BID expression determines the apoptotic fate of cancer cells after abrogation of the spindle assembly checkpoint by AURKB or TTK inhibitors
- Autores
- Bertran Alamillo, Jordi; Giménez Capitán, Ana; Román, Ruth; Talbot, Sara; Whiteley, Rebecca; Floch, Nicolas; Martinez Perez, Elizabeth; Martin, Matthew J.; Smith, Paul D.; Sullivan, Ivana; Terp, Mikkel G.; Saeh, Jamal; Marino Buslje, Cristina; Fabbri, Giulia; Guo, Grace; Xu, Man; Tornador, Cristian; Aguilar Hernández, Andrés; Reguart, Noemí; Ditzel, Henrik J.; Martínez Bueno, Alejandro; Nabau Moretó, Núria; Gascó, Amaya; Rosell, Rafael; Pease, J. Elizabeth; Polanska, Urszula M.; Travers, Jon; Urosevic, Jelena; Molina Vila, Miguel A.
- Año de publicación
- 2023
- Idioma
- inglés
- Tipo de recurso
- artículo
- Estado
- versión publicada
- Descripción
- Background: Drugs targeting the spindle assembly checkpoint (SAC), such as inhibitors of Aurora kinase B (AURKB) and dual specific protein kinase TTK, are in different stages of clinical development. However, cell response to SAC abrogation is poorly understood and there are no markers for patient selection. Methods: A panel of 53 tumor cell lines of different origins was used. The effects of drugs were analyzed by MTT and flow cytometry. Copy number status was determined by FISH and Q-PCR; mRNA expression by nCounter and RT-Q-PCR and protein expression by Western blotting. CRISPR-Cas9 technology was used for gene knock-out (KO) and a doxycycline-inducible pTRIPZ vector for ectopic expression. Finally, in vivo experiments were performed by implanting cultured cells or fragments of tumors into immunodeficient mice. Results: Tumor cells and patient-derived xenografts (PDXs) sensitive to AURKB and TTK inhibitors consistently showed high expression levels of BH3-interacting domain death agonist (BID), while cell lines and PDXs with low BID were uniformly resistant. Gene silencing rendered BID-overexpressing cells insensitive to SAC abrogation while ectopic BID expression in BID-low cells significantly increased sensitivity. SAC abrogation induced activation of CASP-2, leading to cleavage of CASP-3 and extensive cell death only in presence of high levels of BID. Finally, a prevalence study revealed high BID mRNA in 6% of human solid tumors. Conclusions: The fate of tumor cells after SAC abrogation is driven by an AURKB/ CASP-2 signaling mechanism, regulated by BID levels. Our results pave the way to clinically explore SAC-targeting drugs in tumors with high BID expression.
Fil: Bertran Alamillo, Jordi. Quiron Dexeus University Hospital; España
Fil: Giménez Capitán, Ana. Quiron Dexeus University Hospital; España
Fil: Román, Ruth. Quiron Dexeus University Hospital; España
Fil: Talbot, Sara. Quiron Dexeus University Hospital; España
Fil: Whiteley, Rebecca. Quiron Dexeus University Hospital; España
Fil: Floch, Nicolas. Astrazeneca; Reino Unido
Fil: Martinez Perez, Elizabeth. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina
Fil: Martin, Matthew J.. Astrazeneca; Reino Unido
Fil: Smith, Paul D.. Astrazeneca; Reino Unido
Fil: Sullivan, Ivana. Hospital de la Santa Creu I Sant Pau; España. Hospital Universitari Dexeus; España
Fil: Terp, Mikkel G.. University of Southern Denmark; Dinamarca
Fil: Saeh, Jamal. Astrazeneca; Reino Unido
Fil: Marino Buslje, Cristina. Fundación Instituto Leloir; Argentina
Fil: Fabbri, Giulia. Astrazeneca; Reino Unido
Fil: Guo, Grace. Astrazeneca; Reino Unido
Fil: Xu, Man. Astrazeneca; Reino Unido
