Author: "Gálvez Buerba, Eva Mª" - Searchworks@Jio Institute Digital Library Search Results

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1. Selective detection of active extracellular granzyme A by using a novel fluorescent immunoprobe with application to inflammatory diseases

Author: Instituto de Salud Carlos III, Ministerio de Ciencia, Innovación y Universidades (España), European Commission, Gobierno de Aragón, Agencia Estatal de Investigación (España), European Research Council, Ministerio de Economía y Competitividad (España), Senán Salinas, Ana [0009-0009-5597-851X], Comas, Laura [0000-0002-3843-1231], Esteban, Patricia [0000-0003-4123-3524], Garzón, Marcela [0000-0001-6778-0636], Santiago, Llipsy [0000-0002-1861-5981], Domingo, María Pilar [0000-0002-6829-8769], Ramírez-Labrada, Ariel [0000-0002-3888-7036], Paño, José Ramón [0000-0002-9600-8116], Vendrell, Marc [0000-0002-5392-9740], Pardo, Julián [0000-0003-0154-0730], Arias, Maykel [0000-0002-9730-2210], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Gálvez Buerba, Eva Mª [eva@icb.csic.es], Arias, Maykel [maykelariascabrero@gmail.com], Senán Salinas, Ana, Comas, Laura, Esteban, Patricia, Garzón, Marcela, Cheng, Zhiming, Santiago, Llipsy, Domingo, María Pilar, Ramírez-Labrada, Ariel, Paño, José Ramón, Vendrell, Marc, Pardo, Julián, Arias, Maykel, Gálvez Buerba, Eva Mª, Instituto de Salud Carlos III, Ministerio de Ciencia, Innovación y Universidades (España), European Commission, Gobierno de Aragón, Agencia Estatal de Investigación (España), European Research Council, Ministerio de Economía y Competitividad (España), Senán Salinas, Ana [0009-0009-5597-851X], Comas, Laura [0000-0002-3843-1231], Esteban, Patricia [0000-0003-4123-3524], Garzón, Marcela [0000-0001-6778-0636], Santiago, Llipsy [0000-0002-1861-5981], Domingo, María Pilar [0000-0002-6829-8769], Ramírez-Labrada, Ariel [0000-0002-3888-7036], Paño, José Ramón [0000-0002-9600-8116], Vendrell, Marc [0000-0002-5392-9740], Pardo, Julián [0000-0003-0154-0730], Arias, Maykel [0000-0002-9730-2210], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Gálvez Buerba, Eva Mª [eva@icb.csic.es], Arias, Maykel [maykelariascabrero@gmail.com], Senán Salinas, Ana, Comas, Laura, Esteban, Patricia, Garzón, Marcela, Cheng, Zhiming, Santiago, Llipsy, Domingo, María Pilar, Ramírez-Labrada, Ariel, Paño, José Ramón, Vendrell, Marc, Pardo, Julián, Arias, Maykel, and Gálvez Buerba, Eva Mª
Abstract: Granzymes (Gzms), a family of serine proteases, expressed by immune and nonimmune cells, present perforin-dependent and independent intracellular and extracellular functions. When released in the extracellular space, GzmA, with trypsin-like activity, is involved in the pathophysiology of different inflammatory diseases. However, there are no validated specific systems to detect active forms of extracellular GzmA, making it difficult to assess its biological relevance and potential use as a biomarker. Here, we have developed fluorescence-energy resonance-transfer (FRET)-based peptide probes (FAM-peptide-DABCYL) to specifically detect GzmA activity in tissue samples and biological fluids in both mouse and human samples during inflammatory diseases. An initial probe was developed and incubated with GzmA and different proteases like GzmB and others with similar cleavage specificity as GzmA like GzmK, thrombin, trypsin, kallikrein, or plasmin. After measuring fluorescence, the probe showed very good specificity and sensitivity for human and mouse GzmA when compared to GzmB, its closest homologue GzmK, and with thrombin. The specificity of this probe was further refined by incubating the samples in a coated plate with a GzmA-specific antibody before adding the probe. The results show a high specific detection of soluble GzmA even when compared with other soluble proteases with very similar cleavage specificity like thrombin, GzmK, trypsin, kallikrein, or plasmin, which shows nearly no fluorescence signal. The high specific detection of GzmA was validated, showing that using pure proteins and serum and tissue samples from GzmA-deficient mice presented a significant reduction in the signal compared with WT mice. The utility of this system in humans was confirmed, showing that GzmA activity was significantly higher in serum samples from septic patients in comparison with healthy donors. Our results present a new immunoprobe with utility to detect extracellular GzmA activity
Published: 2024

2. Supporting information for Selective detection of active extracellular granzyme A by using a novel fluorescent immunoprobe with application to inflammatory diseases [Dataset]

Author: Senán Salinas, Ana [0009-0009-5597-851X], Comas, Laura [0000-0002-3843-1231], Esteban, Patricia [0000-0003-4123-3524], Garzón, Marcela [0000-0001-6778-0636], Santiago, Llipsy [0000-0002-1861-5981], Domingo, María Pilar [0000-0002-6829-8769], Ramírez-Labrada, Ariel [0000-0002-3888-7036], Paño, José Ramón [0000-0002-9600-8116], Vendrell, Marc [0000-0002-5392-9740], Pardo, Julián [0000-0003-0154-0730], Arias, Maykel [0000-0002-9730-2210], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Gálvez Buerba, Eva Mª [eva@icb.csic.es], Arias, Maykel [maykelariascabrero@gmail.com], Senán Salinas, Ana, Comas, Laura, Esteban, Patricia, Garzón, Marcela, Santiago, Llipsy, Domingo, María Pilar, Ramírez-Labrada, Ariel, Paño, José Ramón, Vendrell, Marc, Pardo, Julián, Arias, Maykel, Gálvez Buerba, Eva Mª, Senán Salinas, Ana [0009-0009-5597-851X], Comas, Laura [0000-0002-3843-1231], Esteban, Patricia [0000-0003-4123-3524], Garzón, Marcela [0000-0001-6778-0636], Santiago, Llipsy [0000-0002-1861-5981], Domingo, María Pilar [0000-0002-6829-8769], Ramírez-Labrada, Ariel [0000-0002-3888-7036], Paño, José Ramón [0000-0002-9600-8116], Vendrell, Marc [0000-0002-5392-9740], Pardo, Julián [0000-0003-0154-0730], Arias, Maykel [0000-0002-9730-2210], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Gálvez Buerba, Eva Mª [eva@icb.csic.es], Arias, Maykel [maykelariascabrero@gmail.com], Senán Salinas, Ana, Comas, Laura, Esteban, Patricia, Garzón, Marcela, Santiago, Llipsy, Domingo, María Pilar, Ramírez-Labrada, Ariel, Paño, José Ramón, Vendrell, Marc, Pardo, Julián, Arias, Maykel, and Gálvez Buerba, Eva Mª
Abstract: Supplementary table 1. Concentration of trypsin-like proteases presenting similar enzyme activity using a common substrate.-- The substrate Nɑ-CBZ-L-Lysine thiobenzyl ester hydrochloride was incubated with hGzmA (66.7 nM), hGzmK (2.4 nM), mGzmA (4 nm), Kallikrein (3.7 nM), Plasmin (4.3 nM) and Trypsin (0.4 nM) for 30 min as described in methods. The absorbance was measured. The values obtained at each time were subtracted from the substrate signal in the absence of enzymes. Data represent the mean of three independent replicates.
Published: 2024

3. Biomarkers of immunotherapy response in patients with non-small-cell lung cancer: microbiota composition, short-chain fatty acids, and intestinal permeability

Author: Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (España), European Commission, Gobierno de Aragón, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Moratiel-Pellitero, Alba [0009-0000-9486-6793], Zapata, María [0000-0001-6654-8106], Gascón, Marta [0000-0002-6811-6654], Sesma, Andrea [0000-0001-7209-266X], Ramírez-Labrada, Ariel [0000-0002-3888-7036], Martínez Lostao, Luis [0000-0003-3043-147X], Domingo, María Pilar [0000-0002-6829-8769], Esteban, Patricia [0000-0003-4123-3524], Yubero, Alfonso [0000-0003-4995-0325], Barbero-Herranz, Raquel [0000-0001-8845-1137], Moreno Blanco, Ana [0000-0003-3220-1117], Paño, José Ramón [0000-0002-9600-8116], Lastra, Rodrigo [0000-0002-7498-7798], Pardo, Julián [0000-0003-0154-0730], Isla, Dolores [0000-0002-2483-198X], Campo, Rosa del [0000-0003-1147-7923], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Moratiel-Pellitero, Alba, Zapata, María, Gascón, Marta, Sesma, Andrea, Quílez, Elisa, Ramirez-Labrada, Ariel, Martínez Lostao, Luis, Domingo, María Pilar, Esteban, Patricia, Yubero, Alfonso, Barbero-Herranz, Raquel, Moreno Blanco, Ana, Paño, José Ramón, Lastra, Rodrigo, Pardo, Julián, Isla, Dolores, Campo, Rosa del, Gálvez Buerba, Eva Mª, Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (España), European Commission, Gobierno de Aragón, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Moratiel-Pellitero, Alba [0009-0000-9486-6793], Zapata, María [0000-0001-6654-8106], Gascón, Marta [0000-0002-6811-6654], Sesma, Andrea [0000-0001-7209-266X], Ramírez-Labrada, Ariel [0000-0002-3888-7036], Martínez Lostao, Luis [0000-0003-3043-147X], Domingo, María Pilar [0000-0002-6829-8769], Esteban, Patricia [0000-0003-4123-3524], Yubero, Alfonso [0000-0003-4995-0325], Barbero-Herranz, Raquel [0000-0001-8845-1137], Moreno Blanco, Ana [0000-0003-3220-1117], Paño, José Ramón [0000-0002-9600-8116], Lastra, Rodrigo [0000-0002-7498-7798], Pardo, Julián [0000-0003-0154-0730], Isla, Dolores [0000-0002-2483-198X], Campo, Rosa del [0000-0003-1147-7923], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Moratiel-Pellitero, Alba, Zapata, María, Gascón, Marta, Sesma, Andrea, Quílez, Elisa, Ramirez-Labrada, Ariel, Martínez Lostao, Luis, Domingo, María Pilar, Esteban, Patricia, Yubero, Alfonso, Barbero-Herranz, Raquel, Moreno Blanco, Ana, Paño, José Ramón, Lastra, Rodrigo, Pardo, Julián, Isla, Dolores, Campo, Rosa del, and Gálvez Buerba, Eva Mª
Abstract: There is evidence of the influence of the intestinal microbiota on the response to immunotherapy in cancer. In addition, we lack markers of response to treatment and toxicity, which obliges us to continue our search for them. In this work, we recruited patients with non-small-cell lung cancer receiving immunotherapy who contributed a fecal and blood sample. We analyzed the possible relationship between the response to immune checkpoint inhibitors and the occurrence of immune-related adverse events, the composition (16S rDNA amplification) and functionality (abundance of short-chain fatty acids) of the gut microbiota, and intestinal membrane permeability as a human factor. No correlations were detected between analytical markers and clinical evolution, with a marked individuality of the gut microbiota in terms of composition, but homogeneity in its functionality and permeability. Immune checkpoint inhibitors have been proposed as the standard treatment for different stages of non-small-cell lung cancer in multiple indications. Not all patients benefit from these treatments, however, and certain patients develop immune-related adverse events. Although the search for predictors of response to these drugs is a major field of research, these issues have yet to be resolved. It has been postulated that microbiota could play a relevant role in conditioning the response to cancer treatments; however, the human factor of intestinal permeability also needs to be considered as it is closely related to the regulation of host–microbiota interaction. In this article, we analyzed the possible relationship between the response to immune checkpoint inhibitors and the onset of immune-related adverse events, gut microbiota status, and intestinal membrane permeability. In a pioneering step, we also measured short-chain fatty acid content in feces. Although the correlation analyses failed to identify predictive biomarkers, even when all variables were integrated, our patients’ microbial
Published: 2024

4. Multiparametric in vitro and in vivo analysis of the safety profile of self-assembling peptides

Author: Istituto Nazionale per l'Assicurazione Contro Gli Infortuni sul Lavoro, Ministero della Salute, Governo Italiano, Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (España), Instituto de Salud Carlos III, European Commission, Gobierno de Aragón, Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), Aspanoa, Asociación Carrera de la Mujer Ciudad de Monzón, Universidad de Zaragoza, Banco Santander, Asociación Española Contra el Cáncer, Fundación Científica Asociación Española Contra el Cáncer, Ramírez-Labrada, Ariel [0000-0002-3888-7036], Santiago, Llipsy [0000-0002-1861-5981], Pesini, Cecilia [0000-0002-8707-2722], Arias, Maykel [0000-0002-9730-2210], Ciulla, Maria Gessica [0000-0001-8738-1712], Forouharshad, Mahdi [0000-0002-6139-9110], Pardo, Julián [0000-0003-0154-0730], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Gelain, Fabrizio [0000-0002-2624-5853], Ramírez-Labrada, Ariel, Santiago, Llipsy, Pesini, Cecilia, Arrieta, Marta, Arias, Maykel, Calvo Pérez, Adanys, Ciulla, Maria Gessica, Forouharshad, Mahdi, Pardo, Julián, Gálvez Buerba, Eva Mª, Gelain, Fabrizio, Istituto Nazionale per l'Assicurazione Contro Gli Infortuni sul Lavoro, Ministero della Salute, Governo Italiano, Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (España), Instituto de Salud Carlos III, European Commission, Gobierno de Aragón, Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), Aspanoa, Asociación Carrera de la Mujer Ciudad de Monzón, Universidad de Zaragoza, Banco Santander, Asociación Española Contra el Cáncer, Fundación Científica Asociación Española Contra el Cáncer, Ramírez-Labrada, Ariel [0000-0002-3888-7036], Santiago, Llipsy [0000-0002-1861-5981], Pesini, Cecilia [0000-0002-8707-2722], Arias, Maykel [0000-0002-9730-2210], Ciulla, Maria Gessica [0000-0001-8738-1712], Forouharshad, Mahdi [0000-0002-6139-9110], Pardo, Julián [0000-0003-0154-0730], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Gelain, Fabrizio [0000-0002-2624-5853], Ramírez-Labrada, Ariel, Santiago, Llipsy, Pesini, Cecilia, Arrieta, Marta, Arias, Maykel, Calvo Pérez, Adanys, Ciulla, Maria Gessica, Forouharshad, Mahdi, Pardo, Julián, Gálvez Buerba, Eva Mª, and Gelain, Fabrizio
Abstract: Self-assembling peptides (SAPs) have gained significant attention in biomedicine because of their unique properties and ability to undergo molecular self-assembly driven by non-covalent interactions. By manipulating their composition and structure, SAPs can form well-ordered nanostructures with enhanced selectivity, stability and biocompatibility. SAPs offer advantages such as high chemical and biological diversity and the potential for functionalization. However, studies concerning its potentially toxic effects are very scarce, a limitation that compromises its potential translation to humans. This study investigates the potentially toxic effects of six different SAP formulations composed of natural amino acids designed for nervous tissue engineering and amenable to ready cross-linking boosting their biomechanical properties. All methods were performed in accordance with the relevant guidelines and regulations. A wound-healing assay was performed to evaluate how SAPs modify cell migration. The results in vitro demonstrated that SAPs did not induce genotoxicity neither skin sensitization. In vivo, SAPs were well-tolerated without any signs of acute systemic toxicity. Interestingly, SAPs were found to promote the migration of endothelial, macrophage, fibroblast, and neuronal-like cells in vitro, supporting a high potential for tissue regeneration. These findings contribute to the development and translation of SAP-based biomaterials for biomedical applications.
Published: 2024

5. CAR Immunotherapy for the treatment of infectious diseases: a systematic review

Author: Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (España), Instituto de Salud Carlos III, European Commission, Gobierno de Aragón, Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), Aspanoa, Asociación Carrera de la Mujer Ciudad de Monzón, Universidad de Zaragoza, Banco Santander, Asociación Española Contra el Cáncer, Morte Romea, Elena [0000-0001-9262-2461], Pesini, Cecilia [0000-0002-8707-2722], Pellejero, Galadriel [0000-0002-2728-5435], Martínez Lostao, Luis [0000-0003-3043-147X], Toyas, Carla [0000-0002-4217-6317], Redrado, Sergio [0000-0002-8404-0012], Dolader, Elena [0009-0007-5333-4214], Arias, Maykel [0000-0002-9730-2210], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Sanz-Pamplona, Rebeca [0000-0002-2187-3527], Pardo, Julián [0000-0003-0154-0730], Paño, José Ramón [0000-0002-9600-8116], Ramírez-Labrada, Ariel [0000-0002-3888-7036], Ramírez-Labrada, Ariel [aramirezlabrada@yahoo.es], Morte Romea, Elena, Pesini, Cecilia, Pellejero, Galadriel, Martínez-Lostao, Luis, Loscos, Silvia, Toyas, Carla, Redrado, Sergio, Dolader, Elena, Arias, Maykel, Gálvez Buerba, Eva Mª, Sanz-Pamplona, Rebeca, Pardo, Julián, Paño, José Ramón, Ramírez-Labrada, Ariel, Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (España), Instituto de Salud Carlos III, European Commission, Gobierno de Aragón, Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), Aspanoa, Asociación Carrera de la Mujer Ciudad de Monzón, Universidad de Zaragoza, Banco Santander, Asociación Española Contra el Cáncer, Morte Romea, Elena [0000-0001-9262-2461], Pesini, Cecilia [0000-0002-8707-2722], Pellejero, Galadriel [0000-0002-2728-5435], Martínez Lostao, Luis [0000-0003-3043-147X], Toyas, Carla [0000-0002-4217-6317], Redrado, Sergio [0000-0002-8404-0012], Dolader, Elena [0009-0007-5333-4214], Arias, Maykel [0000-0002-9730-2210], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Sanz-Pamplona, Rebeca [0000-0002-2187-3527], Pardo, Julián [0000-0003-0154-0730], Paño, José Ramón [0000-0002-9600-8116], Ramírez-Labrada, Ariel [0000-0002-3888-7036], Ramírez-Labrada, Ariel [aramirezlabrada@yahoo.es], Morte Romea, Elena, Pesini, Cecilia, Pellejero, Galadriel, Martínez-Lostao, Luis, Loscos, Silvia, Toyas, Carla, Redrado, Sergio, Dolader, Elena, Arias, Maykel, Gálvez Buerba, Eva Mª, Sanz-Pamplona, Rebeca, Pardo, Julián, Paño, José Ramón, and Ramírez-Labrada, Ariel
Abstract: Immunotherapy treatments aim to modulate the host’s immune response to either mitigate it in inflammatory/autoimmune disease or enhance it against infection or cancer. Among different immunotherapies reaching clinical application during the last years, chimeric antigen receptor (CAR) immunotherapy has emerged as an effective treatment for cancer where different CAR T cells have already been approved. Yet their use against infectious diseases is an area still relatively poorly explored, albeit with tremendous potential for research and clinical application. Infectious diseases represent a global health challenge, with the escalating threat of antimicrobial resistance underscoring the need for alternative therapeutic approaches. This review aims to systematically evaluate the current applications of CAR immunotherapy in infectious diseases and discuss its potential for future applications. Notably, CAR cell therapies, initially developed for cancer treatment, are gaining recognition as potential remedies for infectious diseases. The review sheds light on significant progress in CAR T cell therapy directed at viral and opportunistic fungal infections.
Published: 2024

