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1. Impact of antibiotics, corticosteroids, and microbiota on immunotherapy efficacy in patients with non-small cell lung cancer

Author: Zapata-García, María, Moratiel-Pellitero, Alba, Isla, Dolores, Gálvez, Eva, Gascón-Ruiz, Marta, Sesma, Andrea, Barbero, Raquel, Galeano, Javier, del Campo, Rosa, Ocáriz, Maitane, Quílez, Elisa, Cruellas, Mara, Remírez-Labrada, Ariel, Pardo, Julián, Martínez-Lostao, Luis, Domingo, María Pilar, Esteban, Patricia, Torres-Ramón, Irene, Yubero, Alfonso, Paño, José Ramón, and Lastra, Rodrigo
Published: 2024
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2. Efficacy and safety of a structured de-escalation from antipseudomonal β-lactams in bloodstream infections due to Enterobacterales (SIMPLIFY): an open-label, multicentre, randomised trial

Author: De Cueto, Marina, Borreguero, Irene, Nieto Aranda, Javier, Sousa Domínguez, Adrián, González-Rico, Claudia, Fariñas, María Carmen, Fernández Ávila, María Luisa, Romero Palacios, Alberto, Guerrero Sánchez, Francisca María, Rúa Gómez, Marta, Bilbao del Olmo, Idoia, Calbo, Esther, Dietl, Beatriz, Ibarguren Pinilla, Maialen, Gómez-Ruiz de Arbulo, Marta, Torres Beceiro, Isabel, Machuca, Isabel, Cano, Ángela, Giner Oncina, Livia, Pinargote Celorio, Héctor, Cendejas, Emilio, Romero Gómez, María, Argüelles Curto, Adrián, Reguero, José María, Díaz-López, María Dolores, Paño, José Ramón, López-Cortés, Luis Eduardo, Delgado-Valverde, Mercedes, Moreno-Mellado, Elisa, Goikoetxea Aguirre, Josune, Guio Carrión, Laura, Blanco Vidal, María José, López Soria, Leyre Mónica, Pérez-Rodríguez, María Teresa, Martínez Lamas, Lucía, Arnaiz de las Revillas, Francisco, Armiñanzas, Carlos, Ruiz de Alegría-Puig, Carlos, Jiménez Aguilar, Patricia, del Carmen Martínez-Rubio, María, Sáez-Bejar, Carmen, de las Cuevas, Carmen, Martín-Aspas, Andrés, Galán, Fátima, Yuste, José Ramón, Leiva-León, José, Bou, Germán, Capón González, Patricia, Boix-Palop, Lucía, Xercavins-Valls, Mariona, Goenaga-Sánchez, Miguel Ángel, Anza, Diego Vicente, Castón, Juan José, Rufián, Manuel Recio, Merino, Esperanza, Rodríguez, Juan Carlos, Loeches, Belén, Cuervo, Guillermo, Guerra Laso, José Manuel, Plata, Antonio, Pérez Cortés, Salvador, López Mato, Pablo, Sierra Monzón, José Luis, Rosso-Fernández, Clara, Bravo-Ferrer, José María, Retamar-Gentil, Pilar, and Rodríguez-Baño, Jesús
Published: 2024
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3. 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

4. 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

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

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

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

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

7. Immune response in SARS-CoV-2 infection

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

8. Biomarkers of Immunotherapy Response in Patients with Non-Small-Cell Lung Cancer: Microbiota Composition, Short-Chain Fatty Acids, and Intestinal Permeability

Author: Moratiel-Pellitero, Alba, primary, Zapata-García, María, additional, Gascón-Ruiz, Marta, additional, Sesma, Andrea, additional, Quílez, Elisa, additional, Ramirez-Labrada, Ariel, additional, Martínez-Lostao, Luis, additional, Domingo, María Pilar, additional, Esteban, Patricia, additional, Yubero, Alfonso, additional, Barbero-Herranz, Raquel, additional, Moreno-Blanco, Ana, additional, Paño, José Ramón, additional, Lastra, Rodrigo, additional, Pardo, Julián, additional, Isla, Dolores, additional, del Campo, Rosa, additional, and Gálvez, Eva, additional
Published: 2024
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9. Efficacy and safety of a structured de-escalation from antipseudomonal β-lactams in bloodstream infections due to Enterobacterales (SIMPLIFY): an open-label, multicentre, randomised trial

Author: López-Cortés, Luis Eduardo, primary, Delgado-Valverde, Mercedes, additional, Moreno-Mellado, Elisa, additional, Goikoetxea Aguirre, Josune, additional, Guio Carrión, Laura, additional, Blanco Vidal, María José, additional, López Soria, Leyre Mónica, additional, Pérez-Rodríguez, María Teresa, additional, Martínez Lamas, Lucía, additional, Arnaiz de las Revillas, Francisco, additional, Armiñanzas, Carlos, additional, Ruiz de Alegría-Puig, Carlos, additional, Jiménez Aguilar, Patricia, additional, del Carmen Martínez-Rubio, María, additional, Sáez-Bejar, Carmen, additional, de las Cuevas, Carmen, additional, Martín-Aspas, Andrés, additional, Galán, Fátima, additional, Yuste, José Ramón, additional, Leiva-León, José, additional, Bou, Germán, additional, Capón González, Patricia, additional, Boix-Palop, Lucía, additional, Xercavins-Valls, Mariona, additional, Goenaga-Sánchez, Miguel Ángel, additional, Anza, Diego Vicente, additional, Castón, Juan José, additional, Rufián, Manuel Recio, additional, Merino, Esperanza, additional, Rodríguez, Juan Carlos, additional, Loeches, Belén, additional, Cuervo, Guillermo, additional, Guerra Laso, José Manuel, additional, Plata, Antonio, additional, Pérez Cortés, Salvador, additional, López Mato, Pablo, additional, Sierra Monzón, José Luis, additional, Rosso-Fernández, Clara, additional, Bravo-Ferrer, José María, additional, Retamar-Gentil, Pilar, additional, Rodríguez-Baño, Jesús, additional, De Cueto, Marina, additional, Borreguero, Irene, additional, Nieto Aranda, Javier, additional, Sousa Domínguez, Adrián, additional, González-Rico, Claudia, additional, Fariñas, María Carmen, additional, Fernández Ávila, María Luisa, additional, Romero Palacios, Alberto, additional, Guerrero Sánchez, Francisca María, additional, Rúa Gómez, Marta, additional, Bilbao del Olmo, Idoia, additional, Calbo, Esther, additional, Dietl, Beatriz, additional, Ibarguren Pinilla, Maialen, additional, Gómez-Ruiz de Arbulo, Marta, additional, Torres Beceiro, Isabel, additional, Machuca, Isabel, additional, Cano, Ángela, additional, Giner Oncina, Livia, additional, Pinargote Celorio, Héctor, additional, Cendejas, Emilio, additional, Romero Gómez, María, additional, Argüelles Curto, Adrián, additional, Reguero, José María, additional, Díaz-López, María Dolores, additional, and Paño, José Ramón, additional
Published: 2024
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10. A subset of PD-1-expressing CD56bright NK cells identifies patients with good response to immune checkpoint inhibitors in lung cancer

