Stratification of radiosensitive brain metastases based on an actionable S100A9/RAGE resistance mechanism

Whole-brain radiotherapy (WBRT) is the treatment backbone for many patients with brain metastasis; however, its efficacy in preventing disease progression and the associated toxicity have questioned the clinical impact of this approach and emphasized the need for alternative treatments. Given the limited therapeutic options available for these patients and the poor understanding of the molecular mechanisms underlying the resistance of metastatic lesions to WBRT, we sought to uncover actionable targets and biomarkers that could help to refine patient selection. Through an unbiased analysis of experimental in vivo models of brain metastasis resistant to WBRT, we identified activation of the S100A9–RAGE–NF-κB–JunB pathway in brain metastases as a potential mediator of resistance in this organ. Targeting this pathway genetically or pharmacologically was sufficient to revert the WBRT resistance and increase therapeutic benefits in vivo at lower doses of radiation. In patients with primary melanoma, lung or breast adenocarcinoma developing brain metastasis, endogenous S100A9 levels in brain lesions correlated with clinical response to WBRT and underscored the potential of S100A9 levels in the blood as a noninvasive biomarker. Collectively, we provide a molecular framework to personalize WBRT and improve its efficacy through combination with a radiosensitizer that balances therapeutic benefit and toxicity.We thank all members of the Brain Metastasis Group and A. Chalmers, E. Wagner, O. Fernández-Capetillo, R. Ciérvide and A. Hidalgo for critical discussion of the manuscript; the CNIO Core Facilities for their excellent assistance; and Fox Chase Cancer Center Transgenic Facility for generation of S100A9 mice. We thank EuCOMM repository for providing S100A9 targeted embryonic stem cells. We also thank J. Massagué (MSKCC) for some of the BrM cell lines and M. Bosenberg (Yale) for the YUMM1.1 cell line. Samples from patients included in this study that provided by the Girona Biomedical Research Institute (IDIBGI) (Biobanc IDIBGI, B.0000872) are integrated into the Spanish National Biobanks Network and in the Xarxa de Bancs de Tumors de Catalunya (XBTC) financed by the Pla Director d’Oncologia de Catalunya. All patients consented to the storage of these samples in the biobank and for their use in research projects. This study was funded by MINECO (SAF2017-89643-R) (M.V.), Fundació La Marató de TV3 (201906-30-31-32) (J.B.-B., M.V. and A.C.), Fundación Ramón Areces (CIVP19S8163) (M.V.) and CIVP20S10662 (E.O.P.), Worldwide Cancer Research (19-0177) (M.V. and E.C.-J.M.), Cancer Research Institute (Clinic and Laboratory Integration Program CRI Award 2018 (54545) (M.V.), AECC (Coordinated Translational Groups 2017 (GCTRA16015SEOA) (M.V.), LAB AECC 2019 (LABAE19002VALI) (M.V.), ERC CoG (864759) (M.V.), Portuguese Foundation for Science and Technology (SFRH/bd/100089/2014) (C.M.), Boehringer-Ingelheim Fonds MD Fellowship (L.M.), La Caixa International PhD Program Fellowship-Marie Skłodowska-Curie (LCF/BQ/DI17/11620028) (P.G.-G.), La Caixa INPhINIT Fellowship (LCF/BQ/DI19/11730044) (A.P.-A.), MINECO-Severo Ochoa PhD Fellowship (BES-2017-081995) (L.A.-E.) and an AECC postdoctoral fellowship (POSTD19016PRIE) (N.P.). M.V. is an EMBO YIP member (4053). Additional support was provided by Gertrud and Erich Roggenbuck Stiftung (M.M.), Science Foundation Ireland Frontiers for the Future Award (19/FFP/6443) (L.Y.), Science Foundation Ireland Strategic Partnership Programme, Precision Oncology Ireland (18/SPP/3522) (L.Y.), Breast Cancer Now Fellowship Award with the generous support of Walk the Walk (2019AugSF1310) (D.V.), Science Foundation Ireland (20/FFP-P/8597) (D.V.), Paradifference Foundation (C.F.-T.), “la Caixa” Foundation (ID 100010434) (A.I.), European Union’s Horizon 2020 research and innovation programme under Marie Skłodowska-Curie grant agreement 847648 (CF/BQ/PI20/11760029) (A.I.), Champalimaud Centre for the Unknown (N.S.), Lisboa Regional Operational Programme (Lisboa 2020) (LISBOA01-0145-FEDER-022170) (N.S.), NCI (R01 CA227629; R01 CA218133) (S.I.G.), Fundació Roses Contra el Càncer (J.B.-B.), Ministerio de Universidades FPU Fellowship (FPU 18/00069) (P.T.), MICIN-Agencia Estatal de Investigación Fellowships (PRE2020-093032 and BES-2017-080415) (P.M. and E. Cintado, respectively), Ministerio de Ciencia, Innovación y Universidades-E050251 (PID2019-110292RB-I00) (J.L.T.), FCT (PTDC/MED-ONC/32222/2017) (C.C.F.), Fundação Millennium bcp (C.C.F.), private donations (C.C.F.) and the Foundation for Applied Cancer Research in Zurich (E.L.R. and M.W.)

