II Jornada Mentores - octubre 2021
Permanent URI for this collectionhttps://hdl.handle.net/20.500.12105/14558
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Publication Evolución de la mortalidad atribuible al alcohol en España según edad, sexo, causa de muerte y tipo de bebedor (2001-2017)(Socidrogalcohol, 2023-07-01) Donat López, Marta; Sordo, Luis; Belza Egozcue, Maria Jose; Hoyos, Juan; Regidor, Enrique; Barrio, Gregorio; Plan Nacional de Drogas (España); Instituto de Salud Carlos III[ES] En España no hay estimaciones recientes de la mortalidad atribuible a alcohol con datos de consumo de alcohol españoles. El objetivo es estimarla y conocer la evolución entre 2001 y 2017 en personas ≥15 años, según sexo, edad, periodo, causa de muerte y tipo de bebedor. Se utilizó el enfoque causa específico y la ecuación de Levin. El consumo de las encuestas se corrigió por subestimación con respecto a las estadísticas de ventas y se consideró el consumo pasado y los atracones de alcohol. El número medio anual de muertes atribuibles a alcohol en 2010-2017 fue 14.927, un 58,6% prematuras (<75 años). La tasa de mortalidad atribuible a alcohol estandarizada por edad fue 39,4/ 100.000 habitantes, representando un 3,9% de la mortalidad general. Usando porcentajes estandarizados un 68,7% correspondió a bebedores de alto riesgo. Las causas de mortalidad atribuible a alcohol más frecuentes fueron cáncer (43,8%) y enfermedades digestivas (32,9%). La tasa de mortalidad atribuible a alcohol fue 3,5 veces mayor en hombres que en mujeres (con cocientes más elevados para jóvenes y causas externas). Entre 2001-2009 y 2010-2017 la tasa media anual disminuyó un 16,8% (60,7% en 15-34 años; 19,4% en hombres y 9,8% en mujeres). La contribución de los bebedores de alto riesgo y de las enfermedades digestivas y causas externas al riesgo de mortalidad atribuible a alcohol disminuyó ligeramente entre los dos períodos, mientras que aumentó la contribución del cáncer y enfermedades circulatorias. Estas estimaciones son conservadoras. La contribución del alcohol a la mortalidad general es importante en España, requiriendo medidas colectivas para reducirla. [EN] There are no recent estimates of alcohol-attributable mortality in Spain with Spanish alcohol consumption data. The objective is to estimate it and know its evolution between 2001 and 2017 in people ≥15 years, according to sex, age, period, cause of death and type of drinker. The cause-specific approach and Levin's equation were used. Survey consumption was corrected for underestimation with respect to sales statistics, and past consumption and binge drinking were considered. The average annual number of deaths attributable to alcohol in 2010-2017 was 14,927, 58.6% of which were premature (<75 years). The age-standardized alcohol-attributable mortality rate was 39.4/100,000 inhabitants, representing 3.9% of overall mortality. Using standardized percentages, 68.7% corresponded to heavy drinkers. The most frequent causes of alcohol-attributable mortality were cancer (44.7%) and digestive diseases (33.2%). The rate of alcohol-attributable mortality was 3.5 times higher in men than in women (with higher ratios for young people and external causes). Between 2001-2009 and 2010-2017, the average annual rate decreased 16.8% (60.7% in 15-34 years; 19.4% in men and 9.8% in women). The contribution of heavy drinkers, digestive diseases and external causes to the risk of alcohol-attributable mortality decreased slightly between the two periods, while the contribution of cancer and circulatory diseases increased. These estimates are conservative. The contribution of alcohol to overall mortality is significant in Spain, requiring collective action to reduce it.Publication Programa de Mentores ISCIII. Publicaciones de los mentorizados(2022) Instituto de Salud Carlos III. Programa de Mentores del ISCIIIListado de publicaciones de los alumnos del Programa de Mentores del ISCIII.Publication Effectiveness of mRNA vaccine boosters against infection with the SARS-CoV-2 omicron (B.1.1.529) variant in Spain: a nationwide cohort study(Elsevier, 2022-06-02) Monge Corella, Susana; Rojas-Benedicto, Ayelén; Olmedo, Carmen; Mazagatos, Clara; Sierra, María José; Limia, Aurora; Martín-Merino, Elisa; Larrauri, Amparo; Hernán, Miguel A; IBERCovidBackground: The omicron (B.1.1.529) variant of SARS-CoV-2 has increased capacity to elude immunity and cause breakthrough infections. The aim of this study was to estimate the effectiveness of mRNA-based vaccine boosters (third dose) against infection with the omicron variant by age, sex, time since complete vaccination, type of primary vaccine, and type of booster. Methods: In this nationwide cohort study, we linked data from three nationwide population registries in Spain (Vaccination Registry, Laboratory Results Registry, and National Health System registry) to select community-dwelling individuals aged 40 years or older, who completed their primary vaccine schedule at least 3 months before the start of follow-up, and had not tested positive for SARS-CoV-2 since the start of the pandemic. On each day between Jan 3, and Feb 6, 2022, we matched individuals who received a booster mRNA vaccine and controls of the same sex, age group, postal code, type of vaccine, time since primary vaccination, and number of previous tests. We estimated risk of laboratory-confirmed SARS-CoV-2 