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

11. Recomendaciones GEMICOMED/GEIRAS-SEIMC para el manejo de las infecciones y colonizaciones por Candida auris

Author: Alastruey-Izquierdo, Ana, Asensio, Angel, Besoli, Anna, Calabuig, Eva, Fernández-Ruiz, Mario, Garcia-Vidal, Carolina, Gasch, Oriol, Guinea, Jesús, Martín-Gomez, María Teresa, Paño, Jose Ramón, Ramirez, Paula, Ruiz-Gaitán, Alba, Salavert, Miguel, Tasias, Mariona, Viñuela, Lourdes, and Pemán, Javier
Published: 2019
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12. Executive summary: Diagnosis and Treatment of Catheter-Related Bloodstream Infection: Clinical Guidelines of the Spanish Society of Clinical Microbiology and Infectious Diseases (SEIMC) and the Spanish Society of Intensive Care Medicine and Coronary Units (SEMICYUC)

Author: Chaves, Fernando, Garnacho-Montero, Josèc), del Pozo, Josèc) Luis, Bouza, Emilio, Capdevila, Josèc) Antonio, de Cueto, Marina, Domínguez, M. Ángeles, Esteban, Jaime, Fernández-Hidalgo, Nuria, Fernández Sampedro, Marta, Fortún, Jesús, Guembe, María, Lorente, Leonardo, Paño, Jose Ramón, Ramírez, Paula, Salavert, Miguel, Sánchez, Miguel, and Vallèc)s, Jordi
Published: 2018
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13. 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

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

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

15. Executive summary of the consensus document of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) on the diagnosis and antimicrobial treatment of infections due to carbapenem-resistant Gram-negative bacteria

Author: Pintado, Vicente, Ruiz-Garbajosa, Patricia, Aguilera-Alonso, David, Baquero-Artigao, Fernando, Bou, Germán, Cantón, Rafael, Grau, Santiago, Gutiérrez-Gutiérrez, Belén, Larrosa, Nieves, Machuca, Isabel, Martínez-Martínez, Luis, Montero, María Milagro, Morte-Romea, Elena, Oliver, Antonio, Paño, José Ramón, Sorlí, Luisa, Pintado, Vicente, Ruiz-Garbajosa, Patricia, Aguilera-Alonso, David, Baquero-Artigao, Fernando, Bou, Germán, Cantón, Rafael, Grau, Santiago, Gutiérrez-Gutiérrez, Belén, Larrosa, Nieves, Machuca, Isabel, Martínez-Martínez, Luis, Montero, María Milagro, Morte-Romea, Elena, Oliver, Antonio, Paño, José Ramón, and Sorlí, Luisa
Abstract: [EN] Infections caused by multidrug resistant Gram-negative bacteria are becoming a worldwide problem due to their increasing incidence and associated high mortality. Carbapenem-resistant bacteria such as Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii are the most important in clinical practice. The objective of these guidelines is to update the recommendations for the diagnosis and treatment of infections caused by these multidrug resistant bacteria. Although ‘old’ antibiotics such as aminoglycosides, colistin, or tigecycline are frequently used for therapy of these bacteria, the ‘new’ beta-lactams such as ceftazidime–avibactam, ceftolozane–tazobactam, meropenem–vaborbactam, imipenem–cilastatin–relebactam or cefiderocol are progressively becoming the first-line therapy for most of these microorganisms. The Spanish Society of Infectious Diseases and Clinical Microbiology (Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica) designated a panel of experts in the field to provide evidence-based recommendations in response to common clinical questions. This document is primarily focused on microbiological diagnosis, clinical management, and targeted antimicrobial therapy of these infections, with special attention to defining the role of the new antimicrobials in the treatment of these bacteria., [ES] Las infecciones causadas por bacterias gramnegativas multirresistentes se han convertido en un problema mundial debido a su creciente incidencia y alta mortalidad asociada. Las bacterias resistentes a carbapenémicos como Klebsiella pneumoniae, Pseudomonas aeruginosa y Acinetobacter baumannii son las más importantes en la práctica clínica. El objetivo de este documento de consenso es actualizar las recomendaciones sobre diagnóstico y tratamiento de las infecciones causadas por estas bacterias multirresistentes. Aunque los antibióticos ‘antiguos’ como aminoglucósidos, colistina o tigeciclina se utilizan con frecuencia en el tratamiento de estas bacterias, los ‘nuevos’ betalactámicos como ceftazidima-avibactam, ceftolozano-tazobactam, meropenem-vaborbactam, imipenem-cilastatina-relebactam o cefiderocol se están convirtiendo de forma progresiva en el tratamiento de primera elección para la mayoría de estos microorganismos. La Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica ha designado un grupo de expertos en la materia para elaborar una guía de recomendaciones basadas en la evidencia sobre las cuestiones clínicas más habituales. Este documento está principalmente centrado en el diagnóstico microbiológico, el manejo clínico y el tratamiento dirigido de estas infecciones, con especial referencia a definir el papel de los nuevos antimicrobianos en el tratamiento de estas bacterias.
Published: 2023

16. Antimicrobial stewardship in hospitals: Expert recommendation guidance document for activities in specific populations, syndromes and other aspects (PROA-2) from SEIMC, SEFH, SEMPSPGS, SEMICYUC and SEIP

