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Body temperature must be monitored in patients receiving Hospital-at-Home (HaH) care for COVID-19 and other infectious diseases. Continuous temperature telemonitoring (CTT) detects fever and patient deterioration early, facilitating decision-making. We performed a validation clinical study assessing the safety, comfort, and impact on healthcare practice of Viture®, a CTT system, compared with a standard digital axillary thermometer in 208 patients with COVID-19 and other infectious diseases treated in HaH at the Navarra University Hospital (HUN). Overall, 3258 pairs of measurements showed a clinical bias of −0.02 °C with limits of agreement of −0.96/+0.92 °C, a 95% acceptance rate, and a mean absolute deviation of 0.36 (SD 0.30) °C. Viture® detected 3 times more febrile episodes and revealed fever in 50% more patients compared with spot measurements. Febrile episodes were detected 7.23 h (mean) earlier and modified the diagnostic and/or therapeutic approach in 43.2% of patients. Viture® was validated for use in a clinical setting and was more effective in detecting febrile episodes than conventional methods. [ABSTRACT FROM AUTHOR]

Major Depressive Disorder (MDD) is one of the most disabling diseases in the world. MDD is traditionally diagnosed based on a patient's symptoms, which can lead to misdiagnosis. Although the pathogenic mechanisms of MDD are unknown, several studies have identified mitochondrial dysfunction as a central factor in the onset and progression of MDD. In the context of MDD, alterations in mitochondrial metabolism can lead to imbalances in energy production and oxidative stress, contributing to the disorder´s underlying pathophysiological mechanisms. Consequently, the identification of mitochondrial dysfunction as a key biomarker for early and accurate diagnosis of MDD represents a significant challenge. Faced with the limits of traditional treatments with antidepressants, new pharmacological therapeutic targets are being investigated such as ketamine/esketamine, psychedelics, or anti-inflammatories. All of these drugs show potential antidepressant effects due to their speed of action and ability to modulate neuroplasticity and/or motor processing. In parallel, non-pharmacological therapeutic targets are studied, like Transcranial Magnetic Stimulation (TMS) and Deep Brain Stimulation (DBS), recognized for their ability to modulate neuronal activity and offer treatment alternatives. As cellular activity is directly related to mitochondrial respiration, the aim of this review is examining the link between mitochondrial dysfunction and MDD, assessing how mitochondrial biomarkers could provide a more objective and precise diagnostic tool, and exploring other treatments in addition to traditional antidepressants, with a specific focus on emerging therapeutic targets. Finally, a detailed analysis of the strengths, weaknesses, opportunities, and threats of these approaches was carried out, highlighting the key challenges that must be addressed. [ABSTRACT FROM AUTHOR]

Bipolar plates (BPs) are one of the most important components of polymer electrolyte membrane fuel cells (PEMFCs) because of their important role in gas and water management, electrical performance, and mechanical stability. Therefore, promising materials for use as BPs should meet several technical targets established by the United States Department of Energy (DOE). Thus far, in the literature, many materials have been reported for possible applications in BPs. Of these, polymer composites reinforced with carbon allotropes are one of the most prominent. Therefore, in this review article, we present the progress and critical analysis on the use of carbon material-reinforced polymer composites as BPs materials in PEMFCs. Based on this review, it is observed that numerous polymer composites reinforced with carbon allotropes have been produced in the literature, and most of the composites synthesized and characterized for their possible application in BPs meet the DOE requirements. However, these composites can still be improved before their use for BPs in PEMFCs. [ABSTRACT FROM AUTHOR]

This research investigates the post-earthquake performances of structures in four rural villages in the Moroccan Atlas, emphasizing common construction system characteristics and design flaws that render buildings susceptible to seismic events. Village selection was based on a prior multispectral satellite-image study, proving effective for planning high-impact, post-earthquake field campaigns. The significance of this research resides in on-site data collection, facilitating the physical assessment of earthquake-induced damage and identification of inherent vulnerabilities in construction systems. The constructions in the study area exhibited structural design deficiencies, inadequate construction techniques, and urban modifiers, leading to damage extensively documented in the literature, as well as less-documented unique damage. Predominant seismic-design shortcomings in the study area included subpar material quality, insufficient earthquake-resistant design, and unskilled labor. In situ data were complemented by a global geospatial approach using differential synthetic aperture radar interferometry with Copernicus Sentinel 1 data. Once calibrated the proposed methodology with field data, the analysis of remote sensing processing results, allow assessing the damages in other earthquake-affected areas, including those not visited in the field but also impacted by the seismic event. [ABSTRACT FROM AUTHOR]

Municipal biowaste management is at the core of the transition towards a circular bioeconomy in the EU. However, most urban systems are still far from being aligned with these principles. This paper addresses the case of the Metropolitan Area of Barcelona. The current system of biowaste management is compared with a more sustainable alternative scenario. Regulatory and non-regulatory drivers and barriers for the transition from the current state to the alternative scenario are identified and later transformed into policy recommendations using a multi-stakeholder approach. This paper focuses on the separate collection of biowaste and the production of biomethane. Increasing the quantity and quality of separate biowaste collection is a prerequisite for the market-relevant production of biogas from anaerobic digestion that can be converted into biomethane. The results show that more efficient collection systems such as door-to-door or smart bins together with tax incentives such as the pay-as-you-throw principle are key to increasing the amount of collected biowaste, while targeted communication combined with controls and penalties are key to minimizing impurities. In addition to financial incentives for the construction of new anaerobic digestion plants, financial incentive systems are also required for the biomethane sector to ensure competitiveness with fossil fuels. [ABSTRACT FROM AUTHOR]

Ischemia is the main cause of cell death in retinal diseases such as vascular occlusions, diabetic retinopathy, glaucoma, or retinopathy of prematurity. Although excitotoxicity is considered the primary mechanism of cell death during an ischemic event, antagonists of glutamatergic receptors have been unsuccessful in clinical trials with patients suffering ischemia or stroke. Our main purpose was to analyze if the transient receptor potential channel 7 (TRPM7) could contribute to retinal dysfunction in retinal pathologies associated with ischemia. By using an experimental model of acute retinal ischemia, we analyzed the changes in retinal function by electroretinography and the changes in retinal morphology by optical coherence tomography (OCT) and OCT-angiography (OCTA). Immunohistochemistry was performed to assess the pattern of TRPM7 and its expression level in the retina. Our results show that ischemia elicited a decrease in retinal responsiveness to light stimuli along with reactive gliosis and a significant increase in the expression of TRPM7 in Müller cells. TRPM7 could emerge as a new drug target to be explored in retinal pathologies associated with ischemia. [ABSTRACT FROM AUTHOR]