infection using the Kaplan-Meier method and compared groups using risk ratios (RR) and risk differences. Vaccine effectiveness was calculated as one minus RR. Findings: Between Jan 3, and Feb 6, 2022, 3 111 159 matched pairs were included in our study. Overall, the estimated effectiveness from day 7 to 34 after a booster was 51·3% (95% CI 50·2-52·4). Estimated effectiveness was 52·5% (51·3-53·7) for an mRNA-1273 booster and 46·2% (43·5-48·7) for a BNT162b2 booster. Effectiveness was 58·6% (55·5-61·6) if primary vaccination had been with ChAdOx1 nCoV-19 (Oxford-AstraZeneca), 55·3% (52·3-58·2) with mRNA-1273 (Moderna), 49·7% (48·3-51·1) with BNT162b2 (Pfizer-BioNTech), and 48·0% (42·5-53·7) with Ad26.COV2.S (Janssen). Estimated effectiveness was 43·6% (40·0-47·1) when the booster was administered between 151 days and 180 days after complete vaccination and 52·2% (51·0-53·3) if administered more than 180 days after primary scheduled completion. Interpretation: Booster mRNA vaccine-doses were moderately effective in preventing infection with the omicron variant of SARS-CoV-2 for over a month after administration, which indicates their suitability as a strategy to limit the health effects of COVID-19 in periods of omicron variant domination. Estimated effectiveness was higher for mRNA-1273 compared with BNT162b2 and increased with time between completed primary vaccination and booster.Publication CD44 In Sarcomas: A Comprehensive Review and Future Perspectives(Frontiers Media, 2022-06-17) Fernández-Tabanera, Enrique; Melero-Fernández de Mera, Raquel María; Alonso, Javier; Instituto de Salud Carlos III; Asociación Pablo Ugarte contra el cáncer infantil; Candela Ribera. Asociación contra el sarcoma de Ewing; Asociación Todos somos Iván; Fundación la Sonrisa de Alex para la investigación y el tratamiento del sarcoma de Ewing; Centro de Investigación Biomédica en Red - CIBERER (Enfermedades Raras)It is widely accepted that the tumor microenvironment, particularly the extracellular matrix, plays an essential role in the development of tumors through the interaction with specific protein-membrane receptors. One of the most relevant proteins in this context is the transmembrane protein CD44. The role of CD44 in tumor progression, invasion, and metastasis has been well established in many cancers, although a comprehensive review concerning its role in sarcomas has not been published. CD44 is overexpressed in most sarcomas and several in vitro and in vivo experiments have shown a direct effect on tumor progression, dissemination, and drug resistance. Moreover, CD44 has been revealed as a useful marker for prognostic and diagnostic (CD44v6 isoform) in osteosarcoma. Besides, some innovative treatments such as HA-functionalized liposomes therapy have become an excellent CD44-mediated intracellular delivery system for osteosarcoma. Unfortunately, the reduced number of studies deciphering the prognostic/diagnostic value of CD44 in other sarcoma subgroups, neither than osteosarcoma, in addition to the low number of patients involved in those studies, have produced inconclusive results. In this review, we have gone through the information available on the role of CD44 in the development, maintenance, and progression of sarcomas, analyzing their implications at the prognostic, therapeutic, and mechanistic levels. Moreover, we illustrate how research involving the specific role of CD44 in the different sarcoma subgroups could suppose a chance to advance towards a more innovative perspective for novel therapies and future clinical trials.Publication Mortalidad atribuible al alcohol en España 2001-2017. Metodología y resultados(Ministerio de Sanidad (España), 2020) Donat López, Marta; Sordo, Luis; Belza Egozcue, Maria Jose; Barrio, Gregorio; Instituto de Salud Carlos III; Plan Nacional de Drogas (España)Introducción: La estimación de la mortalidad atribuible a alcohol en la población es un componente esencial a la hora de conocer el impacto global del alcohol sobre el bienestar humano, y puede utilizarse para determinar prioridades, asignar recursos en salud pública y evaluar las políticas relacionadas con el alcohol. En España las estimaciones disponibles se han basado en datos sobre la distribución poblacional y los patrones de consumo de alcohol procedentes de otros países, o en datos españoles sin corregir por la subestimación del con sumo que es habitual en los autoinformes de las encuestas poblacionales. Esto ha conducido a que se disponga de estimaciones muy dispares y a una considerable incertidumbre a la hora de utilizar la información en la toma de decisiones. Es necesario, pues, obtener estimaciones de la mortalidad atribuible a alcohol en España utilizando datos empíricos sobre consumo de alcohol procedentes de fuentes españolas corregidos por subestimación del consumo en las encuestas con respecto a los registros de ventas de bebidas alcohólicas. Objetivo: Estimar la mortalidad atribuible a alcohol en España durante 2001-2017 según sexo, edad, comunidad autónoma, causa de muerte y tipo de consumo, así como su evolución temporal, utilizando fundamentalmente sistemas de información españoles para estimar el consumo poblacional de alcohol.Métodos: Se ha estimado la mortalidad atribuible a alcohol en la población residente en España de 15 años y más durante 2001-2017, utilizando el enfoque de causa específica, lo que implica