6. Immune response in SARS-CoV-2 infection

Author: Morte Romea, Elena [0000-0001-9262-2461], Uranga Murillo, Iratxe [0000-0001-8411-984X], Hidalgo, Sandra [0000-0003-1629-9978], Ramírez-Labrada, Ariel [0000-0002-3888-7036], Miguel, Diego de [0000-0002-8486-8514], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Martínez Lostao, Luis [0000-0003-3043-147X], Pellejero, Galadriel [0000-0002-2728-5435], Pardo, Julián [0000-0003-0154-0730], Paño, José Ramón [0000-0002-9600-8116], Morte Romea, Elena, Uranga Murillo, Iratxe, Hidalgo, Sandra, Ramírez-Labrada, Ariel, Miguel, Diego de, Gálvez Buerba, Eva Mª, Martínez Lostao, Luis, Pellejero, Galadriel, Letona Jiménez, Santiago, Pardo, Julián, Paño, José Ramón, Morte Romea, Elena [0000-0001-9262-2461], Uranga Murillo, Iratxe [0000-0001-8411-984X], Hidalgo, Sandra [0000-0003-1629-9978], Ramírez-Labrada, Ariel [0000-0002-3888-7036], Miguel, Diego de [0000-0002-8486-8514], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Martínez Lostao, Luis [0000-0003-3043-147X], Pellejero, Galadriel [0000-0002-2728-5435], Pardo, Julián [0000-0003-0154-0730], Paño, José Ramón [0000-0002-9600-8116], Morte Romea, Elena, Uranga Murillo, Iratxe, Hidalgo, Sandra, Ramírez-Labrada, Ariel, Miguel, Diego de, Gálvez Buerba, Eva Mª, Martínez Lostao, Luis, Pellejero, Galadriel, Letona Jiménez, Santiago, Pardo, Julián, and Paño, José Ramón
Abstract: We analyzed several parameters of the immune response of COVID-19 patients who required hospital admission, com paring them to healthy donors (HDs) and other patients admitted for respiratory infections not caused by SARS-CoV-2 (non-COV-RTI). We focused on the main cells involved in innate immunity and soluble inflammatory factors that regulate their activity.
Published: 2024

7. Nanobody based immunotherapy for the treatment of invasive fungal infections

Author: Gobierno de Aragón, European Commission, Agencia Estatal de Investigación (España), Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (España), Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (España), Redrado, Sergio [0000-0002-8404-0012], Dolader, Elena [0009-0007-5333-4214], Macías León, Javier [0000-0001-6815-6720], Domingo, María Pilar [0000-0002-6829-8769], Esteban, Patricia [0000-0003-4123-3524], Arias, Maykel [0000-0002-9730-2210], Ramírez-Labrada, Ariel [0000-0002-3888-7036], Pardo, Julián [0000-0003-0154-0730], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Sánchez-Martínez, Diego, Redrado, Sergio, Dolader, Elena, Macías León, Javier, Domingo, María Pilar, Esteban, Patricia, Arias, Maykel, Ramírez-Labrada, Ariel, Hurtado-Guerrero, R., Pardo, Julián, Gálvez Buerba, Eva Mª, Gobierno de Aragón, European Commission, Agencia Estatal de Investigación (España), Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (España), Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (España), Redrado, Sergio [0000-0002-8404-0012], Dolader, Elena [0009-0007-5333-4214], Macías León, Javier [0000-0001-6815-6720], Domingo, María Pilar [0000-0002-6829-8769], Esteban, Patricia [0000-0003-4123-3524], Arias, Maykel [0000-0002-9730-2210], Ramírez-Labrada, Ariel [0000-0002-3888-7036], Pardo, Julián [0000-0003-0154-0730], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Sánchez-Martínez, Diego, Redrado, Sergio, Dolader, Elena, Macías León, Javier, Domingo, María Pilar, Esteban, Patricia, Arias, Maykel, Ramírez-Labrada, Ariel, Hurtado-Guerrero, R., Pardo, Julián, and Gálvez Buerba, Eva Mª
Abstract: The invasive fungal infections ratios of mortality are between 25% and 70% depending on the type of microorganism and the population at risk, affecting mostly immunocompromised patients. Aspergillus spp. and Cryptococcus spp. are two of the main responsible for these infections. The late non-specific diagnosis and the increasing resistance of the strains highlight the importance of finding new therapeutic alternatives.
Published: 2024

8. A subset of PD-1-expressing CD56bright NK cells identifies patients with good response to immune checkpoint inhibitors in lung cancer

Author: European Commission, Gobierno de Aragón, Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, Aspanoa, Asociación Carrera de la Mujer Ciudad de Monzón, Bristol Myers Squibb Foundation, Roche, Ministerio de Ciencia, Innovación y Universidades (España), Gascón, Marta [0000-0002-6811-6654], Ramírez-Labrada, Ariel [0000-0002-3888-7036], Lastra, Rodrigo [0000-0002-7498-7798], Martínez Lostao, Luis [0000-0003-3043-147X], Paño, José Ramón [0000-0002-9600-8116], Sesma, Andrea [0000-0001-7209-266X], Zapata, María [0000-0001-6654-8106], Torres-Ramón, Irene [0000-0003-3387-0558], Yubero, Alfonso [0000-0003-4995-0325], Domingo, María Pilar [0000-0002-6829-8769], Esteban, Patricia [0000-0003-4123-3524], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Pardo, Julián [0000-0003-0154-0730], Isla, Dolores [0000-0002-2483-198X], Gascón, Marta, Ramírez-Labrada, Ariel, Lastra, Rodrigo, Martínez-Lostao, Luis, Paño, José Ramón, Sesma, Andrea, Zapata, María, Moratiel, Alba, Quílez, María Elisa, Torres-Ramón, Irene, Yubero, Alfonso, Domingo, María Pilar, Esteban, Patricia, Gálvez Buerba, Eva Mª, Pardo, Julián, Isla, Dolores, European Commission, Gobierno de Aragón, Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, Aspanoa, Asociación Carrera de la Mujer Ciudad de Monzón, Bristol Myers Squibb Foundation, Roche, Ministerio de Ciencia, Innovación y Universidades (España), Gascón, Marta [0000-0002-6811-6654], Ramírez-Labrada, Ariel [0000-0002-3888-7036], Lastra, Rodrigo [0000-0002-7498-7798], Martínez Lostao, Luis [0000-0003-3043-147X], Paño, José Ramón [0000-0002-9600-8116], Sesma, Andrea [0000-0001-7209-266X], Zapata, María [0000-0001-6654-8106], Torres-Ramón, Irene [0000-0003-3387-0558], Yubero, Alfonso [0000-0003-4995-0325], Domingo, María Pilar [0000-0002-6829-8769], Esteban, Patricia [0000-0003-4123-3524], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Pardo, Julián [0000-0003-0154-0730], Isla, Dolores [0000-0002-2483-198X], Gascón, Marta, Ramírez-Labrada, Ariel, Lastra, Rodrigo, Martínez-Lostao, Luis, Paño, José Ramón, Sesma, Andrea, Zapata, María, Moratiel, Alba, Quílez, María Elisa, Torres-Ramón, Irene, Yubero, Alfonso, Domingo, María Pilar, Esteban, Patricia, Gálvez Buerba, Eva Mª, Pardo, Julián, and Isla, Dolores
Abstract: (1) Despite the effectiveness of immune checkpoint inhibitors (ICIs) in lung cancer, there is a lack of knowledge about predictive biomarkers. The objective of our study is to analyze different subsets of T-lymphocytes and natural killer (NK) cells as predictive biomarkers in a cohort of patients with nonsmall cell lung cancer (NSCLC) treated with ICI. (2) This is an observational, prospective study with 55 NSCLC patients treated with ICI. A total of 43 T and NK cell subsets are analyzed in peripheral blood, including the main markers of exhaustion, differentiation, memory, activation, and inhibition. (3) Regarding the descriptive data, Granzyme B+CD4+ Treg lymphocytes stand out (median 17.4%), and within the NK populations, most patients presented cytotoxic NK cells (CD56+CD3−CD16+GranzymeB+; median 94.8%), and about half of them have highly differentiated adaptive-like NK cells (CD56+CD3−CD16+CD57+ (mean 59.8%). A statistically significant difference was observed between the expression of PD1 within the CD56bright NK cell subpopulation (CD56+CD3−CD16−PD-1+) (p = 0.047) and a better OS. (4) Circulating immune cell subpopulations are promising prognostic biomarkers for ICI. Pending on validation with a larger sample, here we provide an analysis of the major circulating T and NK cell subsets involved in cancer immunity, with promising results despite a small sample size.
Published: 2023

9. Supplementary material for Integrated analysis of circulating immune cellular and soluble mediators reveals specific COVID19 signatures at hospital admission with utility for prediction of clinical outcomes [Dataset]

Author: European Commission, Gobierno de Aragón, Instituto de Salud Carlos III, Fundación Banco Santander, Universidad de Zaragoza, Agencia Estatal de Investigación (España), Fundación Inocente Inocente, Aspanoa, Asociación Carrera de la Mujer Ciudad de Monzón, Asociación Española Contra el Cáncer, Ministerio de Ciencia, Innovación y Universidades (España), ARAID Foundation, Uranga Murillo, Iratxe [0000-0001-8411-984X], Morte Romea, Elena [0000-0001-9262-2461], Hidalgo, Sandra [0000-0003-1629-9978], Pesini, Cecilia [0000-0002-8707-2722], García-Mulero, Sandra [0000-0003-4931-1267], Sierra Monzón, José L. [0000-0002-8796-2717], Santiago, Llipsy [0000-0002-1861-5981], Arias, Maykel [0000-0002-9730-2210], Miguel, Diego de [0000-0002-8486-8514], Encabo-Berzosa, M. Mar [0000-0001-5533-804X], Gracia Tello, Borja [0000-0003-3248-2908], Sanz-Pamplona, Rebeca [0000-0002-2187-3527], Martínez Lostao, Luis [0000-0003-3043-147X], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Paño, José Ramón [0000-0002-9600-8116], Ramírez-Labrada, Ariel [0000-0002-3888-7036], Pardo, Julián [0000-0003-0154-0730], Paño, José Ramón; Ramírez-Labrada, Ariel; Pardo, Julián, Uranga Murillo, Iratxe, Morte Romea, Elena, Hidalgo, Sandra, Pesini, Cecilia, García-Mulero, Sandra, Sierra Monzón, José L., Santiago, Llipsy, Arias, Maykel, Miguel, Diego de, Encabo-Berzosa, M. Mar, Gracia Tello, Borja, Sanz-Pamplona, Rebeca, Martínez-Lostao, Luis, Gálvez Buerba, Eva Mª, Paño, José Ramón, Ramírez-Labrada, Ariel, Pardo, Julián, European Commission, Gobierno de Aragón, Instituto de Salud Carlos III, Fundación Banco Santander, Universidad de Zaragoza, Agencia Estatal de Investigación (España), Fundación Inocente Inocente, Aspanoa, Asociación Carrera de la Mujer Ciudad de Monzón, Asociación Española Contra el Cáncer, Ministerio de Ciencia, Innovación y Universidades (España), ARAID Foundation, Uranga Murillo, Iratxe [0000-0001-8411-984X], Morte Romea, Elena [0000-0001-9262-2461], Hidalgo, Sandra [0000-0003-1629-9978], Pesini, Cecilia [0000-0002-8707-2722], García-Mulero, Sandra [0000-0003-4931-1267], Sierra Monzón, José L. [0000-0002-8796-2717], Santiago, Llipsy [0000-0002-1861-5981], Arias, Maykel [0000-0002-9730-2210], Miguel, Diego de [0000-0002-8486-8514], Encabo-Berzosa, M. Mar [0000-0001-5533-804X], Gracia Tello, Borja [0000-0003-3248-2908], Sanz-Pamplona, Rebeca [0000-0002-2187-3527], Martínez Lostao, Luis [0000-0003-3043-147X], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Paño, José Ramón [0000-0002-9600-8116], Ramírez-Labrada, Ariel [0000-0002-3888-7036], Pardo, Julián [0000-0003-0154-0730], Paño, José Ramón; Ramírez-Labrada, Ariel; Pardo, Julián, Uranga Murillo, Iratxe, Morte Romea, Elena, Hidalgo, Sandra, Pesini, Cecilia, García-Mulero, Sandra, Sierra Monzón, José L., Santiago, Llipsy, Arias, Maykel, Miguel, Diego de, Encabo-Berzosa, M. Mar, Gracia Tello, Borja, Sanz-Pamplona, Rebeca, Martínez-Lostao, Luis, Gálvez Buerba, Eva Mª, Paño, José Ramón, Ramírez-Labrada, Ariel, and Pardo, Julián
Abstract: Supplementary materials and methods: sample processing, flow cytometry, high dimensional flow cytometry data analysis, multiplex plasma protein analyses, granzyme activity assay in serum, statistics. Supplementary figure legends (1-5). Supplementary table legends (1-7).
Published: 2022

10. Fluorogenic Granzyme A substrates enable real-time imaging of adaptive immune cell activity

Author: Gobierno de Aragón, Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (España), Instituto de Salud Carlos III, European Commission, Ministerio de Ciencia, Innovación y Universidades (España), Medical Research Council (UK), Cancer Research UK, European Research Council, Mendive-Tapia, Lorena [0000-0002-3406-5203], Kitamura, Takanori [0000-0003-2032-3918], Samarakoon, Youhani [0000-0002-9845-4232], Roberts, Edward W. [0000-0002-8229-1715], Arias, Maykel [0000-0002-9730-2210], Pardo, Julián [0000-0003-0154-0730], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Cheng, Zhiming, Thompson, Emily J., Mendive-Tapia, Lorena, Scott, Jamie I., Benson, Sam, Kitamura, Takanori, Senán Salinas, Ana, Samarakoon, Youhani, Roberts, Edward W., Arias, Maykel, Pardo, Julián, Gálvez Buerba, Eva Mª, Gobierno de Aragón, Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (España), Instituto de Salud Carlos III, European Commission, Ministerio de Ciencia, Innovación y Universidades (España), Medical Research Council (UK), Cancer Research UK, European Research Council, Mendive-Tapia, Lorena [0000-0002-3406-5203], Kitamura, Takanori [0000-0003-2032-3918], Samarakoon, Youhani [0000-0002-9845-4232], Roberts, Edward W. [0000-0002-8229-1715], Arias, Maykel [0000-0002-9730-2210], Pardo, Julián [0000-0003-0154-0730], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Cheng, Zhiming, Thompson, Emily J., Mendive-Tapia, Lorena, Scott, Jamie I., Benson, Sam, Kitamura, Takanori, Senán Salinas, Ana, Samarakoon, Youhani, Roberts, Edward W., Arias, Maykel, Pardo, Julián, and Gálvez Buerba, Eva Mª
Abstract: Cytotoxic immune cells, including T lymphocytes (CTLs) and natural killer (NK) cells, are essential components of the host response against tumors. CTLs and NK cells secrete granzyme A (GzmA) upon recognition of cancer cells; however, there are very few tools that can detect physiological levels of active GzmA with high spatiotemporal resolution. Herein, we report the rational design of the near-infrared fluorogenic substrates for human GzmA and mouse GzmA. These activity-based probes display very high catalytic efficiency and selectivity over other granzymes, as shown in tissue lysates from wild-type and GzmA knock-out mice. Furthermore, we demonstrate that the probes can image how adaptive immune cells respond to antigen-driven recognition of cancer cells in real time.
Published: 2022

11. Characterisation of circulating immune cells in a cohort of non-small cell lung cancer patients treated with immunotherapy

Author: Gascón, Marta [0000-0002-6811-6654], Cruellas, Mara [0000-0002-6953-9675], Esteban, Patricia [0000-0003-4123-3524], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Lastra, Rodrigo [0000-0002-7498-7798], Martínez Lostao, Luis [0000-0003-3043-147X], Ocáriz, Maitane [0000-0002-7557-7264], Paño, José Ramón [0000-0002-9600-8116], Quílez Bermejo, J. [0000-0003-2808-1036], Ramírez-Labrada, Ariel [0000-0002-3888-7036], Sesma Goñi, Andrea [0000-0001-7209-266X], Torres-Ramón, Irene [0000-0003-3387-0558], Yubero, Alfonso [0000-0003-4995-0325], Zapata, María [0000-0001-6654-8106], Isla, Dolores [0000-0002-2483-198X], Gascón, Marta, Pardo, Julián, Cruellas, Mara, Esteban, Patricia, Gálvez Buerba, Eva Mª, Lastra, Rodrigo, Martínez-Lostao, Luis, Ocáriz, Maitane, Paño, José Ramón, Quílez Bermejo, J., Ramírez-Labrada, Ariel, Sesma Goñi, Andrea, Torres-Ramón, Irene, Yubero, Alfonso, Zapata, María, Isla, Dolores, Gascón, Marta [0000-0002-6811-6654], Cruellas, Mara [0000-0002-6953-9675], Esteban, Patricia [0000-0003-4123-3524], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Lastra, Rodrigo [0000-0002-7498-7798], Martínez Lostao, Luis [0000-0003-3043-147X], Ocáriz, Maitane [0000-0002-7557-7264], Paño, José Ramón [0000-0002-9600-8116], Quílez Bermejo, J. [0000-0003-2808-1036], Ramírez-Labrada, Ariel [0000-0002-3888-7036], Sesma Goñi, Andrea [0000-0001-7209-266X], Torres-Ramón, Irene [0000-0003-3387-0558], Yubero, Alfonso [0000-0003-4995-0325], Zapata, María [0000-0001-6654-8106], Isla, Dolores [0000-0002-2483-198X], Gascón, Marta, Pardo, Julián, Cruellas, Mara, Esteban, Patricia, Gálvez Buerba, Eva Mª, Lastra, Rodrigo, Martínez-Lostao, Luis, Ocáriz, Maitane, Paño, José Ramón, Quílez Bermejo, J., Ramírez-Labrada, Ariel, Sesma Goñi, Andrea, Torres-Ramón, Irene, Yubero, Alfonso, Zapata, María, and Isla, Dolores
Abstract: [Introduction] Immunotherapy in lung cancer has been one of the most relevant therapeutic advances in recent years. Although many studies demonstrate its antitumor activity, there is still a great lack of knowledge about which may be the best prognostic biomarkers. In recent years, several studies suggest that different immune cell populations might be useful biomarkers to predict immunotherapy efficacy. Among them are specific T cell subsets, natural killer (NK) cells or the ratio between cytotoxic CD8+ T and regulatory CD4+ T (Treg) lymphocytes. In this sense, the objective of our study is to provide a detailed analysis of different circulating immune cell subsets within T and NK cell populations in a cohort of patients with non-small cell lung cancer (NSCLC) treated with immune-checkpoint inhibitors (ICI) and analyze their prognostic value., [Methods] Observational, prospective and analytical study of a cohort of 55 patients diagnosed with NSCLC (unresectable stage III and IV) receiving ICI. Demographic, clinical and tumor variables are collected, as well as a peripheral blood sample. A total of 43 cell subpopulations of CD4+ and CD8+ T and NK cells, including the main exhaustion, differentiation, memory, activation and inhibition markers are analyzed in peripheral blood, correlated with treatment response and survival..., [Results] 55 patients were included (70.9% men) with a median age of 65 years. Regarding histology, there were 40% squamous cell carcinomas and 60% adenocarcinomas, 70.9% being stage IV. After minimum of one year of follow-up, 56.4% of patients had progressed with a median overall survival of 19 months (CI: 11.13-26.87). Regarding the descriptive data of the analyzed cell populations, the regulatory Granzyme B+ CD4+ T lymphocytes stand out with a median of 17.4% (SD 24.4%) and memory CD4+ and CD8+ Tz..., [Conclusions] Circulating immune cell subpopulations are among the most promising prognostic biomarkers for ICI. Here we provide a detailed descriptive analysis of the main circulating T and NK cell subsets involved in cancer immunity in a cohort of NSCLC patients. Some of the results suggest dysfunctional T and NK cell responses that might be related with ICI efficacy, which relevance to predict survival and treatment outcome will be shortly available
Published: 2022

