Author: "Santiago, Llipsy" - Searchworks@Jio Institute Digital Library Search Results

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145 results on '"Santiago, Llipsy"'

1. Seroprevalence of anti-SARS-CoV-2 antibodies in household domestic ferrets (Mustela putorius furo) in Spain, 2019–2023

Author: Giner, Jacobo, Lebrero, María Eugenia, Trotta, Michele, Rueda, Pablo, Vilalta, Laura, Verde, Maite, Hurtado-Guerrero, Ramón, Pardo, Julián, Lacasta, Delia, Santiago, Llipsy, Arias, Maykel, Peña-Fresneda, Natacha, Montesinos, Andrés, Pérez, María D., Fernández, Antonio, and Villanueva-Saz, Sergio
Published: 2024
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2. The dynamics of neutralizing antibodies against SARS-CoV-2 in cats naturally exposed to virus reveals an increase in antibody activity after re-infection

Author: Villanueva-Saz, Sergio, Martínez, Marivi, Rueda, Pablo, Bolea, Sara, Pérez, María Dolores, Verde, Maite, Yzuel, Andrés, Hurtado-Guerrero, Ramón, Pardo, Julián, Santiago, Llipsy, Fernández, Antonio, and Arias, Maykel
Published: 2023
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3. A cross-sectional serosurvey of SARS-CoV-2 and co-infections in stray cats from the second wave to the sixth wave of COVID-19 outbreaks in Spain

Author: Villanueva-Saz, Sergio, Martínez, Mariví, Giner, Jacobo, González, Ana, Tobajas, Ana Pilar, Pérez, María Dolores, Lira-Navarrete, Erandi, González-Ramírez, Andrés Manuel, Macías-León, Javier, Verde, Maite, Yzuel, Andrés, Hurtado-Guerrero, Ramón, Arias, Maykel, Santiago, Llipsy, Aguiló-Gisbert, Jordi, Ruíz, Héctor, Lacasta, Delia, Marteles, Diana, and Fernández, Antonio
Published: 2023
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4. 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

5. 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

6. 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

7. The dynamics of neutralizing antibodies against SARS-CoV-2 in cats naturally exposed to virus reveals an increase in antibody activity after re-infection

Author: ARAID Foundation, Ministerio de Ciencia, Innovación y Universidades (España), Gobierno de Aragón, European Commission, Instituto de Salud Carlos III, Fundación Banco Santander, Universidad de Zaragoza, Agencia Estatal de Investigación (España), Villanueva-Saz, Sergio [0000-0001-6209-4282], Pardo, Julián [0000-0003-0154-0730], Santiago, Llipsy [0000-0002-1861-5981], Fernández Casanovas, Antonio [0000-0002-2557-4890], Arias, Maykel [0000-0002-9730-2210], Villanueva-Saz, Sergio, Martínez, Mariví, Rueda, Pablo, Bolea, Sara, Pérez, María Dolores, Verde, Maite, Yzuel, Andrés, Hurtado-Guerrero, R., Pardo, Julián, Santiago, Llipsy, Fernández Casanovas, Antonio, Arias, Maykel, ARAID Foundation, Ministerio de Ciencia, Innovación y Universidades (España), Gobierno de Aragón, European Commission, Instituto de Salud Carlos III, Fundación Banco Santander, Universidad de Zaragoza, Agencia Estatal de Investigación (España), Villanueva-Saz, Sergio [0000-0001-6209-4282], Pardo, Julián [0000-0003-0154-0730], Santiago, Llipsy [0000-0002-1861-5981], Fernández Casanovas, Antonio [0000-0002-2557-4890], Arias, Maykel [0000-0002-9730-2210], Villanueva-Saz, Sergio, Martínez, Mariví, Rueda, Pablo, Bolea, Sara, Pérez, María Dolores, Verde, Maite, Yzuel, Andrés, Hurtado-Guerrero, R., Pardo, Julián, Santiago, Llipsy, Fernández Casanovas, Antonio, and Arias, Maykel
Abstract: Severe Acute Respiratory Syndrome Coronavirus 2 is the causative agent of Coronavirus Disease 2019 in humans. To date, little is known about the persistence of antibodies against SARS-CoV-2 in animals under natural conditions, in particular susceptible pets such as cat. This study reports the detection and monitoring of the humoral response against SARS-CoV-2 including the detection of immunoglobulins G specific for receptor binding domain of SARS-CoV-2 spike protein by an enzyme-linked immunosorbent assay and neutralizing antibodies by virus neutralization assay. Results showed that these antibodies last longer than 16 months in two naturally apparently healthy infected cats with the absence of clinicopathological findings during the follow-up. Moreover, re-infection is also possible with an important increase in virus neutralization test titers in both animals with no evident systemic signs found during each physical examination and with values of hematologic and biochemical parameters inside the normal reference intervals. Our results confirm a slow but progressive decrease of the kinetics and immunity of neutralizing antibodies in cats after the infection. Furthermore, similar to humans SARS-CoV-2 reinfection can stimulate an increase of the neutralizing antibodies determined by these two serological techniques in domestic cats.
Published: 2023

