to incorporate almost 20% of this molecule and show high stability at physiological pH, with no non-specific release. Based on their surface charge, some of these CPT loaded nanoMOFs present improved cell internalization in in vitro experiments. Moreover, a strong response to acid pH is observed, with up to four fold drug discharge at pH 5, which boost intracellular release by endosomolytic activity. These novel DDSs will help to achieve safe delivery of the very cytotoxic CPT, allowing to reduce the therapeutic dose and minimizing drug secondary effects. (C) 2019 Elsevier Inc. All rights reserved.Financial support of the Spanish Ministry of Economy and Competitiveness (projects TEC2016-80976-R and SEV-2016-0683) is gratefully acknowledged. A.C.G. thanks the La Caixa Foundation for a Ph.D. scholarship. We fully appreciate the assistance of the Electron Microscopy Service of the Universitat Politecnica de Valencia.Cabrera-García, A.; Checa-Chavarria, E.; Rivero-Buceta, EM.; Moreno Manzano, V.; Fernandez Jover, E.; Botella Asuncion, P. (2019). Amino modified metal-organic frameworks as pH-responsive nanoplatforms for safe delivery of camptothecin. Journal of Colloid and Interface Science. 541:163-174. https://doi.org/10.1016/j.jcis.2019.01.042S16317454

A Hyaluronic Acid Demilune Scaffold and Polypyrrole-Coated Fibers Carrying Embedded Human Neural Precursor Cells and Curcumin for Surface Capping of Spinal Cord Injuries

[EN] Tissue engineering, including cell transplantation and the application of biomaterials and bioactive molecules, represents a promising approach for regeneration following spinal cord injury (SCI). We designed a combinatorial tissue-engineered approach for the minimally invasive treatment of SCI¿a hyaluronic acid (HA)-based scaffold containing polypyrrole-coated fibers (PPY) combined with the RAD16-I self-assembling peptide hydrogel (Corning® PuraMatrix¿peptide hydrogel (PM)), human induced neural progenitor cells (iNPCs), and a nanoconjugated form of curcumin (CURC). In vitro cultures demonstrated that PM preserves iNPC viability and the addition of CURC reduces apoptosis and enhances the outgrowth of Nestin-positive neurites from iNPCs, compared to nonembedded iNPCs. The treatment of spinal cord organotypic cultures also demonstrated that CURC enhances cell migration and prompts a neuron-like morphology of embedded iNPCs implanted over the tissue slices. Following sub-acute SCI by traumatic contusion in rats, the implantation of PMembedded iNPCs and CURC with PPY fibers supported a significant increase in neuro-preservation (as measured by greater III-tubulin staining of neuronal fibers) and decrease in the injured area (as measured by the lack of GFAP staining). This combination therapy also restricted platelet-derived growth factor expression, indicating a reduction in fibrotic pericyte invasion. Overall, these findings support PM-embedded iNPCs with CURC placed within an HA demilune scaffold containing PPY fibers as a minimally invasive combination-based alternative to cell transplantation alone.This research was funded by the Science by Women program, Women for Africa Foundation to H.E. and the grants FEDER/Ministerio de Ciencia e Innovacion-Agencia Estatal de Investigacion [RTI2018-095872-B-C21 and -C22/ERDF]; Part of the equipment employed in this work was funded by Generalitat Valenciana and cofinanced with ERDF funds (OP ERDF of Comunitat Valenciana 2014-2020). RISEUP project FetOpen in H2020 Program: H2020-FETOPEN-2018-2019-2020-01.Elkhenany, H.; Bonilla, P.; Giraldo-Reboloso, E.; Alastrue Agudo, A.; Edel, MJ.; Vicent, MJ.; Gisbert-Roca, F.... (2021). A Hyaluronic Acid Demilune Scaffold and Polypyrrole-Coated Fibers Carrying Embedded Human Neural Precursor Cells and Curcumin for Surface Capping of Spinal Cord Injuries. Biomedicines. 9(12):1-19. https://doi.org/10.3390/biomedicines9121928S11991

