Effects of immobilized VEGF on endothelial progenitor cells cultured on silicon substituted and nanocrystalline hydroxyapatites

Vascular endothelial growth factor (VEGF) plays an essential role in angiogenesis and vascular homeostasis. Endothelial progenitor cells (EPCs) are primitive bone marrow cells participating in neovascularization and revascularization processes, which also promote bone regeneration. Synthetic hydroxyapatite (HA) has been widely used in bone repair and implant coatings. In HA-based materials, small levels of ionic substitution by silicon (Si) have significant effects on osteoclastic and osteoblastic responses. Moreover, nanocrystalline hydroxyapatites (nano-HA) display enhanced bioreactivity and beneficial effects in bone formation. In this work, the angiogenic potential of VEGF-121 adsorbed on crystalline and nanocrystalline HAs with different Si proportion is evaluated with endothelial-like cells derived from EPCs cultured on nano-HA, nano-SiHA0.25, nano-SiHA0.4, HA, SiHA0.25 and SiHA0.4 disks. The Si amount incorporated for x ¼ 0.25 is enough to yield changes in the textural parameters and surface charge without decomposing the HA phase. Si substitution for x ¼ 0.4 does not result in pure Si-substituted apatites. Si probably remains at the grain boundaries as amorphous silica in nano-SiHA0.4 and SiHA0.4 is decomposed in a-TCP and HA after 1150 �C treatment. Immobilized VEGF on nano-HA, nano-SiHA0.25, nano-SiHA0.4, HA, SiHA0.25 and SiHA0.4 maintains its function exerting a local regulation of the cell response. The crystallite size and topography of nanocrystalline HAs could produce insufficient and weak contacts with endothelial-like cells triggering anoikis. Concerning Si proportion, the best results are obtained with SiHA0.25/VEGF and nano- SiHA0.25/VEGF disks. All these results suggest the potential utility of SiHA0.25/VEGF and nano-SiHA0.25/VEGF for bone repair and tissue engineering by promoting angiogenesis

Modulación de factores de transcripción Nrf2 y NF-κB por esculetina en células leucémicas humanas

La esculetina (6,7-dihidroxicumarina) es un antioxidante que modula el balance redox en diferentes células. Además posee propiedades antiinflamatorias y antitumorales. Se ha estudiado el efecto antitumoral de esculetina en células de leucemia humana promielocítica aguda NB4. Se ha analizado la respuesta antioxidante celular (actividad de la enzima superóxido dismutasa –SOD–) con la modulación de los niveles de factores de transcripción (Nrf2 y NF-κB)

Modulación de factores de transcripción Nrf2 y NF-κB por esculetina en células leucémicas humanas

La esculetina (6,7-dihidroxicumarina) es un antioxidante que modula el balance redox en diferentes células. Además posee propiedades antiinflamatorias y antitumorales. Se ha estudiado el efecto antitumoral de esculetina en células de leucemia humana promielocítica aguda NB4. Se ha analizado la respuesta antioxidante celular (actividad de la enzima superóxido dismutasa –SOD–) con la modulación de los niveles de factores de transcripción (Nrf2 y NF-κB)

ISG15 and ISGylation is required for pancreatic cancer stem cell mitophagy and metabolic plasticity

Pancreatic cancer stem cells (PaCSCs) drive pancreatic cancer tumorigenesis, chemoresistance and metastasis. While eliminating this subpopulation of cells would theoretically result in tumor eradication, PaCSCs are extremely plastic and can successfully adapt to targeted therapies. In this study, we demonstrate that PaCSCs increase expression of interferon-stimulated gene 15 (ISG15) and protein ISGylation, which are essential for maintaining their metabolic plasticity. CRISPR-mediated ISG15 genomic editing reduces overall ISGylation, impairing PaCSCs self-renewal and their in vivo tumorigenic capacity. At the molecular level, ISG15 loss results in decreased mitochondrial ISGylation concomitant with increased accumulation of dysfunctional mitochondria, reduced oxidative phosphorylation (OXPHOS) and impaired mitophagy. Importantly, disruption in mitochondrial metabolism affects PaCSC metabolic plasticity, making them susceptible to prolonged inhibition with metformin in vivo. Thus, ISGylation is critical for optimal and efficient OXPHOS by ensuring the recycling of dysfunctional mitochondria, and when absent, a dysregulation in mitophagy occurs that negatively impacts PaCSC stemness

Structure des grands bassins glaciaires dans le nord de la péninsule ibérique: comparaison entre les vallées d'Andorre (Pyrénées orientales), du Gállego (Pyrénées centrales) et du Trueba (Chaîne Cantabrique).