12. PD-1 is expressed in cytotoxic granules of NK cells and rapidly mobilized to the cell membrane following recognition of tumor cells

Author: European Commission, Gobierno de Aragón, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Fundación Inocente Inocente, Aspanoa, Asociación Carrera de la Mujer Ciudad de Monzón, ARAID Foundation, Fundación Agencia Aragonesa para la Investigación y el Desarrollo, Fundación Científica Asociación Española Contra el Cáncer, Pesini, Cecilia [0000-0002-8707-2722], Hidalgo, Sandra [0000-0003-1629-9978], Arias, Maykel [0000-0002-9730-2210], Santiago, Llipsy [0000-0002-1861-5981], Calvo, Carlota [0000-0003-1864-4050], Ocáriz, Maitane [0000-0002-7557-7264], Isla, Dolores [0000-0002-2483-198X], Lanuza, Pilar M. [0000-0001-7328-2094], Agustín Ferrández, M. J. [0000-0003-0450-4196], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Ramírez-Labrada, Ariel [0000-0002-3888-7036], Pardo, Julián [0000-0003-0154-0730], Pesini, Cecilia, Hidalgo, Sandra, Arias, Maykel, Santiago, Llipsy, Calvo, Carlota, Ocáriz, Maitane, Isla, Dolores, Lanuza, Pilar M., Agustín Ferrández, M. J., Gálvez Buerba, Eva Mª, Ramírez-Labrada, Ariel, Pardo, Julián, European Commission, Gobierno de Aragón, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Fundación Inocente Inocente, Aspanoa, Asociación Carrera de la Mujer Ciudad de Monzón, ARAID Foundation, Fundación Agencia Aragonesa para la Investigación y el Desarrollo, Fundación Científica Asociación Española Contra el Cáncer, Pesini, Cecilia [0000-0002-8707-2722], Hidalgo, Sandra [0000-0003-1629-9978], Arias, Maykel [0000-0002-9730-2210], Santiago, Llipsy [0000-0002-1861-5981], Calvo, Carlota [0000-0003-1864-4050], Ocáriz, Maitane [0000-0002-7557-7264], Isla, Dolores [0000-0002-2483-198X], Lanuza, Pilar M. [0000-0001-7328-2094], Agustín Ferrández, M. J. [0000-0003-0450-4196], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Ramírez-Labrada, Ariel [0000-0002-3888-7036], Pardo, Julián [0000-0003-0154-0730], Pesini, Cecilia, Hidalgo, Sandra, Arias, Maykel, Santiago, Llipsy, Calvo, Carlota, Ocáriz, Maitane, Isla, Dolores, Lanuza, Pilar M., Agustín Ferrández, M. J., Gálvez Buerba, Eva Mª, Ramírez-Labrada, Ariel, and Pardo, Julián
Abstract: The contribution of the T cell-related inhibitory checkpoint PD-1 to the regulation of NK cell activity is still not clear with contradictory results concerning its expression and role in the modulation of NK cell cytotoxicity. We provide novel key findings on the mechanism involved in the regulation of PD-1 expression on NK cell membrane and its functional consequences for the elimination of cancer cells. In contrast to freshly isolated NK cells from cancer patients, those from healthy donors did not express PD-1 on the cell membrane. However, when healthy NK cells were incubated with tumor target cells, membrane PD-1 expression increased, concurrent with the CD107a surface mobilization. This finding suggested that PD-1 was translocated to the cell membrane during NK cell degranulation after contact with target cells. Indeed, cytosolic PD-1 was expressed in freshly-isolated-NK cells and partly co-localized with CD107a and GzmB, confirming that membrane PD-1 corresponded to a pool of preformed PD-1. Moreover, NK cells that had mobilized PD-1 to the cell membrane presented a significantly reduced antitumor activity on PD-L1-expressing-tumor cells in vitro and in vivo, which was partly reversed by using anti-PD-1 blocking antibodies. Our results indicate that NK cells from healthy individuals express cytotoxic granule-associated PD-1, which is rapidly mobilized to the cell membrane after interaction with tumor target cells. This novel finding helps to understand how PD-1 expression is regulated on NK cell membrane and the functional consequences of this expression during the elimination of tumor cells, which will help to design more efficient NK cell-based cancer immunotherapies.
Published: 2022

13. All about (NK cell-mediated) death in two acts and an unexpected encore: initiation, execution and activation of adaptive immunity

Author: Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (España), European Commission, Gobierno de Aragón, Agencia Estatal de Investigación (España), Aspanoa, Asociación Carrera de la Mujer Ciudad de Monzón, ARAID Foundation, Asociación Española Contra el Cáncer, Ministerio de Ciencia, Innovación y Universidades (España), Ramírez-Labrada, Ariel [0000-0002-3888-7036], Pesini, Cecilia [0000-0002-8707-2722], Santiago, Llipsy [0000-0002-1861-5981], Hidalgo, Sandra [0000-0003-1629-9978], Uranga Murillo, Iratxe [0000-0001-8411-984X], Arias, Maykel [0000-0002-9730-2210], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Pardo, Julián [0000-0003-0154-0730], Ramírez-Labrada, Ariel, Pesini, Cecilia, Santiago, Llipsy, Hidalgo, Sandra, Calvo Pérez, Adanys, Oñate, Carmen, Andrés Tovar, Alejandro, Garzón Tituaña, Marcela, Uranga Murillo, Iratxe, Arias, Maykel, Gálvez Buerba, Eva Mª, Pardo, Julián, Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (España), European Commission, Gobierno de Aragón, Agencia Estatal de Investigación (España), Aspanoa, Asociación Carrera de la Mujer Ciudad de Monzón, ARAID Foundation, Asociación Española Contra el Cáncer, Ministerio de Ciencia, Innovación y Universidades (España), Ramírez-Labrada, Ariel [0000-0002-3888-7036], Pesini, Cecilia [0000-0002-8707-2722], Santiago, Llipsy [0000-0002-1861-5981], Hidalgo, Sandra [0000-0003-1629-9978], Uranga Murillo, Iratxe [0000-0001-8411-984X], Arias, Maykel [0000-0002-9730-2210], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Pardo, Julián [0000-0003-0154-0730], Ramírez-Labrada, Ariel, Pesini, Cecilia, Santiago, Llipsy, Hidalgo, Sandra, Calvo Pérez, Adanys, Oñate, Carmen, Andrés Tovar, Alejandro, Garzón Tituaña, Marcela, Uranga Murillo, Iratxe, Arias, Maykel, Gálvez Buerba, Eva Mª, and Pardo, Julián
Abstract: NK cells are key mediators of immune cell-mediated cytotoxicity toward infected and transformed cells, being one of the main executors of cell death in the immune system. NK cells recognize target cells through an array of inhibitory and activating receptors for endogenous or exogenous pathogen-derived ligands, which together with adhesion molecules form a structure known as immunological synapse that regulates NK cell effector functions. The main and best characterized mechanisms involved in NK cell-mediated cytotoxicity are the granule exocytosis pathway (perforin/granzymes) and the expression of death ligands. These pathways are recognized as activators of different cell death programmes on the target cells leading to their destruction. However, most studies analyzing these pathways have used pure recombinant or native proteins instead of intact NK cells and, thus, extrapolation of the results to NK cell-mediated cell death might be difficult. Specially, since the activation of granule exocytosis and/or death ligands during NK cell-mediated elimination of target cells might be influenced by the stimulus received from target cells and other microenvironment components, which might affect the cell death pathways activated on target cells. Here we will review and discuss the available experimental evidence on how NK cells kill target cells, with a special focus on the different cell death modalities that have been found to be activated during NK cell-mediated cytotoxicity; including apoptosis and more inflammatory pathways like necroptosis and pyroptosis. In light of this new evidence, we will develop the new concept of cell death induced by NK cells as a new regulatory mechanism linking innate immune response with the activation of tumour adaptive T cell responses, which might be the initiating stimulus that trigger the cancer-immunity cycle. The use of the different cell death pathways and the modulation of the tumour cell molecular machinery regulating them might
Published: 2022

14. Adoptive NK cell transfer as a treatment in colorectal cancer patients: analyses of tumour cell determinants correlating with efficacy in vitro and in vivo

Author: Aspanoa, Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (España), European Commission, Fundación Inocente Inocente, Asociación Carrera de la Mujer Ciudad de Monzón, Gobierno de Aragón, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), ARAID Foundation, Institut Català d'Oncologia, Ministerio de Economía, Industria y Competitividad (España), Centro de Investigación Biomédica en Red Epidemiología y Salud Pública (España), Agència de Gestió d'Ajuts Universitaris i de Recerca, European Cooperation in Science and Technology, Lanuza, Pilar M. [0000-0001-7328-2094], Alonso, M. Henar [0000-0003-0285-5451], Hidalgo, Sandra [0000-0003-1629-9978], Uranga Murillo, Iratxe [0000-0001-8411-984X], García-Mulero, Sandra [0000-0003-4931-1267], Sanjuan, Xavier [0000-0002-5253-822X], Santiago, Llipsy [0000-0002-1861-5981], Comas, Laura [0000-0002-3843-1231], Redrado, Sergio [0000-0002-8404-0012], Pazo-Cid, Roberto [0000-0002-8026-7391], Jaime Sánchez, Paula [0000-0002-8731-4269], Pesini, Cecilia [0000-0002-8707-2722], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Ramírez-Labrada, Ariel [0000-0002-3888-7036], Arias, Maykel [0000-0002-9730-2210], Sanz-Pamplona, Rebeca [0000-0002-2187-3527], Pardo, Julián [0000-0003-0154-0730], Lanuza, Pilar M., Alonso, M. Henar, Hidalgo, Sandra, Uranga Murillo, Iratxe, García-Mulero, Sandra, Arnau, Raquel, Santos Vivas, Cristina, Sanjuan, Xavier, Santiago, Llipsy, Comas, Laura, Redrado, Sergio, Pazo-Cid, Roberto, Agustín Ferrández, M. J., Jaime Sánchez, Paula, Pesini, Cecilia, Gálvez Buerba, Eva Mª, Ramírez-Labrada, Ariel, Arias, Maykel, Sanz-Pamplona, Rebeca, Pardo, Julián, Aspanoa, Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (España), European Commission, Fundación Inocente Inocente, Asociación Carrera de la Mujer Ciudad de Monzón, Gobierno de Aragón, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), ARAID Foundation, Institut Català d'Oncologia, Ministerio de Economía, Industria y Competitividad (España), Centro de Investigación Biomédica en Red Epidemiología y Salud Pública (España), Agència de Gestió d'Ajuts Universitaris i de Recerca, European Cooperation in Science and Technology, Lanuza, Pilar M. [0000-0001-7328-2094], Alonso, M. Henar [0000-0003-0285-5451], Hidalgo, Sandra [0000-0003-1629-9978], Uranga Murillo, Iratxe [0000-0001-8411-984X], García-Mulero, Sandra [0000-0003-4931-1267], Sanjuan, Xavier [0000-0002-5253-822X], Santiago, Llipsy [0000-0002-1861-5981], Comas, Laura [0000-0002-3843-1231], Redrado, Sergio [0000-0002-8404-0012], Pazo-Cid, Roberto [0000-0002-8026-7391], Jaime Sánchez, Paula [0000-0002-8731-4269], Pesini, Cecilia [0000-0002-8707-2722], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Ramírez-Labrada, Ariel [0000-0002-3888-7036], Arias, Maykel [0000-0002-9730-2210], Sanz-Pamplona, Rebeca [0000-0002-2187-3527], Pardo, Julián [0000-0003-0154-0730], Lanuza, Pilar M., Alonso, M. Henar, Hidalgo, Sandra, Uranga Murillo, Iratxe, García-Mulero, Sandra, Arnau, Raquel, Santos Vivas, Cristina, Sanjuan, Xavier, Santiago, Llipsy, Comas, Laura, Redrado, Sergio, Pazo-Cid, Roberto, Agustín Ferrández, M. J., Jaime Sánchez, Paula, Pesini, Cecilia, Gálvez Buerba, Eva Mª, Ramírez-Labrada, Ariel, Arias, Maykel, Sanz-Pamplona, Rebeca, and Pardo, Julián
Abstract: [Background]: Colorectal cancer (CRC) is a heterogeneous disease with variable mutational profile and tumour microenvironment composition that influence tumour progression and response to treatment. While chemoresistant and poorly immunogenic CRC remains a challenge, the development of new strategies guided by biomarkers could help stratify and treat patients. Allogeneic NK cell transfer emerges as an alternative against chemoresistant and poorly immunogenic CRC., [Methods]: NK cell-related immunological markers were analysed by transcriptomics and immunohistochemistry in human CRC samples and correlated with tumour progression and overall survival. The anti-tumour ability of expanded allogeneic NK cells using a protocol combining cytokines and feeder cells was analysed in vitro and in vivo and correlated with CRC mutational status and the expression of ligands for immune checkpoint (IC) receptors regulating NK cell activity., [Results]: HLA-I downmodulation and NK cell infiltration correlated with better overall survival in patients with a low-stage (II) microsatellite instability-high (MSI-H) CRC, suggesting a role of HLA-I as a prognosis biomarker and a potential benefit of NK cell immunotherapy. Activated allogeneic NK cells were able to eliminate CRC cultures without PD-1 and TIM-3 restriction but were affected by HLA-I expression. In vivo experiments confirmed the efficacy of the therapy against both HLA+ and HLA− CRC cell lines. Concomitant administration of pembrolizumab failed to improve tumour control., [Conclusions]: Our results reveal an immunological profile of CRC tumours in which immunogenicity (MSI-H) and immune evasion mechanisms (HLA downmodulation) favour NK cell immunosurveillance at early disease stages. Accordingly, we have shown that allogeneic NK cell therapy can target tumours expressing mutations conferring poor prognosis regardless of the expression of T cell-related inhibitory IC ligands. Overall, this study provides a rationale for a new potential basis for CRC stratification and NK cell-based therapy.
Published: 2022

15. Integration of in silico and in vitro analysis of gliotoxin production reveals a narrow range of producing fungal species

Author: Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (España), European Commission, Gobierno de Aragón, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Aspanoa, Gilead Sciences, Asociación Carrera de la Mujer Ciudad de Monzón, ARAID Foundation, Redrado, Sergio [0000-0002-8404-0012], Esteban, Patricia [0000-0003-4123-3524], Domingo, María Pilar [0000-0002-6829-8769], Rezusta, Antonio [0000-0001-7294-245X], Ramírez-Labrada, Ariel [0000-0002-3888-7036], Arias, Maykel [0000-0002-9730-2210], Pardo, Julián [0000-0003-0154-0730], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Redrado, Sergio, Esteban, Patricia, Domingo, María Pilar, López Gómez, Concepción, Rezusta, Antonio, Ramírez-Labrada, Ariel, Arias, Maykel, Pardo, Julián, Gálvez Buerba, Eva Mª, Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (España), European Commission, Gobierno de Aragón, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Aspanoa, Gilead Sciences, Asociación Carrera de la Mujer Ciudad de Monzón, ARAID Foundation, Redrado, Sergio [0000-0002-8404-0012], Esteban, Patricia [0000-0003-4123-3524], Domingo, María Pilar [0000-0002-6829-8769], Rezusta, Antonio [0000-0001-7294-245X], Ramírez-Labrada, Ariel [0000-0002-3888-7036], Arias, Maykel [0000-0002-9730-2210], Pardo, Julián [0000-0003-0154-0730], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Redrado, Sergio, Esteban, Patricia, Domingo, María Pilar, López Gómez, Concepción, Rezusta, Antonio, Ramírez-Labrada, Ariel, Arias, Maykel, Pardo, Julián, and Gálvez Buerba, Eva Mª
Abstract: Gliotoxin is a fungal secondary metabolite with impact on health and agriculture since it might act as virulence factor and contaminate human and animal food. Homologous gliotoxin (GT) gene clusters are spread across a number of fungal species although if they produce GT or other related epipolythiodioxopiperazines (ETPs) remains obscure. Using bioinformatic tools, we have identified homologous gli gene clusters similar to the A. fumigatus GT gene cluster in several fungal species. In silico study led to in vitro confirmation of GT and Bisdethiobis(methylthio)gliotoxin (bmGT) production in fungal strain cultures by HPLC detection. Despite we selected most similar homologous gli gene cluster in 20 different species, GT and bmGT were only detected in section Fumigati species and in a Trichoderma virens Q strain. Our results suggest that in silico gli homology analyses in different fungal strains to predict GT production might be only informative when accompanied by analysis about mycotoxin production in cell cultures.
Published: 2022

16. Characterisation of circulating immune cells in a cohort of non-small cell lung cancer patients treated with immunotherapy