Author: Cercenado, Emilia, Rodríguez-Baño, Jesús, Alfonso, José Luis, Calbo, Esther, Escosa-García, Luis, Fernández-Polo, Aurora, García-Rodríguez, Julio, Garnacho-Montero, José, Gil-Navarro, María Victoria, Grau, Santiago, Gudiol, Carlota, Horcajada, Juan Pablo, Larrosa, Nieves, Martínez, Carmen, Molina, José, Nuvials, Xavier, Oliver, Antonio, Paño, José Ramón, Pérez-Rodríguez, María Teresa, Ramírez, Paula, Rey-Biel, Pedro, Vidal, Pablo, Retamar Gentil, Pilar, Cercenado, Emilia, Rodríguez-Baño, Jesús, Alfonso, José Luis, Calbo, Esther, Escosa-García, Luis, Fernández-Polo, Aurora, García-Rodríguez, Julio, Garnacho-Montero, José, Gil-Navarro, María Victoria, Grau, Santiago, Gudiol, Carlota, Horcajada, Juan Pablo, Larrosa, Nieves, Martínez, Carmen, Molina, José, Nuvials, Xavier, Oliver, Antonio, Paño, José Ramón, Pérez-Rodríguez, María Teresa, Ramírez, Paula, Rey-Biel, Pedro, Vidal, Pablo, and Retamar Gentil, Pilar
Abstract: [EN] In 2012, The Spanish Societies of Infectious Diseases and Clinical Microbiology (SEIMC), Hospital Pharmacy (SEFH), and Preventive Medicine, Public Health and Healthcare Management (SEMPSGS) lead a consensus document including recommendations for the implementation of antimicrobial stewardship (AMS) programs (AMSP; PROA in Spanish) in acute care hospitals in Spain. While these recommendations were critical for the development of these programs in many centres, there is a need for guidance in the development of AMS activities for specific patient populations, syndromes or other specific aspects which were not included in the previous document or have developed significantly since then. The objective of this expert recommendation guidance document is to review the available information about these activities in these patient populations or circumstances, and to provide guidance recommendations about them. With this objective the SEIMC, SEFH, SEMPSPGS, the Spanish Society of Intensive Care Medicine (SEMICYUC) and the Spanish Pediatric Infectious Disease Society (SEIP) selected a panel of experts who chose the different aspects to include in the document. Because of the lack of high-level evidence in the implementation of the activities, the panel opted to perform a narrative review of the literature for the different topics for which recommendations were agreed by consensus. The document was open to public consultation for the members of these societies for their comments and suggestions, which were reviewed and considered by the panel., [ES] En 2012, las Sociedades Españolas de Enfermedades Infecciosas y Microbiología Clínica (SEIMC), Farmacia Hospitalaria (SEFH) y Medicina Preventiva, Salud Pública y Gestión Sanitaria (SEMPSPGS) lideraron un documento de consenso que incluía recomendaciones para la implementación de Programas de optimización del uso de antimicrobianos (PROA) en hospitales de agudos en España. Si bien estas recomendaciones fueron críticas para el desarrollo de estos programas en muchos centros, actualmente es necesario establecer unas guías para la implementación de las actividades de los PROA en determinadas poblaciones de pacientes, síndromes clínicos y otros aspectos específicos que no se incluyeron en el documento previo o que desde entonces se han desarrollado significativamente. El objetivo de esta guía de recomendaciones de expertos es revisar la información disponible acerca de esas actividades en estas poblaciones o circunstancias de pacientes y proporcionar unas recomendaciones que sirvan de guía sobre ellas. Con este objetivo, la SEIMC, la SEFH y la SEMPSPGS, así como la Sociedad Española de Medicina Intensiva, Crítica y Unidades Coronarias (SEMICYUC) y la Sociedad Española de Infectología Pediátrica (SEIP), seleccionaron un panel de expertos que eligieron los diferentes aspectos a incluir en el documento. Debido a la ausencia de evidencia de alto nivel en la implementación de las diferentes actividades, el panel optó por realizar una revisión narrativa de la literatura de los diferentes aspectos, en los que las recomendaciones se acordaron por consenso. El documento se abrió para consulta pública a los miembros de estas sociedades para sus comentarios y sugerencias, que fueron revisadas y consideradas por el panel.
Published: 2023

17. Management of Patients with Suspected or Confirmed Antibiotic Allergy: Executive Summary of Guidelines from the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC), the Spanish Society of Allergy and Clinical Immunology (SEAIC), the Spanish Society of Hospital Pharmacy (SEFH) and the Spanish Society of Intensive Medicine and Coronary Care Units (SEMICYUC)

Author: Paño, José Ramón, Moreno-Rodilla, Esther, Cobo, Sara, Cubero-Saldaña, José Luis, Periañez-Párraga, Leonor, Pozo, José Luis del, Retamar-Genti, Pilar, Rodríguez-Oviedo, Alejandro, Torres-Jaén, María José, Vidal-Cortes, Pablo, Colás-Sanz, Carlos, Paño, José Ramón, Moreno-Rodilla, Esther, Cobo, Sara, Cubero-Saldaña, José Luis, Periañez-Párraga, Leonor, Pozo, José Luis del, Retamar-Genti, Pilar, Rodríguez-Oviedo, Alejandro, Torres-Jaén, María José, Vidal-Cortes, Pablo, and Colás-Sanz, Carlos
Abstract: Suspected or confirmed antibiotic allergy is a frequent clinical circumstance that influences antimicrobial prescription and often leads to the avoidable use of less efficacious and/or more toxic or costly drugs than first-line antimicrobials. Optimizing antimicrobial therapy in patients with antibiotic allergy labels has become one of the priorities of antimicrobial stewardship programs in several countries. These guidelines aim to make recommendations for the systematic approach to patients with suspected or confirmed antibiotic allergy based on current evidence. An expert panel (11 members of various scientific societies) formulated questions about the management of patients with suspected or confirmed antibiotic allergy. A systematic literature review was performed by a medical librarian. The questions were distributed among panel members who selected the most relevant references, summarized the evidence, and formulated graded recommendations when possible. The answers to all the questions were finally reviewed by all panel members. A systematic approach to patients with suspected or confirmed antibiotic allergy was recommended to improve antibiotic selection and, consequently, clinical outcomes. A clinically oriented, 3-category risk-stratification strategy was recommended for patients with suspected antibiotic allergy. Complementary assessments should consider both clinical risk category and preferred antibiotic agent. Empirical therapy recommendations for the most relevant clinical syndromes in patients with suspected or confirmed ß-lactam allergy were formulated, as were recommendations on the implementation and monitoring of the impact of the guidelines. Antimicrobial stewardship programs and allergists should design and implement activities that facilitate the most appropriate use of antibiotics in these patients.
Published: 2023