8. Seroprevalence of anti-SARS-CoV-2 antibodies in household domestic ferrets (Mustela putorius furo) in Spain, 2019–2023

Author: Giner, Jacobo, primary, Lebrero, María Eugenia, additional, Trotta, Michele, additional, Rueda, Pablo, additional, Vilalta, Laura, additional, Verde, Maite, additional, Hurtado-Guerrero, Ramón, additional, Pardo, Julián, additional, Lacasta, Delia, additional, Santiago, Llipsy, additional, Arias, Maykel, additional, Peña-Fresneda, Natacha, additional, Montesinos, Andrés, additional, Pérez, María D., additional, Fernández, Antonio, additional, and Villanueva-Saz, Sergio, additional
Published: 2023
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9. The Untold Story of Granzymes in Oncoimmunology: Novel Opportunities with Old Acquaintances

Author: Arias, Maykel, Martínez-Lostao, Luis, Santiago, Llipsy, Ferrandez, Angel, Granville, David J., and Pardo, Julián
Published: 2017
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10. 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

11. 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

12. 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

13. 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

14. Antigen-specific primed cytotoxic T cells eliminate tumour cells in vivo and prevent tumour development, regardless of the presence of anti-apoptotic mutations conferring drug resistance

Author: Jaime-Sánchez, Paula, Catalán, Elena, Uranga-Murillo, Iratxe, Aguiló, Nacho, Santiago, Llipsy, M Lanuza, Pilar, de Miguel, Diego, A Arias, Maykel, and Pardo, Julián
Published: 2018
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15. Granzyme-A deficiency attenuates experimental osteoarthritis in mice, but perforin deficiency does not

Author: Calvo, Jorge, primary, Santiago, Llipsy, additional, Arias, Maykel, additional, Pardo, Julián, additional, Albareda, Jorge, additional, Martínez-Lostao, Luis, additional, and García-Alvarez, Felícito, additional
Published: 2023
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16. Granzyme-A deficiency attenuates experimental osteoarthritis in mice, but perforin deficiency does not

Author: Universidad de Zaragoza, European Commission, Gobierno de Aragón, Agencia Estatal de Investigación (España), Ministerio de Ciencia, Innovación y Universidades (España), Ministerio de Ciencia e Innovación (España), Instituto de Salud Carlos III, Calvo Ibar, Jorge, Santiago, Llipsy, Arias, Maykel, Pardo, Julián, Albareda, Jorge, Martínez-Lostao, Luis, García-Alvarez, Felícito, Universidad de Zaragoza, European Commission, Gobierno de Aragón, Agencia Estatal de Investigación (España), Ministerio de Ciencia, Innovación y Universidades (España), Ministerio de Ciencia e Innovación (España), Instituto de Salud Carlos III, Calvo Ibar, Jorge, Santiago, Llipsy, Arias, Maykel, Pardo, Julián, Albareda, Jorge, Martínez-Lostao, Luis, and García-Alvarez, Felícito
Abstract: [Objectives]: This study aims to assess the development of osteoarthritis (OA) in granzyme A- (gzmA) and B- (gzmB) and perforin- (perf) knockout mice., [Materials and methods]: A total of 75 male and female C57BL/6 (eight to nine-week-old) mice were allocated to: gzmA-deficient (gzmA-/-) (11 females, 8 males), gzmB-deficient (gzmB-/-) (9 females, 8 males), perf-deficient (perf-/-) (10 females, 9 males), and control group (10 females, 10 males). Osteoarthritis was induced in the right knee by instability of the meniscus medial ligament. Sham surgery was practiced in the left knee. Knee samples obtained eight weeks after surgery were stained (Safranin-O) and blindly scored in lateral and medial femur and tibia using the Osteoarthritis Research Society International scale (OARSI) (from Grade 0, cartilage intact to 6, deformation), (five stages from 0, no OA to 4, >50% surface involvement); OARSI score (grade x stage); and a semi-quantitative scale from Grade 0 (normal) to 6 (cartilage erosion >80%)., [Results]: Significantly higher values in all scales in the right knees compared to the left knees in male and female mice were observed (p<0.05). Males of all strains showed in the right knee higher values than females on all scales. Deficiency of perforin did not modify OA severity in any sex. The gzmA-/- females presented less degenerative changes than the other groups., [Conclusion]: Our study results show that sex plays an important role in the development of experimental OA in mice. Deficiency of gzmA can protect from the development of OA in female mice.
Published: 2023

