Análisis genético de la fosfatasa CDC14B en mamíferos

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid. Facultad de Medicina. Departamento de Bioquímica. Fecha de lectura: 17 de Febrero de 2011

Targeting Mitotic Exit Leads to Tumor Regression In Vivo: Modulation by Cdk1, Mastl, and the PP2A/B55α,δ Phosphatase

SummaryTargeting mitotic exit has been recently proposed as a relevant therapeutic approach against cancer. By using genetically engineered mice, we show that the APC/C cofactor Cdc20 is essential for anaphase onset in vivo in embryonic or adult cells, including progenitor/stem cells. Ablation of Cdc20 results in efficient regression of aggressive tumors, whereas current mitotic drugs display limited effects. Yet, Cdc20 null cells can exit from mitosis upon inactivation of Cdk1 and the kinase Mastl (Greatwall). This mitotic exit depends on the activity of PP2A phosphatase complexes containing B55α or B55δ regulatory subunits. These data illustrate the relevance of critical players of mitotic exit in mammals and their implications in the balance between cell death and mitotic exit in tumor cells

Cdc14b regulates mammalian RNA polymerase II and represses cell cycle transcription

This work is licensed under a Creative Commons Attribution-NonCommercial.Cdc14 is an essential phosphatase in yeast but its role in the mammalian cell cycle remains obscure. We report here that Cdc14b-knockout cells display unscheduled induction of multiple cell cycle regulators resulting in early entry into DNA replication and mitosis from quiescence. Cdc14b dephosphorylates Ser5 at the C-terminal domain (CTD) of RNA polymerase II, a major substrate of cyclin-dependent kinases. Lack of Cdc14b results in increased CTD-Ser5 phosphorylation, epigenetic modifications that mark active chromatin, and transcriptional induction of cell cycle regulators. These data suggest a function for mammalian Cdc14 phosphatases in the control of transcription during the cell cycle.This work was funded by grants from the Association for International Cancer Research (AICR #08-0188), Foundation Ramón Areces, and the Spanish Ministry of Science and Innovation (MICINN; BFU2008-04293 to M.S.; SAF2009-07973 to M.M.). The Cell Division and Cancer Group of the CNIO is supported by the OncoCycle Programme (S-BIO-0283-2006) from the Comunidad de Madrid, the OncoBIO Consolider-Ingenio 2010 Programme (CSD2007- 00017) from the MICINN, Madrid, and the European Union Seventh Framework Programme (MitoSys project; HEALTH-F5-2010-241548).Peer Reviewe

Targeting mitotic exit leads to tumor regression in vivo: Modulation by Cdk1, Mastl, and the PP2A/B55α,δ phosphatase

Targeting mitotic exit has been recently proposed as a relevant therapeutic approach against cancer. By using genetically engineered mice, we show that the APC/C cofactor Cdc20 is essential for anaphase onset in vivo in embryonic or adult cells, including progenitor/stem cells. Ablation of Cdc20 results in efficient regression of aggressive tumors, whereas current mitotic drugs display limited effects. Yet, Cdc20 null cells can exit from mitosis upon inactivation of Cdk1 and the kinase Mastl (Greatwall). This mitotic exit depends on the activity of PP2A phosphatase complexes containing B55α or B55δ regulatory subunits. These data illustrate the relevance of critical players of mitotic exit in mammals and their implications in the balance between cell death and mitotic exit in tumor cells. © 2010 Elsevier Inc.E.M., M.G., and M.E are supported by fellowships from the Ministerio de Ciencia e Innovación (MICINN). M.T. and H.Y. are supported by Marie Curie Cancer Care and the Association for International Cancer Research (AICR). M.M. and S.M. wish to acknowledge the Fundación Cientíica de la Asociación Española contra el Cáncer for financial support. I.G.-H. and S.M. are supported by grants BFU2008-01808, Consolider CSD2007-00015, and Junta de Castilla y León Grupo de Excelencia GR 265. The Cell Division and Cancer group of the CNIO is funded by the MICINN (SAF2009-07973), Consolider-Ingenio 2010 Programme (CSD2007-00017), Comunidad de Madrid (OncoCycle Programme; S-BIO-0283-2006), Fundación Ramón Areces, AICR (08-0188), and the MitoSys project (HEALTH-F5-2010-241548; European Union Seventh Framework Program).Peer Reviewe

Evaluation of a quality improvement intervention to reduce anastomotic leak following right colectomy (EAGLE): pragmatic, batched stepped-wedge, cluster-randomized trial in 64 countries

Background Anastomotic leak affects 8 per cent of patients after right colectomy with a 10-fold increased risk of postoperative death. The EAGLE study aimed to develop and test whether an international, standardized quality improvement intervention could reduce anastomotic leaks. Methods The internationally intended protocol, iteratively co-developed by a multistage Delphi process, comprised an online educational module introducing risk stratification, an intraoperative checklist, and harmonized surgical techniques. Clusters (hospital teams) were randomized to one of three arms with varied sequences of intervention/data collection by a derived stepped-wedge batch design (at least 18 hospital teams per batch). Patients were blinded to the study allocation. Low- and middle-income country enrolment was encouraged. The primary outcome (assessed by intention to treat) was anastomotic leak rate, and subgroup analyses by module completion (at least 80 per cent of surgeons, high engagement; less than 50 per cent, low engagement) were preplanned. Results A total 355 hospital teams registered, with 332 from 64 countries (39.2 per cent low and middle income) included in the final analysis. The online modules were completed by half of the surgeons (2143 of 4411). The primary analysis included 3039 of the 3268 patients recruited (206 patients had no anastomosis and 23 were lost to follow-up), with anastomotic leaks arising before and after the intervention in 10.1 and 9.6 per cent respectively (adjusted OR 0.87, 95 per cent c.i. 0.59 to 1.30; P = 0.498). The proportion of surgeons completing the educational modules was an influence: the leak rate decreased from 12.2 per cent (61 of 500) before intervention to 5.1 per cent (24 of 473) after intervention in high-engagement centres (adjusted OR 0.36, 0.20 to 0.64; P < 0.001), but this was not observed in low-engagement hospitals (8.3 per cent (59 of 714) and 13.8 per cent (61 of 443) respectively; adjusted OR 2.09, 1.31 to 3.31). Conclusion Completion of globally available digital training by engaged teams can alter anastomotic leak rates. Registration number: NCT04270721 (http://www.clinicaltrials.gov)

Delaying surgery for patients with a previous SARS-CoV-2 infection

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