Impact of Undernourishment on the Pharmacokinetics of Erlotinib and Gefitinib in Rats

The relationship between nutritional status and pharmacokinetics has been previously studied for classical anticancer drugs, but this relationship remains unexplored for modern therapies involving targeted drugs and new administration routes. In this context, the main objective of this thesis was to evaluate, in undernourished and well-nourished Wistar rats, the impact of undernourishment on the pharmacokinetics of erlotinib and gefitinib, two novel orally administered targeted-drugs. The research investigation was divided into three main experiments: • Evaluation of analytical and molecular alterations associated with undernourishment • In situ intestinal perfusion studies • In vivo pharmacokinetics studies This Doctoral Thesis yielded the following conclusions: 1. Undernourishment causes significant alterations on mRNA expression levels of intestinal and hepatic metabolic enzymes (Cyp1A1, Cyp1A2 and UDP) and transporter proteins (OATP, MRP2 and P-gp). In liver tissue, mRNA levels of all the quantified metabolic enzymes, except for cytochromes, were diminished in undernourishment status. On the other side, alterations of mRNA levels in intestinal tissue do not follow a particular trend and the final outcome is dependent on the assayed intestinal segment and on the evaluated enzyme. 2. The observed alterations in alanine-aminotransferase and aspartate-aminotransferase hepatic enzymes, along with the reduction of albumin plasmatic concentration, confirm the occurrence of hepatic damage as a result of undernourishment status. Likewise, the decreased count of blood cells corroborates bone-marrow dysfunction under protein-energy under-nutrition. 3. A passive diffusion uptake process and an active secretion process control erlotinib intestinal absorption through both of the assayed intestinal segments. This active secretion process is sensitive to nutritional status and to the presence of levofloxacin. 4. A passive diffusion uptake process governs gefitinib intestinal absorption, which proved not to be influenced by the addition of sodium azide to the perfusion solution. Furthermore, under this in situ assay conditions, alterations of gefitinib absorption process did not take place as a consequence of the nutritional status of rats. 5. A two-compartment model proved to describe best the pharmacokinetic profiles both for erlotinib and gefitinib. 6. A 5% decrease in erlotinib clearance takes place in undernourishment status. Drug bioavailability in magnitude (f) and rate (ka) are dependent on nutritional status and on the type of dispersion system employed for oral administration: • Bioavailability in magnitude is incomplete only when erlotinib suspension is administered to norm-nourished rats. • Absorption rate constant is 52% lower when erlotinib solution is administered in undernourished rats as compared to the administration in norm-nourished rats. These results yield an expected 20% higher area under the concentration-time curve for erlotinib in undernourished patients as compared with norm-nourished ones. 7. Volume of distribution and bioavailability parameters for gefitinib are increased 30 and 50%, respectively, in protein-energy undernourishment status. This preclinical results yield simulation outcomes, which indicate that minimum trough concentration and area under the concentration-time curve in undernourished patients are expected to be 50% higher when compared to norm-nourished patients. 8. The response of the organism to compensate the deficiencies generated by an inadequate energy and protein intake is very complex. Consequently, general pharmacokinetic changes in undernourishment status are very variable, difficult to predict and dependent on the evaluated drug, given that all LADME processes are sensitive to these alterations.The relationship between nutritional status and pharmacokinetics has been previously studied for classical anticancer drugs, but this relationship remains unexplored for modern therapies involving targeted drugs and new administration routes. In this context, the main objective of this thesis was to evaluate, in undernourished and well-nourished Wistar rats, the impact of undernourishment on the pharmacokinetics of erlotinib and gefitinib, two novel orally administered targeted-drugs. The research investigation was divided into three main experiments: • Evaluation of analytical and molecular alterations associated with undernourishment • In situ intestinal perfusion studies • In vivo pharmacokinetics studies This Doctoral Thesis yielded the following conclusions: 1. Undernourishment causes significant alterations on mRNA expression levels of intestinal and hepatic metabolic enzymes (Cyp1A1, Cyp1A2 and UDP) and transporter proteins (OATP, MRP2 and P-gp). In liver tissue, mRNA levels of all the quantified metabolic enzymes, except for cytochromes, were diminished in undernourishment status. On the other side, alterations of mRNA levels in intestinal tissue do not follow a particular trend and the final outcome is dependent on the assayed intestinal segment and on the evaluated enzyme. 2. The observed alterations in alanine-aminotransferase and aspartate-aminotransferase hepatic enzymes, along with the reduction of albumin plasmatic concentration, confirm the occurrence of hepatic damage as a result of undernourishment status. Likewise, the decreased count of blood cells corroborates bone-marrow dysfunction under protein-energy under-nutrition. 3. A passive diffusion uptake process and an active secretion process control erlotinib intestinal absorption through both of the assayed intestinal segments. This active secretion process is sensitive to nutritional status and to the presence of levofloxacin. 4. A passive diffusion uptake process governs gefitinib intestinal absorption, which proved not to be influenced by the addition of sodium azide to the perfusion solution. Furthermore, under this in situ assay conditions, alterations of gefitinib absorption process did not take place as a consequence of the nutritional status of rats. 5. A two-compartment model proved to describe best the pharmacokinetic profiles both for erlotinib and gefitinib. 6. A 5% decrease in erlotinib clearance takes place in undernourishment status. Drug bioavailability in magnitude (f) and rate (ka) are dependent on nutritional status and on the type of dispersion system employed for oral administration: • Bioavailability in magnitude is incomplete only when erlotinib suspension is administered to norm-nourished rats. • Absorption rate constant is 52% lower when erlotinib solution is administered in undernourished rats as compared to the administration in norm-nourished rats. These results yield an expected 20% higher area under the concentration-time curve for erlotinib in undernourished patients as compared with norm-nourished ones. 7. Volume of distribution and bioavailability parameters for gefitinib are increased 30 and 50%, respectively, in protein-energy undernourishment status. This preclinical results yield simulation outcomes, which indicate that minimum trough concentration and area under the concentration-time curve in undernourished patients are expected to be 50% higher when compared to norm-nourished patients. 8. The response of the organism to compensate the deficiencies generated by an inadequate energy and protein intake is very complex. Consequently, general pharmacokinetic changes in undernourishment status are very variable, difficult to predict and dependent on the evaluated drug, given that all LADME processes are sensitive to these alterations