Fil: Tornador, Cristian. Teresa Moretó Foundation And Wholegenix Sl; España
Fil: Aguilar Hernández, Andrés. Hospital Universitari Dexeus; España
Fil: Reguart, Noemí. Hospital Clinic Barcelona; España
Fil: Ditzel, Henrik J.. University of Southern Denmark,; Dinamarca. Odense University Hospital; Dinamarca
Fil: Martínez Bueno, Alejandro. Hospital Universitari Dexeus; España
Fil: Nabau Moretó, Núria. Teresa Moretó Foundation And Wholegenix Sl; España
Fil: Gascó, Amaya. Astrazeneca; Reino Unido
Fil: Rosell, Rafael. Germans Trias I Pujol Research Institute; España. Hospital Universitari Dexeus; España
Fil: Pease, J. Elizabeth. Astrazeneca; Reino Unido
Fil: Polanska, Urszula M.. Astrazeneca; Reino Unido
Fil: Travers, Jon. Astrazeneca; Reino Unido
Fil: Urosevic, Jelena. Astrazeneca; Reino Unido
Fil: Molina Vila, Miguel A.. Hospital Universitari Dexeus; España - Materia
-
ABROGATION
AURKB INHIBITOR
BID
BIOMARKER
CASP-2
CELL CYCLE
SPINDLE ASSEMBLY CHECKPOINT (SAC)
TTK INHIBITOR
TUMOR - Nivel de accesibilidad
- acceso abierto
- Condiciones de uso
- https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
- Repositorio
.jpg)
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/230099
Ver los metadatos del registro completo
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BID expression determines the apoptotic fate of cancer cells after abrogation of the spindle assembly checkpoint by AURKB or TTK inhibitorsBertran Alamillo, JordiGiménez Capitán, AnaRomán, RuthTalbot, SaraWhiteley, RebeccaFloch, NicolasMartinez Perez, ElizabethMartin, Matthew J.Smith, Paul D.Sullivan, IvanaTerp, Mikkel G.Saeh, JamalMarino Buslje, CristinaFabbri, GiuliaGuo, GraceXu, ManTornador, CristianAguilar Hernández, AndrésReguart, NoemíDitzel, Henrik J.Martínez Bueno, AlejandroNabau Moretó, NúriaGascó, AmayaRosell, RafaelPease, J. ElizabethPolanska, Urszula M.Travers, JonUrosevic, JelenaMolina Vila, Miguel A.ABROGATIONAURKB INHIBITORBIDBIOMARKERCASP-2CELL CYCLESPINDLE ASSEMBLY CHECKPOINT (SAC)TTK INHIBITORTUMORhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Background: Drugs targeting the spindle assembly checkpoint (SAC), such as inhibitors of Aurora kinase B (AURKB) and dual specific protein kinase TTK, are in different stages of clinical development. However, cell response to SAC abrogation is poorly understood and there are no markers for patient selection. Methods: A panel of 53 tumor cell lines of different origins was used. The effects of drugs were analyzed by MTT and flow cytometry. Copy number status was determined by FISH and Q-PCR; mRNA expression by nCounter and RT-Q-PCR and protein expression by Western blotting. CRISPR-Cas9 technology was used for gene knock-out (KO) and a doxycycline-inducible pTRIPZ vector for ectopic expression. Finally, in vivo experiments were performed by implanting cultured cells or fragments of tumors into immunodeficient mice. Results: Tumor cells and patient-derived xenografts (PDXs) sensitive to AURKB and TTK inhibitors consistently showed high expression levels of BH3-interacting domain death agonist (BID), while cell lines and PDXs with low BID were uniformly resistant. Gene silencing rendered BID-overexpressing cells insensitive to SAC abrogation while ectopic BID expression in BID-low cells significantly increased sensitivity. SAC abrogation induced activation of CASP-2, leading to cleavage of CASP-3 and extensive cell death only in presence of high levels of BID. Finally, a