40 results on '"Villarreal, Jaime"'
Search Results
2. NFIC regulates ribosomal biology and ER stress in pancreatic acinar cells and restrains PDAC initiation
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Cobo, Isidoro, Paliwal, Sumit, Bodas, Cristina, Felipe, Irene, Melià-Alomà, Júlia, Torres, Ariadna, Martínez-Villarreal, Jaime, Malumbres, Marina, García, Fernando, Millán, Irene, del Pozo, Natalia, Park, Joo-Cheol, MacDonald, Ray J., Muñoz, Javier, Méndez, Raúl, and Real, Francisco X.
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- 2023
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3. Integrating socioeconomic and ecological data into restoration practice.
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Villarreal‐Rosas, Jaramar, Brown, Christopher J., Andradi‐Brown, Dominic A., Domínguez, Ricardo, Jacobo, Pilar, Martínez, Anuar, Mascote, Coral, Najera, Eduardo, Paiz, Yves, Vázquez Moran, Víctor Hugo, Villarreal, Jaime, and Adame, María F.
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RESTORATION ecology ,MANGROVE ecology ,ABSOLUTE sea level change ,BIOSPHERE reserves ,NONGOVERNMENTAL organizations ,SOCIAL accounting - Abstract
Copyright of Conservation Biology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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- 2024
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4. Kinematic comparison of the use of walking sticks versus a rolling walker during gait in adult degenerative scoliosis patients
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Haddas, Ram, Villarreal, Jaime, and Lieberman, Isador H.
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- 2020
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5. Publisher Correction: Pancreatic duct ligation reduces premalignant pancreatic lesions in a Kras model of pancreatic adenocarcinoma in mice
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Cáceres, Marta, Quesada, Rita, Iglesias, Mar, Real, Francisco X., Villamonte, Maria, de Villarreal, Jaime Martinez, Pérez, Mónica, Andaluz, Ana, Moll, Xavier, Berjano, Enrique, Dorcaratto, Dimitri, Sánchez-Velázquez, Patricia, Grande, Luís, and Burdío, Fernando
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- 2021
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6. Secondary resistance to anti-EGFR therapy by transcriptional reprogramming in patient-derived colorectal cancer models
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Vangala, Deepak, Ladigan, Swetlana, Liffers, Sven T., Noseir, Soha, Maghnouj, Abdelouahid, Götze, Tina-Maria, Verdoodt, Berlinda, Klein-Scory, Susanne, Godfrey, Laura, Zowada, Martina K., Huerta, Mario, Edelstein, Daniel L., de Villarreal, Jaime Martinez, Marqués, Miriam, Kumbrink, Jörg, Jung, Andreas, Schiergens, Tobias, Werner, Jens, Heinemann, Volker, Stintzing, Sebastian, Lindoerfer, Doris, Mansmann, Ulrich, Pohl, Michael, Teschendorf, Christian, Bernhardt, Christiane, Wolters, Heiner, Stern, Josef, Usta, Selami, Viebahn, Richard, Admard, Jacob, Casadei, Nicolas, Fröhling, Stefan, Ball, Claudia R., Siveke, Jens T., Glimm, Hanno, Tannapfel, Andrea, Schmiegel, Wolff, and Hahn, Stephan A.
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- 2021
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7. Pancreatic duct ligation reduces premalignant pancreatic lesions in a Kras model of pancreatic adenocarcinoma in mice
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Cáceres, Marta, Quesada, Rita, Iglesias, Mar, Real, Francisco X., Villamonte, Maria, de Villarreal, Jaime Martinez, Pérez, Mónica, Andaluz, Ana, Moll, Xavier, Berjano, Enrique, Dorcaratto, Dimitri, Sánchez-Velázquez, Patricia, Grande, Luís, and Burdío, Fernando
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- 2020
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8. Contribution of BRCA1 and BRCA2 germline mutations to early onset breast cancer: a series from north of Morocco
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Bakkach, Joaira, Mansouri, Mohamed, Derkaoui, Touria, Loudiyi, Ali, El Fahime, ElMostafa, Barakat, Amina, Ghailani Nourouti, Naima, Martinez De Villarreal, Jaime, Cortijo Bringas, Carlos, and Bennani Mechita, Mohcine
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- 2020
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9. Urothelial organoids originating from Cd49fhigh mouse stem cells display Notch-dependent differentiation capacity
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Santos, Catarina P., Lapi, Eleonora, Martínez de Villarreal, Jaime, Álvaro-Espinosa, Laura, Fernández-Barral, Asunción, Barbáchano, Antonio, Domínguez, Orlando, Laughney, Ashley M., Megías, Diego, Muñoz, Alberto, and Real, Francisco X.
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- 2019
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10. Viajeros a la luna: Federico y Frederic
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Villarreal, Jaime Moreno
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- 1999
11. LA CALCOMANÍA DE JOSÉ CASTRO LEÑERO
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Villarreal, Jaime Moreno
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- 1998
12. RODOLFO NIETO LOS SERES FRATERNOS
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Villarreal, Jaime Moreno
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- 1997
13. JULIO GALÁN: TEORÍA DEL MUÑECO
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Villarreal, Jaime Moreno
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- 1996
14. Mitochondrial localization of the Forkhead box class O transcription factor FOXO3a in brain
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Caballero-Caballero, Aurelien, Engel, Tobias, Martinez-Villarreal, Jaime, Sanz-Rodriguez, Amaya, Chang, Patrick, Dunleavy, Mark, Mooney, Claire M., Jimenez-Mateos, Eva M., Schindler, Clara K., and Henshall, David C.
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- 2013
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15. Natural killer cells act as an extrinsic barrier for in vivo reprogramming.
