Advanced targeted therapies in cancer: Drug nanocarriers, the future of chemotherapy

Cancer is the second worldwide cause of death, exceeded only by cardiovascular diseases. It is characterized by uncontrolled cell proliferation and an absence of cell death that, except for hematological cancers, generates an abnormal cell mass or tumor. This primary tumor grows thanks to new vascularization and, in time, acquires metastatic potential and spreads to other body sites, which causes metastasis and finally death. Cancer is caused by damage or mutations in the genetic material of the cells due to environmental or inherited factors. While surgery and radiotherapy are the primary treatment used for local and non-metastatic cancers, anti-cancer drugs (chemotherapy, hormone and biological therapies) are the choice currently used in metastatic cancers. Chemotherapy is based on the inhibition of the division of rapidly growing cells, which is a characteristic of the cancerous cells, but unfortunately, it also affects normal cells with fast proliferation rates, such as the hair follicles, bone marrow and gastrointestinal tract cells, generating the characteristic side effects of chemotherapy. The indiscriminate destruction of normal cells, the toxicity of conventional chemotherapeutic drugs, as well as the development of multidrug resistance, support the need to find new effective targeted treatments based on the changes in the molecular biology of the tumor cells. These novel targeted therapies, of increasing interest as evidenced by FDA-approved targeted cancer drugs in recent years, block biologic transduction pathways and/or specific cancer proteins to induce the death of cancer cells by means of apoptosis and stimulation of the immune system, or specifically deliver chemotherapeutic agents to cancer cells, minimizing the undesirable side effects. Although targeted therapies can be achieved directly by altering specific cell signaling by means of monoclonal antibodies or small molecules inhibitors, this review focuses on indirect targeted approaches that mainly deliver chemotherapeutic agents to molecular targets overexpressed on the surface of tumor cells. In particular, we offer a detailed description of different cytotoxic drug carriers, such as liposomes, carbon nanotubes, dendrimers, polymeric micelles, polymeric conjugates and polymeric nanoparticles, in passive and active targeted cancer therapy, by enhancing the permeability and retention or by the functionalization of the surface of the carriers, respectively, emphasizing those that have received FDA approval or are part of the most important clinical studies up to date. These drug carriers not only transport the chemotherapeutic agents to tumors, avoiding normal tissues and reducing toxicity in the rest of the body, but also protect cytotoxic drugs from degradation, increase the half-life, payload and solubility of cytotoxic agents and reduce renal clearance.Despite the many advantages of all the anticancer drug carriers analyzed, only a few of them have reached the FDA approval, in particular, two polymer-protein conjugates, five liposomal formulations and one polymeric nanoparticle are available in the market, in contrast to the sixteen FDA approval of monoclonal antibodies. However, there are numerous clinical trials in progress of polymer-protein and polymer-drug conjugates, liposomal formulations, including immunoliposomes, polymeric micelles and polymeric nanoparticles. Regarding carbon nanotubes or dendrimers, there are no FDA approvals or clinical trials in process up to date due to their unresolved toxicity. Moreover, we analyze in detail the more promising and advanced preclinical studies of the particular case of polymeric nanoparticles as carriers of different cytotoxic agents to active and passive tumor targeting published in the last 5 years, since they have a huge potential in cancer therapy, being one of the most widely studied nano-platforms in this field in the last years. The interest that these formulations have recently achieved is stressed by the fact that 90% of the papers based on cancer therapeutics with polymeric nanoparticles have been published in the last 6 years (PubMed search).Authors acknowledge financial support from University of Salamanca, Spain. AFM work is supported by grants FIS PI13/02846 and RTICC RD12/0036/0001 from Instituto de Salud Carlos III (ISCIII), Spain, and grant SA181U13 from JCyL, Spain. EPH work is supported by grant FS/25-2014 from Fundación en Memoria de D. Samuel Solórzano Barruso, Spain.Peer Reviewe

Comentarios sobre la flora rupestre del Moncayo.

