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Nowadays, hyaluronic acid (HA) eye drops are widely used to combat ophthalmic dry eye disease (DED). Till the date, almost all commercialized HA eye drops are single-ingredient despite not displaying significantly different clinical effects (Artelac Splash®). Consequently, scientists are making great efforts to combine HA with other compounds to overcome more successfully DED (trometamol in Hyabak®, sorbitol in HyloComod®). Gamma-polyglutamic acid (γ-PGA) is another novel polymer that could induce a powerful synergistic effect on HA for DED treatment. To the best of our knowledge, eye drops combining HA and γ-PGA neither have been marketed nor scientific studies have been published so far. Fortunately, DayDrop Advanced® eye drop has been recently commercialized with HA + γ-PGA technology. In this work, DayDrop Advanced®, Hyabak®, HyloComod® and Artelac Splash® were compared evaluating their efficacy to treat DED and residence time in eye due to their distinct physicochemical and rheological properties. As key research point, DayDrop Advanced® demonstrated an improved immediate hydration, protection against corneal dehydration, anti-inflammatory, anti-hyaluronidase and ocular mucoadhesion activities than the rest of artificial tears. These phenomena highlight new generation DayDrop Advanced® combining HA + γ-PGA technology as the leading eye drops to treat more durably and effectively DED.

Traditional wound dressings have not been able to satisfy the needs of the regenerative medicine biomedical area. With the aim of improving tissue regeneration, nanofiber-based wound dressings fabricated by electrospinning (ES) processes have emerged as a powerful approach. Nowadays, nanofiber-based bioactive dressings are mainly developed with a combination of natural and synthetic polymers, such as polycaprolactone (PCL) and chitosan (CHI). Accordingly, herein, PCL/CHI nanofibers have been developed with varying PCL:CHI weight ratios (9:1, 8:2 and 7:3) or CHI viscosities (20, 100 and 600 mPa·s) using a novel alternating current ES (ACES) process. Such nanofibers were thoroughly characterized by determining physicochemical and nanomechanical properties, along with wettability, absorption capacity and hydrolytic plus enzymatic stability. Furthermore, PCL/CHI nanofiber biological safety was validated in terms of cytocompatibility and hemocompatibility (hemolysis < 2%), in addition to a notable antibacterial performance (bacterial reductions of 99.90% for S. aureus and 99.91% for P. aeruginosa). Lastly, the enhanced wound healing activity of PCL/CHI nanofibers was confirmed thanks to their ability to remarkably promote cell proliferation, which make them ideal candidates for long-term applications such as wound dressings.

A significant number of people worldwide suffers from knee osteoarthritis (KOA), a chronic and painful disease that is linked to aging, traumatological events and sports medicine. Clinical research indicates that KOA exhibit an altered synovial fluid (SF) with lower endogenous hyaluronic acid (HA) concentration and viscoelastic properties. Nowadays, viscosupplementation by intra-articular HA injections is the most common treatment to restore endogenous HA performance in osteoarthritic SF. In this work, TrHCROSS®, Durolane®, Regenflex®Bio-plus and Monovisc® commercial crosslinked HA viscosupplements were compared in vitro against enzymatic degradation. As key research point, TrHCROSS® demonstrated a considerably increased enzymatic stability compared to the rest of examined viscosupplements, which highlights TrHCROSS® prolonged residence time in joint space reducing more durably and effectively osteoarthritic knee pain. Subsequently, an in-depth physicochemical characterization was realized to support efficacy and stability results of viscosupplements. All in all, TrHCROSS®, developed by SARE® technology, was found to be more successful in treating more durably and effectively KOA based on the remarkable outcomes of conducted trials, which were appropriate findings for the current research investigation.

The article presents the RuralYU university entrepreneurship project, developed by the Youth University Design (YUDesign) Spontaneous Generation (GE) group of the School of Design Engineering (ETSID), at the Polytechnic University of Valencia (UPV). RuralYU aspires to reduce rural depopulation in collaboration with university students, who, by carrying out academic work, cover specific needs with the aim of strengthening rural development. The idea of ​​an inter-university collaboration programme with the rural world arose after having won the Vodafone Foundation’s Project Lab 2021 national contest within the framework of GLOBAL CHANGE with the proposal “RuralLife4Good. Accommodation grant programme for the empowerment of rural environments”. The winning proposal, which was implemented as a pilot project in Ràfol de Salem during the 2021-2022 academic year, values ​​the importance of the university at the service of society, in this case as an axis of urgent and necessary activation to avoid rural abandonment.

