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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.

Prostate cancer (PCa) is one of the leading causes of cancer-related deaths among men. Consequently, the identification of novel molecular targets for treatment is urgently needed to improve patients' outcomes. Our group recently reported that some elements of the cellular machinery controlling alternative-splicing might be useful as potential novel therapeutic tools against advanced PCa. However, the presence and functional role of RBM22, a key spliceosome component, in PCa remains unknown. Therefore, RBM22 levels were firstly interrogated in 3 human cohorts and 2 preclinical mouse models (TRAMP/Pbsn-Myc). Results were validated in in silico using 2 additional cohorts. Then, functional effects in response to RBM22 overexpression (proliferation, migration, tumorspheres/colonies formation) were tested in PCa models in vitro (LNCaP, 22Rv1, and PC-3 cell-lines) and in vivo (xenograft). High throughput methods (ie, RNA-seq, nCounter PanCancer Pathways Panel) were performed in RBM22 overexpressing cells and xenograft tumors. We found that RBM22 levels were down-regulated (mRNA and protein) in PCa samples, and were inversely associated with key clinical aggressiveness features. Consistently, a gradual reduction of RBM22 from non-tumor to poorly differentiated PCa samples was observed in transgenic models (TRAMP/Pbsn-Myc). Notably, RBM22 overexpression decreased aggressiveness features in vitro , and in vivo. These actions were associated with the splicing dysregulation of numerous genes and to the downregulation of critical upstream regulators of cell-cycle (i.e., CDK1/CCND1/EPAS1). Altogether, our data demonstrate that RBM22 plays a critical pathophysiological role in PCa and invites to suggest that targeting negative regulators of RBM22 expression/activity could represent a novel therapeutic strategy to tackle this disease. RBM22 is downregulated in PCa, and its levels (RNA and protein) are inversely associated with tumor-aggressiveness features in human cohorts and transgenic mice models. RBM22 overexpression reduces aggressiveness features in PCa models in vitro and in vivo, through the dysregulation of the splicing process (i.e., increasing alternative first exon and exon skipping splicing events) and downregulation of CDK1, EPAS1 and ATR genes [Display omitted] [ABSTRACT FROM AUTHOR]

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.

Although literature on open eco-innovation has recently increased, empirical research on this topic in traditional low-tech sectors is still relatively scarce. The present paper examines how open innovation activities can promote eco-innovations in the food industry, an industry that is sometimes considered a technological laggard with traditionally low cooperation. The paper focuses on the relationship between a firm's interactions with stakeholders, particularly the breadth and the depth of the firm's knowledge network and the firm's propensity to develop different types of eco-innovations. Using a novel and more accurate measure of breadth and depth and addressing endogeneity with instrumental variables, the paper studies their influence on technological eco-innovation in a random sample of 279 food firms in Spain. The results show that coordination difficulties and bounded rationality explain an inverted U shape in the relationship of breadth of external knowledge sources and the propensity to eco-innovate both in product and process eco-innovations. Additionally, our findings confirm that it is important to rely on deep, frequent and intense relationships with stakeholders in order to create the required atmosphere to foster fluent knowledge sharing among partners specially to develop eco-process innovations, but a learning effect appears. Future research should extend the analysis to other countries and sectors to address the limitations of this study. • External search breadth is positively related to eco-innovation propensity. • Coordination with partners diminishes eco-innovation propensity. • Deep relationships improve knowledge flow among partners. • Deep, frequent and intense relationships foster eco-process innovations. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) is one of the most common cancers types among men. Development and progression of PCa is associated with aberrant expression of oncogenic splicing-variants (eg, AR-v7), suggesting that dysregulation of the splicing process might represent a potential actionable target for PCa. Expression levels (mRNA and protein) of SF3B1, one of the main components of the splicing machinery, were analyzed in different cohorts of PCa patients (clinically localized [n = 84], highly aggressive PCa [n = 42], and TCGA dataset [n = 497]). Functional and mechanistic assays were performed in response to pladienolide-B in nontumor and tumor-derived prostate cells. Our results revealed that SF3B1 was overexpressed in PCa tissues and its levels were associated with clinically relevant PCa-aggressive features (eg, metastasis/AR-v7 expression). Moreover, inhibition of SF3B1 activity by pladienolide-B reduced functional parameters of aggressiveness (proliferation/migration/tumorspheres-formation/apoptosis) in PCa cell lines, irrespective of AR-v7 expression, and reduced viability of primary PCa cells. Antitumor actions of pladienolide-B involved: (1) inhibition of PI3K/AKT and JNK signaling pathways, (2) modulation of tumor markers and splicing variants (AR-v7/In1-ghrelin), and (3) regulation of key components of mRNA homeostasis-associated machineries (spliceosome/SURF/EJC). Altogether, our results demonstrated that SF3B1 is overexpressed and associated with malignant features in PCa, and its inhibition reduces PCa aggressiveness, suggesting that SF3B1 could represent a novel prognostic biomarker and a therapeutic target in PCa. [ABSTRACT FROM AUTHOR]