Author: Gascón, Marta, Pardo, Julián, Cruellas, Mara, Esteban, Patricia, Gálvez Buerba, Eva Mª, Lastra, Rodrigo, Martínez Lostao, Luis, Ocariz, Maitane, Paño, José Ramón, Quílez Bermejo, J., Ramírez-Labrada, Ariel, Sesma Goñi, Andrea, Torres-Ramón, Irene, Yubero, Alfonso, Zapata, María, Isla, Dolores, Gascón, Marta, Cruellas, Mara, Esteban, Patricia, Gálvez Buerba, Eva Mª, Lastra, Rodrigo, Martínez Lostao, Luis, Ocáriz, Maitane, Paño, José Ramón, Quílez Bermejo, J., Ramírez-Labrada, Ariel, Sesma Goñi, Andrea, Torres-Ramón, Irene, Yubero, Alfonso, Zapata, María, and Isla, Dolores
Subjects: Inmune cells, Biomarker, Lung cancer, Inmune chekpoint inhibitors
Abstract: from the 2022 World Conference on Lung Cancer, 6-9 August 2022, Vienna (Austria).-- EP16.01-014., [Introduction] Immunotherapy in lung cancer has been one of the most relevant therapeutic advances in recent years. Although many studies demonstrate its antitumor activity, there is still a great lack of knowledge about which may be the best prognostic biomarkers. In recent years, several studies suggest that different immune cell populations might be useful biomarkers to predict immunotherapy efficacy. Among them are specific T cell subsets, natural killer (NK) cells or the ratio between cytotoxic CD8+ T and regulatory CD4+ T (Treg) lymphocytes. In this sense, the objective of our study is to provide a detailed analysis of different circulating immune cell subsets within T and NK cell populations in a cohort of patients with non-small cell lung cancer (NSCLC) treated with immune-checkpoint inhibitors (ICI) and analyze their prognostic value., [Methods] Observational, prospective and analytical study of a cohort of 55 patients diagnosed with NSCLC (unresectable stage III and IV) receiving ICI. Demographic, clinical and tumor variables are collected, as well as a peripheral blood sample. A total of 43 cell subpopulations of CD4+ and CD8+ T and NK cells, including the main exhaustion, differentiation, memory, activation and inhibition markers are analyzed in peripheral blood, correlated with treatment response and survival..., [Results] 55 patients were included (70.9% men) with a median age of 65 years. Regarding histology, there were 40% squamous cell carcinomas and 60% adenocarcinomas, 70.9% being stage IV. After minimum of one year of follow-up, 56.4% of patients had progressed with a median overall survival of 19 months (CI: 11.13-26.87). Regarding the descriptive data of the analyzed cell populations, the regulatory Granzyme B+ CD4+ T lymphocytes stand out with a median of 17.4% (SD 24.4%) and memory CD4+ and CD8+ Tz..., [Conclusions] Circulating immune cell subpopulations are among the most promising prognostic biomarkers for ICI. Here we provide a detailed descriptive analysis of the main circulating T and NK cell subsets involved in cancer immunity in a cohort of NSCLC patients. Some of the results suggest dysfunctional T and NK cell responses that might be related with ICI efficacy, which relevance to predict survival and treatment outcome will be shortly available
Published: 2022

17. Análisis de la actividad antimicrobiana de la Gliotoxina en diferentes microorganismos de interés clínico

Author: Esteban, Patricia, Arias, Maykel, Millán-Lou, María Isabel, Redrado, Sergio, Domingo, María Pilar, García, Matilde, Gómez Lapuente, María Ángeles, Roc, Lourdes, López Gómez, Concepción, Pardo, Julián, Rezusta, Antonio, Gálvez Buerba, Eva Mª, Esteban, Patricia, Arias, Maykel, Redrado, Sergio, Domingo, María Pilar, Pardo, Julián, Rezusta, Antonio, Gálvez Buerba, Eva Mª, Esteban, Patricia [0000-0003-4123-3524], Arias, Maykel [0000-0002-9730-2210], Redrado, Sergio [0000-0002-8404-0012], Domingo, María Pilar [0000-0002-6829-8769], Pardo, Julián [0000-0003-0154-0730], Rezusta, Antonio [0000-0001-7294-245X], and Gálvez Buerba, Eva Mª [0000-0001-6928-5516]
Subjects: Micotoxina, Modelo animal, Gliotoxina, Antimicrobiano
Abstract: Trabajo presentado en el XXIV Congreso Nacional de la Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica (SEIMC), celebrado de manera virtual del 5-11 junio de 2021., [Introducción/Objetivos]: la gliotoxina es una micotoxina producida por Aspergillus fumigatus y otros hongos del género Aspergillus. Es un metabolito secundario perteneciente a la familia de las epipolitiodioxopiperazinas, caracterizada por la presencia de un puente disulfuro interno en un anillo de piperazina, que parece ser necesario para la mayoría de las propiedades biológicas de este compuesto. Se ha demostrado que la gliotoxina es un factor de virulencia durante la aspergilosis invasiva y presenta una toxicidad notable contra las células de mamíferos. Sin embargo, las evidencias científicas sobre su potencial actividad antimicrobiana son escasas. Por lo tanto, este trabajo tiene como objetivo evaluar su eficacia antibiótica contra microorganismos de interés clínico como Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa; y antifúngico contra Candida albicans y Candida glabrata. [Material y métodos]: la sensibilidad a la gliotoxina de diferentes cepas (incluidas las farmacorresistentes) de los microorganismos indicados se analizó por diferentes métodos: métodos de difusión en disco (antibiogramas/antifungigramas), estudio de curvas de tiempo-mortalidad, métodos de microdilución y ensayo MTT. Para los aislados de Candida, los resultados fueron confirmados mediante el análisis de la muerte celular por citometría de flujo. [Resultados]: Los resultados sugieren una potente actividad antimicrobiana de gliotoxina contra Candida albicans y Staphylococcus aureus, incluso en las cepas resistentes a azoles y a meticilina, respectivamente. En el caso de Escherichia coli y Candida glabrata, la gliotoxina ejerce una acción antimicrobiana moderada. Sin embargo, Pseudomonas aeruginosa parece ser resistente a la gliotoxina. [Conclusiones]: Nuestros resultados indican que la gliotoxina es efectiva contra Candida albicans y Staphylococcus aureus por lo que podría usarse como una alternativa para el tratamiento de infecciones causadas por cepas resistentes a antibióticos/antifúngicos. Sin embargo, será necesario aclarar aún más los mecanismos por los cuales la gliotoxina ejerce este efecto y probar en modelos apropiados in vivo la viabilidad de su uso teniendo en cuenta los posibles efectos secundarios debido a su toxicidad. En este sentido, planeamos analizar su eficacia y seguridad en un modelo de infección cutánea causada por Staphylococcus aureus.
Published: 2021

18. Granzyme A inhibition reduces inflammation and increases survival during abdominal sepsis

Author: Garzón, Marcela [0000-0001-6778-0636], Comas, Laura [0000-0002-3843-1231], Santiago, Llipsy [0000-0002-1861-5981], Uranga Murillo, Iratxe [0000-0001-8411-984X], Ramírez-Labrada, Ariel [0000-0002-3888-7036], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Pardo, Julián [0000-0003-0154-0730], Arias, Maykel [0000-0002-9730-2210], Garzón, Marcela, Comas, Laura, Santiago, Llipsy, Uranga Murillo, Iratxe, Ramírez-Labrada, Ariel, Gálvez Buerba, Eva Mª, Pardo, Julián, Arias, Maykel, Garzón, Marcela [0000-0001-6778-0636], Comas, Laura [0000-0002-3843-1231], Santiago, Llipsy [0000-0002-1861-5981], Uranga Murillo, Iratxe [0000-0001-8411-984X], Ramírez-Labrada, Ariel [0000-0002-3888-7036], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Pardo, Julián [0000-0003-0154-0730], Arias, Maykel [0000-0002-9730-2210], Garzón, Marcela, Comas, Laura, Santiago, Llipsy, Uranga Murillo, Iratxe, Ramírez-Labrada, Ariel, Gálvez Buerba, Eva Mª, Pardo, Julián, and Arias, Maykel
Abstract: Peritonitis is one of the most common causes of sepsis. Evidence suggests that Granzyme A (GzmA), a serine protease mainly expressed by NK and T cells, could act as proinflammatory mediator and could play an important role in the pathogenesis of sepsis. Here, we aim to analyze the role and therapeutic potential of GzmA in the pathogenesis of peritoneal sepsis.
Published: 2021

19. Determination of the concentration of IgG against the spike receptor-binding domain that predicts the viral neutralizing activity of convalescent plasma and serum against SARS-CoV-2

Author: Gobierno de Aragón, Fundación Banco Santander, Universidad de Zaragoza, Instituto de Salud Carlos III, European Commission, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Fundación Inocente Inocente, Aspanoa, Asociación Carrera de la Mujer Ciudad de Monzón, ARAID Foundation, Santiago, Llipsy [0000-0002-1861-5981], Uranga Murillo, Iratxe [0000-0001-8411-984X], Arias, Maykel [0000-0002-9730-2210], González Ramírez, Andrés Manuel [0000-0002-5838-0857], Macías León, Javier [0000-0001-6815-6720], Moreo, Eduardo [0000-0002-0182-201X], Redrado, Sergio [0000-0002-8404-0012], Taleb, V. [0000-0001-9224-5854], Lira-Navarrete, Erandi [0000-0003-2462-7580], Hurtado-Guerrero, R. [0000-0002-3122-9401], Encabo-Berzosa, M. Mar [0000-0001-5533-804X], Hidalgo, Sandra [0000-0003-1629-9978], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Ramírez-Labrada, Ariel [0000-0002-3888-7036], Miguel, Diego de [0000-0002-8486-8514], Benito, Rafael [0000-0001-5134-1006], Fernández Casanovas, Antonio [0000-0002-2557-4890], Serrano Barcos, Laura [0000-0002-9291-9801], Yuste, Cristina [0000-0003-3667-523X], Villanueva-Saz, Sergio [0000-0001-6209-4282], Paño, José Ramón [0000-0002-9600-8116], Pardo, Julián [0000-0003-0154-0730], Santiago, Llipsy, Uranga Murillo, Iratxe, Arias, Maykel, González Ramírez, Andrés Manuel, Macías-León, Javier, Moreo, Eduardo, Redrado, Sergio, García García, Ana, Taleb, V., Lira-Navarrete, Erandi, Hurtado-Guerrero, R., Aguiló, Nacho, Encabo-Berzosa, M. Mar, Hidalgo, Sandra, Gálvez Buerba, Eva Mª, Ramírez-Labrada, Ariel, Miguel, Diego de, Benito, Rafael, Miranda, Patricia, Fernández Casanovas, Antonio, Domingo, José María, Serrano Barcos, Laura, Yuste, Cristina, Villanueva-Saz, Sergio, Paño, José Ramón, Pardo, Julián, Gobierno de Aragón, Fundación Banco Santander, Universidad de Zaragoza, Instituto de Salud Carlos III, European Commission, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Fundación Inocente Inocente, Aspanoa, Asociación Carrera de la Mujer Ciudad de Monzón, ARAID Foundation, Santiago, Llipsy [0000-0002-1861-5981], Uranga Murillo, Iratxe [0000-0001-8411-984X], Arias, Maykel [0000-0002-9730-2210], González Ramírez, Andrés Manuel [0000-0002-5838-0857], Macías León, Javier [0000-0001-6815-6720], Moreo, Eduardo [0000-0002-0182-201X], Redrado, Sergio [0000-0002-8404-0012], Taleb, V. [0000-0001-9224-5854], Lira-Navarrete, Erandi [0000-0003-2462-7580], Hurtado-Guerrero, R. [0000-0002-3122-9401], Encabo-Berzosa, M. Mar [0000-0001-5533-804X], Hidalgo, Sandra [0000-0003-1629-9978], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Ramírez-Labrada, Ariel [0000-0002-3888-7036], Miguel, Diego de [0000-0002-8486-8514], Benito, Rafael [0000-0001-5134-1006], Fernández Casanovas, Antonio [0000-0002-2557-4890], Serrano Barcos, Laura [0000-0002-9291-9801], Yuste, Cristina [0000-0003-3667-523X], Villanueva-Saz, Sergio [0000-0001-6209-4282], Paño, José Ramón [0000-0002-9600-8116], Pardo, Julián [0000-0003-0154-0730], Santiago, Llipsy, Uranga Murillo, Iratxe, Arias, Maykel, González Ramírez, Andrés Manuel, Macías-León, Javier, Moreo, Eduardo, Redrado, Sergio, García García, Ana, Taleb, V., Lira-Navarrete, Erandi, Hurtado-Guerrero, R., Aguiló, Nacho, Encabo-Berzosa, M. Mar, Hidalgo, Sandra, Gálvez Buerba, Eva Mª, Ramírez-Labrada, Ariel, Miguel, Diego de, Benito, Rafael, Miranda, Patricia, Fernández Casanovas, Antonio, Domingo, José María, Serrano Barcos, Laura, Yuste, Cristina, Villanueva-Saz, Sergio, Paño, José Ramón, and Pardo, Julián
Abstract: Passive immunization with hyperimmune plasma from convalescent patients has been proposed as a potentially useful treatment for COVID-19. Nevertheless, its efficacy in patients with COVID-19 remains uncertain. Thus, the establishment and validation of standardized methods that predict the viral neutralizing (VN) activity of plasma against SARS-CoV-2 is of utmost importance to appraise its therapeutic value. Using an in-house quantitative ELISA test and two independent cohorts with a total of 345 donors, we found that plasma and serum from most convalescent donors contained IgG antibodies specific to the spike receptor-binding domain (RBD) of SARS-CoV-2, with varying concentrations which correlate with previous disease severity and gender. Anti-RBD IgG plasma concentration significantly correlated with the plasma/serum VN activity against SARS-CoV-2 in vitro., Several hundred millions of people have been diagnosed of coronavirus disease 2019 (COVID-19), causing millions of deaths and a high socioeconomic burden. SARS-CoV-2, the causative agent of COVID-19, induces both specific T- and B-cell responses, being antibodies against the virus detected a few days after infection. Passive immunization with hyperimmune plasma from convalescent patients has been proposed as a potentially useful treatment for COVID-19. Using an in-house quantitative ELISA test, we found that plasma from 177 convalescent donors contained IgG antibodies specific to the spike receptor-binding domain (RBD) of SARS-CoV-2, although at very different concentrations which correlated with previous disease severity and gender. Anti-RBD IgG plasma concentrations significantly correlated with the plasma viral neutralizing activity (VN) against SARS-CoV-2 in vitro. Similar results were found using an independent cohort of serum from 168 convalescent health workers. These results validate an in-house RBD IgG ELISA test in a large cohort of COVID-19 convalescent patients and indicate that plasma from all convalescent donors does not contain a high enough amount of anti-SARS-CoV-2-RBD neutralizing IgG to prevent SARS-CoV-2 infection in vitro. The use of quantitative anti-RBD IgG detection systems might help to predict the efficacy of the passive immunization using plasma from patients recovered from SARS-CoV-2.
Published: 2021

20. In vitro and in vivo antibacterial activity of gliotoxin alone and in combination with antibiotics against staphylococcus aureus

Author: European Commission, Gobierno de Aragón, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Aspanoa, Gilead Sciences, Asociación Carrera de la Mujer Ciudad de Monzón, ARAID Foundation, Esteban, Patricia [0000-0003-4123-3524], Redrado, Sergio [0000-0002-8404-0012], Comas, Laura [0000-0002-3843-1231], Domingo, María Pilar [0000-0002-6829-8769], Algarate, Sonia [0000-0002-0036-663], Rezusta, Antonio [0000-0001-7294-245X], Pardo, Julián [0000-0003-0154-0730], Arias, Maykel [0000-0002-9730-2210], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Esteban, Patricia, Redrado, Sergio, Comas, Laura, Domingo, María Pilar, Millán-Lou, María Isabel, Seral, Cristina, Algarate, Sonia, López Gómez, Concepción, Rezusta, Antonio, Pardo, Julián, Arias, Maykel, Gálvez Buerba, Eva Mª, European Commission, Gobierno de Aragón, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Aspanoa, Gilead Sciences, Asociación Carrera de la Mujer Ciudad de Monzón, ARAID Foundation, Esteban, Patricia [0000-0003-4123-3524], Redrado, Sergio [0000-0002-8404-0012], Comas, Laura [0000-0002-3843-1231], Domingo, María Pilar [0000-0002-6829-8769], Algarate, Sonia [0000-0002-0036-663], Rezusta, Antonio [0000-0001-7294-245X], Pardo, Julián [0000-0003-0154-0730], Arias, Maykel [0000-0002-9730-2210], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Esteban, Patricia, Redrado, Sergio, Comas, Laura, Domingo, María Pilar, Millán-Lou, María Isabel, Seral, Cristina, Algarate, Sonia, López Gómez, Concepción, Rezusta, Antonio, Pardo, Julián, Arias, Maykel, and Gálvez Buerba, Eva Mª
Abstract: Multidrug-resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) is one of the major causes of hospital-acquired and community infections and pose a challenge to the human health care system. Therefore, it is important to find new drugs that show activity against these bacteria, both in monotherapy and in combination with other antimicrobial drugs. Gliotoxin (GT) is a mycotoxin produced by Aspergillus fumigatus and other fungi of the Aspergillus genus. Some evidence suggests that GT shows antimicrobial activity against S. aureus in vitro, albeit its efficacy against multidrug-resistant strains such as MRSA or vancomycin-intermediate S. aureus (VISA) strainsis not known. This work aimed to evaluate the antibiotic efficacy of GT as monotherapy or in combination with other therapeutics against MRSA in vitro and in vivo using a Caenorhabditis elegans infection model.
Published: 2021

21. How could antibiotics, probiotics, and corticoids modify microbiota and its influence in cancer immune checkpoint inhibitors: a review

Author: Cruellas, Mara [0000-0002-6953-9675], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Gascón, Marta [0000-0002-6811-6654], Isla, Dolores [0000-0002-2483-198X], Lastra, Rodrigo [0000-0002-7498-7798], Martínez Lostao, Luis [0000-0003-3043-147X], Ocáriz, Maitane [0000-0002-7557-7264], Pardo, Julián [0000-0003-0154-0730], Ramírez-Labrada, Ariel [0000-0002-3888-7036], Sesma, Andrea [0000-0001-7209-266X], Torres-Ramón, Irene [0000-0003-3387-0558], Paño, José Ramón [0000-0002-9600-8116], Cruellas, Mara, Yubero, Alfonso, Zapata, María, Gálvez Buerba, Eva Mª, Gascón, Marta, Isla, Dolores, Lastra, Rodrigo, Martínez-Lostao, Luis, Ocáriz, Maitane, Pardo, Julián, Ramírez-Labrada, Ariel, Sesma, Andrea, Torres-Ramón, Irene, Paño, José Ramón, Cruellas, Mara [0000-0002-6953-9675], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Gascón, Marta [0000-0002-6811-6654], Isla, Dolores [0000-0002-2483-198X], Lastra, Rodrigo [0000-0002-7498-7798], Martínez Lostao, Luis [0000-0003-3043-147X], Ocáriz, Maitane [0000-0002-7557-7264], Pardo, Julián [0000-0003-0154-0730], Ramírez-Labrada, Ariel [0000-0002-3888-7036], Sesma, Andrea [0000-0001-7209-266X], Torres-Ramón, Irene [0000-0003-3387-0558], Paño, José Ramón [0000-0002-9600-8116], Cruellas, Mara, Yubero, Alfonso, Zapata, María, Gálvez Buerba, Eva Mª, Gascón, Marta, Isla, Dolores, Lastra, Rodrigo, Martínez-Lostao, Luis, Ocáriz, Maitane, Pardo, Julián, Ramírez-Labrada, Ariel, Sesma, Andrea, Torres-Ramón, Irene, and Paño, José Ramón
Abstract: Immunotherapy has become a new paradigm in oncology, improving outcomes for several types of cancer. However, there are some aspects about its management that remain uncertain. One of the key points that needs better understanding is the interaction between immunotherapy and gut microbiome and how modulation of the microbiome might modify the efficacy of immunotherapy. Consequently, the negative impact of systemic antibiotics and corticosteroids on the efficacy of immunotherapy needs to be clarified.
Published: 2021

