Nanoparticle-Catalyzed Transamination under Tumor Microenvironment Conditions: A Novel Tool to Disrupt the Pool of Amino Acids and GSSG in Cancer Cells.

Catalytic cancer therapy targets cancer cells by exploiting the specific characteristics of the tumor microenvironment (TME). TME-based catalytic strategies rely on the use of molecules already present in the TME. Amino groups seem to be a suitable target, given the abundance of proteins and peptides in biological environments. Here we show that catalytic CuFe2O4 nanoparticles are able to foster transaminations with different amino acids and pyruvate, another key molecule present in the TME. We observed a significant in cellulo decrease in glutamine and alanine levels up to 48 h after treatment. In addition, we found that di- and tripeptides also undergo catalytic transamination, thereby extending the range of the effects to other molecules such as glutathione disulfide (GSSG). Mechanistic calculations for GSSG transamination revealed the formation of an imine between the oxo group of pyruvate and the free -NH2 group of GSSG. Our results highlight transamination as alternative to the existing toolbox of catalytic therapies.

Cellular Alterations Due to Direct and Indirect Interaction of Nanomaterials with Nucleic Acids.

Deoxyribonucleic acid (DNA) represents the main reservoir of genetic information in the cells, which is why it is protected in the nucleus. Entry into the nucleus is, in general, difficult, as the nuclear membrane is a selective barrier to molecules longer than 40 kDa. However, in some cases, the size of certain nanoparticles (NPs) allows their internalization into the nucleus, thus causing a direct effect on the DNA structure. NPs can also induce indirect effects on DNA through reactive oxygen species (ROS) generation. In this context, nanomaterials are emerging as a disruptive tool for the development of novel therapies in a broad range of biomedical fields; although their effect on cell viability is commonly studied, further interactions with DNA or indirect alterations triggered by the internalization of these materials are not always clarified, since the small size of these materials makes them perfectly suitable for interaction with subcellular structures, such as the nucleus. In this context, and using as a reference the predicted interactions presented in a computational model, we describe and discuss the observed direct and indirect effects of the implicated nanomaterials on DNA.

Nanomedicine Targeting Cuproplasia in Cancer: Labile Copper Sequestration Using Polydopamine Particles Blocks Tumor Growth In Vivo through Altering Metabolism and Redox Homeostasis.

Copper plays critical roles as a metal active site cofactor and metalloallosteric signal for enzymes involved in cell proliferation and metabolism, making it an attractive target for cancer therapy. In this study, we investigated the efficacy of polydopamine nanoparticles (PDA NPs), classically applied for metal removal from water, as a therapeutic strategy for depleting intracellular labile copper pools in triple-negative breast cancer models through the metal-chelating groups present on the PDA surface. By using the activity-based sensing probe FCP-1, we could track the PDA-induced labile copper depletion while leaving total copper levels unchanged and link it to the selective MDA-MB-231 cell death. Further mechanistic investigations revealed that PDA NPs increased reactive oxygen species (ROS) levels, potentially through the inactivation of superoxide dismutase 1 (SOD1), a copper-dependent antioxidant enzyme. Additionally, PDA NPs were found to interact with the mitochondrial membrane, resulting in an increase in the mitochondrial membrane potential, which may contribute to enhanced ROS production. We employed an in vivo tumor model to validate the therapeutic efficacy of PDA NPs. Remarkably, in the absence of any additional treatment, the presence of PDA NPs alone led to a significant reduction in tumor volume by a factor of 1.66 after 22 days of tumor growth. Our findings highlight the potential of PDA NPs as a promising therapeutic approach for selectively targeting cancer by modulating copper levels and inducing oxidative stress, leading to tumor growth inhibition as shown in these triple-negative breast cancer models.

Superfluorinated Extracellular Vesicles for In Vivo Imaging by 19F-MRI.

Extracellular vesicles (EVs) play a crucial role in cell-to-cell communication and have great potential as efficient delivery vectors. However, a better understanding of EV in vivo behavior is hampered by the limitations of current imaging tools. In addition, chemical labels present the risk of altering the EV membrane features and, thus, in vivo behavior. 19F-MRI is a safe bioimaging technique providing selective images of exogenous probes. Here, we present the first example of fluorinated EVs containing PERFECTA, a branched molecule with 36 magnetically equivalent 19F atoms. A PERFECTA emulsion is given to the cells, and PERFECTA-containing EVs are naturally produced. PERFECTA-EVs maintain the physicochemical features, morphology, and biological fingerprint as native EVs but exhibit an intense 19F-NMR signal and excellent 19F relaxation times. In vivo 19F-MRI and tumor-targeting capabilities of stem cell-derived PERFECTA-EVs are also proved. We propose PERFECTA-EVs as promising biohybrids for imaging biodistribution and delivery of EVs throughout the body.

