T22-PE24-H6 Nanotoxin Selectively Kills CXCR4-High Expressing AML Patient Cells In Vitro and Potently Blocks Dissemination In Vivo

Altres ajuts: EU COST Action CA 17140; CERCA Programme/Generalitat de Catalunya; ICREA AcademiaDespite advances in the development of targeted therapies for acute myeloid leukemia (AML), most patients relapse. For that reason, it is still necessary to develop novel therapies that improve treatment effectiveness and overcome drug resistance. We developed T22-PE24-H6, a protein nanoparticle that contains the exotoxin A from the bacterium Pseudomonas aeruginosa and is able to specifically deliver this cytotoxic domain to CXCR4 + leukemic cells. Next, we evaluated the selective delivery and antitumor activity of T22-PE24-H6 in CXCR4 + AML cell lines and BM samples from AML patients. Moreover, we assessed the in vivo antitumor effect of this nanotoxin in a disseminated mouse model generated from CXCR4 + AML cells. T22-PE24-H6 showed a potent, CXCR4-dependent antineoplastic effect in vitro in the MONO-MAC-6 AML cell line. In addition, mice treated with nanotoxins in daily doses reduced the dissemination of CXCR4 + AML cells compared to buffer-treated mice, as shown by the significant decrease in BLI signaling. Furthermore, we did not observe any sign of toxicity or changes in mouse body weight, biochemical parameters, or histopathology in normal tissues. Finally, T22-PE24-H6 exhibited a significant inhibition of cell viability in CXCR4 high AML patient samples but showed no activity in CXCR4 low samples. These data strongly support the use of T22-PE24-H6 therapy to benefit high-CXCR4-expressing AML patients

A multivalent Ara-C-prodrug nanoconjugate achieves selective ablation of leukemic cells in an acute myeloid leukemia mouse model

Altres ajuts: EU COST Action CA 17140 ; CIBER-BBN [CB06/01/1031 and 4NanoMets to R.M., VENOM4CANCER to A.V., NANOREMOTE to E.V. and NANOLINK to U·U.] ; CERCA Programme/Generalitat de Catalunya ; ICREA Academia Award. Fundació la Marató de TV3 201-941-30-31-32.Current therapy in acute myeloid leukemia (AML) is based on chemotherapeutic drugs administered at high doses, lacking targeting selectivity and displaying poor therapeutic index because of severe adverse effects. Here, we develop a novel nanoconjugate that combines a self-assembled, multivalent protein nanoparticle, targeting the CXCR4 receptor, with an Oligo-Ara-C prodrug, a pentameric form of Ara-C, to highly increase the delivered payload to target cells. This 13.4 nm T22-GFP-H6-Ara-C nanoconjugate selectively eliminates CXCR4 AML cells, which are protected by its anchoring to the bone marrow (BM) niche, being involved in AML progression and chemotherapy resistance. This nanoconjugate shows CXCR4-dependent internalization and antineoplastic activity in CXCR4 AML cells in vitro. Moreover, repeated T22-GFP-H6-Ara-C administration selectively eliminates CXCR4 leukemic cells in BM, spleen and liver. The leukemic dissemination blockage induced by T22-GFP-H6-Ara-C is significantly more potent than buffer or Oligo-Ara-C-treated mice, showing no associated on-target or off-target toxicity and, therefore, reaching a highly therapeutic window. In conclusion, T22-GFP-H6-Ara-C exploits its 11 ligands-multivalency to enhance target selectivity, while the Oligo-Ara-C prodrug multimeric form increases 5-fold its payload. This feature combination offers an alternative nanomedicine with higher activity and greater tolerability than current intensive or non-intensive chemotherapy for AML patients

Factors Associated With Short-Term Eradication of Rectal Colonization by KPC-2 Producing Klebsiella pneumoniae in an Outbreak Setting

