Search

Summary: Pancreatic ductal adenocarcinoma (PDAC) represents the most prevalent type of pancreatic cancer and ranks among the most aggressive tumours, with a 5-year survival rate of less than 11%. Projections indicate that by 2030, it will become the second leading cause of cancer-related deaths. PDAC presents distinctive hallmarks contributing to its dismal prognosis: (i) late diagnosis, (ii) heterogenous and complex mutational landscape, (iii) high metastatic potential, (iv) dense fibrotic stroma, (v) immunosuppressive microenvironment, and (vi) high resistance to therapy. Mounting evidence has shown a role for TAM (Tyro3, AXL, MerTK) family of tyrosine kinase receptors in PDAC initiation and progression. This review aims to describe the impact of TAM receptors on the defining hallmarks of PDAC and discuss potential future directions using these proteins as novel biomarkers for early diagnosis and targets for precision therapy in PDAC, an urgent unmet clinical need.

Abstract Accumulation of lipid-laden macrophages within the arterial neointima is a critical step in atherosclerotic plaque formation. Here, we show that reduced levels of the cellular plasticity factor ZEB1 in macrophages increase atherosclerotic plaque formation and the chance of cardiovascular events. Compared to control counterparts (Zeb1 WT/Apoe KO), male mice with Zeb1 ablation in their myeloid cells (Zeb1 ∆M/Apoe KO) have larger atherosclerotic plaques and higher lipid accumulation in their macrophages due to delayed lipid traffic and deficient cholesterol efflux. Zeb1 ∆M/Apoe KO mice display more pronounced systemic metabolic alterations than Zeb1 WT/Apoe KO mice, with higher serum levels of low-density lipoproteins and inflammatory cytokines and larger ectopic fat deposits. Higher lipid accumulation in Zeb1 ∆M macrophages is reverted by the exogenous expression of Zeb1 through macrophage-targeted nanoparticles. In vivo administration of these nanoparticles reduces atherosclerotic plaque formation in Zeb1 ∆M/Apoe KO mice. Finally, low ZEB1 expression in human endarterectomies is associated with plaque rupture and cardiovascular events. These results set ZEB1 in macrophages as a potential target in the treatment of atherosclerosis.

Transcranial direct current stimulation (tDCS) has emerged as a potential intervention to improve physical performance. This study investigates the effects of tDCS applied to the primary motor cortex (M1) and dorsolateral prefrontal cortex (DLPFC) on performance in a maximal effort task, specifically the No-Jump Burpee exercise. Twenty healthy male subjects (26.0 ± 4.91 years) completed three experimental conditions (a-DLPFC, a-M1, and SHAM) in a double-blind crossover design. Prior to the performance of burpees to exhaustion, tDCS (2 mA, 20 min) was administered. The total number of repetitions, vastus lateralis muscle oxygen saturation, heart rate, and subjective perception of exertion (RPE) during exercise were measured. Repeated ANOVAs showed a significant effect of condition on the number of repetitions (p < 0.001). Subjects performed more repetitions under the M1 condition (68 ± 19.5) compared to DLPFC (63 ± 17.9) and SHAM (58 ± 18.0), with significant differences between all conditions. This study demonstrates that tDCS can improve performance in a physical endurance task such as the No-Jump Burpee. The findings suggest that tDCS may be a viable ergogenic tool for improving athletic performance. Future research should explore the underlying mechanisms and the practical application of these results in long-term physical training programs (NCT06472882).

Abstract Aims Inhibitors of SGLT2 (SGLT2i) have shown a positive impact in patients with chronic heart failure and reduced ejection fraction (HFrEF). Nonetheless, the direct effects of SGLT2i on cardiac cells and how their association with main drugs used for HFrEF affect the behaviour and signalling pathways of myocardial fibroblasts are still unknown. We aimed to determine the effects of dapagliflozin alone and in combination with sacubitril/valsartan (LCZ696) or spironolactone on the function of myocardial fibroblasts of patients with heart failure and reduced ejection fraction (HFrEF). Methods and results Myocardial fibroblasts isolated from HFrEF patients (n = 5) were treated with dapagliflozin alone (1 nM–1 μM) or combined with LCZ696 (100 nM) or spironolactone (100 nM). The migratory rate was determined by wound‐healing scratch assay. Expression of heart failure (HF) markers and signalling pathways activation were analysed with multiplexed protein array. Commercially available cardiac fibroblasts from healthy donors were used as Control (n = 4). Fibroblasts from HFrEF show higher migratory rate compared with control (P = 0.0036), and increased expression of HF markers [fold‐change (Log2): COL1A1–1.3; IL‐1b–1.9; IL‐6–1.7; FN1–2.9 (P