Introduction: Treatment of Peritoneal Surface Malignancies (PSM) with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has achieved results never seen before in these patients, which classically have a poor prognosis. The possibility of conducting clinical trials in these diseases is complicated, since some of them are rare, so the analysis of large databases provides very valuable scientific information. The aim of this study is to analyze the global results of the National Registry of the Spanish Group of Peritoneal Oncologic Surgery (REGECOP), whose objective is to register all patients scheduled for HIPEC nationwide. Methods: This is a retrospective analysis of the data recorded in the REGECOP from 36 Spanish hospitals from 2001 to 2021. There were 4159 surgical interventions in 3980 patients. Results: 66% are women and 34% are men with a median age of 59 years (range 17–86). 41.5% of the patients were treated for Peritoneal Metastases (PM) of colorectal cancer (CRC); 32.4% were women with ovarian cancer (OC) with PM; 12.8% were treated for pseudomyxoma peritonei (PMP); 6.2% had PM from gastric cancer (GC); 4.9% had PM of non-conventional origin; and, finally, 2.1% of cases were patients diagnosed with peritoneal mesothelioma. The median Peritoneal Cancer Index (PCI) was 9 (0–39), and complete cytoreduction was achieved in 81.7% of the procedures. Severe morbidity (Dindo–Clavien grade III–IV) was observed in 17.7% of surgeries, with 2.1% mortality. Median hospital stay was 11 days (0–259). Median overall survival (OS) was 41 months for CRC patients, 55 months for women with OC, was not reached in PMP patients, was 14 months for GC patients, and 66 months in mesothelioma patients. Conclusions: large databases provide extremely useful data. CRS with HIPEC in referral centers is a safe treatment with encouraging oncologic results in PSM. [ABSTRACT FROM AUTHOR]

Background: Skin and soft tissue infections are one of the main causes of consultations worldwide. The objective was to determine the treatment of a group of patients with uncomplicated skin and soft tissue infections in Colombia. Methods: Follow-up study of a cohort of patients with skin infections who were treated in the Colombian Health System. Sociodemographic, clinical and pharmacological variables were identified. Treatments were evaluated using clinical practice guidelines for skin infections. Results: A total of 400 patients were analyzed. They had a median age of 38.0 years and 52.3% were men. The most commonly used antibiotics were cephalexin (39.0%), dicloxacillin (28.0%) and clindamycin (18.0%). A total of 49.8% of the subjects received inappropriate antibiotics, especially those with purulent infections (82.0%). Being cared for in an outpatient clinic (OR: 2.09; 95% CI: 1.06–4.12), presenting pain (OR: 3.72; 95% CI: 1.41–9.78) and having a purulent infection (OR: 25.71; 95% CI: 14.52–45.52) were associated with a higher probability of receiving inappropriate antibiotics. Conclusions: Half of patients with uncomplicated skin and soft tissue infections were treated with antibiotics that were not recommended by clinical practice guidelines. This inappropriate use of antibiotics occurred in the vast majority of patients with purulent infections because the antimicrobials used had no effect on methicillin-resistant Staphylococcus aureus. [ABSTRACT FROM AUTHOR]

In the 10th century, the arrabales of Córdoba underwent a process of rapid growth, triggered by the growing political authority of the capital of the western caliphate. This involved the urbanisation of erstwhile agricultural areas, with new streets and public buildings such as baths, mosques, and funduqs, as well as whole blocks of houses. Domestic blocks generally took the shape of lines of houses that were similar in plan. Among domestic models, which invariably revolved around a courtyard, the most basic type—rectangular in plan, with a central courtyard and a bay on either side—was also the most numerous. This work examines the characteristics and expansions of these buildings, in order to better understand the process that led to the crystallisation of Andalusi urban fabrics. [ABSTRACT FROM AUTHOR]

The aim of this work was to develop niosomes for the ocular delivery of epalrestat, a drug that inhibits the polyol pathway and protects diabetic eyes from damage linked to sorbitol production and accumulation. Cationic niosomes were made using polysorbate 60, cholesterol, and 1,2-di-O-octadecenyl-3-trimethylammonium propane. The niosomes were characterized using dynamic light scattering, zeta-potential, and transmission electron microscopy to determine their size (80 nm; polydispersity index 0.3 to 0.5), charge (−23 to +40 mV), and shape (spherical). The encapsulation efficiency (99.76%) and the release (75% drug release over 20 days) were measured with dialysis. The ocular irritability potential (non-irritating) was measured using the Hen's Egg Test on the Chorioallantoic Membrane model, and the blood glucose levels (on par with positive control) were measured using the gluc-HET model. The toxicity of the niosomes (non-toxic) was monitored using a zebrafish embryo model. Finally, corneal and scleral permeation was assessed with the help of Franz diffusion cells and confirmed with Raman spectroscopy. Niosomal permeation was higher than an unencapsulated drug in the sclera, and accumulation in tissues was confirmed with Raman. The prepared niosomes show promise to encapsulate and carry epalrestat through the eye to meet the need for controlled drug systems to treat the diabetic eye. [ABSTRACT FROM AUTHOR]

Training in emotional regulation skills is one of the most important resources for the adaptation of athletes to contexts of sports pressure, especially during competitions. This study explored the effects of a mindfulness programme (Flow Meditation) on levels of impulsivity, mood and pre-competition anxiety-state in a sample of athletes (N = 41, 22.83 ± 5.62 years). Participants were randomly assigned to an intervention group (N = 21; 14 males and 7 females) which received the intervention over 10 weeks (a weekly session) and a control group (wait-list; N = 20; 13 males and 7 females). The variables under study were assessed through different questionnaires at pre- and post-test (T1–T2) in both groups. The mindfulness intervention was effective in reducing impulsivity (cognitive (t = −4.48, p ≤ 0.001, Cohen's d = 1.40), both motor (t = −4.03, p ≤ 0.001, Cohen's d = 1.20) and unplanned (t = −5.32, p ≤ 0.001, Cohen's d = 1.66)), mood (tension (t = −4.40, p ≤ 0.001, Cohen's d = 1.37), depression (t = −4.56, p ≤ 0.001, Cohen's d = 1.42), anger (t = −7.80, p ≤ 0.001, Cohen's d = 2.47), somatic anxiety (t = −5.28, p ≤ 0.001, Cohen's d = 1.65), and cognitive anxiety (t = −6.62, p ≤ 0.001, Cohen's d = 2.07) in the intervention group compared to the control group and with large to very large effect sizes. Mindfulness is a factor that enhances athletes' ability to cope with high sport pressure and the healthy management of competition (e.g., fear of failure), or with their daily life. [ABSTRACT FROM AUTHOR]