Prostate-specific antigen (PSA) is the gold-standard marker to screen prostate cancer (PCa) nowadays. Unfortunately, its lack of specificity and sensitivity makes the identification of novel tools to diagnose PCa an urgent medical need. In this context, microRNAs (miRNAs) have emerged as potential sources of non-invasive diagnostic biomarkers in several pathologies. Therefore, this study was aimed at assessing for the first time the dysregulation of the whole plasma miRNome in PCa patients and its putative implication in PCa from a personalized perspective (i.e., obesity condition). Plasma miRNome from a discovery cohort (18 controls and 19 PCa patients) was determined using an Affymetrix-miRNA array, showing that the expression of 104 miRNAs was significantly altered, wherein six exhibited a significant receiver operating characteristic (ROC) curve to distinguish between control and PCa patients (area under the curve [AUC] = 1). Then, a systematic validation using an independent cohort (135 controls and 160 PCa patients) demonstrated that miR-107 was the most profoundly altered miRNA in PCa (AUC = 0.75). Moreover, miR-107 levels significantly outperformed the ability of PSA to distinguish between control and PCa patients and correlated with relevant clinical parameters (i.e., PSA). These differences were more pronounced when considering only obese patients (BMI > 30). Interestingly, miR-107 levels were reduced in PCa tissues versus non-tumor tissues (n = 84) and in PCa cell lines versus non-tumor cells. In vitro miR-107 overexpression altered key aggressiveness features in PCa cells (i.e., proliferation, migration, and tumorospheres formation) and modulated the expression of important genes involved in PCa pathophysiology (i.e., lipid metabolism [i.e., FASN] and splicing process). Altogether, miR-107 might represent a novel and useful personalized diagnostic and prognostic biomarker and a potential therapeutic tool in PCa, especially in obese patients.

Additive manufacturing (AM), frequently cited as three-dimensional (3D) printing, is a relatively new manufacturing technique for biofabrication, also called 3D manufacture with biomaterials and cells. Recent advances in this field will facilitate further improvement of personalized healthcare solutions. In this regard, tailoring several healthcare products such as implants, prosthetics, and in vitro models, would have been extraordinarily arduous beyond these technologies. Three-dimensional-printed structures with a multiscale porosity are very interesting manufacturing processes in order to boost the capability of composite scaffolds to generate bone tissue. The use of biomimetic hydroxyapatite as the main active ingredient for bioinks is a helpful approach to obtain these advanced materials. Thus, 3D-printed biomimetic composite designs may produce supplementary biological and physical benefits. Three-dimensional bioprinting may turn to be a bright solution for regeneration of bone tissue as it enables a proper spatio-temporal organization of cells in scaffolds. Different types of bioprinting technologies and essential parameters which rule the applicability of bioinks are discussed in this review. Special focus is made on hydroxyapatite as an active ingredient for bioinks design. The goal of such bioinks is to reduce the constraints of commonly applied treatments by enhancing osteoinduction and osteoconduction, which seems to be exceptionally promising for bone regeneration.

Drawing on the Sustainable Development Goals of the UN 2030 Agenda, the implementation of circular economy business models (CEBMs) is key for reducing the impacts of business production modes on the environment and is especially suited to, and necessary in, the bioeconomy sector. The purpose of this literature review article is to analyse how firms in this sector can achieve a higher level of circularity in their business models, and how this circularity is positive for the triple bottom line. Building on the theories of social capital, new institutionalism and the triple bottom line (TBL), this article proposes a model to better understand how forest bioeconomy firms can develop high-circularity business models that lead them to excel on the TBL. This study combines internal aspects of the business (e.g., social capital, dynamic capabilities, entrepreneurial orientation) with situational variables (social/cultural, regulatory, technological, economic/financial drivers) to explain the level of circularity of business models in bioeconomy firms, as a prior step to enhancing their TBL. The interactionist model proposed is new to the literature and improves our understanding of how the level of circularity of a BM can be enhanced. The propositions derived will help to structure and design future research.