Les grandes vallées glaciaires de la Péninsule Ibérique sont situées dans la chaîne pyrénéo-cantabrique, principalement dans le bassin de l'Èbre. Ainsi, les vallées d'Andorre, de la Noguera Pallaresa et de la haute vallée du Gállego, dans les Pyrénées, ont eu des appareils glaciaires longs de 42, 50 et 40 km respectivement. Dans les vallées du Sil (bassin du Miño) et du Trueba, dans la Chaîne Cantabrique, ils atteignaient 42 et 16,5 km (Serrano-Cañadas, 1996 ; Gómez-Ortiz et al., 2001 ; Turu & Peña, 2006a et b ; Redondo-Vega et al., 2006). L'une des caractéristiques géomorphologiques de la plupart de ces vallées est l'existence d'une dépression morphologique du substratum dans les parties moyennes et terminales, interprétée comme la conséquence de l'érosion glaciaire. Dans tous les cas, on observe une architecture litho-stratigraphique commune (Vilaplana & Casas, 1983 ; Bordonau et al., 1989 ; Bordonau, 1992 ; Turu et al., 2002) représentée par trois unités géoélectriques : une unité inférieure très épaisse, avec des résistivités électriques basses (70 - 200 Ohms par mètre), qui traduit la présence de matériaux fins considérés comme d'origine lacustre ; une unité intermédiaire, moins épaisse, avec des valeurs de résistivité plus élevées (400 - 800 Ohms par mètre), pouvant être interprétée comme un système fluvio-deltaïque pro-glaciaire et une unité géoélectrique supérieure, avec des valeurs de résistivité très variables (100 - 1500 Ohms par mètre), constituée de sédiments alluviaux subactuels. La comparaison des données de type géophysique et géomécanique (sismique à réfraction et essais pressiométriques) montre que l'unité intermédiaire, considérée comme d'origine fluvio-deltaïque, présente des valeurs de vitesse sismique anormalement élevées, ainsi que de hautes valeurs de consolidation. Cette observation effectuée pour la première fois dans la vallée d'Andorre (Turu, 2000) montre des remarquables corrélations entre les hautes vitesses sismiques et les valeurs élevées de consolidation, ainsi que la très nette corrélation entre les hautes valeurs de consolidation et les tills sous-glaciaires. Elle permet d'interpréter l'unité intermédiaire comme essentiellement glaciaire et de remettre en question le modèle simple d'une séquence de comblement lacustre et deltaïque proposé jusqu´à maintenant

Risk factors for developing ventilator-associated lower respiratory tract infection in patients with severe COVID-19:a multinational, multicentre study, prospective, observational study

Around one-third of patients diagnosed with COVID-19 develop a severe illness that requires admission to the Intensive Care Unit (ICU). In clinical practice, clinicians have learned that patients admitted to the ICU due to severe COVID-19 frequently develop ventilator-associated lower respiratory tract infections (VA-LRTI). This study aims to describe the clinical characteristics, the factors associated with VA-LRTI, and its impact on clinical outcomes in patients with severe COVID-19. This was a multicentre, observational cohort study conducted in ten countries in Latin America and Europe. We included patients with confirmed rtPCR for SARS-CoV-2 requiring ICU admission and endotracheal intubation. Only patients with a microbiological and clinical diagnosis of VA-LRTI were included. Multivariate Logistic regression analyses and Random Forest were conducted to determine the risk factors for VA-LRTI and its clinical impact in patients with severe COVID-19. In our study cohort of 3287 patients, VA-LRTI was diagnosed in 28.8% [948/3287]. The cumulative incidence of ventilator-associated pneumonia (VAP) was 18.6% [610/3287], followed by ventilator-associated tracheobronchitis (VAT) 10.3% [338/3287]. A total of 1252 bacteria species were isolated. The most frequently isolated pathogens were Pseudomonas aeruginosa (21.2% [266/1252]), followed by Klebsiella pneumoniae (19.1% [239/1252]) and Staphylococcus aureus (15.5% [194/1,252]). The factors independently associated with the development of VA-LRTI were prolonged stay under invasive mechanical ventilation, AKI during ICU stay, and the number of comorbidities. Regarding the clinical impact of VA-LRTI, patients with VAP had an increased risk of hospital mortality (OR [95% CI] of 1.81 [1.40-2.34]), while VAT was not associated with increased hospital mortality (OR [95% CI] of 1.34 [0.98-1.83]). VA-LRTI, often with difficult-to-treat bacteria, is frequent in patients admitted to the ICU due to severe COVID-19 and is associated with worse clinical outcomes, including higher mortality. Identifying risk factors for VA-LRTI might allow the early patient diagnosis to improve clinical outcomes. Trial registration: This is a prospective observational study; therefore, no health care interventions were applied to participants, and trial registration is not applicable