Background: KPC-producing Klebsiella pneumoniae (KPCKP) is a threat for patients admitted to healthcare institutions. Objectives: To assess the efficacy of several decolonization strategies for KPCKP rectal carriage. Methods: Observational study performed in a 750-bed university center from July to October 2018 on the efficacy of a 10-day non-absorbable oral antibiotic (NAA) regimen (colistin 10 mg/ml, amikacin 8 mg/ml, and nystatin 30 mg/ml, 10 ml/6 h) vs. the same regimen followed by a probiotic (Vivomixx®) for 20 days in adult patients with KPCKP rectal colonization acquired during an outbreak. Results: Seventy-three patients colonized by KPCKP were included, of which 21 (29%) did not receive any treatment and 52 (71.2%) received NAA either alone (n = 26, 35.6%) or followed by a probiotic (n = 26, 35.6%). Eradication was observed in 56 (76.7%) patients and the only variable significantly associated with it was not receiving systemic antibiotics after diagnosis of rectal carriage [22/24 (91.6%) vs. 34/49 (69.3%), p = 0.04]. Eradication in patients receiving NAA plus probiotic was numerically but not significantly higher than that of controls [23/26 (88.4%) vs. 15/21 (71.4%), p = 0.14] and of those receiving only NAA (OR = 3.4, 95% CI = 0.78-14.7, p = 0.09). Conclusion: In an outbreak setting, rectal carriage of KPCKP persisted after a mean of 36 days in about one quarter of patients. The only factor associated with eradication was not receiving systemic antibiotic after diagnosis. A 10-day course of NAA had no impact on eradication. Probiotics after NAA may increase the decolonization rate, hence deserving further study

Spatial distribution of fishing fleets in a future Fishery Protected Area in the Malaga Bay (Northwestern Alboran Sea).

Málaga Bay is an important area from the icthyoplankton viewpoint where it is possible to find more than 80 species belonging to 68 genera and 41 families. Furthermore, the bay is an essential spawning and nursery area for many species of commercial interest, such as sardine (Sardina pilchardus), anchovy (Engraulis encrasicolus), Atlantic horse-mackerel (Trachurus trachurus), Mediterranean horse-mackerel (T. mediterraneus) or hake (Merluccius merluccius). Local bottom trawl, purse seine and polyvalent artisanal fleets, have traditionally fished in this bay targeting on many species of fishes, crustaceans and molluscs. An ecological and fisheries study was undertaken in 2013 and 2014 with the purpose of assessing the suitability of Málaga Bay as a Fishery Protected Area. One of the important aspects taken into account is the spatial distribution of the fishing effort to evaluate its impact in the area. The findings achieved in this study are essential and valuable information for a proper fisheries management integrating the ecosystem-based approach into fisheries advice. The results show that Málaga Bay supports a heavy fishing pressure in all the fishing grounds which may affect both its commercial resources and sedimentary habitats.Versión del edito

Deregulated cellular circuits driving immunoglobulins and complement consumption associate with the severity of COVID-19 patients

SARS-CoV-2 infection causes an abrupt response by the host immune system, which is largely responsible for the outcome of COVID-19. We investigated whether the specific immune responses in the peripheral blood of 276 patients were associated with the severity and progression of COVID-19. At admission, dramatic lymphopenia of T, B, and NK cells is associated with severity. Conversely, the proportion of B cells, plasmablasts, circulating follicular helper T cells (cTfh) and CD56–CD16+ NK-cells increased. Regarding humoral immunity, levels of IgM, IgA, and IgG were unaffected, but when degrees of severity were considered, IgG was lower in severe patients. Compared to healthy donors, complement C3 and C4 protein levels were higher in mild and moderate, but not in severe patients, while the activation peptide of C5 (C5a) increased from the admission in every patient, regardless of their severity. Moreover, total IgG, the IgG1 and IgG3 isotypes, and C4 decreased from day 0 to day 10 in patients who were hospitalized for more than two weeks, but not in patients who were discharged earlier. Our study provides important clues to understand the immune response observed in COVID-19 patients, associating severity with an imbalanced humoral response, and identifying new targets for therapeutic interventionThe study was funded by grants SAF2017- 82886-R to FS-M from the Ministerio de Economía y Competitividad, and from “La Caixa Banking Foundation” (HR17-00016) to FS-M. Grant PI018/01163 to CMC and grant PI19/00549 to AA were funded by Fondo de Investigaciones Sanitarias, Ministerio de Sanidad y Consumo, Spain. SAF2017-82886-R, PI018/01163 and PI19/00549 grants were also co-funded by European Regional Development Fund, ERDF/FEDER. This work has been funded by grants Fondo Supera COVID (CRUE-Banco de Santander) to FSM, and “Ayuda Covid 2019” from Comunidad de Madri

Benthic-demersal communities of circalittoral soft bottoms of Málaga Bay

The Bay of Málaga is located in a biodiversity hotspot with high productivity that favors a wide variety of commercial and non-commercial species as well as fishing fleet types. Benthic and demersal fauna from circalittoral soft bottoms of this bay have been studied using a benthic dredge (8 sampling stations in December 2013) and an otter trawl (8 sampling stations on a seasonal basis). Sediment and water properties have also been studied in order to analyze their relationships with the benthic and demersal communities. A total of 287 spp. have been found, being molluscs and fishes the most diverse and abundant ones in the samples. A low number of species (44 spp.) were only collected with both sampling gears, indicating the importance on combining sampling methods in biodiversity studies. Benthic dredge samples displayed some differences in relation to depth and sediment types, whereas differences of otter trawl samples seemed to be more influenced by seasonal changes. SIMPER analyses indicated that temporal variation was due to seasonal changes of abundance of some species of commercial interest. This seasonal variability should be taken into account in further management of this area as a potential new Fisheries Reserve.Versión del edito