Unveiling the interplay between homogeneous and heterogeneous catalytic mechanisms in copper-iron nanoparticles working under chemically relevant tumour conditions.

The present work sheds light on a generally overlooked issue in the emerging field of bio-orthogonal catalysis within tumour microenvironments (TMEs): the interplay between homogeneous and heterogeneous catalytic processes. In most cases, previous works dealing with nanoparticle-based catalysis in the TME focus on the effects obtained (e.g. tumour cell death) and attribute the results to heterogeneous processes alone. The specific mechanisms are rarely substantiated and, furthermore, the possibility of a significant contribution of homogeneous processes by leached species - and the complexes that they may form with biomolecules - is neither contemplated nor pursued. Herein, we have designed a bimetallic catalyst nanoparticle containing Cu and Fe species and we have been able to describe the whole picture in a more complex scenario where both homogeneous and heterogeneous processes are coupled and fostered under TME relevant chemical conditions. We investigate the preferential leaching of Cu ions in the presence of a TME overexpressed biomolecule such as glutathione (GSH). We demonstrate that these homogeneous processes initiated by the released by Cu-GSH interactions are in fact responsible for the greater part of the cell death effects found (GSH, a scavenger of reactive oxygen species, is depleted and highly active superoxide anions are generated in the same catalytic cycle). The remaining solid CuFe nanoparticle becomes an active catalyst to supply oxygen from oxygen reduced species, such as superoxide anions (by-product from GSH oxidation) and hydrogen peroxide, another species that is enriched in the TME. This activity is essential to sustain the homogeneous catalytic cycle in the oxygen-deprived tumour microenvironment. The combined heterogeneous-homogeneous mechanisms revealed themselves as highly efficient in selectively killing cancer cells, due to their higher GSH levels compared to healthy cell lines.

Transfer of photothermal nanoparticles using stem cell derived small extracellular vesicles for in vivo treatment of primary and multinodular tumours.

The main current challenges in oncology are (1) avoiding systemic side effects in therapy, and (2) developing alternative treatment strategies for metastatic tumours. Nanomedicine was assumed to provide answers to these issues, but delivering enough therapeutic nanoparticles (NPs) to tumours still remains a huge challenge in nanomaterials-based treatments. Extracellular vesicles (EVs) play a key role in cell communication processes and can be combined with nanomaterials to improve their targeting capabilities. In this work, we leverage the ability of EVs derived from stem cells to reach tumour areas successfully, being used as delivery vehicles for nanoparticles acting as hyperthermia agents. Once small extracellular vesicles (sEVs) loaded with NIR-sensitive hollow gold NPs reached primary subcutaneous solid tumours, they were irradiated with a NIR laser and almost complete tumour remission was obtained. More interestingly, those sEV vehicles were also able to reach multinodular areas similar to those on advanced metastatic phases, eradicating most tumour growth regions in multiple cancerous nodules located in the pancreas region.

Six Collective Challenges for Sustainability of Almería Greenhouse Horticulture.