17. Mouse Model of Colitis-Associated Colorectal Cancer (CAC): Isolation and Characterization of Mucosal-Associated Lymphoid Cells

Author: Santiago, Llipsy, primary, Castro, Marta, additional, Pardo, Julián, additional, and Arias, Maykel, additional
Published: 2018
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18. Hemizygous Granzyme A Mice Expressing the hSOD1G93A Transgene Show Slightly Extended Lifespan

Author: Moreno-Martinez, Laura, primary, Santiago, Llipsy, additional, de la Torre, Miriam, additional, Calvo, Ana Cristina, additional, Pardo, Julián, additional, and Osta, Rosario, additional
Published: 2022
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19. A cross-sectional serosurvey of SARS-CoV-2 and co-infections in stray cats from the second wave to the sixth wave of COVID-19 outbreaks in Spain

Author: Villanueva-Saz, Sergio, primary, Martínez, Mariví, additional, Giner, Jacobo, additional, González, Ana, additional, Tobajas, Ana Pilar, additional, Pérez, María Dolores, additional, Lira-Navarrete, Erandi, additional, González-Ramírez, Andrés Manuel, additional, Macías-León, Javier, additional, Verde, Maite, additional, Yzuel, Andrés, additional, Hurtado-Guerrero, Ramón, additional, Arias, Maykel, additional, Santiago, Llipsy, additional, Aguiló-Gisbert, Jordi, additional, Ruíz, Héctor, additional, Lacasta, Delia, additional, Marteles, Diana, additional, and Fernández, Antonio, additional
Published: 2022
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20. 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

21. 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

22. 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

23. 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

24. No Evidence of SARS-CoV-2 Infection in Wild Mink (Mustela lutreola and Neogale vison) from Northern Spain during the First Two Years of Pandemic

Author: Villanueva-Saz, Sergio, primary, Giner, Jacobo, additional, Palomar, Ana María, additional, Gómez, María Asunción, additional, Põdra, Madis, additional, Aranda, María del Carmen, additional, Jiménez, María de los Ángeles, additional, Lizarraga, Patricia, additional, Hernández, Raquel, additional, Portillo, Aránzazu, additional, Oteo, José Antonio, additional, Ruíz-Arrondo, Ignacio, additional, Pérez, María Dolores, additional, Tobajas, Ana Pilar, additional, Verde, Maite, additional, Lacasta, Delia, additional, Marteles, Diana, additional, Hurtado-Guerrero, Ramón, additional, Santiago, Llipsy, additional, Ruíz, Héctor, additional, and Fernández, Antonio, additional
Published: 2022
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25. PD-1 is expressed in cytotoxic granules of NK cells and rapidly mobilized to the cell membrane following recognition of tumor cells

Author: Pesini, Cecilia, primary, Hidalgo, Sandra, additional, Arias, Maykel A., additional, Santiago, Llipsy, additional, Calvo, Carlota, additional, Ocariz-Díez, Maitane, additional, Isla, Dolores, additional, Lanuza, Pilar M., additional, Agustín, M José, additional, Galvez, Eva M, additional, Ramírez-Labrada, Ariel, additional, and Pardo, Julián, additional
Published: 2022
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26. 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: Lanuza, Pilar M., primary, Alonso, M. Henar, additional, Hidalgo, Sandra, additional, Uranga-Murillo, Iratxe, additional, García-Mulero, Sandra, additional, Arnau, Raquel, additional, Santos, Cristina, additional, Sanjuan, Xavier, additional, Santiago, Llipsy, additional, Comas, Laura, additional, Redrado, Sergio, additional, Pazo-Cid, Roberto, additional, Agustin-Ferrández, M. Jose, additional, Jaime-Sánchez, Paula, additional, Pesini, Cecilia, additional, Gálvez, Eva M., additional, Ramírez-Labrada, Ariel, additional, Arias, Maykel, additional, Sanz-Pamplona, Rebeca, additional, and Pardo, Julián, additional
Published: 2022
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27. 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