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

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

19. Study protocol for a randomized clinical trial to assess 7 versus 14-days of treatment for Pseudomonas aeruginosa bloodstream infections (SHORTEN-2 trial)

Author: Molina, José, Rosso-Fernández, Clara, Montero-Mateos, Enrique, Paño, José Ramón, Solla, María, Guisado-Gil, Ana Belén, Álvarez-Marín, Rocío, Pachón Ibáñez, María Eugenia, Gimeno, Adelina, Martín-Gutiérrez, Guillermo, Lepe, José A., Cisneros, José Miguel, Ministerio de Sanidad (España), and Instituto de Salud Carlos III
Subjects: Adult, Treatment Outcome, Multidisciplinary, Sepsis, Pseudomonas aeruginosa, Humans, Pseudomonas Infections, Anti-Bacterial Agents, Randomized Controlled Trials as Topic
Abstract: Research priorities in Antimicrobial Stewardship (AMS) have rapidly evolved in the last decade. The need for a more efficient use of antimicrobials have fueled plenty of studies to define the optimal duration for antibiotic treatments, and yet, there still are large areas of uncertainty in common clinical scenarios. Pseudomonas aeruginosa has been pointed as a priority for clinical research, but it has been unattended by most randomized trials tackling the effectiveness of short treatments. The study protocol of the SHORTEN-2 trial is presented as a practical example of new ways to approach common obstacles for clinical research in AMS., The trial obtained competitive, public funding from the Spanish Ministry of Health (Instituto de Salud Carlos III, reference ICI21/00075, www.isciii.es).
Published: 2022

20. 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

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

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

22. Mapping the Serum Proteome of COVID-19 Patients; Guidance for Severity Assessment

Author: Nuñez, Estefanía, primary, Orera, Irene, additional, Carmona-Rodríguez, Lorena, additional, Paño, José Ramón, additional, Vázquez, Jesús, additional, and Corrales, Fernando J., additional
Published: 2022
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23. Serum active Granzyme A: a new biomarker that contributes to the pathogenesis of peritoneal sepsis

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

24. 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

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

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

26. Results of the survey among participating centers regarding diagnostic and clinical routines for the management of BSI-PA

Author: Molina, José, Rosso-Fernández, Clara, Montero-Mateos, Enrique, Paño, José Ramón, Solla, María, Guisado-Gil, Ana Belén, Álvarez-Marín, Rocío, Pachón-Ibáñez, M. E., Gimeno, Adelina, Martín-Gutiérrez, Guillermo, Lepe, José A., Cisneros, José Miguel, Molina, José, Rosso-Fernández, Clara, Montero-Mateos, Enrique, Paño, José Ramón, Solla, María, Guisado-Gil, Ana Belén, Álvarez-Marín, Rocío, Pachón-Ibáñez, M. E., Gimeno, Adelina, Martín-Gutiérrez, Guillermo, Lepe, José A., and Cisneros, José Miguel
Abstract: S4 File. Results of the survey among participating centers regarding diagnostic and clinical routines for the management of BSI-PA
Published: 2022

27. Definitions for main trial variables. Study protocol for a randomized clinical trial to assess 7 versus 14-days of treatment for Pseudomonas aeruginosa bloodstream infections (SHORTEN-2 trial)

Author: Molina, José, Rosso-Fernández, Clara, Montero-Mateos, Enrique, Paño, José Ramón, Solla, María, Guisado-Gil, Ana Belén, Álvarez-Marín, Rocío, Pachón-Ibáñez, M. E., Gimeno, Adelina, Martín-Gutiérrez, Guillermo, Lepe, José A., Cisneros, José Miguel, Molina, José, Rosso-Fernández, Clara, Montero-Mateos, Enrique, Paño, José Ramón, Solla, María, Guisado-Gil, Ana Belén, Álvarez-Marín, Rocío, Pachón-Ibáñez, M. E., Gimeno, Adelina, Martín-Gutiérrez, Guillermo, Lepe, José A., and Cisneros, José Miguel
Published: 2022

28. Full-length study protocol (English). Study protocol for a randomized clinical trial to assess 7 versus 14-days of treatment for Pseudomonas aeruginosa bloodstream infections (SHORTEN-2 trial)

Author: Molina, José, Rosso-Fernández, Clara, Montero-Mateos, Enrique, Paño, José Ramón, Solla, María, Guisado-Gil, Ana Belén, Álvarez-Marín, Rocío, Pachón-Ibáñez, M. E., Gimeno, Adelina, Martín-Gutiérrez, Guillermo, Lepe, José A., Cisneros, José Miguel, Molina, José, Rosso-Fernández, Clara, Montero-Mateos, Enrique, Paño, José Ramón, Solla, María, Guisado-Gil, Ana Belén, Álvarez-Marín, Rocío, Pachón-Ibáñez, M. E., Gimeno, Adelina, Martín-Gutiérrez, Guillermo, Lepe, José A., and Cisneros, José Miguel
Abstract: Efficacy and safety of 7 versus 14 days of antibiotic treatment for Pseudomonas aeruginosa bacteraemia: a multicentre, randomized clinical trial (SHORTEN-2) with a DOOR/RADAR analysis.
Published: 2022

29. Full-length study protocol (Spanish). Study protocol for a randomized clinical trial to assess 7 versus 14-days of treatment for Pseudomonas aeruginosa bloodstream infections (SHORTEN-2 trial)