Globally, current food consumption and trade are placing unprecedented demand on agricultural systems and increasing pressure on natural resources, requiring tradeoffs between food security and environmental impacts especially given the tension between market-driven agriculture and agro-ecological goals. In order to illustrate the wicked social, economic and environmental challenges and processes to find transformative solutions, we focus on the largest concentration of greenhouses in the world located in the semi-arid coastal plain of South-east Spain. Almería family farming, predominantly cooperative, greenhouse intensive production, commenced after the 1960s and has resulted in very significant social and economic benefits for the region, while also having important negative environmental and biodiversity impacts, as well as creating new social challenges. The system currently finds itself in a crisis of diminishing economic benefits and increasing environmental and social dilemmas. Here, we present the outcomes of multi-actor, transdisciplinary research to review and provide collective insights for solutions-oriented research on the sustainability of Almeria's agricultural sector. The multi-actor, transdisciplinary process implemented collectively, and supported by scientific literature, identified six fundamental challenges to transitioning to an agricultural model that aims to ameliorate risks and avoid a systemic collapse, whilst balancing a concern for profitability with sustainability: (1) Governance based on a culture of shared responsibility for sustainability, (2) Sustainable and efficient use of water, (3) Biodiversity conservation, (4) Implementing a circular economy plan, (5) Technology and knowledge transfer, and (6) Image and identity. We conclude that the multi-actor transdisciplinary approach successfully facilitated the creation of a culture of shared responsibility among public, private, academic, and civil society actors. Notwithstanding plural values, challenges and solutions identified by consensus point to a nascent acknowledgement of the strategic necessity to locate agricultural economic activity within social and environmental spheres.This paper demonstrates the need to establish transdisciplinary multi-actor work-schemes to continue collaboration and research for the transition to an agro-ecological model as a means to remain competitive and to create value.

Recomendaciones para aplicar la terapia de observación acción en accidente cerebrovascular. Revisión de la literatura / Recommendation for appliying action observation therapy in stroke. Literature review

Objetivos: unificar los criterios para la aplicación clínica de la terapia de observación de acción en accidente cerebrovascular. Métodos: realizamos una revisión bibliográfica en los meses de febrero y marzo de 2023, incluyendo siete artículos que cumplían los criterios de selección. Resultados: tras analizar los estudios, la mayoría utiliza la terapia de observación acción para tratar pacientes con accidente cerebrovascular sin otras patologías añadidas, realizando valoración del miembro superior parético, con proyección de vídeos, y ejecución de las actividades o actos motores tras su visualización. Conclusiones: se unifican los criterios con el uso de la técnica en pacientes con un primer accidente cerebrovascular unilateral, sin patologías añadidas que afecten a su aplicación; valorando las capacidades y funcionalidad de los pacientes; visualizando vídeos de actos motores o tares funcionales proyectados en primera persona, y ejecutando las tareas observadas, con el apoyo verbal o físico del terapeuta si es necesario.(AU)

Objective: unify the criteria for the clinical application of action observation therapy in stroke. Methods: we carried out a bibliographic review in the months of February and March 2023, including seven articles that met the selection criteria. Results: after analyzing the studies, the majority use action observation therapy to treat patients with stroke without other added pathologies, carrying out assessment of the paretic upper limb, with video projection, and execution of the activities or motor acts after viewing them. Conclusions: the criteria are unified with the use of the technique in patients with a first unilateral stroke, without additional pathologies that affect its application; assessing the abilities and functionality of patients; viewing videos of motor acts or functional tasks projected in first person, and executing the observed tasks, with the therapist's verbal or physical support if necessary.(AU)

An evaluation by potential IVF/Donor Oocyte patients of the Use and Handling of the Bemfola® Pen compared with the Gonal-f® Pen and Puregon Pen® / Evaluación del uso y manejo de la pluma Bemfola® en comparación con el de la pluma Gonal-f® y la pluma Puregon® en pacientes potenciales de FIV/ donantes de ovocitos

BACKGROUND: Since the 1990s recombinant human FSH (r-hFSH), such as Gonal-f® and Puregon®, have been in widespread use for fertility treatment [1]. More recently Bemfola®, biosimilar to r-hFSH, has been introduced with similar efficacy and safety to Gonal-f® [2], but delivered in a novel, innovative injector pen system (Reddot design award 2011). The Bemfola® pen (BP) is a single-use, disposable pen available in five different presentations (i.e., 75IU, 150IU, 225IU, 300IU and 450IU), each of which provides a range of doses that it can deliver. Non-compliance to hormonal treatment regimens might be a critical issue to reach therapeutic goals. The use of pens by patients is often limited by factors such as fear of injection, but can be also related to the device itself [3-6]. Therefore, easy-to-use devices may also positively influence physicians» hormonal prescribing habits and patient's compliance. Accordingly, this user acceptance study aimed to assess the use of the Bemfola® pen in a population of potential users with regard to the easiness and convenience of handling of the Bemfola® Pen in comparison to the Gonal-f® pen and Puregon® pen. Material and Methods Randomised and single-blind study with three-arm user test. The investigation was conducted in females who considered undergoing hormonal treatment for the first time (naïve) and who were considering to start an IVF or donor egg treatment cycle. A total of 10 centers from Spain participated in this investigation. This study of user acceptance included 460 females qualifying for potential patients considering a therapy with follicle stimulating hormone. Users received the three pens in a randomized, consecutive sequence, completed for each of the pen one questionnaire (same for all 3 pens) and thereafter completed a concluding questionnaire comparing the handling, convenience and indicating their preference among the 3 pens. No self-injections were performed and an application pad for injections was used. Results The Bemfola® pen showed the highest scorings and strong preferences in all pen features assessed and achieved the highest proportion of best choice compared to both the Gonal-f® and Puregon®. pen. Conclusions The results indicated significant preferences of women, who intended to undergo a hormonal treatment, for the Bemfola® pen compared to both the Puregon® pen and the Gonal-f® pen