prevalence study revealed high BID mRNA in 6% of human solid tumors. Conclusions: The fate of tumor cells after SAC abrogation is driven by an AURKB/ CASP-2 signaling mechanism, regulated by BID levels. Our results pave the way to clinically explore SAC-targeting drugs in tumors with high BID expression.Fil: Bertran Alamillo, Jordi. Quiron Dexeus University Hospital; EspañaFil: Giménez Capitán, Ana. Quiron Dexeus University Hospital; EspañaFil: Román, Ruth. Quiron Dexeus University Hospital; EspañaFil: Talbot, Sara. Quiron Dexeus University Hospital; EspañaFil: Whiteley, Rebecca. Quiron Dexeus University Hospital; EspañaFil: Floch, Nicolas. Astrazeneca; Reino UnidoFil: Martinez Perez, Elizabeth. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Martin, Matthew J.. Astrazeneca; Reino UnidoFil: Smith, Paul D.. Astrazeneca; Reino UnidoFil: Sullivan, Ivana. Hospital de la Santa Creu I Sant Pau; España. Hospital Universitari Dexeus; EspañaFil: Terp, Mikkel G.. University of Southern Denmark; DinamarcaFil: Saeh, Jamal. Astrazeneca; Reino UnidoFil: Marino Buslje, Cristina. Fundación Instituto Leloir; ArgentinaFil: Fabbri, Giulia. Astrazeneca; Reino UnidoFil: Guo, Grace. Astrazeneca; Reino UnidoFil: Xu, Man. Astrazeneca; Reino UnidoFil: Tornador, Cristian. Teresa Moretó Foundation And Wholegenix Sl; EspañaFil: Aguilar Hernández, Andrés. Hospital Universitari Dexeus; EspañaFil: Reguart, Noemí. Hospital Clinic Barcelona; EspañaFil: Ditzel, Henrik J.. University of Southern Denmark,; Dinamarca. Odense University Hospital; DinamarcaFil: Martínez Bueno, Alejandro. Hospital Universitari Dexeus; EspañaFil: Nabau Moretó, Núria. Teresa Moretó Foundation And Wholegenix Sl; EspañaFil: Gascó, Amaya. Astrazeneca; Reino UnidoFil: Rosell, Rafael. Germans Trias I Pujol Research Institute; España. Hospital Universitari Dexeus; EspañaFil: Pease, J. Elizabeth. Astrazeneca; Reino UnidoFil: Polanska, Urszula M.. Astrazeneca; Reino UnidoFil: Travers, Jon. Astrazeneca; Reino UnidoFil: Urosevic, Jelena. Astrazeneca; Reino UnidoFil: Molina Vila, Miguel A.. Hospital Universitari Dexeus; EspañaBioMed Central2023-12info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/230099Bertran Alamillo, Jordi; Giménez Capitán, Ana; Román, Ruth; Talbot, Sara; Whiteley, Rebecca; et al.; BID expression determines the apoptotic fate of cancer cells after abrogation of the spindle assembly checkpoint by AURKB or TTK inhibitors; BioMed Central; Molecular Cancer; 22; 1; 12-2023; 1-241476-4598CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1186/s12943-023-01815-winfo:eu-repo/semantics/altIdentifier/url/https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-023-01815-winfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:50:33Zoai:ri.conicet.gov.ar:11336/230099instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-03 09:50:33.782CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse |
| dc.title.none.fl_str_mv |
BID expression determines the apoptotic fate of cancer cells after abrogation of the spindle assembly checkpoint by AURKB or TTK inhibitors |
| title |
BID expression determines the apoptotic fate of cancer cells after abrogation of the spindle assembly checkpoint by AURKB or TTK inhibitors |
| spellingShingle |
BID expression determines the apoptotic fate of cancer cells after abrogation of the spindle assembly checkpoint by AURKB or TTK inhibitors Bertran Alamillo, Jordi ABROGATION AURKB INHIBITOR BID BIOMARKER CASP-2 CELL CYCLE SPINDLE ASSEMBLY CHECKPOINT (SAC) TTK INHIBITOR TUMOR |