estimar las muertes atribuibles a alcohol (MAAs) para determinadas causas específicas seleccionadas por su relación causal aceptada con el consumo de alcohol y sumarlas posteriormente. Las causas de muerte se seleccionaron basándose en las publicaciones más recientes, principalmente revisiones sistemáticas y metanálisis, que valoran el riesgo de desarrollar determinados problemas de salud o enfermedades asociados al consumo de alcohol. No se incluyeron aquellos problemas o enfermedades en las que no existe aún suficiente evidencia sobre la causalidad del alcohol o para cuantificar las relaciones de riesgo. El número de muertes por las causas selecciona das según edad, sexo, comunidad autónoma de residencia y año-calendario se obtuvieron del registro de mortalidad del Instituto Nacional de Estadística (INE). El nº de MAAs por una causa específica dada se estimó multiplicando el número de muertes registradas por esa causa por su Fracción Atribuible Poblacional a Alcohol (FAP). Para las causas completa o directamente atribuibles a alcohol se asignó una FAP de uno. Para las causas parcialmente atribuibles a alcohol se estimaron FAPs específicas para España según sexo, grupo de edad (15-34, 35-54, 55-74 y ≥75), período-calendario (2001-2009 y 2010-2017) y cantidad de alcohol consumida (≤19, 20-39, 40-49, 50-59, 60-79, 80-99 y ≥100 gramos de alcohol puro/día), combinando las prevalencias de consumo de alcohol corregidas por subestimación con funciones de riesgo relativo obtenidas de metanálisis internacionales. Las fuentes de información para el cálculo de las prevalencias de consumo corregidas fueron la Encuesta Nacional de Salud (2001, 2006, 2011 y 2017), la Encuesta Europea de Salud en España (2009 y 2014) y los registros de ventas de bebidas alcohólicas, principalmente las estimaciones de consumo realizadas por la Agencia Tributaria a partir de los ingresos por impuestos especiales al alcohol. Se calcularon varios indicadores de mortalidad atribuible a alcohol, centrándose especialmente en las tasas de MAA estandarizadas por edad y en los porcentajes estandarizados por edad que expresan la contribución del alcohol al riesgo de mortalidad general y la contribución al riesgo total de MAA del consumo excesivo regular de alcohol y de distintos grupos de causas de muerte relacionadas con alcohol (cáncer, enfermedades circulatorias, infecciosas, metabólicas, digestivas, neurológicas/mentales, otras enfermedades y causas externas). Para estandarizar las tasas se utilizó como referencia la estructura de edad de la población estándar europea de 2013. Los denominadores de las tasas se obtuvieron de las Cifras de Población del INE. Los indicadores se calcularon por sexo, grupo de edad (15-34, 35-54, 55-74 años y >=75 años), comunidad autónoma y periodo calendario (2001-2009 y 2010-2017). Para comparar el riesgo de mortalidad atribuible a alcohol entre grupos (por ejemplo, hombres y mujeres) se utilizaron la razón y la diferencia de tasas estandarizadas por edad. En el caso de la comparación entre períodos la razón de tasas se transformó en porcentaje de cambio. Resultados: Se estima que en 2010-2017 en los residentes en España de ≥15 años el con sumo de alcohol causó anualmente una media de 15960 muertes y a la vez evitó 471 muertes, con un saldo global de 15489 muertes atribuibles a alcohol (MAA). Un 73,8% de las MAA ocurrieron en hombres y un 55,7% fueron prematuras, es decir, ocurrieron antes de los 75 años. El riesgo poblacional de MAA, medido por la tasa media anual de MAA estandarizada por edad, fue de 40,9 por cada 100.000 habitantes, 3,8 veces mayor en hombres (69,3 por 100.000) que en mujeres (18,1 por 100.000). Por comunidad autónoma los riesgos más altos se observaron en Asturias (46,0), Andalucía (44,7), Galicia (43,9) y Ceuta y Melilla (43,9), y los más bajos en Madrid (32,2), Navarra (36,5) y Castilla-La Mancha (36,7). El riesgo aumentaba considerablemente con la edad, tanto en hombres como en mujeres. Usando porcentajes estandarizados por edad, la contribución del alcohol a la mortalidad general en los residentes en España de ≥15 años en 2010-2017 fue de un 4,0% (5,4% en hombres y 2,3% en mujeres), observándose la mayor contribución en País Vasco (4,5%), Galicia (4,4%), La Rioja (4,3%) y Astur as (4,3%), y la menor en Extremadura (3,4%), Ceuta/Melilla (3,6%), Madrid y Castilla-La Mancha (3,7%). Las causas de muerte que más contribuyeron al riesgo total de MAA fueron cáncer (43,0%) y enfermedades digestivas (25,9%), con una contribución de causas externas y cáncer mayor en hombres que en mujeres y lo contrario en el caso de enfermedades circulatorias y digestivas. Un 79,9% de las MAA (82,8% en hombres y 69,0% en mujeres) fueron atribuibles al consumo excesivo (≥60 g/día en hombres y ≥40 g/día en mujeres). La mayor contribución del alcohol al riesgo de mortalidad general se observó en el grupo de 35-54 años (10,0%), alcanzando un 11,9% en los hombres de esa edad. En general la contribución del consumo excesivo de alcohol al riesgo total de MAA aumentaba con la edad, con un máximo en el grupo 75 años y más (85,6%). Las causas de muerte con mayor contribución al riesgo total de MAA fueron causas externas en el grupo 15-34 años (82,6%), y cáncer a partir de esa edad, especialmente en el grupo 55-74 años (52,9%). Entre 2001-2009 y 2010-2017 en los residentes en España de ≥15 años la tasa de MAA estandarizada