Cannabis has been used for decades as a palliative therapy in the treatment of cancer. This is because of its beneficial effects on the pain and nausea that patients can experience as a result of chemo/radiotherapy. Tetrahydrocannabinol and cannabidiol are the main compounds present in Cannabis sativa, and both exert their actions through a receptor-mediated mechanism and through a non-receptor-mediated mechanism, which modulates the formation of reactive oxygen species. These oxidative stress conditions might trigger lipidic changes, which would compromise cell membrane stability and viability. In this sense, numerous pieces of evidence describe a potential antitumor effect of cannabinoid compounds in different types of cancer, although controversial results limit their implementation. In order to further investigate the possible mechanism involved in the antitumoral effects of cannabinoids, three extracts isolated from Cannabis sativa strains with high cannabidiol content were analyzed. Cell mortality, cytochrome c oxidase activity and the lipid composition of SH-SY5Y cells were determined in the absence and presence of specific cannabinoid ligands, with and without antioxidant pre-treatment. The cell mortality induced by the extracts in this study appeared to be related to the inhibition of the cytochrome c oxidase activity and to the THC concentration. This effect on cell viability was similar to that observed with the cannabinoid agonist WIN55,212-2. The effect was partially blocked by the selective CB1 antagonist AM281, and the antioxidant α-tocopherol. Moreover, certain membrane lipids were affected by the extracts, which demonstrated the importance of oxidative stress in the potential antitumoral effects of cannabinoids. [ABSTRACT FROM AUTHOR]

The purinergic receptor P2X7 (P2X7R) is implicated in all neurodegenerative diseases of the central nervous system. It is also involved in the retinal degeneration associated with glaucoma, age-related macular degeneration, and diabetic retinopathy, and its overexpression in the retina is evident in these disorders. Retinitis pigmentosa is a progressive degenerative disease that ultimately leads to blindness. Here, we investigated the expression of P2X7R during disease progression in the rd10 mouse model of RP. As the purinergic receptor P2X4 is widely co-expressed with P2X7R, we also studied its expression in the retina of rd10 mice. The expression of P2X7R and P2X4R was examined by immunohistochemistry, flow cytometry, and western blotting. In addition, we analyzed retinal functionality by electroretinographic recordings of visual responses and optomotor tests and retinal morphology. We found that the expression of P2X7R and P2X4R increased in rd10 mice concomitant with disease progression, but with different cellular localization. Our findings suggest that P2X7R and P2X4R might play an important role in RP progression, which should be further analyzed for the pharmacological treatment of inherited retinal dystrophies. [ABSTRACT FROM AUTHOR]

Cellular senescence is one of the main contributors to some neurodegenerative disorders. The early detection of senescent cells or their related effects is a key aspect in treating disease progression. In this functional deterioration, oxidative stress and lipid peroxidation play an important role. Endogenous antioxidant compounds, such as α-tocopherol (vitamin E), can mitigate these undesirable effects, particularly lipid peroxidation, by blocking the reaction between free radicals and unsaturated fatty acid. While the antioxidant actions of α-tocopherol have been studied in various systems, monitoring the specific effects on cell membrane lipids at scales compatible with large screenings has not yet been accomplished. Understanding the changes responsible for this protection against one of the consequences of senescence is therefore necessary. Thus, the goal of this study was to determinate the changes in the lipid environment of a Paraquat-treated human astrocytic cell line, as a cellular oxidative stress model, and the specific actions of the antioxidant, α-tocopherol, using cell membrane microarray technology, MALDI-MS and lipidomic analysis. The stress induced by Paraquat exposure significantly decreased cell viability and triggered membrane lipid changes, such as an increase in certain species of ceramides that are lipid mediators of apoptotic pathways. The pre-treatment of cells with α-tocopherol mitigated these effects, enhancing cell viability and modulating the lipid profile in Paraquat-treated astrocytes. These results demonstrate the lipid modulation effects of α-tocopherol against Paraquat-promoted oxidative stress and validate a novel analytical high-throughput method combining cell cultures, microarray technology, MALDI-MS and multivariate analysis to study antioxidant compounds against cellular senescence. [ABSTRACT FROM AUTHOR]

Ruthenium(II) arene complexes exhibit promising chemotherapeutic properties. In this study, the effect of the counter anion in Ru(II) complexes was evaluated by analyzing the biological effect of two Ru(II) p-cymene derivatives with the 1,10-phenanthroline-5,6-dione ligand of general-formula [(η6-arene)Ru(L)Cl][X] X = CF3SO3 (JHOR10) and PF6 (JHOR11). The biological activity of JHOR10 and JHOR11 was examined in the ovarian carcinoma cell line A2780, colorectal carcinoma cell line HCT116, doxorubicin-resistant HCT116 (HCT116-Dox) and in normal human dermal fibroblasts. Both complexes JHOR10 and JHOR11 displayed an antiproliferative effect on A2780 and HCT116 cell lines, and low cytotoxicity in fibroblasts. Interestingly, JHOR11 also showed antiproliferative activity in the HCT116-Dox cancer cell line, while JHOR10 was inactive. Studies in A2780 cells showed that JHOR11 induced the production of reactive oxygen species (ROS) that trigger autophagy and cellular senescence, but no apoptosis induction. Further analysis showed that JHOR11 presented no tumorigenicity, with no effect in the cellular mobility, as evaluated by thye wound scratch assay, and no anti- or pro-angiogenic effect, as evaluated by the ex-ovo chorioallantoic membrane (CAM) assay. Importantly, JHOR11 presented no toxicity in chicken and zebrafish embryos and reduced in vivo the proliferation of HCT116 injected into zebrafish embryos. These results show that these are suitable complexes for clinical applications with improved tumor cell cytotoxicity and low toxicity, and that counter-anion alteration might be a viable clinical strategy for improving chemotherapy outcomes in multidrug-resistant (MDR) tumors. [ABSTRACT FROM AUTHOR]

Oxidative stress (OS) and inflammation are known to play an important role in chronic diseases, including cancer, and specifically colorectal cancer (CRC). The main objective of this study was to explore the diagnostic potential of OS markers in patients with CRC, which may translate into an early diagnosis of the disease. To do this, we compared results with those in a group of healthy controls and assessed whether there were significant differences. In addition, we explored possible correlations with the presence of tumors and tumor stage, with anemia and with inflammatory markers used in clinical practice. The study included 80 patients with CRC and 60 healthy controls. The following OS markers were analyzed: catalase (CAT), reduced glutathione (GSH) and oxidized glutathione (GSSG) in serum; and 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) and F2-isoprotanes in urine (F2-IsoPs). Tumor markers (CEA and CA 19.9), anemia markers (hemoglobin, hematocrit and medium corpuscular volume) and inflammatory markers (leukocytes, neutrophils, N/L index, platelets, fibrinogen, C-reactive protein, CRP and IL-6) were also determined. Comparison of means between patients and controls revealed highly significant differences for all OS markers, with an increase in the prooxidant markers GSSG, GSSG/GSH ratio, 8-oxodG and F2-IsoPs, and a decrease in the antioxidant markers CAT and GSH. Tumor and inflammatory markers (except CRP) correlated positively with GSSG, GSSG/GSH ratio, 8-oxodG and F2-IsoPs, and negatively with CAT and GSH. In view of the results obtained, OS markers may constitute a useful tool for the early diagnosis of CRC patients. [ABSTRACT FROM AUTHOR]