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Melendez, Elena, Chondronasiou, Dafni, Mosteiro, Lluc, de Villarreal, Jaime Martınez, Ferna'ndez-Alfara, Marcos, Lynch, Cian J., Grimm, Dirk, Real, Francisco X., Alcamı, José, Climent, Núria, Pietrocola, Federico, and Serrano, Manuel
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EMBRYONIC stem cells ,KILLER cells ,ACQUISITION of property ,PLURIPOTENT stem cells ,TRANSCRIPTION factors - Abstract
The ectopic expression of the transcription factors OCT4, SOX2, KLF4 and MYC (OSKM) enables reprogramming of differentiated cells into pluripotent embryonic stem cells. Methods based on partial and reversible in vivo reprogramming are a promising strategy for tissue regeneration and rejuvenation. However, little is known about the barriers that impair reprogramming in an in vivo context. We report that natural killer (NK) cells significantly limit reprogramming, both in vitro and in vivo. Cells and tissues in the intermediate states of reprogramming upregulate the expression of NK-activating ligands, such as MULT1 and ICAM1. NK cells recognize and kill partially reprogrammed cells in a degranulation-dependent manner. Importantly, in vivo partial reprogramming is strongly reduced by adoptive transfer of NK cells, whereas it is significantly increased by their depletion. Notably, in the absence of NK cells, the pancreatic organoids derived from OSKM-expressing mice are remarkably large, suggesting that ablating NK surveillance favours the acquisition of progenitor-like properties. We conclude that NK cells pose an important barrier for in vivo reprogramming, and speculate that this concept may apply to other contexts of transient cellular plasticity. [ABSTRACT FROM AUTHOR]
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- 2022
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16. A GATA6-centred gene regulatory network involving HNFs and ΔNp63 controls plasticity and immune escape in pancreatic cancer.
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Kloesch, Bernhard, Ionasz, Vivien, Paliwal, Sumit, Hruschka, Natascha, Martinez de Villarreal, Jaime, Öllinger, Rupert, Mueller, Sebastian, Dienes, Hans Peter, Schindl, Martin, Gruber, Elisabeth S., Stift, Judith, Herndler-Brandstetter, Dietmar, Lomberk, Gwen A., Seidler, Barbara, Saur, Dieter, Rad, Roland, Urrutia, Raul A., Real, Francisco X., and Martinelli, Paola
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GENE regulatory networks ,PANCREATIC tumors ,PANCREATIC cancer ,MEDICAL ethics - Published
- 2022
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17. Cell surface turnover of the glutamate transporter GLT-1 is mediated by ubiquitination/deubiquitination
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Martínez-Villarreal, Jaime, García Tardón, Noemí, Ibáñez, Ignacio, Giménez, Cecilio, and Zafra, Francisco
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- 2012
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18. Time to a Negative SARS-CoV-2 PCR Predicts Delayed Return to Work After Medical Leave in COVID-19 Infected Health Care Workers.
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Villarreal, Jaime, Nieto, Sandra Valeria, Vázquez, Fabián, del Campo, M. Teresa, Mahillo, Ignacio, and de la Hoz, Rafael E.
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OCCUPATIONAL diseases , *POLYMERASE chain reaction , *MULTIVARIATE analysis , *DESCRIPTIVE statistics , *ODDS ratio , *LUNG diseases , *OCCUPATIONAL exposure , *CONFIDENCE intervals , *COVID-19 pandemic , *EMPLOYMENT reentry , *COVID-19 , *TIME - Abstract
Objective: To investigate whether HCWs return to work (RTW) after COVID-19 was associated with time to a negative viral detection test. Methods: To evaluate the association of RTW with an undetectable RT-PCR adjusting for different factors. Results: Three hundred seventy-five HCWs who required medical leave for COVID-19 at a hospital in Madrid. Multivariable analyses confirmed the association of delayed RTW with interval to negative PCR (ORadj 1.12, 95% CI 1.08, 1.17) as well as age, sex, and nursing staff and clinical support services compared to physicians. A predictive model based on those variables is proposed, which had an area under the receiver operating curve of 0.82. Conclusions: Delayed RTW was associated with longer interval to a negative RT-PCR after symptom onset, adjusting for occupational category, age, and sex. [ABSTRACT FROM AUTHOR]
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- 2021
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19. HNF1A plays a context-dependent role in pancreatic cancer initiation and progression.
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Felipe, Irene, Bodas, Cristina, Paliwal, Sumit, Pozo, Natalia del, Martínez de Villarreal, Jaime, Kalisz, Mark, Ferrer, Jorge, and Real, Francisco X.
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- 2023
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20. Screening of BRCA1 and BRCA2 germline mutations in unselected triple‐negative breast cancer patients: A series from north of Morocco.
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Mansouri, Mohammed, Derkaoui, Touria, Bakkach, Joaira, Loudiyi, Ali, Ghailani Nourouti, Naima, Barakat, Amina, Villarreal, Jaime Martínez, Bringas, Carlos Cortijo, and Bennani Mechita, Mohcine
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- 2020
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21. Poema de las cosas
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Villarreal, Jaime Moreno
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- 1984
22. Violencia sexual en zonas posconflicto: reflexiones en torno al caso de la República Centroafricana.
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Maximiliano Jiménez Villarreal, Jaime Edgar and Jiménez Montalvo, Daniel Andrés
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This article exposes allegations of sexual violence from 2015 to 2016 by United Nations peacekeepers during the peace operation of the Central African Republic. The main objective is to highlight accusations of sexual exploitation and abuse and condemn the measures implemented by the United Nations. An attempt is made to answer whether international humanitarian law should judge acts of sexual violence perpetrated by peacekeepers towards civilians in post-conflict zones. The analysis, carried out through bibliographic-documentary research, intends to oppose impunity and reinforce the credibility of peace operations, as well as their personnel as instruments of conflict resolution in the international scenario. [ABSTRACT FROM AUTHOR]
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- 2019
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23. MARIÁTEGUI Y BENJAMIN, EL ITINERARIO DEL INTELECTUAL VANGUARDISTA.
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Villarreal, Jaime
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- 2018
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24. A Phase III Randomized Clinical Trial of a 0.5% Timolol + 0.2% Brimonidine + 2.0% Dorzolamide Fixed Combination, Preservative-Free Ophthalmic Solution vs. 0.5% Timolol + 0.2% Brimonidine + 2.0%...