| title_short |
BID expression determines the apoptotic fate of cancer cells after abrogation of the spindle assembly checkpoint by AURKB or TTK inhibitors |
| title_full |
BID expression determines the apoptotic fate of cancer cells after abrogation of the spindle assembly checkpoint by AURKB or TTK inhibitors |
| title_fullStr |
BID expression determines the apoptotic fate of cancer cells after abrogation of the spindle assembly checkpoint by AURKB or TTK inhibitors |
| title_full_unstemmed |
BID expression determines the apoptotic fate of cancer cells after abrogation of the spindle assembly checkpoint by AURKB or TTK inhibitors |
| title_sort |
BID expression determines the apoptotic fate of cancer cells after abrogation of the spindle assembly checkpoint by AURKB or TTK inhibitors |
| dc.creator.none.fl_str_mv |
Bertran Alamillo, Jordi Giménez Capitán, Ana Román, Ruth Talbot, Sara Whiteley, Rebecca Floch, Nicolas Martinez Perez, Elizabeth Martin, Matthew J. Smith, Paul D. Sullivan, Ivana Terp, Mikkel G. Saeh, Jamal Marino Buslje, Cristina Fabbri, Giulia Guo, Grace Xu, Man Tornador, Cristian Aguilar Hernández, Andrés Reguart, Noemí Ditzel, Henrik J. Martínez Bueno, Alejandro Nabau Moretó, Núria Gascó, Amaya Rosell, Rafael Pease, J. Elizabeth Polanska, Urszula M. Travers, Jon Urosevic, Jelena Molina Vila, Miguel A. |
| author |
Bertran Alamillo, Jordi |
| author_facet |
Bertran Alamillo, Jordi Giménez Capitán, Ana Román, Ruth Talbot, Sara Whiteley, Rebecca Floch, Nicolas Martinez Perez, Elizabeth Martin, Matthew J. Smith, Paul D. Sullivan, Ivana Terp, Mikkel G. Saeh, Jamal Marino Buslje, Cristina Fabbri, Giulia Guo, Grace Xu, Man Tornador, Cristian Aguilar Hernández, Andrés Reguart, Noemí Ditzel, Henrik J. Martínez Bueno, Alejandro Nabau Moretó, Núria Gascó, Amaya Rosell, Rafael Pease, J. Elizabeth Polanska, Urszula M. Travers, Jon Urosevic, Jelena Molina Vila, Miguel A. |
| author_role |
author |
| author2 |
Giménez Capitán, Ana Román, Ruth Talbot, Sara Whiteley, Rebecca Floch, Nicolas Martinez Perez, Elizabeth Martin, Matthew J. Smith, Paul D. Sullivan, Ivana Terp, Mikkel G. Saeh, Jamal Marino Buslje, Cristina Fabbri, Giulia Guo, Grace Xu, Man Tornador, Cristian Aguilar Hernández, Andrés Reguart, Noemí Ditzel, Henrik J. Martínez Bueno, Alejandro Nabau Moretó, Núria Gascó, Amaya Rosell, Rafael Pease, J. Elizabeth Polanska, Urszula M. Travers, Jon Urosevic, Jelena Molina Vila, Miguel A. |
| author2_role |
author author author author author author author author author author author author author author author author author author author author author author author author author author author author |
| dc.subject.none.fl_str_mv |
ABROGATION AURKB INHIBITOR BID BIOMARKER CASP-2 CELL CYCLE SPINDLE ASSEMBLY CHECKPOINT (SAC) TTK INHIBITOR TUMOR |
| topic |
ABROGATION AURKB INHIBITOR BID BIOMARKER CASP-2 CELL CYCLE SPINDLE ASSEMBLY CHECKPOINT (SAC) TTK INHIBITOR TUMOR |
| purl_subject.fl_str_mv |
https://purl.org/becyt/ford/1.6 https://purl.org/becyt/ford/1 |
| dc.description.none.fl_txt_mv |