Hospital-based proton therapy implementation during the COVID pandemic: early clinical and research experience in a European academic institution

Introduction A rapid deploy of unexpected early impact of the COVID pandemic in Spain was described in 2020. Oncology practice was revised to facilitate decision-making regarding multimodal therapy for prevalent cancer types amenable to multidisciplinary treatment in which the radiotherapy component searched more efcient options in the setting of the COVID-19 pandemic, minimizing the risks to patients whilst aiming to guarantee cancer outcomes. Methods A novel Proton Beam Therapy (PBT), Unit activity was analyzed in the period of March 2020 to March 2021. Institutional urgent, strict and mandatory clinical care standards for early diagnosis and treatment of COVID-19 infection were stablished in the hospital following national health-authorities’ recommendations. The temporary trends of patients care and research projects proposals were registered. Results 3 out of 14 members of the professional staf involved in the PBR intra-hospital process had a positive test for COVID infection. Also, 4 out of 100 patients had positive tests before initiating PBT, and 7 out of 100 developed positive tests along the weekly mandatory special checkup performed during PBT to all patients. An update of clinical performance at the PBT Unit at CUN Madrid in the initial 500 patients treated with PBT in the period from March 2020 to November 2022 registers a distribution of 131 (26%) pediatric patients, 63 (12%) head and neck cancer and central nervous system neoplasms and 123 (24%) re-irradiation indications. In November 2022, the activity reached a plateau in terms of patients under treatment and the impact of COVID pandemic became sporadic and controlled by minor medical actions. At present, the clinical data are consistent with an academic practice prospectively (NCT05151952). Research projects and scientifc production was adapted to the pandemic evolution and its infuence upon professional time availability. Seven research projects based in public funding were activated in this period and preliminary data on molecular imaging guided proton therapy in brain tumors and post-irradiation patterns of blood biomarkers are reported. Conclusions Hospital-based PBT in European academic institutions was impacted by COVID-19 pandemic, although clinical and research activities were developed and sustained. In the post-pandemic era, the benefts of online learning will shape the future of proton therapy education

Limits of Life and the Habitability of Mars: The ESA Space Experiment BIOMEX on the ISS

BIOMEX (BIOlogy and Mars EXperiment) is an ESA/Roscosmos space exposure experiment housed within the exposure facility EXPOSE-R2 outside the Zvezda module on the International Space Station (ISS). The design of the multiuser facility supports—among others—the BIOMEX investigations into the stability and level of degradation of space-exposed biosignatures such as pigments, secondary metabolites, and cell surfaces in contact with a terrestrial and Mars analog mineral environment. In parallel, analysis on the viability of the investigated organisms has provided relevant data for evaluation of the habitability of Mars, for the limits of life, and for the likelihood of an interplanetary transfer of life (theory of lithopanspermia). In this project, lichens, archaea, bacteria, cyanobacteria, snow/permafrost algae, meristematic black fungi, and bryophytes from alpine and polar habitats were embedded, grown, and cultured on a mixture of martian and lunar regolith analogs or other terrestrial minerals. The organisms and regolith analogs and terrestrial mineral mixtures were then exposed to space and to simulated Mars-like conditions by way of the EXPOSE-R2 facility. In this special issue, we present the first set of data obtained in reference to our investigation into the habitability of Mars and limits of life. This project was initiated and implemented by the BIOMEX group, an international and interdisciplinary consortium of 30 institutes in 12 countries on 3 continents. Preflight tests for sample selection, results from ground-based simulation experiments, and the space experiments themselves are presented and include a complete overview of the scientific processes required for this space experiment and postflight analysis. The presented BIOMEX concept could be scaled up to future exposure experiments on the Moon and will serve as a pretest in low Earth orbit

The outcome of boosting mitochondrial activity in alcohol-associated liver disease is organ-dependent.