Cement removal during hip or knee arthroplasty revision surgery is technically demanding and prone to severe complications such as periprosthetic fractures, incomplete cement removal, or perforations. Several alternative techniques have been developed to enable complete, accurate, and safe removal of cement from bone, including osteotomies and cortical windows, endoscopic instruments, ultrasound devices, lithotripsy, and laser-assisted removal. We describe a cement-on-cement technique with a sterile, single-use tool for cement removal. The cement is removed piece by piece using a specifically designed device, without osteotomies or cortical windows.

Granular polymer hydrogels based on dynamic covalent bonds are attracting a great deal of interest for the design of injectable biomaterials. Such materials generally exhibit shear-thinning behavior and properties of self-healing/recovery after the extrusion that can be modulated through the interactions between gel microparticles. Herein, bulk macro-hydrogels based on thiolated-hyaluronic acid were produced by disulphide bond formation using oxygen as oxidant at physiological conditions and gelation kinetics were monitored. Three different thiol substitution degrees (SD%: 65%, 30% and 10%) were selected for hydrogel formation and fully characterized as to their stability in physiological medium and morphology. Then, extrusion fragmentation technique was applied to obtain hyaluronic acid microgels with dynamic disulphide bonds that were subsequently sterilized by autoclaving. The resulting granular hyaluronic hydrogels were able to form stable filaments when extruded through a syringe. Rheological characterization and cytotoxicity tests allowed to assess the potential of these materials as injectable biomaterials. The application of extrusion fragmentation for the formation of granular hyaluronic hydrogels and the understanding of the relation between the autoclaving processes and the resulting particle size and rheological properties should expand the development of injectable materials for biomedical applications.

Somatostatin (SST), cortistatin (CORT), and their receptors (SSTR1-5/sst5TMD4-TMD5) comprise a multifactorial hormonal system involved in the regulation of numerous pathophysiological processes. Certain components of this system are dysregulated and play critical roles in the development/progression of different endocrine-related cancers. However, the presence and therapeutic role of this regulatory system in prostate cancer (PCa) remain poorly explored. Accordingly, we performed functional (proliferation/migration/colonies-formation) and mechanistic (Western-blot/qPCR/microfluidic-based qPCR-array) assays in response to SST and CORT treatments and CORT-silencing (using specific siRNA) in different PCa cell models [androgen-dependent (AD): LNCaP; androgen-independent (AI)/castration-resistant PCa (CRPC): 22Rv1 and PC-3], and/or in the normal-like prostate cell-line RWPE-1. Moreover, the expression of SST/CORT system components was analyzed in PCa samples from two different patient cohorts [internal (n = 69); external (Grasso, n = 88)]. SST and CORT treatment inhibited key functional/aggressiveness parameters only in AI-PCa cells. Mechanistically, antitumor capacity of SST/CORT was associated with the modulation of oncogenic signaling pathways (AKT/JNK), and with the significant down-regulation of critical genes involved in proliferation/migration and PCa-aggressiveness (e.g., MKI67/MMP9/EGF). Interestingly, CORT was highly expressed, while SST was not detected, in all prostate cell-lines analyzed. Consistently, endogenous CORT was overexpressed in PCa samples (compared with benign-prostatic-hyperplasia) and correlated with key clinical (i.e., metastasis) and molecular (i.e., SSTR2/SSTR5 expression) parameters. Remarkably, CORT-silencing drastically enhanced proliferation rate and blunted the antitumor activity of SST-analogues (octreotide/pasireotide) in AI-PCa cells. Altogether, we provide evidence that SST/CORT system and SST-analogues could represent a potential therapeutic option for PCa, especially for CRPC, and that endogenous CORT could act as an autocrine/paracrine regulator of PCa progression.