Plan de Comunicación para Creactivitat

Treball Final de Grau en Publicitat i Relacions Públiques. Codi: PU0932. Curs acadèmic: 2019/2020La transformación digital está en constante evolución, ejerciendo su influencia de forma transversal en distintos ámbitos de la sociedad. Ofrece soluciones a todos los sectores: primario, secundario y terciario; aunque es en el sector cuaternario donde se convierte en fundamental, participando en el desarrollo de nuevas tecnologías que serán clave para el futuro. Ejemplo de ello son: la microelectrónica, la programación, la robótica, la industria aeroespacial, las telecomunicaciones o la biotecnología; además, de otras aplicaciones y artefactos como: la impresora 3D, el almacenamiento en nube, la inteligencia artificial, la programación de videojuegos o la configuración de drones. Para aprovechar el potencial que ofrece la transformación digital es imprescindible educar a los alumnos para que aprendan competencias de ámbito digital. En la educación ordinaria española existen cada vez más competencias vinculadas con el ámbito digital, no obstante, el sector de las actividades extraescolares, de ocio y tiempo libre se ha anticipado para ofrecer actividades como la robótica, la programación o la impresión 3D, democratizando el acceso a este tipo de formación en edades muy tempranas. El presente “Trabajo Fin de Grado” nace de la necesidad de dar a conocer y consolidar la robótica como actividad extraescolar desde una empresa de carácter local como Creactivitat, con la finalidad de aprovechar estos conocimientos para avanzar hacia una formación académica, personal y profesional adaptada a las necesidades de la sociedad actual y futura. Por ello, el Plan de Comunicación de Creactivitat apuesta de lleno por la robótica, como herramienta diferenciadora, ofreciendo un proyecto educativo innovador, tecnológico y divertido

PSYCHOMETRIC CHARACTERISTICS OF A SPANISH TRANSLATION OF THE MANCHESTER FOOT PAIN AND DISABILITY INDEX: VALIDATION AND RASCH ANALYSIS