Due to demographic changes, the world’s population is progressively aging. The physiological deterioration of the older adult may lead to reduced balance capacity and increased risk of falls, among others, due to the prevalence of degenerative diseases. Physical exercise can be effective in reducing the risk of disease and slowing functional decline in older people. The aim of the research is to test the effects of aquatic resistance training and dietary education on health indicators, strength, balance, functional autonomy, perception of satisfaction with life. Thirty-four participants aged 69 ± 4 years were randomly assigned into two groups: experimental (aquatic resistance interval training) and control group (no intervention). The intervention consisted of resistance training in an aquatic environment carried out for 14 weeks (three sessions per week: 60 min each). All variables were analyzed twice; pre - post intervention. Aquatic resistance training has positive effects on strength (p < 0.001), functional self-sufficiency (p < 0.001) and aerobic capacity (p < 0.001), however, no significant differences were observed in the perception of satisfaction with life and balance. Research results suggest that older women who engage in regular, scheduled aquatic resistance training have greater autonomy in performing activities of daily living, agility, gait control, and body composition variables (lower fat compartment and greater muscle mass).

Transcranial direct current stimulation (tDCS) has emerged as a potential intervention to improve physical performance. This study investigates the effects of tDCS applied to the primary motor cortex (M1) and dorsolateral prefrontal cortex (DLPFC) on performance in a maximal effort task, specifically the No-Jump Burpee exercise. Twenty healthy male subjects (26.0 ± 4.91 years) completed three experimental conditions (a-DLPFC, a-M1, and SHAM) in a double-blind crossover design. Prior to the performance of burpees to exhaustion, tDCS (2 mA, 20 min) was administered. The total number of repetitions, vastus lateralis muscle oxygen saturation, heart rate, and subjective perception of exertion (RPE) during exercise were measured. Repeated ANOVAs showed a significant effect of condition on the number of repetitions (p < 0.001). Subjects performed more repetitions under the M1 condition (68 ± 19.5) compared to DLPFC (63 ± 17.9) and SHAM (58 ± 18.0), with significant differences between all conditions. This study demonstrates that tDCS can improve performance in a physical endurance task such as the No-Jump Burpee. The findings suggest that tDCS may be a viable ergogenic tool for improving athletic performance. Future research should explore the underlying mechanisms and the practical application of these results in long-term physical training programs (NCT06472882). [ABSTRACT FROM AUTHOR]

Background and Aims: GAS6 signaling, through the TAM receptor tyrosine kinases AXL and MERTK, participates in chronic liver pathologies. Here, we addressed GAS6/TAM involvement in Non-Alcoholic SteatoHepatitis (NASH) development. Methods: GAS6/TAM signaling was analyzed in cultured primary hepatocytes, hepatic stellate cells (HSC) and Kupffer cells (KCs). Axl-/-, Mertk-/- and wild-type C57BL/6 mice were fed with Chow, High Fat Choline-Deficient Methionine-Restricted (HFD) or methionine-choline-deficient (MCD) diet. HSC activation, liver inflammation and cytokine/chemokine production were measured by qPCR, mRNA Array analysis, western blotting and ELISA. GAS6, soluble AXL (sAXL) and MERTK (sMERTK) levels were analyzed in control individuals, steatotic and NASH patients. Results: In primary mouse cultures, GAS6 or MERTK activation protected primary hepatocytes against lipid toxicity via AKT/STAT-3 signaling, while bemcentinib (small molecule AXL inhibitor BGB324) blocked AXL-induced fibrogenesis in primary HSCs and cytokine production in LPS-treated KCs. Accordingly; bemcentinib diminished liver inflammation and fibrosis in MCD- and HFD-fed mice. Upregulation of AXL and ADAM10/ADAM17 metalloproteinases increased sAXL in HFD-fed mice. Transcriptome profiling revealed major reduction in fibrotic- and inflammatory-related genes in HFD-fed mice after bemcentinib administration. HFD-fed Mertk-/- mice exhibited enhanced NASH, while Axl-/- mice were partially protected. In human serum, sAXL levels augmented even at initial stages, whereas GAS6 and sMERTK increased only in cirrhotic NASH patients. In agreement, sAXL increased in HFD-fed mice before fibrosis establishment, while bemcentinib prevented liver fibrosis/inflammation in early NASH. Conclusion: AXL signaling, increased in NASH patients, promotes fibrosis in HSCs and inflammation in KCs, while GAS6 protects cultured hepatocytes against lipotoxicity via MERTK. Bemcentinib, by blocking AXL signaling and increasing GAS6 levels, reduces experimental NASH, revealing AXL as an effective therapeutic target for clinical practice. Keywords: Liver Fibrosis, Hepatic Stellate Cells, Bemcentinib (BGB324), GAS6/TAM Signaling, Liver Inflammation