Hospitality is the main industry in the service sector in Spain, contributing to more than 10% of the gross domestic product and approximately 12% of all employees. Firms in this industry are beginning to adopt eco-innovations to reduce their environmental impact and optimize the use of natural resources. However, most companies do not have the necessary resources to tackle ecoinnovation on their own and need to cooperate with different agents. The purpose of this paper is to examine how open innovation activities can be a source of green innovation in the hospitality industry in Spain. This study contributes to the literature on both open innovation and eco-innovation by focusing on the relationship between a firm's green orientation and its interactions with stakeholders. We develop a model to assess how a firm's relationships with its clients, suppliers, competitors, and research institutions influence its environmental orientation. We propose that the depth and breadth of relationships with stakeholders positively influence the development of eco-innovations. We test our model with a sample of 189 firms from the Technological Innovation Panel (PITEC) database. The empirical analysis reveals that the benefits derived from these relationships follow an inverted U-shaped curve. [ABSTRACT FROM AUTHOR]

Environmental concern has been on the rise in recent years and a proposal for a circular economy (CE) as a tool for sustainable development has received attention from governments, practitioners, and academics. In this sense, the literature on the topic has grown from 12 scientific articles published in 2008 to 2355 in 2020, which represents an almost two hundredfold increase in around a decade. However, CE is a relatively new subject, and much research remains to be conducted; it is therefore important to gain an adequate understanding of the subject to address more specific, related issues. The purpose of this review is to identify the main trends in CE and their evolution. It presents an advanced bibliometric method consisting of a combination of co-word analysis and social network analysis developed to identify the main topics and trends in this field. The results show the evolution of research, frequency, and relevance of the terms studied, links between them, and their density and network visualisation. Bibliometric tools have further been applied to obtain the research outputs of the main journals, as well as the authors and research topics that have been addressed during this period. New directions for future research lines are also proposed. • Exponential rise in Circular Economy research: 12 papers in 2008 and 2300 in 2020 • Split of research in two main areas: conceptualisation and more technical issues • Electronic equipment waste and water issues, as most recurrent research topics • 'Recycle', the most quoted R and 'reuse', the R with the most room for improvement • Change in leading role on Circular Economy research from China to European Union [ABSTRACT FROM AUTHOR]

There is an increasing social and political awareness of the importance of sustainable innovations. Strategic partnerships between policy makers, businesses, researchers and citizens are keys to developing, implementing and applying eco-innovation, essential for the transition to a competitive green economy. Within this innovation ecosystem, universities can play a central role in creating viable alternative models that are driven by environmental sustainability. Based on evidence from the first survey on Eco-innovation in Europe- 'The Eurobarometer 315 Survey on Attitudes of European Entrepreneurs towards Eco-Innovation', the present paper examines the impact of university collaboration on eco-innovating small firms. It also considers how technology push, demand side factors and the regulatory framework, drive eco-innovation in European SMEs. This paper has several implications for managers, as well as for policy makers. For managers, it should be stressed that collaboration with universities is essential to drive all types of eco-innovations. Our findings also suggest that national government should foster cooperation with universities following EU example (eg. European Innovation Partnership in EcoAP), as national policies based on subsidies and fiscal incentives appear to be ineffective. [ABSTRACT FROM AUTHOR]

Despite a growing literature on the importance of environmental activities for firms' strategies, there are still few studies aimed at analysing whether an environmental orientation has any impact on innovation performance. Firms within the chemical industry have a great concern for this subject, due to the larger impact that their decisions could have on the environment. This study focuses on the chemical industry and contributes important findings regarding the relationship between a firm's environmental orientation and its innovation performance. Through a logistic regression model our paper demonstrates the existence of this relationship and its relative importance in comparison with other strategic orientations of the firms (market and costs). The main contribution of this paper is that chemical industry firms with an environmental orientation improve their innovation performance, specifically regarding logistic systems and manufacturing processes. [ABSTRACT FROM AUTHOR]

