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

© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.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.info:eu-repo/semantics/publishedVersio

Human intestinal spirochetosis: an entity associated with sexual transmitted infections

[ES] Introducción: La espiroquetosis intestinal humana (EIH) es una entidad clínica poco estudiada. No obstante, en los últimos años está cobrando una especial relevancia dado que se han descrito un número creciente de casos en personas que viven con virus de inmunodeficiencia humana (VIH) (PVIH) y en pacientes con historia de infecciones de transmisión sexual (ITS) o inmunosupresión. Métodos: Estudio retrospectivo de todos los casos identificados de EIH en un hospital de tercer nivel (Hospital Universitario la Paz, Madrid) entre los años 2014-2021. Resultados: Se identificaron 36 casos de EIH, la mayoría en varones (94%) y con una mediana de edad de 45 años. Diez pacientes eran PVIH (29,4%) y 20 (56%) eran hombres que mantenían sexo con hombres. Si bien las manifestaciones clínicas fueron muy heterogéneas, la más frecuente fue la diarrea crónica (47%), y 25% tuvieron clínica de proctitis; 39% de los pacientes fueron diagnosticados de una ITS en los dos años previos, siendo este hecho más frecuente en PVIH (90 vs. 28%; p < 0,01) que en pacientes sin infección por VIH. La ITS más frecuentemente asociada al diagnóstico de EIH fue la sífilis (31%). Conclusión: La EIH se diagnostica frecuentemente con otras ITS y afecta mayoritariamente a hombres que tienen sexo con hombres, lo cual apoyaría que esta entidad pudiera considerarse como una nueva ITS. [EN] Introduction: Human intestinal spirochetosis (HIE) is a poorly studied clinical entity with variable clinical manifestations. However, in recent years it has gained special relevance because an increasing number of cases have been described in people living with HIV (PWH) and in patients with a history of sexually transmitted infections (STI) or immunosuppression. Methods: retrospective review of all HIE cases identified in a tertiary level hospital(Hospital Universitario la Paz, Madrid) between 2014-2021. Results: 36 cases of HIE were identified. Most cases corresponded to males (94%) with a median age of 45 years. 10 patients (29.4%) were PWH and 20 (56%) were men who had sex with men. Although the clinical manifestations were very heterogeneous, the most frequent was chronic diarrhea (47%), and up to 25% of the subjects had clinical proctitis. 39% percent of patients had been diagnosed with an STI in the previous two years, this characteristic being more frequent in PWH (90% vs 28%; p < 0.01) than in patients without HIV infection. The STI most frequently associated with a diagnosis of HIE was syphilis (31%). Conclusión: HIE is frequently diagnosed with other STIs and affects mostly men who have sex with men, which supports that this entity could be considered as a new STI.S