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Gómez-Aguayo, Francisco, Paczka, José A., Leñero-Córdova, Rubén, Jiménez-Román, Jesús, Davila-Villarreal, Jaime, Hartleben, Curt, Baiza-Durán, Leopoldo, Olvera-Montaño, Oscar, García-Velez, Francisco, and Muñoz-Villegas, Patricia
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- 2018
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25. Spatiotemporal progression of ubiquitinproteasome system inhibition after status epilepticus suggests protective adaptation against hippocampal injury.
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Engel, Tobias, Martinez-Villarreal, Jaime, Henke, Christine, Jimenez-Mateos, Eva M., Sanz-Rodriguez, Amaya, Alves, Mariana, Hernandez-Santana, Yasmina, Brennan, Gary P., Kenny, Aidan, Campbell, Aoife, Lucas, Jose J., and Henshall, David C.
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PROTEASOME inhibitors , *STATUS epilepticus treatment , *HIPPOCAMPUS injuries , *NEUROPLASTICITY , *NEUROTRANSMITTERS - Abstract
Background: The ubiquitin-proteasome-system (UPS) is the major intracellular pathway leading to the degradation of unwanted and/or misfolded soluble proteins. This includes proteins regulating cellular survival, synaptic plasticity and neurotransmitter signaling; processes controlling excitability thresholds that are altered by epileptogenic insults. Dysfunction of the UPS has been reported to occur in a brain region- and cell-specific manner and contribute to disease progression in acute and chronic brain diseases. Prolonged seizures, status epilepticus, may alter UPS function but there has been no systematic attempt to map when and where this occurs in vivo or to determine the consequences of proteasome inhibition on seizure-induced brain injury. Method: To determine whether seizures lead to an impairment of the UPS, we used a mouse model of status epilepticus whereby seizures are triggered by an intra-amygdala injection of kainic acid. Status ilepticus in this model causes cell death in selected brain areas, in particular the ipsilateral CA3 subfield of the hippocampus, and the development of epilepsy after a short latent period. To monitor seizure-induced sfunction of the UPS we used a UPS inhibition reporter mouse expressing the ubiquitin fusion degradation substrate ubiquitinG76V-green fluorescent protein. Treatment with the specific proteasome inhibitorepoxomicin was used to establish the impact of proteasome inhibition on seizure-induced pathology. Results and conclusions: Our studies show that status epilepticus induced by intra-amygdala kainic acid causes select spatio-temporal UPS inhibition which is most evident in damage-resistant regions of the hippocampus, including CA1 pyramidal and dentate granule neurons then appears later in astrocytes. In support of this exerting a beneficial effect, injection of mice with the proteasome inhibitor epoxomicin protected the normally vulnerable hippocampal CA3 subfield from seizure-induced neuronal death in the model. These studies reveal brain region- and cell-specific UPS impairment occurs after seizures and suggest UPS inhibition can protect against seizure-induced brain damage. Identifying networks or pathways regulated through the proteasome after seizures may yield novel target genes for the treatment of seizure-induced cell death and possibly epilepsy. [ABSTRACT FROM AUTHOR]
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- 2017
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26. Three-Dimensional, Digital, and Gross Anatomy of the Lisfranc Ligament.
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Panchbhavi, Vinod K., Molina IV, Domingo, Villarreal, Jaime, Curry, Michael C., and Andersen, Clark R.
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The article reports on research which was conducted to assess the three dimensional anatomy of the Lisfranc ligament and its attachment sites. Researchers evaluated 37 cadaver feet that were dissected to expose the ligament attachments at the Lisfranc joint.They found that the Lisfranc ligament is variable in anatomy and can have a single or double-bundle arrangement and that its area of attachment is larger than that of the plantar ligament.
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- 2013
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27. Constitutive and Regulated Endocytosis of the Glycine Transporter GLYT1b Is Controlled by Ubiquitination.
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Fernández-Sánchez, Enrique, Martínez-Villarreal, Jaime, Giménez, Cecilio, and Zafra, Francisco
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ENDOCYTOSIS , *GLYCINE , *UBIQUITIN , *PHORBOL esters , *PROTEIN kinase C , *MOSAICISM , *LYSINE , *NEURAL transmission - Abstract
The glycine transporter GLYT1 regulates both glycinergic and glutamatergic neurotransmission by controlling the reuptake of glycine at synapses. Trafficking of GLYT1 to and from the cell surface is critical for its function. Activation of PKC down-regulates the activity of GLYT1 through a mechanism that has so far remained uncharacterized. Here we show that GLYT1b undergoes fast constitutive endocytosis that is accelerated by phorbol esters. Both constitutive and regulated endocytosis occur through a dynamin 2and clathrin-dependent pathway, accumulating in the transporter in transferrin-containing endosomes. A chimera with the extracellular and transmembrane domains of the nerve growth factor receptor and the COOH-terminal tail of GLYT1 was efficiently internalized through this clathrin pathway, suggesting the presence of molecular determinants for GLYT1b endocytosis in its COOH-terminal tail. Extensive site-directed mutagenesis in this region of the chimera highlighted the involvement of lysine residues in its internalization. In the context of the full-length transporter, lysine 619 played a prominent role in both the constitutive and phorbol 12-myristate 13-acetate-induced endocytosis of GLYT1b, suggesting the involvement of ubiquitin modification of GLYT1b during the internalization process. Indeed, we show that GLYT1b undergoes ubiquitination and that this process is stimulated by phorbol 12-myristate 13-acetate. In addition, this endocytosis is impaired in an ubiquitination-deficient cell line, further evidence that constitutive and regulated endocytosis of GLYT1b is ubiquitin-dependent. It remains to be determined whether GLYT1b recycling might be affected in pathologies involving alterations to the ubiquitin system, thereby interfering with its influence on inhibitory and excitatory neurotransmission. [ABSTRACT FROM AUTHOR]
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- 2009
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28. Urothelial organoids originating from Cd49fhigh mouse stem cells display Notch-dependent differentiation capacity.