28. No Evidence of SARS-CoV-2 Infection in Wild Mink (Mustela lutreola and Neogale vison) from Northern Spain during the First Two Years of Pandemic

Author: Villanueva-Saz, Sergio, Giner, Jacobo, Palomar, Ana María, Gómez, María Asunción, Põdra, Madis, Aranda, María del Carmen, Jiménez Martínez, María De Los Ángeles, Lizarraga, Patricia, Hernández, Raquel, Portillo, Aránzazu, Oteo, José Antonio, Ruíz-Arrondo, Ignacio, Pérez Alenza, María De Los Dolores, Tobajas, Ana Pilar, Verde, Maite, Lacasta, Delia, Marteles, Diana, Hurtado-Guerrero, Ramón, Santiago, Llipsy, Ruíz, Héctor, Fernández, Antonio, Villanueva-Saz, Sergio, Giner, Jacobo, Palomar, Ana María, Gómez, María Asunción, Põdra, Madis, Aranda, María del Carmen, Jiménez Martínez, María De Los Ángeles, Lizarraga, Patricia, Hernández, Raquel, Portillo, Aránzazu, Oteo, José Antonio, Ruíz-Arrondo, Ignacio, Pérez Alenza, María De Los Dolores, Tobajas, Ana Pilar, Verde, Maite, Lacasta, Delia, Marteles, Diana, Hurtado-Guerrero, Ramón, Santiago, Llipsy, Ruíz, Héctor, and Fernández, Antonio
Abstract: The impact of the SARS-CoV-2 pandemic on wildlife is largely unevaluated, and extended surveillance of animal species is needed to reach a consensus on the role of animals in the emergence and maintenance of SARS-CoV-2. This infection has been detected in farmed and domestic animals and wild animals, mainly in captivity. The interactions or shared resources with wildlife could represent a potential transmission pathway for the SARS-CoV-2 spill over to other wild species and could lead to health consequences or the establishment of new reservoirs in susceptible hosts. This study evaluated the presence of SARS-CoV-2 in European mink (Mustela lutreola) and American mink (Neogale vison) in Spain by enzyme-linked immunosorbent assay (ELISA) using the receptor binding domain (RBD) of Spike antigen in serum samples and/or by RT-qPCR assays in oropharyngeal and rectal swabs. From January 2020 to February 2022, a total of 162 animals (127 European mink and 35 American mink) with no evidence of SARS-CoV-2 infection were included in the study. Antibodies against the SARS-CoV-2 were not found in the serum samples analysed (n = 126), nor was the virus amplified by RT-qPCR (n = 160 swabs). Our results suggest that the potential role of wild mink and the European mink bred in captivity and released to the wild as dispersers of SARS-CoV-2 is so far low. However, wildlife surveillance for early detection of human and animal risks should be continued. In this sense, epidemiological monitoring measures, including serology and molecular analysis, are necessary., Depto. de Medicina y Cirugía Animal, Fac. de Veterinaria, TRUE, pub
Published: 2022