descendió un 16,9% (19,5% en hombres y 9,5% en mujeres). Los descensos afectaron a todas las comunidades autónomas, observándose los mayores descensos relativos en Madrid (-26,9%), Canarias (-19,7%) y País Vasco (-19,6%), y los menores en Comunidad Valenciana (-12,3%) y Castilla-La Mancha (-12,4%) y Cantabria (-12,5%). En el conjunto de España el máximo descenso se observó en el grupo 15-34 años (62,3%), mientras que fue casi inexistente en el grupo de ≥75 años (3,1%). Entre 2001-2009 y 2010-2017 en los residentes en España de ≥15 años la contribución del alcohol al riesgo general de mortalidad se mantuvo prácticamente estable (4,1% y 4,0%), con una pequeña disminución en hombres y un pequeño aumento en mujeres. La contribución disminuyó en todas las comunidades autónomas, con los mayores descensos absolutos en Madrid (-0,27%), Canarias (-0,20%) y País Vasco (-0,20%). Aumentó la contribución al riesgo de mortalidad total atribuible a alcohol de enfermedades circulatorias, y disminuyó la contribución de enfermedades digestivas y causas externas. También disminuyó ligeramente la contribución a dicho riesgo del con sumo excesivo de alcohol en hombres (de 86,5% a 82,8%) y en mujeres (de 72,9% a 69,0%).Por edad, la contribución del alcohol al riesgo de mortalidad general disminuyó bastante en el grupo <55 años, sobre todo en el grupo 15-34 años (de 14,8% a 9,9% en hombres y de 5,2% a 4,5% en mujeres), y aumentó ligeramente en el grupo ≥55 años (≥35 años en mujeres). La disminución de la contribución al riesgo global de MAA de las causas externas se observó sobre todo en el grupo 15-54 años, y la de enfermedades digestivas en el grupo ≥55 años. Por su parte el aumento de la contribución del cáncer se observó sobre todo en el grupo 15-74 años y la de enfermedades circulatorias en el grupo ≥75 años. Finalmente, la disminución de la contribución al riesgo global de MAA del consumo excesivo de alcohol se observó en todos los grupos de edad. Conclusiones: En 2010-2017 se produjeron en España 15489 muertes al año atribuibles a alcohol, siendo un 73,8% en hombres y el 55,7% muertes prematuras. El con sumo de alcohol supuso un 4,0% del riesgo general de mortalidad. Teniendo en cuenta el peso de las muertes prematuras y que la estimación es bastante conservadora, es obvio que el consumo de alcohol sigue representando una carga importante de enfermedad y muerte. Tres de cada cuatro de las muertes atribuibles a alcohol se relacionan con el consumo excesivo, por lo que es prioritario reducir su prevalencia, preferentemente desarrollando estrategias dirigidas a disminuir la cantidad de consumo en el conjunto de la población. En España persisten aún desigualdades territoriales considerables en el riesgo de muerte atribuible a alcohol, por lo que se recomienda reforzar las estrategias preventivas especialmente en las comunidades autónomas con mayor riesgo y donde su descenso ha sido más lento. Este estudio debería servir de base para poner en marcha en España un indicador rutinario de mortalidad atribuible a alcohol que contribuya a monitorizar las consecuencias del consumo de alcohol en la salud y el bienestar de la población y a evaluar las intervenciones dirigidas a reducirlas. Ello implica la mejora de los sistemas de información rutinarios que sirven de base para realizar las estimaciones.Publication Phage‐Derived and Aberrant HaloTag Peptides Immobilized on Magnetic Microbeads for Amperometric Biosensing of Serum Autoantibodies and Alzheimer's Disease Diagnosis(Wiley, 2021) Valverde, Alejandro; Montero-Calle, Ana Maria; Arévalo, Beatriz; Segundo-Acosta, Pablo San; Serafín, Verónica; Alonso‐Navarro, Miren; Solis-Fernandez, Guillermo; Pingarrón, José M; Campuzano, Susana; Barderas Manchado, Rodrigo; Ministerio de Ciencia, Innovación y Universidades (España); Instituto de Salud Carlos III; Comunidad de Madrid (España); Ministerio de Educación, Cultura y Deporte (España); Complutense University of Madrid (España); Ministerio de Economía y Competitividad (España); Research Foundation - Flanders; Ministerio de Ciencia e Innovación (España)An electrochemical biosensing platform for serum autoantibodies (AAbs) detection is reported in this work, exploiting for the first time six Alzheimer's disease (AD)-specific phage-derived and frameshift aberrant HaloTag peptides as receptors, immobilized on magnetic microbeads (MBs) surface and captured on disposable electrodes to perform amperometric detection. Operational analytical characteristics and clinical diagnostic ability of the bioplatform were probed in optimized key experimental conditions by analysing serum AAbs of AD patients and healthy subjects. The value of 100 % obtained for AUC, sensitivity, and selectivity from the all peptides combined ROC curve, indicate full AD-diagnostic capability of the methodology, which was further implemented, as proof of concept, in a POC multiplexing platform to detect the signature in a single test over clinically actionable times (1 h 15 min), opening great promise for the type of diagnosis and AD patients’ monitoring follow-up currently pursued.Publication Multiplexed Biosensing Diagnostic Platforms Detecting Autoantibodies to Tumor-Associated Antigens from Exosomes Released by CRC Cells and Tissue Samples Showed High Diagnostic Ability for Colorectal Cancer(Elsevier, 2021) Montero-Calle, Ana Maria; Aranguren-Abeigon, Itziar; Garranzo-Asensio, Maria; Poves, Carmen; Fernández-Aceñero, María