Quantification of silver nanoparticle uptake and distribution within individual human macrophages by FIB/SEM slice and view

Background: Quantification of nanoparticle (NP) uptake in cells or tissues is very important for safety assessment. Often, electron microscopy based approaches are used for this purpose, which allow imaging at very high resolution. However, precise quantification of NP numbers in cells and tissues remains challenging. The aim of this study was to present a novel approach, that combines precise quantification of NPs in individual cells together with high resolution imaging of their intracellular distribution based on focused ion beam/ scanning electron microscopy (FIB/SEM) slice and view approaches. Results: We quantified cellular uptake of 75 nm diameter citrate stabilized silver NPs (Ag 75 Cit) into an individual human macrophage derived from monocytic THP-1 cells using a FIB/SEM slice and view approach. Cells were treated with 10 μg/ml for 24 h. We investigated a single cell and found in total 3138 ± 722 silver NPs inside this cell. Most of the silver NPs were located in large agglomerates, only a few were found in clusters of fewer than five NPs. Furthermore, we cross-checked our results by using inductively coupled plasma mass spectrometry and could confirm the FIB/SEM results. Conclusions: Our approach based on FIB/SEM slice and view is currently the only one that allows the quantification of the absolute dose of silver NPs in individual cells and at the same time to assess their intracellular distribution at high resolution. We therefore propose to use FIB/SEM slice and view to systematically analyse the cellular uptake of various NPs as a function of size, concentration and incubation time

Plasma Concentrations of Neurofilament Light Chain Protein and Brain-Derived Neurotrophic Factor as Consistent Biomarkers of Cognitive Impairment in Alcohol Use Disorder

For a long time, Substance Use Disorders (SUDs) were not considered a component in the etiology of dementia. The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders introduced substance-induced neurocognitive disorders, incorporating this notion to clinical practice. However, detection and monitoring of neurodegenerative processes in SUD patients remain a major clinical challenge, especially when early diagnosis is required. In the present study, we aimed to investigate new potential biomarkers of neurodegeneration that could predict cognitive impairment in SUD patients: the circulating concentrations of Neurofilament Light chain protein (NfL) and Brain-Derived Neurotrophic Factor (BDNF). Sixty SUD patients were compared with twenty-seven dementia patients and forty healthy controls. SUD patients were recruited and assessed using the Psychiatric Research Interview for Substance and Mental (PRISM) and a battery of neuropsychological tests, including the Montreal Cognitive Assessment test for evaluation of cognitive impairment. When compared to healthy control subjects, SUD patients showed increases in plasma NfL concentrations and NfL/BDNF ratio, as well as reduced plasma BDNF levels. These changes were remarkable in SUD patients with moderate–severe cognitive impairment, being comparable to those observed in dementia patients. NfL concentrations correlated with executive function and memory cognition in SUD patients. The parameters “age”, “NfL/BDNF ratio”, “first time alcohol use”, “age of onset of alcohol use disorder”, and “length of alcohol use disorder diagnosis” were able to stratify our SUD sample into patients with cognitive impairment from those without cognitive dysfunction with great specificity and sensibility. In conclusion, we propose the combined use of NfL and BDNF (NfL/BDNF ratio) to monitor substance-induced neurocognitive disorder.Instituto de Salud Carlos III (ISCIII], Ministerio de Ciencia e Innovación and European Regional Development Funds-European Union (ERDF-EU] grants “Proyectos de Investigación en Salud” PI19/01577, PI19/00886, PI20/01399 and PI22/00427; Grants Programa RICORS RIAPAD (Red de Investigación en Atención Primaria en Adicciones), Programa RETICS Red de Trastornos Adictivos, (RD16/0017/000); Ministerio de Sanidad, Delegación de Gobierno para el Plan Nacional sobre Drogas (PND 2022I020, PND2020/048, PND 2019/040]; Consejería de Salud y Familia, Junta de Andalucía (Neuro-RECA, RIC-0111-2019]. FJP (CPII19/00022] and AS (CPII19/00031] hold “Miguel Servet II” research contracts from the National System of Health, ISCIII, ERDF-EU. FJP also holds a “Nicolas Monardes” contract from Servicio Andaluz de Salud, Consejería de Salud y Familia, Junta de Andalucía (C1-0049-2019]. PA has a research contract (UMA-FEDERJA-076) funded by the Ministry of Economy and Knowledge—Regional Government of Andalucía and ERDF-EU. The funding sources had no further role in the study design; in the collection, analysis, and interpretation of data; in writing of the report; or in the decision to submit the paper for publication

Metoprolol in Critically Ill Patients With COVID-19.