29. Serological evidence of SARS-CoV-2 and co-infections in stray cats in Spain

Author: Villanueva-Saz, Sergio, Giner, Jacobo, Tobajas, Ana Pilar, Pérez, María Dolores, González-Ramírez, Andrés Manuel, Macías-León, Javier, González, Ana, Verde, Maite, Yzuel, Andrés, Hurtado-Guerrero, Ramón, Pardo, Julián, Santiago, Llipsy, Paño-Pardo, José Ramón, Ruíz, Héctor, Lacasta, Delia María, Sánchez, Lourdes, Marteles, Diana, Gracia, Ana Pilar, Fernández, Antonio, Villanueva-Saz, Sergio, Giner, Jacobo, Tobajas, Ana Pilar, Pérez, María Dolores, González-Ramírez, Andrés Manuel, Macías-León, Javier, González, Ana, Verde, Maite, Yzuel, Andrés, Hurtado-Guerrero, Ramón, Pardo, Julián, Santiago, Llipsy, Paño-Pardo, José Ramón, Ruíz, Héctor, Lacasta, Delia María, Sánchez, Lourdes, Marteles, Diana, Gracia, Ana Pilar, and Fernández, Antonio
Abstract: A new coronavirus known as SARS-CoV-2 emerged in Wuhan in 2019 and spread rapidly to the rest of the world causing the pandemic disease named coronavirus disease of 2019 (COVID-19). Little information is known about the impact this virus can cause upon domestic and stray animals. The potential impact of SARS-CoV-2 has become of great interest in cats due to transmission among domestic cats and the severe phenotypes described recently in a domestic cat. In this context, there is a public health warning that needs to be investigated in relation with the epidemiological role of this virus in stray cats. Consequently, in order to know the impact of the possible transmission chain, blood samples were obtained from 114 stray cats in the city of Zaragoza (Spain) and tested for SARS-CoV-2 and other selected pathogens susceptible to immunosuppression including Toxoplasma gondii, Leishmania infantum, feline leukaemia virus (FeLV) and feline immunodeficiency virus (FIV) from January to October 2020. Four cats (3.51%), based on enzyme-linked immunosorbent assay (ELISA) using the receptor binding domain (RBD) of Spike antigen, were seroreactive to SARS-CoV-2. T. gondii, L. infantum, FeLV and FIV seroprevalence was 12.28%, 16.67%, 4.39% and 19.30%, respectively. Among seropositive cats to SARS-CoV-2, three cats were also seropositive to other pathogens including antibodies detected against T. gondii and FIV (n = 1); T. gondii (n = 1); and FIV and L. infantum (n = 1). The subjects giving positive for SARS-CoV-2 were captured in urban areas of the city in different months: January 2020 (2/4), February 2020 (1/4) and July 2020 (1/4). This study revealed, for the first time, the exposure of stray cats to SARS-CoV-2 in Spain and the existence of concomitant infections with other pathogens including T. gondii, L. infantum and FIV, suggesting that immunosuppressed animals might be especially susceptible to SARS-CoV-2 infection.
Published: 2022

30. Granzyme A Contributes to Inflammatory Arthritis in Mice Through Stimulation of Osteoclastogenesis

Author: Santiago, Llipsy, Menaa, Cheikh, Arias, Maykel, Martin, Praxedis, JaimeSánchez, Paula, Metkar, Sunil, Comas, Laura, Erill, Nadina, GonzalezRumayor, Victor, Esser, Erica, Galvez, Eva M., Raja, Sri, Simon, Markus M., Sprague, Stuart M., Gabay, Cem, MartinezLostao, Luis, Pardo, Julian, and Froelich, Christopher J.
Published: 2017
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31. All About (NK Cell-Mediated) Death in Two Acts and an Unexpected Encore: Initiation, Execution and Activation of Adaptive Immunity

Author: Ramírez-Labrada, Ariel, primary, Pesini, Cecilia, additional, Santiago, Llipsy, additional, Hidalgo, Sandra, additional, Calvo-Pérez, Adanays, additional, Oñate, Carmen, additional, Andrés-Tovar, Alejandro, additional, Garzón-Tituaña, Marcela, additional, Uranga-Murillo, Iratxe, additional, Arias, Maykel A., additional, Galvez, Eva M., additional, and Pardo, Julián, additional
Published: 2022
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32. 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

33. Integrated analysis of circulating immune cellular and soluble mediators reveals specific COVID19 signatures at hospital admission with utility for prediction of clinical outcomes

Author: Uranga-Murillo, Iratxe, primary, Morte, Elena, additional, Hidalgo, Sandra, additional, Pesini, Cecilia, additional, García-Mulero, Sandra, additional, Sierra, Jose L., additional, Santiago, Llipsy, additional, Arias, Maykel, additional, De Miguel, Diego, additional, Encabo-Berzosa, María del Mar, additional, Gracia-Tello, Borja, additional, Sanz-Pamplona, Rebeca, additional, Martinez-Lostao, Luis, additional, Galvez, Eva M., additional, Paño-Pardo, Jose R., additional, Ramirez-Labrada, Ariel, additional, and Pardo, Julian, additional
Published: 2022
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34. 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

35. Opposing roles of Granzymes A and B in the immune response to intestinal infection

Author: Vandereyken, Maud, primary, Chawla, Amanpreet Singh, additional, Arias, Maykel, additional, Santiago, Llipsy, additional, Wenner, Nicolas, additional, Thomson, Sarah, additional, Dikovskaya, Dina, additional, Nguyen, Chi, additional, Hinton, Jay C. D., additional, Pardo, Julian, additional, and Swamy, Mahima, additional
Published: 2021
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36. 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