Jesús; Martínez-Useros, Javier; Sanz, Rodrigo; Dziaková, Jana; Rodríguez-Cobos, Javier; Solis-Fernandez, Guillermo; Povedano, Eloy; Gamella, Maria; Torrente-Rodríguez, Rebeca Magnolia; Alonso-Navarro, Miren; de los Ríos, Vivian; Casal, José Ignacio; Domínguez, Gemma; Guzman-Aranguez, Ana; Peláez-García, Alberto; Pingarrón, José Manuel; Campuzano, Susana; Barderas Manchado, Rodrigo; Ministerio de Ciencia e Innovación (España); Autonomous University of Madrid (España); Ministerio de Educación, Cultura y Deporte (España); Research Foundation - Flanders; Ministerio de Economía y Competitividad (España); Instituto de Salud Carlos III; Comunidad de Madrid (España)Colorectal cancer (CRC) is the second leading cause of cancer-related death worldwide. The five-year survival rate of CRC patients depends on the stage at diagnosis, being higher than 80% when CRC is diagnosed in the early stages but lower than 10% when CRC is diagnosed in advanced stages. Autoantibodies against specific CRC autoantigens (tumor-associated antigens (TAAs)) in the sera of patients have been widely demonstrated to aid in early diagnosis. Thus, we herein aim to identify autoantigens target of autoantibodies specific to CRC that possess a significant ability to discriminate between CRC patients and healthy individuals by means of liquid biopsy. To that end, we examined the protein content of the exosomes released by five CRC cell lines and tissue samples from CRC patients by means of immunoprecipitation coupled with mass spectrometry analysis. A total of 103 proteins were identified as potential autoantigens specific to CRC. After bioinformatics and meta-analysis, we selected 15 proteins that are more likely to be actual CRC autoantigens in order to evaluate their role in CRC prognosis by Western blot (WB) and immunohistochemistry (IHC). We found dysregulation at the protein level for 11 of these proteins in both tissue and plasma exosome samples from patients, along with an association of nine of these proteins with CRC prognosis. After validation, all but one showed a statistically significant high diagnostic ability to distinguish CRC patients and individuals with premalignant lesions from healthy individuals, either by luminescence Halotag-based beads, or by a multiplexed biosensing platform involving the use of magnetic microcarriers as solid support modified with covalently immobilized Halotag fusion proteins constructed for CRC detection. Taken together, our results highlight the usefulness of the approach defined here to identify the TAAs specific to chronic diseases; they also demonstrate that the measurement of autoantibody levels in plasma against the TAAs identified here could be integrated into a point-of-care (POC) device for CRC detection with high diagnostic ability.Publication Diagnostic Process in Rare Diseases: Determinants Associated with Diagnostic Delay(Multidisciplinary Digital Publishing Institute (MDPI), 2022-05-26) Benito-Lozano, Juan; Arias-Merino, Greta; Gómez-Martínez, Mario; Ancochea-Díaz, Alba; Aparicio-García, Aitor; Posada De la Paz, Manuel; Alonso-Ferreira, Veronica; Agencia Estatal de Investigación (España); Ministerio de Ciencia e Innovación (España)Many people living with rare disease (RD) report a difficult diagnostic process from the symptom onset until they obtain the definitive diagnosis. The aim of this study was thus to ascertain the diagnostic process in RDs, and explore the determinants related with having to wait for more than one year in this process (defined as “diagnostic delay”). We conducted a case–control study, using a purpose-designed form from the Spanish Rare Diseases Patient Registry for data-collection purposes. A descriptive analysis was performed and multivariate backward logistic regression models fitted. Based on data on 1216 patients living with RDs, we identified a series of determinants associated with experiencing diagnostic delay. These included: having to travel to see a specialist other than that usually consulted in the patient’s home province (OR 2.1; 95%CI 1.6–2.9); visiting more than 10 specialists (OR 2.6; 95%CI 1.7–4.0); being diagnosed in a region other than that of the patient’s residence at the date of symptom onset (OR 2.3; 95%CI 1.5–3.6); suffering from a RD of the nervous system (OR 1.4; 95%CI 1.0–1.8). In terms of time taken to see a specialist, waiting more than 6 months to be referred from the first medical visit was the period of time which most contributed to diagnostic delay (PAR 30.2%). In conclusion, this is the first paper to use a collaborative study based on a nationwide registry to address the diagnostic process of patients living with RDs. While the evidence shows that the diagnostic process experienced by these persons is complex, more studies are needed to determine the implications that this has for their lives and those of their families at a social, educational, occupational, psychological, and financial level.Publication Educational Gradients in Drinking Amount and Heavy Episodic Drinking among Working-Age Men and Women in Spain(Multidisciplinary Digital Publishing Institute (MDPI), 2022-04-05) Donat López, Marta; Barrio, Gregorio; Guerras Moreira, Juan Miguel; Herrero, Lidia; Pulido, Jose; Belza Egozcue, Maria Jose; Regidor, Enrique; Plan Nacional de Drogas (España); Instituto de Salud Carlos III; Instituto