Severe coronavirus disease-2019 (COVID-19) can progress to an acute respiratory distress syndrome (ARDS), which involves alveolar infiltration by activated neutrophils. The beta-blocker metoprolol has been shown to ameliorate exacerbated inflammation in the myocardial infarction setting. The purpose of this study was to evaluate the effects of metoprolol on alveolar inflammation and on respiratory function in patients with COVID-19-associated ARDS. A total of 20 COVID-19 patients with ARDS on invasive mechanical ventilation were randomized to metoprolol (15 mg daily for 3 days) or control (no treatment). All patients underwent bronchoalveolar lavage (BAL) before and after metoprolol/control. The safety of metoprolol administration was evaluated by invasive hemodynamic and electrocardiogram monitoring and echocardiography. Metoprolol administration was without side effects. At baseline, neutrophil content in BAL did not differ between groups. Conversely, patients randomized to metoprolol had significantly fewer neutrophils in BAL on day 4 (median: 14.3 neutrophils/µl [Q1, Q3: 4.63, 265 neutrophils/µl] vs median: 397 neutrophils/µl [Q1, Q3: 222, 1,346 neutrophils/µl] in the metoprolol and control groups, respectively; P = 0.016). Metoprolol also reduced neutrophil extracellular traps content and other markers of lung inflammation. Oxygenation (PaO2:FiO2) significantly improved after 3 days of metoprolol treatment (median: 130 [Q1, Q3: 110, 162] vs median: 267 [Q1, Q3: 199, 298] at baseline and day 4, respectively; P = 0.003), whereas it remained unchanged in control subjects. Metoprolol-treated patients spent fewer days on invasive mechanical ventilation than those in the control group (15.5 ± 7.6 vs 21.9 ± 12.6 days; P = 0.17). In this pilot trial, intravenous metoprolol administration to patients with COVID-19-associated ARDS was safe, reduced exacerbated lung inflammation, and improved oxygenation. Repurposing metoprolol for COVID-19-associated ARDS appears to be a safe and inexpensive strategy that can alleviate the burden of the COVID-19 pandemic.Mr Clemente-Moragón is supported by a fellowship from the Ministerio de Ciencia e Innovación (FPU2017/01932). The CNIC is supported by the ISCIII, the Ministerio de Ciencia e Innovación, and the Pro CNIC Foundation. Dr Ibáñez is supported by the European Commission (ERC-CoG grant No 819775) and by the Spanish Ministry of Science and Innovation (MCN; “RETOS 2019” grant No PID2019- 107332RB-I00). Dr Oliver is supported by funds from the Comunidad de Madrid Programa de Atracción de Talento (2017-T1/BMD-5185). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.S

La arquitectura y el urbanismo del Campus de la Universidad de Alicante como recurso a[tra]ctivo

Es evidente que uno de los principales recursos con los que cuenta la Universidad de Alicante es su Campus, no solo el de San Vicente del Raspeig sino también y además la constelación de Sedes Universitarias y Estaciones Científicas que lo componen. La calidad de sus edificios, todos ellos dignísimos para el fin al que sirven y algunos sencillamente magníficas obras de arquitectura, tanto las de nueva planta como las históricas que albergan las Sedes; la ordenación ejemplar de sus espacios libres donde la vegetación es, por derecho propio, protagonista indiscutible de un proyecto paisajístico modélico; o las esculturas, placas y homenajes y donaciones, embajadas y mecenazgos que salpican el espacio público dotándolo de identidad y cualificándolo, componen un conjunto notable poseedor de un enorme atractivo para la vida de la comunidad universitaria, para sus visitantes y para sus posibles futuros habitantes (nuevos estudiantes, PDI y PAS). El presente proyecto tiene como objetivo poner en valor todo ese patrimonio mediante su conocimiento y difusión a través de diversos canales que pretenden llegar al mayor público posible desde el rigor de la investigación y el atractivo de la presentación de sus resultados

CAR density influences antitumoral efficacy of BCMA CAR T cells and correlates with clinical outcome

Identification of new markers associated with long-term efficacy in patients treated with CAR T cells is a current medical need, particularly in diseases such as multiple myeloma. In this study, we address the impact of CAR density on the functionality of BCMA CAR T cells. Functional and transcriptional studies demonstrate that CAR T cells with high expression of the CAR construct show an increased tonic signaling with up-regulation of exhaustion markers and increased in vitro cytotoxicity but a decrease in in vivo BM infiltration. Characterization of gene regulatory networks using scRNA-seq identified regulons associated to activation and exhaustion up-regulated in CARHigh T cells, providing mechanistic insights behind differential functionality of these cells. Last, we demonstrate that patients treated with CAR T cell products enriched in CARHigh T cells show a significantly worse clinical response in several hematological malignancies. In summary, our work demonstrates that CAR density plays an important role in CAR T activity with notable impact on clinical response