Author: Molina, José, Rosso-Fernández, Clara, Montero-Mateos, Enrique, Paño, José Ramón, Solla, María, Guisado-Gil, Ana Belén, Álvarez-Marín, Rocío, Pachón-Ibáñez, M. E., Gimeno, Adelina, Martín-Gutiérrez, Guillermo, Lepe, José A., Cisneros, José Miguel, Molina, José, Rosso-Fernández, Clara, Montero-Mateos, Enrique, Paño, José Ramón, Solla, María, Guisado-Gil, Ana Belén, Álvarez-Marín, Rocío, Pachón-Ibáñez, M. E., Gimeno, Adelina, Martín-Gutiérrez, Guillermo, Lepe, José A., and Cisneros, José Miguel
Abstract: Eficacia y seguridad de 7 versus 14 días de tratamiento antibiótico para la bacteriemia producida por Pseudomonas aeruginosa: un ensayo clínico multicéntrico, aleatorizado (SHORTEN-2) con un análisis DOOR/RADAR.
Published: 2022

30. Statistical analysis plan. Study protocol for a randomized clinical trial to assess 7 versus 14-days of treatment for Pseudomonas aeruginosa bloodstream infections (SHORTEN-2 trial)

Author: Molina, José, Rosso-Fernández, Clara, Montero-Mateos, Enrique, Paño, José Ramón, Solla, María, Guisado-Gil, Ana Belén, Álvarez-Marín, Rocío, Pachón-Ibáñez, M. E., Gimeno, Adelina, Martín-Gutiérrez, Guillermo, Lepe, José A., Cisneros, José Miguel, Molina, José, Rosso-Fernández, Clara, Montero-Mateos, Enrique, Paño, José Ramón, Solla, María, Guisado-Gil, Ana Belén, Álvarez-Marín, Rocío, Pachón-Ibáñez, M. E., Gimeno, Adelina, Martín-Gutiérrez, Guillermo, Lepe, José A., and Cisneros, José Miguel
Abstract: Efficacy and safety of 7 versus 14 days of antibiotic treatment for Pseudomonas aeruginosa bacteraemia: a multicentre, randomized clinical trial (SHORTEN-2) with a DOOR/RADAR analysis.
Published: 2022

31. List of participating centers. Study protocol for a randomized clinical trial to assess 7 versus 14-days of treatment for Pseudomonas aeruginosa bloodstream infections (SHORTEN-2 trial)

Author: Molina, José, Rosso-Fernández, Clara, Montero-Mateos, Enrique, Paño, José Ramón, Solla, María, Guisado-Gil, Ana Belén, Álvarez-Marín, Rocío, Pachón-Ibáñez, M. E., Gimeno, Adelina, Martín-Gutiérrez, Guillermo, Lepe, José A., Cisneros, José Miguel, Molina, José, Rosso-Fernández, Clara, Montero-Mateos, Enrique, Paño, José Ramón, Solla, María, Guisado-Gil, Ana Belén, Álvarez-Marín, Rocío, Pachón-Ibáñez, M. E., Gimeno, Adelina, Martín-Gutiérrez, Guillermo, Lepe, José A., and Cisneros, José Miguel
Published: 2022

32. Study protocol for a randomized clinical trial to assess 7 versus 14-days of treatment for Pseudomonas aeruginosa bloodstream infections (SHORTEN-2 trial)

Author: Ministerio de Sanidad (España), Instituto de Salud Carlos III, Molina, José, Rosso-Fernández, Clara, Montero-Mateos, Enrique, Paño, José Ramón, Solla, María, Guisado-Gil, Ana Belén, Álvarez-Marín, Rocío, Pachón-Ibáñez, M. E., Gimeno, Adelina, Martín-Gutiérrez, Guillermo, Lepe, José A., Cisneros, José Miguel, Ministerio de Sanidad (España), Instituto de Salud Carlos III, Molina, José, Rosso-Fernández, Clara, Montero-Mateos, Enrique, Paño, José Ramón, Solla, María, Guisado-Gil, Ana Belén, Álvarez-Marín, Rocío, Pachón-Ibáñez, M. E., Gimeno, Adelina, Martín-Gutiérrez, Guillermo, Lepe, José A., and Cisneros, José Miguel
Abstract: Research priorities in Antimicrobial Stewardship (AMS) have rapidly evolved in the last decade. The need for a more efficient use of antimicrobials have fueled plenty of studies to define the optimal duration for antibiotic treatments, and yet, there still are large areas of uncertainty in common clinical scenarios. Pseudomonas aeruginosa has been pointed as a priority for clinical research, but it has been unattended by most randomized trials tackling the effectiveness of short treatments. The study protocol of the SHORTEN-2 trial is presented as a practical example of new ways to approach common obstacles for clinical research in AMS.
Published: 2022

33. European society of clinical microbiology and infectious diseases guidelines for coronavirus disease 2019: an update on treatment of patients with mild/moderate disease

Author: Bartoletti, Michele, Azap, Ozlem, Barać, Aleksandra, Bussini, Linda, Ergonul, Onder, Krause, Robert, Martín Quirós, Alejandro, Paño, José Ramón, Power, Nicholas R., Sibani, Marcella, Szabó, Bálint Gergely, Tsiodras, Sotirios, Zollner-Schwetz, Ines, Rodríguez-Baño, Jesús, Bartoletti, Michele, Azap, Ozlem, Barać, Aleksandra, Bussini, Linda, Ergonul, Onder, Krause, Robert, Martín Quirós, Alejandro, Paño, José Ramón, Power, Nicholas R., Sibani, Marcella, Szabó, Bálint Gergely, Tsiodras, Sotirios, Zollner-Schwetz, Ines, and Rodríguez-Baño, Jesús
Abstract: [Scope] Despite the large availability of vaccines, coronavirus disease 2019 (COVID-19), induced by severe acute respiratory syndrome coronavirus 2, continues to be a major threat for health-care providers and fragile people. A number of options are now available for outpatients with mild-to-moderate COVID-19 at the risk of disease progression for the prevention of deaths or hospitalization., [Methods] A European Society of Clinical Microbiology and Infectious Diseases COVID-19 guidelines task force was established by the European Society of Clinical Microbiology and Infectious Diseases Executive Committee. A small group was established, half appointed by the chair and the remaining selected based on an open call. Each panel met virtually once a week. For all decisions, a simple majority vote was used. A long list of clinical questions using the population, intervention, comparison, outcome format was developed at the beginning of the process. For each population, intervention, comparison, outcome, two panel members performed a literature search, with a third panelist involved in case of inconsistent results. Voting was based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach., [Recommendations] In this update, we focus on anti-viral agents, monoclonal antibodies (mAbs) and other treatment options proposed for patients with mild or moderate COVID-19 who are at the risk of hospitalization or death. Although the use of anti-virals is recommended, especially nirmatrelvir/ritonavir and remdesivir or, alternatively, molnupirarvir, the administration of mAbs against the spike protein strictly depends on circulating variants or the ability to test timely for variants and sub-variants. At the time of writing (April–June 2022), the only active mAb was tixagevimab/cilgavimab given the predominance of the Omicron BA.2, BA.3, BA.4 and BA.5 sub-lineages in Europe. However, considering that the epidemiological scenario is extremely dynamic, constant monitoring of variants of concern is mandatory.
Published: 2022