Background: The Manchester Foot Pain and Disability Index (MFPDI) is a self-assessment questionnaire developed in the UK to measure foot pain and disability in the general population1. It has been translated and validated in several languages 2,3 Objectives: The aim of this study was to conduct cross-cultural adaptation and validation of the MFPDI into Spanish Methods: The cross-cultural adaptation process was undertaken using International Society for Pharmacoeconomics and Outcomes Research (ISPOR)4 recommendations. This involved 8 stages: i) Forward translation, ii) Reconciliation, iii) Back translation, iv) Back translation review, v) Harmonisation, vi) Pilot, vii) Pilot review, and viii) Proofreading. In the validation phase, the MFPDI datasets from the UK (original) and Spain (adapted) were pooled and subjected to Rasch analysis. Fit to the Rasch model, unidimensionality, reliability and cross-cultural invariance is reported Results: The pooled dataset comprised 1015 patients (Spain n=333 and UK n=682) with characteristics summarised in Table 1. Rasch analysis confirmed three subscales for both the Spanish and UK datasets and fit to the Rasch model X2 (df) = 15.945 (12), p = 0.194 and 31.024 (21), p = 0.073, for Spain and UK . The reliability (Person Separation Index - PSI) was .85 and .82 for Spain and UK respectively. Significant cross-cultural non-invariance was present on the Functional and Personal appearance subscales. Adjustment for the bias was achieved by ‘splitting’ the affected subscales and creation of cultural-specific subscales for each country and cultural-general subscale. Fit to the Rasch model was satisfied following cross-cultural adjustment (Table 1). The MFPDI was calibrated into interval-level scales for Spain and UK to enable future data pooling or comparisons. Sampl e size Gender Age Item Fit Residual Person Fit Residual Chi Square Interaction PSI Analysis N Female (%) Mean (SD) Mean SD Mean SD Value (df) p Spain 333 248 (74.4) 51.6 (15.2) -0.164 3.07 - 0.364 0.93 15.95 (12) 0.19 0.85 UK 682 416 (61.0) 55.2 (16.7) -0.366 2.80 - 0.429 0.99 31.02 (21) 0.07 0.82 Pooled 1015 663 (65.4) 52.8 (15.8) -0.766 4.40 - 0.441 1.06 49.17 (27) 0.01 0.84 DIFAdjusted -0.420 2.98 - 0.415 0.98 57.94 (45) 0.09 0.84 Table 1: P = Χ2 interaction probability, (non-significant P = Fit to the model), PSI = Person separation index Conclusions: A gold standard translation process (ISPOR) has been used to develop a Spanish (for Spain) version of the MFPDI, a widely used foot-specific patient-reported outcome measure. Rasch analysis has confirmed that the MFPDI is a robust 3-subscale measure of foot pain, function and appearance in both its English and Spanish versions. Future work can make cross-cultural comparisons using the calibrated scale

Inter-rater and intra-rater reliability of the extended TUG test in elderly participants

Background: To analyse the reliability, variance and execution time of the Extended Timed Up and Go (Extended TUG) test in three age groups of elderly participants (G1: 55–64 years; G2: 65–74 years; G3: 75–85 years). Methods: An analytical cross-sectional study of 114 recruited participants (63 women) of average age 70.17 (± 7.3) years was undertaken. Each participant performed the Extended TUG three consecutive times, with a rest break between tests of 120 s. Both the intragroup and intergroup reliability of the measurements in the Extended TUG were analysed. Results: The reliability of the Extended TUG test is excellent for the first and second decades but drops down to good for the third decade. Specifically, intragroup reliability ranged from 0.784 for G3 to 0.977 for G1 (G2 = 0.858). Intergroup reliability, compared with intragroup reliability, was slightly lower, ranging between 0.779 for G3 and 0.972 for G1 (G2 = 0.853). Conclusion: The reliability of the Extended TUG test progressively decreases with increasing age, being excellent for the younger age groups and good for the oldest age group

Optimization Alternatives for Robust Model-based Design of Synthetic Biological Circuits

[EN] Synthetic biology is reaching the situation where tuning devices by hand is no longer possible due to the complexity of the biological circuits being designed. Thus, mathematical models need to be used in order, not only to predict the behavior of the designed synthetic devices; but to help on the selection of the biological parts, i.e., guidelines for the experimental implementation. However, since uncertainties are inherent to biology, the desired dynamics for the circuit usually requires a trade-off among several goals. Hence, a multi-objective optimization design (MOOD) naturally arises to get a suitable parametrization (or range) of the required kinetic parameters to build a biological device with some desired properties. Biologists have classically addressed this problem by evaluating a set of random Monte Carlo simulations with parameters between an operation range. In this paper, We propose solving the MOOD by means of dynamic programming using both a global multi-objective evolutionary algorithm (MOLA) and a local gradient-based nonlinear programming (NLP) solver. The performance of both alternatives is then checked in the design of a well-known biological circuit: a genetic incoherent feed-forward loop showing adaptive behavior. (C) 2016, IFAC (International Federation of Antomatic Control) Hosting by Elsevier Ltd. All rights reserved.The research leading to these results has received funding from the European Union (FP7/2007-2013 under grant agreement no604068), the Spanish Government (FEDER-CICYT DPI2011-524 28112-C04-01, DPI2014-55276-C5-1-R, DPI2015-70975-P) and the National Council of Scientific and Technologic Development of Brazil (BJT-304804/2014-2). Yadira Boada thanks also grant FPI/2013-3242 of the Universitat Politecnica de ValenciaBoada-Acosta, YF.; Pitarch Pérez, JL.; Vignoni, A.; Reynoso Meza, G.; Picó, J. (2016). Optimization Alternatives for Robust Model-based Design of Synthetic Biological Circuits. IFAC-PapersOnLine. 49(7):821-826. https://doi.org/10.1016/j.ifacol.2016.07.291S82182649