NOP56 belongs to a C/D box small nucleolar ribonucleoprotein complex that is in charge of cleavage and modification of precursor ribosomal RNAs and assembly of the 60S ribosomal subunit. An intronic expansion in NOP56 gene causes Spinocerebellar Ataxia type 36, a typical late-onset autosomal dominant ataxia. Although vertebrate animal models were created for the intronic expansion, none was studied for the loss of function of NOP56. We studied a zebrafish loss-of-function model of the nop56 gene which shows 70% homology with the human gene. We observed a severe neurodegenerative phenotype in nop56 mutants, characterized mainly by absence of cerebellum, reduced numbers of spinal cord neurons, high levels of apoptosis in the central nervous system (CNS) and impaired movement, resulting in death before 7 days post-fertilization. Gene expression of genes related to C/D box complex, balance and CNS development was impaired in nop56 mutants. In our study, we characterized the first NOP56 loss-of-function vertebrate model, which is important to further understand the role of NOP56 in CNS function and development. [ABSTRACT FROM AUTHOR]

This article defines a new concept for real-time factory management—manufacturing maps. Manufacturing maps are generated from two fundamental elements, mini-terms and Petri nets. Mini-terms are sub-times of a technical cycle, the time it takes for any component to perform its task. A mini-term, by definition, is a sub-cycle time and it would only make sense to use the term in connection with production improvement. Previous studies have shown that when the sub-cycle time worsens, this indicates that something unusual is happening, enabling anticipation of line failures. As a result, a mini-term has dual functionality, since, on the one hand, it is a production parameter and, on the other, it is a sensor used for predictive maintenance. This, combined with how easy and cheap it is to extract relevant data from manufacturing lines, has resulted in the mini-term becoming a new paradigm for predictive maintenance, and, indirectly, for production analysis. Applying this parameter using big data for machines and components can enable the complete modeling of a factory using Petri nets. This article presents manufacturing maps as a hierarchical construction of Petri nets in which the lowest level network is a temporary Petri net based on mini-terms, and in which the highest level is a global view of the entire plant. The user of a manufacturing map can select intermediate levels, such as a specific production line, and perform analysis or simulation using real-time data from the mini-term database. As an example, this paper examines the modeling of the 8XY line, a multi-model welding line at the Ford factory in Almussafes (Valencia), where the lower layers are modeled until the mini-term layer is reached. The results, and a discussion of the possible applications of manufacturing maps in industry, are provided at the end of this article. [ABSTRACT FROM AUTHOR]

(1) Background: Glioblastoma is the most frequent and lethal primary tumor of the central nervous system. Through many years, research has brought various advances in glioblastoma treatment. At this time, glioblastoma management is based on maximal safe surgical resection, radiotherapy, and chemotherapy with temozolomide. Recently, bevacizumab has been added to the treatment arsenal for the recurrent scenario. Nevertheless, patients with glioblastoma still have a poor prognosis. Therefore, many efforts are being made in different clinical research areas to find a new alternative to improve overall survival, free-progression survival, and life quality in glioblastoma patients. (2) Methods: Our objective is to recap the actual state-of-the-art in glioblastoma treatment, resume the actual research and future perspectives on immunotherapy, as well as the new synthetic molecules and natural compounds that represent potential future therapies at preclinical stages. (3) Conclusions: Despite the great efforts in therapeutic research, glioblastoma management has suffered minimal changes, and the prognosis remains poor. Combined therapeutic strategies and delivery methods, including immunotherapy, synthetic molecules, natural compounds, and glioblastoma stem cell inhibition, may potentiate the standard of care therapy and represent the next step in glioblastoma management research. [ABSTRACT FROM AUTHOR]

Inherited retinal dystrophies (IRDs) are a large group of genetically and clinically heterogeneous diseases characterized by the progressive degeneration of the retina, ultimately leading to loss of visual function. Oxidative stress and inflammation play fundamental roles in the physiopathology of these diseases. Photoreceptor cell death induces an inflammatory state in the retina. The activation of several molecular pathways triggers different cellular responses to injury, including the activation of microglia to eliminate debris and recruit inflammatory cells from circulation. Therapeutical options for IRDs are currently limited, although a small number of patients have been successfully treated by gene therapy. Many other therapeutic strategies are being pursued to mitigate the deleterious effects of IRDs associated with oxidative metabolism and/or inflammation, including inhibiting reactive oxygen species' accumulation and inflammatory responses, and blocking autophagy. Several compounds are being tested in clinical trials, generating great expectations for their implementation. The present review discusses the main death mechanisms that occur in IRDs and the latest therapies that are under investigation. [ABSTRACT FROM AUTHOR]

Simple Summary: Lymph node metastasis and positive resection margins have been reported to be major determinants of overall survival (OS) and poor recurrence-free survival (RFS) for patients after resection for perihilar cholangiocarcinoma (pCCA). The aim of current study was to assess the prognostic value of positive lymph nodes and resection margin status on OS. We found a major negative effect of positive lymph nodes on survival and recurrence, which, surprisingly, was independent of margin status. ECOG performance status, positive lymph nodes, and the grade of tumor differentiation were found as the main independent indicators of oncological outcome. This suggests that tumor biology and performance status have a higher impact on survival than extended or radical surgery. Background: Lymph node metastasis and positive resection margins have been reported to be major determinants of overall survival (OS) and poor recurrence-free survival (RFS) for patients who underwent resection for perihilar cholangiocarcinoma (pCCA). However, the prognostic value of positive lymph nodes independently from resection margin status on OS has not been evaluated. Methods: From the European Cholangiocarcinoma (ENSCCA) registry, patients who underwent resection for pCCA between 1994 and 2021 were included in this retrospective cohort study. The primary outcome was OS stratified for resection margin and lymph node status. The secondary outcome was recurrence-free survival. Results: A total of 325 patients from 11 different centers and six European countries were included. Of these, 194 (59.7%) patients had negative resection margins. In 113 (34.8%) patients, positive lymph nodes were found. Lymph node status, histological grade, and ECOG performance status were independent prognostic factors for survival. The median OS for N0R0, N0R1, N+R0, and N+R1 was 38, 30, 18, and 12 months, respectively (p < 0.001). Conclusion: These data indicate that in the presence of positive regional lymph nodes, resection margin status does not determine OS or RFS in patients with pCCA. Achieving negative margins in patients with positive nodes should not come at the expense of more extensive surgery and associated higher mortality. [ABSTRACT FROM AUTHOR]