Introducción. El avance de la cirugía torácica abierta a cirugía torácica asistida por vídeo por tres puertos, y sus posteriores efectos en la recuperación de los pacientes, conllevó al desarrollo de la técnica por un solo puerto, que ha mostrado beneficios en el postoperatorio. El objetivo de este estudio fue comparar los resultados postquirúrgicos de los pacientes sometidos a pleurectomía parietal y decorticación pulmonar toracoscópica asistida por video monopuerto y los obtenidos por toracotomía convencional, en una clínica de cuarto nivel, entre 2016 y 2019. Métodos. Estudio descriptivo, en el que se incluyeron 79 pacientes llevados a pleurectomía parietal y decorticación pulmonar por toracoscopia asistida por vídeo monopuerto y 25 pacientes operados por toracotomía convencional. Se evaluaron variables sociodemográficas, clínicas y postoperatorias. Se utilizaron las pruebas de Chi2 o de Fisher y las pruebas t de Student y Mann Whitney. Resultados. La mediana de edad fue menor en el grupo de pacientes operados por toracotomía convencional (28 años, RIC: 26–48, p=0,0005). No hubo diferencia en los tiempos quirúrgicos. Se encontró menor intensidad del dolor y disminución en los días con tubo de tórax, uso de antibióticos, días de UCI y días de estancia hospitalaria en el grupo de pacientes operados por toracoscopia asistida por vídeo monopuerto (p

In recent decades, the expansion of economic activity has been accompanied by negative environmental impacts. In response, there have been dramatic changes worldwide in terms of an increased demand for environmentally friendly products and services. To achieve these eco-innovations, firms have sought to acquire knowledge and implement operational flexibility by cooperating with different agents such as universities through a value cocreation system that is also expected to enhance firms’ performance. Using a sample of 250 companies, the present paper examines the role of cooperation with universities in the development of diverse environmental innovations and building operational flexibility and, through this, improving firm performance. Results show that firms that value cooperation with universities develop a wider range of environmental innovations and increase their sales and benefits.

Hyaluronic acid (HA) injectable biomaterials are currently applied in numerous biomedical areas, beyond their use as dermal fillers. However, bacterial infections and painful inflammations are associated with healthcare complications that can appear after injection, restricting their applicability. Fortunately, HA injectable hydrogels can also serve as drug delivery platforms for the controlled release of bioactive agents with a critical role in the control of certain diseases. Accordingly, herein, HA hydrogels were crosslinked with 1 4-butanediol diglycidyl ether (BDDE) loaded with cefuroxime (CFX), tetracycline (TCN), and amoxicillin (AMX) antibiotics and acetylsalicylic acid (ASA) anti-inflammatory agent in order to promote antibacterial and anti-inflammatory responses. The hydrogels were thoroughly characterized and a clear correlation between the crosslinking grade and the hydrogels’ physicochemical properties was found after rheology, scanning electron microscopy (SEM), thermogravimetry (TGA), and differential scanning calorimetry (DSC) analyses. The biological safety of the hydrogels, expected due to the lack of BDDE residues observed in 1H-NMR spectroscopy, was also corroborated by an exhaustive biocompatibility test. As expected, the in vitro antibacterial and anti-inflammatory activity of the drug-loaded HA-BDDE hydrogels was confirmed against Staphylococcus aureus by significantly decreasing the pro-inflammatory cytokine levels.

Spontaneously formed hydrogels are attracting increasing interest as injectable or wound dressing materials because they do not require additional reactions or toxic crosslinking reagents. Highly valuable properties such as low viscosity before external application, adequate filmogenic capacity, rapid gelation and tissue adhesion are required in order to use them for those therapeutic applications. In addition, biocompatibility and biodegradability are also mandatory. Accordingly, biopolymers, such as hyaluronic acid (HA) and chitosan (CHI), that have shown great potential for wound healing applications are excellent candidates due to their unique physiochemical and biological properties, such as moisturizing and antimicrobial ability, respectively. In this study, both biopolymers were modified by covalent anchoring of catechol groups, and the obtained hydrogels were characterized by studying, in particular, their tissue adhesiveness and film forming capacity for potential skin wound healing applications. Tissue adhesiveness was related to o-quinone formation over time and monitored by visible spectroscopy. Consequently, an opposite effect was observed for both polysaccharides. As gelation advances for HA-CA, it becomes more adhesive, while competitive reactions of quinone in CHI-CA slow down tissue adhesiveness and induce a detriment of the filmogenic properties.

