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981 results on '"Morell, A."'

6. Hydrogenated graphene systems: A novel growth and hydrogenation process

Author

Samuel Escobar Veras, Ernesto Espada, Solimar Collazo, Marcel Grau, Rajesh Katiyar, Vladimir I. Makarov, Brad R. Weiner, and Gerardo Morell

Subjects
SAMs, Hydrogenation, Graphene, Graphane, Graphone, Chemistry, QD1-999
Abstract

Octadecylphosphonic acid self-assembled monolayers were used as a combined carbon and hydrogen source to grow graphene films on sapphire substrates via hot filament chemical vapor deposition. The functionalized substrates were sealed with a thin Cu film and heated to 950°C under Ar flow. After synthesis, the Cu was etched away. The graphene samples then underwent a hydrogenation treatment in the same reactor setup, exposed to a CH4/H2 gas mixture at 820°C for 2 hours. The structure and properties of the graphene films before and after hydrogenation were characterized. Raman spectroscopy was employed to probe the defect-related bands and C-H bonding. X-ray diffraction provided insights into the crystalline structure and interlayer spacing. The ferromagnetic response was measured using a PPMS system across a range of temperatures and magnetic fields. XPS was used to assess the chemical composition and bonding. This multi-step process enabled a detailed evaluation of the novel synthesis protocol and its effects on the resulting hydrogenated graphene material.

Published
2024
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7. The Role of the Gut Microbiota in Sanfilippo Syndrome’s Physiopathology: An Approach in Two Affected Siblings

Author

Raquel Barbero-Herranz, María Garriga-García, Ana Moreno-Blanco, Esther Palacios, Pedro Ruiz-Sala, Saioa Vicente-Santamaría, Sinziana Stanescu, Amaya Belanger-Quintana, Guillem Pintos-Morell, Beatriz Arconada, Rosa del Campo, and José Avendaño-Ortiz

Subjects
Sanfilippo syndrome, gut microbiota, Sus genes, SCFAs, Bacteroides thetaiotaomicron, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

Sanfilippo syndrome, or mucopolysaccharidosis type III (MPS III), is a rare lysosomal disease caused by congenital enzymatic deficiencies in heparan sulfate (HS) degradation, leading to organ dysfunction. The most severe hallmark of MPS III comprises neurological alterations, although gastrointestinal symptoms (GISs) have also been shown to be relevant in many patients. Here, we explored the contribution of the gut microbiota to MPS III GISs. We analyzed the composition and functionality of the gut microbiota in two MPS III siblings with the same mutation (c.544C > T, c.1080delC, in the SGSH gene) and the same diet, but with differences in their GISs, including recurrent diarrhea in one of them. Using 16S sequencing, we observed that the MPS III patients exhibited decreased alpha diversity and a lower abundance of Lachnospiraceae and Bifidobacteriaceae accompanied by a higher abundance of the Ruminococcaceae and Rikenellaceae families than the healthy control subjects. Comparing siblings, we found an increased abundance of Bacteroidaceae and a lower abundance of Ruminococcaceae and Akkermansiaceae in the GIS-free patient. This patient also had a higher relative abundance of Sus genes (SusA, SusB, SusE, and SusG) involved in glycosaminoglycan metabolism. We found higher HS levels in the stool of the two MPS III patients than in healthy volunteers, particularly in the patient with GISs. Functionally, whole fecal metabolites from the patient with GISs induced oxidative stress in vitro in healthy monocytes. Finally, the Bacteroides thetaiotaomicron strain isolated from MPS III stool samples exhibited HS degradation ability. Overall, our results reveal different microbiota compositions and functionalities in MPS III siblings, who exhibited differential gastrointestinal symptomatology. Our study may serve as a gateway to explore the impact of the gut microbiota and its potential to enhance the quality of life in Sanfilippo syndrome patients.

Published
2024
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8. Cardiopulmonary Complications after Pulmonary Embolism in COVID-19

Author

Carla Suarez-Castillejo, Néstor Calvo, Luminita Preda, Rocío Córdova Díaz, Nuria Toledo-Pons, Joaquín Martínez, Jaume Pons, Miquel Vives-Borràs, Pere Pericàs, Luisa Ramón, Amanda Iglesias, Laura Cànaves-Gómez, Jose Luis Valera Felices, Daniel Morell-García, Belén Núñez, Jaume Sauleda, Ernest Sala-Llinàs, and Alberto Alonso-Fernández

Subjects
COVID-19, SARS-CoV-2, pneumonia, thrombosis, pulmonary embolism, follow-up, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

Although pulmonary embolism (PE) is a frequent complication in COVID-19, its consequences remain unknown. We performed pulmonary function tests, echocardiography and computed tomography pulmonary angiography and identified blood biomarkers in a cohort of consecutive hospitalized COVID-19 patients with pneumonia to describe and compare medium-term outcomes according to the presence of PE, as well as to explore their potential predictors. A total of 141 patients (56 with PE) were followed up during a median of 6 months. Post-COVID-19 radiological lung abnormalities (PCRLA) and impaired diffusing capacity for carbon monoxide (DLCOc) were found in 55.2% and 67.6% cases, respectively. A total of 7.3% had PE, and 6.7% presented an intermediate–high probability of pulmonary hypertension. No significant difference was found between PE and non-PE patients. Univariate analysis showed that age > 65, some clinical severity factors, surfactant protein-D, baseline C-reactive protein, and both peak red cell distribution width and Interleukin (IL)-10 were associated with DLCOc < 80%. A score for PCRLA prediction including age > 65, minimum lymphocyte count, and IL-1β concentration on admission was constructed with excellent overall performance. In conclusion, reduced DLCOc and PCRLA were common in COVID-19 patients after hospital discharge, but PE did not increase the risk. A PCRLA predictive score was developed, which needs further validation.

Published
2024
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9. Enhanced electrochemical performance of Bi2O3 via facile synthesis as anode material for ultra-long cycle lifespan lithium-ion batteries

Author

Nischal Oli, Wilber Ortiz Lago, Balram Tripathi, Mohan Bhattarai, Brad R. Weiner, Gerardo Morell, and Ram S. Katiyar

Subjects
Bismuth oxide, Long-lasting, Carboxymethyl cellulose, Fluoroethylene carbonate, Lithium-ion batteries, Industrial electrochemistry, TP250-261, Chemistry, QD1-999
Abstract

The urgent demand for stable electrode materials, especially for the anode, arises in the pursuit of high-energy Li-ion batteries. This research focuses on bismuth oxide (Bi2O3) and uncovers its performance through a straightforward, commercially viable synthesis route, along with the optimization of binders and electrolytes. By employing a sodium carboxymethyl cellulose binder and fluoroethylene carbonate additives, the Bi2O3 anode demonstrates significantly enhanced performance compared to prior studies. It attains an impressive initial capacity of approximately 750 mA h g−1, exhibits excellent rate capability at 1000 mA g−1 and maintains stable cycling performance over 6000 cycles.

Published
2024
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10. Effect of Obstructive Sleep Apnea during Pregnancy on Fetal Development: Gene Expression Profile of Cord Blood

Author

Laura Cànaves-Gómez, Aarne Fleischer, Josep Muncunill-Farreny, María Paloma Gimenez, Ainhoa Álvarez Ruiz De Larrinaga, Andrés Sánchez Baron, Mercedes Codina Marcet, Mónica De-La-Peña, Daniel Morell-Garcia, José Peña Zarza, Concepción Piñas Zebrian, Susana García Fernández, and Alberto Alonso

Subjects
obstructive sleep apnea (OSA), pregnancy, fetal development, gene expression, cord blood, qPCR, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

Obstructive sleep apnea (OSA) is quite prevalent during pregnancy and is associated with adverse perinatal outcomes, but its potential influence on fetal development remains unclear. This study investigated maternal OSA impact on the fetus by analyzing gene expression profiles in whole cord blood (WCB). Ten women in the third trimester of pregnancy were included, five OSA and five non-OSA cases. WCB RNA expression was analyzed by microarray technology to identify differentially expressed genes (DEGs) under OSA conditions. After data normalization, 3238 genes showed significant differential expression under OSA conditions, with 2690 upregulated genes and 548 downregulated genes. Functional enrichment was conducted using gene set enrichment analysis (GSEA) applied to Gene Ontology annotations. Key biological processes involved in OSA were identified, including response to oxidative stress and hypoxia, apoptosis, insulin response and secretion, and placental development. Moreover, DEGs were confirmed through qPCR analyses in additional WCB samples (7 with OSA and 13 without OSA). This highlighted differential expression of several genes in OSA (EGR1, PFN1 and PRKAR1A), with distinct gene expression profiles observed during rapid eye movement (REM)-OSA in pregnancy (PFN1, UBA52, EGR1, STX4, MYC, JUNB, and MAPKAP). These findings suggest that OSA, particularly during REM sleep, may negatively impact various biological processes during fetal development.

Published
2024
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11. On the Magnetization and Entanglement Plateaus in One-Dimensional Confined Molecular Magnets

Author

Javier I. Norambuena Leiva, Emilio A. Cortés Estay, Eric Suarez Morell, and Juan M. Florez

Subjects
molecular magnets, entanglement entropy, matrix product states, magnetization plateaus, Chemistry, QD1-999
Abstract

One-dimensional (1D) magnetic systems offer rich phenomena in the quantum limit, proving more chemically accessible than zero-dimensional or higher-dimensional frameworks. Single-walled carbon nanotubes (SWCNT) have recently been used to encapsulate trimetric nickel(II) acetylacetonate [Nanoscale, 2019, 11, 10615–10621]. Here, we investigate the magnetization on spin chains based on nickel trimers by Matrix Product State (MPS) simulations. Our findings reveal plateaus in the exchange/magnetic-field phase diagram for three coupling configurations, showcasing effective dimeric and trimeric spin-ordering with similar or staggered entanglement across chains. These ordered states allow the qubit-like tuning of specific local magnetic moments, exhibiting disengagement or uniform coupling in entanglement plateaus. This behavior is consistent with the experimental transition from frustrated (3D) to non-frustrated (1D) molecules, corresponding to large and smaller SWCNT diameters. Our study offers insights into the potential of 1D-confined trimers for quantum computation, extending beyond the confinement of trimetric nickel-based molecules in one dimension.

Published
2024
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12. Advanced Optical Microscopy: Unveiling Functional Insights Regarding a Novel PPP2R1A Variant and Its Unreported Phenotype

Author

Mònica Roldán, Gregorio Alexander Nolasco, Lluís Armengol, Marcos Frías, Marta Morell, Manel García-Aragonés, Florencia Epifani, Jordi Muchart, María Luisa Ramírez-Almaraz, Loreto Martorell, Cristina Hernando-Davalillo, Roser Urreizti, and Mercedes Serrano

Subjects
functional studies, cerebellar atrophy, confocal microscopy, neurodevelopmental disorders, pontocerebellar hypoplasia, PPP2R1A, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

The number of genes implicated in neurodevelopmental conditions is rapidly growing. Recently, variants in PPP2R1A have been associated with syndromic intellectual disability and a consistent, but still expanding, phenotype. The PPP2R1A gene encodes a protein subunit of the serine/threonine protein phosphatase 2A enzyme, which plays a critical role in cellular function. We report an individual showing pontocerebellar hypoplasia (PCH), microcephaly, optic and peripheral nerve abnormalities, and an absence of typical features like epilepsy and an abnormal corpus callosum. He bears an unreported variant in an atypical region of PPP2R1A. In silico studies, functional analysis using immunofluorescence, and super-resolution microscopy techniques were performed to investigate the pathogenicity of the variant. This analysis involved a comparative analysis of the patient’s fibroblasts with both healthy control cells and cells from an individual with the previously described phenotype. The results showed reduced expression of PPP2R1A and the presence of aberrant protein aggregates in the patient’s fibroblasts, supporting the pathogenicity of the variant. These findings suggest a potential association between PPP2R1A variants and PCH, expanding the clinical spectrum of PPP2R1A-related neurodevelopmental disorder. Further studies and descriptions of additional patients are needed to fully understand the genotype–phenotype correlation and the underlying mechanisms of this novel phenotype.

Published
2023
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13. Obacunone Photoprotective Effects against Solar-Simulated Radiation–Induced Molecular Modifications in Primary Keratinocytes and Full-Thickness Human Skin

Author

Paula Montero, Maria José Villarroel, Inés Roger, Anselm Morell, Javier Milara, and Julio Cortijo

Subjects
obacunone, photoprotection, full-thickness skin model, photodamage, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

Solar radiation can cause damage to the skin, leading to various adverse effects such as sunburn, reactive oxygen species production, inflammation, DNA damage, and photoaging. To study the potential of photoprotective agents, full-thickness skin models are increasingly being used as in vitro tools. One promising approach to photoprotection involves targeting the redox-sensitive transcription factor Nrf2, which is responsible for regulating various cellular defense mechanisms, including the antioxidant response, inflammatory signaling, and DNA repair. Obacunone, a natural triterpenoid, has been identified as a potent Nrf2 agonist. The present study aims to evaluate the relevance of full-thickness (FT) skin models in photoprotection studies and to explore the potential photoprotective effects of obacunone on those models and in human keratinocytes. Phenion® full-thickness skin models and keratinocytes were incubated with increasing concentrations of obacunone and irradiated with solar-simulated radiation (SSR). Various photodamage markers were evaluated, including histological integrity, oxidative stress, apoptosis, inflammation, photoaging-related dermal markers, and photocarcinogenesis markers. Increasing doses of SSR were found to modulate various biomarkers related to sun damage in the FT skin models. However, obacunone attenuated cytotoxicity, inflammation, oxidative stress, sunburn reaction, photoaging, and photocarcinogenesis in both keratinocytes and full thickness skin models exposed to SSR. These results suggest that obacunone may have potential as a photoprotective agent for preventing the harmful effects of solar radiation on the skin.

Published
2023
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14. Molecular interactions from the density functional theory for chemical reactivity: Interaction chemical potential, hardness, and reactivity principles

Author

Ramón Alain Miranda-Quintana, Farnaz Heidar-Zadeh, Stijn Fias, Allison E. A. Chapman, Shubin Liu, Christophe Morell, Tatiana Gómez, Carlos Cárdenas, and Paul W. Ayers

Subjects
DFT‐density functional theory, chemical reactivity, HSAB (hard-soft-acid-base) concept, chemical potential, variational principle, Chemistry, QD1-999
Abstract

In the first paper of this series, the authors derived an expression for the interaction energy between two reagents in terms of the chemical reactivity indicators that can be derived from density functional perturbation theory. While negative interaction energies can explain reactivity, reactivity is often more simply explained using the “|dμ| big is good” rule or the maximum hardness principle. Expressions for the change in chemical potential (μ) and hardness when two reagents interact are derived. A partial justification for the maximum hardness principle is that the terms that appear in the interaction energy expression often reappear in the expression for the interaction hardness, but with opposite sign.

