Influence of Elastomer Layers in the Quality of Aluminum Parts on Finishing Operations

In finishing processes, the quality of aluminum parts is mostly influenced by static and dynamic phenomena. Different solutions have been studied toward a stable milling process attainment. However, the improvements obtained with the tuning of process parameters are limited by the system stiffness and external dampers devices interfere with the machining process. To deal with this challenge, this work analyzes the suitability of elastomer layers as passive damping elements directly located under the part to be machined. Thus, exploiting the sealing properties of nitrile butadiene rubber (NBR), a suitable flexible vacuum fixture is developed, enabling a proper implementation in the manufacturing process. Two different compounds are characterized under axial compression and under finishing operations. The compression tests present the effect of the feed rate and the strain accumulative effect in the fixture compressive behavior. Despite the higher strain variability of the softer rubber, different milling process parameters, such as the tool feed rate, can lead to a similar compressive behavior of the fixture regardless the elastomer hardness. On the other hand, the characterization of these flexible fixtures is completed over AA2024 floor milling of rigid parts and compared with the use of a rigid part clamping. These results show that, as the cutting speed and the feed rate increases, due to the strain evolution of the rubber, the part quality obtained tend to equalize between the flexible and the rigid clamping of the workpiece. Due to the versatility of the NBR for clamping different part geometries without new fixture redesigns, this leads to a competitive advantage of these flexible solutions against the classic rigid vacuum fixtures. Finally, a model to predict the grooving forces with a bull-nose end mill regardless of the stiffness of the part support is proposed and validated for the working range.This research was funded by Basque Government (Eusko Jaurlaritza) under the ELKARTEK Program, SMAR3NAK project, grant number KK-2019/00051

Thin-Wall Machining of Light Alloys: A Review of Models and Industrial Approaches

Thin-wall parts are common in the aeronautical sector. However, their machining presents serious challenges such as vibrations and part deflections. To deal with these challenges, di erent approaches have been followed in recent years. This work presents the state of the art of thin-wall light-alloy machining, analyzing the problems related to each type of thin-wall parts, exposing the causes of both instability and deformation through analytical models, summarizing the computational techniques used, and presenting the solutions proposed by di erent authors from an industrial point of view. Finally, some further research lines are proposed

Vibrations characterization in milling of low stiffness parts with a rubber-based vacuum fixture

Fixtures are a critical element in machining operations as they are the interface between the part and the machine. These components are responsible for the precise part location on the machine table and for the proper dynamic stability maintenance during the manufacturing operations. Although these two features are deeply related, they are usually studied separately. On the one hand, diverse adaptable solutions have been developed for the clamping of different variable geometries. Parallelly, the stability of the part has been long studied to reduce the forced vibration and the chatter effects, especially on thin parts machining operations typically performed in the aeronautic field, such as the skin panels milling. The present work proposes a commitment between both features by the presentation of an innovative vacuum fixture based on the use of a vulcanized rubber layer. This solution presents high flexibility as it can be adapted to different geometries while providing a proper damping capacity due to the viscoelastic and elastoplastic behaviour of these compounds. Moreover, the sealing properties of these elastomers provide the perfect combination to transform a rubber layer into a flexible vacuum table. Therefore, in order to validate the suitability of this fixture, a test bench is manufactured and tested under uniaxial compression loads and under real finish milling conditions over AA2024 part samples. Finally, a roughness model is proposed and analysed in order to characterize the part vibration sources.Financial support from the Basque Government under theELKARTEK Program (SMAR3NAK project, grant numberKK-2019/00051) is gratefully acknowledged by the authors

Isolation and Quantification of miRNA from the Biomolecular Corona on Mesoporous Silica Nanoparticles

[EN] To understand the factors that control the formation of the biomolecular corona, a systematic study of the adsorption of several miRNAs shown to be important in prostate cancer on amine-functionalized mesoporous silica nanoparticles (MSN-NH2) has been performed. Process parameters including miRNA type, nanoparticle concentration, incubation temperature and incubation time were investigated, as well as the potential competition for adsorption between different miRNA molecules. The influence of proteins and particle PEGylation on miRNA adsorption were also explored. We found that low particle concentrations and physiological temperature both led to increased miRNA adsorption. Adsorption of miRNA was also higher when proteins were present in the same solution; reducing or preventing protein adsorption by PEGylating the MSNs hindered adsorption. Finally, the amount of miRNA adsorbed from human serum by MSN-NH2 was compared to a commercial miRNA purification kit (TaqMan(R), Life Technologies, Carlsbad, CA, USA). MSN-NH2 adsorbed six times as much miRNA as the commercial kit, demonstrating higher sensitivity to subtle up- and downregulation of circulating miRNA in the blood of patients.This research was funded by the Spanish Ministry of Economy and Competitiveness (project PID2019-111436RB-C21), and the Generalitat Valenciana (project PROMETEO/2017/060).Vidaurre Agut, CM.; Rivero-Buceta, EM.; Landry, CC.; Botella Asuncion, P. (2021). Isolation and Quantification of miRNA from the Biomolecular Corona on Mesoporous Silica Nanoparticles. Nanomaterials. 11(5):1-11. https://doi.org/10.3390/nano11051196S11111

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

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

Development of a Prodrug of Camptothecin for Enhanced Treatment of Glioblastoma Multiforme