The popular press, as well as most academic literature, claims that innovation activities are inherently linked to higher company performance. Successful innovations usually increase the firm's market scope or reduce costs, helping firms to obtain superior benefits. Therefore, most innovations are developed with those objectives in mind. Environmental orientation is defined as the managerial recognition of the significance of the impact a company has on the environment, and the need to minimize such impact. Nowadays, environmental motivation for innovation is becoming more and more common as firms are more aware of the consequences of their activities and attempt to be socially responsible. However, most literature on innovation is focused on R&D and on large mature firms, practically neglecting small and medium sized Enterprises - SMEs-, as does the literature on corporate social responsibility. In this paper, we focus on a sample of 1337 start-up SMEs less than 10 years old, from which we obtained information regarding their innovation activities. Our results show that in comparison to cost-oriented innovations, environmental orientation in the development of innovations increases performance. [ABSTRACT FROM AUTHOR]

Eco-innovation is defined as any form of innovation aiming at significant and demonstrable progress towards the goal o sustainable development, through reducing impacts on the environment or achieving a more efficient and responsible use o natural resources, including energy. The chemical industry is usually considered one of the most polluting industries. Ensuring safe production, transport and handling of its products, with care for the environment and in full accordance with regulations, i of key importance for the image and reputation of today's chemical industry. Most chemical companies have been developing and introducing eco-innovations in an attempt to change this negative image. Using a sample of 544 companies in the Spanish chemical industry, we study the factors that have driven these companies to move towards this type of innovation activities. Ou empirical research shows that intra-group sources of innovations, together with clients and industry associations are the main driving forces of eco-innovation in the chemical industry. Furthermore our model establishes that innovations in products services, manufacturing methods and logistical systems are positively related to the achievement of environmental objectives. [ABSTRACT FROM AUTHOR]

Copyright of Revista Española de Cirugía Ortopédica y Traumatologia (English Edition) is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Revista Española de Cirugía Ortopédica y Traumatologia (English Edition) is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Revista Española de Cirugía Ortopédica y Traumatologia (English Edition) is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Despite novel therapeutic strategies, advanced-stage prostate cancer (PCa) remains highly lethal, pointing out the urgent need for effective therapeutic strategies. While dysregulation of the splicing process is considered a cancer hallmark, the role of certain splicing factors remains unknown in PCa. This study focuses on characterizing the levels and role of SRSF6 in this disease. Comprehensive analyses of SRSF6 alterations (copy number/mRNA/protein) were conducted across eight well-characterized PCa cohorts and the Hi-MYC transgenic model. SRSF6 was up-regulated in PCa samples, correlating with adverse clinical parameters. Functional assays, both in vitro (cell proliferation, migration, colony, and tumorsphere formation) and in vivo (xenograft tumors), demonstrated the impact of SRSF6 modulation on critical cancer hallmarks. Mechanistically, SRSF6 regulates the splicing pattern of the histone-chaperone HIRA , consequently affecting the activity of H3.3 in PCa and breast cancer cell models and disrupting pivotal oncogenic pathways (AR and E2F) in PCa cells. These findings underscore SRSF6 as a promising therapeutic target for PCa/advanced-stage PCa.