Background: Dysregulation of splicing variants (SVs) expression has recently emerged as a novel cancer hallmark. Although the generation of aberrant SVs (e.g. AR-v7/sst5TMD4/etc.) is associated to prostate-cancer (PCa) aggressiveness and/or castration-resistant PCa (CRPC) development, whether the molecular reason behind such phenomena might be linked to a dysregulation of the cellular machinery responsible for the splicing process [spliceosome-components (SCs) and splicing-factors (SFs)] has not been yet explored. Methods: Expression levels of 43 key SCs and SFs were measured in two cohorts of PCa-samples: 1) Clinically-localized formalin-fixed paraffin-embedded PCa-samples (n = 84), and 2) highly-aggressive freshly-obtained PCa-samples (n = 42). Findings: A profound dysregulation in the expression of multiple components of the splicing machinery (i.e. 7 SCs/19 SFs) were found in PCa compared to their non-tumor adjacent-regions. Notably, overexpression of SNRNP200, SRSF3 and SRRM1 (mRNA and/or protein) were associated with relevant clinical (e.g. Gleason score, T-Stage, metastasis, biochemical recurrence, etc.) and molecular (e.g. AR-v7 expression) parameters of aggressiveness in PCa-samples. Functional (cell-proliferation/migration) and mechanistic [gene-expression (qPCR) and protein-levels (western-blot)] assays were performed in normal prostate cells (PNT2) and PCa-cells (LNCaP/22Rv1/PC-3/DU145 cell-lines) in response to SNRNP200, SRSF3 and/or SRRM1 silencing (using specific siRNAs) revealed an overall decrease in proliferation/migration-rate in PCa-cells through the modulation of key oncogenic SVs expression levels (e.g. AR-v7/PKM2/XBP1s) and alteration of oncogenic signaling pathways (e.g. p-AKT/p-JNK). Interpretation: These results demonstrate that the spliceosome is drastically altered in PCa wherein SNRNP200, SRSF3 and SRRM1 could represent attractive novel diagnostic/prognostic and therapeutic targets for PCa and CRPC. Keywords: Prostate cancer, Splicing, Spliceosome, SNRNP200, SRSF3, SRRM1, Therapeutic target

A high adherence to a Mediterranean diet has been related to numerous beneficial effects in human health, including a lower incidence and mortality of prostate cancer (PCa). Olive oil is an important source of phenolic bioactive compounds, mainly hydroxytyrosol (HT), of this diet. Because of the growing interest of this compound and its derivatives as a cancer chemopreventive agent, we aimed to compare the in vitro effect of HT isolated from olive mill wastewaters and five semisynthetic alkyl ether, ester, and nitro-derivatives against prostate cancer (PCa) cell lines. The effect in cell proliferation was determined in RWPE-1, LNCaP, 22Rv1, and PC-3 cells by resazurin assay, the effect in cell migration by wound healing assay, and tumorsphere and colony formation were evaluated. The changes in key signaling pathways involved in carcinogenesis were assessed by using a phosphorylation pathway profiling array and by Western blotting. Antiproliferative effects of HT and two lipophilic derivatives [hydroxytyrosyl acetate (HT-Ac)/ethyl hydroxytyrosyl ether (HT-Et)] were significantly higher in cancerous PC-3 and 22Rv1 cells than in non-malignant RWPE-1 cells. HT/HT-Ac/HT-Et significantly reduced migration capacity in RWPE-1 and PC-3 and prostatosphere size and colony formation in 22Rv1, whereas only HT-Ac and HT-Et reduced these functional parameters in PC-3. The cytotoxic effect in 22Rv1 cells was correlated with modifications in the phosphorylation pattern of key proteins, including ERK1/2 and AKT. Consistently, HT-Ac and HT-Et decreased p-AKT levels in PC-3. In sum, our results suggest that HT and its lipophilic derivatives could be considered as potential therapeutic tools in PCa.

Hyaluronic acid (HA) hydrogels display a wide variety of biomedical applications ranging from tissue engineering to drug vehiculization and controlled release. To date, most of the commercially available hyaluronic acid hydrogel formulations are produced under conditions that are not compatible with physiological ones. This review compiles the currently used approaches for the development of hyaluronic acid hydrogels under physiological/mild conditions. These methods include dynamic covalent processes such as boronic ester and Schiff-base formation and click chemistry mediated reactions such as thiol chemistry processes, azide-alkyne, or Diels Alder cycloaddition. Thermoreversible gelation of HA hydrogels at physiological temperature is also discussed. Finally, the most outstanding biomedical applications are indicated for each of the HA hydrogel generation approaches.