34. Mapping the Serum Proteome of COVID-19 Patients; Guidance for Severity Assessment

Author: Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, European Commission, Comunidad de Madrid, Consejo Superior de Investigaciones Científicas (España), Orera Utrilla, Irene [0000-0002-7508-4750], Carmona Rodríguez, Lorena [0000-0001-5937-5577], Vázquez, Jesús [0000-0003-1461-5092], Corrales, Fernando J. [0000-0002-0231-5159], Núñez, Estefanía, Orera Utrilla, Irene, Carmona-Rodríguez, Lorena, Paño, José Ramón, Vázquez, Jesús, Corrales, Fernando J., Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, European Commission, Comunidad de Madrid, Consejo Superior de Investigaciones Científicas (España), Orera Utrilla, Irene [0000-0002-7508-4750], Carmona Rodríguez, Lorena [0000-0001-5937-5577], Vázquez, Jesús [0000-0003-1461-5092], Corrales, Fernando J. [0000-0002-0231-5159], Núñez, Estefanía, Orera Utrilla, Irene, Carmona-Rodríguez, Lorena, Paño, José Ramón, Vázquez, Jesús, and Corrales, Fernando J.
Abstract: Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), whose outbreak in 2019 led to an ongoing pandemic with devastating consequences for the global economy and human health. According to the World Health Organization, COVID-19 has affected more than 481 million people worldwide, with 6 million confirmed deaths. The joint efforts of the scientific community have undoubtedly increased the pace of production of COVID-19 vaccines, but there is still so much uncharted ground to cover regarding the mechanisms of SARS-CoV-2 infection, replication and host response. These issues can be approached by proteomics with unprecedented capacity paving the way for the development of more efficient strategies for patient care. In this study, we present a deep proteome analysis that has been performed on a cohort of 72 COVID-19 patients aiming to identify serum proteins assessing the dynamics of the disease at different age ranges. A panel of 53 proteins that participate in several functions such as acute-phase response and inflammation, blood coagulation, cell adhesion, complement cascade, endocytosis, immune response, oxidative stress and tissue injury, have been correlated with patient severity, suggesting a molecular basis for their clinical stratification. Eighteen protein candidates were further validated by targeted proteomics in an independent cohort of 84 patients including a group of individuals that had satisfactorily resolved SARS-CoV-2 infection. Remarkably, all protein alterations were normalized 100 days after leaving the hospital, which further supports the reliability of the selected proteins as hallmarks of COVID-19 progression and grading. The optimized protein panel may prove its value for optimal severity assessment as well as in the follow up of COVID-19 patients.
Published: 2022

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

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

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

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

38. How Could Antibiotics, Probiotics, and Corticoids Modify Microbiota and Its Influence in Cancer Immune Checkpoint Inhibitors: A Review

Author: Cruellas, Mara, primary, Yubero, Alfonso, additional, Zapata, María, additional, Galvez, Eva M., additional, Gascón, Marta, additional, Isla, Dolores, additional, Lastra, Rodrigo, additional, Martínez-Lostao, Luis, additional, Ocariz, Maitane, additional, Pardo, Julián, additional, Ramírez, Ariel, additional, Sesma, Andrea, additional, Torres-Ramón, Irene, additional, and Paño, José Ramón, additional
Published: 2021
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39. 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

40. Multicentre, randomised, open-label, phase IV–III study to evaluate the efficacy of cloxacillin plus fosfomycin versus cloxacillin alone in adult patients with methicillin-susceptible Staphylococcus aureus bacteraemia: study protocol for the SAFO trial

