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.)

Inflamación relacionada con angiopatía amiloide: características clínicas y respuesta al tratamiento en una serie de casos

Resumen: Introducción: La inflamación relacionada con la angiopatía amiloide es una entidad caracterizada por una respuesta inflamatoria alrededor de los depósitos de beta amiloide de la microcirculación cerebral. Métodos: Revisión retrospectiva de una serie de pacientes con inflamación relacionada con angiopatía amiloide, que cumplieran criterios clínico-radiológicos o con diagnóstico histopatológico confirmado. Resultados: Se incluyeron siete pacientes, cinco varones, con edad media de 79 años. El inicio fue agudo o subagudo en seis de los casos. La clínica más frecuente fue deterioro cognitivo (n = 6), alteraciones de conducta (n = 5), crisis epilépticas (n = 5), focalidad neurológica (n = 4) y cefalea (n = 2). El líquido cefalorraquídeo fue anormal en tres de cinco casos (pleocitosis linfocitaria e hiperproteinorraquia). Las imágenes de resonancia magnética cerebral más frecuentes consistieron en microhemorragias (n = 7), hiperintensidades subcorticales en secuencia T2-FLAIR (n = 7) y realce leptomeníngeo (n = 6). La afectación fue bilateral en tres de los casos, con predominio en regiones parieto-occipitales (n = 5). Se realizó una tomografía por emisión de positrones (PET) de amiloide en dos pacientes, resultando positiva en uno. Se obtuvo la confirmación histopatológica mediante una biopsia en dos de los casos. Todos los sujetos recibieron tratamiento inmunosupresor, objetivándose una respuesta clínica y radiológica inicial favorable, con recaída radiológica en dos de los casos tras la retirada del tratamiento, y mejorando tras la reinstauración. Conclusiones: El diagnóstico resulta imprescindible de cara a iniciar un tratamiento precoz, ya que ha demostrado mejorar el pronóstico y disminuir las recurrencias. Si bien el diagnóstico definitivo es histopatológico, los criterios clínico-radiológicos permiten el diagnóstico de esta entidad sin necesidad de biopsia. Abstract: Introduction: Cerebral amyloid angiopathy–related inflammation (CAA-ri) is an entity characterised by an inflammatory response to β-amyloid deposition in the walls of cerebral microvessels. Methods: We conducted a retrospective review of a series of patients with a diagnosis of CAA-ri according to histopathological study findings or clinical-radiological diagnostic criteria. Results: The study included 7 patients (5 men) with a mean age of 79 years. Disease onset was acute or subacute in 6 patients. The most frequent symptoms were cognitive impairment (n = 6), behavioural alterations (n = 5), epileptic seizures (n = 5), focal neurological signs (n = 4), and headache (n = 2). Cerebrospinal fluid was abnormal in 3 patients (lymphocytic pleocytosis and high protein levels). The most frequent MRI findings were microbleeds (n = 7), subcortical white matter hyperintensities on T2-FLAIR sequences (n = 7), and leptomeningeal enhancement (n = 6). Lesions were bilateral in 3 patients and most frequently involved the parieto-occipital region (n = 5). Amyloid PET studies were performed in 2 patients, one of whom showed pathological findings. Two patients underwent brain biopsy, which confirmed diagnosis. All patients received immunosuppressive therapy. An initially favourable clinical-radiological response was observed in all cases, with 2 patients presenting radiological recurrence after treatment withdrawal, with a subsequent improvement after treatment was resumed. Conclusions: Early diagnosis of CAA-ri is essential: early treatment has been shown to improve prognosis and reduce the risk of recurrence. Although a histopathological study is needed to confirm diagnosis, clinical-radiological criteria enable diagnosis without biopsy

Bilateral staged magnetic resonance-guided focused ultrasound thalamotomy for the treatment of essential tremor: a case series study

BACKGROUND Unilateral magnetic resonance-guided focused ultrasound (FUS) thalamotomy is efficacious for the treatment of medically refractory essential tremor (ET). Viability of bilateral FUS ablation is unexplored. METHODS Patients diagnosed with medically refractory ET and previously treated with unilateral FUS thalamotomy at least 5 months before underwent bilateral treatment. The timepoints were baseline (before first thalamotomy) and FUS1 and FUS2 (4 weeks before and 6 months after second thalamotomy, respectively). The primary endpoint was safety. Efficacy was assessed through the Clinical Rating Scale for Tremor (CRST), which includes subscales for tremor examination (part A), task performance (part B) and tremor-related disability (part C). RESULTS Nine patients were treated. No permanent adverse events were registered. Six patients presented mild gait instability and one dysarthria, all resolving within the first few weeks. Three patients reported perioral hypoesthesia, resolving in one case. Total CRST score improved by 71% from baseline to FUS2 (from 52.3±12 to 15.5±9.4, p<0.001), conveying a 67% reduction in bilateral upper limb A+B (from 32.3±7.8 to 10.8±7.3, p=0.001). Part C decreased by 81% (from 16.4±3.6 to 3.1±2.9, p<0.001). Reduction in head and voice tremor was 66% (from 1.2±0.44 to 0.4±0.54, p=0.01) and 45% (from 1.8±1.1 to 1±0.8, p=0.02), respectively. CONCLUSION Bilateral staged FUS thalamotomy for ET is feasible and might be safe and effective. Voice and head tremor might also improve. A controlled study is warranted