22. Análisis de la actividad antimicrobiana de la Gliotoxina en diferentes microorganismos de interés clínico

Author: Esteban, Patricia [0000-0003-4123-3524], Arias, Maykel [0000-0002-9730-2210], Redrado, Sergio [0000-0002-8404-0012], Domingo, María Pilar [0000-0002-6829-8769], Pardo, Julián [0000-0003-0154-0730], Rezusta, Antonio [0000-0001-7294-245X], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Esteban, Patricia, Arias, Maykel, Millán-Lou, María Isabel, Redrado, Sergio, Domingo, María Pilar, García, Matilde, Gómez Lapuente, María Ángeles, Roc, Lourdes, López Gómez, Concepción, Pardo, Julián, Rezusta, Antonio, Gálvez Buerba, Eva Mª, Esteban, Patricia [0000-0003-4123-3524], Arias, Maykel [0000-0002-9730-2210], Redrado, Sergio [0000-0002-8404-0012], Domingo, María Pilar [0000-0002-6829-8769], Pardo, Julián [0000-0003-0154-0730], Rezusta, Antonio [0000-0001-7294-245X], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Esteban, Patricia, Arias, Maykel, Millán-Lou, María Isabel, Redrado, Sergio, Domingo, María Pilar, García, Matilde, Gómez Lapuente, María Ángeles, Roc, Lourdes, López Gómez, Concepción, Pardo, Julián, Rezusta, Antonio, and Gálvez Buerba, Eva Mª
Abstract: [Introducción/Objetivos]: la gliotoxina es una micotoxina producida por Aspergillus fumigatus y otros hongos del género Aspergillus. Es un metabolito secundario perteneciente a la familia de las epipolitiodioxopiperazinas, caracterizada por la presencia de un puente disulfuro interno en un anillo de piperazina, que parece ser necesario para la mayoría de las propiedades biológicas de este compuesto. Se ha demostrado que la gliotoxina es un factor de virulencia durante la aspergilosis invasiva y presenta una toxicidad notable contra las células de mamíferos. Sin embargo, las evidencias científicas sobre su potencial actividad antimicrobiana son escasas. Por lo tanto, este trabajo tiene como objetivo evaluar su eficacia antibiótica contra microorganismos de interés clínico como Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa; y antifúngico contra Candida albicans y Candida glabrata. [Material y métodos]: la sensibilidad a la gliotoxina de diferentes cepas (incluidas las farmacorresistentes) de los microorganismos indicados se analizó por diferentes métodos: métodos de difusión en disco (antibiogramas/antifungigramas), estudio de curvas de tiempo-mortalidad, métodos de microdilución y ensayo MTT. Para los aislados de Candida, los resultados fueron confirmados mediante el análisis de la muerte celular por citometría de flujo. [Resultados]: Los resultados sugieren una potente actividad antimicrobiana de gliotoxina contra Candida albicans y Staphylococcus aureus, incluso en las cepas resistentes a azoles y a meticilina, respectivamente. En el caso de Escherichia coli y Candida glabrata, la gliotoxina ejerce una acción antimicrobiana moderada. Sin embargo, Pseudomonas aeruginosa parece ser resistente a la gliotoxina. [Conclusiones]: Nuestros resultados indican que la gliotoxina es efectiva contra Candida albicans y Staphylococcus aureus por lo que podría usarse como una alternativa para el tratamiento de infecciones causadas por cepas resistentes a antibiót
Published: 2021

23. Inﬂammatory cell death induced by cytotoxic lymphocytes: a dangerous but necessary liaison

Author: European Commission, Gobierno de Aragón, Ministerio de Ciencia, Innovación y Universidades (España), Instituto de Salud Carlos III, Agencia Estatal de Investigación (España), Fundación Inocente Inocente, Aspanoa, Asociación Carrera de la Mujer Ciudad de Monzón, ARAID Foundation, de Miguel, Diego [0000-0002-8486-8514], Ramírez-Labrada, Ariel [0000-0002-3888-7036], Uranga Murillo, Iratxe [0000-0001-8411-984X], Hidalgo, Sandra [0000-0003-1629-9978], Santiago, Llipsy [0000-0002-1861-5981], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Arias, Maykel [0000-0002-9730-2210], Pardo, Julián [0000-0003-0154-0730], Miguel, Diego de, Ramírez-Labrada, Ariel, Uranga Murillo, Iratxe, Hidalgo, Sandra, Santiago, Llipsy, Gálvez Buerba, Eva Mª, Arias, Maykel, Pardo, Julián, European Commission, Gobierno de Aragón, Ministerio de Ciencia, Innovación y Universidades (España), Instituto de Salud Carlos III, Agencia Estatal de Investigación (España), Fundación Inocente Inocente, Aspanoa, Asociación Carrera de la Mujer Ciudad de Monzón, ARAID Foundation, de Miguel, Diego [0000-0002-8486-8514], Ramírez-Labrada, Ariel [0000-0002-3888-7036], Uranga Murillo, Iratxe [0000-0001-8411-984X], Hidalgo, Sandra [0000-0003-1629-9978], Santiago, Llipsy [0000-0002-1861-5981], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Arias, Maykel [0000-0002-9730-2210], Pardo, Julián [0000-0003-0154-0730], Miguel, Diego de, Ramírez-Labrada, Ariel, Uranga Murillo, Iratxe, Hidalgo, Sandra, Santiago, Llipsy, Gálvez Buerba, Eva Mª, Arias, Maykel, and Pardo, Julián
Abstract: Cytotoxic lymphocytes (CLs), and more specifically Tc and NK cells, are the main executors of cell death in the immune system, playing a key role during both immunosurveillance and immunotherapy. These cells induce regulated cell death (RCD) by different mechanisms, being granular exocytosis and expression of death ligands the most prominent and best characterized ones. Apoptosis, a traditionally considered low-inflammatory type of cell death, has been accepted for years as the paradigm of RCD induced by CLs. However, several recent studies have demonstrated that NK cells and Tc cells can also induce more inflammatory forms of cell death, namely, necroptosis, pyroptosis, and ferroptosis. Activation of these highly inflammatory types of cell death appears to critically contribute to the activation of a successful antitumour immune response. Additionally, the role of specific cell death pathways in immunogenic cell death is still under intense debate, especially considering the interconnections with other inflammatory forms of cell death. These evidences, together with the advent of new cancer immunotherapies, highlight the necessity to deepen our understanding of the link between the cell death triggered by CLs and inflammation. This knowledge will be instrumental to maximize the antitumour potential of immunotherapies, minimizing deleterious effects associated with these treatments. In this review, we will briefly summarize the main features of apoptosis, necroptosis, pyroptosis and ferroptosis, to subsequently discuss the most recent evidences about the role of these RCD pathways during the elimination of cancer cells mediated by CLs and its modulation to increase the efficacy of cancer immunotherapy.
Published: 2021

24. Granzyme A inhibition reduces inflammation and increases survival during abdominal sepsis

Author: Garzón, Marcela, Comas, Laura, Santiago, Llipsy, Uranga Murillo, Iratxe, Ramírez-Labrada, Ariel, Gálvez Buerba, Eva Mª, Pardo, Julián, Arias, Maykel, Garzón, Marcela [0000-0001-6778-0636], Comas, Laura [0000-0002-3843-1231], Santiago, Llipsy [0000-0002-1861-5981], Uranga Murillo, Iratxe [0000-0001-8411-984X], Ramírez-Labrada, Ariel [0000-0002-3888-7036], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Pardo, Julián [0000-0003-0154-0730], Arias, Maykel [0000-0002-9730-2210], Garzón, Marcela, Comas, Laura, Santiago, Llipsy, Uranga Murillo, Iratxe, Ramírez-Labrada, Ariel, Gálvez Buerba, Eva Mª, Pardo, Julián, and Arias, Maykel
Subjects: Inflammation, Sepsis, Granzyme A, Cecal ligation and puncture, Peritonitis
Abstract: 3 figuras.-- Póster presentado en el 42º Congreso SEI, Congreso de la Sociedad Española de Inmunología, formato virtual, 24-26 marzo de 2021, Madrid., Peritonitis is one of the most common causes of sepsis. Evidence suggests that Granzyme A (GzmA), a serine protease mainly expressed by NK and T cells, could act as proinflammatory mediator and could play an important role in the pathogenesis of sepsis. Here, we aim to analyze the role and therapeutic potential of GzmA in the pathogenesis of peritoneal sepsis.
Published: 2021

25. Gliotoxina, un nuevo candidato contra Staphylococcus aureus resistente a meticilina que muestra un efecto sinérgico con fármacos antimicrobianos en el modelo de infección Caenorhabditis elegans

Author: Esteban, Patricia, Redrado, Sergio, Comas, Laura, Domingo, María Pilar, Millán-Lou, María Isabel, Seral, Cristina, Algarate, Sonia, Rezusta, Antonio, Pardo, Julián, Arias, Maykel, Gálvez Buerba, Eva Mª, Esteban, Patricia, Redrado, Sergio, Comas, Laura, Domingo, María Pilar, Algarate, Sonia, Rezusta, Antonio, Pardo, Julián, Arias, Maykel, Gálvez Buerba, Eva Mª, Esteban, Patricia [0000-0003-4123-3524], Redrado, Sergio [0000-0002-8404-0012], Comas, Laura [0000-0002-3843-1231], Domingo, María Pilar [0000-0002-6829-8769], Algarate, Sonia [0000-0002-0036-663], Rezusta, Antonio [0000-0001-7294-245X], Pardo, Julián [0000-0003-0154-0730], Arias, Maykel [0000-0002-9730-2210], and Gálvez Buerba, Eva Mª [0000-0001-6928-5516]
Subjects: Micotoxina, Resistencia, Modelo animal, Antimicrobiano
Abstract: Comunicación oral presentada en el Congreso Virtual de la Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica (SEIMC), 4-6 junio de 2020., [Introducción/Objetivos]: las bacterias resistentes a múltiples fármacos como el Staphylococcus aureus resistente a meticilina (MRSA) se encuentran entre las principales causas de infecciones adquiridas en el hospital o en la comunidad, y representan un desafío para el sistema de salud. Por lo tanto, es importante encontrar nuevos medicamentos que muestren actividad contra estas bacterias, tanto en monoterapia como en combinación con otros medicamentos antimicrobianos. La gliotoxina es una micotoxina producida por Aspergillus fumigatus y otros hongos del género Aspergillus. Alguna evidencia sugiere que la gliotoxina muestra actividad antimicrobiana, especialmente contra S. aureus. Este trabajo tiene como objetivo evaluar la eficacia antibiótica de la gliotoxina como monoterapia o en combinación con otros agentes terapéuticos contra MRSA in vitro e in vivo utilizando un modelo de infección por C. elegans., [Material y métodos]: La sensibilidad de MRSA ATCC700699 contra la gliotoxina se analizó mediante diferentes métodos: difusión en disco, curvas de mortalidad-tiempo y ensayos de microdilución. Los efectos sinérgicos de la gliotoxina con otros medicamentos antiestafilocócicos (vancomicina, ácido fusídico y linezolid) se probaron mediante un ensayo de tablero de ajedrez. Los gusanos sincronizados de C. elegans L4 se infectaron con MRSA. El cultivo se complementó por separado con gliotoxina, vancomicina o su combinación a diferentes concentraciones. La tasa de supervivencia de C. elegans se evaluó manualmente cada 12 h durante 4 días., [Resultados]: El análisis de sensibilidad de MRSA contra la gliotoxina mostró que la gliotoxina tiene una potente actividad antimicrobiana (MIC = 2 µg / ml). Además, se observó actividad sinérgica, cuando la gliotoxina se combinó con vancomicina y ácido fusídico, usando ensayos de tablero de ajedrez y curvas de muerte. Este efecto sinérgico fue confirmado por el software CalcuSyn (IC = 0.15 para 1 µg / ml de gliotoxina combinada con 2 µg / ml de vancomicina). El estudio in vivo de la infección por S. aureus en un modelo de C. elegans mostró que el tratamiento combinado de vancomicina con gliotoxina aumentó un 70% en la tasa de supervivencia de los gusanos infectados con MRSA., [Conclusiones]: nuestros resultados sugieren que la gliotoxina es efectiva contra las cepas de MRSA, lo que indica su posible uso como un nuevo fármaco contra las infecciones por MRSA.
Published: 2020

26. Bismethylgliotoxin is detected in serum from oncohaematological neutropaenic paediatric patients: presentation of two cases of probable IPA with negative galactomanan and positive bmGT

Author: Domingo, María Pilar, Esteban, Patricia, Redrado, Sergio, López Gómez, Concepción, Roc, Lourdes, Aguilar, Yurena, Algara, Olga, Milagro Beamonte, Ana, Calvo, Carlota, Pardo, Julián, Rezusta, Antonio, Gálvez Buerba, Eva Mª, Domingo, María Pilar, Redrado, Sergio, Milagro Beamonte, Ana, Calvo, Carlota, Pardo, Julián, Rezusta, Antonio, Gálvez Buerba, Eva Mª, Domingo, María Pilar [0000-0002-6829-8769], Redrado, Sergio [0000-0002-8404-0012], Milagro Beamonte, Ana [0000-0002-3888-8952], Calvo, Carlota [0000-0003-1864-4050], Pardo, Julián [0000-0003-0154-0730], Rezusta, Antonio [0000-0001-7294-245X], and Gálvez Buerba, Eva Mª [0000-0001-6928-5516]
Subjects: Neutropenia, education, Diagnosis, Invasive aspergillosis, natural sciences, Bis(methylthio)gliotoxin, health care economics and organizations, Cancer
Abstract: of the poster presented at the 30th ECCMID 2020, European Congress of Clinical Microbiology and Infectious Diseases, organized by the European Society of Clinical Microbiology and Infectious Diseases (ESCMID).-- www.eccmid.org .-- www.escmid.org.-- Abstract 6251., [Background] Invasive pulmonary aspergillosis (IPA) is a leading cause of morbidity and mortality in immunocompromised oncohematology pediatric patients. This is mainly due to the absence of optimal diagnostic modalities, which hamper early specific disease detection and treatment. Thus, diagnosis of IA is still challenging and constitutes a major problem during management of pediatric patients at risk of infection, where the number of studies validating different diagnosis biomarkers is more limited. In a previous study, we demonstrated the high diagnostic accuracy of bis(methyl)gliotoxin(bmGT) compared to GM for IPA diagnosis in adults. The objective of this study is to show bmGT suitability for IPA diagnosis in oncopediatric patients in comparison with GM, monitoring the course of bmGT concentration in serum during voriconazole treatment., [Materials/methods] The presence and concentration of bmGT and voriconazole in sequential serum series from 9 oncopediatric patients with febrile neutropenia (retrospective and prospective samples) were simultaneously quantified by High Performance Thin Layer Chromatography (HPTLC) and confirmed using LC/MS/MS by an independent lab., [Results] HPTLC allowed simultaneous sensitive detection of bmGT and voriconazole in serum and BAL of pediatric patients confirmed by LC/MS/MS. We present two patients (17 and 36 months). In the phase of prolonged neutropenia, fever, hypoxemia and pulmonary infiltration compatible with Aspergillosis in high resolution CT are started. In one patient, bmGT was detected earlier than GM, allowing early initiation of treatment, with the voriconazole treatment the GM was negativized and the bmGT levels decreased. In the second patient, GM was negative and bmGT positive in serum and BAL, so treatment with voriconazole was started, then a decrease in bmGT values was detected coinciding with the patient clinical improvement., [Conclusions] The determination of bmGT in pediatric patients allowed the early diagnosis and effective treatment of two cases of IA, being a promising tool in neutropenic pediatric patients at risk of IPA. Identification of bmGT by HPTLC has been confirmed by LC/MS/MS indicating the presence of this biomarker during IPA in pediatric population. Analyses to establish the performance of serum bmGT detection together with beta-d-Glucan, PCR and IL8 to diagnose IPA in pediatric oncohematological patients are ongoing.
Published: 2020