Summary: Background: Early diagnosis is crucial for patients with pancreatic ductal adenocarcinoma (PDAC). The AXL receptor tyrosine kinase is proteolytically processed releasing a soluble form (sAXL) into the blood stream. Here we explore the use of sAXL as a biomarker for PDAC. Methods: AXL was analysed by immunohistochemistry in human pancreatic tissue samples. RNA expression analysis was performed using TCGA/GTEx databases. The plasma concentrations of sAXL, its ligand GAS6, and CA19-9 were studied in two independent cohorts, the HMar cohort (n = 59) and the HClinic cohort (n = 142), including healthy controls, chronic pancreatitis (CP) or PDAC patients, and in a familial PDAC cohort (n = 68). AXL expression and sAXL release were studied in PDAC cell lines and murine models. Findings: AXL is increased in PDAC and precursor lesions as compared to CP or controls. sAXL determined in plasma from two independent cohorts was significantly increased in the PDAC group as compared to healthy controls or CP patients. Patients with high levels of AXL have a lower overall survival. ROC analysis of the plasma levels of sAXL, GAS6, or CA19-9 in our cohorts revealed that sAXL outperformed CA19-9 for discriminating between CP and PDAC. Using both sAXL and CA19-9 increased the diagnostic value. These results were validated in murine models, showing increased sAXL specifically in animals developing PDAC but not those with precursor lesions or acinar tumours. Interpretation: sAXL appears as a biomarker for early detection of PDAC and PDAC–CP discrimination that could accelerate treatment and improve its dismal prognosis. Funding: This work was supported by grants PI20/00625 (PN), RTI2018-095672-B-I00 (AM and PGF), PI20/01696 (MG) and PI18/01034 (AC) from MICINN-FEDER and grant 2017/SGR/225 (PN) from Generalitat de Catalunya.

Energy deficits are often observed in athletes, especially in female athletes, due to the high expenditure of sport and strict diets. Low energy availability can cause serious health problems and affect sport performance. The aim of this study was to evaluate the effects of different personalized dietary plans on physiological and physical factors related to energy deficit syndrome in female professional handball players. Twenty-one professional female handball players, aged 22 ± 4 years, 172.0 ± 5.4 cm and 68.4 ± 6.7 kg, divided into three groups (FD: free diet; MD: Mediterranean diet; and AD: high antioxidant diet), participated in this 12-week randomized controlled trial. Energy expenditure through indirect calorimetry, energy availability, 7 day dietary intake analysis, blood pressure, cholesterol, menstrual function, body composition by both anthropometry and bioelectrical impedance, and strength performance were assessed. All participants showed low energy availability (p < 0.05). In the remaining variables, despite slight improvements, none were significant neither over time nor between the different groups. Low energy availability has been observed in all professional female handball players, which may lead to serious consequences. A longer period of intervention is required to assess the differences between diets and improvements in other parameters.