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Santos, Catarina P., Lapi, Eleonora, Martínez de Villarreal, Jaime, Álvaro-Espinosa, Laura, Fernández-Barral, Asunción, Barbáchano, Antonio, Domínguez, Orlando, Laughney, Ashley M., Megías, Diego, Muñoz, Alberto, and Real, Francisco X.
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ORGANOIDS ,STEM cells ,CYTOLOGY ,CELL proliferation ,GENE expression - Abstract
Understanding urothelial stem cell biology and differentiation has been limited by the lack of methods for their unlimited propagation. Here, we establish mouse urothelial organoids that can be maintained uninterruptedly for >1 year. Organoid growth is dependent on EGF and Wnt activators. High CD49f/ITGA6 expression features a subpopulation of organoid-forming cells expressing basal markers. Upon differentiation, multilayered organoids undergo reduced proliferation, decreased cell layer number, urothelial program activation, and acquisition of barrier function. Pharmacological modulation of PPARγ and EGFR promotes differentiation. RNA sequencing highlighted genesets enriched in proliferative organoids (i.e. ribosome) and transcriptional networks involved in differentiation, including expression of Wnt ligands and Notch components. Single-cell RNA sequencing (scRNA-Seq) analysis of the organoids revealed five clusters with distinct gene expression profiles. Together with the use of γ-secretase inhibitors, scRNA-Seq confirms that Notch signaling is required for differentiation. Urothelial organoids provide a powerful tool to study cell regeneration and differentiation. The biology of the urothelium has been difficult to study given the lack of methods to propagate these cells. Here, the authors generate mouse urothelial organoids derived from bladder urothelial cells with high CD49f/ITGA6 and define what regulates urothelium differentiation, which is PPARγ, EGFR and Notch signalling. [ABSTRACT FROM AUTHOR]
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- 2019
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29. A Novel Dominant Hyperekplexia Mutation Y705C Alters Trafficking and Biochemical Properties of the Presynaptic Glycine Transporter GlyT2.
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Giménez, Cecilio, Pérez-Siles, Gonzalo, Martínez-Villarreal, Jaime, Arribas-González, Esther, Jiménez, Esperanza, Nüñez, Enrique, Juan-Sanz, Jaime de, Fernández-Sánchez, Enrique, García-Tardón, Noemí, Ibáñez, Ignacio, Romanelli, Valeria, Nevado, Julián, James, Victoria M., Topf, Maya, Chung, Seo-Kyung, Thomas, Rhys H., Desviat, Lourdes R., Aragón, Carmen, Zafra, Francisco, and Rees, Mark I.
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STARTLE reaction , *APNEA , *GLYCINE receptors , *NUCLEOTIDE sequence , *DNA , *GENETIC mutation - Abstract
Hyperekplexia or startle disease is characterized by an exaggerated startle response, evoked by tactile or auditory stimuli, producing hypertonia and apnea episodes. Although rare, this orphan disorder can have serious consequences, including sudden infant death. Dominant and recessive mutations in the human glycine receptor (GlyR) α1 gene (GLRA1) are the major cause of this disorder. However, recessive mutations in the presynaptic Na+/Cl--dependent glycine transporter GlyT2 gene (SLC6A5) are rapidly emerging as a second major cause of startle disease. In this study, systematic DNA sequencing of SLC6A5 revealed a new dominant GlyT2 mutation: pY705C (c.2114A→G) in transmembrane domain 11, in eight individuals from Spain and the United Kingdom. Curiously, individuals harboring this mutation show significant variation in clinical presentation. In addition to classical hyperekplexia symptoms, some individuals had abnormal respiration, facial dysmorphism, delayed motor development, or intellectual disability. We functionally characterized this mutation using molecular modeling, electrophysiology, [3H]glycine transport, cell surface expression, and cysteine labeling assays. We found that the introduced cysteine interacts with the cysteine pair Cys-311- Cys-320 in the second external loop of GlyT2. This interaction impairs transporter maturation through the secretory pathway, reduces surface expression, and inhibits transport function. Additionally, Y705C presents altered H+ and Zn2+ dependence of glycine transport that may affect the function of glycinergic neurotransmission in vivo. [ABSTRACT FROM AUTHOR]
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- 2012
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30. Protein Kinase C (PKC)-promoted Endocytosis of Glutamate Transporter GLT-1 Requires Ubiquitin Ligase Nedd4-2-dependent Ubiquitination but Not Phosphorylation.
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García-Tardón, Noemí, González-González, Inmaculada M., Martínez-Villarreal, Jaime, Fernández-Sánchez, Enrique, Giménez, Cecilio, and Zafra, Francisco
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PROTEIN kinases , *ENDOCYTOSIS , *ABSORPTION (Physiology) , *CELL physiology , *PHOSPHORYLATION - Abstract
Glutamate transporter-1 (GLT-1) is the main glutamate transporter in the central nervous system, and its concentration severely decreases in neurodegenerative diseases. The number of transporters in the plasma membrane reflects the balance between their insertion and removal, and it has been reported that the regulated endocytosis of GLT-1 depends on its ubiquitination triggered by protein kinase C (PKC) activation. Here, we identified serine 520 of GLT-1 as the primary target for PKC-dependent phosphorylation, although elimination of this serine did not impair either GLT-1 ubiquitination or endocytosis in response to phorbol esters. In fact, we present evidence indicating that the ubiquitin ligase Nedd4-2 mediates the PKC-dependent ubiquitination and down-regulation of GLT-1. Overexpression of Nedd4-2 increased the ubiquitination of the transporter and promoted its degradation. Moreover, phorbol myristate acetate enhanced Nedd4-2 phosphorylation and the formation of GLT-1_Nedd4-2 complexes, whereas siRNA knockdown of Nedd4-2 prevented ubiquitination, endocytosis, and the concomitant decrease in GLT-1 activity triggered by PKCactivation. These results indicate that GLT-1 endocytosis is independent of its phosphorylation and that Nedd4-2 mediates PKC-dependent down-regulation of the transporter. [ABSTRACT FROM AUTHOR]
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- 2012
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31. La terapia antiangiogénica intravítrea inhibe la angiogénesis patológica y permite la fisiológica en la retinopatía de la prematurez.