C-Reactive Protein as an Early Predictor of Efficacy in Advanced Non-Small-Cell Lung Cancer Patients: A Tumor Dynamics-Biomarker Modeling Framework

In oncology, longitudinal biomarkers reflecting the patient’s status and disease evolution can offer reliable predictions of the patient’s response to treatment and prognosis. By leveraging clinical data in patients with advanced non-small-cell lung cancer receiving first-line chemotherapy, we aimed to develop a framework combining anticancer drug exposure, tumor dynamics (RECIST criteria), and C-reactive protein (CRP) concentrations, using nonlinear mixed-effects models, to evaluate and quantify by means of parametric time-to-event models the significance of early longitudinal predictors of progression-free survival (PFS) and overall survival (OS). Tumor dynamics was characterized by a tumor size (TS) model accounting for anticancer drug exposure and development of drug resistance. CRP concentrations over time were characterized by a turnover model. An x-fold change in TS from baseline linearly affected CRP production. CRP concentration at treatment cycle 3 (day 42) and the difference between CRP concentration at treatment cycles 3 and 2 were the strongest predictors of PFS and OS. Measuring longitudinal CRP allows for the monitoring of inflammatory levels and, along with its reduction across treatment cycles, presents a promising prognostic marker. This framework could be applied to other treatment modalities such as immunotherapies or targeted therapies allowing the timely identification of patients at risk of early progression and/or short survival to spare them unnecessary toxicities and provide alternative treatment decisions

Control del subenfriamiento: una manera de mejorar el rendimiento de condensadores para la producción de agua caliente con un elevado salto de temperatura del agua

El uso de ciclos subcríticos en bombas de calor para la producción de agua caliente se limita a temperaturas relativamente bajas y a saltos de temperatura del agua a calentar también pequeños. Es una buena solución, por ejemplo, para la producción de agua caliente para aplicaciones de calefacción, porque la temperatura del agua es admisible: 35 a 50°C y el salto de temperatura del agua es bajo, por ejemplo, alrededor de 5K. Para la producción de agua caliente sanitaria sin embargo, el salto de temperatura del agua es mucho mayor, por ejemplo, 50K cuando el agua se calienta de 10 a 60ºC. La temperatura del refrigerante en el proceso de condensación es bastante constante, lo que hace que la eficacia del condensador disminuya a elevados saltos de temperatura del agua. Recientemente se han desarrollado calentadores de agua que utilizan CO2 en ciclo transcrítico, ya que han demostrado un buen funcionamiento a elevados saltos de temperatura del agua, ja que se ve beneficiado por un elevado salto de temperaturas en el lado del refrigerante. Por lo tanto, una manera de mejorar la eficacia del condensador en un ciclo subcrítico será produciendo una gran cantidad de sub-enfriamiento, con el consecuente aumento de capacidad y el COP del ciclo. El siguiente artículo presenta dos ciclos diferentes con el fin de obtener el subenfriamiento deseado y la instalación experimental para la comba de calor agua/agua trabajando con propano. Finalmente, algunos resultados preliminares del COP se dan para diferentes condiciones de funcionamiento, tales como temperatura de la fuente de la bomba de calor en el lado caliente y el grado de subenfriamiento. Además, los resultados se comparan con un punto de referencia con cero subenfriamiento y una bomba de calor comercial.Los resultados de este estudio se han desarrollado marco del proyecto europeo FP7 European Project, Next Generation of Heat Pumps working with Natural fluids, NxtHPG. Parte de los trabajos presentados se realizaron por Miquel Pitarch Mocholí con el apoyo financiero de la beca de doctorado de la Universitat Politècnica de València