ANTECEDENTES: Desde la década de los noventa, la hormona foliculoestimulante humana recombinante (hFSH-r) como Gonal-f® y Puregon®, se ha utilizado ampliamente en el tratamiento de la fertilidad [1]. Más recientemente se ha introducido Bemfola®, biosimilar de la hFSH-r con eficacia y seguridad similar a Gonal-f® [2], pero desarrollada con un innovador sistema de pluma inyectora (premio de diseño Reddot, 2011). Bemfola® es una pluma precargada desechable de un solo uso, disponible en cinco presentaciones diferentes (75 UI, 150 UI, 225 UI, 300 UI y 450 UI), cada una de las cuales proporciona un rango de dosis determinado. El no-cumplimiento de las pautas de tratamiento hormonal es un problema fundamental en la consecución de los objetivos terapéuticos. El uso de plumas por las pacientes se ve a menudo limitado por el miedo a la inyección e incluso relacionado con el propio dispositivo [3-6]. Por tanto, los dispositivos de fácil uso pueden influir positivamente tanto en los hábitos de prescripción de terapias hormonales de los médicos como en el cumplimiento del paciente. En consecuencia, el objetivo de este estudio consiste en evaluar el uso de Bemfola® en una población de usuarias potenciales con respecto a la facilidad, y conveniencia en su manejo en comparación con las plumas Gonal-f® y Puregon®. Material y Métodos Estudio aleatorizado y simple ciego de tres ramas de tratamiento. Esta investigación se llevó a cabo en mujeres sin tratamiento previo que estaban considerando bien iniciar un ciclo de FIV o bien ser donantes de ovocitos. En este estudio participaron 10 centros de fertilidad de España. Se incluyeron 460 mujeres cualificadas para ser «pacientes potenciales de terapia hormonal con hormona foliculoestimulante humana recombinante» Las usuarias recibieron las tres plumas (Bemfola®, Gonal-f® y Puregon®) en una secuencia aleatoria y consecutiva, y completaron un cuestionario idéntico por cada una de las plumas, y un cuestionario de conclusión con el fin de comparar el manejo, la comodidad y la preferencia de las tres plumas. En ningún caso se realizaron auto-inyecciones y en su lugar se utilizó una almohadilla de aplicación de inyecciones. Resultados La pluma Bemfola® mostró la mayor puntuación y elevadas preferencias en todas las características evaluadas, y alcanzó la mayor proporción de «mejor» opción en comparación con la pluma Gonal-f® y la pluma Puregon®. Conclusiones Los resultados mostraron preferencias significativas de mujeres que tenían la intención de someterse a un tratamiento hormonal, para la pluma Bemfola® en comparación con las plumas Gonal-f® y Puregon®

Evaluación del uso y manejo de la pluma Bemfola® en comparación con el de la pluma Gonal-f® y la pluma Puregon® en pacientes potenciales de FIV/ donantes de ovocitos / An evaluation by potential IVF/Donor Oocyte patients of the Use and Handling of the Bemfola® Pen compared with the Gonal-f® Pen and Puregon Pen®