Published
2022
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15. Molecular Interactions From the Density Functional Theory for Chemical Reactivity: The Interaction Energy Between Two-Reagents

Author

Ramón Alain Miranda-Quintana, Farnaz Heidar-Zadeh, Stijn Fias, Allison E. A. Chapman, Shubin Liu, Christophe Morell, Tatiana Gómez, Carlos Cárdenas, and Paul W. Ayers

Subjects
chemical reactivity, density functional theory, molecular Interaction analysis, conceptual chemistry, response function, Chemistry, QD1-999
Abstract

Reactivity descriptors indicate where a reagent is most reactive and how it is most likely to react. However, a reaction will only occur when the reagent encounters a suitable reaction partner. Determining whether a pair of reagents is well-matched requires developing reactivity rules that depend on both reagents. This can be achieved using the expression for the minimum-interaction-energy obtained from the density functional reactivity theory. Different terms in this expression will be dominant in different circumstances; depending on which terms control the reactivity, different reactivity indicators will be preferred.

Published
2022
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17. Insight into the Varying Reactivity of Different Catalysts for CO2 Cycloaddition into Styrene Oxide: An Experimental and DFT Study

Author

Angelo Pio Sebaaly, Hugo Dias, Lorraine Christ, Lynda Merzoud, Henry Chermette, Guillaume Hoffmann, and Christophe Morell

Subjects
DFT, non-covalent interactions, catalysis, CO2 capture, mechanistic study, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

The cycloaddition of CO2 into epoxides to form cyclic carbonates is a highly sought-after reaction for its potential to both reduce and use CO2, which is a greenhouse gas. In this paper, we present experimental and theoretical studies and a mechanistic approach for three catalytic systems. First, as Lewis base catalysts, imidazole and its derivatives, then as a Lewis acid catalyst, ZnI2 alone, and after that, the combined system of ZnI2 and imidazole. In the former, we aimed to discover the reasons for the varied reactivities of five Lewis base catalysts. Furthermore, we succeeded in reproducing the experimental results and trends using DFT. To add, we emphasized the importance of non-covalent interactions and their role in reactivity. In our case, the presence of a hydrogen bond was a key factor in decreasing the reactivity of some catalysts, thus leading to lower conversion rates. Finally, mechanistically understanding this 100% atom economy reaction can aid experimental chemists in designing better and more efficient catalytic systems.

Published
2023
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18. Use of Neural Networks and Computer Vision for Spill and Waste Detection in Port Waters: An Application in the Port of Palma (MaJorca, Spain)

Author

Mariano Morell, Pedro Portau, Antoni Perelló, Manuel Espino, Manel Grifoll, and Carlos Garau

Subjects
computer vision, marine litter, marine pollution, monitoring technologies, port water quality, Technology, Engineering (General). Civil engineering (General), TA1-2040, Biology (General), QH301-705.5, Physics, QC1-999, Chemistry, QD1-999
Abstract

Water quality and pollution is the main environmental concern for ports and adjacent coastal waters. Therefore, the development of Port Environmental Management systems often relies on water pollution monitoring. Computer vision is a powerful and versatile tool for an exhaustive and systematic monitoring task. An investigation has been conducted at the Port of Palma de Mallorca (Spain) to assess the feasibility and evaluate the main opportunities and difficulties of the implementation of water pollution monitoring based on computer vision. Experiments on surface slicks and marine litter identification based on random image sets have been conducted. The reliability and development requirements of the method have been evaluated, concluding that computer vision is suitable for these monitoring tasks. Several computer vision techniques based on convolutional neural networks were assessed, finding that Image Classification is the most adequate for marine pollution monitoring tasks due to its high accuracy rates and low training requirements. Image set size for initial training and the possibility to improve accuracy through retraining with increased image sets were considered due to the difficulty in obtaining port spill images. Thus, we have found that progressive implementation can not only offer functional monitoring systems in a shorter time frame but also reduce the total development cost for a system with the same accuracy level.

Published
2022
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19. Formation Mechanism of Inter-Crosslink in DNA by Nitrogen Oxides Pollutants through A Diazonium Intermediate

Author

Noemi Hernandez-Haro, Christian Solis-Calero, Rodrigo Casasnovas, Christophe Morell, Andre Grand, Juan Frau, and Joaquín Ortega-Castro

Subjects
DNA, inter-crosslink, pollutant, nitrogen oxide, DFT, MD, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

Outdoor air pollution is a mixture of multiple atmospheric pollutants, among which nitrogen oxide (NOx) stands out due to its association with several diseases. NOx reactivity can conduct to DNA damage as severe as interstrand crosslinks (ICL) formation, that in turn is able to block DNA replication and transcription. Experimental studies have suggested that the ICL formation due to NOx is realized through a diazonium intermediate (DI). In this work, we have modeled the DI structure, including a DNA double-strand composed of two base pairs GC/CG, being diazotized as one of the guanine nucleotides. The structural stability of DNA with DI lesion was essayed through 500 ns molecular dynamics simulations. It was found that the DNA structure of the oligonucleotide is stable when the DI is present since the loss of a Guanine–Cytosine hydrogen bond is replaced by the presence of two cation-π interactions. Additionally, we have studied the mechanism of formation of a crosslink between the two guanine nucleobases from the modeled DI by carrying out DFT calculations at the M06-L/DNP+ level of theory. Our results show that the mechanism is thermodynamically favored by a strong stabilization of the ICL product, and the process is kinetically viable since its limiting stage is accessible.

Published
2022
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20. Graphene Film Growth on Silicon Carbide by Hot Filament Chemical Vapor Deposition

Author

Sandra Rodríguez-Villanueva, Frank Mendoza, Brad R. Weiner, and Gerardo Morell

Subjects
graphene, hot filament chemical vapor deposition, methane gas, Chemistry, QD1-999
Abstract

The electrical properties of graphene on dielectric substrates, such as silicon carbide (SiC), have received much attention due to their interesting applications. This work presents a method to grow graphene on a 6H-SiC substrate at a pressure of 35 Torr by using the hot filament chemical vapor deposition (HFCVD) technique. The graphene deposition was conducted in an atmosphere of methane and hydrogen at a temperature of 950 °C. The graphene films were analyzed using Raman spectroscopy, scanning electron microscopy, atomic force microscopy, energy dispersive X-ray, and X-ray photoelectron spectroscopy. Raman mapping and AFM measurements indicated that few-layer and multilayer graphene were deposited from the external carbon source depending on the growth parameter conditions. The compositional analysis confirmed the presence of graphene deposition on SiC substrates and the absence of any metal involved in the growth process.

Published
2022
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21. Graphene Growth Directly on SiO2/Si by Hot Filament Chemical Vapor Deposition

Author

Sandra Rodríguez-Villanueva, Frank Mendoza, Alvaro A. Instan, Ram S. Katiyar, Brad R. Weiner, and Gerardo Morell

Subjects
graphene, hot filament chemical vapor deposition, copper catalytic effect, Chemistry, QD1-999
Abstract

We report the first direct synthesis of graphene on SiO2/Si by hot-filament chemical vapor deposition. Graphene deposition was conducted at low pressures (35 Torr) with a mixture of methane/hydrogen and a substrate temperature of 970 °C followed by spontaneous cooling to room temperature. A thin copper-strip was deposited in the middle of the SiO2/Si substrate as catalytic material. Raman spectroscopy mapping and atomic force microscopy measurements indicate the growth of few-layers of graphene over the entire SiO2/Si substrate, far beyond the thin copper-strip, while X-ray photoelectron spectroscopy and energy-dispersive X-ray spectroscopy showed negligible amounts of copper next to the initially deposited strip. The scale of the graphene nanocrystal was estimated by Raman spectroscopy and scanning electron microscopy.

Published
2021
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22. Tepotinib Inhibits Several Drug Efflux Transporters and Biotransformation Enzymes: The Role in Drug-Drug Interactions and Targeting Cytostatic Resistance In Vitro and Ex Vivo

Author

Dimitrios Vagiannis, Youssif Budagaga, Anselm Morell, Yu Zhang, Eva Novotná, Adam Skarka, Sarah Kammerer, Jan-Heiner Küpper, Ivo Hanke, Tomáš Rozkoš, and Jakub Hofman

Subjects
tepotinib, non-small cell lung cancer, multidrug resistance, drug interaction, ABC transporter, cytochrome P450, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

Tepotinib is a novel tyrosine kinase inhibitor recently approved for the treatment of non-small cell lung cancer (NSCLC). In this study, we evaluated the tepotinib’s potential to perpetrate pharmacokinetic drug interactions and modulate multidrug resistance (MDR). Accumulation studies showed that tepotinib potently inhibits ABCB1 and ABCG2 efflux transporters, which was confirmed by molecular docking. In addition, tepotinib inhibited several recombinant cytochrome P450 (CYP) isoforms with varying potency. In subsequent drug combination experiments, tepotinib synergistically reversed daunorubicin and mitoxantrone resistance in cells with ABCB1 and ABCG2 overexpression, respectively. Remarkably, MDR-modulatory properties were confirmed in ex vivo explants derived from NSCLC patients. Furthermore, we demonstrated that anticancer effect of tepotinib is not influenced by the presence of ABC transporters associated with MDR, although monolayer transport assays designated it as ABCB1 substrate. Finally, tested drug was observed to have negligible effect on the expression of clinically relevant drug efflux transporters and CYP enzymes. In conclusion, our findings provide complex overview on the tepotinib’s drug interaction profile and suggest a promising novel therapeutic strategy for future clinical investigations.

Published
2021
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23. Dwell Time Estimation of Import Containers as an Ordinal Regression Problem

Author

Laidy De Armas Jacomino, Miguel Angel Medina-Pérez, Raúl Monroy, Danilo Valdes-Ramirez, Carlos Morell-Pérez, and Rafael Bello

Subjects
dwell time estimation, attribute selection, ordinal regression algorithms, performance metrics for ordinal regression, Technology, Engineering (General). Civil engineering (General), TA1-2040, Biology (General), QH301-705.5, Physics, QC1-999, Chemistry, QD1-999
Abstract

The optimal stacking of import containers in a terminal reduces the reshuffles during the unloading operations. Knowing the departure date of each container is critical for optimal stacking. However, such a date is rarely known because it depends on various attributes. Therefore, some authors have proposed estimation algorithms using supervised classification. Although supervised classifiers can estimate this dwell time, the variable “dwell time” takes ordered values for this problem, suggesting using ordinal regression algorithms. Thus, we have compared an ordinal regression algorithm (selected from 15) against two supervised classifiers (selected from 30). We have set up two datasets with data collected in a container terminal. We have extracted and evaluated 35 attributes related to the dwell time. Additionally, we have run 21 experiments to evaluate both approaches regarding the mean absolute error modified and the reshuffles. As a result, we have found that the ordinal regression algorithm outperforms the supervised classifiers, reaching the lowest mean absolute error modified in 15 (71%) and the lowest reshuffles in 14 (67%) experiments.

Published
2021
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24. Immune-Related Urine Biomarkers for the Diagnosis of Lupus Nephritis

Author

María Morell, Francisco Pérez-Cózar, and Concepción Marañón

Subjects
Lupus nephritis, urine biomarkers, non-invasive diagnosis, immune effector, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

The kidney is one of the main organs affected by the autoimmune disease systemic lupus erythematosus. Lupus nephritis (LN) concerns 30–60% of adult SLE patients and it is significantly associated with an increase in the morbidity and mortality. The definitive diagnosis of LN can only be achieved by histological analysis of renal biopsies, but the invasiveness of this technique is an obstacle for early diagnosis of renal involvement and a proper follow-up of LN patients under treatment. The use of urine for the discovery of non-invasive biomarkers for renal disease in SLE patients is an attractive alternative to repeated renal biopsies, as several studies have described surrogate urinary cells or analytes reflecting the inflammatory state of the kidney, and/or the severity of the disease. Herein, we review the main findings in the field of urine immune-related biomarkers for LN patients, and discuss their prognostic and diagnostic value. This manuscript is focused on the complement system, antibodies and autoantibodies, chemokines, cytokines, and leukocytes, as they are the main effectors of LN pathogenesis.

Published
2021
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25. Human Pose Detection for Robotic-Assisted and Rehabilitation Environments

Author

Óscar G. Hernández, Vicente Morell, José L. Ramon, and Carlos A. Jara

Subjects
human–robot interaction, human pose estimation, robotic rehabilitation, Technology, Engineering (General). Civil engineering (General), TA1-2040, Biology (General), QH301-705.5, Physics, QC1-999, Chemistry, QD1-999
Abstract

Assistance and rehabilitation robotic platforms must have precise sensory systems for human–robot interaction. Therefore, human pose estimation is a current topic of research, especially for the safety of human–robot collaboration and the evaluation of human biomarkers. Within this field of research, the evaluation of the low-cost marker-less human pose estimators of OpenPose and Detectron 2 has received much attention for their diversity of applications, such as surveillance, sports, videogames, and assessment in human motor rehabilitation. This work aimed to evaluate and compare the angles in the elbow and shoulder joints estimated by OpenPose and Detectron 2 during four typical upper-limb rehabilitation exercises: elbow side flexion, elbow flexion, shoulder extension, and shoulder abduction. A setup of two Kinect 2 RGBD cameras was used to obtain the ground truth of the joint and skeleton estimations during the different exercises. Finally, we provided a numerical comparison (RMSE and MAE) among the angle measurements obtained with OpenPose, Detectron 2, and the ground truth. The results showed how OpenPose outperforms Detectron 2 in these types of applications.

Published
2021
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26. QuBiLS-MAS, open source multi-platform software for atom- and bond-based topological (2D) and chiral (2.5D) algebraic molecular descriptors computations

Author

José R. Valdés-Martiní, Yovani Marrero-Ponce, César R. García-Jacas, Karina Martinez-Mayorga, Stephen J. Barigye, Yasser Silveira Vaz d‘Almeida, Hai Pham-The, Facundo Pérez-Giménez, and Carlos A. Morell

Subjects
ToMoCoMD-CARDD, QuBiLS-MAS, Linear, Bilinear and quadratic indices, Atom/bond-based molecular descriptor, Non-stochastic, Information technology, T58.5-58.64, Chemistry, QD1-999
Abstract

Abstract Background In previous reports, Marrero-Ponce et al. proposed algebraic formalisms for characterizing topological (2D) and chiral (2.5D) molecular features through atom- and bond-based ToMoCoMD-CARDD (acronym for Topological Molecular Computational Design-Computer Aided Rational Drug Design) molecular descriptors. These MDs codify molecular information based on the bilinear, quadratic and linear algebraic forms and the graph-theoretical electronic-density and edge-adjacency matrices in order to consider atom- and bond-based relations, respectively. These MDs have been successfully applied in the screening of chemical compounds of different therapeutic applications ranging from antimalarials, antibacterials, tyrosinase inhibitors and so on. To compute these MDs, a computational program with the same name was initially developed. However, this in house software barely offered the functionalities required in contemporary molecular modeling tasks, in addition to the inherent limitations that made its usability impractical. Therefore, the present manuscript introduces the QuBiLS-MAS (acronym for Quadratic, Bilinear and N-Linear mapS based on graph-theoretic electronic-density Matrices and Atomic weightingS) software designed to compute topological (0–2.5D) molecular descriptors based on bilinear, quadratic and linear algebraic forms for atom- and bond-based relations. Results The QuBiLS-MAS module was designed as standalone software, in which extensions and generalizations of the former ToMoCoMD-CARDD 2D-algebraic indices are implemented, considering the following aspects: (a) two new matrix normalization approaches based on double-stochastic and mutual probability formalisms; (b) topological constraints (cut-offs) to take into account particular inter-atomic relations; (c) six additional atomic properties to be used as weighting schemes in the calculation of the molecular vectors; (d) four new local-fragments to consider molecular regions of interest; (e) number of lone-pair electrons in chemical structure defined by diagonal coefficients in matrix representations; and (f) several aggregation operators (invariants) applied over atom/bond-level descriptors in order to compute global indices. This software permits the parallel computation of the indices, contains a batch processing module and data curation functionalities. This program was developed in Java v1.7 using the Chemistry Development Kit library (version 1.4.19). The QuBiLS-MAS software consists of two components: a desktop interface (GUI) and an API library allowing for the easy integration of the latter in chemoinformatics applications. The relevance of the novel extensions and generalizations implemented in this software is demonstrated through three studies. Firstly, a comparative Shannon’s entropy based variability study for the proposed QuBiLS-MAS and the DRAGON indices demonstrates superior performance for the former. A principal component analysis reveals that the QuBiLS-MAS approach captures chemical information orthogonal to that codified by the DRAGON descriptors. Lastly, a QSAR study for the binding affinity to the corticosteroid-binding globulin using Cramer’s steroid dataset is carried out. Conclusions From these analyses, it is revealed that the QuBiLS-MAS approach for atom-pair relations yields similar-to-superior performance with regard to other QSAR methodologies reported in the literature. Therefore, the QuBiLS-MAS approach constitutes a useful tool for the diversity analysis of chemical compound datasets and high-throughput screening of structure–activity data. Graphical abstract .