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

Author: de Miguel, Diego, primary, Ramirez‐Labrada, Ariel, additional, Uranga, Iratxe, additional, Hidalgo, Sandra, additional, Santiago, Llipsy, additional, Galvez, Eva María, additional, Arias, Maykel, additional, and Pardo, Julián, additional
Published: 2021
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38. Absence of SARS-CoV-2 Antibodies in Natural Environment Exposure in Sheep in Close Contact with Humans

Author: Villanueva-Saz, Sergio, primary, Giner, Jacobo, additional, Fernández, Antonio, additional, Lacasta, Delia, additional, Ortín, Aurora, additional, Ramos, Juan José, additional, Ferrer, Luis Miguel, additional, Ruiz de Arcaute, Marta, additional, Tobajas, Ana Pilar, additional, Pérez, María Dolores, additional, Verde, Maite, additional, Marteles, Diana, additional, Hurtado-Guerrero, Ramón, additional, Pardo, Julián, additional, Santiago, Llipsy, additional, González-Ramírez, Andrés Manuel, additional, Macías-León, Javier, additional, García-García, Ana, additional, Taleb, Víctor, additional, Lira-Navarrete, Erandi, additional, Paño-Pardo, José Ramón, additional, and Ruíz, Héctor, additional
Published: 2021
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39. Absence of sars-cov-2 antibodies in natural environment exposure in sheep in close contact with humans

Author: Villanueva-Saz, Sergio, Giner, Jacobo, Fernández, Antonio, Lacasta, Delia, Ortín, Aurora, Ramos, Juan José, Ferrer, Luis Miguel, de Arcaute, Marta Ruiz, Tobajas, Ana Pilar, Pérez, María Dolores, Verde, Maite, Marteles, Diana, Hurtado-Guerrero, Ramón, Pardo, Julián, Santiago, Llipsy, González-Ramírez, Andrés Manuel, Macías-León, Javier, García-García, Ana, Taleb, Víctor, Lira-Navarrete, Erandi, Paño-Pardo, José Ramón, Ruíz, Héctor, Villanueva-Saz, Sergio, Giner, Jacobo, Fernández, Antonio, Lacasta, Delia, Ortín, Aurora, Ramos, Juan José, Ferrer, Luis Miguel, de Arcaute, Marta Ruiz, Tobajas, Ana Pilar, Pérez, María Dolores, Verde, Maite, Marteles, Diana, Hurtado-Guerrero, Ramón, Pardo, Julián, Santiago, Llipsy, González-Ramírez, Andrés Manuel, Macías-León, Javier, García-García, Ana, Taleb, Víctor, Lira-Navarrete, Erandi, Paño-Pardo, José Ramón, and Ruíz, Héctor
Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the zoonotic causative agent of coronavirus disease 2019 (COVID-19) that has caused a pandemic situation with millions of infected humans worldwide. Among domestic animals, there have been limited studies regarding the transmissibility and exposure to the infection in natural conditions. Some animals are exposed and/or susceptible to SARS-CoV-2 infection, such as cats, ferrets and dogs. By contrast, there is no information about the susceptibility of ruminants to SARS-CoV-2. This study tested the antibody response in 90 ovine pre-pandemic serum samples and 336 sheep serum samples from the pandemic period (June 2020 to March 2021). In both cases, the animals were in close contact with a veterinary student community composed of more than 700 members. None of the serum samples analyzed was seroreactive based on an enzyme-linked immunosorbent assay (ELISA) using the receptor-binding domain (RBD) of the spike antigen. In this sense, no statistical difference was observed compared to the pre-pandemic sheep. Our results suggest that it seems unlikely that sheep could play a relevant role in the epidemiology of SARS-CoV-2 infection. This is the first study to report the absence of evidence of sheep exposure to SARS-CoV-2 in natural conditions.
Published: 2021