Simple Summary: Discovering new strategies for cancer treatment is critical, considering that each year millions of deaths are caused by this disease. In this sense, therapies based on nanomedicine are an innovative approach for cancer treatment, not only because they make it possible to perform targeted therapy, but also because they can improve patients' quality of life. A key step to transfer new treatments from bench to beside is in vivo evaluation of a therapy, where zebrafish as a model organism has a fundamental role. Zebrafish has several benefits that make it ideal for studying the therapeutic capacity of novel nanotechnology-based anticancer therapies. In this review, we evaluate the potential of the nanomedicine and zebrafish synergy to achieve personalized treatments for cancer. Cancer causes millions of deaths each year and thus urgently requires the development of new therapeutic strategies. Nanotechnology-based anticancer therapies are a promising approach, with several formulations already approved and in clinical use. The evaluation of these therapies requires efficient in vivo models to study their behavior and interaction with cancer cells, and to optimize their properties to ensure maximum efficacy and safety. In this way, zebrafish is an important candidate due to its high homology with the human genoma, its large offspring, and the ease in developing specific cancer models. The role of zebrafish as a model for anticancer therapy studies has been highly evidenced, allowing researchers not only to perform drug screenings but also to evaluate novel therapies such as immunotherapies and nanotherapies. Beyond that, zebrafish can be used as an "avatar" model for performing patient-derived xenografts for personalized medicine. These characteristics place zebrafish in an attractive position as a role model for evaluating novel therapies for cancer treatment, such as nanomedicine. [ABSTRACT FROM AUTHOR]

Bullying has a negative impact on adolescents' emotional and social development, especially in the case of victims. This study aims to explore the association of engagement in bullying behaviours, for both the victim and aggressor, with psychological well-being. A non-experimental, cross-sectional and correlational quantitative study was designed, with the participation of 570 students between 14 and 15 years old (SD 0.99), of which 50.5% were girls and 49.5% boys, who were selected through stratified random sampling. Mean differences, bivariate correlations and multiple linear regressions were calculated to study the relationship between bullying and psychological well-being. Victims scored lower for subjective well-being, with the educational and social implications that this means. As for the aggressors, who scored higher on well-being than non-aggressors, the question is raised as to whether well-being increases with aggression or whether aggression is the result of lower levels of well-being. Female bullying victims belonging to the older age group are the participant profile with the lowest well-being scores. This gender perspective can be considered not only with regards to coexistence and bullying prevention plans but also shows the need to promote psychological well-being to educate towards equality. [ABSTRACT FROM AUTHOR]

Drug side effects are one of the main reasons for treatment withdrawal during clinical trials. Reactive oxygen species formation is involved in many of the drug side effects, mainly by interacting with the components of the cellular respiration. Thus, the early detection of these effects in the drug discovery process is a key aspect for the optimization of pharmacological research. To this end, the superoxide formation of a series of drugs and compounds with antidepressant, antipsychotic, anticholinergic, narcotic, and analgesic properties was evaluated in isolated bovine heart membranes and on cell membrane microarrays from a collection of human tissues, together with specific inhibitors of the mitochondrial electron transport chain. Fluphenazine and PB28 promoted similar effects to those of rotenone, but with lower potency, indicating a direct action on mitochondrial complex I. Moreover, nefazodone, a drug withdrawn from the market due to its mitochondrial hepatotoxic effects, evoked the highest superoxide formation in human liver cell membranes, suggesting the potential of this technology to anticipate adverse effects in preclinical phases. [ABSTRACT FROM AUTHOR]

Psychophysical methods allow us to measure the relationship between stimuli and sensory perception. Of these, Detection Threshold (DT) allows us to know the minimum concentration to produce taste identification. Given this, we wonder whether, for example, wine tasting experts are more capable of perceiving their sensory properties than other people, or whether they can distinguish them because they are better able to “describe” them. To verify this, this study analyses the influence of having prior knowledge of the name astringency and, failing that, to detect it and distinguish it between the four basic tastes. One-hundred-and-sixty-two university students with an average age of 19.43 (SD = 2.55) years were assigned to three experimental conditions: an experimental group (G.2) without previous knowledge of the name astringency and with alimentary satiety, and two control groups, both with previous knowledge of the name, these being G.1, with satiety, and G.3, with hunger. DT was collected for the four basic tastes and astringencies. Results showed significant differences in the identification of astringency, being the least identified experimental group with respect to the control groups. It is striking that G.2, without prior knowledge of the name, identified astringency as a bitter taste in most cases. This supports our hypothesis of the importance of attending to linguistic cognitive processes when psychophysically estimating taste in humans. [ABSTRACT FROM AUTHOR]

Background: Zebrafish (Danio rerio) is a model organism for the study of human cancer. Compared with the murine model, the zebrafish model has several properties ideal for personalized therapies. The transparency of the zebrafish embryos and the development of the pigment-deficient "casper" zebrafish line give the capacity to directly observe cancer formation and progression in the living animal. Automatic quantification of cellular proliferation in vivo is critical to the development of personalized medicine. Methods: A new methodology was defined to automatically quantify the cancer cellular evolution. ZFTool was developed to establish a base threshold that eliminates the embryo autofluorescence, automatically measures the area and intensity of GFP (green-fluorescent protein) marked cells, and defines a proliferation index. Results: The proliferation index automatically computed on different targets demonstrates the efficiency of ZFTool to provide a good automatic quantification of cancer cell evolution and dissemination. Conclusion: Our results demonstrate that ZFTool is a reliable tool for the automatic quantification of the proliferation index as a measure of cancer mass evolution in zebrafish, eliminating the influence of its autofluorescence. [ABSTRACT FROM AUTHOR]

Biallelic mutations in RECQL4 gene, a caretaker of the genome, cause Rothmund-Thomson type-II syndrome (RTS-II) and confer increased cancer risk if they damage the helicase domain. We describe five families exemplifying clinical and allelic heterogeneity of RTS-II, and report the effect of pathogenic RECQL4 variants by in silico predictions and transcripts analyses. Complete phenotype of patients #39 and #42 whose affected siblings developed osteosarcoma correlates with their c.[1048_1049del], c.[1878+32_1878+55del] and c.[1568G>C;1573delT], c.[3021_3022del] variants which damage the helicase domain. Literature survey highlights enrichment of these variants affecting the helicase domain in patients with cancer outcome raising the issue of strict oncological surveillance. Conversely, patients #29 and #19 have a mild phenotype and carry, respectively, the unreported homozygous c.3265G>T and c.3054A>G variants, both sparing the helicase domain. Finally, despite matching several criteria for RTS clinical diagnosis, patient #38 is heterozygous for c.2412_2414del; no pathogenic CNVs out of those evidenced by high-resolution CGH-array, emerged as contributors to her phenotype. [ABSTRACT FROM AUTHOR]