Published
2017
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27. Efficient treatment of esophageal nutrition bezoars: dissolution outmatches removal—the Zurich approach

Author

Fritz Murray, Silvia Lang, Michael Scharl, Patrick R. Bader, Bernhard Morell, Philipp K. Buehler, Christoph Gubler, University of Zurich, and Morell, Bernhard

Subjects
medicine.medical_specialty, Enteral feeding, 610 Medicine & health, Hydrochloric acid, Case Report, Enteral administration, Gastroenterology, Patient care, Bezoars, chemistry.chemical_compound, Enteral Nutrition, Esophagus, Internal medicine, Enteral feed bezoar, medicine, Humans, 2715 Gastroenterology, Dissolution, Sodium bicarbonate, business.industry, Critically ill, Endoscopy, General Medicine, 10219 Clinic for Gastroenterology and Hepatology, chemistry, Solubility, 10023 Institute of Intensive Care Medicine, business
Abstract

Enteral feed bezoars are difficult to treat and can lead to serious adverse events. There is no standardized treatment approach and various strategies have been suggested. We herein describe three cases of successful dissolutions of feed bezoars consisting of Promote® Fibre Plus with sodium bicarbonate 8.4% in critically ill patients. To provide the rationale for this approach, the effect of sodium bicarbonate 8.4% on enteral feed concretions was studied in vitro. First, Promote® Fibres Plus was incubated with hydrochloric acid with gradually decreasing pH values to establish a pH at which the solution solidifies. The resulting enteral feed concretion was exposed to sodium bicarbonate 8.4% and Coca Cola®. All patients were successfully treated with sodium bicarbonate 8.4% without the need of lengthy or repeat endoscopies. In vitro, Promote® Fibres Plus solidifies when acidified below a pH of 4.6. The resulting enteral feed concretions dissolved when exposed to sodium bicarbonate 8.4%. Incubation with Coca Cola® had no effect. We provide evidence that enteral feed bezoars consisting of Promote® Fibres Plus can be efficiently and safely treated with sodium bicarbonate 8.4% offering a new approach for daily patient care.

Published
2021

29. Advances in the Monitoring of Algal Blooms by Remote Sensing: A Bibliometric Analysis

Author

Maria-Teresa Sebastiá-Frasquet, Jesús-A Aguilar-Maldonado, Iván Herrero-Durá, Eduardo Santamaría-del-Ángel, Sergio Morell-Monzó, and Javier Estornell

Subjects
phytoplankton, ocean colour, chlorophyll a, SeaWiFS, CZCS, MODIS, Technology, Engineering (General). Civil engineering (General), TA1-2040, Biology (General), QH301-705.5, Physics, QC1-999, Chemistry, QD1-999
Abstract

Since remote sensing of ocean colour began in 1978, several ocean-colour sensors have been launched to measure ocean properties. These measures have been applied to study water quality, and they specifically can be used to study algal blooms. Blooms are a natural phenomenon that, due to anthropogenic activities, appear to have increased in frequency, intensity, and geographic distribution. This paper aims to provide a systematic analysis of research on remote sensing of algal blooms during 1999–2019 via bibliometric technique. This study aims to reveal the limitations of current studies to analyse climatic variability effect. A total of 1292 peer-reviewed articles published between January 1999 and December 2019 were collected. We read all the literature individually to build a database. The number of publications increased since 2004 and reached the maximum value of 128 in 2014. The publications originated from 47 countries, but the number of papers published from the top 10 countries accounted for 77% of the total publications. To be able to distinguish between climate variability and changes of anthropogenic origin for a specific variable is necessary to define the baseline. However, long-term monitoring programs of phytoplankton are very scarce; only 1% of the articles included in this study analysed at least three decades and most of the existing algal blooms studies are based on sporadic sampling and short-term research programs.

Published
2020
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30. New Immunosuppressive Therapies in Uveitis Treatment

Author

Salvador Mérida, Elena Palacios, Amparo Navea, and Francisco Bosch-Morell

Subjects
uveitis, corticoids, cytokines, antibody, immunosuppressive, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

Uveitis is an inflammatory process that initially starts in the uvea, but can also affect other adjacent eye structures, and is currently the fourth cause of blindness in developed countries. Corticoids are probably the most widespread treatment, but resorting to other immunosuppressive treatments is a frequent practice. Since the implication of different cytokines in uveitis has been well demonstrated, the majority of recent treatments for this disease include inhibitors or antibodies against these. Nevertheless, adequate treatment for each uveitis type entails a difficult therapeutic decision as no clear recommendations are found in the literature, despite the few protocolized clinical assays and many case-control studies done. This review aims to present, in order, the mechanisms and main indications of the most modern immunosuppressive drugs against cytokines.

Published
2015
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31. The density polarization reveals directions of electron displacements due to the substituent effect: Analysis performed on a metal‐organic Mo‐Oxo catalyst

Author

Christophe Morell, Jorge Ignacio Martínez-Araya, Universidad Andrés Bello [Santiago] (UNAB), Chemometrics and Theoretical Chemistry - Chimiométrie et chimie théorique, Institut des Sciences Analytiques (ISA), Institut de Chimie du CNRS (INC)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), and Fondo Nacional de Desarrollo Cientifico y Tecnologico, Grant/Award Number: 1181504

Subjects
metal, Conceptual Density, Substituent, 010402 general chemistry, 01 natural sciences, Catalysis, chemistry.chemical_compound, 0103 physical sciences, Pyridine, [CHIM]Chemical Sciences, Reactivity (chemistry), density polarization, Polarization (electrochemistry), organic Mo-oxo complexes, ComputingMilieux_MISCELLANEOUS, mesomeric effect, 010304 chemical physics, Geminal, Ligand, linear response function, General Chemistry, Mesomeric effect, 0104 chemical sciences, [CHIM.THEO]Chemical Sciences/Theoretical and/or physical chemistry, Computational Mathematics, Crystallography, chemistry, Functional Theory, substituent effect
Abstract

Some Mo-oxo complexes bearing pyridine rings have the capability for dihydrogen production from water. However, energy barrier and overall energy vary depending on the effect exerted by several substituent groups located at different positions around one or more pyridine rings which are ligands of these compounds. Based on the Karunadasa and coworkers investigation where the para-position was experimentally tested in compounds derivatised from the 2,6-bis[1,1-bis(2-pyridil)ethyl]-pyridine oxo-molybdenum complex synthesized (Karunadasa et al., Nature, 2010, 464, 1329), we tested the combined effect of electron-withdrawing and electron-donating groups simulated as perturbations represented by point-charges. Then, we used the density polarization concept, δρ(r), a local reactivity descriptor corresponding to the partially integrated linear response function, χ(r, r') (a non-local reactivity descriptor), which is able to reveal different displacements of π-electrons on molecular structures. We perturbed the para-positions in the pentadentate ligand 2,6-bis[1,1-bis(2-pyridil)ethyl]-pyridine in the Mo-based complex by means of point-charges. They were located in three different configurations of the organic ligand (trans, geminal, and cis) which could help to explain energy barriers and overall energy of reactions catalyzed by this type of Mo-complexes. Our results indicate that the trans configuration of point-charges induces the most amount of fraction of electron shifted on the complex. A Mo-based complex bearing the same trans configuration for electron-withdrawing and electron-donating substituent groups (cyano and amino, respectively), leads to a kinetically more favorable H2 release than the cis or geminal configuration of the substituent groups aforementioned.

Published
2021

32. Predicted structure and selectivity of 3d transition metal complexes with glutamic N,N-bis(carboxymethyl) acid

Author

Lynda Merzoud, Fatima Mechachti, Aicha Lakehal, Christophe Morell, Salima Lakehal, Henry Chermette, Lab Chim Mat & Vivants Activite & Reactivite, University of Batna Hadj Lakhder [Algeria], Inst Sci Terre & Univers, University of Batna2, Chemometrics and Theoretical Chemistry - Chimiométrie et chimie théorique, Institut des Sciences Analytiques (ISA), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), and S. L. acknowledges the financial support of the Algerian Ministry of Higher Education and Scientific Research and the DGRSDT. The GENCI/CINES (Project cpt2130) and the PSMN of the ENS-Lyon are acknowledged for HPC resources/computer time.

Subjects
Ligand, chemistry.chemical_element, Crystallographic data, 02 engineering and technology, General Chemistry, 010402 general chemistry, 021001 nanoscience & nanotechnology, 01 natural sciences, Copper, Catalysis, 0104 chemical sciences, Gas phase, [CHIM.THEO]Chemical Sciences/Theoretical and/or physical chemistry, Solvent, Crystallography, Transition metal, chemistry, Octahedron, [CHIM.ANAL]Chemical Sciences/Analytical chemistry, Materials Chemistry, [CHIM]Chemical Sciences, 0210 nano-technology, Selectivity
Abstract

The complexation of transition metals with a rather new aminopolycarboxilic ligand, the glutamic N,N-bis(carboxymethyl) acid (GLDA) is investigated using the density functional at the PBE/TPZ level of theory. In order to predict the selectivity of metals and to gain insight into factors influencing the calculated log K values, the GLDA ligand is studied in the gas phase and in solvent with the electrostatic COSMO model. In the absence of crystallographic data, most complexes prefer a pentacoordinated structure in gas phase. On the contrary, in presence of solvent the two structures can coexist, copper excepted, which does not adopt the octahedral form. Good correlations are found between the experimental thermodynamic values and several calculated parameters such as charge transfer, bond descriptors, or bonding free energy energies. The obtained calculations show that, copper excepted, the complexes are octahedral and for a selective separation of cations, the copper cation will be the first to be efficiently complexed.

Published
2021

33. Synthesis, Characterization and Fabrication of Graphene/Boron Nitride Nanosheets Heterostructure Tunneling Devices

Author

Muhammad Sajjad, Vladimir Makarov, Frank Mendoza, Muhammad S. Sultan, Ali Aldalbahi, Peter X. Feng, Wojciech M. Jadwisienczak, Brad R. Weiner, and Gerardo Morell

Subjects
graphene, boron nitride nanosheets, heterostructures, tunneling device, 2D materials, Chemistry, QD1-999
Abstract

Various types of 2D/2D prototype devices based on graphene (G) and boron nitride nanosheets (BNNS) were fabricated to study the charge tunneling phenomenon pertinent to vertical transistors for digital and high frequency electronics. Specifically, G/BNNS/metal, G/SiO2, and G/BNNS/SiO2 heterostructures were investigated under direct current (DC-bias) conditions at room temperature. Bilayer graphene and BNNS were grown separately and transferred subsequently onto the substrates to fabricate 2D device architectures. High-resolution transmission electron microscopy confirmed the bilayer graphene structure and few layer BNNS sheets having a hexagonal B3-N3 lattice. The current vs voltage I(V) data for the G/BNNS/Metal devices show Schottky barrier characteristics with very low forward voltage drop, Fowler-Nordheim behavior, and 10−4 Ω/sq. sheet resistance. This result is ascribed to the combination of fast electron transport within graphene grains and out-of-plane tunneling in BNNS that circumvents grain boundary resistance. A theoretical model based on electron tunneling is used to qualitatively describe the behavior of the 2D G/BNNS/metal devices.

Published
2019
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34. Effects of different amendments (organic matter and hydrogel) on the actual evapotranspiration and crop coefficient of turf grass under field conditions *

Author

Arianna Renau-Pruñonosa, M. V. Esteller, Gladys L. Bandenay, and Ignacio Morell

Subjects
Mediterranean climate, chemistry.chemical_classification, lysimètre, coefficient d'agriculture (Kc), Soil Science, évapotranspiration (ETa), Turf grass, Crop coefficient, crop coefficient (Kc), chemistry, Agronomy, evapotranspiration (ETa), matière organique, climat méditerranéen, Evapotranspiration, Lysimeter, Environmental science, Organic matter, hydrogel, lysimeters, Agronomy and Crop Science, organic matter, Field conditions
Abstract

The irrigation schedule in arid areas has to be efficient in order to reduce losses due to evaporation and deep infiltration. Irrigation optimization poses the need to establish with precision the value of actual evapotranspiration (ETa), and the crop coefficient (Kc). The water soil availability can be increased using hydrogel and organic matter amendments, and their effects could vary ETa and Kc. The aim of this study was to determine the ETa, and Kc of an experimental site with lysimeters on the Spanish Mediterranean coast cropped with a turf grass variety, Agrostis stolonifera ‐L‐93, under field conditions, and amended with hydrogel and organic matter. Reference evapotranspiration (ET0) was determined from meteorological data (FAO‐Penman‐Monteith equation). ETa was calculated from the water balance, and Kc was obtained by dividing ETa by ET0. Kc was calculated and compared on a yearly, monthly and daily basis. In summer, the differences between amendments become manifest:Unamended lysimeter (100% sand) had Kc values (0.92‐1.16), similar to organic matter amended lysimeter (0.99‐1.17). Maximum and minimum Kc values for the hydrogel amended lysimeters (1.04‐1.52) were higher than those from the other because of the ability of this compound to retain water, which facilitated evapotranspiration. Finally, hydrogel helped to maintain the turf grass quality.