EScUDERO, A.; PAYARON, 5.; HERRERO, A. & ÁLvAREZ FERNÁNDEZ, 1. 1994. Comentanos sobre La flora rupestre del Moncayo. Botanico Complutensis 19: 89-108. El Moncayo es un macizo montañoso de gran interés biogeográfico. El conocimiento de su flora y vegetación atrajo a los botánicos desde antiguo: Asso visil.ó la zona en 1778, y esta atracción ha continuado hasta la actualidad. Se presentan comentarios de interés corológico, ecológico y taxonómico sobre 37 táxones -ecolectados en medios rupestres. Entre ellos destacan: Sas-ifiaga níoncoyensis, Cerastium arvense subsp. arvense, Linaria a/pino, Coclileario pyí-eííaic-a,Silene saxifraga, etc

Multivariable controller design for the cooling system of a PEM fuel cell by considering nearly optimal solutions in a multi-objective optimization approach

[EN] This paper presents a design for the multivariable control of a cooling system in a PEM (proton exchange membrane) fuel cell stack. This system is complex and challenging enough: interactions between variables, highly nonlinear dynamic behavior, etc. This design is carried out using a multiobjective optimization methodology. There are few previous works that address this problem using multiobjective techniques. Also, this work has, as a novelty, the consideration of, in addition to the optimal controllers, the nearly optimal controllers nondominated in their neighborhood (potentially useful alternatives). In the multiobjective optimization problem approach, the designer must make decisions that include design objectives; parameters of the controllers to be estimated; and the conditions and characteristics of the simulation of the system. However, to simplify the optimization and decision stages, the designer does not include all the desired scenarios in the multiobjective problem definition. Nevertheless, these aspects can be analyzed in the decision stage only for the controllers obtained with a much less computational cost. At this stage, the potentially useful alternatives can play an important role. These controllers have significantly different parameters and therefore allow the designer to make a final decision with additional valuable information. Nearly optimal controllers can obtain an improvement in some aspects not included in the multiobjective optimization problem. For example, in this paper, various aspects are analyzed regarding potentially useful solutions, such as (1) the influence of certain parameters of the simulator; (2) the sample time of the controller; (3) the effect of stack degradation; and (4) the robustness. Therefore, this paper highlights the relevance of this in-depth analysis using the methodology proposed in the design of the multivariable control of the cooling system of a PEM fuel cell. This analysis can modify the final choice of the designer.This study was supported in part by the Ministerio de Ciencia, Innovacion y Universidades (Spain) (grant no. RTI2018-096904-B-I00) and by the Generalitat Valenciana regional government through project AICO/2019/055.Pajares-Ferrando, A.; Blasco, X.; Herrero Durá, JM.; Simarro Fernández, R. (2020). Multivariable controller design for the cooling system of a PEM fuel cell by considering nearly optimal solutions in a multi-objective optimization approach. Complexity. 2020:1-17. https://doi.org/10.1155/2020/8649428S1172020Gunantara, N. (2018). A review of multi-objective optimization: Methods and its applications. Cogent Engineering, 5(1), 1502242. doi:10.1080/23311916.2018.1502242Engau, A., & Wiecek, M. M. (2007). Generating ε-efficient solutions in multiobjective programming. European Journal of Operational Research, 177(3), 1566-1579. doi:10.1016/j.ejor.2005.10.023Loridan, P. (1984). ?-solutions in vector minimization problems. Journal of Optimization Theory and Applications, 43(2), 265-276. doi:10.1007/bf00936165White, D. J. (1986). Epsilon efficiency. Journal of Optimization Theory and Applications, 49(2), 319-337. doi:10.1007/bf00940762Pajares, A., Blasco, X., Herrero, J. M., & Reynoso-Meza, G. (2018). A Multiobjective Genetic Algorithm for the Localization of Optimal and Nearly Optimal Solutions Which Are Potentially Useful: nevMOGA. Complexity, 2018, 1-22. doi:10.1155/2018/1792420Schutze, O., Vasile, M., & Coello, C. A. C. (2011). Computing the Set of Epsilon-Efficient Solutions in Multiobjective Space Mission Design. Journal of Aerospace Computing, Information, and Communication, 8(3), 53-70. doi:10.2514/1.46478Pajares, A., Blasco, X., Herrero, J. M., & Reynoso-Meza, G. (2019). A New