El reto de la inclusión de los Objetivos de Desarrollo Sostenible en la formación inicial de profesores de secundaria: creación del MOOC curso cero sobre educación y ODS, inclusión en asignaturas y en trabajos fin de máster

Memoria ID-041. Ayudas de la Universidad de Salamanca para la innovación docente, curso 2021-2022

Optimasi Portofolio Resiko Menggunakan Model Markowitz MVO Dikaitkan dengan Keterbatasan Manusia dalam Memprediksi Masa Depan dalam Perspektif Al-Qur`an

Risk portfolio on modern finance has become increasingly technical, requiring the use of sophisticated mathematical tools in both research and practice. Since companies cannot insure themselves completely against risk, as human incompetence in predicting the future precisely that written in Al-Quran surah Luqman verse 34, they have to manage it to yield an optimal portfolio. The objective here is to minimize the variance among all portfolios, or alternatively, to maximize expected return among all portfolios that has at least a certain expected return. Furthermore, this study focuses on optimizing risk portfolio so called Markowitz MVO (Mean-Variance Optimization). Some theoretical frameworks for analysis are arithmetic mean, geometric mean, variance, covariance, linear programming, and quadratic programming. Moreover, finding a minimum variance portfolio produces a convex quadratic programming, that is minimizing the objective function ðð¥with constraintsð ð 𥠥 ðandð´ð¥ = ð. The outcome of this research is the solution of optimal risk portofolio in some investments that could be finished smoothly using MATLAB R2007b software together with its graphic analysis

Search for heavy resonances decaying to two Higgs bosons in final states containing four b quarks

A search is presented for narrow heavy resonances X decaying into pairs of Higgs bosons (H) in proton-proton collisions collected by the CMS experiment at the LHC at root s = 8 TeV. The data correspond to an integrated luminosity of 19.7 fb(-1). The search considers HH resonances with masses between 1 and 3 TeV, having final states of two b quark pairs. Each Higgs boson is produced with large momentum, and the hadronization products of the pair of b quarks can usually be reconstructed as single large jets. The background from multijet and t (t) over bar events is significantly reduced by applying requirements related to the flavor of the jet, its mass, and its substructure. The signal would be identified as a peak on top of the dijet invariant mass spectrum of the remaining background events. No evidence is observed for such a signal. Upper limits obtained at 95 confidence level for the product of the production cross section and branching fraction sigma(gg -> X) B(X -> HH -> b (b) over barb (b) over bar) range from 10 to 1.5 fb for the mass of X from 1.15 to 2.0 TeV, significantly extending previous searches. For a warped extra dimension theory with amass scale Lambda(R) = 1 TeV, the data exclude radion scalar masses between 1.15 and 1.55 TeV

Measurement of the top quark mass using charged particles in pp collisions at root s=8 TeV

Peer reviewe

Search for supersymmetry in events with one lepton and multiple jets in proton-proton collisions at root s=13 TeV

Peer reviewe

MUSiC : a model-unspecific search for new physics in proton-proton collisions at root s=13TeV

Results of the Model Unspecific Search in CMS (MUSiC), using proton-proton collision data recorded at the LHC at a centre-of-mass energy of 13 TeV, corresponding to an integrated luminosity of 35.9 fb(-1), are presented. The MUSiC analysis searches for anomalies that could be signatures of physics beyond the standard model. The analysis is based on the comparison of observed data with the standard model prediction, as determined from simulation, in several hundred final states and multiple kinematic distributions. Events containing at least one electron or muon are classified based on their final state topology, and an automated search algorithm surveys the observed data for deviations from the prediction. The sensitivity of the search is validated using multiple methods. No significant deviations from the predictions have been observed. For a wide range of final state topologies, agreement is found between the data and the standard model simulation. This analysis complements dedicated search analyses by significantly expanding the range of final states covered using a model independent approach with the largest data set to date to probe phase space regions beyond the reach of previous general searches.Peer reviewe