Mixto de Investigación Escuela Nacional de SanidadAlcohol-related harm decreases as socioeconomic position increases, although sometimes the opposite happens with alcohol intake. The objective was to know the educational gradient in monthly measures of drinking amount and heavy episodic drinking (HED) among people aged 25-64 years in Spain from 1997-2017. Such gradient was characterized with the relative percent change (PC) in drinking measures per year of education from generalized linear regression models after adjusting for age, year, region, marital status and immigration status. Among men, the PCs were significantly positive (p < 0.05) for prevalence of <21 g alcohol/day (2.9%) and 1-3 HED days (1.4%), and they were negative for prevalences of 21-40 g/day (-1.1%), >40 g/day (-6.0%) and ≥4 HED days (-3.2%), while among women they ranged from 3.6% to 5.7%. The gradient in prevalences of >40 g/day (men) and >20 g/day (women) was greatly attenuated after additionally adjusting for HED, while that of ≥4 HED days was only slightly attenuated after additionally adjusting for drinking amount. Among women, the gradients, especially in HED measures, seem steeper in 2009-2017 than in 1997-2007. Educational inequality remained after additional adjustment for income and occupation, although it decreased among women. These results can guide preventive interventions and help explain socioeconomic inequalities in alcohol-related harm.Publication Cellular Heterogeneity and Cooperativity in Glioma Persister Cells Under Temozolomide Treatment(Frontiers Media, 2022-05-25) Rabé, Marion; Fonteneau, Lucie; Oliver, Lisa; Morales-Molina, Alvaro; Jubelin, Camille; Garcia-Castro, Javier; Heymann, Dominique; Gratas, Catherine; Vallette, François M.; Ligue Nationale Contre le Cancer (Francia)We have observed a drug-tolerant/persister state in a human glioblastoma (GBM) cell line after exposure to temozolomide, the standard-of-care chemotherapeutic agent for GBM. We used a multicolor lentiviral genetic barcode labeling to follow cell population evolution during temozolomide treatment. We observed no change in the distribution of the different colored populations of cells in persister or resistant cells suggesting that pre-existing minor subpopulations, which would be expected to be restricted to a single color, were not amplified/selected during the response to the drug. We have previously identified four genes (CHI3L1, FAT2, KLK5, and HB-EGF) that were over-expressed during the persister stage. Single-cell analysis of these four genes indicated that they were expressed in different individual cells ruling out the existence of a single persister-specific clone but suggesting rather a global answer. Even so, the transitory silencing of CHI3L1, FAT2, or KLK5 influenced the expression of the other three genes and the survival of U251 cells in absence of temozolomide. Since proteins encoded by the four genes are all localized in the extracellular matrix or interact within the extracellular compartment, we propose that cellular interactions and communications are important during the persister stage before the acquisition of chemo-resistance. Thus, persisters might be a new therapeutically relevant target in GBM.Publication Metodología utilizada para estimar la mortalidad atribuible a alcohol en España, 2001-2017(Sociedad Científica Española de Estudios sobre el Alcohol, el Alcoholismo y las otras Toxicomanías, 2021-06-15) Donat López, Marta; Sordo, Luis; Guerras Moreira, Juan Miguel; Politi, Julieta; Pulido, Jose; Barrio, Gregorio; Plan Nacional de Drogas (España); Instituto de Salud Carlos III[ES] El objetivo es describir y discutir los métodos y asunciones para estimar la mortalidad atribuible a alcohol en España en 2001-2017. Se estimó el nº medio anual de muertes atribuibles a alcohol (MAAs) basándose en 19 grupos de causas de muerte relacionadas con alcohol (18 parcialmente atribuibles y uno directamente atribuible), y 20 fracciones atribuibles poblacionales al alcohol (FAPs) para cada grupo de causas, resultantes de combinar sexo, 5 grupos de edad, y los períodos 2001-2009 y 2010-2017. Las muertes por causa se obtuvieron del Instituto Nacional de Estadística. Para las causas parcialmente atribuibles se calcularon FAPs específicas para España, usando la fórmula de Levin con datos de exposición al alcohol procedentes de encuestas de salud y estadísticas de ventas, y riesgos relativos procedentes de metanálisis internacionales. Se consideraron las prevalencias anuales de exbebedores y de siete niveles de consumo diario de alcohol. Se corrigió la subestimación del consumo medio diario autoinformado con respecto a las estadísticas de venta, multiplicando por un factor de 1,58-3,18, dependiendo del año-calendario. Se calcularon tasas de MAA y porcentajes de la mortalidad general atribuibles a alcohol estandarizados por edad, según sexo, grupo de edad, periodo-calendario, tipo de bebedor y comunidad autónoma. Se realizaron análisis de sensibilidad observando cómo cambiaban las estimaciones de MAA al hacerlo algunas opciones metodológicas, como el criterio de exbebedor o la introducción de un período de latencia. The objective is to describe and discuss methods and assumptions to estimate the mortality attributable to alcohol in Spain in 2001-2017. [EN] The annual mean number of deaths attributable to alcohol (DAAs) was estimated