All retinal disorders, regardless of their aetiology, involve the activation of oxidative stress and apoptosis pathways. The administration of neuroprotective factors is crucial in all phases of the pathology, even when vision has been completely lost. The retina is one of the most susceptible tissues to reactive oxygen species damage. On the other hand, proper development and functioning of the retina requires a precise balance between the processes of proliferation, differentiation and programmed cell death. The life-or-death decision seems to be the result of a complex balance between pro- and anti-apoptotic signals. It has been recently shown the efficacy of natural products to slow retinal degenerative process through different pathways. In this review, we assess the neuroprotective effect of two compounds used in the ancient pharmacopoeia. On one hand, it has been demonstrated that administration of the saffron constituent safranal to P23H rats, an animal model of retinitis pigmentosa, preserves photoreceptor morphology and number, the capillary network and the visual response. On the other hand, it has been shown that systemic administration of tauroursodeoxycholic acid (TUDCA), the major component of bear bile, to P23H rats preserves cone and rod structure and function, together with their contact with postsynaptic neurons. The neuroprotective effects of safranal and TUDCA make these compounds potentially useful for therapeutic applications in retinal degenerative diseases. [ABSTRACT FROM AUTHOR]

The development of new approaches to obtain optically pure β-hydroxy esters is an important area in synthetic organic chemistry since they are precursors of other high value compounds. Herein, the kinetic resolution of racemic β-hydroxy esters using a planar-chiral DMAP derivative catalyst is presented. Following this procedure, a range of aromatic β-hydroxy esters was obtained in excellent selectivities (up to s = 107) and high enantiomeric excess (up to 99% ee). Furthermore, the utility of the present method was demonstrated in the synthesis of (S)-3-hydroxy-N-methyl-3-phenylpropanamide, a key intermediate for bioactive molecules such as fluoxetine, tomoxetine or nisoxetine, in its enantiomerically pure form. [ABSTRACT FROM AUTHOR]

Air-quality monitoring and analysis are initial parts of a comprehensive strategy to prevent air pollution in cities. In such a context, statistical tools play an important role in determining the time-series trends, locating areas with high pollutant concentrations, and building predictive models. In this work, we analyzed the spatio-temporal behavior of the pollutant PM10 in the Monterrey Metropolitan Area (MMA), Mexico during the period 2010–2018 by applying statistical analysis to the time series of seven environmental stations. First, we used experimental variograms and scientific visualization to determine the general trends and variability in time. Then, fractal exponents (the Hurst rescaled range and Higuchi algorithm) were used to analyze the long-term dependence of the time series and characterize the study area by correlating that dependence with the geographical parameters of each environmental station. The results suggest a linear decrease in PM10 concentration, which showed an annual cyclicity. The autumn-winter period was the most polluted and the spring-summer period was the least. Furthermore, it was found that the highest average concentrations are located in the western and high-altitude zones of the MMA, and that average concentration is related in a quadratic way to the Hurst and Higuchi exponents, which in turn are related to some geographic parameters. Therefore, in addition to the results for the MMA, the present paper shows three practical statistical methods for analyzing the spatio-temporal behavior of air quality. [ABSTRACT FROM AUTHOR]

It is largely assumed that the teleost retina shows continuous and active proliferative and neurogenic activity throughout life. However, when delving into the teleost literature, one finds that assumptions about a highly active and continuous proliferation in the adult retina are based on studies in which proliferation was not quantified in a comparative way at the different life stages or was mainly studied in juveniles/young adults. Here, we performed a systematic and comparative study of the constitutive proliferative activity of the retina from early developing (2 days post-fertilisation) to aged (up to 3–4 years post-fertilisation) zebrafish. The mitotic activity and cell cycle progression were analysed by using immunofluorescence against pH3 and PCNA, respectively. We observed a decline in the cell proliferation in the retina with ageing despite the occurrence of a wave of secondary proliferation during sexual maturation. During this wave of secondary proliferation, the distribution of proliferating and mitotic cells changes from the inner to the outer nuclear layer in the central retina. Importantly, in aged zebrafish, there is a virtual disappearance of mitotic activity. Our results showing a decline in the proliferative activity of the zebrafish retina with ageing are of crucial importance since it is generally assumed that the fish retina has continuous proliferative activity throughout life. [ABSTRACT FROM AUTHOR]

The remarkable adsorption capacity of graphene-derived materials has prompted their examination in composite materials suitable for deployment in treatment of contaminated waters. In this study, crosslinked calcium alginate–graphene oxide beads were prepared and activated by exposure to pH 4 by using 0.1M HCl. The activated beads were investigated as novel adsorbents for the removal of organic pollutants (methylene blue dye and the pharmaceuticals famotidine and diclofenac) with a range of physicochemical properties. The effects of initial pollutant concentration, temperature, pH, and adsorbent dose were investigated, and kinetic models were examined for fit to the data. The maximum adsorption capacities qmax obtained were 1334, 35.50 and 36.35 mg g−1 for the uptake of methylene blue, famotidine and diclofenac, respectively. The equilibrium adsorption had an alignment with Langmuir isotherms, while the kinetics were most accurately modelled using pseudo- first-order and second order models according to the regression analysis. Thermodynamic parameters such as ΔG°, ΔH° and ΔS° were calculated and the adsorption process was determined to be exothermic and spontaneous. [ABSTRACT FROM AUTHOR]

Background: Cancer metastasis is a deathly process, and a better understanding of the different steps is needed. The shedding of circulating tumor cells (CTCs) and CTC-cluster from the primary tumor, its survival in circulation, and homing are key events of the metastasis cascade. In vitro models of CTCs and in vivo models of metastasis represent an excellent opportunity to delve into the behavior of metastatic cells, to gain understanding on how secondary tumors appear. Methods: Using the zebrafish embryo, in combination with the mouse and in vitro assays, as an in vivo model of the spatiotemporal development of metastases, we study the metastatic competency of breast cancer CTCs and CTC-clusters and the molecular mechanisms. Results: CTC-clusters disseminated at a lower frequency than single CTCs in the zebrafish and showed a reduced capacity to invade. A temporal follow-up of the behavior of disseminated CTCs showed a higher survival and proliferation capacity of CTC-clusters, supported by their increased resistance to fluid shear stress. These data were corroborated in mouse studies. In addition, a differential gene signature was observed, with CTC-clusters upregulating cell cycle and stemness related genes. Conclusions: The zebrafish embryo is a valuable model system to understand the biology of breast cancer CTCs and CTC-clusters. [ABSTRACT FROM AUTHOR]