Published
2020

35. G protein–coupled receptor Gpr115 (Adgrf4) is required for enamel mineralization mediated by ameloblasts

Author

Erich T. Boger, Robert J. Morell, Daniel Martin, Keigo Yoshizaki, Tomoko Ikeuchi, Aya Yamada, Tsutomu Iwamoto, Susana de Vega, Christopher K. E. Bleck, Yuta Chiba, Takashi Nakamura, Yoshihiko Yamada, Ryoko Hino, Kan Saito, Hiroyuki Inuzuka, Craig Rhodes, and Satoshi Fukumoto

Subjects
0301 basic medicine, Cell physiology, G protein, Biochemistry, Receptors, G-Protein-Coupled, Mice, 03 medical and health sciences, stomatognathic system, Ameloblasts, medicine, Animals, Dental Enamel, Receptor, Molecular Biology, Cells, Cultured, G protein-coupled receptor, Mice, Knockout, 030102 biochemistry & molecular biology, Enamel paint, Chemistry, Cell Biology, Epithelium, Rats, Cell biology, stomatognathic diseases, Enamel mineralization, 030104 developmental biology, medicine.anatomical_structure, visual_art, visual_art.visual_art_medium, Ameloblast, Developmental Biology
Abstract

Dental enamel, the hardest tissue in the human body, is derived from dental epithelial cell ameloblast-secreted enamel matrices. Enamel mineralization occurs in a strictly synchronized manner along with ameloblast maturation in association with ion transport and pH balance, and any disruption of these processes results in enamel hypomineralization. G protein–coupled receptors (GPCRs) function as transducers of external signals by activating associated G proteins and regulate cellular physiology. Tissue-specific GPCRs play important roles in organ development, although their activities in tooth development remain poorly understood. The present results show that the adhesion GPCR Gpr115 (Adgrf4) is highly and preferentially expressed in mature ameloblasts and plays a crucial role during enamel mineralization. To investigate the in vivo function of Gpr115, knockout (Gpr115-KO) mice were created and found to develop hypomineralized enamel, with a larger acidic area because of the dysregulation of ion composition. Transcriptomic analysis also revealed that deletion of Gpr115 disrupted pH homeostasis and ion transport processes in enamel formation. In addition, in vitro analyses using the dental epithelial cell line cervical loop–derived dental epithelial (CLDE) cell demonstrated that Gpr115 is indispensable for the expression of carbonic anhydrase 6 (Car6), which has a critical role in enamel mineralization. Furthermore, an acidic condition induced Car6 expression under the regulation of Gpr115 in CLDE cells. Thus, we concluded that Gpr115 plays an important role in enamel mineralization via regulation of Car6 expression in ameloblasts. The present findings indicate a novel function of Gpr115 in ectodermal organ development and clarify the molecular mechanism of enamel formation.

Published
2020

36. Selective inhibition of aldo-keto reductase 1C3: a novel mechanism involved in midostaurin and daunorubicin synergism

Author

Vladimír Wsól, Neslihan Büküm, Anselm Morell, Petra Danielisová, Eva Novotná, and Jaroslav Milan

Subjects
0301 basic medicine, Daunorubicin, Health, Toxicology and Mutagenesis, Context (language use), 010501 environmental sciences, Reductase, Toxicology, 01 natural sciences, 03 medical and health sciences, chemistry.chemical_compound, hemic and lymphatic diseases, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Midostaurin, Enzyme Inhibitors, Receptor, Biotransformation, 0105 earth and related environmental sciences, Aldo-keto reductase, Aldo-Keto Reductase Family 1 Member C3, Drug Synergism, General Medicine, HCT116 Cells, Staurosporine, Leukemia, Myeloid, Acute, 030104 developmental biology, fms-Like Tyrosine Kinase 3, chemistry, Cell culture, Cancer research, Cytarabine, Colorectal Neoplasms, medicine.drug
Abstract

Midostaurin is an FMS-like tyrosine kinase 3 receptor (FLT3) inhibitor that provides renewed hope for treating acute myeloid leukaemia (AML). The limited efficacy of this compound as a monotherapy contrasts with that of its synergistic combination with standard cytarabine and daunorubicin (Dau), suggesting a therapeutic benefit that is not driven only by FLT3 inhibition. In an AML context, the activity of the enzyme aldo-keto reductase 1C3 (AKR1C3) is a crucial factor in chemotherapy resistance, as it mediates the intracellular transformation of anthracyclines to less active hydroxy metabolites. Here, we report that midostaurin is a potent inhibitor of Dau inactivation mediated by AKR1C3 in both its recombinant form as well as during its overexpression in a transfected cell model. Likewise, in the FLT3- AML cell line KG1a, midostaurin was able to increase the cellular accumulation of Dau and significantly decrease its metabolism by AKR1C3 simultaneously. The combination of those mechanisms increased the nuclear localization of Dau, thus synergizing its cytotoxic effects on KG1a cells. Our results provide new in vitro evidence of how the therapeutic activity of midostaurin could operate beyond targeting the FLT3 receptor.

Published
2020

37. Interactions of antileukemic drugs with daunorubicin reductases: could reductases affect the clinical efficacy of daunorubicin chemoregimens?

Author

Eva Novotná, Vladimír Wsól, Jakub Hofman, Neslihan Büküm, Anselm Morell, and Petra Danielisová

Subjects
0301 basic medicine, CBR1, Daunorubicin, Health, Toxicology and Mutagenesis, Antineoplastic Agents, 010501 environmental sciences, Pharmacology, Toxicology, 01 natural sciences, 03 medical and health sciences, Pharmacokinetics, medicine, Humans, Anthracyclines, Carbonyl Reductase (NADPH), Cladribine, neoplasms, IC50, 0105 earth and related environmental sciences, chemistry.chemical_classification, Antibiotics, Antineoplastic, General Medicine, Metabolism, Alcohol Oxidoreductases, Leukemia, Myeloid, Acute, 030104 developmental biology, Enzyme, chemistry, Cytarabine, medicine.drug
Abstract

Although novel anticancer drugs are being developed intensively, anthracyclines remain the gold standard in the treatment of acute myeloid leukaemia (AML). The reductive conversion of daunorubicin (Dau) to less active daunorubicinol (Dau-ol) is an important mechanism that contributes to the development of pharmacokinetic anthracycline resistance. Dau is a key component in many AML regimes, in which it is combined with many drugs, including all-trans-retinoic acid (ATRA), cytarabine, cladribine and prednisolone. In the present study, we investigated the influence of these anticancer drugs on the reductive Dau metabolism mediated by the aldo–keto reductases AKR1A1, 1B10, 1C3, and 7A2 and carbonyl reductase 1 (CBR1). In incubation experiments with recombinant enzymes, cladribine and cytarabine did not significantly inhibit the activity of the tested enzymes. Prednisolone inhibited AKR1C3 with an IC50 of 41.73 µM, while ATRA decreased the activity of AKR1B10 (IC50 = 78.33 µM) and AKR1C3 (IC50 = 1.17 µM). Subsequent studies showed that AKR1C3 inhibition mediated by ATRA exhibited tight binding (Kiapp = 0.54 µM). Further, the combination of 1 µM ATRA with different concentrations of Dau demonstrated synergistic effects in HCT116 and KG1a human cells expressing AKR1C3. Our results suggest that ATRA-mediated inhibition of AKR1C3 can contribute to the mechanisms that are hidden beyond the beneficial clinical outcome of the ATRA–Dau combination.

Published
2020

38. The Fate of Homograft Versus Polytetrafluoroethylene Conduits After Neonatal Truncus Arteriosus Repair

Author

Carlos E Diaz Castrillon, Victor O. Morell, Laura Seese, and Harma K. Turbendian

Subjects
Male, Reoperation, Cardiac Catheterization, medicine.medical_specialty, Heart Ventricles, Pulmonary Artery, 030204 cardiovascular system & hematology, Truncus arteriosus, Blood Vessel Prosthesis Implantation, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, medicine.artery, medicine, Humans, Transplantation, Homologous, Ventricular outflow tract, Stenosis, Pulmonary Artery, Polytetrafluoroethylene, Proportional Hazards Models, business.industry, Graft Survival, Graft Occlusion, Vascular, Infant, Newborn, General Medicine, Plastic Surgery Procedures, Allografts, Truncus Arteriosus, Persistent, Blood Vessel Prosthesis, Prosthesis Failure, Treatment Outcome, 030228 respiratory system, chemistry, Pediatrics, Perinatology and Child Health, Pulmonary artery, Cardiology, Female, Vascular Grafting, Surgery, Cardiology and Cardiovascular Medicine, business
Abstract

Background: Despite significant improvement in outcomes with truncus arteriosus (TA) repair, right ventricular outflow tract (RVOT) reconstruction with a right ventricular to pulmonary artery (RV-to-PA) conduit remains a source of long-term reintervention and reoperation. This study evaluated our experience with reintervention in homograft and polytetrafluoroethylene (PTFE) RV-to-PA conduits in neonates. Methods: Primary TA repairs from 2004 to 2016 at a single institution were included. Stratification was based on RVOT reconstruction with PTFE or homograft conduit. Primary outcome was operative conduit replacement. Secondary outcomes included the rates and types of catheter-based conduit interventions. Results: Twenty-eight patients underwent primary TA repair and 89.3% (n = 25) of them had RVOT reconstruction with a homograft (28.0%, n = 7) or PTFE (72.0%, n = 18) conduit. Rates of reoperation for conduit replacement and catheter-based interventions were similar between those with PTFE and homograft conduits (85.7% vs 72.2%, P = .49 and 57.1% vs 83.3%, P = .11, respectively). Additionally, the median time to conduit replacement and catheter-based conduit interventions were comparable. In multivariable analysis, conduit size, but not conduit type, was a predictor of conduit revision (hazard ratio: 1.66, 95% confidence interval: 1.11-2.49, P = .02). At five-year and ten-year follow-up, patients with PTFE conduits had better survival than those with homograft conduits (100.0% vs 71.4%, P = .02); however, no mortalities were associated with conduit reoperations or catheter-based reinterventions. Conclusions: Polytetrafluoroethylene and homograft RVOT reconstruction in neonatal TA repair demonstrate similar durability as defined by reoperation and reintervention rates. The validation of the durability of PTFE conduits in neonatal TA repair requires confirmatory studies in larger cohorts.

Published
2020

39. Medicinal plants and natural products as neuroprotective agents in age-related macular degeneration

Author

T. Ortega, Francisco Bosch-Morell, Isabel Martínez-Solís, M Amparo Sanahuja, Pilar Soriano, Encarna Castillo, Nuria Acero, M. Eugenia González-Rosende, Victoria Villagrasa, Dolores Muñoz-Mingarro, Producción Científica UCH 2020, UCH. Departamento de Ciencias Biomédicas, and UCH. Departamento de Farmacia

Subjects
0301 basic medicine, Antioxidant, genetic structures, medicine.medical_treatment, Nervous system - Degeneration - Treatment, Review, Pharmacology, medicine.disease_cause, lcsh:RC346-429, Azafrán - Uso terapéutico, law.invention, 0302 clinical medicine, Vitaminas - Uso terapéutico, law, Ginkgo biloba - Therapeutic use, age-related macular degeneration, bilberry, blueberry, curcuma, carotenoids, ginkgo, polyphenols, saffron, vitamins, Medicinal plants, Carotenoid, Vitamins - Therapeutic use, Estrés oxidativo, chemistry.chemical_classification, biology, Saffron - Therapeutic use, Retina - Diseases - Treatment, Eye - Diseases - Treatment, Sistema nervioso - Degeneración - Tratamiento, Oxidative stress, Carotenoids - Therapeutic use, Ojos - Enfermedades - Tratamiento, Medicinal plants - Therapeutic use, ginkgo1, Ginkgo biloba - Uso terapéutico, Neuroprotection, 03 medical and health sciences, Developmental Neuroscience, medicine, Curcuma, lcsh:Neurology. Diseases of the nervous system, business.industry, Macular degeneration, biology.organism_classification, medicine.disease, eye diseases, Carotenoides - Uso terapéutico, 030104 developmental biology, chemistry, Plantas medicinales - Uso terapéutico, sense organs, Phytotherapy, business, 030217 neurology & neurosurgery, Retina - Enfermedades - Tratamiento
Abstract

Este artículo se encuentra disponible en la siguiente URL: https://www.nrronline.org/temp/NeuralRegenRes15122207-4877537_133255.pdf En este artículo también participa: Pilar Soriano. The retina may suffer neurodegenerative damages, as other tissues of the central nervous system do, and serious eye diseases may develop. One of them is age-related macular degeneration, which causes progressive loss of vision due to retina degeneration. Treatment of age-related macular degeneration focuses on antioxidant agents and anti-vascular endothelial growth factor compounds, among others, that prevent/ diminish oxidative stress and reduce neovascularisation respectively. The phytochemicals, medicinal plants and/or plant-diet supplements might be a useful adjunct in prevention or treatment of age-related macular degeneration owing to their antioxidant and anti-vascular endothelial growth factor properties. This review article presents the most investigated plants and natural products in relation to age-related macular degeneration, such as saffron, ginkgo, bilberry and blueberry, curcuma or turmeric, carotenoids, polyphenols, and vitamins C and E. This study provides up-to-date information on the effects, treatments, safety and efficiency of these phytotherapy products.

Published
2020

40. Extracellular vesicles from recombinant cell factories improve the activity and efficacy of enzymes defective in lysosomal storage disorders

Author

Rosa Mendoza, Zamira V. Díaz-Riascos, Sandra Mancilla, Lorenzo Albertazzi, Natalia García-Aranda, Ana Boullosa, Antonio Villaverde, Monica Mandaña, Patricia González, Ibane Abasolo, Anna Rosell, Guillem Pintos-Morell, José Luis Corchero, Josefina Casas, Simó Schwartz, Alba Grayston, Joaquin Seras-Franzoso, Roger Riera, Elena García-Fruitós, Marc Moltó-Abad, Institut Català de la Salut, [Seras-Franzoso J, González P, Schwartz S Jr] Drug Delivery & Targeting, CIBBIM-Nanomedicine, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Barcelona, Spain. [Díaz-Riascos ZV, García-Aranda N, Mandaña M, Boullosa A, Mancilla S, Abasolo I] Drug Delivery & Targeting, CIBBIM-Nanomedicine, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Barcelona, Spain. Functional Validation & Preclinical Research (FVPR), CIBBIM-Nanomedicine, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. [Corchero JL] Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Barcelona, Spain. Institut de Biotecnologia i de Biomedicina (IBB) and Department of Genetics and Microbiology, Universitat Autònoma de Barcelona, Bellaterra, Spain. [Grayston A, Rosell A] Neurovascular Research Laboratory, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. [Moltó-Abad M, Pintos-Morell G] Drug Delivery & Targeting, CIBBIM-Nanomedicine, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. Division of Rare Diseases, Reference Center for Hereditary Metabolic Disorders (CSUR, XUEC, MetabERN, and CIBER-ER). Vall d’Hebron Hospital Universitari, Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus

Subjects
Male, 0301 basic medicine, Hydrolases, Cell, Sanfilippo syndrome, Otros calificadores::Otros calificadores::Otros calificadores::/enzimología [Otros calificadores], law.invention, Mice, chemistry.chemical_compound, 0302 clinical medicine, law, Cells::Cellular Structures::Extracellular Space::Extracellular Vesicles [ANATOMY], Cloning, Molecular, Research Articles, Mice, Knockout, chemistry.chemical_classification, Trihexosylceramides, Brain, Enzyme replacement therapy, Recombinant Proteins, Cell biology, N-sulfoglucosamine sulfohydrolase, medicine.anatomical_structure, Metabolisme - Trastorns, 030220 oncology & carcinogenesis, Recombinant DNA, Pharmaceutical Vehicles, Research Article, Histology, Globotriaosylceramide, CHO Cells, Nutritional and Metabolic Diseases::Metabolic Diseases::Metabolism, Inborn Errors::Lysosomal Storage Diseases [DISEASES], Lysosomal storage disorders, Enzims extracel·lulars - Ús terapèutic, lysosomal storage disorders, Extracellular Vesicles, 03 medical and health sciences, Cricetulus, In vivo, medicine, Animals, Humans, Alpha-galactosidase A, enfermedades nutricionales y metabólicas::enfermedades metabólicas::alteraciones congénitas del metabolismo::enfermedades por almacenamiento lisosómico [ENFERMEDADES], Fabry disease, QH573-671, alpha‐galactosidase A, células::estructuras celulares::espacio extracelular::vesículas extracelulares [ANATOMÍA], N‐sulfoglucosamine sulfohydrolase, Cell Biology, medicine.disease, Lysosomal Storage Diseases, Mice, Inbred C57BL, HEK293 Cells, 030104 developmental biology, Enzyme, chemistry, alpha-Galactosidase, Drug delivery, Lysosomes, Cytology, Other subheadings::Other subheadings::Other subheadings::/enzymology [Other subheadings]
Abstract