27. Serum active Granzyme A: a new biomarker that contributes to the pathogenesis of peritoneal sepsis

Author: Garzón, Marcela, Sierra Monzón, José L., Comas, Laura, Uranga Murillo, Iratxe, Morte Romea, Elena, Algarate, Sonia, Ushakova, Tatiana Khaliulina, Seral, Cristina, Luque Gómez, Pilar, Paño, José Ramón, Gálvez Buerba, Eva Mª, Arias, Maykel, Pardo, Julián, Garzón, Marcela, Sierra Monzón, José L., Comas, Laura, Uranga Murillo, Iratxe, Morte Romea, Elena, Algarate, Sonia, Ushakova, Tatiana Khaliulina, Luque Gómez, Pilar, Paño, José Ramón, Gálvez Buerba, Eva Mª, Arias, Maykel, Pardo, Julián, Garzón, Marcela [0000-0001-6778-0636], Sierra Monzón, José L. [0000-0002-8796-2717], Comas, Laura [0000-0002-3843-1231], Uranga Murillo, Iratxe [0000-0001-8411-984X], Morte Romea, Elena [0000-0001-9262-2461], Algarate, Sonia [0000-0002-0036-6630], Ushakova, Tatiana Khaliulina [0000-0002-7930-2129], Luque Gómez, Pilar [0000-0001-7790-409X], Paño, José Ramón [0000-0002-9600-8116], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Arias, Maykel [0000-0002-9730-2210], and Pardo, Julián [0000-0003-0154-0730]
Subjects: Granzyme, natural sciences, Peritoneal sepsis, Biomarkers
Abstract: of the work presented at the 30th ECCMID 2020, European Congress of Clinical Microbiology and Infectious Diseases, organized by the European Society of Clinical Microbiology and Infectious Diseases (ESCMID).-- www.eccmid.org .-- www.escmid.org.-- Accepted abstract 1508., [Background] Peritonitis is one of the most common leading cause of sepsis. Recent evidence suggests that Granzyme A (GzmA), a serine protease mainly expressed in NK cells and T cells, could act as a proinflammatory mediator and could play an important role in the pathogenesis of sepsis. This work aims to analyze the role of serum GzmA as a biomarker and therapeutic target in peritoneal sepsis., [Materials/methods] Concentration and enzyme activity of soluble GzmA were sequentially analyzed in serum from healthy donors and patients with peritonitis and were correlated with the Sequential Organ Failure Assessment (SOFA) score. Peritonitis was induced in C57Bl/6 (Wt) and GzmA-KO mice by cecal ligation and puncture (CLP). Mice were treated intraperitoneally with antibiotics and with serpinb6b, a specific GzmA inhibitor, for 5 days. Mouse survival was monitored during 14 days and the levels of serum proinflammatory cytokines and bacterial load in blood and spleen were analyzed at 6 and 24h from CLP., [Results] We have found high levels of GzmA in serum of patient with peritonitis. Most importantly, we observed that GzmA activity in serum correlates with SOFA score, suggesting that active GzmA could play an important role in sepsis development in peritonitis patients and could be a new biomarker of sepsis severity. In order to analyze the therapeutical potential of soluble GzmA in peritoneal sepsis, we used the CLP mouse model. After peritonitis induction, GzmA-KO mice exhibit increased survival compared with Wt mice, which correlated with reduced levels of proinflammatory cytokines in serum. The analysis of bacterial load in blood and spleen showed no differences between Wt and GzmA-KO mice suggesting that GzmA does not play an important role in bacterial control. Treatment with serpinb6b reduced mortality, which correlated with reduced cytokine serum levels in serum, confirming the therapeutical potential of gzmA to treat peritoneal sepsis., [Conclusions] Our findings confirm that soluble GzmA plays an important role in the pathogenesis of sepsis and could be a new therapeutic target and a biomarker for the treatment of peritoneal sepsis.
Published: 2020

28. Bismethylgliotoxin is detected in serum from oncohaematological neutropaenic paediatric patients: presentation of two cases of probable IPA with negative galactomanan and positive bmGT

Author: Domingo, María Pilar [0000-0002-6829-8769], Redrado, Sergio [0000-0002-8404-0012], Milagro Beamonte, Ana [0000-0002-3888-8952], Calvo, Carlota [0000-0003-1864-4050], Pardo, Julián [0000-0003-0154-0730], Rezusta, Antonio [0000-0001-7294-245X], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Domingo, María Pilar, Esteban, Patricia, Redrado, Sergio, López Gómez, Concepción, Roc, Lourdes, Aguilar, Yurena, Algara, Olga, Milagro Beamonte, Ana, Calvo, Carlota, Pardo, Julián, Rezusta, Antonio, Gálvez Buerba, Eva Mª, Domingo, María Pilar [0000-0002-6829-8769], Redrado, Sergio [0000-0002-8404-0012], Milagro Beamonte, Ana [0000-0002-3888-8952], Calvo, Carlota [0000-0003-1864-4050], Pardo, Julián [0000-0003-0154-0730], Rezusta, Antonio [0000-0001-7294-245X], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Domingo, María Pilar, Esteban, Patricia, Redrado, Sergio, López Gómez, Concepción, Roc, Lourdes, Aguilar, Yurena, Algara, Olga, Milagro Beamonte, Ana, Calvo, Carlota, Pardo, Julián, Rezusta, Antonio, and Gálvez Buerba, Eva Mª
Abstract: [Background] Invasive pulmonary aspergillosis (IPA) is a leading cause of morbidity and mortality in immunocompromised oncohematology pediatric patients. This is mainly due to the absence of optimal diagnostic modalities, which hamper early specific disease detection and treatment. Thus, diagnosis of IA is still challenging and constitutes a major problem during management of pediatric patients at risk of infection, where the number of studies validating different diagnosis biomarkers is more limited. In a previous study, we demonstrated the high diagnostic accuracy of bis(methyl)gliotoxin(bmGT) compared to GM for IPA diagnosis in adults. The objective of this study is to show bmGT suitability for IPA diagnosis in oncopediatric patients in comparison with GM, monitoring the course of bmGT concentration in serum during voriconazole treatment., [Materials/methods] The presence and concentration of bmGT and voriconazole in sequential serum series from 9 oncopediatric patients with febrile neutropenia (retrospective and prospective samples) were simultaneously quantified by High Performance Thin Layer Chromatography (HPTLC) and confirmed using LC/MS/MS by an independent lab., [Results] HPTLC allowed simultaneous sensitive detection of bmGT and voriconazole in serum and BAL of pediatric patients confirmed by LC/MS/MS. We present two patients (17 and 36 months). In the phase of prolonged neutropenia, fever, hypoxemia and pulmonary infiltration compatible with Aspergillosis in high resolution CT are started. In one patient, bmGT was detected earlier than GM, allowing early initiation of treatment, with the voriconazole treatment the GM was negativized and the bmGT levels decreased. In the second patient, GM was negative and bmGT positive in serum and BAL, so treatment with voriconazole was started, then a decrease in bmGT values was detected coinciding with the patient clinical improvement., [Conclusions] The determination of bmGT in pediatric patients allowed the early diagnosis and effective treatment of two cases of IA, being a promising tool in neutropenic pediatric patients at risk of IPA. Identification of bmGT by HPTLC has been confirmed by LC/MS/MS indicating the presence of this biomarker during IPA in pediatric population. Analyses to establish the performance of serum bmGT detection together with beta-d-Glucan, PCR and IL8 to diagnose IPA in pediatric oncohematological patients are ongoing.
Published: 2020

29. Serum active Granzyme A: a new biomarker that contributes to the pathogenesis of peritoneal sepsis

Author: Garzón, Marcela [0000-0001-6778-0636], Sierra Monzón, José L. [0000-0002-8796-2717], Comas, Laura [0000-0002-3843-1231], Uranga Murillo, Iratxe [0000-0001-8411-984X], Morte Romea, Elena [0000-0001-9262-2461], Algarate, Sonia [0000-0002-0036-6630], Ushakova, Tatiana Khaliulina [0000-0002-7930-2129], Luque Gómez, Pilar [0000-0001-7790-409X], Paño, José Ramón [0000-0002-9600-8116], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Arias, Maykel [0000-0002-9730-2210], Pardo, Julián [0000-0003-0154-0730], Garzón, Marcela, Sierra Monzón, José L., Comas, Laura, Uranga Murillo, Iratxe, Morte Romea, Elena, Algarate, Sonia, Ushakova, Tatiana Khaliulina, Seral, Cristina, Luque Gómez, Pilar, Paño, José Ramón, Gálvez Buerba, Eva Mª, Arias, Maykel, Pardo, Julián, Garzón, Marcela [0000-0001-6778-0636], Sierra Monzón, José L. [0000-0002-8796-2717], Comas, Laura [0000-0002-3843-1231], Uranga Murillo, Iratxe [0000-0001-8411-984X], Morte Romea, Elena [0000-0001-9262-2461], Algarate, Sonia [0000-0002-0036-6630], Ushakova, Tatiana Khaliulina [0000-0002-7930-2129], Luque Gómez, Pilar [0000-0001-7790-409X], Paño, José Ramón [0000-0002-9600-8116], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Arias, Maykel [0000-0002-9730-2210], Pardo, Julián [0000-0003-0154-0730], Garzón, Marcela, Sierra Monzón, José L., Comas, Laura, Uranga Murillo, Iratxe, Morte Romea, Elena, Algarate, Sonia, Ushakova, Tatiana Khaliulina, Seral, Cristina, Luque Gómez, Pilar, Paño, José Ramón, Gálvez Buerba, Eva Mª, Arias, Maykel, and Pardo, Julián
Abstract: [Background] Peritonitis is one of the most common leading cause of sepsis. Recent evidence suggests that Granzyme A (GzmA), a serine protease mainly expressed in NK cells and T cells, could act as a proinflammatory mediator and could play an important role in the pathogenesis of sepsis. This work aims to analyze the role of serum GzmA as a biomarker and therapeutic target in peritoneal sepsis., [Materials/methods] Concentration and enzyme activity of soluble GzmA were sequentially analyzed in serum from healthy donors and patients with peritonitis and were correlated with the Sequential Organ Failure Assessment (SOFA) score. Peritonitis was induced in C57Bl/6 (Wt) and GzmA-KO mice by cecal ligation and puncture (CLP). Mice were treated intraperitoneally with antibiotics and with serpinb6b, a specific GzmA inhibitor, for 5 days. Mouse survival was monitored during 14 days and the levels of serum proinflammatory cytokines and bacterial load in blood and spleen were analyzed at 6 and 24h from CLP., [Results] We have found high levels of GzmA in serum of patient with peritonitis. Most importantly, we observed that GzmA activity in serum correlates with SOFA score, suggesting that active GzmA could play an important role in sepsis development in peritonitis patients and could be a new biomarker of sepsis severity. In order to analyze the therapeutical potential of soluble GzmA in peritoneal sepsis, we used the CLP mouse model. After peritonitis induction, GzmA-KO mice exhibit increased survival compared with Wt mice, which correlated with reduced levels of proinflammatory cytokines in serum. The analysis of bacterial load in blood and spleen showed no differences between Wt and GzmA-KO mice suggesting that GzmA does not play an important role in bacterial control. Treatment with serpinb6b reduced mortality, which correlated with reduced cytokine serum levels in serum, confirming the therapeutical potential of gzmA to treat peritoneal sepsis., [Conclusions] Our findings confirm that soluble GzmA plays an important role in the pathogenesis of sepsis and could be a new therapeutic target and a biomarker for the treatment of peritoneal sepsis.
Published: 2020

30. Microbiota and lung cancer. Opportunities and challenges for improving immunotherapy efficacy

Author: Bristol-Myers Squibb, Gilead Sciences, Pfizer, European Commission, Gobierno de Aragón, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Fundación Inocente Inocente, Aspanoa, Asociación Carrera de la Mujer Ciudad de Monzón, ARAID Foundation, AstraZeneca, Roche, Merck Sharp & Dohme, Pierre Fabre, Ocáriz, Maitane [0000-0002-7557-7264], Cruellas, Mara [0000-0002-6953-9675], Gascón, Marta [0000-0002-6811-6654], Martínez Lostao, Luis [0000-0003-3043-147X], Ramírez-Labrada, Ariel [0000-0002-3888-7036], Sesma, Andrea [0000-0001-7209-266X], Torres-Ramón, Irene [0000-0003-3387-0558], Yubero, Alfonso [0000-0003-4995-0325], Pardo, Julián [0000-0003-0154-0730], Isla, Dolores [0000-0002-2483-198X], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Ocáriz, Maitane, Cruellas, Mara, Gascón, Marta, Lastra, Rodrigo, Martínez-Lostao, Luis, Ramírez-Labrada, Ariel, Paño, José Ramón, Sesma, Andrea, Torres-Ramón, Irene, Yubero, Alfonso, Pardo, Julián, Isla, Dolores, Gálvez Buerba, Eva Mª, Bristol-Myers Squibb, Gilead Sciences, Pfizer, European Commission, Gobierno de Aragón, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Fundación Inocente Inocente, Aspanoa, Asociación Carrera de la Mujer Ciudad de Monzón, ARAID Foundation, AstraZeneca, Roche, Merck Sharp & Dohme, Pierre Fabre, Ocáriz, Maitane [0000-0002-7557-7264], Cruellas, Mara [0000-0002-6953-9675], Gascón, Marta [0000-0002-6811-6654], Martínez Lostao, Luis [0000-0003-3043-147X], Ramírez-Labrada, Ariel [0000-0002-3888-7036], Sesma, Andrea [0000-0001-7209-266X], Torres-Ramón, Irene [0000-0003-3387-0558], Yubero, Alfonso [0000-0003-4995-0325], Pardo, Julián [0000-0003-0154-0730], Isla, Dolores [0000-0002-2483-198X], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Ocáriz, Maitane, Cruellas, Mara, Gascón, Marta, Lastra, Rodrigo, Martínez-Lostao, Luis, Ramírez-Labrada, Ariel, Paño, José Ramón, Sesma, Andrea, Torres-Ramón, Irene, Yubero, Alfonso, Pardo, Julián, Isla, Dolores, and Gálvez Buerba, Eva Mª
Abstract: The advances in molecular biology and the emergence of Next Generation Sequencing (NGS) have revealed that microbiome composition is closely related with health and disease, including cancer. This relationship affects different levels of cancer such as development, progression, and response to treatment including immunotherapy. The efficacy of immune checkpoint inhibitors (ICIs) may be influenced by the concomitant use of antibiotics before, during or shortly after treatment with ICIs. Nevertheless, the linking mechanism between microbiote, host immunity and cancer is not clear and the role of microbiota manipulation and analyses in cancer management has not been clinically validated yet. Regarding the use of microbiome as biomarker to predict ICI efficacy it has been recently shown that the use of biochemical serum markers to monitor intestinal permeability and loss of barrier integrity, like citrulline, could be useful to monitor microbiota changes and predict ICI efficacy. There are still many unknowns about the role of these components, their relationship with the microbiota, with the use of antibiotics and the response to immunotherapy. The next challenge in microbiome research will be to identify individual microbial species that causally affect lung cancer phenotypes and response to ICI and disentangle the underlying mechanisms. Thus, further analyses in patients with lung cancer receiving treatment with ICIs and its correlation with the composition of the microbiota in different organs including the respiratory tract, peripheral blood and intestinal tract could be useful to predict the efficacy of ICIs and its modulation with antibiotic use.
Published: 2020

31. The multifaceted function of granzymes in sepsis: some facts and a lot to discover

Author: European Commission, Gobierno de Aragón, Ministerio de Economía y Competitividad (España), Instituto de Salud Carlos III, Fundación Banco Santander, Universidad de Zaragoza, Ministerio de Ciencia, Innovación y Universidades (España), ARAID Foundation, Garzón, Marcela [0000-0001-6778-0636], Arias, Maykel [0000-0002-9730-2210], Sierra Monzón, José L. [0000-0002-8796-2717], Morte Romea, Elena [0000-0001-9262-2461], Santiago, Llipsy [0000-0002-1861-5981], Ramírez-Labrada, Ariel [0000-0002-3888-7036], Martínez Lostao, Luis [0000-0003-3043-147X], Paño, José Ramón [0000-0002-9600-8116], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Pardo, Julián [0000-0003-0154-0730], Garzón, Marcela, Arias, Maykel, Sierra Monzón, José L., Morte Romea, Elena, Santiago, Llipsy, Ramírez-Labrada, Ariel, Martínez-Lostao, Luis, Paño, José Ramón, Gálvez Buerba, Eva Mª, Pardo, Julián, European Commission, Gobierno de Aragón, Ministerio de Economía y Competitividad (España), Instituto de Salud Carlos III, Fundación Banco Santander, Universidad de Zaragoza, Ministerio de Ciencia, Innovación y Universidades (España), ARAID Foundation, Garzón, Marcela [0000-0001-6778-0636], Arias, Maykel [0000-0002-9730-2210], Sierra Monzón, José L. [0000-0002-8796-2717], Morte Romea, Elena [0000-0001-9262-2461], Santiago, Llipsy [0000-0002-1861-5981], Ramírez-Labrada, Ariel [0000-0002-3888-7036], Martínez Lostao, Luis [0000-0003-3043-147X], Paño, José Ramón [0000-0002-9600-8116], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Pardo, Julián [0000-0003-0154-0730], Garzón, Marcela, Arias, Maykel, Sierra Monzón, José L., Morte Romea, Elena, Santiago, Llipsy, Ramírez-Labrada, Ariel, Martínez-Lostao, Luis, Paño, José Ramón, Gálvez Buerba, Eva Mª, and Pardo, Julián
Abstract: Sepsis is a serious global health problem. In addition to a high incidence, this syndrome has a high mortality and is responsible for huge health expenditure. The pathophysiology of sepsis is very complex and it is not well-understood yet. However, it is widely accepted that the initial phase of sepsis is characterized by a hyperinflammatory response while the late phase is characterized by immunosuppression and immune anergy, increasing the risk of secondary infections. Granzymes (Gzms) are a family of serine proteases classified according to their cleavage specificity. Traditionally, it was assumed that all Gzms acted as cytotoxic proteases. However, recent evidence suggests that GzmB is the one with the greatest cytotoxic capacity, while the cytotoxicity of others such as GzmA and GzmK is not clear. Recent studies have found that GzmA, GzmB, GzmK, and GzmM act as pro-inflammatory mediators. Specially, solid evidences show that GzmA and GzmK function as extracellular proteases that regulate the inflammatory response irrespectively of its ability to induce cell death. Indeed, studies in animal models indicate that GzmA is involved in the cytokine release syndrome characteristic of sepsis. Moreover, the GZM family also could regulate other biological processes involved in sepsis pathophysiology like the coagulation cascade, platelet function, endothelial barrier permeability, and, in addition, could be involved in the immunosuppressive stage of sepsis. In this review, we provide a comprehensive overview on the contribution of these novel functions of Gzms to sepsis and the new therapeutic opportunities emerging from targeting these proteases for the treatment of this serious health problem.
Published: 2020

32. Gliotoxina, un nuevo candidato contra Staphylococcus aureus resistente a meticilina que muestra un efecto sinérgico con fármacos antimicrobianos en el modelo de infección Caenorhabditis elegans

