Suchergebnisse

The procurement Directives have enabled member States of the European Union to manage public social services through a non-contractual formula. In Spain, this possibility has been realized in "social agreements", regulated through the Social Services Laws of the Autonomous Communities. These are agreements to be entered into between the Administration in charge of or responsible for the services and private entities, normally non-profit organizations. However, the nature and legal regime of these social agreements, as it results from the current regulation, raises some doubts. They should be resolved as their widespread use reveals the strengths and weaknesses of this figure and the case law resolves them. ; Las Directivas de la Unión Europea en materia de contratación han habilitado la posibilidad de que los Estados miembros puedan gestionar los servicios sociales públicos a través de fórmulas no contractuales. En España, esa posibilidad se ha concretado en los denominados conciertos sociales, regulados a través de las leyes de Servicios Sociales de las Comunidades Autónomas. Se trata de acuerdos a celebrar entre la Administración titular o responsable de los servicios y entidades de carácter privado, normalmente, sin ánimo de lucro. La naturaleza y el régimen jurídico de estos conciertos sociales, tal y como deriva de la regulación vigente, plantea, no obstante, algunas dudas que deberán ir resolviéndose a medida que su uso generalizado evidencie las fortalezas y debilidades de esta figura y la jurisprudencia resuelva al respecto.

The Anaphase-promoting complex/cyclosome (APC/C) cofactor Cdh1 modulates cell proliferation by targeting multiple cell-cycle regulators for ubiquitin-dependent degradation. Lack of Cdh1 results in structural and numerical chromosome aberrations, a hallmark of genomic instability. By using a proteomic approach in Cdh1-null cells and mouse tissues, we have identified kinesin Eg5 and topoisomerase 2α as Cdh1 targets involved in the maintenance of genomic stability. These proteins are ubiquitinated and degraded through specific KEN and D boxes in a Cdh1-dependent manner. Whereas Cdh1-null cells display partial resistance to Eg5 inhibitors such as monastrol, lack of Cdh1 results in a dramatic sensitivity to Top2α poisons as a consequence of increased levels of trapped Top2α-DNA complexes. Chemical inhibition of the APC/C in cancer cells results in increased sensitivity to Top2α poisons. This work identifies in vivo targets of the mammalian APC/C-Cdh1 complex and reveals synthetic lethal interactions of relevance in anticancer treatments. ; We thank Angeles Almeida, Thomas U. Mayer, William T. Beck, Anthony A. Hyman, Jan-Michael Peters, Eusebio Manchado, and Scott Lowe for reagents. M. E., A.J.L.-C., and M.A.-F. were supported by the Spanish Ministry of Education, Culture and Sports, the AECC Scientific Foundation, and the EU-PEOPLE programme, respectively. Work in the O.F.-C. laboratory was supported by grants from the Spanish Ministry of Economy and Competitiveness (MINECO; SAF2011-23753), the Association for International Cancer Research (120229), the Howard Hughes Medical Institute, and the European Research Council (ERC-210520). Work in the H.Y. laboratory was funded by grants from Marie Curie Cancer Care and Cancer Research UK. Work in M.M.'s laboratory was funded by grants from the Foundation Ramon Areces, MINECO (SAF2012-38215), the OncoCycle Programme (S2010/BMD-2470) from the Comunidad de Madrid, and the European Union Seventh Framework Programme (MitoSys project; HEALTH-F5-2010-241548). ; Sí

This study was supported by grants from the Plan Nacional de I+D+I 2013-2016 ISCIII (PI16/00280 and PI19/00560) to JMGP), CIBERONC (CB16/12/00390 to JPR), the Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Ayudas a Grupos PCTI Principado de Asturias (IDI2018/155 to JPR), Fundación Bancaria Caja de Ahorros de Asturias-IUOPA, and the FEDER Funding Program from the European Union.