40. 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: Santiago, Llipsy, Uranga-Murillo, Iratxe, Arias, Maykel, González-Ramírez, Andrés Manuel, Macías-León, Javier, Moreo, Eduardo, Redrado, Sergio, García-García, Ana, Taleb, Víctor, Lira-Navarrete, Erandi, Hurtado-Guerrero, Ramón, Aguilo, Nacho, Encabo-Berzosa, Maria Del Mar, Hidalgo, Sandra, Galvez, Eva M., Ramirez-Labrada, Ariel, de Miguel, Diego, Benito, Rafael, Miranda, Patricia, Fernández, Antonio, Domingo, José María, Serrano, Laura, Yuste, Cristina, Villanueva-Saz, Sergio, Paño-Pardo, José Ramón, Pardo, Julián, Santiago, Llipsy, Uranga-Murillo, Iratxe, Arias, Maykel, González-Ramírez, Andrés Manuel, Macías-León, Javier, Moreo, Eduardo, Redrado, Sergio, García-García, Ana, Taleb, Víctor, Lira-Navarrete, Erandi, Hurtado-Guerrero, Ramón, Aguilo, Nacho, Encabo-Berzosa, Maria Del Mar, Hidalgo, Sandra, Galvez, Eva M., Ramirez-Labrada, Ariel, de Miguel, Diego, Benito, Rafael, Miranda, Patricia, Fernández, Antonio, Domingo, José María, Serrano, Laura, Yuste, Cristina, Villanueva-Saz, Sergio, Paño-Pardo, José Ramón, and Pardo, Julián
Abstract: 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

41. Sars‐cov‐2 seroprevalence in household domestic ferrets (Mustela putorius furo)

Author: Giner, Jacobo, Villanueva‐saz, Sergio, Tobajas, Ana Pilar, Pérez, María Dolores, González, Ana, Verde, Maite, Yzuel, Andrés, García‐garcía, Ana, Taleb, Víctor, Lira‐navarrete, Erandi, Hurtado‐guerrero, Ramón, Pardo, Julián, Santiago, Llipsy, Paño, José Ramón, Ruíz, Héctor, Lacasta, Delia, Fernández, Antonio, Giner, Jacobo, Villanueva‐saz, Sergio, Tobajas, Ana Pilar, Pérez, María Dolores, González, Ana, Verde, Maite, Yzuel, Andrés, García‐garcía, Ana, Taleb, Víctor, Lira‐navarrete, Erandi, Hurtado‐guerrero, Ramón, Pardo, Julián, Santiago, Llipsy, Paño, José Ramón, Ruíz, Héctor, Lacasta, Delia, and Fernández, Antonio
Abstract: Animal infections with SARS‐CoV‐2 have been reported in different countries and several animal species have been proven to be susceptible to infection with SARS‐CoV‐2 both naturally and by experimental infection. Moreover, infections under natural conditions in more than 20 mink farms have been reported where humans could have been the source of infection for minks. However, little information is available about the susceptibility of pet animals under natural conditions and currently there is no SARS‐CoV‐2 epidemiological assessment occurrence in household ferrets. In this study, the presence of SARS‐CoV‐2 antibodies was evaluated in serum samples obtained from 127 household ferrets (Mustela putorius furo) in the Province of Valencia (Spain). Two ferrets tested positive to SARS‐CoV‐2 (1.57%) by in‐house enzyme‐linked immunosorbent assay based on receptor binding domain (RBD) of Spike antigen. Furthermore, anti‐ RBD SARS‐CoV‐2 antibodies persisted at detectable levels in a seropositive SARS‐CoV‐2 domestic ferret beyond 129 days since the first time antibodies were detected. This study reports for the first time the evidence of household pet ferrets exposure to SARS‐CoV‐2 in Spain to date.
Published: 2021

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

Author: de Miguel, Diego, Ramirez‐Labrada, Ariel, Uranga, Iratxe, Hidalgo, Sandra, Santiago, Llipsy, Galvez, Eva María, Arias, Maykel, and Pardo, Julián
Subjects: CELL death, KILLER cells, LYMPHOCYTES, CANCER cells, PYROPTOSIS, IMMUNE response
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. [ABSTRACT FROM AUTHOR]
Published: 2022
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43. Serological evidence of SARS‐CoV‐2 and co‐infections in stray cats in Spain