based on 19 groups of alcohol-related causes of death (18 partially attributable and one directly attributable), and 20 alcohol population-attributable fractions (PAFs), resulting from combining sex, 5 age groups, and the periods 2001-2009 and 2010-2017, for each cause group. Deaths from causes were obtained from the Spanish National Institute of Statistics. For partially attributable causes, Spain-specific PAFs were calculated using the Levin formula with alcohol exposure data from health surveys and sales statistics, and relative risks from international meta-analyses. Annual prevalences of ex-drinkers and seven levels of daily alcohol consumption were considered. The underestimation of self-reported daily average consumption with respect to the sales statistics was corrected by multiplying by a factor of 1.58-3.18, depending on the calendar year. DAA rates standardized by age and standardized proportions of general mortality attributable to alcohol, according to sex, age group, calendar period, type of drinker and autonomous community were calculated. Sensitivity analyses were performed to assess how the DAA estimates changed when changing some methodological options, such as the ex-drinker criterion or the introduction of a latency period.Publication Effects of local factors on adaptation to heat in Spain (1983-2018)(Elsevier, 2022-06) Navas-Martin, Miguel Angel; Lopez-Bueno, Jose Antonio; Diaz-Jimenez, Julio; Follos, F; Vellón, JM; Mirón, Isidro Juan; Luna, María Yolanda; Sánchez-Martínez, G; Culqui, Dante Roger; Linares-Gil, Cristina; Instituto de Salud Carlos III; Ministerio para la Transición Ecológica y el Reto Demográfico (España); National University of Distance Education (España)The European Union is currently immersed in policy development to address the effects of climate change around the world. Key plans and processes for facilitating adaptation to high temperatures and for reducing the adverse effects on health are among the most urgent measures. Therefore, it is necessary to understand those factors that influence adaptation. The aim of this study was to provide knowledge related to the social, climate and economic factors that are related to the evolution of minimum mortality temperatures (MMT) in Spain in the rural and urban contexts, during the 1983-2018 time period. For this purpose, local factors were studied regarding their relationship to levels of adaptation to heat. MMT is an indicator that allows for establishing a relationship to between mortality and temperature, and is a valid indicator to assess the capacity of adaptation to heat of a certain population. MMT is obtained through the maximum daily temperature and daily mortality of the study period. The evolution of MMT values for Spain was established in a previous paper. An ecological, longitudinal and retrospective study was carried out. Generalized linear models (GLM) were performed to identify the variables that appeared to be related to adaptation. The adaptation was calculated as the difference in variation in MMT based on the average increase in maximum daily temperatures. In terms of adaptation to heat, urban populations have adapted more than non-urban populations. Seventy-nine percent (n = 11) of urban provinces have adapted to heat, compared to twenty-one percent (n = 3) of rural provinces that have not adapted. In terms of urban zones, income level and habituation to heat (values over the 95th percentile) were variables shown to be related to adaptation. In contrast, among non-urban provinces, a greater number of housing rehabilitation licenses and a greater number of health professionals were variables associated with higher increases in MMT, and therefore, with adaptation. These results highlight the need to carry out studies that allow for identifying the local factors that are most relevant and influential in population adaptation. More studies carried out at a small scale are needed.Publication Transgenesis in parasitic helminths: a brief history and prospects for the future(BioMed Central (BMC), 2022-03-28) Quinzo, Mónica; Perteguer-Prieto, Maria Jesus; Brindley, Paul J; Loukas, A; Sotillo, Javier; Instituto de Salud Carlos IIIHelminth infections impact the health of hundreds of millions of persons globally and also cause important economic losses in livestock farming. Methodological limitations as well as the low attention given to the study of helminths have impacted biological research and, thus, the procurement of accurate diagnosis and effective treatments. Understanding the biology of helminths using genomic and proteomic approaches could contribute to advances in understanding host-helminth interactions and lead to new vaccines, drugs and diagnostics. Despite the significant advances in genomics in the last decade, the lack of methodological adaptation of current transgenesis techniques has hampered the progression of post-genomic research in helminthology. However, the application of new techniques, such as CRISPR, to the study of trematodes and nematodes has opened new avenues for genome editing-powered functional genomics for these pathogens. This review summarises the historical advances in functional genomics in parasitic helminths and highlights pending limitations that will need to be overcome to deploy transgenesis tools.Publication RedLabRA; a Spanish Network of Microbiology Laboratories for the