Author: Esteban, Patricia [0000-0003-4123-3524], Redrado, Sergio [0000-0002-8404-0012], Comas, Laura [0000-0002-3843-1231], Domingo, María Pilar [0000-0002-6829-8769], Algarate, Sonia [0000-0002-0036-663], Rezusta, Antonio [0000-0001-7294-245X], Pardo, Julián [0000-0003-0154-0730], Arias, Maykel [0000-0002-9730-2210], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Esteban, Patricia, Redrado, Sergio, Comas, Laura, Domingo, María Pilar, Millán-Lou, María Isabel, Seral, Cristina, Algarate, Sonia, Rezusta, Antonio, Pardo, Julián, Arias, Maykel, Gálvez Buerba, Eva Mª, Esteban, Patricia [0000-0003-4123-3524], Redrado, Sergio [0000-0002-8404-0012], Comas, Laura [0000-0002-3843-1231], Domingo, María Pilar [0000-0002-6829-8769], Algarate, Sonia [0000-0002-0036-663], Rezusta, Antonio [0000-0001-7294-245X], Pardo, Julián [0000-0003-0154-0730], Arias, Maykel [0000-0002-9730-2210], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Esteban, Patricia, Redrado, Sergio, Comas, Laura, Domingo, María Pilar, Millán-Lou, María Isabel, Seral, Cristina, Algarate, Sonia, Rezusta, Antonio, Pardo, Julián, Arias, Maykel, and Gálvez Buerba, Eva Mª
Abstract: [Introducción/Objetivos]: las bacterias resistentes a múltiples fármacos como el Staphylococcus aureus resistente a meticilina (MRSA) se encuentran entre las principales causas de infecciones adquiridas en el hospital o en la comunidad, y representan un desafío para el sistema de salud. Por lo tanto, es importante encontrar nuevos medicamentos que muestren actividad contra estas bacterias, tanto en monoterapia como en combinación con otros medicamentos antimicrobianos. La gliotoxina es una micotoxina producida por Aspergillus fumigatus y otros hongos del género Aspergillus. Alguna evidencia sugiere que la gliotoxina muestra actividad antimicrobiana, especialmente contra S. aureus. Este trabajo tiene como objetivo evaluar la eficacia antibiótica de la gliotoxina como monoterapia o en combinación con otros agentes terapéuticos contra MRSA in vitro e in vivo utilizando un modelo de infección por C. elegans., [Material y métodos]: La sensibilidad de MRSA ATCC700699 contra la gliotoxina se analizó mediante diferentes métodos: difusión en disco, curvas de mortalidad-tiempo y ensayos de microdilución. Los efectos sinérgicos de la gliotoxina con otros medicamentos antiestafilocócicos (vancomicina, ácido fusídico y linezolid) se probaron mediante un ensayo de tablero de ajedrez. Los gusanos sincronizados de C. elegans L4 se infectaron con MRSA. El cultivo se complementó por separado con gliotoxina, vancomicina o su combinación a diferentes concentraciones. La tasa de supervivencia de C. elegans se evaluó manualmente cada 12 h durante 4 días., [Resultados]: El análisis de sensibilidad de MRSA contra la gliotoxina mostró que la gliotoxina tiene una potente actividad antimicrobiana (MIC = 2 µg / ml). Además, se observó actividad sinérgica, cuando la gliotoxina se combinó con vancomicina y ácido fusídico, usando ensayos de tablero de ajedrez y curvas de muerte. Este efecto sinérgico fue confirmado por el software CalcuSyn (IC = 0.15 para 1 µg / ml de gliotoxina combinada con 2 µg / ml de vancomicina). El estudio in vivo de la infección por S. aureus en un modelo de C. elegans mostró que el tratamiento combinado de vancomicina con gliotoxina aumentó un 70% en la tasa de supervivencia de los gusanos infectados con MRSA., [Conclusiones]: nuestros resultados sugieren que la gliotoxina es efectiva contra las cepas de MRSA, lo que indica su posible uso como un nuevo fármaco contra las infecciones por MRSA.
Published: 2020

33. The influence of lung microbiota on lung carcinogenesis, immunity, and immunotherapy

Author: Ramírez-Labrada, Ariel [0000-0002-3888-7036], Isla, Dolores [0000-0002-2483-198X], Artal, A. [0000-0002-9778-706X], Arias, Maykel [0000-0002-9730-2210], Rezusta, Antonio [0000-0001-7294-245X], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Ramírez-Labrada, Ariel, Isla, Dolores, Artal, A., Arias, Maykel, Rezusta, Antonio, Pardo, Julián, Gálvez Buerba, Eva Mª, Ramírez-Labrada, Ariel [0000-0002-3888-7036], Isla, Dolores [0000-0002-2483-198X], Artal, A. [0000-0002-9778-706X], Arias, Maykel [0000-0002-9730-2210], Rezusta, Antonio [0000-0001-7294-245X], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Ramírez-Labrada, Ariel, Isla, Dolores, Artal, A., Arias, Maykel, Rezusta, Antonio, Pardo, Julián, and Gálvez Buerba, Eva Mª
Abstract: Microbiota have emerged as key modulators of both the carcinogenic process and the immune response against cancer cells, and, thus, it seems to influence the efficacy of immunotherapy. While most studies have focused on analyzing the influence of gut microbiota, its composition substantially differs from that in the lung. Here, we describe how microbial life in the lungs is associated with host immune status in the lungs and, thus, how the identification of the microbial populations in the lower respiratory tract rather than in the gut might be key to understanding the lung carcinogenic process and to predict the efficacy of different treatments. Understanding the influence of lung microbiota on host immunity may identify new therapeutic targets and help to design new immunotherapy approaches to treat lung cancer.
Published: 2020

34. Inﬂammatory cell death induced by cytotoxic lymphocytes: a dangerous but necessary liaison

Author: Miguel, Diego de, Ramírez-Labrada, Ariel, Uranga Murillo, Iratxe, Hidalgo, Sandra, Santiago, Llipsy, Gálvez Buerba, Eva Mª, Arias, Maykel, Pardo, Julián, European Commission, Gobierno de Aragón, Ministerio de Ciencia, Innovación y Universidades (España), Instituto de Salud Carlos III, Agencia Estatal de Investigación (España), Fundación Inocente Inocente, Aspanoa, Asociación Carrera de la Mujer Ciudad de Monzón, ARAID Foundation, de Miguel, Diego [0000-0002-8486-8514], Ramírez-Labrada, Ariel [0000-0002-3888-7036], Uranga Murillo, Iratxe [0000-0001-8411-984X], Hidalgo, Sandra [0000-0003-1629-9978], Santiago, Llipsy [0000-0002-1861-5981], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Arias, Maykel [0000-0002-9730-2210], and Pardo, Julián [0000-0003-0154-0730]
Subjects: Inflammation, Immunosurveillance, Necroptosis, Pyroptosis, Ferroptosis, Apoptosis, Immunotherapy, Immunogenic cell death
Abstract: 2 figures. Cytotoxic lymphocytes (CLs), and more specifically Tc and NK cells, are the main executors of cell death in the immune system, playing a key role during both immunosurveillance and immunotherapy. These cells induce regulated cell death (RCD) by different mechanisms, being granular exocytosis and expression of death ligands the most prominent and best characterized ones. Apoptosis, a traditionally considered low-inflammatory type of cell death, has been accepted for years as the paradigm of RCD induced by CLs. However, several recent studies have demonstrated that NK cells and Tc cells can also induce more inflammatory forms of cell death, namely, necroptosis, pyroptosis, and ferroptosis. Activation of these highly inflammatory types of cell death appears to critically contribute to the activation of a successful antitumour immune response. Additionally, the role of specific cell death pathways in immunogenic cell death is still under intense debate, especially considering the interconnections with other inflammatory forms of cell death. These evidences, together with the advent of new cancer immunotherapies, highlight the necessity to deepen our understanding of the link between the cell death triggered by CLs and inflammation. This knowledge will be instrumental to maximize the antitumour potential of immunotherapies, minimizing deleterious effects associated with these treatments. In this review, we will briefly summarize the main features of apoptosis, necroptosis, pyroptosis and ferroptosis, to subsequently discuss the most recent evidences about the role of these RCD pathways during the elimination of cancer cells mediated by CLs and its modulation to increase the efficacy of cancer immunotherapy. Work in the JP laboratory is funded by the FEDER (Fondo Europeo de Desarrollo Regional, Gobierno de Aragón, Group B29_17R), Ministerio de Ciencia, Innovación e Universidades (MCNU), Health National Institute Carlos III, Agencia Estatal de Investigación (SAF2017-83120-C2-1-R; PID2020-113963RB-I00), Fundación Inocente Inocente, ASPANOA and Carrera de la Mujer de Monzón. EMG is funded by Agencia Estatal de Investigación (SAF2017-83120-C2-1-R and PID2020-113963RB-I00). DDM is supported by a postdoctoral fellowship ‘Sara Borrell’, LS by a PhD fellowship (FPI) from the Ministry of Science, Innovation and Universities. IUM and SH are supported by a PhD fellowship from Aragon Government. MA is supported by a postdoctoral fellowship ‘Juan de la Cierva-formación’ from the Ministry of Science, Innovation and Universities, and JP is supported by the ARAID Foundation.
Published: 2021

35. The multifaceted function of granzymes in sepsis: some facts and a lot to discover

Author: Garzón, Marcela, Arias, Maykel, Sierra Monzón, José L., Morte Romea, Elena, Santiago, Llipsy, Ramírez-Labrada, Ariel, Martínez Lostao, Luis, Paño, José Ramón, Gálvez Buerba, Eva Mª, Pardo, Julián, European Commission, Gobierno de Aragón, Ministerio de Economía y Competitividad (España), Instituto de Salud Carlos III, Fundación Banco Santander, Universidad de Zaragoza, Ministerio de Ciencia, Innovación y Universidades (España), ARAID Foundation, Garzón, Marcela [0000-0001-6778-0636], Arias, Maykel [0000-0002-9730-2210], Sierra Monzón, José L. [0000-0002-8796-2717], Morte Romea, Elena [0000-0001-9262-2461], Santiago, Llipsy [0000-0002-1861-5981], Ramírez-Labrada, Ariel [0000-0002-3888-7036], Martínez Lostao, Luis [0000-0003-3043-147X], Paño, José Ramón [0000-0002-9600-8116], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], and Pardo, Julián [0000-0003-0154-0730]
Subjects: inflammatory cytokine, Endothelial (dys)function, Coagulopathy, Sepsis, Granzymes, Immunosuppression
Abstract: 1 figure, 1 table Sepsis is a serious global health problem. In addition to a high incidence, this syndrome has a high mortality and is responsible for huge health expenditure. The pathophysiology of sepsis is very complex and it is not well-understood yet. However, it is widely accepted that the initial phase of sepsis is characterized by a hyperinflammatory response while the late phase is characterized by immunosuppression and immune anergy, increasing the risk of secondary infections. Granzymes (Gzms) are a family of serine proteases classified according to their cleavage specificity. Traditionally, it was assumed that all Gzms acted as cytotoxic proteases. However, recent evidence suggests that GzmB is the one with the greatest cytotoxic capacity, while the cytotoxicity of others such as GzmA and GzmK is not clear. Recent studies have found that GzmA, GzmB, GzmK, and GzmM act as pro-inflammatory mediators. Specially, solid evidences show that GzmA and GzmK function as extracellular proteases that regulate the inflammatory response irrespectively of its ability to induce cell death. Indeed, studies in animal models indicate that GzmA is involved in the cytokine release syndrome characteristic of sepsis. Moreover, the GZM family also could regulate other biological processes involved in sepsis pathophysiology like the coagulation cascade, platelet function, endothelial barrier permeability, and, in addition, could be involved in the immunosuppressive stage of sepsis. In this review, we provide a comprehensive overview on the contribution of these novel functions of Gzms to sepsis and the new therapeutic opportunities emerging from targeting these proteases for the treatment of this serious health problem. This work was supported in part by FEDER/Gobierno de Aragón (group B29), Ministerio de Economia y Competitividad [SAF2014-54763-C2-1 and SAF2017-83120-C2-1-R (JP-P), SAF2014-54763-C2-2-R (EG)] and Instituto de Salud Carlos III (PI16-00526, LM-L; PI18/00527, JP-P). Predoctoral grants/contracts from Fundacion Santander/Universidad de Zaragoza (LS and MA), Ministerio de Ciencia, Innovación y Universidades (MG-T). MA has a Juan de la Cierva Contract (Ministerio de Ciencia, Innovación y Universidades) and JS-M a Rio Hortega Contract (Instituto de Salud Carlos III). JP was supported by Fundación Aragon I+D (ARAID).
Published: 2020

36. Gliotoxin, a new candidate against methicillin-resistant Staphylococcus aureus showing synergistic effect with classical antimicrobial drugs in Caenorhabditis elegans infection model

Author: Esteban, Patricia, Redrado, Sergio, Comas, Laura, Seral, Cristina, Pardo, Julián, Arias, Maykel, Gálvez Buerba, Eva Mª, Redrado, Sergio [0000-0002-8404-0012], Comas, Laura [0000-0002-3843-1231], Pardo, Julián [0000-0003-0154-0730], Arias, Maykel [0000-0002-9730-2210], and Gálvez Buerba, Eva Mª [0000-0001-6928-5516]
Subjects: Gliotoxin, Aspergillus spp, Antimicrobial drugs, Antimicrobial resistance, Methicillin-resistant Staphylococcus aureus (MRSA)
Abstract: of the work presented at the 30th ECCMID 2020, European Congress of Clinical Microbiology and Infectious Diseases, organized by the European Society of Clinical Microbiology and Infectious Diseases (ESCMID).-- www.eccmid.org .-- www.escmid.org.-- Abstract 6144. [Background] Multidrug-resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) is among the major causes of hospital-acquired and community infections, and pose a challenge to the human health care system. Therefore, it is important to find new drugs that show activity against these bacteria, both in monotherapy and in combination with other antimicrobial drugs. Gliotoxin is a mycotoxin produced by Aspergillus fumigatus and other fungi of the Aspergillus genus. Some evidence suggests that gliotoxin shows antimicrobial activity, especially against S. aureus. This work aims to evaluate the antibiotic efficacy of gliotoxin as monotherapy or in combination with other therapeutic against MRSA in vitro and in vivo using a C. elegans infection model. [Materials/methods] MRSA ATCC700699 sensitivity against gliotoxin was analysed by different methods: disc diffusion, time-mortality curves, microdilution assays. The synergistic effects of gliotoxin with others anti-staphylococcal drugs (vancomycin, fusidic acid and linezolid) were tested by a checkerboard assay. Transformed synchronized C. elegans L4 worms were infected with MRSA. The culture was supplemented separately with gliotoxin, vancomycin or its combination to different concentrations. The survival rate of C. elegans was scored manually every 12h for 4 days. [Results] Sensitivity analysis of MRSA against gliotoxin showed that gliotoxin has a potent antimicrobial activity (MIC = 2 μg/ml). In addition, synergistic activity was observed, when the gliotoxin was combined with vancomycin and fusidic acid, using checkerboard and time-kill assays. This synergistic effect was confirmed by CalcuSyn software (CI = 0.15 for 1 μg/ml of gliotoxin combined with 2 μg/ml of vancomycin). The in vivo study of S. aureus infection in a C. elegans model showed that combined treatment of vancomycin with gliotoxin increased 70% in survival rate of the MRSA-infected worms. [Conclusions] Our results suggest that gliotoxin is effective against MRSA strains indicating their potential use as a new drug against MRSA infections.
Published: 2020

37. Intracellular delivery of biologically-active fungal metabolite gliotoxin using magnetic nanoparticles

Author: Agencia Estatal de Investigación (España), Gobierno de Aragón, Ministerio de Economía y Competitividad (España), Consejo Superior de Investigaciones Científicas (España), Asociación de Padres de Niños con Cáncer de Aragón, Ministerio de Ciencia, Innovación y Universidades (España), European Commission, Polo, Ester [0000-0001-8870-5280], Domingo, María Pilar [0000-0002-6829-8769], Arias, Maykel [0000-0002-9730-2210], Martínez Lostao, Luis [0000-0003-3043-147X], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Comas, Laura, Polo, Ester, Domingo, María Pilar, Hernández, Yulán, Arias, Maykel, Esteban, Patricia, Martínez-Lostao, Luis, Pardo, Julián, Fuente, Jesús M. de la, Gálvez Buerba, Eva Mª, Agencia Estatal de Investigación (España), Gobierno de Aragón, Ministerio de Economía y Competitividad (España), Consejo Superior de Investigaciones Científicas (España), Asociación de Padres de Niños con Cáncer de Aragón, Ministerio de Ciencia, Innovación y Universidades (España), European Commission, Polo, Ester [0000-0001-8870-5280], Domingo, María Pilar [0000-0002-6829-8769], Arias, Maykel [0000-0002-9730-2210], Martínez Lostao, Luis [0000-0003-3043-147X], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Comas, Laura, Polo, Ester, Domingo, María Pilar, Hernández, Yulán, Arias, Maykel, Esteban, Patricia, Martínez-Lostao, Luis, Pardo, Julián, Fuente, Jesús M. de la, and Gálvez Buerba, Eva Mª
Abstract: Gliotoxin (GT), a secondary metabolite produced by Aspergillus molds, has been proposed as a potential anti-tumor agent. Here we have developed a nanoparticle approach to enhance delivery of GT in tumor cells and establish a basis for its potential use as therapeutical drug. GT bound to magnetic nanoparticles (MNPs) retained a high anti-tumor activity, correlating with efficient intracellular delivery, which was increased in the presence of glucose. Our results show that the attachment of GT to MNPs by covalent bonding enhances intracellular GT delivery without affecting its biological activity. This finding represents the first step to use this potent anti-tumor agent in the treatment of cancer.
Published: 2019

38. Concentration of IgG against the Spike Receptor-Binding Domain predicts the viral neutralization activity of convalescent plasma and serum against SARS-CoV-2

Author: Santiago, Llipsy, Uranga Murillo, Iratxe, Arias, Maykel, Moreo, Eduardo, Hidalgo, Sandra, Gálvez Buerba, Eva Mª, Ramírez-Labrada, Ariel, Miguel, Diego de, Paño, José Ramón, and Pardo, Julián
Subjects: Coronavirus, Convalescent plasma, SARS-CoV-2, IgG, ELISA, Antibodies
Abstract: Poster presentado en el 42º SEI Congreso de la Sociedad Española de Inmunología, 24-26 marzo 2021, Madrid, formato virtual., SARS-CoV-2 is the virus responsible for the Covid-19 pandemic, due to its rapid propagation and the initial lack of vaccines or appropriate treatments. Nowadays, despite different vaccines available, the main treatments are palliative, focused on supplemental oxygen and anti-inflammatory therapy. Passive immunization could be an effective and economic treatment once standarized. It consists of the transfer of pathogen-specific antibodies to patients whose immune system has not originated a response yet. The donors’ antibodies neutralize and attenuate pathogen replication. Besides, an antibody against the Receptor-Binding Domain of Spike (RBD) would block the interaction of the virus with ACE2 and its entry in the cell. Here, an in-house RBG IgG ELISA test has been validated using a cohort of more than 320 samples of convalescent plasma and serum and adapted to quantify the concentration of plasma RBD IgG and its correlation with the SARS-CoV-2 neutralizing activity in vitro.
Published: 2021

39. Development of a new nanobody against opportunistic infections caused Aspergillus fumigatus o Cryptococcus neoformans

Author: Redrado, Sergio, Macías, Javier, Esteban, Patricia, Comas, Laura, Arias, Maykel, Rezusta, Antonio, Hurtado-Guerrero, R., Pardo, Julián, and Gálvez Buerba, Eva Mª
Subjects: Cryptococcus, Aspergillus, Nanobody
Abstract: Póster presentado en el 42º SEI, Congreso de la Sociedad Española de Inmunología, formato virtual, 24-26 marzo de 2021, Madrid., Fungal diseases affect annually more than 150 million people and mortality rounds around 1,7 million people. Furthermore, drug resistance among fungal species is steadily increasing during last years, so new treatments for fungal diseases are required. We report a camelid nanobody which shows in vitro inhibitory capabilities against A. fumigatus and C. neoformans β-1,3-glucanosyltransferases and reduces the growth rates of both fungi. This inhibitory nanobody has been tested in C. elegans models of aspergillosis and cryptococcosis, obtaining an improvement in survival rates. Such results led us to verify its effectiveness in murine models of aspergillosis and cryptococcosis, in which similar performance was also obtained. In this way, our findings reveal that inhibitory nanobodies targeted against fungal crucial enzymes can be used as novel antibiotics which may improve therapeutic outcome.
Published: 2021