Exosomes derived from mesenchymal stem cells enhance radiotherapy-induced cell death in tumor and metastatic tumor foci

We have recently shown that radiotherapy may not only be a successful local and regional treatment but, when combined with MSCs, may also be a novel systemic cancer therapy. This study aimed to investigate the role of exosomes derived from irradiated MSCs in the delay of tumor growth and metastasis after treatment with MSC + radiotherapy (RT). The tumor cell loss rates found after treatment with the combination of MSC and RT and for exclusive RT, were: 44.4% % and 12,1%, respectively. Concomitant and adjuvant use of RT and MSC, increased the mice surviving time 22,5% in this group, with regard to the group of mice treated with exclusive RT and in a 45,3% respect control group. Moreover, the number of metastatic foci found in the internal organs of the mice treated with MSC + RT was 60% less than the mice group treated with RT alone. We reasoned that the exosome secreted by the MSC, could be implicated in tumor growth delay and metastasis control after treatment. Our results show that exosomes derived form MSCs, combined with radiotherapy, are determinant in the enhancement of radiation effects observed in the control of metastatic spread of melanoma cells and suggest that exosome-derived factors could be involved in the bystander, and abscopal effects found after treatment of the tumors with RT plus MSC. Radiotherapy itself may not be systemic, although it might contribute to a systemic effect when used in combination with mesenchymal stem cells owing the ability of irradiated MSCs-derived exosomes to increase the control of tumor growth and metastasis.This work was supported by CNPq, Conselho Nacional de Desenvolvimento Científico e Tecnológico – Brasil, Junta de Andalucía, project of Excellence from Junta de Andalucía P12-CTS-383 to FJO, Spanish Ministry of Economy and Competitiveness SAF2015-70520-R to FJO and JMRdA, RTICC RD12/0036/0026 and CIBER Cáncer ISCIII CB16/12/00421 to FJO

Innocampus Explora: una aproximación multidisciplinar a la problemática ambiental

[ES] Presentamos las actividades del proyecto de innovación Innocampus Explora desarrollado en el campus de Burjassot-Paterna de la Universitat de València y cuyo objetivo principal es mostrar la interrelación existente entre los diferentes grados científicos y técnicos del campus. En la presente anualidad, el equipo de trabajo integrado por estudiantes y profesores de todos las facultades y escuelas del campus de Burjassot-Paterna, ha desarrollado actividades en torno a la problemática medioambiental. Una visión transversal e interdisciplinar de los problemas de los usos del plástico y de la energía nuclear que enlaza con varios de los Objetivos de Desarrollo Sostenible (ODS) dictados por Naciones Unidas. Con el desarrollo de este proyecto contribuimos a una formación transversal de calidad para todos los estudiantes participantes.[EN] We present the activities of the Innocampus Explora innovation project developed on the Burjassot-Paterna campus of the Universitat de València and whose main objective is to show the interrelation between the different scientific and technical degrees on campus. In this year, the work team made up of students and professors from all the faculties and schools of the Burjassot-Paterna campus, have carried out activities around environmental issues. A cross-sectional and interdisciplinary vision of the problems of the uses of plastic and nuclear energy that link with several of the Sustainable Development Goals (SDGs) dictated by the United Nations. With the development of this project we contribute to quality transversal training for all participating students.Moros Gregorio, J.; Quílez Asensio, A.; Jimenez Romero, D.; Blas Medina, A.; Giménez Escamilla, I.; Amorós Hernández, L.; Giner, L.... (2021). Innocampus Explora: una aproximación multidisciplinar a la problemática ambiental. En IN-RED 2020: VI Congreso de Innovación Educativa y Docencia en Red. Editorial Universitat Politècnica de València. 1003-1014. https://doi.org/10.4995/INRED2020.2020.11996OCS1003101

Recommendations for treatment with recombinant human growth hormone in pediatric patients in Colombia