Point of View in Multivariable Controller Tuning Under Multiobjective Optimization by Considering Nearly Optimal Solutions. IEEE Access, 7, 66435-66452. doi:10.1109/access.2019.2915556Fredriksson, A., Forsgren, A., & Hårdemark, B. (2011). Minimax optimization for handling range and setup uncertainties in proton therapy. Medical Physics, 38(3), 1672-1684. doi:10.1118/1.3556559Lee, J., & Johnson, G. E. (1993). Optimal tolerance allotment using a genetic algorithm and truncated Monte Carlo simulation. Computer-Aided Design, 25(9), 601-611. doi:10.1016/0010-4485(93)90075-yAndújar, J. M., & Segura, F. (2009). Fuel cells: History and updating. A walk along two centuries. Renewable and Sustainable Energy Reviews, 13(9), 2309-2322. doi:10.1016/j.rser.2009.03.015Mehta, V., & Cooper, J. S. (2003). Review and analysis of PEM fuel cell design and manufacturing. Journal of Power Sources, 114(1), 32-53. doi:10.1016/s0378-7753(02)00542-6De las Heras, A., Vivas, F. J., Segura, F., Redondo, M. J., & Andújar, J. M. (2018). Air-cooled fuel cells: Keys to design and build the oxidant/cooling system. Renewable Energy, 125, 1-20. doi:10.1016/j.renene.2018.02.077Kandlikar, S. G., & Lu, Z. (2009). Thermal management issues in a PEMFC stack – A brief review of current status. Applied Thermal Engineering, 29(7), 1276-1280. doi:10.1016/j.applthermaleng.2008.05.009Yan, Q., Toghiani, H., & Causey, H. (2006). Steady state and dynamic performance of proton exchange membrane fuel cells (PEMFCs) under various operating conditions and load changes. Journal of Power Sources, 161(1), 492-502. doi:10.1016/j.jpowsour.2006.03.077Maghanki, M. M., Ghobadian, B., Najafi, G., & Galogah, R. J. (2013). Micro combined heat and power (MCHP) technologies and applications. Renewable and Sustainable Energy Reviews, 28, 510-524. doi:10.1016/j.rser.2013.07.053Notter, D. A., Kouravelou, K., Karachalios, T., Daletou, M. K., & Haberland, N. T. (2015). Life cycle assessment of PEM FC applications: electric mobility and μ-CHP. Energy & Environmental Science, 8(7), 1969-1985. doi:10.1039/c5ee01082aMartinez, S., Michaux, G., Salagnac, P., & Bouvier, J.-L. (2017). Micro-combined heat and power systems (micro-CHP) based on renewable energy sources. Energy Conversion and Management, 154, 262-285. doi:10.1016/j.enconman.2017.10.035Elmer, T., Worall, M., Wu, S., & Riffat, S. B. (2015). Fuel cell technology for domestic built environment applications: State of-the-art review. Renewable and Sustainable Energy Reviews, 42, 913-931. doi:10.1016/j.rser.2014.10.080Hawkes, A., Staffell, I., Brett, D., & Brandon, N. (2009). Fuel cells for micro-combined heat and power generation. Energy & Environmental Science, 2(7), 729. doi:10.1039/b902222hEllamla, H. R., Staffell, I., Bujlo, P., Pollet, B. G., & Pasupathi, S. (2015). Current status of fuel cell based combined heat and power systems for residential sector. Journal of Power Sources, 293, 312-328. doi:10.1016/j.jpowsour.2015.05.050Strahl, S., & Costa-Castelló, R. (2017). Temperature control of open-cathode PEM fuel cells. IFAC-PapersOnLine, 50(1), 11088-11093. doi:10.1016/j.ifacol.2017.08.2492Zhang, G., & Kandlikar, S. G. (2012). A critical review of cooling techniques in proton exchange membrane fuel cell stacks. International Journal of Hydrogen Energy, 37(3), 2412-2429. doi:10.1016/j.ijhydene.2011.11.010Navarro Gimenez, S., Herrero Dura, J. M., Blasco Ferragud, F. X., & Simarro Fernandez, R. (2019). Control-Oriented Modeling of the Cooling Process of a PEMFC-Based $\mu$ -CHP System. IEEE Access, 7, 95620-95642. doi:10.1109/access.2019.2928632Herrero, J. M., García-Nieto, S., Blasco, X., Romero-García, V., Sánchez-Pérez, J. V., & Garcia-Raffi, L. M. (2008). Optimization of sonic crystal attenuation properties by ev-MOGA multiobjective evolutionary algorithm. Structural and Multidisciplinary Optimization, 39(2), 203-215. doi:10.1007/s00158-008-0323-7Bristol, E. (1966). On a new measure of interaction for multivariable process control. IEEE Transactions on Automatic Control, 11(1), 133-134. doi:10.1109/tac.1966.1098266Blasco, X., Herrero, J. M., Sanchis, J., & Martínez, M. (2008). A new graphical visualization of n-dimensional Pareto front for decision-making in multiobjective optimization. Information Sciences, 178(20), 3908-3924. doi:10.1016/j.ins.2008.06.010Schmittinger, W., & Vahidi, A. (2008). A review of the main parameters influencing long-term performance and durability of PEM fuel cells. Journal of Power Sources, 180(1), 1-14. doi:10.1016/j.jpowsour.2008.01.07