The clinical success of cisplatin, carboplatin, and oxaliplatin has sparked the interest of medicinal inorganic chemistry to synthesize and study compounds with non-platinum metal centers. Despite Ru(II)–polypyridyl complexes being widely studied and well established for their antitumor properties, there are not enough in vivo studies to establish the potentiality of this type of compound. Therefore, we report to the best of our knowledge the first in vivo study of Ru(II)–polypyridyl complexes against breast cancer with promising results. In order to conduct our study, we used MCF7 zebrafish xenografts and ruthenium complexes [Ru(bipy)2(C12H8N6-N,N)][CF3SO3]2Ru1 and [{Ru(bipy)2}2(μ-C12H8N6-N,N)][CF3SO3]4Ru2, which were recently developed by our group. Ru1 and Ru2 reduced the tumor size by an average of 30% without causing significant signs of lethality when administered at low doses of 1.25 mg·L−1. Moreover, the in vitro selectivity results were confirmed in vivo against MCF7 breast cancer cells. Surprisingly, this work suggests that both the mono- and the dinuclear Ru(II)–polypyridyl compounds have in vivo potential against breast cancer, since there were no significant differences between both treatments, highlighting Ru1 and Ru2 as promising chemotherapy agents in breast cancer therapy. [ABSTRACT FROM AUTHOR]

New nanoparticles and biomaterials are increasingly being used in biomedical research for drug delivery, diagnostic applications, or vaccines, and they are also present in numerous commercial products, in the environment and workplaces. Thus, the evaluation of the safety and possible therapeutic application of these nanomaterials has become of foremost importance for the proper progress of nanotechnology. Due to economical and ethical issues, in vitro and in vivo methods are encouraged for the testing of new compounds and/or nanoparticles, however in vivo models are still needed. In this scenario, zebrafish (Danio rerio) has demonstrated potential for toxicological and pharmacological screenings. Zebrafish presents an innate immune system, from early developmental stages, with conserved macrophage phenotypes and functions with respect to humans. This fact, combined with the transparency of zebrafish, the availability of models with fluorescently labelled macrophages, as well as a broad variety of disease models offers great possibilities for the testing of new nanoparticles. Thus, with a particular focus on macrophage–nanoparticle interaction in vivo, here, we review the studies using zebrafish for toxicological and biodistribution testing of nanoparticles, and also the possibilities for their preclinical evaluation in various diseases, including cancer and autoimmune, neuroinflammatory, and infectious diseases. [ABSTRACT FROM AUTHOR]

The neural crest is a multipotent cell population that develops from the dorsal neural fold of vertebrate embryos in order to migrate extensively and differentiate into a variety of tissues. A number of gene regulatory networks coordinating neural crest cell specification and differentiation have been extensively studied to date. Although several publications suggest a common role for microRNA-145 (miR-145) in molecular reprogramming for cell cycle regulation and/or cellular differentiation, little is known about its role during in vivo cranial neural crest development. By modifying miR-145 levels in zebrafish embryos, abnormal craniofacial development and aberrant pigmentation phenotypes were detected. By whole-mount in situ hybridization, changes in expression patterns of col2a1a and Sry-related HMG box (Sox) transcription factors sox9a and sox9b were observed in overexpressed miR-145 embryos. In agreement, zebrafish sox9b expression was downregulated by miR-145 overexpression. In silico and in vivo analysis of the sox9b 3′UTR revealed a conserved potential miR-145 binding site likely involved in its post-transcriptional regulation. Based on these findings, we speculate that miR-145 participates in the gene regulatory network governing zebrafish chondrocyte differentiation by controlling sox9b expression. [ABSTRACT FROM AUTHOR]

Complement overactivation has been reported in most patients with Barraquer–Simons syndrome (BSS), a rare form of acquired partial lipodystrophy. Complement Factor D (FD) is a serine protease with a crucial role in the activation of the alternative pathway of the complement system, which is mainly synthesized by adipose tissue. However, its role in the pathogenesis of BSS has not been addressed. In this study, plasma FD concentration was measured in 13 patients with BSS, 20 patients with acquired generalized lipodystrophy, 22 patients with C3 glomerulopathy (C3G), and 50 healthy controls. Gene expression and immunohistochemistry studies were assayed using atrophied adipose tissue from a patient with BSS. We found significantly elevated FD levels in BSS cases compared with the remaining cohorts (p < 0.001). There were no significant differences in FD levels between sexes but FD was strongly and directly associated with age in BSS (r = 0.7593, p = 0.0036). A positive correlation between FD and C3 was seen in patients with C3G, characterized by decreased FD levels due to chronic C3 consumption, but no correlation was detected for BSS. Following mRNA quantification in the patient's adipose tissue, we observed decreased CFD and C3 but elevated C5 transcript levels. In contrast, the increased FD staining detected in the atrophied areas reflects the effects of persistent tissue damage on the adipose tissue, thus providing information on the ongoing pathogenic process. Our results suggest that FD could be a reliable diagnostic biomarker involved in the pathophysiology of BSS by promoting unrestrained local complement system activation in the adipose tissue environment. [ABSTRACT FROM AUTHOR]

Autosomal recessive ataxias are much less well studied than autosomal dominant ataxias and there are no clearly defined systems to classify them. Autosomal recessive ataxias, which are characterized by neuronal and multisystemic features, have significant overlapping symptoms with other complex multisystemic recessive disorders. The generation of animal models of neurodegenerative disorders increases our knowledge of their cellular and molecular mechanisms and helps in the search for new therapies. Among animal models, the zebrafish, which shares 70% of its genome with humans, offer the advantages of being small in size and demonstrating rapid development, making them optimal for high throughput drug and genetic screening. Furthermore, embryo and larval transparency allows to visualize cellular processes and central nervous system development in vivo. In this review, we discuss the contributions of zebrafish models to the study of autosomal recessive ataxias characteristic phenotypes, behavior, and gene function, in addition to commenting on possible treatments found in these models. Most of the zebrafish models generated to date recapitulate the main features of recessive ataxias. [ABSTRACT FROM AUTHOR]

Simple Summary: Glioblastoma (GBM) is one of the greatest challenges facing neuro-oncology today. Current treatments are far from satisfactory and, given the poor prognosis of the disease, therapeutic efforts are focused on palliative management rather than curative intervention. Here, we review the cellular heterogeneity of GBM, including tumor cells and microglia/macrophages among others, as well as the genetic, epigenetic and metabolic alterations controlling its initiation and progression. Then, we describe the genetic and xenotransplantation zebrafish models established in the last few years for the study of GBM physiopathology and for testing new drugs to improve the treatment of the disease. Taking this information into account, forthcoming studies using zebrafish models of GBM are expected to shed light on better diagnosis and treatments, thus providing hope for GBM patients. Glioblastoma (GBM) is the most common of all brain malignant tumors; it displays a median survival of 14.6 months with current complete standard treatment. High heterogeneity, aggressive and invasive behavior, the impossibility of completing tumor resection, limitations for drug administration and therapeutic resistance to current treatments are the main problems presented by this pathology. In recent years, our knowledge of GBM physiopathology has advanced significantly, generating relevant information on the cellular heterogeneity of GBM tumors, including cancer and immune cells such as macrophages/microglia, genetic, epigenetic and metabolic alterations, comprising changes in miRNA expression. In this scenario, the zebrafish has arisen as a promising animal model to progress further due to its unique characteristics, such as transparency, ease of genetic manipulation, ethical and economic advantages and also conservation of the major brain regions and blood–brain–barrier (BBB) which are similar to a human structure. A few papers described in this review, using genetic and xenotransplantation zebrafish models have been used to study GBM as well as to test the anti-tumoral efficacy of new drugs, their ability to interact with target cells, modulate the tumor microenvironment, cross the BBB and/or their toxicity. Prospective studies following these lines of research may lead to a better diagnosis, prognosis and treatment of patients with GBM. [ABSTRACT FROM AUTHOR]