MLIP causes recessive myopathy with rhabdomyolysis, myalgia and baseline elevated serum creatine kinase

Striated muscle needs to maintain cellular homeostasis in adaptation to increases in physiological and metabolic demands. Failure to do so can result in rhabdomyolysis. The identification of novel genetic conditions associated with rhabdomyolysis helps to shed light on hitherto unrecognized homeostatic mechanisms. Here we report seven individuals in six families from different ethnic backgrounds with biallelic variants in MLIP, which encodes the muscular lamin A/C-interacting protein, MLIP. Patients presented with a consistent phenotype characterized by mild muscle weakness, exercise-induced muscle pain, variable susceptibility to episodes of rhabdomyolysis, and persistent basal elevated serum creatine kinase levels. The biallelic truncating variants were predicted to result in disruption of the nuclear localizing signal of MLIP. Additionally, reduced overall RNA expression levels of the predominant MLIP isoform were observed in patients' skeletal muscle. Collectively, our data increase the understanding of the genetic landscape of rhabdomyolysis to now include MLIP as a novel disease gene in humans and solidifies MLIP's role in normal and diseased skeletal muscle homeostasis

Biodiversity 2016. Status and Trends of Colombian Continental Biodiversity

This third volume of the annual report on biodiversity in Colombia continues the editorial line that begun in 2014. Using novel analytical and graphic proposals, these reports have the goal of communicating the contents to a broad public, making it available for discussion without sacrificing the quality of information. The challenge of communication continues to be a major part of the institutional project, and the new languages with which we are learning to communicate with society and other institutions are an experiment that we expect to be increasingly gratifying. The report for 2017 is already under construction and it counts on new digital technologies so the power of a colombian vital connection may be entirely expressed. The included content evidences that we are still far away from having a systematic follow-up about most of the topics related to the management of biodiversity and ecosystem services, which is the only way to evaluate the effectiveness of policies and investments made by society. In fact, a limitation that is recognized is that of identifying positive or negative changes that affect different levels of organization of life on this planet; therefore, our global navigation route of the Aichi targets is still to be verified. An additional purpose of this process includes the invitation of all Colombians to contribute in constructing and maintaining basic monitoring indicators for management since it is impossible to identify long-term trends of flora and fauna in the country without the support of institutions, researchers, and citizens. This challenge is immense in a megadiverse country such as Colombia. For this reason, the report will continue to open its pages to experts, and even indigenous peoples or local communities, for them to present their perspectives about environmental change and its effects on biodiversity in a systematic and documented manner. This has the objective of stimulating the commitment of everyone in the management of biodiversity and ecosystem services. The only way of overcoming the risk of extinction is through the active process of social learning in which all sectors assume a part of the complex responsibility in protecting the forms of life of the country, a roughly counted tenth of all creatures on Earth. I thank all the people that contributed in this Report, those who have supported us in the phases of production, and all readers and users, who are the ultimate judges of its utility.Bogotá, D. C

Biodiversidad 2016. Estado y Tendencias de la Biodiversidad Continental de Colombia

Esta tercera entrega del reporte anual de la biodiversidad en Colombia profundiza en la línea editorial iniciada el año 2014 mediante nuevas propuestas analíticas y gráficas, con la intención de garantizar que la información llegue a todos los públicos y pueda ser discutida de manera amena sin sacrificio de calidad. La apuesta comunicativa sigue siendo central en el proyecto institucional y los nuevos lenguajes con los que estamos aprendiendo a conversar con la sociedad y las instituciones son un experimento que esperamos sea cada vez más satisfactorio: ya estamos construyendo la versión 2017 con el apoyo de las nuevas tecnologías digitales de manera que la potencia de la conexión vital colombiana se exprese en toda su capacidad. Por los contenidos es evidente que aún distamos mucho de tener una capacidad de seguimiento sistemático para la mayoría de temas relativos a la gestión de la biodiversidad y los servicios ecosistémicos, la única manera de evaluar si las medidas de política y las inversiones que realiza la sociedad están teniendo los efectos deseados. De hecho, parte de las limitaciones reconocidas por robustamente los cambios positivos o negativos que afectan los diferentes niveles de organización de la vida planetaria, por lo cual las mismas metas de Aichi, nuestra carta de navegación global, están pendientes de verificación. Un propósito adicional de este proceso es la invitación a todos los colombianos para contribuir con la construcción y alimentación de los indicadores básicos de seguimiento a la gestión, ya que es imposible identificar las tendencias de largo plazo en que están inmersas la flora y fauna colombianas sin el apoyo de las instituciones, los investigadores y los ciudadanos: en el país de la megadiversidad, el reto es inmenso. Por este motivo, este reporte irá abriendo sus páginas a expertos, incluso indígenas o de comunidades locales, para que presenten de manera sistemática y documentada sus perspectivas del cambio ambiental y sus efectos en la biodiversidad, con el ánimo de promover el compromiso de todos en su gestión. La única manera de superar el riesgo de extinción es mediante un activo proceso de aprendizajes sociales que haga que todos los sectores asuman una parte de la compleja responsabilidad que significa proteger todas las formas de vida del país, una décima parte mal contada de las planetarias. Agradezco a las decenas de personas que contribuyeron con este reporte, a quienes nos han apoyado en todas las etapas de producción y a sus lectores y usuarios, quienes son en último término los jueces de su utilidad.Bogotá, D. C