Validation of a new methodological approach for the selection of wire-coil inserts in thermal equipment

The use of wire-coils is especially relevant at low Reynolds numbers (below the critical number to turbulent flow in smooth tubes) according to its inherent positive features such as the advance of transition onset and, if they present suitable geometric characteristics, the establishment of an extended transitional flow in a critical Reynolds number interval [ReCL − ReCT ], with a predictable friction coefficient and Nusselt number. This paper presents the experimental validation of a new methodology based on the evaluation of a non-dimensional geometry-based parameter: the TSP (Transition Shape Parameter) that allows to predict the friction coefficient evolution with wire-coil inserts and enables to compute the extension of the transitional flow region. The close relationship between hydraulic and thermal performance of wire-coil inserts makes this methodology a valuable tool for selecting the most appropriate wire-coil geometry for a given tubular heat exchanger. It is observed that to promote an increase in heat transfer, the value of the ReCL of the wire coil must be less than the operating Reynolds number range of the equipment. Thus, the ReCL − ReCT interval of the insert should fall into this range. In order to validate the methodological approach, an application to harp-type solar thermal collectors with typical Reynolds number range [40–6000] is presented. Four representative wire-coils, with a wide geometrical range characterized by TSP values of 759, 196, 35.3 and 3.1 (exhibiting significant differentiated behaviours in their friction factor curves and critical Reynolds numbers) were inserted inside the risers of a modified solar collector and experimentally tested at laboratory conditions. Static temperature at different locations at the absorber plate, and pressure drop were measured to obtain friction factor and Nusselt number inside riser covering the laminar, transitional and low-turbulent regions. For a general application with friction factor constraints the most suitable wire-coil geometry is the TSPW02 = 196 with a range of critical Reynolds number of ReCL = 663 and ReCT = 2286 and Nuw02/Nus = 2.21 for Re = [300 − 3000] with f w02/fs = 3, 82. However, for the case study presented (a harp-type solar collector) it is feasible to insert the third wire-coil geometry TSPW03 = 35.3 due to its early transition, with a range of critical Reynolds number of ReCL = 364 and ReCT = 2324, and Nuw/Nus = 1.35 for Re = 300 with a high friction factor augmentation f w03/fs = 18.84. This geometry also promotes the highest absorber temperature reduction. The greatest temperature reduction is observed in the range of Reynolds numbers [700–2000], reaching approximately 6 ◦C, which represents approximately 15 %The authors gratefully acknowledge to European Regional Development Fund and Ministerio de Ciencia e Innovación - Agencia Estatal de Investigación for the financial support of the project ALTES: “Active Latent Thermal Energy Storage”, Ref. PGC2018-100864-B-C21