[EN] A novel therapeutic approach for glioblastoma multiforme (GBM) therapy has been carried out through in vitro and in vivo testing by using the prodrug camptothecin-20-O-(5-aminolevulinate) (CPT-ALA). The incorporation of ALA to CPT may promote uptake of the cytotoxic molecule by glioblastoma cells where the heme synthesis pathway is active, improving the therapeutic action and reducing the side effects over healthy tissue. The antitumor properties of CPT-ALA have been tested on different GBM cell lines (U87, U251, and C6) as well as in an orthotopic GBM model in rat, where potential toxicity in central nervous system cells was analyzed. In vitro results indicated no significant differences in the cytotoxic effect over the different GBM cell lines for CPT and CPT-ALA, albeit cell mortality induced by CPT over normal cell lines was significantly higher than CPT-ALA. Moreover, intracranial GBM in rat was significantly reduced (30% volume) with 2 weeks of CPT-ALA treatment with no significant side effects or alterations to the well-being of the animals tested. 5-ALA moiety enhances CPT diffusion into tumors due to solubility improvement and its metabolic-based targeting, increasing the CPT cytotoxic effect on malignant cells while reducing CPT diffusion to other proliferative healthy tissue. We demonstrate that CPT-ALA blocks proliferation of GBM cells, reducing the infiltrative capacity of GBM and promoting the success of surgical removal, which improves life expectancy by reducing tumor recurrence.Financial support from Spanish Ministry of Economy and Competitiveness (Projects PID2019-111436RB-C21 and SEV2016-0683) and the Generalitat Valenciana (Project PROMETEO/2017/060) is gratefully acknowledged. We thank Prof. Luis Fernandez (Group of Structural Mechanics and Materials Modellings-GEMM, University of Zaragoza, Spain) for donation of human GBM cell lines. We are grateful to Dr. Lawrence Humphreys (CIBER-BBN) for critical reading of the manuscriptCheca-Chavarria, E.; Rivero-Buceta, EM.; Sanchez Martos, MA.; Martinez Navarrete, G.; Soto-Sanchez, C.; Botella Asuncion, P.; Fernandez Jover, E. (2021). Development of a Prodrug of Camptothecin for Enhanced Treatment of Glioblastoma Multiforme. Molecular Pharmaceutics. 18(4):1558-1572. https://doi.org/10.1021/acs.molpharmaceut.0c009681558157218

Protein Corona over Mesoporous Silica Nanoparticles: Influence of the Pore Diameter on Competitive Adsorption and Application to Prostate Cancer Diagnostics

[EN] Diagnostic tests based on proteomics analysis can have significant advantages over more traditional biochemical tests. However, low molecular weight (MW) protein biomarkers are difficult to identify by standard mass spectrometric analysis, as they are usually present at low concentrations and are masked by more abundant resident proteins. We have previously shown that mesoporous silica nanoparticles are able to capture a predominantly low MW protein fraction from the serum, as compared to the protein corona (PC) adsorbed onto dense silica nanoparticles. In this study, we begin by further investigating this effect using liquid chromatography-mass spectrometry (LC-MS)/MS and thermogravimetric analysis (TGA) to compare the MW of the proteins in the coronas of mesoporous silica nanoparticles with the same particle size but different pore diameters. Next, we examine the process by which two proteins, one small and one large, adsorb onto these mesoporous silica nanoparticles to establish a theory of why the corona becomes enriched in low MW proteins. Finally, we use this information to develop a novel system for the diagnosis of prostate cancer. An elastic net statistical model was applied to LC-MS/MS protein coronas from the serum of 22 cancer patients, identifying proteins specific to each patient group. These studies help to explain why low MW proteins predominate in the coronas of mesoporous silica nanoparticles, and they illustrate the ability of this information to supplement more traditional diagnostic tests.Financial support from the University of Vermont, the Spanish Ministry of Economy and Competitiveness (projects TEC2016-80976-R and SEV-2016-0683), and the Generalitat Valenciana (project PROMETEO/2017/060), is gratefully acknowledged. We thank Dr. Jaime Font de Mora for his assistance in the clinical sample collection and Dr. David Herva ' s for the statistical study supervision. We also appreciate the assistance of the electron microscopy service of the Universitat Politecnica de Valencia.Vidaurre Agut, CM.; Rivero-Buceta, EM.; Romaní-Cubells, E.; Clemments, AM.; Vera Donoso, CD.; Landry, C.; Botella Asuncion, P. (2019). Protein Corona over Mesoporous Silica Nanoparticles: Influence of the Pore Diameter on Competitive Adsorption and Application to Prostate Cancer Diagnostics. ACS Omega. 4(5):8852-8861. https://doi.org/10.1021/acsomega.9b00460S885288614

Is diet partly responsible for differences in COVID-19 death rates between and within countries?

Correction: Volume: 10 Issue: 1 Article Number: 44 DOI: 10.1186/s13601-020-00351-w Published: OCT 26 2020Reported COVID-19 deaths in Germany are relatively low as compared to many European countries. Among the several explanations proposed, an early and large testing of the population was put forward. Most current debates on COVID-19 focus on the differences among countries, but little attention has been given to regional differences and diet. The low-death rate European countries (e.g. Austria, Baltic States, Czech Republic, Finland, Norway, Poland, Slovakia) have used different quarantine and/or confinement times and methods and none have performed as many early tests as Germany. Among other factors that may be significant are the dietary habits. It seems that some foods largely used in these countries may reduce angiotensin-converting enzyme activity or are anti-oxidants. Among the many possible areas of research, it might be important to understand diet and angiotensin-converting enzyme-2 (ACE2) levels in populations with different COVID-19 death rates since dietary interventions may be of great benefit.Peer reviewe