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González-Cortés, Jesús Hernán, López-Portillo, Alejandro Martínez, Treviño-Cavazos, Ezequiel E., Cavazos-Adame, Humberto, Mohamed-Noriega, Karim, Dávila-Villarreal, Jaime F., Marabotto-Serna, Carlos Francisco, and Mohamed-Hamsho, Jesús
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NEOVASCULARIZATION inhibitors , *RETINAL diseases , *BEVACIZUMAB , *ANTINEOPLASTIC agents , *RANIBIZUMAB , *NEOVASCULARIZATION - Abstract
Aim: The use of intravitreal antiangiogenic therapy has showed good results in angiogenesis-dependent intraocular diseases. In this small case series study, the biologic effects on physiological angiogenesis and pathological angiogenesis in the retina of patients with retinopathy of prematurity (ROP) after treatment of either bevacizumab or ranibizumab, is described. Methods: In this non-comparative, prospective, experimental and interventional case series study, we injected a single dose of either bevacizumab or ranibizumab into the vitreous of 20 eyes of 10 patients with ROP. Patients included in this study were prematures with stage 3, zone I, or posterior zone II with or without plus disease and patients with stage 4 a, any zone. Clinical response and any evidence of ocular toxicities were documented both pre- and post-injection by RetCam retinal images. Results: After one week of intavitreal injection of bevacizumab or ranibizumab, all eyes had significant inhibition of angiogenesis without affecting the development of normal retina vasculature. After six weeks, all eyes showed completed vasculature of the retina without any sign of pathological angiogenesis. We found no differences between bevacizumab and ranibizumab results. Neither local nor systemic adverse effects occurred in 18 eyes, two eyes with ROP stage 4 a, developed a central retinal fibrosis. Conclusions: Intravitreal therapy with bevacizumab or ranibizumab inhibits pathological angiogenesis and allows the developement of normal vasculature of the retina in ROP. This study proves that intravitreal antiangiogenic therapy does not cause inhibition of physiological angiogenesis in the retinal vessels and may suggest that the same could happen in the systemic vasculature process. [ABSTRACT FROM AUTHOR]
- Published
- 2013
32. La terapia antiangiogénica intravítrea inhibe la angiogéne-sis patológica y permite la fisiológica en la retinopatía de la prematurez.
- Author
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González-Cortés, Jesús Hernán, Martínez López-Portillo, Alejandro, Treviño-Cavazos, Ezequiel E., Cavazos-Adame, Humberto, Mohamed-Noriega, Karim, Dávila-Villarreal, Jaime F., Marabotto-Serna, Carlos Francisco, and Mohamed-Hamsho, Jesús
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NEOVASCULARIZATION inhibitors , *BEVACIZUMAB , *ANTINEOPLASTIC agents , *RANIBIZUMAB , *NEOVASCULARIZATION , *RETINAL diseases - Abstract
Aim: The use of intravitreal antiangiogenic therapy has showed good results in angiogenesis-dependent intraocular diseases. In this small case series study, the biologic effects on physiological angiogenesis and pathological angiogenesis in the retina of patients with retinopathy of prematurity (ROP) after treatment of either bevacizumab or ranibizumab, is described. Methods: In this non-comparative, prospective, experimental and interventional case series study, we injected a single dose of either bevacizumab or ranibizumab into the vitreous of 20 eyes of 10 patients with ROP. Patients included in this study were prematures with stage 3, zone I, or posterior zone II with or without plus disease and patients with stage 4 a, any zone. Clinical response and any evidence of ocular toxicities were documented both pre- and post-injection by RetCam retinal images. Results: After one week of intavitreal injection of bevacizumab or ranibizumab, all eyes had significant inhibition of angiogenesis without affecting the development of normal retina vasculature. After six weeks, all eyes showed completed vasculature of the retina without any sign of pathological angiogenesis. We found no differences between bevacizumab and ranibizumab results. Neither local nor systemic adverse effects occurred in 18 eyes, two eyes with ROP stage 4 a, developed a central retinal fibrosis. Conclusions: Intravitreal therapy with bevacizumab or ranibizumab inhibits pathological angiogenesis and allows the developement of normal vasculature of the retina in ROP. This study proves that intravitreal antiangiogenic therapy does not cause inhibition of physiological angiogenesis in the retinal vessels and may suggest that the same could happen in the systemic vasculature process. [ABSTRACT FROM AUTHOR]
- Published
- 2013
33. Valor de la angiografía en el plan terapéutico del edema macular diabético.
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González Cortés, Jesús Hernán, Treviño Cavazos, Ezequiel Enrique, López-Portillo, Alejandro Martínez, González Treviño, Juan Luis, Dávila Villarreal, Jaime Fernando, and Hamscho, Jesús Mohamed
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RETINAL degeneration , *EYE laser surgery , *DIABETES complications , *THERAPEUTICS , *FLUORESCENCE angiography , *STEREOGRAPHS , *METABOLIC disorder treatment , *EDEMA , *LIGHT coagulation - Abstract
Purpose: To determine the importance of fluorescein angiography in planning laser treatment for the clinically significant diabetic macular edema. Methods: Prospective study of 84 eyes of 54 diabetic patients with clinical significant macular edema, each case was documented with stereoscopic color photographs and a corresponding fluorescein angiogram The therapeutic plan was established after analyzing twice every case, the first time based only on the photographs and the second time based on both, the photographs and the angiograms. We compared the ability of the retina specialist to plan laser treatment with and without the use of fluorescein angiography. Results: In 85.7% of cases the ability of the specialist to decide laser treatment after the photograph analysis without the use of fluorescein angiographies was the same compared with the therapeutic plan based upon using the angiograms 14.3% showed small differences between both analyses. Conclusions: Fluorescein angiography improves the accuracy of laser treatment planning for clinically significant macular edema. [ABSTRACT FROM AUTHOR]