Nonparametric frequency response identification for Dc-Dc converters based on spectral analysis with automatic determination of the perturbation amplitude

Digital control for high switching frequency converter enables new features on DC-DC power conversion for a minimum cost. Frequency response identification is one such enabled functionality used in auto tunning, measurement of components to assess the converter’s state of health, or system stability monitoring. High accuracy, flexibility to operate in open or closed loop, and minimum impact in the converter’s regular operation are the frequency response identification system’s goals. We propose in this paper a nonparametric identification system addressing these main goals. First, it can autoadjust the perturbation size to reduce the perturbation’s impact on the converter’s output quantities. Second, as it is based on spectral analysis, it is suitable for open and closed-loop operation. Third, we demonstrate the identification system’s high accuracy, achieving a very low difference between the experimental measurements and the discrete model used as reference.This research was founded by the Spanish Ministry of Ciencia, Innovacióon y Universidades and FEDER funds through the research project EPIIOT under Grant DPI2017-88062-R, and by the Madrid Government (Comunidad de Madrid-Spain) under the Multiannual Agreement with UC3M in the line of Excellence of University Professors (EPUC3M26), and in the context of the V PRICIT (Regional Programme of Research and Technological Innovation)

Non-inverting and Non-isolated Magnetically Coupled Buck-Boost Bidirectional DC-DC Converter

A new non-isolated DC-DC converter with non-inverting output and buck-boost operation, named Magnetically Coupled Buck-Boost Bidirectional converter (MCB³), is presented in this paper. The MCB³ passive components arrangement connects the input and output ports getting an equivalent behavior to that of the Dual Active Bridge (DAB) converter, but in a non-isolated topology. This equivalency allows applying Triple Phase Shift (TPS) modulation to MCB³. TPS is known to minimize conduction losses and to achieve soft-switching at any load in the DAB converter. Throughout the paper, the features of the DAB converter are used as a reference to show the main features of the proposed converter. Moreover, other modulation strategies based on TPS modulation are used in MCB³ to operate within the minimum losses path.The multiple operation modes found on the MCB³ under TPS modulation are identified, classified, and used to find the operating points that minimize the switching and conduction losses over the power range. The analysis is shown for the boost mode that is the worst-case design. MCB³ and DAB topologies are designed and simulated for the same specification to validate the theoretical study. Finally, experimental measurements on 460W-prototypes for both topologies corroborate the equivalent operation and the main features of the MCB³.This work was supported in part by the Ministry of Economy and Competitiveness and ERDF funds through the Research Project “Energy Storage and Management System for Hybrid Electric Cars based on Fuel Cell, Battery and Supercapacitors” ELECTRICAR-AG- (DPI2014-53685-C2-1-R), and in part by the Research Projects CONEXPOT (DPI2017-84572-C2-2-R) and EPIIOT (DPI2017-88062-R