Author: Instituto de Salud Carlos III, Ministerio de Economía, Industria y Competitividad (España), Red Española de Investigación en Patología Infecciosa, Grillo, Sara, Cuervo, Guillermo, Carratalà, Jordi, San Juan, Rafael, Aguado, José María, Morata, Laura, Gómez-Zorrilla, Silvia, López-Contreras, Joaquín, Gasch, Oriol, Gomila-Grange, Aina, Iftimie, Simona, García-Prado, Graciano, Calbo, Esther, Boix-Palop, Lucía, Oriol, Isabel, Jover-Sáenz, Alfredo, López-Cortés, Luis Eduardo, Euba, Gorane, Aguirregabiria, Malen, García-País, María José, Gioia, Francesca, Paño, José Ramón, Pedro-Botet, María Luisa, Benítez, Rosa María, Pérez-Rodríguez, María Teresa, Meije, Yolanda, Loeches, Belén, Horna, Gestrudis, Berbel, Dàmaris, Domínguez, María Ángeles, Padullés, Ariadna, Cobo, Sara, Hereu, Pilar, Videla, Sebastián, Tebé, Cristian, Pallarès, Natalia, Miró, José María, Pujol, Miquel, Instituto de Salud Carlos III, Ministerio de Economía, Industria y Competitividad (España), Red Española de Investigación en Patología Infecciosa, Grillo, Sara, Cuervo, Guillermo, Carratalà, Jordi, San Juan, Rafael, Aguado, José María, Morata, Laura, Gómez-Zorrilla, Silvia, López-Contreras, Joaquín, Gasch, Oriol, Gomila-Grange, Aina, Iftimie, Simona, García-Prado, Graciano, Calbo, Esther, Boix-Palop, Lucía, Oriol, Isabel, Jover-Sáenz, Alfredo, López-Cortés, Luis Eduardo, Euba, Gorane, Aguirregabiria, Malen, García-País, María José, Gioia, Francesca, Paño, José Ramón, Pedro-Botet, María Luisa, Benítez, Rosa María, Pérez-Rodríguez, María Teresa, Meije, Yolanda, Loeches, Belén, Horna, Gestrudis, Berbel, Dàmaris, Domínguez, María Ángeles, Padullés, Ariadna, Cobo, Sara, Hereu, Pilar, Videla, Sebastián, Tebé, Cristian, Pallarès, Natalia, Miró, José María, and Pujol, Miquel
Abstract: [Introduction] Methicillin-susceptible Staphylococcus aureus (MSSA) bacteraemia is a frequent condition, with high mortality rates. There is a growing interest in identifying new therapeutic regimens able to reduce therapeutic failure and mortality observed with the standard of care of beta-lactam monotherapy. In vitro and small-scale studies have found synergy between cloxacillin and fosfomycin against S. aureus. Our aim is to test the hypothesis that cloxacillin plus fosfomycin achieves higher treatment success than cloxacillin alone in patients with MSSA bacteraemia., [Methods] We will perform a superiority, randomised, open-label, phase IV–III, two-armed parallel group (1:1) clinical trial at 20 Spanish tertiary hospitals. Adults (≥18 years) with isolation of MSSA from at least one blood culture ≤72 hours before inclusion with evidence of infection, will be randomly allocated to receive either cloxacillin 2 g/4-hour intravenous plus fosfomycin 3 g/6-hour intravenous or cloxacillin 2 g/4-hour intravenous alone for 7 days. After the first week, sequential treatment and total duration of antibiotic therapy will be determined according to clinical criteria by the attending physician. Primary endpoints: (1) Treatment success at day 7, a composite endpoint comprising all the following criteria: patient alive, stable or with improved quick-Sequential Organ Failure Assessment score, afebrile and with negative blood cultures for MSSA at day 7. (2) Treatment success at test of cure (TOC) visit: patient alive and no isolation of MSSA in blood culture or at another sterile site from day 8 until TOC (12 weeks after randomisation). We assume a rate of treatment success of 74% in the cloxacillin group. Accepting alpha risk of 0.05 and beta risk of 0.2 in a two-sided test, 183 subjects will be required in each of the control and experimental groups to obtain statistically significant difference of 12% (considered clinically significant)., [Ethics and dissemination] Ethical approval has been obtained from the Ethics Committee of Bellvitge University Hospital (AC069/18) and from the Spanish Medicines and Healthcare Product Regulatory Agency (AEMPS, AC069/18), and is valid for all participating centres under existing Spanish legislation. The results will be presented at international meetings and will be made available to patients and funders., [Trial registration number] The protocol has been approved by AEMPS with the Trial Registration Number EudraCT 2018-001207-37. ClinicalTrials.gov Identifier: NCT03959345; Pre-results.
Published: 2021

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

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

42. 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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43. Intratumoral versus Circulating Lymphoid Cells as Predictive Biomarkers in Lung Cancer Patients Treated with Immune Checkpoint Inhibitors: Is the Easiest Path the Best One?

Author: Gascon, Marta, Isla, Dolores, Cruellas, Mara, Galvez, Eva M., Lastra, Rodrigo, Ocariz, Maitane, Paño, José Ramón, Ramirez, Ariel, Sesma, Andrea, Torres-Ramón, Irene, Yubero, Alfonso, Pardo, Julián, and Martinez-Lostao, Luis
Abstract: The molecular and cell determinants that modulate immune checkpoint (ICI) efficacy in lung cancer are still not well understood. However, there is a necessity to select those patients that will most benefit from these new treatments. Recent studies suggest the presence and/or the relative balance of specific lymphoid cells in the tumor microenvironment (TEM) including the T cell (activated, memory, and regulatory) and NK cell (CD56dim/bright) subsets, and correlate with a better response to ICI. The analyses of these cell subsets in peripheral blood, as a more accessible and homogeneous sample, might facilitate clinical decisions concerning fast prediction of ICI efficacy. Despite recent studies suggesting that lymphoid circulating cells might correlate with ICI efficacy and toxicity, more analyses and investigation are required to confirm if circulating lymphoid cells are a relevant picture of the lung TME and could be instrumental as ICI response biomarkers. This short review is aimed to discuss the recent advances in this fast-growing field.
Published: 2020

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

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

45. Intratumoral versus circulating lymphoid cells as predictive biomarkers in lung cancer patients treated with immune checkpoint inhibitors: Is the easiest path the best one?

Author: Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Gobierno de Aragón, European Commission, Gascón, Marta, Isla, Dolores, Cruellas, Mara, Gálvez Buerba, Eva Mª, Lastra, Rodrigo, Ocáriz, Maitane, Paño, José Ramón, Ramírez-Labrada, Ariel, Sesma, Andrea, Torres-Ramón, Irene, Yubero, Alfonso, Pardo, Julián, Martínez-Lostao, Luis, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Gobierno de Aragón, European Commission, Gascón, Marta, Isla, Dolores, Cruellas, Mara, Gálvez Buerba, Eva Mª, Lastra, Rodrigo, Ocáriz, Maitane, Paño, José Ramón, Ramírez-Labrada, Ariel, Sesma, Andrea, Torres-Ramón, Irene, Yubero, Alfonso, Pardo, Julián, and Martínez-Lostao, Luis
Abstract: The molecular and cell determinants that modulate immune checkpoint (ICI) efficacy in lung cancer are still not well understood. However, there is a necessity to select those patients that will most benefit from these new treatments. Recent studies suggest the presence and/or the relative balance of specific lymphoid cells in the tumor microenvironment (TEM) including the T cell (activated, memory, and regulatory) and NK cell (CD56dim/bright) subsets, and correlate with a better response to ICI. The analyses of these cell subsets in peripheral blood, as a more accessible and homogeneous sample, might facilitate clinical decisions concerning fast prediction of ICI efficacy. Despite recent studies suggesting that lymphoid circulating cells might correlate with ICI efficacy and toxicity, more analyses and investigation are required to confirm if circulating lymphoid cells are a relevant picture of the lung TME and could be instrumental as ICI response biomarkers. This short review is aimed to discuss the recent advances in this fast-growing field.
Published: 2020

46. From Tumor Mutational Burden to Blood T Cell Receptor: Looking for the Best Predictive Biomarker in Lung Cancer Treated with Immunotherapy