In the present study the use of extracellular vesicles (EVs) as vehicles for therapeutic enzymes in lysosomal storage disorders was explored. EVs were isolated from mammalian cells overexpressing alpha‐galactosidase A (GLA) or N‐sulfoglucosamine sulfohydrolase (SGSH) enzymes, defective in Fabry and Sanfilippo A diseases, respectively. Direct purification of EVs from cell supernatants was found to be a simple and efficient method to obtain highly active GLA and SGSH proteins, even after EV lyophilization. Likewise, EVs carrying GLA (EV‐GLA) were rapidly uptaken and reached the lysosomes in cellular models of Fabry disease, restoring lysosomal functionality much more efficiently than the recombinant enzyme in clinical use. In vivo, EVs were well tolerated and distributed among all main organs, including the brain. DiR‐labelled EVs were localized in brain parenchyma 1 h after intra‐arterial (internal carotid artery) or intravenous (tail vein) administrations. Moreover, a single intravenous administration of EV‐GLA was able to reduce globotriaosylceramide (Gb3) substrate levels in clinically relevant tissues, such kidneys and brain. Overall, our results demonstrate that EVs from cells overexpressing lysosomal enzymes act as natural protein delivery systems, improving the activity and the efficacy of the recombinant proteins and facilitating their access to organs neglected by conventional enzyme replacement therapies., This study has been supported by ISCIII (PI18_00871 co‐founded by Fondo Europeo de Desarrollo Regional (FEDER)), and CIBER‐BBN (EXPLORE) granted to IA. Different CIBER‐BBN units of ICTS ‘NANBIOSIS’ have participated in this work (https://www.nanbiosis.es/platform-units/), more specifically the U1/Protein Production Platform for protein purification, Unit 6 for NTA analysis and TFF purification and U20/FVPR for in vivo assays.

Published
2021

41. Biomarkers in Fabry Disease. Implications for Clinical Diagnosis and Follow-up

Author

Carnicer-Cáceres, Clara, Arranz-Amo, Jose Antonio, Cea-Arestin, Cristina, Camprodon-Gomez, Maria, Moreno-Martinez, David, Lucas-Del-Pozo, Sara, Moltó Abad, Marc, Tigri-Santiña, Ariadna, Agraz Pamplona, Irene, Rodriguez-Palomares, Jose F.., Hernández-Vara, Jorge, Armengol-Bellapart, Mar, del Toro, Mireia, Pintos-Morell, Guillem, Universitat Autònoma de Barcelona, Institut Català de la Salut, [Carnicer-Cáceres C, Arranz-Amo JA, Cea-Arestin C] Laboratori d'Errors Innats del Metabolisme, Laboratoris Clínics, Vall d’Hebron Hospital, Barcelona, Spain. [Camprodon-Gomez M] Servei de Medicina Interna, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Unitat de Malalties Metabòliques Hereditàries, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Moreno-Martinez D] Servei de Medicina Interna, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Unitat de Malalties Metabòliques Hereditàries, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Lysosomal Storage Disorders Unit, Royal Free Hospital NHS Foundation Trust and University College London, London WC1E 6BT, UK. [Lucas-Del-Pozo S] Laboratori de Malalties Neurodegeneratives, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain. Servei de Neurologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK. [Moltó-Abad M] Validació Funcional i Investigació Preclínica, Distribució de Fàrmacs i Grup d'Orientació, CIBIM-Nanomedicina, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), 08035 Barcelona, Spain. [Tigri-Santiña A] Unitat de Malalties Metabòliques Hereditàries, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Agraz-Pamplona I] Servei de Nefrologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Rodriguez-Palomares JF] Servei de Cardiologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Hernández-Vara J, Armengol-Bellapart M] Laboratori de Malalties Neurodegeneratives, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain. Servei de Neurologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Del-Toro-Riera M] Unitat de Malalties Metabòliques Hereditàries, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Servei de Neurologia Pediàtrica, Unitat de Malalties Metabòliques Hereditàries, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Pintos-Morell G] Unitat de Malalties Metabòliques Hereditàries, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Validació Funcional i Investigació Preclínica, Distribució de Fàrmacs i Grup d'Orientació, CIBIM-Nanomedicina, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain, and Vall d'Hebron Barcelona Hospital Campus

Subjects
0301 basic medicine, Cardiomyopathy, lcsh:Medicine, Vasculopathy, Review, Disease, 030204 cardiovascular system & hematology, Gb3, Bioinformatics, factores biológicos::biomarcadores [COMPUESTOS QUÍMICOS Y DROGAS], chemistry.chemical_compound, Metabolisme, Errors congènits del - Diagnòstic, enfermedades y anomalías neonatales congénitas y hereditarias::enfermedades genéticas congénitas::enfermedades genéticas ligadas al cromosoma X::enfermedades y anomalías neonatales congénitas y hereditarias::enfermedades genéticas congénitas::enfermedades y anomalías neonatales congénitas y hereditarias::enfermedades genéticas congénitas::enfermedades y anomalías neonatales congénitas y hereditarias::enfermedades genéticas congénitas::enfermedad de Fabry [ENFERMEDADES], 0302 clinical medicine, Chronic kidney disease, Other subheadings::/diagnosis [Other subheadings], Medicine, terapéutica::farmacoterapia::terapia enzimática::tratamiento de sustitución enzimática [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Late-onset phenotype, late-onset phenotype, Kidney, inflammatory response, General Medicine, Enzyme replacement therapy, Phenotype, medicine.anatomical_structure, Enzims - Regulació, Marcadors bioquímics, Congenital, Hereditary, and Neonatal Diseases and Abnormalities::Genetic Diseases, Inborn::Genetic Diseases, X-Linked::Congenital, Hereditary, and Neonatal Diseases and Abnormalities::Genetic Diseases, Inborn::Congenital, Hereditary, and Neonatal Diseases and Abnormalities::Genetic Diseases, Inborn::Congenital, Hereditary, and Neonatal Diseases and Abnormalities::Genetic Diseases, Inborn::Fabry Disease [DISEASES], Classic phenotype, Otros calificadores::/diagnóstico [Otros calificadores], Globotriaosylceramide, lyso-Gb3, Biological Factors::Biomarkers [CHEMICALS AND DRUGS], 03 medical and health sciences, Lysosome, vasculopathy, fabry disease, Fabry disease, business.industry, lcsh:R, biomarkers, Inflammatory response, medicine.disease, 030104 developmental biology, chemistry, Lyso-gb3, business, cardiomyopathy, Therapeutics::Drug Therapy::Enzyme Therapy::Enzyme Replacement Therapy [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], chronic kidney disease, Biomarkers, classic phenotype
Abstract

Biomarcadores; Fenotipo clásico; Enfermedad de Fabry Biomarkers; Classic phenotype; Fabry disease Biomarcadors; Fenotip clàssic; Malaltia de Fabry Fabry disease (FD) is a lysosomal storage disorder caused by deficient alpha-galactosidase A activity in the lysosome due to mutations in the GLA gene, resulting in gradual accumulation of globotriaosylceramide and other derivatives in different tissues. Substrate accumulation promotes different pathogenic mechanisms in which several mediators could be implicated, inducing multiorgan lesions, mainly in the kidney, heart and nervous system, resulting in clinical manifestations of the disease. Enzyme replacement therapy was shown to delay disease progression, mainly if initiated early. However, a diagnosis in the early stages represents a clinical challenge, especially in patients with a non-classic phenotype, which prompts the search for biomarkers that help detect and predict the evolution of the disease. We have reviewed the mediators involved in different pathogenic mechanisms that were studied as potential biomarkers and can be easily incorporated into clinical practice. Some accumulation biomarkers seem to be useful to detect non-classic forms of the disease and could even improve diagnosis of female patients. The combination of such biomarkers with some response biomarkers, may be useful for early detection of organ injury. The incorporation of some biomarkers into clinical practice may increase the capacity of detection compared to that currently obtained with the established diagnostic markers and provide more information on the progression and prognosis of the disease. The research has not received any external funding.

Published
2021

42. Clinical features and health-related quality of life in adult patients with mucopolysaccharidosis IVA: the Spanish experience

Author

Elena Arranz Canales, Elisenda Cortès-Saladelafont, Elena Martín-Hernández, Ricardo Gil Sánchez, Guillem Pintos-Morell, Javier Blasco-Alonso, Mónica A. López Rodríguez, David Moreno-Martinez, Encarna Guillén-Navarro, María Juliana Ballesta-Martínez, María Teresa García-Silva, María L. Couce, Pilar Quijada-Fraile, Montserrat Morales Conejo, Salvador García Morillo, Marc Moltó-Abad, Institut Català de la Salut, [Quijada-Fraile P, Martín-Hernández E] Unidad de Enfermedades Mitocondriales y Enfermedades Metabólicas Hereditarias, Servicio de Pediatría, Hospital Universitario 12 de Octubre, CSUR Enfermedades Metabólicas, MetabERN, Instituto de Investigación Sanitaria Hospital 12 de octubre (imas12), CIBERER, Madrid, Spain. [Arranz Canales E] Servicio de Medicina Interna, CSUR Enfermedades Metabólicas, MetabERN, Instituto de Investigación Sanitaria Hospital 12 de octubre (imas12), Hospital Universitario 12 de Octubre, Madrid, Spain. [Ballesta-Martínez MJ, Guillén-Navarro E] Sección de Genética Médica, Hospital Clínico Universitario Virgen de la Arrixaca, IMIB Arrixaca, Universidad de Murcia, Murcia, Spain. CIBERER-ISCIII, Madrid, Spain. [Pintos-Morell G, Moltó-Abad M] Divisió de Malalties Minoritàries, Centre de Referència de Trastorns Metabòlics Hereditaris, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Moreno-Martínez D] Divisió de Malalties Minoritàries, Centre de Referència de Trastorns Metabòlics Hereditaris, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Lysosomal Storage Disorders Unit, The Royal Free Hospital NHS Foundation Trust and University College London, London, UK, and Vall d'Hebron Barcelona Hospital Campus

Subjects
Adult, Ligamentous laxity, medicine.medical_specialty, Health-related quality of life, Mucopolysaccharidosis, Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores], Other subheadings::Other subheadings::/drug therapy [Other subheadings], Hip dysplasia (canine), Young Adult, chemistry.chemical_compound, Elosulfase alfa, Quality of life, Interquartile range, Internal medicine, medicine, Hip Dislocation, Humans, Enzyme Replacement Therapy, Pharmacology (medical), Malalties rares - Tractament, Mucopolysaccharidosis IVA, Elosulfase alfa, Health-related quality of life, Mobility, Morquio A syndrome, Mucopolysaccharidosis IVA, terapéutica::farmacoterapia::terapia enzimática::tratamiento de sustitución enzimática [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Genetics (clinical), ambiente y salud pública::salud pública::medidas epidemiológicas::demografía::estado de salud::calidad de vida [ATENCIÓN DE SALUD], Mobility, business.industry, Research, Enzims - Ús terapèutic, Mucopolysaccharidosis IV, General Medicine, Enzyme replacement therapy, medicine.disease, Self Care, Environment and Public Health::Public Health::Epidemiologic Measurements::Demography::Health Status::Quality of Life [HEALTH CARE], Metabolisme, Errors congènits del - Tractament, enfermedades nutricionales y metabólicas::enfermedades metabólicas::alteraciones congénitas del metabolismo::trastornos congénitos del metabolismo de los carbohidratos::mucopolisacaridosis::enfermedades nutricionales y metabólicas::enfermedades metabólicas::alteraciones congénitas del metabolismo::mucopolisacaridosis IV [ENFERMEDADES], chemistry, Dysplasia, Quality of Life, Medicine, Nutritional and Metabolic Diseases::Metabolic Diseases::Metabolism, Inborn Errors::Carbohydrate Metabolism, Inborn Errors::Mucopolysaccharidoses::Nutritional and Metabolic Diseases::Metabolic Diseases::Metabolism, Inborn Errors::Mucopolysaccharidosis IV [DISEASES], sense organs, business, Morquio A syndrome, Therapeutics::Drug Therapy::Enzyme Therapy::Enzyme Replacement Therapy [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT]
Abstract

Background Mucopolysaccharidosis (MPS) IVA or Morquio A syndrome is a progressive and disabling disease characterized by a deficiency of the enzyme N-acetylgalactosamine-6-sulphate sulphatase. Its clinical presentation is very heterogeneous and poorly understood in adults. The aim of this study was to describe the clinical manifestations of MPS IVA in adult patients in Spain and to assess their health-related quality of life (HRQoL). Results Thirty-three patients from nine reference centres participated in the study. The median age was 32 (interquartile range [IQR]: 20.5–40.5) years. The phenotype was classical in 54.5% of patients, intermediate in 33.3% of patients, and non-classical in 12.1% of patients. The most common clinical manifestation was bone dysplasia, with a median height of 118 (IQR: 106–136) cm. Other frequent clinical manifestations were hearing loss (75.7%), ligamentous laxity (72.7%), odontoid dysplasia (69.7%), limb deformities that required orthopaedic aids (mainly hip dysplasia and genu valgus) (63.6%), and corneal clouding (60.6%). In addition, 36.0% of patients had obstructive sleep apnoea/hypopnoea syndrome and 33.3% needed non-invasive ventilation. Cervical surgery and varisation osteotomy were the most common surgical interventions (36.4% each). Almost 80% of patients had mobility problems and 36.4% used a wheelchair at all times. Furthermore, 87.9% needed help with self-care, 33.3% were fully dependent, and 78.8% had some degree of pain. HRQoL according to the health assessment questionnaire was 1.43 (IQR: 1.03–2.00) in patients with the non-classical phenotype, but 2.5 (IQR: 1.68–3.00) in those with the classical phenotype. Seven patients were initiated on enzyme replacement therapy (ERT), but two of them were lost to follow-up. Lung function improved in four patients and slightly worsened in one patient. The distance achieved in the six-minute walk test increased in the four patients who could perform it. HRQoL was better in patients treated with elosulfase alfa, with a median (IQR) of 1.75 (1.25–2.34) versus 2.25 (1.62–3.00) in patients not treated with ERT. Conclusions The study provides real-world data on patients with MPS IVA. Limited mobility, difficulties with self-care, dependence, and pain were common, together with poor HRQoL. The severity and heterogeneity of clinical manifestations require the combined efforts of multidisciplinary teams.