Background: Drugs targeting the spindle assembly checkpoint (SAC), such as inhibitors of Aurora kinase B (AURKB) and dual specific protein kinase TTK, are in different stages of clinical development. However, cell response to SAC abrogation is poorly understood and there are no markers for patient selection. Methods: A panel of 53 tumor cell lines of different origins was used. The effects of drugs were analyzed by MTT and flow cytometry. Copy number status was determined by FISH and Q-PCR; mRNA expression by nCounter and RT-Q-PCR and protein expression by Western blotting. CRISPR-Cas9 technology was used for gene knock-out (KO) and a doxycycline-inducible pTRIPZ vector for ectopic expression. Finally, in vivo experiments were performed by implanting cultured cells or fragments of tumors into immunodeficient mice. Results: Tumor cells and patient-derived xenografts (PDXs) sensitive to AURKB and TTK inhibitors consistently showed high expression levels of BH3-interacting domain death agonist (BID), while cell lines and PDXs with low BID were uniformly resistant. Gene silencing rendered BID-overexpressing cells insensitive to SAC abrogation while ectopic BID expression in BID-low cells significantly increased sensitivity. SAC abrogation induced activation of CASP-2, leading to cleavage of CASP-3 and extensive cell death only in presence of high levels of BID. Finally, a prevalence study revealed high BID mRNA in 6% of human solid tumors. Conclusions: The fate of tumor cells after SAC abrogation is driven by an AURKB/ CASP-2 signaling mechanism, regulated by BID levels. Our results pave the way to clinically explore SAC-targeting drugs in tumors with high BID expression. Fil: Bertran Alamillo, Jordi. Quiron Dexeus University Hospital; España Fil: Giménez Capitán, Ana. Quiron Dexeus University Hospital; España Fil: Román, Ruth. Quiron Dexeus University Hospital; España Fil: Talbot, Sara. Quiron Dexeus University Hospital; España Fil: Whiteley, Rebecca. Quiron Dexeus University Hospital; España Fil: Floch, Nicolas. Astrazeneca; Reino Unido Fil: Martinez Perez, Elizabeth. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina Fil: Martin, Matthew J.. Astrazeneca; Reino Unido Fil: Smith, Paul D.. Astrazeneca; Reino Unido Fil: Sullivan, Ivana. Hospital de la Santa Creu I Sant Pau; España. Hospital Universitari Dexeus; España Fil: Terp, Mikkel G.. University of Southern Denmark; Dinamarca Fil: Saeh, Jamal. Astrazeneca; Reino Unido Fil: Marino Buslje, Cristina. Fundación Instituto Leloir; Argentina Fil: Fabbri, Giulia. Astrazeneca; Reino Unido Fil: Guo, Grace. Astrazeneca; Reino Unido Fil: Xu, Man. Astrazeneca; Reino Unido Fil: Tornador, Cristian. Teresa Moretó Foundation And Wholegenix Sl; España Fil: Aguilar Hernández, Andrés. Hospital Universitari Dexeus; España Fil: Reguart, Noemí. Hospital Clinic Barcelona; España Fil: Ditzel, Henrik J.. University of Southern Denmark,; Dinamarca. Odense University Hospital; Dinamarca Fil: Martínez Bueno, Alejandro. Hospital Universitari Dexeus; España Fil: Nabau Moretó, Núria. Teresa Moretó Foundation And Wholegenix Sl; España Fil: Gascó, Amaya. Astrazeneca; Reino Unido Fil: Rosell, Rafael. Germans Trias I Pujol Research Institute; España. Hospital Universitari Dexeus; España Fil: Pease, J. Elizabeth. Astrazeneca; Reino Unido Fil: Polanska, Urszula M.. Astrazeneca; Reino Unido Fil: Travers, Jon. Astrazeneca; Reino Unido Fil: Urosevic, Jelena. Astrazeneca; Reino Unido Fil: Molina Vila, Miguel A.. Hospital Universitari Dexeus; España |
| description |