- Published
- 2008
34. A common CTRB misfolding variant associated with pancreatic cancer risk causes ER stress and inflammation in mice.
- Author
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Bodas C, Felipe I, Chanez B, Lafarga M, López de Maturana E, Martínez-de-Villarreal J, Del Pozo N, Malumbres M, Vargiu P, Cayuela A, Peset I, Connelly KE, Hoskins JW, Méndez R, Amundadottir LT, Malats N, Ortega S, and Real FX
- Abstract
Objective: Genome wide association studies have identified an exon 6 CTRB2 deletion variant that associates with increased risk of pancreatic cancer. To acquire evidence on its causal role, we developed a new mouse strain carrying an equivalent variant in Ctrb1 , the mouse orthologue of CTRB2 ., Design: We used CRISPR/Cas9 to introduce a 707bp deletion in Ctrb1 encompassing exon 6 ( Ctrb1
Δexon6 ). This mutation closely mimics the human deletion variant. Mice carrying the mutant allele were extensively profiled at 3 months to assess their phenotype., Results: Ctrb1Δexon6 mutant mice express a truncated CTRB1 that accumulates in the ER. The pancreas of homozygous mutant mice displays reduced chymotrypsin activity and total protein synthesis. The histological aspect of the pancreas is inconspicuous but ultrastructural analysis shows evidence of dramatic ER stress and cytoplasmic and nuclear inclusions. Transcriptomic analyses of the pancreas of mutant mice reveals acinar program down-regulation and increased activity of ER stress-related and inflammatory pathways. Heterozygous mice have an intermediate phenotype. Agr2 is one of the most up-regulated genes in mutant pancreata. Ctrb1Δexon6 mice exhibit impaired recovery from acute caerulein-induced pancreatitis. Administration of TUDCA or sulindac partially alleviates the phenotype. A transcriptomic signature derived from the mutant pancreata is significantly enriched in normal human pancreas of CTRB2 exon 6 deletion variant carriers from the GTEx cohort., Conclusions: This mouse strain provides formal evidence that the Ctrb1Δexon6 variant causes ER stress and inflammation in vivo , providing an excellent model to understand its contribution to pancreatic ductal adenocarcinoma development and to identify preventive strategies., Summary Box: What is already known about this subject?: - CTRB2 is one of the most abundant proteins produced by human pancreatic acinar cells. - A common exon 6 deletion variant in CTRB2 has been associated with an increased risk of pancreatic ductal adenocarcinoma. - Misfolding of digestive enzymes is associated with pancreatic pathology. What are the new findings?: - We developed a novel genetic model that recapitulates the human CTRB2 deletion variant in the mouse orthologue, Ctrb1 . - Truncated CTRB1 misfolds and accumulates in the ER; yet, mutant mice display a histologically normal pancreas at 3 months age.- CTRB1 and associated chaperones colocalize in the ER, the cytoplasm, and the nucleus of acinar cells.- Transcriptomics analysis reveals reduced activity of the acinar program and increased activity of pathways involved in ER stress, unfolded protein response, and inflammation.- Mutant mice are sensitized to pancreatic damage and do not recover properly from a mild caerulein-induced pancreatitis.- TUDCA administration partially relieves the ER stress in mutant mice. How might it impact on clinical practice in the foreseeable future?: - The new mouse model provides a tool to identify the mechanisms leading to increased pancreatic cancer risk in CTRB2 exon 6 carriers. - The findings suggest that drugs that cause ER stress relief and/or reduce inflammation might provide preventive opportunities.- Published
- 2024
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35. BPTF cooperates with MYCN and MYC to link neuroblastoma cell cycle control to epigenetic cellular states.
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Felipe I, Martínez-de-Villarreal J, Patel K, Martínez-Torrecuadrada J, Grossmann LD, Roncador G, Cubells M, Farrell A, Kendsersky N, Sabroso-Lasa S, Sancho-Temiño L, Torres K, Martinez D, Perez JM, García F, Pogoriler J, Moreno L, Maris JM, and Real FX
- Abstract
The nucleosome remodeling factor BPTF is required for the deployment of the MYC-driven transcriptional program. Deletion of one Bptf allele delays tumor progression in mouse models of pancreatic cancer and lymphoma. In neuroblastoma, MYCN cooperates with the transcriptional core regulatory circuitry (CRC). High BPTF levels are associated with high-risk features and decreased survival. BPTF depletion results in a dramatic decrease of cell proliferation. Bulk RNA-seq, single-cell sequencing, and tissue microarrays reveal a positive correlation of BPTF and CRC transcription factor expression. Immunoprecipitation/mass spectrometry shows that BPTF interacts with MYCN and the CRC proteins. Genome-wide distribution analysis of BPTF and CRC in neuroblastoma reveals a dual role for BPTF: 1) it co-localizes with MYCN/MYC at the promoter of genes involved in cell cycle and 2) it co-localizes with the CRC at super-enhancers to regulate cell identity. The critical role of BPTF across neuroblastoma subtypes supports its relevance as a therapeutic target.
- Published
- 2024
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36. Tumor and Stromal Cell Targeting with Nintedanib and Alpelisib Overcomes Intrinsic Bladder Cancer Resistance.
- Author
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Marqués M, Corral S, Sánchez-Díaz M, Del Pozo N, Martínez de Villarreal J, Schweifer N, Zagorac I, Hilberg F, and Real FX
- Subjects
- Humans, Mice, Animals, Phosphatidylinositol 3-Kinases therapeutic use, Stromal Cells, Cell Line, Tumor, Lung Neoplasms drug therapy, Urinary Bladder Neoplasms drug therapy, Urinary Bladder Neoplasms genetics
- Abstract
Bladder cancer is a highly prevalent tumor, requiring the urgent development of novel therapies, especially for locally advanced and metastatic disease. Nintedanib is a potent antifibrotic angio-kinase inhibitor, which has shown clinical efficacy in combination with chemotherapy in patients with locally advanced muscle-invasive bladder cancer. Nintedanib inhibits fibroblast growth factor receptors (FGFRs), validated targets in patients with bladder cancer harboring FGFR3/2 genetic alterations. Here, we aimed at studying its mechanisms of action to understand therapy resistance, identify markers predictive of response, and improve the design of future clinical trials. We have used a panel of genetically well-characterized human bladder cancer cells to identify the molecular and transcriptomic changes induced upon treatment with nintedanib, in vitro and in vivo, at the tumor and stroma cell levels. We showed that bladder cancer cells display an intrinsic resistance to nintedanib treatment in vitro, independently of their FGFR3 status. However, nintedanib has higher antitumor activity on mouse xenografts. We have identified PI3K activation as a resistance mechanism against nintedanib in bladder cancer and evidenced that the combination of nintedanib with the PI3K inhibitor alpelisib has synergistic antitumor activity. Treatment with this combination is associated with cell-cycle inhibition at the tumoral and stromal levels and potent nontumor cell autonomous effects on α-smooth muscle actin-positive tumor infiltrating cells and tumor vasculature. The combination of nintedanib with PI3K inhibitors not only reversed bladder cancer resistance to nintedanib but also enhanced its antiangiogenic effects., (©2023 American Association for Cancer Research.)