Published
2021

43. Protein- and polysaccharide-based particles used for Pickering emulsion stabilisation

Author

Vânia Regina Nicoletti, Amparo Quiles, P. Morell, Isabel Hernando, and Elisa Franco Ribeiro

Subjects
Materials science, TECNOLOGIA DE ALIMENTOS, General Chemical Engineering, Emulsion stability, engineering.material, Polysaccharide, 01 natural sciences, Colloid, 0404 agricultural biotechnology, Biopolymers, Pickering HIPEs, 0103 physical sciences, Amphiphile, Copolymer, chemistry.chemical_classification, 010304 chemical physics, Protein-polysaccharide complexes, Food-grade Pickering stabilisers, 04 agricultural and veterinary sciences, General Chemistry, Polymer, 040401 food science, Pickering emulsion, chemistry, Chemical engineering, engineering, Wetting, Biopolymer, Food Science
Abstract

[EN] A few protein- and polysaccharide-based particles can function as effective stabilisers in multi-phase food systems. Combining both polymer-based particles and tailoring the wettability of colloidal systems result in particlestabilised emulsions with great stability. High internal phase emulsions (HIPEs) have also been produced using such particles giving rise to a more stable, highly viscous structure. Thus, the purpose here is to review the advantages and disadvantages of using protein, polysaccharide and protein-polysaccharide complexes and conjugates for stabilising emulsions, highlighting the composites of amphiphilic protein-polysaccharide particles that can function as outstanding copolymer stabilising agents. The current challenges and emerging research trends are exploring renewable, sustainable, clean-label, and eco-friendly biopolymer particles that are effective as Pickering stabilisers., The authors would like to thank the project RTI-2018-099738-B-C22 from the 'Ministerio de Ciencia, Innovacion y Universidades', the Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior - Brazil (CAPES) Finance Code 001, and Sao Paulo Research Foundation (FAPESP - Grant number 2016/227278) . They would also like to thank Phillip John Bentley for assistance correcting the manuscript's English.

Published
2021

44. Influence of water regimes and herbicides for control of purple nutsedge ( Cyperus rotundus )

Author

Mauricio Morell and Duy Le

Subjects
Water shortage stress, Perennial plant, Physiology, Randomized block design, Biomass, Weed management, Plant Science, Biology, Weed control, Biochemistry, chemistry.chemical_compound, chemistry, Agronomy, Glyphosate, Cyperus rotundus, Herbicide, Weed, Agronomy and Crop Science, Water content, Purple nutsedge
Abstract

Background: Purple nutsedge is a weed that has a tough profuse underground tuber system, and is predominantly a perennial species in many crops. Objective: To evaluate the influence of different water regimes to the effectiveness of herbicides used for controlling the purple nutsedge. Methods: Experiment was arranged in a Randomized complete block design (RCBD) with a two-factor factorial design and three replications. The net-house tests were conducted with six treatments and two different water regimes of “watered daily” and “watered weekly”. The tested herbicides were florpyrauxifen-benzyl, halosulfuron-methyl, 2,4-D and glyphosate. Results: Water shortage reduced the weed control efficacy of four tested herbicides. Herbicide efficacy improved when plants were watered daily, the high level of sedge biomass reduction at 60 DAT observed in florpyrauxifen-benzyl (30 g ai ha-1) and halosulfuron-methyl (50 g a.i ha-1) treatment. Glyphosate (480 g ai.ha-1) and 2,4-D (360 g ai.ha-1) exhibited moderate control efficacy on purple nutsedge under daily watered condition. Conclusions: The water regime was a critical component of purple nutsedge herbicide control program. Maintaining soil moisture by watering daily improved the herbicide efficiency and reliability for the management of purple nutsedge.

Published
2021

45. Polarisation of Electron Density and Electronic Effects: Revisiting the Carbon–Halogen Bonds

Author

Christophe Morell, Frédéric Guégan, Laurent Joubert, Sébastien Menant, Vincent Tognetti, Henry Chermette, Lynda Merzoud, Chemometrics and Theoretical Chemistry - Chimiométrie et chimie théorique, Institut des Sciences Analytiques (ISA), Institut de Chimie du CNRS (INC)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie des Milieux et Matériaux de Poitiers (IC2MP), Université de Poitiers-Institut national des sciences de l'Univers (INSU - CNRS)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Chimie Organique et Bioorganique : Réactivité et Analyse (COBRA), Institut Normand de Chimie Moléculaire Médicinale et Macromoléculaire (INC3M), Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie Organique Fine (IRCOF), Université de Rouen Normandie (UNIROUEN), and Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Electron density, Materials science, Pharmaceutical Science, chemistry.chemical_element, 010402 general chemistry, 01 natural sciences, Article, Analytical Chemistry, QD241-441, electron polarisation, conceptual DFT, 0103 physical sciences, Drug Discovery, Electronic effect, Molecule, Reactivity (chemistry), Physical and Theoretical Chemistry, 010304 chemical physics, [CHIM.ORGA]Chemical Sciences/Organic chemistry, reactivity/selectivity descriptors, Organic Chemistry, chemical bonding, 3. Good health, 0104 chemical sciences, [CHIM.THEO]Chemical Sciences/Theoretical and/or physical chemistry, Chemical bond, chemistry, Chemistry (miscellaneous), Chemical physics, Halogen, Molecular Medicine, Selectivity, Carbon
Abstract

International audience; Electronic effects (inductive and mesomeric) are of fundamental importance to understand the reactivity and selectivity of a molecule. In this article, polarisation temperature is used as a principal index to describe how electronic effects propagate in halogeno-alkanes and halogeno-alkenes. It is found that as chain length increases, polarisation temperature decreases. As expected, polarisation is much larger for alkenes than for alkanes. Finally, the polarisation mode of the carbon–fluorine bond is found to be quite different and might explain the unusual reactivity of fluoride compounds.

Published
2021
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46. Graphene Oxide/ZnS:Mn Nanocomposite Functionalized with Folic Acid as a Nontoxic and Effective Theranostic Platform for Breast Cancer Treatment

Author

Daysi Diaz-Diestra, Bibek Thapa, Dayra Badillo-Diaz, Juan Beltran-Huarac, Gerardo Morell, and Brad R. Weiner

Subjects
drug delivery, quantum dots, reduced graphene oxide, chemotherapy, theranostics, Chemistry, QD1-999
Abstract

Nanoparticle-based cancer theranostic agents generally suffer of poor dispersability in biological media, re-agglomeration over time, and toxicity concerns. To address these challenges, we developed a nanocomposite consisting of chemically-reduced graphene oxide combined with manganese-doped zinc sulfide quantum dots and functionalized with folic acid (FA-rGO/ZnS:Mn). We studied the dispersion stability, Doxorubicin (DOX) loading and release efficiency, target specificity, internalization, and biocompatibility of FA-rGO/ZnS:Mn against folate-rich breast cancer cells, and compared to its uncoated counterpart (rGO/ZnS:Mn). The results indicate that DOX is adsorbed on the graphene surface via π–π stacking and hydrophobic interaction, with enhanced loading (~35%) and entrapment (~60%) efficiency that are associated to the chelation of DOX and surface Zn2+ ions. DOX release is favored under acidic conditions reaching a release of up to 95% after 70 h. Membrane integrity of the cells assessed by Lactate dehydrogenase (LDH) release indicate that the surface passivation caused by folic acid (FA) functionalization decreases the strong hydrophobic interaction between the cell membrane wall and the edges/corners of graphene flakes. Chemotherapeutic effect assays reveal that the cancer cell viability was reduced up to ~50% at 3 µg/mL of DOX-FA-rGO/ZnS:Mn exposure, which is more pronounced than those obtained for free DOX at the same doses. Moreover, DOX-rGO/ZnS:Mn did not show any signs of toxicity. An opposite trend was observed for cells that do not overexpress the folate receptors, indicating that FA functionalization endows rGO/ZnS:Mn with an effective ability to discriminate positive folate receptor cancerous cells, enhancing its drug loading/release efficiency as a compact drug delivery system (DDS). This study paves the way for the potential use of functionalized rGO/ZnS:Mn nanocomposite as a platform for targeted cancer treatment.

Published
2018
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47. Non-Steroidal Biphenyl Gelators: Correlation of Xerogel Structure with Solid-State Structure and Circular Dichroism Spectroscopy

Author

H. Cristina Geiger, David K. Geiger, William R. Roberts, Dominic L. Morell, Paul Huttunen, Jennifer L. Schulman, Melanie Tran, and Dori Farthing

Subjects
organogels, XRD, SEM, CD, gelation, Science, Chemistry, QD1-999, Inorganic chemistry, QD146-197, General. Including alchemy, QD1-65
Abstract

Because the factors favoring the formation of well-formed single crystals are dissimilar to those conducive to gel formation, few examples of single-crystal structural characterizations of organogelators are found in the literature. A series of biphenyl methyl and ethyl diester derivatives of varying chain length were synthesized and their gelation abilities explored. X-ray diffraction of single crystals of one of the gelators reveals a columnar extended structure. Based on XRD results for xerogels obtained from the reported organogelators, the members of the series are isostructural and so also adopt a columnar superstructure. Scanning electron microscopy (SEM) was used for the investigation of the morphology of the xerogels, which display either platelet-like morphologies or more typical entangled twisted ribbon-like aggregates. The gels exhibit chirality, which depends on the sol-gel transition history, as observed by induced circular dichroism (ICD) spectroscopy.

Published
2018
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48. A computational investigation of the selectivity and mechanism of the Lewis acid catalyzed oxa‐Diels–Alder cycloaddition of substituted diene with benzaldehyde

Author

Abdelmalek Khorief Nacereddine, Christophe Morell, Henry Chermette, Lynda Merzoud, Lab Phys Chem & Biol Mat, Higher Normal Sch Technol Educ Skikda, Chemometrics and Theoretical Chemistry - Chimiométrie et chimie théorique, Institut des Sciences Analytiques (ISA), Institut de Chimie du CNRS (INC)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), and Ministry of Higher Education and Scientific Research of the Algerian Government, Grant/Award Number: B00L01UN230120180010

Subjects
chemistry.chemical_classification, 010304 chemical physics, Diene, Chemistry, Alkene, General Chemistry, Interaction energy, 010402 general chemistry, 01 natural sciences, Chemical reaction, Cycloaddition, 0104 chemical sciences, Chemical kinetics, [CHIM.THEO]Chemical Sciences/Theoretical and/or physical chemistry, Computational Mathematics, chemistry.chemical_compound, Computational chemistry, 0103 physical sciences, Lewis acids and bases, ComputingMilieux_MISCELLANEOUS, Natural bond orbital
Abstract

The selectivity and the mechanism of the uncatalyzed and AlCl3 catalyzed hetero-Diels-Alder reaction (HDR) between ([E]-4-methylpenta-2,4-dienyloxy)(tert-butyl)dimethylsilane 1 and benzaldehyde 2 have been studied using density functional theory at the MPWB1K/6-31G(d) level of theory. The uncatalyzed HDR between diene 1 and alkene 2 is characterized by a polar character and proceeds via an asynchronous one-step mechanism for the meta paths and synchronous for the ortho ones. In the presence of AlCl3 catalyst, the mechanism changes to be stepwise, while the first step is the rate-determining step. The activation energies widely decrease, and the polar character increases dramatically. A large analysis of the mechanism is performed using the activation strain model/energy decomposition analysis (ASM/EDA) model, the natural bond orbital (NBO) and state specific dual descriptors (SSDDs). The obtained results indicate that the combined interaction energy associated with the distortion of the reactants in these HDR are at the origin of the observed kinetics. NBO analyses were applied to estimate the Lewis-acid catalyst donor-acceptor interaction with the molecular system. The SSDD analysis shed light into the orientation effects on the reaction kinetics by providing important information about charge transfer interactions during the chemical reaction. It indicates that the more favorable HDR pathway have the lowest excitation energies, facilitating the interaction between diene 1 and benzaldehyde 2 moieties. Non-covalent interaction (NCI) and QTAIM analyses of the meta-endo structure indicate that the presence of several weak NCIs formed at this approach is at the origin of the meta-endo selectivity.

Published
2021

49. Immune-Related Urine Biomarkers for the Diagnosis of Lupus Nephritis

Author

Francisco Pérez-Cózar, Concepción Marañón, and Maria Morell

Subjects
0301 basic medicine, QH301-705.5, Urinary system, Lupus nephritis, Review, immune effector, Disease, Catalysis, Inorganic Chemistry, Pathogenesis, 03 medical and health sciences, 0302 clinical medicine, Immune system, Non-invasive diagnosis, medicine, Humans, Lupus Erythematosus, Systemic, Biology (General), Physical and Theoretical Chemistry, QD1-999, Molecular Biology, Spectroscopy, Autoantibodies, Inflammation, 030203 arthritis & rheumatology, Autoimmune disease, Kidney, business.industry, Organic Chemistry, Autoantibody, urine biomarkers, Complement System Proteins, General Medicine, Prognosis, medicine.disease, Computer Science Applications, Chemistry, Early Diagnosis, 030104 developmental biology, medicine.anatomical_structure, Urine biomarkers, Immunology, Immunoglobulin Light Chains, business, Immune effector, Biomarkers, non-invasive diagnosis
Abstract

This research was funded by IMI2-JU project GA#831434 (3TR) and IMI-JU project GA#115565 [118]. The JU receives support from the European Union's Horizon 2020 Research and Innovation Programme and EFPIA. The authors also acknowledge funding from Consejeria de la Salud y Familias de la Junta de Andalucia (PIER-0118-2019 and C2-0002-1019) and Instituto de Salud Carlos III (PI18/00082), partly supported by European FEDER funds., The kidney is one of the main organs affected by the autoimmune disease systemic lupus erythematosus. Lupus nephritis (LN) concerns 30–60% of adult SLE patients and it is significantly associated with an increase in the morbidity and mortality. The definitive diagnosis of LN can only be achieved by histological analysis of renal biopsies, but the invasiveness of this technique is an obstacle for early diagnosis of renal involvement and a proper follow-up of LN patients under treatment. The use of urine for the discovery of non-invasive biomarkers for renal disease in SLE patients is an attractive alternative to repeated renal biopsies, as several studies have described surrogate urinary cells or analytes reflecting the inflammatory state of the kidney, and/or the severity of the disease. Herein, we review the main findings in the field of urine immune-related biomarkers for LN patients, and discuss their prognostic and diagnostic value. This manuscript is focused on the complement system, antibodies and autoantibodies, chemokines, cytokines, and leukocytes, as they are the main effectors of LN pathogenesis., IMI2-JU project 831434, IMI-JU project 115565, European Union's Horizon 2020 Research and Innovation Programme, EFPIA, Junta de Andalucia PIER-0118-2019 C2-0002-1019, Instituto de Salud Carlos III European Commission PI18/00082, European Commission