Author: Sesma, Andrea, primary, Pardo, Julián, additional, Cruellas, Mara, additional, Gálvez, Eva M., additional, Gascón, Marta, additional, Isla, Dolores, additional, Martínez-Lostao, Luis, additional, Ocáriz, Maitane, additional, Paño, José Ramón, additional, Quílez, Elisa, additional, Ramírez, Ariel, additional, Torres-Ramón, Irene, additional, Yubero, Alfonso, additional, Zapata, María, additional, and Lastra, Rodrigo, additional
Published: 2020
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47. Microbiota and Lung Cancer. Opportunities and Challenges for Improving Immunotherapy Efficacy

Author: Ocáriz-Díez, Maitane, primary, Cruellas, Mara, additional, Gascón, Marta, additional, Lastra, Rodrigo, additional, Martínez-Lostao, Luis, additional, Ramírez-Labrada, Ariel, additional, Paño, José Ramón, additional, Sesma, Andrea, additional, Torres, Irene, additional, Yubero, Alfonso, additional, Pardo, Julián, additional, Isla, Dolores, additional, and Gálvez, Eva M., additional
Published: 2020
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48. Intratumoral versus Circulating Lymphoid Cells as Predictive Biomarkers in Lung Cancer Patients Treated with Immune Checkpoint Inhibitors: Is the Easiest Path the Best One?

Author: Gascón, Marta, primary, Isla, Dolores, additional, Cruellas, Mara, additional, Gálvez, Eva M., additional, Lastra, Rodrigo, additional, Ocáriz, Maitane, additional, Paño, José Ramón, additional, Ramírez, Ariel, additional, Sesma, Andrea, additional, Torres-Ramón, Irene, additional, Yubero, Alfonso, additional, Pardo, Julián, additional, and Martínez-Lostao, Luis, additional
Published: 2020
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49. Mastitis granulomatosa idiopática

Author: Delgado, Elena, primary, Sánchez, Laura, additional, Mejía, Elaine, additional, Paño, José Ramón, additional, Güemes, Antonio, additional, and Gil, Ismael, additional
Published: 2020
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50. La formación de grado en enfermedades infecciosas, resistencia y uso de antibióticos desde la perspectiva de los estudiantes de Medicina

Author: Sánchez-Fabra, David, Dyar, Oliver J., Pozo, José Luis del, Amiguet, Juan Antonio, Colmenero, Juan de Dios, Fariñas, María del Carmen, López-Medrano, Francisco, Portilla, Joaquín, Praena-Segovia, Julia, Torre-Cisneros, Julián, Rodríguez-Baño, Jesús, Pulcini, Céline, Paño, José Ramón, Sánchez-Fabra, David, Dyar, Oliver J., Pozo, José Luis del, Amiguet, Juan Antonio, Colmenero, Juan de Dios, Fariñas, María del Carmen, López-Medrano, Francisco, Portilla, Joaquín, Praena-Segovia, Julia, Torre-Cisneros, Julián, Rodríguez-Baño, Jesús, Pulcini, Céline, and Paño, José Ramón
Abstract: [Introducción] Una de las principales herramientas para optimizar el uso de los antibióticos es la formación de los prescriptores. El objetivo de este trabajo es conocer la opinión de los estudiantes de Medicina españoles sobre la formación en enfermedades infecciosas., [Material y métodos] Se distribuyó un cuestionario on line anonimizado entre estudiantes de sexto curso a través de distintos canales. El cuestionario incluyó 45 preguntas sobre conocimientos, actitudes y percepciones sobre el diagnóstico, resistencia antimicrobiana, uso de antibióticos y la formación de pregrado en enfermedades infecciosas., [Resultados] Se recibieron un total de 441 encuestas de 21 facultades. Se obtuvieron 374 respuestas (84,8%) de las 8 facultades más representadas, con una tasa de respuesta del 28,9%. La mayoría de los alumnos se sentían preparados para identificar los signos clínicos de infección (418; 94,8%) y para interpretar correctamente las pruebas de laboratorio (382; 86,6%). Reconocieron saber elegir un antibiótico con seguridad sin consultar libros ni guías (178; 40,4%). Solo 107 alumnos (24,3%) consideraron haber recibido suficiente formación en el uso prudente de los antimicrobianos. Respecto a los métodos de aprendizaje, se percibieron como más útiles la discusión de casos clínicos, los rotatorios en servicios o unidades de enfermedades infecciosas y los talleres de pequeños grupos: se evaluaron favorablemente en un 76,9; en un 76 y en un 68,8% de los casos, respectivamente., [Conclusión] Los estudiantes de Medicina se encuentran más seguros en el diagnóstico de enfermedades infecciosas que en el tratamiento antibiótico. Asimismo, sienten la necesidad de recibir mayor formación en antibioterapia y uso prudente en antibióticos., [Introduction]] One of the main tools to optimize antibiotics use is education of prescribers. The aim of this article is to study undergraduate education in the field of infectious diseases, antimicrobial resistance and antibiotic stewardship from the perspective of Spanish medical students., [Material and methods] An anonymous online questionnaire was distributed among sixth grade students using different channels in Europe, within the ESGAP Student-Prepare survey. The questionnaire included 45 questions about knowledge, attitudes and perceptions about diagnosis, bacterial resistance, use of antibiotics and undergraduate training in infectious diseases. We present here the Spanish results., [Results] A total of 441 surveys were received from 21 medical schools. A total of 374 responses (84.8%) were obtained from the 8 most represented faculties, with a response rate of 28.9%. Most students felt adequately prepared to identify clinical signs of infection (418; 94.8%) and to accurately interpret laboratory tests (382; 86.6%). A total of 178 (40.4%) acknowledged being able to choose an antibiotic with confidence without consulting books or guidelines. Only 107 (24.3%) students considered that they had received sufficient training in judicious use of antibiotics. Regarding learning methods, the discussion of clinical cases, infectious diseases units rotatories and small group workshops were considered the most useful, being evaluated favorably in 76.9%, 76% and 68.8% of the cases., [Conclusion] Medical students feel more confident in the diagnosis of infectious diseases than in antibiotic treatment. They also feel the need to receive more training in antibiotics and judicious antibiotic use.
Published: 2019

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