- Published
- 2023
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37. Pseudoalignment tools as an efficient alternative to detect repeated transposable elements in scRNAseq data.
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de Villarreal JM, Kalisz M, Piedrafita G, Graña-Castro O, Chondronasiou D, Serrano M, and Real FX
- Subjects
- Animals, Single-Cell Gene Expression Analysis, Exome Sequencing, RNA, Mammals genetics, Epigenesis, Genetic, DNA Transposable Elements
- Abstract
Motivation: Transposable elements (TE) have played a major role in configuring the structures of mammalian genomes through evolution. In normal conditions, the expression of these elements is repressed by different epigenetic regulation mechanisms such as DNA methylation, histone modification and regulation by small RNAs. TE re-activation is associated with stemness potential acquisition, regulation of innate immunity and disease, such as cancer. However, the vast majority of current knowledge in the field is based on bulk expression studies, and very little is known on cell-type- or state-specific expression of TE-derived transcripts. Therefore, cost-efficient single-cell-resolution TE expression analytical approaches are needed., Results: We have implemented an analytical approach based on pseudoalignment to consensus sequences to incorporate TE expression information to scRNAseq data., Availability and Implementation: All the data and code implemented are available as Supplementary data and in: https://github.com/jmzvillarreal/kallisto_TE_scRNAseq., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2022. Published by Oxford University Press.)
- Published
- 2023
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38. Deciphering the roadmap of in vivo reprogramming toward pluripotency.
- Author
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Chondronasiou D, Martínez de Villarreal J, Melendez E, Lynch CJ, Pozo ND, Kovatcheva M, Aguilera M, Prats N, Real FX, and Serrano M
- Subjects
- Humans, Cellular Reprogramming genetics, Kruppel-Like Transcription Factors genetics, Kruppel-Like Transcription Factors metabolism, Octamer Transcription Factor-3 metabolism, SOXB1 Transcription Factors metabolism, Cell Differentiation genetics, Fibroblasts metabolism, Kruppel-Like Factor 4, Pluripotent Stem Cells metabolism, Induced Pluripotent Stem Cells
- Abstract
Differentiated cells can be converted into pluripotent stem cells by expressing the transcription factors OCT4, SOX2, KLF4, and MYC (OSKM) in a process known as reprogramming. Here, using single-cell RNA sequencing of pancreas undergoing reprogramming, we identify markers along the trajectory from acinar cell identity to pluripotency. These markers allow direct in situ visualization of cells undergoing dedifferentiation and acquiring features of early and advanced intermediate reprogramming. We also find that a fraction of cells do not dedifferentiate upon OSKM expression and are characterized by stress markers of the REG3 and AP-1 families. Importantly, most markers of intermediate reprogramming in the pancreas are also observed in stomach, colon, and cultured fibroblasts expressing OSKM. Among them is LY6A, a protein characteristic of progenitor cells and generally upregulated during tissue repair. Our roadmap defines intermediate reprogramming states that could be functionally relevant for tissue regeneration and rejuvenation., Competing Interests: Conflict of interests M.S. is shareholder and advisor of Senolytic Therapeutics, Inc., Life Biosciences, Inc, Rejuveron Senescence Therapeutics, AG, and Altos Labs, Inc. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
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39. Phase I, multicenter, open-label study of intravenous VCN-01 oncolytic adenovirus with or without nab-paclitaxel plus gemcitabine in patients with advanced solid tumors.