Kwapa: Gente del río. Estrategias transmedia de impacto social

En este reporte se encuentra toda la documentación del trabajo realizado durante el período de otoño 2022 dentro del proyecto de aplicación profesional Alter Código en el cual se siguió trabajando en la realización del videojuego “A orillas del río” y en la producción del documental de etnoficción “Déjennos pescar”. En el documental etnoficción se tuvo como objetivo principal el rodaje en comunidades cucapá en Baja California, a partir de esto se implementaron diversas estrategias para lograrlo. Como resultado de lo anterior, se abrió un crowdfunding junto con una estrategia de difusión en redes sociales que incluyó, además, la participación en el festival universitario y la producción de stickers para lograr mayor impacto. En el videojuego el objetivo principal consistió en desarrollar una demo jugable cuyo resultado deja definida una dirección concreta para continuar a futuro. Además, permite mostrar las herramientas que se van a implementar como tomar objetos, seleccionar, agarrar e interactuar entre personajes y el entorno. En términos de colaboración se creó un cuadernillo ilustrado para mostrar a niños y adolescentes cucapá y, de este modo, sentar las bases de retroalimentación respecto al desarrollo de la historia y diseño de personajes. Por último, el viaje de producción proveyó de material para seguir desarrollando eldocumental, al mismo tiempo que permitió al equipo de videojuego sentar las bases de una retroalimentación con base en una metodología, desde la perspectiva emic, en la que nuestros colaboradores son co-productores del sentido.ITESO, A.C

IL-6 serum levels predict severity and response to tocilizumab in COVID-19: An observational study

Background: Patients with coronavirus disaese 2019 (COVID-19) can develop a cytokine release syndrome that eventually leads to acute respiratory distress syndrome requiring invasive mechanical ventilation (IMV). Because IL-6 is a relevant cytokine in acute respiratory distress syndrome, the blockade of its receptor with tocilizumab (TCZ) could reduce mortality and/or morbidity in severe COVID-19. Objective: We sought to determine whether baseline IL-6 serum levels can predict the need for IMV and the response to TCZ. Methods: A retrospective observational study was performed in hospitalized patients diagnosed with COVID-19. Clinical information and laboratory findings, including IL-6 levels, were collected approximately 3 and 9 days after admission to be matched with preadministration and postadministration of TCZ. Multivariable logistic and linear regressions and survival analysis were performed depending on outcomes: need for IMV, evolution of arterial oxygen tension/fraction of inspired oxygen ratio, or mortality. Results: One hundred forty-six patients were studied, predominantly males (66%); median age was 63 years. Forty-four patients (30%) required IMV, and 58 patients (40%) received treatment with TCZ. IL-6 levels greater than 30 pg/mL was the best predictor for IMV (odds ratio, 7.1; P < .001). Early administration of TCZ was associated with improvement in oxygenation (arterial oxygen tension/fraction of inspired oxygen ratio) in patients with high IL-6 (P = .048). Patients with high IL-6 not treated with TCZ showed high mortality (hazard ratio, 4.6; P = .003), as well as those with low IL-6 treated with TCZ (hazard ratio, 3.6; P = .016). No relevant serious adverse events were observed in TCZ-treated patients. Conclusions: Baseline IL-6 greater than 30 pg/mL predicts IMV requirement in patients with COVID-19 and contributes to establish an adequate indication for TCZ administrationThis study was funded by Spanish Ministry of Economy, Industry and Competitiveness (MINECO) and Instituto de Salud Carlos III (grant nos. RD16/0011/0012 and PI18/ 0371 to I.G.A., grant no. PI19/00549 to A.A., and grant no. SAF2017-82886-R to F.S.-M.) and co-funded by the European Regional Development Fund. The study was also funded by ‘‘La Caixa Banking Foundation’’ (grant no. HR17-00016 to F.S.-M.) and ‘‘Fondos Supera COVID19’’ by Banco de Santander and CRUE. None of these sponsors have had any role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publicatio

Evolución de la farmacovigilancia: análisis de los resultados sobre el conocimiento de farmacovigilancia entre profesionales sanitarios y pacientes