Background: Drugs targeting the spindle assembly checkpoint (SAC), such as inhibitors of Aurora kinase B (AURKB) and dual specific protein kinase TTK, are in different stages of clinical development. However, cell response to SAC abrogation is poorly understood and there are no markers for patient selection. Methods: A panel of 53 tumor cell lines of different origins was used. The effects of drugs were analyzed by MTT and flow cytometry. Copy number status was determined by FISH and Q-PCR; mRNA expression by nCounter and RT-Q-PCR and protein expression by Western blotting. CRISPR-Cas9 technology was used for gene knock-out (KO) and a doxycycline-inducible pTRIPZ vector for ectopic expression. Finally, in vivo experiments were performed by implanting cultured cells or fragments of tumors into immunodeficient mice. Results: Tumor cells and patient-derived xenografts (PDXs) sensitive to AURKB and TTK inhibitors consistently showed high expression levels of BH3-interacting domain death agonist (BID), while cell lines and PDXs with low BID were uniformly resistant. Gene silencing rendered BID-overexpressing cells insensitive to SAC abrogation while ectopic BID expression in BID-low cells significantly increased sensitivity. SAC abrogation induced activation of CASP-2, leading to cleavage of CASP-3 and extensive cell death only in presence of high levels of BID. Finally, a prevalence study revealed high BID mRNA in 6% of human solid tumors. Conclusions: The fate of tumor cells after SAC abrogation is driven by an AURKB/ CASP-2 signaling mechanism, regulated by BID levels. Our results pave the way to clinically explore SAC-targeting drugs in tumors with high BID expression. |
| publishDate |
2023 |
| dc.date.none.fl_str_mv |
2023-12 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion http://purl.org/coar/resource_type/c_6501 info:ar-repo/semantics/articulo |
| format |
article |
| status_str |
publishedVersion |
| dc.identifier.none.fl_str_mv |
http://hdl.handle.net/11336/230099 Bertran Alamillo, Jordi; Giménez Capitán, Ana; Román, Ruth; Talbot, Sara; Whiteley, Rebecca; et al.; BID expression determines the apoptotic fate of cancer cells after abrogation of the spindle assembly checkpoint by AURKB or TTK inhibitors; BioMed Central; Molecular Cancer; 22; 1; 12-2023; 1-24 1476-4598 CONICET Digital CONICET |
| url |
http://hdl.handle.net/11336/230099 |
| identifier_str_mv |
Bertran Alamillo, Jordi; Giménez Capitán, Ana; Román, Ruth; Talbot, Sara; Whiteley, Rebecca; et al.; BID expression determines the apoptotic fate of cancer cells after abrogation of the spindle assembly checkpoint by AURKB or TTK inhibitors; BioMed Central; Molecular Cancer; 22; 1; 12-2023; 1-24 1476-4598 CONICET Digital CONICET |
| dc.language.none.fl_str_mv |
eng |
| language |
eng |
| dc.relation.none.fl_str_mv |
info:eu-repo/semantics/altIdentifier/doi/10.1186/s12943-023-01815-w info:eu-repo/semantics/altIdentifier/url/https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-023-01815-w |
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info:eu-repo/semantics/openAccess https://creativecommons.org/licenses/by-nc-sa/2.5/ar/ |
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openAccess |
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https://creativecommons.org/licenses/by-nc-sa/2.5/ar/ |
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application/pdf application/pdf |
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BioMed Central |
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BioMed Central |
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dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar |
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