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Garcia-Carbonero R, Bazan-Peregrino M, Gil-Martín M, Álvarez R, Macarulla T, Riesco-Martinez MC, Verdaguer H, Guillén-Ponce C, Farrera-Sal M, Moreno R, Mato-Berciano A, Maliandi MV, Torres-Manjon S, Costa M, Del Pozo N, Martínez de Villarreal J, Real FX, Vidal N, Capella G, Alemany R, Blasi E, Blasco C, Cascalló M, and Salazar R
- Subjects
- Adenoviridae genetics, Albumins, Antineoplastic Combined Chemotherapy Protocols adverse effects, Deoxycytidine analogs & derivatives, Humans, Hyaluronoglucosaminidase therapeutic use, Paclitaxel, Gemcitabine, Pancreatic Neoplasms, Adenocarcinoma pathology, Pancreatic Neoplasms drug therapy
- Abstract
Background: VCN-01 is an oncolytic adenovirus (Ad5 based) designed to replicate in cancer cells with dysfunctional RB1 pathway, express hyaluronidase to enhance virus intratumoral spread and facilitate chemotherapy and immune cells extravasation into the tumor. This phase I clinical trial was aimed to find the maximum tolerated dose/recommended phase II dose (RP2D) and dose-limiting toxicity (DLT) of the intravenous delivery of the replication-competent VCN-01 adenovirus in patients with advanced cancer., Methods: Part I: patients with advanced refractory solid tumors received one single dose of VCN-01. Parts II and III: patients with pancreatic adenocarcinoma received VCN-01 (only in cycle 1) and nab-paclitaxel plus gemcitabine (VCN-concurrent on day 1 in Part II, and 7 days before chemotherapy in Part III). Patients were required to have anti-Ad5 neutralizing antibody (NAbs) titers lower than 1/350 dilution. Pharmacokinetic and pharmacodynamic analyses were performed., Results: 26% of the patients initially screened were excluded based on high NAbs levels. Sixteen and 12 patients were enrolled in Part I and II, respectively: RP2D were 1×10
13 viral particles (vp)/patient (Part I), and 3.3×1012 vp/patient (Part II). Fourteen patients were included in Part III: there were no DLTs and the RP2D was 1×1013 vp/patient. Observed DLTs were grade 4 aspartate aminotransferase increase in one patient (Part I, 1×1013 vp), grade 4 febrile neutropenia in one patient and grade 5 thrombocytopenia plus enterocolitis in another patient (Part II, 1×1013 vp). In patients with pancreatic adenocarcinoma overall response rate were 50% (Part II) and 50% (Part III). VCN-01 viral genomes were detected in tumor tissue in five out of six biopsies (day 8). A second viral plasmatic peak and increased hyaluronidase serum levels suggested replication after intravenous injection in all patients. Increased levels of immune biomarkers (interferon-γ, soluble lymphocyte activation gene-3, interleukin (IL)-6, IL-10) were found after VCN-01 administration., Conclusions: Treatment with VCN-01 is feasible and has an acceptable safety. Encouraging biological and clinical activity was observed when administered in combination with nab-paclitaxel plus gemcitabine to patients with pancreatic adenocarcinoma., Trial Registration Number: NCT02045602., Competing Interests: Competing interests: MB-P, MF-S, AM-B, MVM, EB, CB and MC are employees, and RS is consultant for VCN Biosciences. MC and RAle are co-inventors of one patent application concerning the expression of hyaluronidase by oncolytic adenoviruses and both have ownership interest in VCN Biosciences. RG-C has provided scientific advice and/or received honoraria or funding for continuous medical education from AAA, Advanz Pharma, Amgen, Bayer, BMS, HMP, Ipsen, Merck, Midatech Pharma, MSD, Novartis, PharmaMar, Pfizer, Pierre Fabre, Roche, Servier and Sanofi, and has received research support from Pfizer, BMS and MSD., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)- Published
- 2022
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40. Combined MEK and PI3K/p110β Inhibition as a Novel Targeted Therapy for Malignant Mesothelioma Displaying Sarcomatoid Features.
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Marqués M, Tranchant R, Risa-Ebrí B, Suárez-Solís ML, Fernández LC, Carrillo-de-Santa-Pau E, Del Pozo N, Martínez de Villarreal J, Meiller C, Allory Y, Blum Y, Pirker C, Hegedus B, Barry ST, Carnero A, Berger W, Jean D, and Real FX
- Subjects
- Aniline Compounds pharmacology, Aniline Compounds therapeutic use, Animals, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Benzimidazoles pharmacology, Benzimidazoles therapeutic use, Cell Proliferation drug effects, Chromones pharmacology, Chromones therapeutic use, Class I Phosphatidylinositol 3-Kinases metabolism, Disease Models, Animal, Epithelium pathology, Female, Gene Knock-In Techniques, Humans, Lung Neoplasms genetics, Lung Neoplasms pathology, Mesothelioma genetics, Mesothelioma pathology, Mesothelioma, Malignant, Mice, Mice, Knockout, Mitogen-Activated Protein Kinase Kinases metabolism, Molecular Targeted Therapy methods, PTEN Phosphohydrolase genetics, Peritoneal Neoplasms genetics, Peritoneal Neoplasms pathology, Peritoneum pathology, Pleura pathology, Pleural Neoplasms genetics, Pleural Neoplasms pathology, Primary Cell Culture, Prognosis, Protein Kinase Inhibitors therapeutic use, Tumor Suppressor Protein p53 genetics, Antineoplastic Combined Chemotherapy Protocols pharmacology, Class I Phosphatidylinositol 3-Kinases antagonists & inhibitors, Lung Neoplasms drug therapy, Mesothelioma drug therapy, Mitogen-Activated Protein Kinase Kinases antagonists & inhibitors, Peritoneal Neoplasms drug therapy, Pleural Neoplasms drug therapy, Protein Kinase Inhibitors pharmacology
- Abstract
Among malignant mesotheliomas (MM), the sarcomatoid subtype is associated with higher chemoresistance and worst survival. Due to its low incidence, there has been little progress in the knowledge of the molecular mechanisms associated with sarcomatoid MM, which might help to define novel therapeutic targets. In this work, we show that loss of PTEN expression is frequent in human sarcomatoid MM and PTEN expression levels are lower in sarcomatoid MM than in the biphasic and epithelioid subtypes. Combined Pten and Trp53 deletion in mouse mesothelium led to nonepithelioid MM development. In Pten;Trp53 -null mice developing MM, the Gαi2-coupled receptor subunit activated MEK/ERK and PI3K, resulting in aggressive, immune-suppressed tumors. Combined inhibition of MEK and p110β/PI3K reduced mouse tumor cell growth in vitro . Therapeutic inhibition of MEK and p110β/PI3K using selumetinib (AZD6244, ARRY-142886) and AZD8186, two drugs that are currently in clinical trials, increased the survival of Pten ; Trp53 -null mice without major toxicity. This drug combination effectively reduced the proliferation of primary cultures of human pleural (Pl) MM, implicating nonepithelioid histology and high vimentin, AKT1/2, and Gαi2 expression levels as predictive markers of response to combined MEK and p110β/PI3K inhibition. Our findings provide a rationale for the use of selumetinib and AZD8186 in patients with MM with sarcomatoid features. This constitutes a novel targeted therapy for a poor prognosis and frequently chemoresistant group of patients with MM, for whom therapeutic options are currently lacking. SIGNIFICANCE: Mesothelioma is highly aggressive; its sarcomatoid variants have worse prognosis. Building on a genetic mouse model, a novel combination therapy is uncovered that is relevant to human tumors., (©2020 American Association for Cancer Research.)
- Published
- 2020
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