Resumen Los datos de las condiciones del aire en el interior de los edificios son aspectos ampliamente recogidos en la normativa internacional. En la intervención educativa de nivel superior se considera un práctica recomendable valorar la predisposición al estudio y las sensaciones de los estudiantes sobre el efecto sobre su rendimiento académico en función de variables ambientales. Los parámetros de confort en los centros educativos no contemplan las singularidades propias de un proceso de aprendizaje. La visión de los estudiantes de cómo les afectan las diferentes variables medioambientales es estudiada. Aquellos aspectos que más les preocupan o la conciencia que tienen de sus propias percepciones ayudan a mejorar las condiciones del entorno y eso a su vez les posibilita a alcanzar de una mejor manera sus objetivos. Es importante manifestar la preocupación que tienen los estudiantes sobre la calidad del aire, los rangos de temperatura, humedad, etc y si hay otros factores que consideren importantes. La sensibilidad o el valor de la resiliencia ante factores climáticos de cada individuo han de ser un factor clave para encontrar los límites aceptables. Por tanto, se procesa en este estudio de forma transversal los datos aportados por las encuestas. La toma de datos se hace en varias fases para poder tomar opiniones de determinados aspectos en periodos diferentes pues, el estar condicionados por un clima extremo puntual, puede afectar a la percepción. Se recopila la información también de los profesionales docentes ya que su percepción puede tener una influencia decisiva en la gestión de equipos y de personas no vinculadas con el proceso de aprendizaje para tomar referencias externas. Se determina si existe una desviación excesiva comparando con la percepción con los usuarios mayoritarios. Abstract The data of the air conditions in the interior of the buildings are aspects broadly gathered in the international norm. In higher education intervention, it is considered a good practice to assess student's predisposition to study and feelings about the effect on their academic performance as a function of environmental variables. The comfort parameters in the educational centers do not contemplate the peculiarities characteristic of a learning process. The students' view of how they affect the different environmental variables is studied. Those aspects that most concern them or the awareness that they have of their own perceptions help improve the conditions of the environment and that in turn enables them to reach their goals better. It is important to express students' concerns about air quality, temperature ranges, humidity, etc., and whether there are other factors that they consider important. The sensitivity or value of resilience to each individual's climatic factors must be a key factor in finding acceptable limits. Therefore, the data provided by the surveys are processed in a transversal way. The data collection is done in several phases to be able to take opinions of certain aspects in different periods because, being conditioned by a extreme climatic moment, can affect the perception. Information is also collected from teaching professionals as their perception can have a decisive influence on the management of teams and people not linked to the learning process to take external references. It is determined whether there is an excessive deviation compared to the perception with the majority users.

Sorafenib and regorafenib, multikinase inhibitors (MKIs) used as standard chemotherapeutic agents for hepatocellular carcinoma (HCC), generate reactive oxygen species (ROS) during cancer treatment. Antioxidant supplements are becoming popular additions to our diet, particularly glutathione derivatives and mitochondrial-directed compounds. To address their possible interference during HCC chemotherapy, we analyzed the effect of common antioxidants using hepatoma cell lines and tumor spheroids. In liver cancer cell lines, sorafenib and regorafenib induced mitochondrial ROS production and potent cell death after glutathione depletion. In contrast, cabozantinib only exhibited oxidative cell death in specific HCC cell lines. After sorafenib and regorafenib administration, antioxidants such as glutathione methyl ester and the superoxide scavenger MnTBAP decreased cell death and ROS production, precluding the MKI activity against hepatoma cells. Interestingly, sorafenib-induced mitochondrial damage caused PINK/Parkin-dependent mitophagy stimulation, altered by increased ROS production. Finally, in sorafenib-treated tumor spheroids, while ROS induction reduced tumor growth, antioxidant treatments favored tumor development. In conclusion, the anti-tumor activity of specific MKIs, such as regorafenib and sorafenib, is altered by the cellular redox status, suggesting that uncontrolled antioxidant intake during HCC treatment should be avoided or only endorsed to diminish chemotherapy-induced side effects, always under medical scrutiny.