R-RAS2 overexpression in tumors of the human central nervous system

Malignant tumors of the central nervous system (CNS) are the 10th most frequent cause of cancer mortality. Despite the strong malignancy of some such tumors, oncogenic mutations are rarely found in classic members of the RAS family of small GTPases. This raises the question as to whether other RAS family members may be affected in CNS tumors, excessively activating RAS pathways. The RAS-related subfamily of GTPases is that which is most closely related to classical Ras and it currently contains 3 members: RRAS, RRAS2 and RRAS3. While R-RAS and R-RAS2 are expressed ubiquitously, R-RAS3 expression is restricted to the CNS. Significantly, both wild type and mutated RRAS2 (also known as TC21) are overexpressed in human carcinomas of the oral cavity, esophagus, stomach, skin and breast, as well as in lymphomas. Hence, we analyzed the expression of R-RAS2 mRNA and protein in a wide variety of human CNS tumors and we found the R-RAS2 protein to be overexpressed in all of the 90 CNS cancer samples studied, including glioblastomas, astrocytomas and oligodendrogliomas. However, R-Ras2 was more strongly expressed in low grade (World Health Organization grades I-II) rather than high grade (grades III-IV) tumors, suggesting that R-RAS2 is overexpressed in the early stages of malignancy. Indeed, R-RAS2 overexpression was evident in pre-malignant hyperplasias, both at the mRNA and protein levels. Nevertheless, such dramatic changes in expression were not evident for the other two subfamily members, which implies that RRAS2 is the main factor triggering neural transformation.This work was supported by grants SAF2012-31279 from the ‘Comisión Interministerial de Ciencia y Tecnología’ and the ‘Ramón y Cajal’ program (RYC-2010-06251, to B.C.). We also thank the Fundación Ramón Areces for its institutional support of the ‘Centro de Biología Molecular Severo Ochoa’

Wind speed description and power density in northern Spain

Wind resources are increasingly being investigated as a clean alternative for generating energy. This paper analyses the daily wind speed recorded at 46 automatic weather stations located in Navarre, northern Spain, in 2005e2015. Key points are the surface density of stations and the range of time that ensure a faithful depiction of wind speed together with surface calculations from image analysis and correlation with height. Different statistics were used. Median wind speed at 10 m was low, about 3.3 m s 1 and its interquartile range was narrow, about 2.3 m s 1. Nearly half the surface shows a median wind speed above 3.0 m s 1. The method of moments was employed to calculate the parameters of the Weibull distribution. Around half of the surface presented a shape parameter above 2.25 and the scale parameter was above 4 m s 1 for nearly 41% of the region. Although wind resources are not suitable for wind turbine applications in most of the region, since the wind speed is low in low-lying areas, about 12% of the region is suitable for stand-alone applications and, moreover, a substantial part of the region, around 23%, presents satisfactory wind resources for the installation of wind turbines.Ministry of Economy and Competitiveness and ERDF funds (project numbers CGL2009-11979 and CGL2014-53948-P

General Analysis of Switching Modes in a Dual Active Bridge with Triple Phase Shift Modulation

This paper provides an exhaustive analysis of the Dual-Active-Bridge with Triple-Phase-Shift (DAB-TPS) modulation and other simpler ones, identifying all the possible switching modes to operate the DAB in both power flow directions, and for any input-to-output voltage range and output power. This study shows four cases and seven switching modes for each case when the energy flows in one direction. That means that the DAB operates up to fifty-six different switching modes when the energy flows in both directions. Analytical expressions for the inductor current, the output power, and the boundaries between switching modes are provided for all cases. Additionally, the combination of control variables to achieve Zero-Voltage-Switching (ZVS) or Zero-Current-Switching (ZCS) is provided for each case and switching mode, by showing which switching modes obtain ZVS or ZCS for the whole power range and all switches—independent of the input-to-output voltage ratio. Therefore, the most interesting cases, switching mode and modulation for using the DAB are identified. Additionally, experimental validation has been carried out with a 250 W prototype. This analysis is a proper tool to design the DAB in the optimum switching mode, reducing the RMS current and achieving to increase efficiency and the power density.This research was funded by the Spanish Ministry of Economy and Competitiveness and ERDF, grant number DPI2014-53685-C2-1-R