Flatfoot in Müller-Weiss syndrome: a case series

<p>Abstract</p> <p>Introduction</p> <p>Spontaneous osteonecrosis of the navicular bone in adults is a rare entity, known as Müller-Weiss syndrome. We report here on our experience with six patients with Müller-Weiss syndrome accompanied by flatfoot deformity, but on a literature search found no reports on this phenomenon. Because the natural history and treatment are controversial, an understanding of how to manage this deformity may be helpful for surgeons when choosing the most appropriate operative procedure.</p> <p>Case presentation</p> <p>Six patients (five women, one man; average age, 54 years) with flatfoot caused by osteonecrosis of the navicular bone were followed up between January 2005 and December 2008 (mean follow-up period, 23.2 months). Conservative treatment, such as physical therapy, and non-steroidal anti-inflammatory drugs were used, but failed. Physical examinations revealed flattening of the medial arch of the involved foot and mild tenderness at the mid-tarsal joint. Weight-bearing X-rays (anterior-posterior and lateral views), computed tomography, and MRI scans were performed for each case. Talonavicular joint arthrodesis was performed in cases of single talonavicular joint arthritis. Triple arthrodesis was performed in cases of triple joint arthritis to reconstruct the medial arch. Clinical outcomes were assessed using the American Orthopaedic Foot and Ankle Society ankle-hindfoot scale; the scores were 63.0 pre-operatively and 89.8 post-operatively. All patients developed bony fusion.</p> <p>Conclusions</p> <p>The reason for the development of flatfoot in patients with Müller-Weiss syndrome is unknown. Surgical treatment may achieve favorable outcomes in terms of deformity correction, pain relief, and functional restoration. The choice of operative procedure may differ in patients with both flatfoot and posterior tibial tendon dysfunction.</p

Origin and trajectory of the teaching team forMultidisciplinary Biosanitary Education (IKAsasun)

El objetivo de este trabajo es dar a conocer el origen y la trayectoria del equipo docente estructurado IKAsasun (edIKDit-18-2, equipo docente para la Enseñanza Multidisciplinar Biosanitaria). El equipo está compuesto por personal docente investigador adscrito a los Campus de Leioa (Facultad de Medicina y Enfermería) y de Vitoria-Gasteiz (Facultad de Farmacia) de la Universidad del País Vasco/Euskal Herriko Unibertsitatea (UPV/EHU). La docencia que se imparte comprende a distintas disciplinas de Grados mayoritariamente relacionados con las Ciencias de la Salud (Enfermería, Farmacia, Fisioterapia, Medicina, Nutrición Humana y Dietética, Odontología, Ciencia y Tecnología de los Alimentos y Ciencias Ambientales). Desde el inicio de la andadura como equipo docente en el año 2015, el grupo ha participado en dos Proyectos de Innovación Educativa(PIE) subvencionados por la UPV/EHU (PIE nº 40 y nº 96). Estos proyectos están dirigidos a ayudar al alumnado a desarrollar, de una manera eficaz, las competencias específicas y transversales propias de cada Grado y a conseguir que se involucren en su propio aprendizaje. En ambos proyectos se ha incidido en la importancia de trabajar en equipos multidisciplinares, apostando por la utilización de metodologías de aprendizaje activo. En el primero de ellos (PIE nº 40; 2015-2017), se planteó la participación activa del alumnado en la resolución de casos clínicos complejos que requieren una bordaje multidisciplinar para garantizar la asistencia integral al paciente. En el segundo proyecto(PIE nº 96; 2018-2020), se llevó a cabo un abordaje multidisciplinar de temas relacionados con la salud biomédica y científica desde distintos Grados, y posterior divulgación enfocada a diferentes sectores de la sociedad. Los resultados obtenidos tras el desarrollo de ambos proyectos han sido muy alentadores, y alumnado, profesorado y personas externas colaboradoras han valorado muy positivamente la experiencia, que ha quedado reflejada en varias publicaciones y comunicaciones a congresos.The aim of this work is to provide an insight into the origin and background of theIKAsasun structured teaching team (edIKDit-18-2, teaching team for Multidisciplinary BiosanitaryEducation). Team is formed by an interdisciplinary group of teachers and researchers that belongsto the Campuses of Leioa (Faculty of Medicine and Nursing) and Vitoria-Gasteiz (Faculty ofPharmacy) of the University of the Basque Country (UPV/EHU). The teaching activity of thegroup covers different disciplines of the Degrees mostly related to Health Sciences (Nursing,Pharmacy, Physiotherapy, Medicine, Human Nutrition and Dietetics, Dentistry, EnvironmentalSciences and Food Sciences and Technology). Since the beginning of the journey as a teachingteam in 2015, the group has participated in two educational innovation projects (PIE) funded bythe UPV/EHU (PIE no. 40 and 96) aimed at helping students to effectively develop the specificand transversal competences of each degree, and to get them involved in their own learning.These projects have emphasized the importance of working in multidisciplinary teams, promotingthe implementation of active learning methodologies. In the first project (2015-2017), we proposedthe resolution of complex clinical cases that require a multidisciplinary approach to ensureintegral patient care. In the second one (2018-2020), we proposed a multidisciplinary approach toissues related to biomedical and scientific health from different Degrees, and their subsequentdissemination focusing on different sectors of society. The results obtained after the developmentof both projects have been very encouraging and both students, teaching staff and externalcollaborators have valued the experience very positively, which has been reflected in severalpublications and communications to conferences