40. TIM3, LAG3, CXCL10 and GzmA reveal as main hallmarks of inflammatory profiles in Covid-19 patiens

Author: Hidalgo, Sandra, Morte Romea, Elena, Pesini, Cecilia, Uranga Murillo, Iratxe, Sierra Monzón, José L., Martínez Lázaro, Beatriz, Paño, José Ramón, Gálvez Buerba, Eva Mª, and Pardo, Julián
Subjects: Inflammation, Immune, SARS-CoV-2, CXCL10, Granzyme A, COVID-19, TIM3, Cytokine, LAG3
Abstract: Comunicación oral presentada en el 42º SEI Congreso de la Sociedad Española de Inmunología, 24-26 marzo 2021, Madrid, formato virtual.
Published: 2021

41. Expression of infiltrating bone marrow natural killer cell receptors in pediatric acute leukemia

Author: Mestre Durán, Carmen, Hidalgo, Sandra, Ferreras, Cristina, Uranga, Cecilia, Clares, Laura, Navarro Zapata, Alfonso, Calvo, Carlota, Aguilar, Yurena, Guerra-García, Pilar, Escudero, Adela, Pernas, Alicia, Gálvez Buerba, Eva Mª, Galán, Víctor, González, Berta, Ramírez-Labrada, Ariel, Pardo, Julián, and Pérez-Martínez, Antonio
Subjects: Leukemia, Bone marrow, NK cells
Abstract: of the poster presented at SIOP 2021, the 53th Annual Congress of the International Society of Pediatric Oncology, Virtual, 21-24 october 2021.-- E-Poster Topic: Disease Orientated / AS01 Haematology / AS01.a Acute Lymphoblastic Leukaemia.-- PV0061 / #709.
Published: 2021

42. Estudio fenotípico de células NK infiltradas en médula ósea (BiNK) en pacientes pediátricos con leucemia aguda

Author: Mestre Durán, Carmen, Hidalgo, Sandra, Ferreras, Cristina, Uranga, Cecilia, Navarro Zapata, Alfonso, Calvo, Carlota, Clares, Laura, Martín-Cortázar, Carla, Aguilar, Yurena, Al-akioui, Karima, Escudero, Adela, Pernas, Alicia, Galán, Víctor, Guerra-García, Pilar, Gálvez Buerba, Eva Mª, González, Berta, Ramírez-Labrada, Ariel, Pardo, Julián, and Pérez-Martínez, Antonio
Subjects: Médula ósea, NK células, Cancer
Abstract: 3 figuras.-- Comunicación oral presentada en el LXIII Congreso Nacional de la SEHH (Sociedad Española de Hematología y Hemoterapia) y XXXVII Congreso Nacional de la SETH (Sociedad Española de Trombosis y Hemostasia), Pamplona, 14-16 Octubre 2021. [Introducción] La leucemia es el cáncer más común en la población pediátrica. Aproximadamente el 20% de los pacientes con leucemia linfoide aguda (LLA) y el 40% con leucemia mieloide aguda (LMA) recaen de la enfermedad. Es de vital importancia en el contexto de la recaída el estudio de la pérdida de la inmunovigilancia y el papel que presentan las células NK en este contexto. Para tratar de disminuir las tasas de recaída de la enfermedad. El objetivo de este estudio es evaluar el fenotipo y papel de las células NK infiltradas en médula ósea (BiNK) en pacientes con LLA y LMA. [Métodos] Se recogieron células mononucleares de médula ósea (BMMCs) procedentes de pacientes pediátricos con LLA-B (n=16) y LMA (n=4) en el Hospital Universitario La Paz. Se monitorizaron y analizaron las BiNK en el diagnóstico, seguimiento y recaída de la enfermedad. Se analizó su fenotipo mediante citometría de flujo, comprobando la expresión en superficie de los siguientes receptores activadores e inhibidores: CD56, CD3, CD16, NKG2D, NKp44, NKp46, CD69, CD57, TIM-3, LAG- 3, PD-1. Se examinaron también 3 ligandos de las células BiNK presentes en las células blásticas de los pacientes: PD-1, LAG-3 y TIM-3. Se estudió además la capacidad funcional de las células BiNK a través del ensayo de degranulación CD107a, por citometría de flujo. [Resultados] Los pacientes con LLA mostraron niveles similares de células BiNK en las diferentes fases del estudio, mientras que los pacientes con LMA presentaron una menor infiltración de las células BiNK durante el seguimiento y recaída de la enfermedad (Figura 1). Al diagnóstico se observa una alta expresión de los receptores activadores NKp46, NKG2D y CD57, mientras que los receptores inhibidores muestran una baja expresión en LLA y LMA. Los ligandos de los receptores inhibidores de células BiNK se encuentran altamente expresados en las células blásticas en pacientes con LLA y LMA (Figura 2). Durante el seguimiento de la enfermedad, la subpoblación CD56+ CD16- en las células BiNK de pacientes con LMA presentan una reducción de los receptores activadores. En el contexto de la recaída, las células BiNK muestran una expresión disminuida de NKG2D en pacientes con LLA y LMA. Los receptores inhibidores mantienen una expresión baja a excepción la LMA en recaída, donde se observa un aumento de la expresión de TIM-3 en las células BiNK. Esto se corresponde con una elevada expresión de su ligando, Galectina-9, en las células blásticas. No obstante, los ligandos analizados disminuyen respecto al diagnóstico en los pacientes con LLA, a excepción de Galectina-9. La capacidad degranulativa de las células BiNK se mantiene en los pacientes con LLA y LMA en recaída respecto al diagnóstico (Figura 3). [Conclusión] Las células BiNK procedentes de pacientes con leucemia aguda muestran gran heterogeneidad en la expresión de receptores. Los pacientes con LMA presentan una menor infiltración de células BiNK, así como una escasa capacidad degranulativa en el diagnóstico y recaída de la enfermedad.
Published: 2021

43. Traitement des infections ou maladies fongiques

Author: Hurtado-Guerrero, R., Pardo, Julián, Gálvez Buerba, Eva Mª, Arroyo Nombela, Francisco Javier, and Muyldermans, Serge
Abstract: The present invention refers to the treatment of fungal infections or diseases by using specific affinity reagents, such as nanobodies, which specifically bind the fungal β-1,3-glucanosyltransferase gel4., Universidad de Zaragoza, Fundación Agencia Aragonesa para la Investigación y el Desarrollo (ARAID), Universidad Complutense de Madrid, Vrije Universiteit Brussel, Consejo Superior de Investigaciones Científicas, A1 Solicitud de patente con informe sobre el estado de la técnica
Published: 2020

44. Analysis of the inflammatory cytokine and cell immunity profile in blood that predicts disease severity in COVID-19 patients

Author: Hidalgo, Sandra, Morte Romea, Elena, Pesini, Cecilia, Uranga Murillo, Iratxe, Sierra Monzón, José L., Martínez Lázaro, Beatriz, Paño, José Ramón, Gálvez Buerba, Eva Mª, Pardo, Julián, Hidalgo, Sandra, Morte Romea, Elena, Pesini, Cecilia, Uranga Murillo, Iratxe, Sierra Monzón, José L., Martínez Lázaro, Beatriz, Paño, José Ramón, Gálvez Buerba, Eva Mª, and Pardo, Julián
Published: 2021

45. Preparations for invasion: modulation of host lung immunity during pulmonary aspergillosis by gliotoxin and other fungal secondary metabolites

Author: European Commission, Gobierno de Aragón, Asociación de Padres de Niños con Cáncer de Aragón, Ministerio de Economía y Competitividad (España), Instituto de Salud Carlos III, Arias, Maykel [0000-0002-9730-2210], Santiago, Llipsy [0000-0002-1861-5981], Vidal-García, Matxalen [0000-0002-3551-7320], Lanuza, Pilar M. [0000-0001-7328-2094], Rezusta, Antonio [0000-0001-7294-245X], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Arias, Maykel, Santiago, Llipsy, Vidal-García, Matxalen, Redrado, Sergio, Lanuza, Pilar M., Comas, Laura, Domingo, María Pilar, Rezusta, Antonio, Gálvez Buerba, Eva Mª, European Commission, Gobierno de Aragón, Asociación de Padres de Niños con Cáncer de Aragón, Ministerio de Economía y Competitividad (España), Instituto de Salud Carlos III, Arias, Maykel [0000-0002-9730-2210], Santiago, Llipsy [0000-0002-1861-5981], Vidal-García, Matxalen [0000-0002-3551-7320], Lanuza, Pilar M. [0000-0001-7328-2094], Rezusta, Antonio [0000-0001-7294-245X], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Arias, Maykel, Santiago, Llipsy, Vidal-García, Matxalen, Redrado, Sergio, Lanuza, Pilar M., Comas, Laura, Domingo, María Pilar, Rezusta, Antonio, and Gálvez Buerba, Eva Mª
Abstract: Pulmonary aspergillosis is a severe infectious disease caused by some members of the Aspergillus genus, that affects immunocompetent as well as immunocompromised patients. Among the different disease forms, Invasive Aspergillosis is the one causing the highest mortality, mainly, although not exclusively, affecting neutropenic patients. This genus is very well known by humans, since different sectors like pharmaceutical or food industry have taken advantage of the biological activity of some molecules synthetized by the fungus, known as secondary metabolites, including statins, antibiotics, fermentative compounds or colorants among others. However, during infection, in response to a hostile host environment, the fungal secondary metabolism is activated, producing different virulence factors to increase its survival chances. Some of these factors also contribute to fungal dissemination and invasion of adjacent and distant organs. Among the different secondary metabolites produced by Aspergillus spp. Gliotoxin (GT) is the best known and better characterized virulence factor. It is able to generate reactive oxygen species (ROS) due to the disulfide bridge present in its structure. It also presents immunosuppressive activity related with its ability to killmammalian cells and/or inactivate critical immune signaling pathways like NFkB. In this comprehensive review, we will briefly give an overview of the lung immune response against Aspergillus as a preface to analyse the effect of different secondary metabolites on the host immune response, with a special attention to GT. We will discuss the results reported in the literature on the context of the animal models employed to analyse the role of GT as virulence factor, which is expected to greatly depend on the immune status of the host: why should you hide when nobody is seeking for you? Finally, GT immunosuppressive activity will be related with different human diseases predisposing to invasive aspergillosis in order to h
Published: 2018

46. Expansion of allogeneic NK cells with efficient antibody-dependent cell cytotoxicity against multiple tumors

Author: Université de Montpellier, Ligue Nationale contre le Cancer (France), Institut National du Cancer (France), Université de Tours, Institut National de la Santé et de la Recherche Médicale (France), Centre National de la Recherche Scientifique (France), Institut National de la Recherche Agronomique (France), Centre Hospitalier Régional Universitaire de Tours, Institut du Cancer de Montpellier, European Commission, Région Occitanie / Pyrénées-Méditerranée, Ministerio de Economía y Competitividad (España), Centre Hospitalier Régional Universitaire de Montpellier, Allende-Vega, Nerea [0000-0001-5569-6461], Orecchioni, Stefania [0000-0002-6781-7002], Talarico, Giovanna [0000-0001-5051-6468], Anel Bernal, Luis Alberto [0000-0002-5175-8394], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Martineau, Pierre [0000-0002-7993-7183], Bertolini, Francesco [0000-0001-5660-3255], Cartron, Guillaume [0000-0003-0659-9635], Villalba, Martín [0000-0002-4385-4888], Sánchez-Martínez, Diego, Allende-Vega, Nerea, Orecchioni, Stefania, Talarico, Giovanna, Cornillon, Amelie, Vo, Dang-Nghiem, Rene, Celine, Lu, Zhao-Yang, Krzywinska, Ewelina, Anel Bernal, Luis Alberto, Gálvez Buerba, Eva Mª, Pardo, Julián, Robert, Bruno, Martineau, Pierre, Hicheri, Yosr, Bertolini, Francesco, Cartron, Guillaume, Villalba, Martín, Université de Montpellier, Ligue Nationale contre le Cancer (France), Institut National du Cancer (France), Université de Tours, Institut National de la Santé et de la Recherche Médicale (France), Centre National de la Recherche Scientifique (France), Institut National de la Recherche Agronomique (France), Centre Hospitalier Régional Universitaire de Tours, Institut du Cancer de Montpellier, European Commission, Région Occitanie / Pyrénées-Méditerranée, Ministerio de Economía y Competitividad (España), Centre Hospitalier Régional Universitaire de Montpellier, Allende-Vega, Nerea [0000-0001-5569-6461], Orecchioni, Stefania [0000-0002-6781-7002], Talarico, Giovanna [0000-0001-5051-6468], Anel Bernal, Luis Alberto [0000-0002-5175-8394], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Martineau, Pierre [0000-0002-7993-7183], Bertolini, Francesco [0000-0001-5660-3255], Cartron, Guillaume [0000-0003-0659-9635], Villalba, Martín [0000-0002-4385-4888], Sánchez-Martínez, Diego, Allende-Vega, Nerea, Orecchioni, Stefania, Talarico, Giovanna, Cornillon, Amelie, Vo, Dang-Nghiem, Rene, Celine, Lu, Zhao-Yang, Krzywinska, Ewelina, Anel Bernal, Luis Alberto, Gálvez Buerba, Eva Mª, Pardo, Julián, Robert, Bruno, Martineau, Pierre, Hicheri, Yosr, Bertolini, Francesco, Cartron, Guillaume, and Villalba, Martín
Abstract: Monoclonal antibodies (mAbs) have significantly improved the treatment of certain cancers. However, in general mAbs alone have limited therapeutic activity. One of their main mechanisms of action is to induce antibody-dependent cell-mediated cytotoxicity (ADCC), which is mediated by natural killer (NK) cells. Unfortunately, most cancer patients have severe immune dysfunctions affecting NK activity. This can be circumvented by the injection of allogeneic, expanded NK cells, which is safe. Nevertheless, despite their strong cytolytic potential against different tumors, clinical results have been poor. Methods: We combined allogeneic NK cells and mAbs to improve cancer treatment. We generated expanded NK cells (e-NK) with strong in vitro and in vivo ADCC responses against different tumors and using different therapeutic mAbs, namely rituximab, obinutuzumab, daratumumab, cetuximab and trastuzumab. Results: Remarkably, e-NK cells can be stored frozen and, after thawing, armed with mAbs. They mediate ADCC through degranulation-dependent and -independent mechanisms. Furthermore, they overcome certain anti-apoptotic mechanisms found in leukemic cells. Conclusion: We have established a new protocol for activation/expansion of NK cells with high ADCC activity. The use of mAbs in combination with e-NK cells could potentially improve cancer treatment.
Published: 2018

47. Efecto de nanopartículas de oro sobre el microambiente inmunológico tumoral

Author: Comas, Laura, Uranga Murillo, Iratxe, Artiga, Álvaro, Serrano, Inés, Arias, Maykel, Fuente, Jesús M. de la, Pardo, Julián, and Gálvez Buerba, Eva Mª
Subjects: Cancer microenvironment, Inflammation, Inflamación, Microambiente tumoral, Gold nanoparticles, Nanopartículas de oro, Nanopartículas poliméricas, Polymeric nanoparticles
Abstract: Trabajo presentado en el III Workshop de NanoOncología, 14-15 de Enero de 2020, en la Facultad de Medicina de la Universidad de Zaragoza (España).
Published: 2020

48. Nuevas dianas terapéuticas en sepsis

Author: Arias, Maykel, Garzón, Marcela, Comas, Laura, Uranga Murillo, Iratxe, Santiago, Llipsy, Pardo, Julián, and Gálvez Buerba, Eva Mª
Subjects: Granzimas, Biomarcadores, Sepsis, Peritoneal sepsis
Abstract: Trabajo presentado en el III Workshop NanoOncología en Zaragoza, celebrado del 14 al 15 de enero de 2020, en la Facultad de Medicina de la Universidad de Zaragoza.
Published: 2020

49. Desarrollo de un nuevo nanobody frente a infecciones por Aspergillus fumigatus y otros mohos oportunistas

Author: Redrado, Sergio, Macías, Javier, Castro-López, Jorge, Esteban, Patricia, Comas, Laura, Arias, Maykel, Rezusta, Antonio, Hurtado-Guerrero, R., Pardo, Julián, and Gálvez Buerba, Eva Mª
Subjects: Cryptococcus, Aspergillus, Nanobody
Abstract: Trabajo presentado en el III Workshop NanoOncología en Zaragoza, celebrado del 14 al 15 de enero de 2020, en la Facultad de Medicina de la Universidad de Zaragoza.
Published: 2020

50. Utilidad clínica del biomarcador bismetilgliotoxina para el manejo de pacientes en riesgo de infección viral después del trasplante de progenitores hematopoyético alogénico

Author: Vallejo, Miren, Viguria, M. Cruz, Zudaire Ripa, Teresa, Solán, Laura, Gayoso, J., Champ, Diana, Domingo, María Pilar, Redrado, Sergio, Gálvez Buerba, Eva Mª, Fernández-Irigoyen, Joaquín, Santamaría, Enrique, Ostiz, Ainhoa, Rojas, Elvira, Ibáñez Beroiz, Berta, Sánchez, María Piva, Zabalza, Amaya, and Ramírez, Natalia
Subjects: Biomarcadores, Bismetilgliotoxina, Trasplante de progenitores hematopoyéticos
Abstract: 2 tablas.-- PO-195.-- Póster presentado en el LXII Congreso Nacional de la SEHH XXXVI Congreso Nacional de la SETH, Virtual, 26-30 de octubre, 2020., Gliotoxina (GT) es la toxina producida mayoritariamentepor las cepas de Aspergillus fumigatus(AF). Bismetil-gliotoxina (bmGT),metabolito secundario y de mayor estabilidad que GT, se ha detectadoen el suero de pacientes con infección fúngica invasiva (IFI) y constituyeun marcador más sensible y específico que el galactomanano (GM) enel diagnóstico de IFI. Estudios in vitro han demostrado que entre las fun-ciones inmunosupresoras de la GT está la de bloquear la función fisi-ológica de los linfocitos T (LT). El objetivo del estudio es identificar lapresencia de bmGT en pacientes que reciben un trasplante de progen-itores hematopoyéticos alogénico (alo-TPH) y conocer su potencial in-munoregulador sobre la funcionalidad de los LT anti-virales de estospacientes.
Published: 2020

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