Published
2021

50. Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial

Author

Zobair M Younossi, Vlad Ratziu, Rohit Loomba, Mary Rinella, Quentin M Anstee, Zachary Goodman, Pierre Bedossa, Andreas Geier, Susanne Beckebaum, Philip N Newsome, David Sheridan, Muhammad Y Sheikh, James Trotter, Whitfield Knapple, Eric Lawitz, Manal F Abdelmalek, Kris V Kowdley, Aldo J Montano-Loza, Jerome Boursier, Philippe Mathurin, Elisabetta Bugianesi, Giuseppe Mazzella, Antonio Olveira, Helena Cortez-Pinto, Isabel Graupera, David Orr, Lise Lotte Gluud, Jean-Francois Dufour, David Shapiro, Jason Campagna, Luna Zaru, Leigh MacConell, Reshma Shringarpure, Stephen Harrison, Arun J Sanyal, Manal Abdelmalek, Gary Abrams, Humberto Aguilar, Aijaz Ahmed, Elmar Aigner, Guruprasad Aithal, Aftab Ala, William Alazawi, Agustin Albillos, Michael Allison, Sfa Al-Shamma, Raul Andrade, Pietro Andreone, Mario Angelico, Victor Ankoma-Sey, Quentin Anstee, Rodolphe Anty, Victor Araya, Juan Ignacio Arenas Ruiz, Perttu Arkkila, Marty Arora, Tarik Asselah, Jennifer Au, Oyekoya Ayonrinde, Robert James Bailey, Maya Balakrishnan, Kiran Bambha, Meena Bansal, Sidney Barritt, John Bate, Jorge Beato, Jaideep Behari, Pablo Bellot, Ziv Ben Ari, Michael Bennett, Marina Berenguer, Benedetta Terziroli Beretta-Piccoli, Thomas Berg, Maurizio Bonacini, Lucia Bonet, Brian Borg, Marc Bourliere, William Bowman, David Bradley, Marija Brankovic, Marius Braun, Jean-Pierre Bronowicki, Savino Bruno, Cindy Cai, Amy Calderon, José Luis Calleja Panero, Elizabeth Carey, Michal Carmiel, Jose Antonio Carrión, Matthew Cave, Cristina Chagas, Tawfik Chami, Alan Chang, Allan Coates, Jeremy Cobbold, Charlote Costentin, Kathleen Corey, Lynsey Corless, Javier Crespo, Oscar Cruz Pereira, Victor de Ledinghen, Andrew deLemos, Moises Diago, Mamie Dong, Jean-François Dufour, Predrag Dugalic, Winston Dunn, Magby Elkhashab, Michael Epstein, Maria Desamparados Escudero-Garcia, Ohad Etzion, Larry Evans, Robert Falcone, Conrado Fernandez, Jose Ferreira, Scott Fink, Kevin Finnegan, Roberto Firpi-Morell, Annarosa Floreani, Thierry Fontanges, Ryan Ford, Ewan Forrest, Andrew Fowell, Anna Ludovica Fracanzani, Sven Francque, Bradley Freilich, Juan Frias, Michael Fuchs, Javier Fuentes, Michael Galambos, Juan Gallegos, Anja Geerts, Jacob George, Maged Ghali, Reem Ghalib, Pierre Gholam, Pere Gines, Norman Gitlin, Tobias Goeser, John Goff, Stuart Gordon, Frederic Gordon, Odile Goria, Shaun Greer, Alla Grigorian, Henning Gronbaek, Maeva Guillaume, Naresh Gunaratnam, Dina Halegoua-De Marzio, Bilal Hameed, Stephanie Hametner, James Hamilton, Marek Hartleb, Tarek Hassanein, Dieter Häussinger, Paul Hellstern, Robert Herring, Eva Heurich, Christophe Hezode, Holger Hinrichsen, Peter Holland Fischer, Yves Horsmans, Jonathan Huang, Hyder Hussaini, Antoine Jakiche, Lennox Jeffers, Blake Jones, Rosa Jorge, Francisco Jorquera, Shoba Joshi, Alisan Kahraman, Kelly Kaita, Nicholas Karyotakis, Zeid Kayali, Stergios Kechagias, Thomas Kepczyk, Mandana Khalili, Hicham Khallafi, Johannes Kluwe, Anita Kohli, Kevin Korenblat, Kris Kowdley, Aleksander Krag, Richard Krause, Andreas Kremer, Karen Krok, Miodrag Krstic, Marcelo Kugelmas, Sonal Kumar, Scott Kuwada, Damien Labarriere, Michelle Lai, Wim Laleman, Pietro Lampertico, Alice Lee, Vincent Leroy, Steven Lidofsky, Tina Huey Lim, Joseph Lim, Donald Lipkis, Ester Little, Amadeo Lonardo, Michelle Long, Velimir Anthony Christopher Luketic, Yoav Lurie, Guilherme Macedo, Joana Magalhaes, Mihály Makara, Benedict Maliakkal, Michael Manns, Pinelopi Manousou, Parvez Mantry, Giulio Marchesini, Carla Marinho, Paul Marotta, Hanns-Ulrich Marschall, Linda Martinez, Marlyn Mayo, Mark McCullen, William McLaughlin, Uta Merle, Raphael Merriman, Apurva Modi, Esther Molina, Aldo Montano-Loza, Carlos Monteverde, Amilcar Morales Cardona, Sulleman Moreea, Christophe Moreno, Filomena Morisco, Abdullah Mubarak, Beat Muellhaupt, Sandeep Mukherjee, Tobias Müller, Aleksandar Nagorni, Jahnavi Naik, Guy Neff, Moises Nevah, Philip Newsome, Eric Nguyen-Khac, Mazen Noureddin, Jude Oben, Hans Orlent, James Orr, Grisell Ortiz-Lasanta, Violaine Ozenne, Prashant Pandya, Angelo Paredes, James Park, Joykumar Patel, Keyur Patel, Sonali Paul, Heather Patton, Markus Peck-Radosavljevic, Salvatore Petta, Stephen Pianko, Anna Piekarska, Neville Pimstone, Joseph Pisegna, Paul Pockros, Stanislas Pol, Michael Porayko, John Poulos, David Pound, Joe Pouzar, Jose Presa Ramos, Nikolaos Pyrsopoulos, Nila Rafiq, Kate Muller, Alnoor Ramji, Ravi Ravinuthala, Chakradhar Reddy, Gautham Reddy K G, K. Rajender Reddy K R, Frederic Regenstein, Robert Reindollar, Justin Reynolds, Andres Riera, Jose Rivera Acosta, Geert Robaeys, Stuart Roberts, Federico Rodriguez-Perez, Sandor Romero, Manuel Romero-Gomez, Raymond Rubin, Mariagrazia Rumi, Simon Rushbrook, Christian Rust, Michael Ryan, Rifaat Safadi, Adnan Said, Kimmo Salminen, Didier Samuel, John Santoro, Arun Sanyal, Souvik Sarkar, Cynthia Schaeffer, Jörn Schattenberg, Ingolf Schiefke, Eugene Schiff, Wolfgang Schmidt, Jeffrey Schneider, Jeoffrey Schouten, Michael Schultz, Giada Sebastiani, David Semela, Thomas Sepe, Aasim Sheikh, Muhammad Sheikh, Kenneth Sherman, Oren Shibolet, Mitchell Shiffman, Asma Siddique, Cyril Sieberhagen, Samuel Sigal, Katarzyna Sikorska, Krzysztof Simon, Marie Sinclair, Richard Skoien, Joel Solis, Siddharth Sood, Bob Souder, James Spivey, Per Stal, Laura Stinton, Simone Strasser, Petar Svorcan, Gyongzi Szabo, Andrew Talal, Edward Tam, Brent Tetri, Paul Thuluvath, Hillel Tobias, Krzysztof Tomasiewicz, Dawn Torres, Albert Tran, Michael Trauner, Christian Trautwein, Emanuel Tsochatzis, Esther Unitt, Victor Vargas, Istvan Varkonyi, Ella Veitsman, Umberto Vespasiani Gentilucci, David Victor, John Vierling, Catherine Vincent, Aron Vincze, Manfred von der Ohe, Natasha Von Roenn, Raj Vuppalanchi, Michael Waters, Kymberly Watt, Julia Wattacheril, Martin Weltman, Amanda Wieland, Gregory Wiener, Alonzo Williams A, Jeffrey Williams J, Jason Wilson, Maria Yataco, Eric Yoshida, Ziad Younes, Liyun Yuan, Adam Zivony, Donald Zogg, Heinz Zoller, Fabien Zoulim, Eli Zuckerman, Massimo Zuin, Younossi Z.M., Ratziu V., Loomba R., Rinella M., Anstee Q.M., Goodman Z., Bedossa P., Geier A., Beckebaum S., Newsome P.N., Sheridan D., Sheikh M.Y., Trotter J., Knapple W., Lawitz E., Abdelmalek M.F., Kowdley K.V., Montano-Loza A.J., Boursier J., Mathurin P., Bugianesi E., Mazzella G., Olveira A., Cortez-Pinto H., Graupera I., Orr D., Gluud L.L., Dufour J.-F., Shapiro D., Campagna J., Zaru L., MacConell L., Shringarpure R., Harrison S., Sanyal A.J., Abdelmalek M., Abrams G., Aguilar H., Ahmed A., Aigner E., Aithal G., Ala A., Alazawi W., Albillos A., Allison M., Al-Shamma S., Andrade R., Andreone P., Angelico M., Ankoma-Sey V., Anstee Q., Anty R., Araya V., Arenas Ruiz J.I., Arkkila P., Arora M., Asselah T., Au J., Ayonrinde O., Bailey R.J., Balakrishnan M., Bambha K., Bansal M., Barritt S., Bate J., Beato J., Behari J., Bellot P., Ben Ari Z., Bennett M., Berenguer M., Beretta-Piccoli B.T., Berg T., Bonacini M., Bonet L., Borg B., Bourliere M., Bowman W., Bradley D., Brankovic M., Braun M., Bronowicki J.-P., Bruno S., Cai C., Calleja Panero J.L., Carey E., Carmiel M., Carrion J.A., Cave M., Chagas C., Chami T., Chang A., Coates A., Cobbold J., Corey K., Corless L., Crespo J., Cruz Pereira O., de Ledinghen V., deLemos A., Diago M., Dugalic P., Dunn W., Elkhashab M., Epstein M., Escudero-Garcia M.D., Etzion O., Evans L., Falcone R., Fernandez C., Ferreira J., Fink S., Finnegan K., Firpi-Morell R., Floreani A., Fontanges T., Ford R., Forrest E., Fowell A., Fracanzani A.L., Francque S., Freilich B., Frias J., Fuchs M., Fuentes J., Galambos M., Gallegos J., Geerts A., George J., Ghali M., Ghalib R., Gholam P., Gines P., Gitlin N., Goeser T., Goff J., Gordon S., Gordon F., Goria O., Greer S., Grigorian A., Gronbaek H., Guillaume M., Gunaratnam N., Halegoua-De Marzio D., Hameed B., Hametner S., Hamilton J., Hartleb M., Hassanein T., Haussinger D., Hellstern P., Herring R., Heurich E., Hezode C., Hinrichsen H., Holland Fischer P., Horsmans Y., Huang J., Jakiche A., Jeffers L., Jones B., Jorge R., Jorquera F., Kahraman A., Kaita K., Karyotakis N., Kayali Z., Kechagias S., Kepczyk T., Khalili M., Khallafi H., Kluwe J., Kohli A., Korenblat K., Kowdley K., Krag A., Krause R., Kremer A., Krok K., Krstic M., Kugelmas M., Kumar S., Labarriere D., Lai M., Lampertico P., Lee A., Leroy V., Lidofsky S., Lim T.H., Lim J., Lipkis D., Little E., Lonardo A., Long M., Lurie Y., Macedo G., Makara M., Maliakkal B., Manns M., Manousou P., Mantry P., Marchesini G., Marinho C., Marotta P., Marschall H.-U., Mayo M., McCullen M., McLaughlin W., Merriman R., Modi A., Molina E., Montano-Loza A., Monteverde C., Moreea S., Moreno C., Morisco F., Mubarak A., Muellhaupt B., Mukherjee S., Muller T., Nagorni A., Naik J., Neff G., Nevah M., Newsome P., Nguyen-Khac E., Noureddin M., Oben J., Orlent H., Orr J., Ortiz-Lasanta G., Ozenne V., Pandya P., Paredes A., Park J., Patel J., Patel K., Uta M., Patton H., Peck-Radosavljevic M., Petta S., Pianko S., Piekarska A., Pimstone N., Pockros P., Pol S., Porayko M., Poulos J., Pound D., Pouzar J., Presa Ramos J., Pyrsopoulos N., Rafiq N., Muller K., Ramji A., Ravinuthala R., Reddy C., Reddy K G G., Reddy K R K.R., Regenstein F., Reindollar R., Riera A., Rivera Acosta J., Robaeys G., Roberts S., Rodriguez-Perez F., Romero-Gomez M., Rubin R., Rumi M., Rushbrook S., Rust C., Ryan M., Safadi R., Said A., Salminen K., Samuel D., Santoro J., Sanyal A., Sarkar S., Schaeffer C., Schattenberg J., Schiefke I., Schiff E., Schmidt W., Schneider J., Schouten J., Schultz M., Sebastiani G., Semela D., Sepe T., Sheikh A., Sheikh M., Sherman K., Shibolet O., Shiffman M., Siddique A., Sieberhagen C., Sigal S., Sikorska K., Simon K., Sinclair M., Skoien R., Solis J., Sood S., Souder B., Spivey J., Stal P., Stinton L., Strasser S., Svorcan P., Szabo G., Talal A., Tam E., Tetri B., Thuluvath P., Tobias H., Tomasiewicz K., Torres D., Trauner M., Trautwein C., Tsochatzis E., Unitt E., Vargas V., Varkonyi I., Veitsman E., Vespasiani Gentilucci U., Victor D., Vierling J., Vincent C., Vincze A., von der Ohe M., Von Roenn N., Vuppalanchi R., Waters M., Watt K., Weltman M., Wieland A., Wiener G., Williams A A., Williams J J., Wilson J., Yataco M., Yoshida E., Younes Z., Yuan L., Zivony A., Zogg D., Zoller H., Zoulim F., Zuckerman E., Zuin M., Repositório da Universidade de Lisboa, Younossi, Z. M., Ratziu, V., Loomba, R., Rinella, M., Anstee, Q. M., Goodman, Z., Bedossa, P., Geier, A., Beckebaum, S., Newsome, P. N., Sheridan, D., Sheikh, M. Y., Trotter, J., Knapple, W., Lawitz, E., Abdelmalek, M. F., Kowdley, K. V., Montano-Loza, A. J., Boursier, J., Mathurin, P., Bugianesi, E., Mazzella, G., Olveira, A., Cortez-Pinto, H., Graupera, I., Orr, D., Gluud, L. L., Dufour, J. -F., Shapiro, D., Campagna, J., Zaru, L., Macconell, L., Shringarpure, R., Harrison, S., Sanyal, A. J., Abdelmalek, M., Abrams, G., Aguilar, H., Ahmed, A., Aigner, E., Aithal, G., Ala, A., Alazawi, W., Albillos, A., Allison, M., Al-Shamma, S., Andrade, R., Andreone, P., Angelico, M., Ankoma-Sey, V., Anstee, Q., Anty, R., Araya, V., Arenas Ruiz, J. I., Arkkila, P., Arora, M., Asselah, T., Au, J., Ayonrinde, O., Bailey, R. J., Balakrishnan, M., Bambha, K., Bansal, M., Barritt, S., Bate, J., Beato, J., Behari, J., Bellot, P., Ben Ari, Z., Bennett, M., Berenguer, M., Beretta-Piccoli, B. T., Berg, T., Bonacini, M., Bonet, L., Borg, B., Bourliere, M., Bowman, W., Bradley, D., Brankovic, M., Braun, M., Bronowicki, J. -P., Bruno, S., Cai, C., Calleja Panero, J. L., Carey, E., Carmiel, M., Carrion, J. A., Cave, M., Chagas, C., Chami, T., Chang, A., Coates, A., Cobbold, J., Corey, K., Corless, L., Crespo, J., Cruz Pereira, O., de Ledinghen, V., Delemos, A., Diago, M., Dugalic, P., Dunn, W., Elkhashab, M., Epstein, M., Escudero-Garcia, M. D., Etzion, O., Evans, L., Falcone, R., Fernandez, C., Ferreira, J., Fink, S., Finnegan, K., Firpi-Morell, R., Floreani, A., Fontanges, T., Ford, R., Forrest, E., Fowell, A., Fracanzani, A. L., Francque, S., Freilich, B., Frias, J., Fuchs, M., Fuentes, J., Galambos, M., Gallegos, J., Geerts, A., George, J., Ghali, M., Ghalib, R., Gholam, P., Gines, P., Gitlin, N., Goeser, T., Goff, J., Gordon, S., Gordon, F., Goria, O., Greer, S., Grigorian, A., Gronbaek, H., Guillaume, M., Gunaratnam, N., Halegoua-De Marzio, D., Hameed, B., Hametner, S., Hamilton, J., Hartleb, M., Hassanein, T., Haussinger, D., Hellstern, P., Herring, R., Heurich, E., Hezode, C., Hinrichsen, H., Holland Fischer, P., Horsmans, Y., Huang, J., Jakiche, A., Jeffers, L., Jones, B., Jorge, R., Jorquera, F., Kahraman, A., Kaita, K., Karyotakis, N., Kayali, Z., Kechagias, S., Kepczyk, T., Khalili, M., Khallafi, H., Kluwe, J., Kohli, A., Korenblat, K., Kowdley, K., Krag, A., Krause, R., Kremer, A., Krok, K., Krstic, M., Kugelmas, M., Kumar, S., Labarriere, D., Lai, M., Lampertico, P., Lee, A., Leroy, V., Lidofsky, S., Lim, T. H., Lim, J., Lipkis, D., Little, E., Lonardo, A., Long, M., Lurie, Y., Macedo, G., Makara, M., Maliakkal, B., Manns, M., Manousou, P., Mantry, P., Marchesini, G., Marinho, C., Marotta, P., Marschall, H. -U., Mayo, M., Mccullen, M., Mclaughlin, W., Merriman, R., Modi, A., Molina, E., Montano-Loza, A., Monteverde, C., Moreea, S., Moreno, C., Morisco, F., Mubarak, A., Muellhaupt, B., Mukherjee, S., Muller, T., Nagorni, A., Naik, J., Neff, G., Nevah, M., Newsome, P., Nguyen-Khac, E., Noureddin, M., Oben, J., Orlent, H., Orr, J., Ortiz-Lasanta, G., Ozenne, V., Pandya, P., Paredes, A., Park, J., Patel, J., Patel, K., Uta, M., Patton, H., Peck-Radosavljevic, M., Petta, S., Pianko, S., Piekarska, A., Pimstone, N., Pockros, P., Pol, S., Porayko, M., Poulos, J., Pound, D., Pouzar, J., Presa Ramos, J., Pyrsopoulos, N., Rafiq, N., Muller, K., Ramji, A., Ravinuthala, R., Reddy, C., Reddy K G, G., Reddy K R, K. R., Regenstein, F., Reindollar, R., Riera, A., Rivera Acosta, J., Robaeys, G., Roberts, S., Rodriguez-Perez, F., Romero-Gomez, M., Rubin, R., Rumi, M., Rushbrook, S., Rust, C., Ryan, M., Safadi, R., Said, A., Salminen, K., Samuel, D., Santoro, J., Sanyal, A., Sarkar, S., Schaeffer, C., Schattenberg, J., Schiefke, I., Schiff, E., Schmidt, W., Schneider, J., Schouten, J., Schultz, M., Sebastiani, G., Semela, D., Sepe, T., Sheikh, A., Sheikh, M., Sherman, K., Shibolet, O., Shiffman, M., Siddique, A., Sieberhagen, C., Sigal, S., Sikorska, K., Simon, K., Sinclair, M., Skoien, R., Solis, J., Sood, S., Souder, B., Spivey, J., Stal, P., Stinton, L., Strasser, S., Svorcan, P., Szabo, G., Talal, A., Tam, E., Tetri, B., Thuluvath, P., Tobias, H., Tomasiewicz, K., Torres, D., Trauner, M., Trautwein, C., Tsochatzis, E., Unitt, E., Vargas, V., Varkonyi, I., Veitsman, E., Vespasiani Gentilucci, U., Victor, D., Vierling, J., Vincent, C., Vincze, A., von der Ohe, M., Von Roenn, N., Vuppalanchi, R., Waters, M., Watt, K., Weltman, M., Wieland, A., Wiener, G., Williams A, A., Williams J, J., Wilson, J., Yataco, M., Yoshida, E., Younes, Z., Yuan, L., Zivony, A., Zogg, D., Zoller, H., Zoulim, F., Zuckerman, E., Zuin, M., Younossi, Zobair M, Ratziu, Vlad, Loomba, Rohit, Rinella, Mary, Anstee, Quentin M, Goodman, Zachary, Bedossa, Pierre, Geier, Andrea, Beckebaum, Susanne, Newsome, Philip N, Sheridan, David, Sheikh, Muhammad Y, Trotter, Jame, Knapple, Whitfield, Lawitz, Eric, Abdelmalek, Manal F, Kowdley, Kris V, Montano-Loza, Aldo J, Boursier, Jerome, Mathurin, Philippe, Bugianesi, Elisabetta, Mazzella, Giuseppe, Olveira, Antonio, Cortez-Pinto, Helena, Graupera, Isabel, Orr, David, Gluud, Lise Lotte, Dufour, Jean-Francoi, Shapiro, David, Campagna, Jason, Zaru, Luna, MacConell, Leigh, Shringarpure, Reshma, Harrison, Stephen, Sanyal, Arun J, Abdelmalek, Manal, Abrams, Gary, Aguilar, Humberto, Ahmed, Aijaz, Aigner, Elmar, Aithal, Guruprasad, Ala, Aftab, Alazawi, William, Albillos, Agustin, Allison, Michael, Al-Shamma, Sfa, Andrade, Raul, Andreone, Pietro, Angelico, Mario, Ankoma-Sey, Victor, Anstee, Quentin, Anty, Rodolphe, Araya, Victor, Arenas Ruiz, Juan Ignacio, Arkkila, Perttu, Arora, Marty, Asselah, Tarik, Au, Jennifer, Ayonrinde, Oyekoya, Bailey, Robert Jame, Balakrishnan, Maya, Bambha, Kiran, Bansal, Meena, Barritt, Sidney, Bate, John, Beato, Jorge, Behari, Jaideep, Bellot, Pablo, Ben Ari, Ziv, Bennett, Michael, Berenguer, Marina, Beretta-Piccoli, Benedetta Terziroli, Berg, Thoma, Bonacini, Maurizio, Bonet, Lucia, Borg, Brian, Bourliere, Marc, Bowman, William, Bradley, David, Brankovic, Marija, Braun, Mariu, Bronowicki, Jean-Pierre, Bruno, Savino, Cai, Cindy, Calleja Panero, José Lui, Carey, Elizabeth, Carmiel, Michal, Carrión, Jose Antonio, Cave, Matthew, Chagas, Cristina, Chami, Tawfik, Chang, Alan, Coates, Allan, Cobbold, Jeremy, Corey, Kathleen, Corless, Lynsey, Crespo, Javier, Cruz Pereira, Oscar, de Ledinghen, Victor, deLemos, Andrew, Diago, Moise, Dufour, Jean-Françoi, Dugalic, Predrag, Dunn, Winston, Elkhashab, Magby, Epstein, Michael, Escudero-Garcia, Maria Desamparado, Etzion, Ohad, Evans, Larry, Falcone, Robert, Fernandez, Conrado, Ferreira, Jose, Fink, Scott, Finnegan, Kevin, Firpi-Morell, Roberto, Floreani, Annarosa, Fontanges, Thierry, Ford, Ryan, Forrest, Ewan, Fowell, Andrew, Fracanzani, Anna Ludovica, Francque, Sven, Freilich, Bradley, Frias, Juan, Fuchs, Michael, Fuentes, Javier, Galambos, Michael, Gallegos, Juan, Geerts, Anja, George, Jacob, Ghali, Maged, Ghalib, Reem, Gholam, Pierre, Gines, Pere, Gitlin, Norman, Goeser, Tobia, Goff, John, Gordon, Stuart, Gordon, Frederic, Goria, Odile, Greer, Shaun, Grigorian, Alla, Gronbaek, Henning, Guillaume, Maeva, Gunaratnam, Naresh, Halegoua-De Marzio, Dina, Hameed, Bilal, Hametner, Stephanie, Hamilton, Jame, Hartleb, Marek, Hassanein, Tarek, Häussinger, Dieter, Hellstern, Paul, Herring, Robert, Heurich, Eva, Hezode, Christophe, Hinrichsen, Holger, Holland Fischer, Peter, Horsmans, Yve, Huang, Jonathan, Jakiche, Antoine, Jeffers, Lennox, Jones, Blake, Jorge, Rosa, Jorquera, Francisco, Kahraman, Alisan, Kaita, Kelly, Karyotakis, Nichola, Kayali, Zeid, Kechagias, Stergio, Kepczyk, Thoma, Khalili, Mandana, Khallafi, Hicham, Kluwe, Johanne, Kohli, Anita, Korenblat, Kevin, Kowdley, Kri, Krag, Aleksander, Krause, Richard, Kremer, Andrea, Krok, Karen, Krstic, Miodrag, Kugelmas, Marcelo, Kumar, Sonal, Labarriere, Damien, Lai, Michelle, Lampertico, Pietro, Lee, Alice, Leroy, Vincent, Lidofsky, Steven, Lim, Tina Huey, Lim, Joseph, Lipkis, Donald, Little, Ester, Lonardo, Amadeo, Long, Michelle, Lurie, Yoav, Macedo, Guilherme, Makara, Mihály, Maliakkal, Benedict, Manns, Michael, Manousou, Pinelopi, Mantry, Parvez, Marchesini, Giulio, Marinho, Carla, Marotta, Paul, Marschall, Hanns-Ulrich, Mayo, Marlyn, McCullen, Mark, McLaughlin, William, Merriman, Raphael, Modi, Apurva, Molina, Esther, Montano-Loza, Aldo, Monteverde, Carlo, Moreea, Sulleman, Moreno, Christophe, Morisco, Filomena, Mubarak, Abdullah, Muellhaupt, Beat, Mukherjee, Sandeep, Müller, Tobia, Nagorni, Aleksandar, Naik, Jahnavi, Neff, Guy, Nevah, Moise, Newsome, Philip, Nguyen-Khac, Eric, Noureddin, Mazen, Oben, Jude, Orlent, Han, Orr, Jame, Ortiz-Lasanta, Grisell, Ozenne, Violaine, Pandya, Prashant, Paredes, Angelo, Park, Jame, Patel, Joykumar, Patel, Keyur, Uta, Merle, Patton, Heather, Peck-Radosavljevic, Marku, Petta, Salvatore, Pianko, Stephen, Piekarska, Anna, Pimstone, Neville, Pockros, Paul, Pol, Stanisla, Porayko, Michael, Poulos, John, Pound, David, Pouzar, Joe, Presa Ramos, Jose, Pyrsopoulos, Nikolao, Rafiq, Nila, Muller, Kate, Ramji, Alnoor, Ravinuthala, Ravi, Reddy, Chakradhar, Reddy K G, Gautham, Reddy K R, K. Rajender, Regenstein, Frederic, Reindollar, Robert, Riera, Andre, Rivera Acosta, Jose, Robaeys, Geert, Roberts, Stuart, Rodriguez-Perez, Federico, Romero-Gomez, Manuel, Rubin, Raymond, Rumi, Mariagrazia, Rushbrook, Simon, Rust, Christian, Ryan, Michael, Safadi, Rifaat, Said, Adnan, Salminen, Kimmo, Samuel, Didier, Santoro, John, Sanyal, Arun, Sarkar, Souvik, Schaeffer, Cynthia, Schattenberg, Jörn, Schiefke, Ingolf, Schiff, Eugene, Schmidt, Wolfgang, Schneider, Jeffrey, Schouten, Jeoffrey, Schultz, Michael, Sebastiani, Giada, Semela, David, Sepe, Thoma, Sheikh, Aasim, Sheikh, Muhammad, Sherman, Kenneth, Shibolet, Oren, Shiffman, Mitchell, Siddique, Asma, Sieberhagen, Cyril, Sigal, Samuel, Sikorska, Katarzyna, Simon, Krzysztof, Sinclair, Marie, Skoien, Richard, Solis, Joel, Sood, Siddharth, Souder, Bob, Spivey, Jame, Stal, Per, Stinton, Laura, Strasser, Simone, Svorcan, Petar, Szabo, Gyongzi, Talal, Andrew, Tam, Edward, Tetri, Brent, Thuluvath, Paul, Tobias, Hillel, Tomasiewicz, Krzysztof, Torres, Dawn, Trauner, Michael, Trautwein, Christian, Tsochatzis, Emanuel, Unitt, Esther, Vargas, Victor, Varkonyi, Istvan, Veitsman, Ella, Vespasiani Gentilucci, Umberto, Victor, David, Vierling, John, Vincent, Catherine, Vincze, Aron, von der Ohe, Manfred, Von Roenn, Natasha, Vuppalanchi, Raj, Waters, Michael, Watt, Kymberly, Weltman, Martin, Wieland, Amanda, Wiener, Gregory, Williams A, Alonzo, Williams J, Jeffrey, Wilson, Jason, Yataco, Maria, Yoshida, Eric, Younes, Ziad, Yuan, Liyun, Zivony, Adam, Zogg, Donald, Zoller, Heinz, Zoulim, Fabien, Zuckerman, Eli, Zuin, Massimo, and REGENERATE Study Investigators