Origen y trayectoria del equipo docente para la Enseñanza Multidisciplinar Biosanitaria (IKAsasun)

The aim of this work is to provide an insight into the origin and background of the IKAsasun structured teaching team (edIKDit-18-2, teaching team for  Multidisciplinary Biosanitary Education). Team is formed by an interdisciplinary group of teachers and researchers that belongs to the Campuses of Leioa (Faculty of Medicine and Nursing) and Vitoria-Gasteiz (Faculty of Pharmacy) of the University of the Basque Country (UPV/EHU). The teaching activity of the group covers different disciplines of the Degrees mostly  related to Health Sciences (Nursing, Pharmacy, Physiotherapy, Medicine, Human Nutrition and Dietetics, Dentistry, Environmental Sciences and Food Sciences and Technology). Since the beginning of the journey as a teaching team in 2015, the group has participated in two educational innovation projects (PIE) funded by the UPV/EHU (PIE no. 40 and 96) aimed at helping students to effectively develop the specific and transversal competences of each degree, and to get them involved in their own learning. Theseprojects have emphasized the importance of working in multidisciplinary teams, promoting the implementation of active learning methodologies. In the first project (2015-2017), we proposed the resolution of complex clinical cases that require a multidisciplinary approach to ensure integral patient care. In the second one (2018-2020), we proposed a multidisciplinary approach to issues related to biomedical and scientific health from different Degrees, and their subsequent dissemination focusing on different sectors of society. The results obtained after the development of both projects have been very encouraging and both students, teaching staff and external collaborators have valued the experience very positively, which has been reflected in several publications and communications to conferences.El objetivo de este trabajo es dar a conocer el origen y la trayectoria del equipo docente estructurado IKAsasun (edIKDit-18-2, equipo docente para la Enseñanza Multidisciplinar Biosanitaria). El equipo está compuesto por personal docente investigador adscrito a los Campus de Leioa (Facultad de Medicina y Enfermería) y de Vitoria-Gasteiz (Facultad de Farmacia) de la Universidad del País Vasco/Euskal Herriko Unibertsitatea (UPV/EHU). La docencia que se imparte comprende a distintas disciplinas de Grados mayoritariamente relacionados con las Ciencias de la Salud (Enfermería, Farmacia, Fisioterapia, Medicina, Nutrición Humana y Dietética, Odontología, Ciencia y Tecnología de los Alimentos y Ciencias Ambientales). Desde el inicio de la andadura como equipo docente en el año 2015, el grupo ha participado en dos Proyectos de Innovación Educativa (PIE) subvencionados por la UPV/EHU (PIE nº 40 y nº 96). Estos proyectos están dirigidos a ayudar al alumnado a desarrollar, de una manera eficaz, las competencias específicas y transversales propias de cada Grado y a conseguir que se involucren en su propio aprendizaje. En ambos proyectos se ha incidido en la  importancia de trabajar en equipos multidisciplinares, apostando por la utilización de metodologías de aprendizaje activo. En el primero de ellos (PIE nº 40; 2015-2017), se planteó la participación activa del alumnado en la resolución de casos clínicos complejos que requieren un abordaje multidisciplinar para garantizar la asistencia integral al paciente. En el segundo proyecto (PIE nº 96; 2018-2020), se llevó a cabo un abordaje multidisciplinar de temas relacionados con la salud biomédica y científica desde distintos Grados, y posterior divulgación enfocada a diferentes sectores de la sociedad. Los resultados obtenidos tras el desarrollo de ambos proyectos han sido muy alentadores, y alumnado, profesorado y personas externas colaboradoras han valorado muy positivamente la experiencia, que ha quedado reflejada en varias publicaciones y comunicaciones a congresos