El objetivo de la tesis fue estudiar la evolución de la Farmacovigilancia, analizando la legislación, estructura y funcionamiento, considerando además, otras formas de vigilancia. Evaluamos el grado de conocimiento y actitud de los farmacéuticos (estableciendo las diferencias entre los farmacéuticos de farmacia comunitaria y los de farmacia hospitalaria) y de los pacientes, su grado de notificación de Reacciones Adversas a Medicamentos (RAM) y la necesidad de formación. Para ello, se diseñaron dos cuestionarios, uno para los profesionales y otro para los pacientes, con doce preguntas cada uno de ellos. La distribución y recogida de los cuestionarios se realizó vía “on line” con la colaboración de los Colegios Oficiales de Farmacéuticos, la Sociedad Española de Farmacia Hospitalaria, y con la colaboración, entre otras, de la Asociación Española de Trasplantados, Foro Español de Pacientes y Plataforma de Organizaciones de Pacientes durante el periodo de noviembre del año 2018 a junio del año 2019. La población diana fueron los farmacéuticos colegiados o pertenecientes a la Sociedad Española de Farmacia Hospitalaria y los pacientes..

Conocimiento y actitud sobre prácticas en farmacovigilancia de los profesionales farmacéuticos de farmacia comunitaria y farmacia hospitalaria en España

Background: The justification of the study was to assess the degree of knowledge of Spanish pharmacists in the field of Pharmacovigilance, their degree of notification of adverse drug reactions and their need for training, establishing the differences between community pharmacy pharmacist and those of hospital pharmacy. Methods: A questionnaire with twelve questions on Pharmacovigilance was designed. The distribution and collection of the questionnaires were carried out via online in collaboration with the Official Colleges of Pharmacists and the Spanish Society of Hospital Pharmacy during the period from November 2018 to June 2019. The target population were the pharmacists registered or belonging to the Spanish Society of Hospital Pharmacy. The results were processed using a descriptive and analytical analysis. The qualitative variables were presented with their frequency distribution and the quantitative with their mean and standard deviation. Results: 99% of hospital pharmacists said they had evidence of suspected adverse reactions and 96.9% of them ever reported. 73.5% of community pharmacists stated that they had knowledge of suspected adverse reactions but only 48.7% confirmed that they notified them. In general, the pharmacists surveyed agreed on the importance of Pharmacovigilance and believed that the quality of treatments could be improved and the Spanish health system would be saved if Pharmacovigilance was applied more. Conclusions: Our results indicated that hospital pharmacists report much more adverse drug reactions than community pharmacist does. It also hospital pharmacists who know best the obligations they have with Pharmacovigilance. The surveyed pharmacists thought that the development of actions in Pharmacovigilance would increase the adherence of pharmaceutical professionals to the notification and would imply improvements in the quality of treatments, the rational use of medications and patient safety.Fundamentos: La justificación del estudio fue evaluar el grado de conocimiento de los farmacéuticos españoles en el ámbito de la Farmacovigilancia, su grado de notificación de Reacciones Adversas a Medicamentos (RAM) y su necesidad de formación, estableciendo las diferencias entre los farmacéuticos de farmacia comunitaria (FC) y los de farmacia hospitalaria (FH). Métodos: Se diseñó un cuestionario con doce preguntas sobre Farmacovigilancia. La distribución y recogida de los cuestionarios se realizo vía online con la colaboración de los Colegios Oficiales de Farmacéuticos y la Sociedad Española de Farmacia Hospitalaria, durante el periodo de noviembre de 2018 a junio de 2019.La población diana fueron los farmacéuticos colegiados o pertenecientes a la Sociedad Española de Farmacia Hospitalaria. Los resultados fueron procesados mediante un análisis descriptivo y analítico. Las variables cualitativas se presentaron con su distribución de frecuencias y las cuantitativas con su media y desviación estándar. Resultados: El 99% de los FH afirmaron haber tenido constancia de una RAM y el 96,9% de ellos la notificaron. El 73,5% de los FC declararon que tuvieron constancia de una RAM pero sólo el 48,7% confirmaron que la notificaran. En general, los farmacéuticos encuestados estaban de acuerdo en la importancia de la Farmacovigilancia, y opinaban que se podría mejorar la calidad de los tratamientos y se ahorraría en el sistema de salud español si se aplicara más la Farmacovigilancia. Conclusiones: Nuestros resultados indican que los FH notifican más una RAM que los FC. También son los FH los que conocen mejor las obligaciones que tienen con Farmacovigilancia. Los farmacéuticos encuestados piensan que el desarrollo de actuaciones en Farmacovigilancia, aumentaría la adhesión de los profesionales a la notificación e implicaría mejoras en la calidad de los tratamientos, el uso racional de los medicamentos y la seguridad del paciente