Subjects
Male, Biopsy, Clinical Trial, Phase III, Administration, Oral, 030204 cardiovascular system & hematology, Chronic liver disease, Settore MED/04, Biomarkers/analysis, Gastroenterology, chemistry.chemical_compound, 0302 clinical medicine, Liver Function Tests, Non-alcoholic Fatty Liver Disease, Clinical endpoint, Medicine, 030212 general & internal medicine, 610 Medicine & health, Chenodeoxycholic Acid/administration & dosage, education.field_of_study, Liver Function Test, Research Support, Non-U.S. Gov't, Fatty liver, Obeticholic acid, NASH, OBETICHOLIC ACID, General Medicine, Middle Aged, Multicenter Study, Randomized Controlled Trial, Administration, Female, Biomarkers, Chenodeoxycholic Acid, Double-Blind Method, Humans, Human, Oral, medicine.medical_specialty, Population, Placebo, 03 medical and health sciences, Research Support, N.I.H., Extramural, Internal medicine, Journal Article, education, Intention-to-treat analysis, business.industry, Biomarker, Interim analysis, medicine.disease, Non-alcoholic Fatty Liver Disease/drug therapy, chemistry, Human medicine, business
Abstract

© 2019 Elsevier Ltd. All rights reserved., Background: Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. Methods: In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH, non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2-F3, or F1 with at least one accompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpoints for the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2-F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. Findings: Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1-F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2-F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1-F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). Interpretation: Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes.

Published
2019
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