Recently, new strategies for treating class III malocclusions have appeared. Skeletal anchorage appears to reduce the dentoalveolar effects while maximising the orthopaedic effect in growing patients. The purpose of this systematic review and meta-analysis is to examine the effectiveness of bone anchorage devices for interceptive treatment of skeletal class III malocclusions. Searches were made in the Pubmed, Embase, Scopus and Cochrane databases, as well as in a grey literature database, and were complemented by hand-searching. The criteria for eligibility were: patients who had undergone orthodontic treatment with skeletal anchorage (miniplates and miniscrews). Patients with syndromes or craniofacial deformities or who had undergone maxillofacial surgery were excluded. The following variables were recorded for each article: author, year of publication, type of study, sample size, dropouts, demographic variables, treatment carried out, radiographic study (2D or 3D), follow-up time, and quality of the articles on the Newcastle-Ottawa Scale. The means and confidence intervals of the following variables were employed: Wits, overjet, ANB, SNA and SNB. Initially, 239 articles were identified. After removing the duplicates and applying the selection criteria, 9 were included in the qualitative synthesis and 7 in the quantitative synthesis (meta-analysis). It may be concluded that skeletal anchorage is an effective treatment for improving skeletal Class III malocclusion, but when compared with other traditional treatments such as disjunction and face mask, there is no clear evidence that skeletal anchorage improves the results.

Stable hyaluronic acid nanogels were obtained following the water-in-oil microemulsion method by covalent crosslinking with three biocompatible crosslinking agents: Divinyl sulfone, 1,4-butanediol diglycidyl ether (BDDE), and poly(ethylene glycol) bis(amine). All nanoparticles showed a pH-sensitive swelling behavior, according to the pKa value of hyaluronic acid, as a consequence of the ionization of the carboxylic moieties, as it was corroborated by zeta potential measurements. QELS studies were carried out to study the influence of the chemical structure of the crosslinking agents on the particle size of the obtained nanogels. In addition, the effect of the molecular weight of the biopolymer and the degree of crosslinking on the nanogels dimensions was also evaluated for BDDE crosslinked nanoparticles, which showed the highest pH-responsive response.

Sustainability in the water sector in Europe is a major concern, and compliance with the current legislation alone does not seem to be enough to face major challenges like climate change or population growth and concentration. The greatest potential for improvement appears when companies decide to take a step forward and go beyond environmental legislation. This study focuses on the environmental responsibility (ER) of European small and medium-sized enterprises (SMEs) in the water and waste management sector and analyzes the drivers that lead these firms to the adoption of more sustainable practices. Our results show that up to 40% of European SMEs within this industry display environmental responsibility. Market pull has a low incidence in encouraging ER, while values and the strategic decisions of entrepreneurs seem decisive. Policy makers should prioritize subsidies over fiscal incentives because they show greater potential to promote the adoption of environmental responsibility among these firms.

La poesía siempre ha estado presente en la enseñanza de español para extranjeros. Unas veces como pretexto para enseñar lengua, otras como texto literario en sí mismo, muchas otras para ilustrar aspectos culturales. El problema es saber cómo poder integrarla en nuestros cursos mediante tareas motivadoras para los estudiantes. Una manera atractiva de incitar a los alumnos es formar parte de un proyecto global y real presentado como concurso.

La poesía siempre ha estado presente en la enseñanza de español para extranjeros. Unas veces como pretexto para enseñar lengua, otras como texto literario en sí mismo, muchas otras para ilustrar aspectos culturales. El problema es saber cómo poder integrarla en nuestros cursos mediante tareas motivadoras para los estudiantes. Una manera atractiva de incitar a los alumnos es formar parte de un proyecto global y real presentado como concurso.

A partir de Las lobas de arrabal (1920) y su relación con el decadentismo se reflexiona sobre los cambios efectuados en la narrativa del cambio de siglo. La novela modernista se impregna de artificiosidad en busca de un efecto lírico, que a menudo se logra mediante la tensión entre lo bello y lo feo, lo sublime y lo canalla, lo elevado y lo abyecto. Surge de este modo un lirismo negro que constituye una pieza clave del modernismo español y que, sin embargo, en muchas ocasiones ha sido desatendido y hasta despreciado por el discurso crítico.