BACKGROUND AND AIMS Alcohol-associated liver disease (ALD) accounts for 70% of liver-related deaths in Europe, with no effective approved therapies. Although mitochondrial dysfunction is one of the earliest manifestations of alcohol-induced injury, restoring mitochondrial activity remains a problematic strategy due to oxidative stress. Here, we identify methylation-controlled J protein (MCJ) as a mediator for ALD progression and hypothesize that targeting MCJ may help in recovering mitochondrial fitness without collateral oxidative damage. APPROACH AND RESULTS C57BL/6 mice [wild-type (Wt)] Mcj knockout and Mcj liver-specific silencing (MCJ-LSS) underwent the NIAAA dietary protocol (Lieber-DeCarli diet containing 5% (vol/vol) ethanol for 10 days, plus a single binge ethanol feeding at day 11). To evaluate the impact of a restored mitochondrial activity in ALD, the liver, gut, and pancreas were characterized, focusing on lipid metabolism, glucose homeostasis, intestinal permeability, and microbiota composition. MCJ, a protein acting as an endogenous negative regulator of mitochondrial respiration, is downregulated in the early stages of ALD and increases with the severity of the disease. Whole-body deficiency of MCJ is detrimental during ALD because it exacerbates the systemic effects of alcohol abuse through altered intestinal permeability, increased endotoxemia, and dysregulation of pancreatic function, which overall worsens liver injury. On the other hand, liver-specific Mcj silencing prevents main ALD hallmarks, that is, mitochondrial dysfunction, steatosis, inflammation, and oxidative stress, as it restores the NAD + /NADH ratio and SIRT1 function, hence preventing de novo lipogenesis and improving lipid oxidation. CONCLUSIONS Improving mitochondrial respiration by liver-specific Mcj silencing might become a novel therapeutic approach for treating ALD.This work was supported by grants from Ministerio de Ciencia e Innovación, Programa Retos-Colaboración RTC2019-007125-1 (for Jorge Simon and Maria Luz Martinez-Chantar); Ministerio de Economía, Industria y Competitividad, Retos a la Sociedad AGL2017- 86927R (for F.M.); Instituto de Salud Carlos III, Proyectos de Investigación en Salud DTS20/00138 and DTS21/00094 (for Jorge Simon and Maria Luz Martinez-Chantar, and Asis Palazon. respectively); Instituto de Salud Carlos III, Fondo de Investigaciones Sanitarias co-founded by European Regional Development Fund/European Social Fund, “Investing in your future” PI19/00819, “Una manera de hacer Europa” FIS PI20/00765, and PI21/01067 (for Jose J. G. Marin., Pau Sancho-Bru,. and Mario F. Fraga respectively); Departamento de Industria del Gobierno Vasco (for Maria Luz Martinez-Chantar); Asturias Government (PCTI) co-funding 2018-2023/ FEDER IDI/2021/000077 (for Mario F. Fraga.); Ministerio de Ciencia, Innovación y Universidades MICINN: PID2020-117116RB-I00, CEX2021-001136-S PID2020-117941RB-I00, PID2020-11827RB-I00 and PID2019-107956RA-100 integrado en el Plan Estatal de Investigación Científica y Técnica y Innovación, cofinanciado con Fondos FEDER (for Maria Luz Martinez-Chantar, Francisco J Cubero., Yulia A Nevzorova and Asis Palazon); Ayudas Ramón y Cajal de la Agencia Estatal de Investigación RY2013-13666 and RYC2018- 024183-I (for Leticia Abecia and Asis Palazon); European Research Council Starting Grant 804236 NEXTGEN-IO (for Asis Palazon); The German Research Foundation SFB/TRR57/P04, SFB1382-403224013/ A02 and DFG NE 2128/2-1 (for Francisco J Cubero and Yulia A Nevzorova); National Institute of Health (NIH)/National Institute of Alcohol Abuse and Alcoholism (NIAAA) 1U01AA026972-01 (For Pau Sancho-Bru); Junta de Castilla y León SA074P20 (for Jose J. G. Marin); Junta de Andalucía, Grupo PAIDI BIO311 (for Franz Martin); CIBERER Acciones Cooperativas y Complementarias Intramurales ACCI20-35 (for Mario F. Fraga); Ministerio de Educación, Cultura y Deporte FPU17/04992 (for Silvia Ariño); Fundació Marato TV3 201916-31 (for Jose J. G. Marin.); Ainize Pena-Cearra is a fellow of the University of the Basque Country (UPV/ EHU); BIOEF (Basque Foundation for Innovation and Health Research); Asociación Española contra el Cáncer (Maria Luz Martinez-Chantar and Teresa C. Delgado.); Fundación Científica de la Asociación Española Contra el Cáncer (AECC Scientific Foundation) Rare Tumor Calls 2017 (for Maria Luz Martinez-Chantar); La Caixa Foundation Program (for Maria Luz Martinez-Chantar); Proyecto Desarrollo Tecnologico CIBERehd (for Maria Luz Martinez-Chantar); Ciberehd_ISCIII_MINECO is funded by the Instituto de Salud Carlos III.S