ANTECEDENTES: Desde la década de los noventa, la hormona foliculoestimulante humana recombinante (hFSH-r) como Gonal-f® y Puregon®, se ha utilizado ampliamente en el tratamiento de la fertilidad [1]. Más recientemente se ha introducido Bemfola®, biosimilar de la hFSH-r con eficacia y seguridad similar a Gonal-f® [2], pero desarrollada con un innovador sistema de pluma inyectora (premio de diseño Reddot, 2011). Bemfola® es una pluma precargada desechable de un solo uso, disponible en cinco presentaciones diferentes (75 UI, 150 UI, 225 UI, 300 UI y 450 UI), cada una de las cuales proporciona un rango de dosis determinado. El no-cumplimiento de las pautas de tratamiento hormonal es un problema fundamental en la consecución de los objetivos terapéuticos. El uso de plumas por las pacientes se ve a menudo limitado por el miedo a la inyección e incluso relacionado con el propio dispositivo [3-6]. Por tanto, los dispositivos de fácil uso pueden influir positivamente tanto en los hábitos de prescripción de terapias hormonales de los médicos como en el cumplimiento del paciente. En consecuencia, el objetivo de este estudio consiste en evaluar el uso de Bemfola® en una población de usuarias potenciales con respecto a la facilidad, y conveniencia en su manejo en comparación con las plumas Gonal-f® y Puregon®. Material y MÉTODOS: Estudio aleatorizado y simple ciego de tres ramas de tratamiento. Esta investigación se llevó a cabo en mujeres sin tratamiento previo que estaban considerando bien iniciar un ciclo de FIV o bien ser donantes de ovocitos. En este estudio participaron 10 centros de fertilidad de España. Se incluyeron 460 mujeres cualificadas para ser «pacientes potenciales de terapia hormonal con hormona foliculoestimulante humana recombinante». Las usuarias recibieron las tres plumas (Bemfola®, Gonal-f® y Puregon®) en una secuencia aleatoria y consecutiva, y completaron un cuestionario idéntico por cada una de las plumas, y un cuestionario de conclusión con el fin de comparar el manejo, la comodidad y la preferencia de las tres plumas. En ningún caso se realizaron auto-inyecciones y en su lugar se utilizó una almohadilla de aplicación de inyecciones. RESULTADOS: La pluma Bemfola® mostró la mayor puntuación y elevadas preferencias en todas las características evaluadas, y alcanzó la mayor proporción de «mejor» opción en comparación con la pluma Gonal-f® y la pluma Puregon®. CONCLUSIONES: Los resultados mostraron preferencias significativas de mujeres que tenían la intención de someterse a un tratamiento hormonal, para la pluma Bemfola® en comparación con las plumas Gonal-f® y Puregon®

BACKGROUND: Since the 1990s recombinant human FSH (r-hFSH), such as Gonal-f® and Puregon®, have been in widespread use for fertility treatment [1]. More recently Bemfola® has been introduced with familiar efficacy and safety to Gonal-f® [2], but delivered in a novel, innovative injector pen system (Reddot design award 2011). The Bemfola® pen (BP) is a singleuse, disposable pen available in five different presentations (i.e., 75IU, 150IU, 225IU, 300IU and 450IU), each of which provides a range of doses that it can deliver. Non-compliance to hormonal treatment regimens might be a critical issue to reach therapeutic goals. The use of pens by patients is often limited by factors such as fear of injection, but can be also related to the device itself [3-6]. Therefore, easy-to-use devices may also positively influence physicians' hormonal prescribing habits and patient's compliance. Accordingly, this user acceptance study aimed to assess the use of the Bemfola® pen in a population of potential users with regard to the easiness and convenience of handling of the Bemfola® Pen in comparison to the Gonal-f® pen and Puregon® pen. Material and methods Randomised and single-blind study with three-arm user test. The investigation was conducted in females who considered undergoing hormonal treatment for the first time (naïve) and who were considering to start an IVF or donor egg treatment cycle. A total of two 10 centres from Spain participated in this investigation. This study of user acceptance included 460 females qualifying for potential patients considering a therapy with follicle stimulating hormone. Users received the three pens in a randomized, consecutive sequence, complete for each of the pen one questionnaire (same for all 3 pens) and thereafter complete a concluding questionnaire comparing the handling, convenience and indicating their preference among the 3 pens. No self-injections were performed and an application pad for injections was used. Results The Bemfola® pen showed the highest scorings and strong preferences in all pen features assessed and achieved the highest proportion of best choice compared to both, the Gonal-f® and Puregon® pen. Conclusions The results indicated significant preferences of women, who intended to undergo a hormonal treatment, for the Bemfola® pen compared to both the Puregon® pen and the Gonal-f® pen