Author: Villanueva‐Saz, Sergio, primary, Giner, Jacobo, additional, Tobajas, Ana Pilar, additional, Pérez, María Dolores, additional, González‐Ramírez, Andrés Manuel, additional, Macías‐León, Javier, additional, González, Ana, additional, Verde, Maite, additional, Yzuel, Andrés, additional, Hurtado‐Guerrero, Ramón, additional, Pardo, Julián, additional, Santiago, Llipsy, additional, Paño‐Pardo, José Ramón, additional, Ruíz, Héctor, additional, Lacasta, Delia María, additional, Sánchez, Lourdes, additional, Marteles, Diana, additional, Gracia, Ana Pilar, additional, and Fernández, Antonio, additional
Published: 2021
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44. 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: Santiago, Llipsy, primary, Uranga-Murillo, Iratxe, additional, Arias, Maykel, additional, González-Ramírez, Andrés Manuel, additional, Macías-León, Javier, additional, Moreo, Eduardo, additional, Redrado, Sergio, additional, García-García, Ana, additional, Taleb, Víctor, additional, Lira-Navarrete, Erandi, additional, Hurtado-Guerrero, Ramón, additional, Aguilo, Nacho, additional, del Mar Encabo-Berzosa, Maria, additional, Hidalgo, Sandra, additional, Galvez, Eva M., additional, Ramirez-Labrada, Ariel, additional, de Miguel, Diego, additional, Benito, Rafael, additional, Miranda, Patricia, additional, Fernández, Antonio, additional, Domingo, José María, additional, Serrano, Laura, additional, Yuste, Cristina, additional, Villanueva-Saz, Sergio, additional, Paño-Pardo, José Ramón, additional, and Pardo, Julián, additional
Published: 2021
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45. SARS-CoV-2 Seroprevalence in Household Domestic Ferrets (Mustela putorius furo)

Author: Giner, Jacobo, primary, Villanueva-Saz, Sergio, additional, Tobajas, Ana Pilar, additional, Pérez, María Dolores, additional, González, Ana, additional, Verde, Maite, additional, Yzuel, Andrés, additional, García-García, Ana, additional, Taleb, Víctor, additional, Lira-Navarrete, Erandi, additional, Hurtado-Guerrero, Ramón, additional, Pardo, Julián, additional, Santiago, Llipsy, additional, Paño, José Ramón, additional, Ruíz, Héctor, additional, Lacasta, Delia, additional, and Fernández, Antonio, additional
Published: 2021
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46. 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

47. 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

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

Author: Garzón-Tituaña, Marcela, primary, Sierra-Monzón, José L, additional, Comas, Laura, additional, Santiago, Llipsy, additional, Khaliulina-Ushakova, Tatiana, additional, Uranga-Murillo, Iratxe, additional, Ramirez-Labrada, Ariel, additional, Tapia, Elena, additional, Morte-Romea, Elena, additional, Algarate, Sonia, additional, Couty, Ludovic, additional, Camerer, Eric, additional, Bird, Phillip I, additional, Seral, Cristina, additional, Luque, Pilar, additional, Paño-Pardo, José R, additional, Galvez, Eva M, additional, Pardo, Julián, additional, and Arias, Maykel, additional
Published: 2021
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49. Biological relevance of Granzymes A and K during E. coli sepsis

Author: Uranga-Murillo, Iratxe, primary, Tapia, Elena, additional, Garzón-Tituaña, Marcela, additional, Ramirez-Labrada, Ariel, additional, Santiago, Llipsy, additional, Pesini, Cecilia, additional, Esteban, Patricia, additional, Roig, Francisco J, additional, Galvez, Eva M, additional, Bird, Phillip I, additional, Pardo, Julián, additional, and Arias, Maykel, additional
Published: 2021
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50. Extracellular Granzyme A Promotes Colorectal Cancer Development by Enhancing Gut Inflammation

Author: Santiago, Llipsy, primary, Castro, Marta, additional, Sanz-Pamplona, Rebeca, additional, Garzón, Marcela, additional, Ramirez-Labrada, Ariel, additional, Tapia, Elena, additional, Moreno, Víctor, additional, Layunta, Elena, additional, Gil-Gómez, Gabriel, additional, Garrido, Marta, additional, Peña, Raúl, additional, Lanuza, Pilar M., additional, Comas, Laura, additional, Jaime-Sanchez, Paula, additional, Uranga-Murillo, Iratxe, additional, del Campo, Rosa, additional, Pelegrín, Pablo, additional, Camerer, Eric, additional, Martínez-Lostao, Luis, additional, Muñoz, Guillermo, additional, Uranga, José A., additional, Alcalde, Anabel, additional, Galvez, Eva M., additional, Ferrandez, Angel, additional, Bird, Phillip I., additional, Metkar, Sunil, additional, Arias, Maykel A., additional, and Pardo, Julian, additional
Published: 2020
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