Abstract: Genetics play a significant role in venous thromboembolism (VTE), yet current clinical laboratory-based testing identifies a known heritable thrombophilia (factor V Leiden, prothrombin gene mutation G20210A, or a deficiency of protein C, protein S, or antithrombin) in only a minority of VTE patients. We hypothesized that a substantial number of VTE patients could have lesser-known thrombophilia mutations. To test this hypothesis, we performed whole-exome sequencing (WES) in 64 patients with VTE, focusing our analysis on a novel 55-gene extended thrombophilia panel that we compiled. Our extended thrombophilia panel identified a probable disease-causing genetic variant or variant of unknown significance in 39 of 64 study patients (60.9%), compared with 6 of 237 control patients without VTE (2.5%) (P < .0001). Clinical laboratory-based thrombophilia testing identified a heritable thrombophilia in only 14 of 54 study patients (25.9%). The majority of WES variants were either associated with thrombosis based on prior reports in the literature or predicted to affect protein structure based on protein modeling performed as part of this study. Variants were found in major thrombophilia genes, various SERPIN genes, and highly conserved areas of other genes with established or potential roles in coagulation or fibrinolysis. Ten patients (15.6%) had >1 variant. Sanger sequencing performed in family members of 4 study patients with and without VTE showed generally concordant results with thrombotic history. WES and extended thrombophilia testing are promising tools for improving our understanding of VTE pathogenesis and identifying inherited thrombophilias.

Las metodologías de aprendizaje tradicionales no son coherentes con los procesos de aprendizaje y descriptivos que irrumpen en las disciplinas de la mano de programas informáticos. La evolución del campo de las enseñanzas técnicas es muy veloz. Sin embargo, no hay tecnología que sea lo suficientemente rápida en su implantación que no permita el introducir nuevas formas de enseñanza.No debemos equivocarnos al hablar de aprendizaje multidimensional solamente en el sentido, que se le ha dado a veces, de aquel que proviene de diferentes fuentes (de la escuela, del entorno laboral, del barrio, de la familia,…) Se trata de darle un sentido de literalidad, basándose en las características dimensionales que en este caso se adoptan de los sistemas gráficos BIM (Building Information Modeling). En una primera fase se lleva a cabo en las disciplinas MEP (referentes a las instalaciones Mecánicas, Eléctricas e Hidrosanitarias–Plomería.) Para ello hacemos una pequeña descripción de las dimensiones consideradas agrupadas, por tratarse de un resumen, que las identifique con las actividades propuestas. No se trata solamente de un modelo creador, que es como está diseñado, sino también se ha realizado una adaptación como modelo descriptivo. Se usa las dimensiones 1D y 2D para definir las condiciones de partida del aprendizaje, representar a grandes rasgos la tecnología a estudiar y poder empezar a utilizar métodos gráficos para la comprensión del objeto de aprendizaje. Se usan las dimensiones 3D a 7D para la definición pormenorizada y el conocimiento profundo que van desde aspectos que incluyen: definición material, procesos de ejecución, costes, incidencia medioambiental, ciclo de vida y mantenimiento. La dimensión 8D propone la Socialización del aprendizaje. Debate y compartir las soluciones aportadas o analizar las propuestas de futuro. La dimensión 9D consiste en una Evaluación crítica. Nos permite contrastar el nivel de profundización, se incluye en el aprendizaje. Llegar a saber el LOD (Level of Development) a que ha llegado cada estudiante nos permite reiniciar el proceso con garantías de mejora. Abstract Traditional learning methodologies are not coherent with the learning and descriptive processes that break into the disciplines in the hand of software. The evolution of the field of technical education is very fast. However, there is no technology that is fast enough in its implementation that does not allow the introduction of new forms of teaching. We should not be mistaken when speaking of multidimensional learning only in the sense that it has sometimes been given of that which comes from different sources [1] (school, work environment, neighborhood, family, ...) Tries to give it a sense of literality, based on the dimensional characteristics that in this case are adopted of the BIM (Building Information Modeling). In the first phase it is carried out in the disciplines MEP (referring to the Mechanical, Electrical and Hydro sanitary-Plumbing facilities). To do this we make a small description of the dimensions considered grouped, as a summary that identifies them with the proposed activities. It is not only a creative model, which is how it is designed, but also an adaptation has been made as a descriptive model. Dimensions 1D and 2D are used to define the starting conditions of learning, to outline the technology to be studied and to be able to begin to use graphic methods for understanding the learning object. 3D dimensions to 7D are used for detailed definition and in-depth knowledge ranging from aspects including: material definition, execution processes, costs, environmental impact, life cycle and maintenance. The 8D dimension proposes the Socialization of learning. Debate and share the solutions provided or analyze future proposals. The 9D dimension consists of a Critical Assessment. It allows us to compare the level of deepening, is included in the learning. Getting to know the LOD (Level of Development) to which each student has arrived allows us to restart the process with guarantees of improvement.