Novel biomarkers and therapeutic strategies for prostate-cancer (PCa) are required to overcome its lethal progression. The dysregulation/implication of the RNA-Exosome-complex (REC; cellular machinery controlling the 3'-5'processing/degradation of most RNAs) in different cancer-types, including PCa, is poorly known. Herein, different cellular/molecular/preclinical approaches with human PCa-samples (tissues and/or plasma of 7 independent cohorts), and in-vitro/in-vivo PCa-models were used to comprehensively characterize the REC-profile and explore its role in PCa. Moreover, isoginkgetin (REC-inhibitor) effects were evaluated on PCa-cells. We demonstrated a specific dysregulation of the REC-components in PCa-tissues, identifying the Poly(A)-Binding-Protein-Nuclear 1 (PABPN1) factor as a critical regulator of major cancer hallmarks. PABPN1 is consistently overexpressed in different human PCa-cohorts and associated with poor-progression, invasion and metastasis. PABPN1 silencing decreased relevant cancer hallmarks in multiple PCa-models (proliferation/migration/tumourspheres/colonies, etc.) through the modulation of key cancer-related lncRNAs (PCA3/FALEC/DLEU2) and mRNAs (CDK2/CDK6/CDKN1A). Plasma PABPN1 levels were altered in patients with metastatic and tumour-relapse. Finally, pharmacological inhibition of REC-activity drastically inhibited PCa-cell aggressiveness. Altogether, the REC is drastically dysregulated in PCa, wherein this novel molecular event/mechanism, especially PABPN1 alteration, may be potentially exploited as a novel prognostic and therapeutic tool for PCa., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Prostate cancer (PCa) is one of the leading causes of cancer-related deaths among men. Consequently, the identification of novel molecular targets for treatment is urgently needed to improve patients' outcomes. Our group recently reported that some elements of the cellular machinery controlling alternative-splicing might be useful as potential novel therapeutic tools against advanced PCa. However, the presence and functional role of RBM22, a key spliceosome component, in PCa remains unknown. Therefore, RBM22 levels were firstly interrogated in 3 human cohorts and 2 preclinical mouse models (TRAMP/Pbsn-Myc). Results were validated in in silico using 2 additional cohorts. Then, functional effects in response to RBM22 overexpression (proliferation, migration, tumorspheres/colonies formation) were tested in PCa models in vitro (LNCaP, 22Rv1, and PC-3 cell-lines) and in vivo (xenograft). High throughput methods (ie, RNA-seq, nCounter PanCancer Pathways Panel) were performed in RBM22 overexpressing cells and xenograft tumors. We found that RBM22 levels were down-regulated (mRNA and protein) in PCa samples, and were inversely associated with key clinical aggressiveness features. Consistently, a gradual reduction of RBM22 from non-tumor to poorly differentiated PCa samples was observed in transgenic models (TRAMP/Pbsn-Myc). Notably, RBM22 overexpression decreased aggressiveness features in vitro, and in vivo. These actions were associated with the splicing dysregulation of numerous genes and to the downregulation of critical upstream regulators of cell-cycle (i.e., CDK1/CCND1/EPAS1). Altogether, our data demonstrate that RBM22 plays a critical pathophysiological role in PCa and invites to suggest that targeting negative regulators of RBM22 expression/activity could represent a novel therapeutic strategy to tackle this disease., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

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.

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., Competing Interests: The authors declare no competing interests., (© 2022 The Author(s).)

Background: Obesity is a metabolic chronic disease with important associated morbidities and mortality. Bariatric surgery is the most effective treatment for maintaining long-term weight loss in severe obesity and, consequently, for decreasing obesity-related complications, including chronic inflammation., Aim: To explore changes in components of the inflammasome machinery after bariatric surgery and their relation with clinical/biochemical parameters at baseline and 6 months after bariatric surgery., Patients and Methods: Twenty-two patients with morbid-obesity that underwent bariatric surgery (sleeve gastrectomy and Roux-en-Y gastric bypass) were included. Epidemiological/clinical/anthropometric/biochemical evaluation was performed at baseline and 6 months after bariatric surgery. Inflammasome components and inflammatory-associated factors [nucleotide-binding oligomerization domain-like receptors (NLRs), inflammasome activation components, cytokines and inflammation/apoptosis-related components, and cell-cycle and DNA-damage regulators) were evaluated in peripheral blood mononuclear cells (PBMCs) at baseline and 6 months after bariatric surgery. Clinical molecular correlations/associations were analyzed. Functional parameters (lipid accumulation/viability/apoptosis) were analyzed in response to specific inflammasome components silencing in liver HepG2 cells)., Results: A profound dysregulation of inflammasome components after bariatric surgery was found, especially in NLRs and cell-cycle and DNA damage regulators. Several components were associated with baseline metabolic comorbidities including type 2 diabetes (C-C motif chemokine ligand 2/C-X-C motif chemokine receptor 1/sirtuin 1), hypertension (absent in melanoma 2/ASC/purinergic receptor P2X 7), and dyslipidemia [C-X-C motif chemokine ligand 3 (CXCL3)/NLR family pyrin domain containing (NLRP) 7) and displayed changes in their molecular profile 6 months after bariatric surgery. The gene expression fingerprint of certain factors NLR family CARD domain containing 4 (NLRC4)/NLRP12/CXCL3)/C-C motif chemokine ligand 8/toll-like receptor 4) accurately differentiated pre- and postoperative PBMCs. Most changes were independent of the performed surgical technique. Silencing of NLRC4/NLRP12 resulted in altered lipid accumulation, apoptosis rate, and cell viability in HepG2 cells., Conclusion: Bariatric surgery induces a profound alteration in the gene expression pattern of components of the inflammasome machinery in PBMCs. Expression and changes of certain inflammasome components are associated to baseline metabolic comorbidities, including type 2 diabetes, and may be related to the improvement and reversion of some obesity-related comorbidities after bariatric surgery., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)