Multimodal Retrieval of the Scattering Parameters of a Coaxial-to-Waveguide Transition

In this paper a multimode characterization of coaxial to waveguide transition is carried out by means of inverse techniques. The multimode coaxial-to-waveguide transition is characterized with the generalized scattering matrix (GSM). A number of measured standards considering shorts is used to extract the matrices. By using optimizing techniques, such as genetic algorithms (GA) and a gradient descent (GD) based method the multimodal scattering matrix is calculated with the help of a fitness function that compares the standards with analytical calculations. The same measurement set up using uniquely shorts has been simulated and the GSM results have been retrieved, thus validating the proposed technique. This method easily allows working in the multimode range of waveguides, thus increasing considerably the bandwidth of classical applications such as permittivity characterization. Benefits and drawbacks of the implementation are also discussed

Aproximación 2-D a la eficacia del apantallamiento de carcasas metálicas

In this work an approximated method to obtain Shielding Effectiveness of metallic enclosures with an aperture is evaluated. The method consists of the analysis of the 2-D transversal cut of the structure through a numerical method. A Finite Element Method based CAD tool, has been used in order to obtain the results for the susceptibility analysis of the structure. To obtain the level of energy coupling between the inner and outer part of the cavity an empirical formula is used. Shielding Effectiveness of metallic enclosures with different sizes and apertures has been analysed and good agreement has been found between the 2-D approximated method and measurements. This tool can be used to study shielding properties of materials and the effects of enclosure contents, PCBs, I/O devices, etc.Este trabajo ha sido financiado por la Fundación Séneca, Agencia Regional de Ciencia y Tecnología, a través del proyecto 00700/PPC/04

DVINO: A RISC-V vector processor implemented in 65nm technology

This paper describes the design, verification, implementation and fabrication of the Drac Vector IN-Order (DVINO) processor, a RISC-V vector processor capable of booting Linux jointly developed by BSC, CIC-IPN, IMB-CNM (CSIC), and UPC. The DVINO processor includes an internally developed two-lane vector processor unit as well as a Phase Locked Loop (PLL) and an Analog-to-Digital Converter (ADC). The paper summarizes the design from architectural as well as logic synthesis and physical design in CMOS 65nm technology.The DRAC project is co-financed by the European Union Regional Development Fund within the framework of the ERDF Operational Program of Catalonia 2014-2020 with a grant of 50% of total eligible cost. The authors are part of RedRISCV which promotes activities around open hardware. The Lagarto Project is supported by the Research and Graduate Secretary (SIP) of the Instituto Politecnico Nacional (IPN) from Mexico, and by the CONACyT scholarship for Center for Research in Computing (CIC-IPN).Peer ReviewedArticle signat per 43 autors/es: Guillem Cabo∗, Gerard Candón∗, Xavier Carril∗, Max Doblas∗, Marc Domínguez∗, Alberto González∗, Cesar Hernández†, Víctor Jiménez∗, Vatistas Kostalampros∗, Rubén Langarita∗, Neiel Leyva†, Guillem López-Paradís∗, Jonnatan Mendoza∗, Francesco Minervini∗, Julian Pavón∗, Cristobal Ramírez∗, Narcís Rodas∗, Enrico Reggiani∗, Mario Rodríguez∗, Carlos Rojas∗, Abraham Ruiz∗, Víctor Soria∗, Alejandro Suanes‡, Iván Vargas∗, Roger Figueras∗, Pau Fontova∗, Joan Marimon∗, Víctor Montabes∗, Adrián Cristal∗, Carles Hernández∗, Ricardo Martínez‡, Miquel Moretó∗§, Francesc Moll∗§, Oscar Palomar∗§, Marco A. Ramírez†, Antonio Rubio§, Jordi Sacristán‡, Francesc Serra-Graells‡, Nehir Sonmez∗, Lluís Terés‡, Osman Unsal∗, Mateo Valero∗§, Luís Villa† // ∗Barcelona Supercomputing Center (BSC), Barcelona, Spain. Email: [email protected]; †Centro de Investigación en Computación, Instituto Politécnico Nacional (CIC-IPN), Mexico City, Mexico; ‡ Institut de Microelectronica de Barcelona, IMB-CNM (CSIC), Spain. Email: [email protected]; §Universitat Politecnica de Catalunya (UPC), Barcelona, Spain. Email: [email protected] (author's final draft