Acute porphyria attacks are associated with the strong up-regulation of hepatic heme synthesis and over-production of neurotoxic heme precursors. First-line therapy is based on carbohydrate loading. However, altered glucose homeostasis could affect its efficacy. Our first aim was to investigate the prevalence of insulin resistance (IR) in an observational case-control study including 44 Spanish patients with acute intermittent porphyria (AIP) and 55 age-, gender- and BMI-matched control volunteers. Eight patients (18.2%) and one control (2.3%, p = 0.01) showed a high HOMA-IR index (cut-off ≥ 3.4). Patients with IR and hyperinsulinemia showed clinically stable disease. Thus, the second aim was to evaluate the effect of the co-administration of glucose and a fast-acting or new liver-targeted insulin (the fusion protein of insulin and apolipoprotein A-I, Ins-ApoAI) in AIP mice. The combination of glucose and the Ins-ApoAI promoted partial but sustained protection against hepatic heme synthesis up-regulation compared with glucose alone or co-injected with fast-acting insulin. In a prevention study, Ins-ApoAI improved symptoms associated with a phenobarbital-induced attack but maintained high porphyrin precursor excretion, probably due to the induction of hepatic mitochondrial biogenesis mediated by apolipoprotein A-I. In conclusion, a high prevalence of IR and hyperinsulinemia was observed in patients with AIP. The experimental data provide proof-of-concept for liver-targeted insulin as a way of enhancing glucose therapy for AIP. [ABSTRACT FROM AUTHOR]

Simple Summary: Due to their intrinsic aggressiveness, cancer stem cells (CSCs) represent an essential target for the design of effective treatments against pancreatic cancer, one of the deadliest tumors. As pancreatic CSCs are particularly dependent on the activity of their mitochondria, we here focus on mitochondrial dynamics as a critical process in the homeostasis of these organelles. We find that pancreatic CSCs rely on mitochondrial fission, and its pharmacological inhibition by mDivi-1 resulted in the accumulation of dysfunctional mitochondria, provoking an energy crisis and cell death in this subpopulation. Consequently, mDivi-1 blocked cellular functions related to cancer aggressiveness such as in vivo tumorigenicity, invasiveness, and chemoresistance. Our data suggest that the inhibition of mitochondrial fission represents a promising target for designing new multimodal therapies to fight pancreatic cancer. Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest tumors, partly due to its intrinsic aggressiveness, metastatic potential, and chemoresistance of the contained cancer stem cells (CSCs). Pancreatic CSCs strongly rely on mitochondrial metabolism to maintain their stemness, therefore representing a putative target for their elimination. Since mitochondrial homeostasis depends on the tightly controlled balance between fusion and fission processes, namely mitochondrial dynamics, we aim to study this mechanism in the context of stemness. In human PDAC tissues, the mitochondrial fission gene DNM1L (DRP1) was overexpressed and positively correlated with the stemness signature. Moreover, we observe that primary human CSCs display smaller mitochondria and a higher DRP1/MFN2 expression ratio, indicating the activation of the mitochondrial fission. Interestingly, treatment with the DRP1 inhibitor mDivi-1 induced dose-dependent apoptosis, especially in CD133+ CSCs, due to the accumulation of dysfunctional mitochondria and the subsequent energy crisis in this subpopulation. Mechanistically, mDivi-1 inhibited stemness-related features, such as self-renewal, tumorigenicity, and invasiveness and chemosensitized the cells to the cytotoxic effects of Gemcitabine. In summary, mitochondrial fission is an essential process for pancreatic CSCs and represents an attractive target for designing novel multimodal treatments that will more efficiently eliminate cells with high tumorigenic potential. [ABSTRACT FROM AUTHOR]

This study represents a novel proof of concept of the clinical utility of miRNAs from exhaled breath condensate (EBC) as biomarkers of lung cancer (LC). Genome-wide miRNA profiling and machine learning analysis were performed on EBC from 21 healthy volunteers and 21 LC patients. The levels of 12 miRNAs were significantly altered in EBC from LC patients where a specific signature of miR-4507, miR-6777-5p and miR-451a distinguished these patients with high accuracy. Besides, a distinctive miRNA profile between LC adenocarcinoma and squamous cell carcinoma was observed, where a combined panel of miR-4529-3p, miR-8075 and miR-7704 enabling discrimination between them. EBC levels of miR-6777-5p, 6780a-5p and miR-877-5p predicted clinical outcome at 500 days. Two additional miRNA signatures were also associated with other clinical features such as stage and invasion status. Dysregulated EBC miRNAs showed potential target genes related to LC pathogenesis, including CDKN2B, PTEN, TP53, BCL2, KRAS and EGFR. We conclude that EBC miRNAs might allow the identification, stratification and monitorization of LC, which could lead to the development of precision medicine in this and other respiratory diseases. [ABSTRACT FROM AUTHOR]

Hereditary dominant ataxias are a heterogeneous group of neurodegenerative conditions causing cerebellar dysfunction and characterized by progressive motor incoordination. Despite many efforts put into the study of these diseases, there are no effective treatments yet. Zebrafish models are widely used to characterize neuronal disorders due to its conserved vertebrate genetics that easily support genetic edition and their optic transparency that allows observing the intact CNS and its connections. In addition, its small size and external fertilization help to develop high throughput assays of candidate drugs. Here, we discuss the contributions of zebrafish models to the study of dominant ataxias defining phenotypes, genetic function, behavior and possible treatments. In addition, we review the zebrafish models created for X-linked repeat expansion diseases X-fragile/fragile-X tremor ataxia. Most of the models reviewed here presented neuronal damage and locomotor deficits. However, there is a generalized lack of zebrafish adult heterozygous models and there are no knock-in zebrafish models available for these diseases. The models created for dominant ataxias helped to elucidate gene function and mechanisms that cause neuronal damage. In the future, the application of new genetic edition techniques would help to develop more accurate zebrafish models of dominant ataxias. [ABSTRACT FROM AUTHOR]