En Colombia, actualmente no existen parámetros claros para el diagnóstico de pacientes con talla baja, ni sobre el tratamiento de esta población con hormona de crecimiento recombinante humana (somatropina), lo cual se ve favorecido por la diversidad de programas de formación de profesionales en endocrinología pediátrica. En respuesta a esta problemática se realizó el primer acuerdo colombiano de expertos en talla baja liderado por la Asociación Colegio Colombiana de Endocrinología Pediátrica (ACCEP); este trabajo contó con la participación y el aval de expertos clínicos de importantes instituciones de salud públicas y privadas del país, además de expertos metodológicos del instituto Keralty, quienes garantizaron la estandarización del uso de la somatropina. Después de realizar una minuciosa revisión de la literatura, se propone la unificación de definiciones, un algoritmo diagnóstico, los parámetros de referencia de las pruebas bioquímicas y dinámicas, una descripción de las consideraciones de uso de la somatropina para el tratamiento de las patologías con aprobación por la entidad regulatoria de medicamentos y alimentos en Colombia y, por último, un formato de consentimiento informado y de ficha técnica del medicamento.In Colombia there are no guidelines for diagnosis and management of patients with short stature and for the use of recombinanthuman growth hormone, mainly caused by the diversity of training centers in pediatric endocrinology. In response to this situation,the Asociación Colegio Colombiana de Endocrinología Pediátrica leds the first colombian short stature expert committee in order tostandardize the use of human recombinant growth hormone. This work had the participation and endorsement of a consortium ofclinical experts representing the Sociedad Colombiana de Pediatría, Secretaría Distrital de Salud de Bogotá- Subred Integrada deServicios de Salud Suroccidente, Fundación Universitaria Sanitas, Universidad de los Andes and some public and private healthinstitutions in the country, in addition to the participation of methodological experts from the Instituto Global de Excelencia ClínicaKeralty. By reviewing the literature and with the best available evidence, we proposed to unify definitions, a diagnostic algorithm,biochemical and dynamic tests with their reference parameters, a description of the considerations about growth hormone use amongthe indications approved by regulatory agency for medications and food in Colombia and finally a proposal for an informed consentand a medication fact sheet available for parents and patients.https://orcid.org/0000-0002-7856-7213https://orcid.org/0000-0003-2241-7854Revista Nacional - Indexad

Famílies botàniques de plantes medicinals

Facultat de Farmàcia, Universitat de Barcelona. Ensenyament: Grau de Farmàcia, Assignatura: Botànica Farmacèutica, Curs: 2013-2014, Coordinadors: Joan Simon, Cèsar Blanché i Maria Bosch.Els materials que aquí es presenten són els recull de 175 treballs d’una família botànica d’interès medicinal realitzats de manera individual. Els treballs han estat realitzat per la totalitat dels estudiants dels grups M-2 i M-3 de l’assignatura Botànica Farmacèutica durant els mesos d’abril i maig del curs 2013-14. Tots els treballs s’han dut a terme a través de la plataforma de GoogleDocs i han estat tutoritzats pel professor de l’assignatura i revisats i finalment co-avaluats entre els propis estudiants. L’objectiu principal de l’activitat ha estat fomentar l’aprenentatge autònom i col·laboratiu en Botànica farmacèutica

Latin American study of hereditary breast and ovarian cancer LACAM : a genomic epidemiology approach

Q2Q1Artículo original1-13Purpose: Hereditary Breast and Ovarian Cancer (HBOC) syndrome is responsible for ~5–10% of all diagnosed breast and ovarian cancers. Breast cancer is the most common malignancy and the leading cause of cancer-related mortality among women in Latin America (LA). The main objective of this study was to develop a comprehensive understanding of the genomic epidemiology of HBOC throughout the establishment of The Latin American consortium for HBOC-LACAM, consisting of specialists from 5 countries in LA and the description of the genomic results from the first phase of the study. Methods: We have recruited 403 individuals that fulfilled the criteria for HBOC from 11 health institutions of Argentina, Colombia, Guatemala, Mexico and Peru. A pilot cohort of 222 individuals was analyzed by NGS gene panels. One hundred forty-three genes were selected on the basis of their putative role in susceptibility to different hereditary cancers. Libraries were sequenced in MiSeq (Illumina, Inc.) and PGM (Ion Torrent-Thermo Fisher Scientific) platforms. Results: The overall prevalence of pathogenic variants was 17% (38/222); the distribution spanned 14 genes and varied by country. The highest relative prevalence of pathogenic variants was found in patients from Argentina (25%, 14/57), followed by Mexico (18%, 12/68), Guatemala (16%, 3/19), and Colombia (13%, 10/78). Pathogenic variants were found in BRCA1 (20%) and BRCA2 (29%) genes. Pathogenic variants were found in other 12 genes, including high and moderate risk genes such as MSH2, MSH6, MUTYH, and PALB2. Additional pathogenic variants were found in HBOC unrelated genes such as DCLRE1C, WRN, PDE11A, and PDGFB. Conclusion: In this first phase of the project, we recruited 403 individuals and evaluated the germline genetic alterations in an initial cohort of 222 patients among 4 countries. Our data show for the first time in LA the distribution of pathogenic variants in a broad set of cancer susceptibility genes in HBOC. Even though we used extended gene panels, there was still a high proportion of patients without any detectable pathogenic variant, which emphasizes the larger, unexplored genetic nature of the disease in these populations