Surveillance of Antibiotic Resistant Microorganisms(Sociedad Española de Quimioterapia (SEQ), 2021-09) Cañada-Garcia, Javier Enrique; Perez-Vazquez, Maria; Oteo-Iglesias, JesusThere is an urgent need to control the clinical and public health impact that antibiotic resistance (AR) causes worldwide. Any measure for its control must be based on an up-to-date and comprehensive knowledge of the situation. However, it is difficult to determine the current dimension of AR because a large part of the available information is based on heterogeneous, insufficiently unified and retrospective data. The integration of genomic information in the surveillance of AR is another important factor for improvement. The Spanish Network of Laboratories for the Surveillance of Resistant Microorganisms (RedLabRA) is a structured network of interconnected microbiology laboratories developed within the Spanish National Plan against Antibiotic Resistance. Its main objective is to support the diagnosis of resistance to antibiotics, integrating molecular characterization in the surveillance.Publication A genetic cluster of MDR Enterobacter cloacae complex ST78 harbouring a plasmid containing bla VIM-1 and mcr-9 in the Netherlands(Oxford University Press, 2021-06) Hendrickx, Antoni PA; Debast, Sylvia; Perez-Vazquez, Maria; Schoffelen, Annelot F; Notermans, Daan W; Landman, Fabian; Wielders, Cornelia C H; Flipse, Jacky; de Haan, Angela; Witteveen, Sandra; van Santen-Verheuvel, Marga; de Greeff, Sabine C; Kuijper, Ed; Schouls, Leo M; Dutch CPE surveillance Study Group; Cañada-Garcia, Javier Enrique; Government of NetherlandsBackground: Carbapenemases produced by Enterobacterales are often encoded by genes on transferable plasmids and represent a major healthcare problem, especially if the plasmids contain additional antibiotic resistance genes. As part of Dutch national surveillance, 50 medical microbiological laboratories submit their Enterobacterales isolates suspected of carbapenemase production to the National Institute for Public Health and the Environment for characterization. All isolates for which carbapenemase production is confirmed are subjected to next-generation sequencing. Objectives: To study the molecular characteristics of a genetic cluster of Enterobacter cloacae complex isolates collected in Dutch national surveillance in the period 2015-20 in the Netherlands. Methods: Short- and long-read genome sequencing was used in combination with MLST and pan-genome MLST (pgMLST) analyses. Automated antimicrobial susceptibility testing (AST), the Etest for meropenem and the broth microdilution test for colistin were performed. The carbapenem inactivation method was used to assess carbapenemase production. Results: pgMLST revealed that nine E. cloacae complex isolates from three different hospitals in the Netherlands differed by <20 alleles and grouped in a genetic cluster termed EclCluster-013. Seven isolates were submitted by one hospital in 2016-20. EclCluster-013 isolates produced carbapenemase and were from ST78, a globally disseminated lineage. EclCluster-013 isolates harboured a 316 078 bp IncH12 plasmid carrying the bla VIM-1 carbapenemase and the novel mcr-9 colistin resistance gene along with genes encoding resistance to different antibiotic classes. AST showed that EclCluster-013 isolates were MDR, but susceptible to meropenem (<2 mg/L) and colistin (<2 mg/L). Conclusions: The EclCluster-013 reported here represents an MDR E. cloacae complex ST78 strain containing an IncH12 plasmid carrying both the bla VIM-1 carbapenemase and the mcr-9 colistin resistance gene.Publication Provirus reactivation is impaired in HIV-1 infected individuals on treatment with dasatinib and antiretroviral therapy(Elsevier, 2021-06-26) Vigon-Hernandez, Lorena; Martinez-Roman, Paula; Rodriguez Mora, Sara; Torres, Montserrat; Puertas, Maria C; Mateos, Elena; Salgado, María; Navarro, Antonio; Sánchez-Conde, Matilde; Ambrosioni, Juan; Cervero, Miguel; Wyen, Christoph; Hoffmann, Christian; Miró, José María; Alcamí, José; Podzamczer, Daniel; García-Gutiérrez, Valentín; Martinez-Picado, Javier; Briz, Veronica; Lopez-Huertas, Maria Rosa; Planelles, Vicente; Coiras, Mayte; Multidisciplinary Group of Study of HIV-1 Reservoir MGS-HIVRES; Instituto de Salud Carlos III; Consorci Institut D Investigacions Biomediques August Pi I Sunyer; National Institutes of Health (Estados Unidos); Ministerio de Ciencia e Innovación (España); Red de Investigación Cooperativa en Investigación en Sida (España); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)The latent viral reservoir formed by HIV-1, mainly in CD4+ T cells, is responsible for the failure of antiretroviral therapy (ART) to achieve a complete elimination of the virus in infected individuals. We previously determined that CD4+ T cells from individuals with chronic myeloid leukemia (CML) on treatment with dasatinib are resistant to HIV-1 infection ex vivo. The main mechanism for this antiviral effect is the preservation of SAMHD1 activity. In this study, we aimed to evaluate the impact of dasatinib on the viral reservoir of HIV-infected individuals with CML who were on simultaneous treatment with ART and dasatinib. Due to the low estimated incidence of HIV-1 infection and CML (1:65,000), three male individuals were recruited in Spain and Germany. These individuals had been on treatment with standard ART and dasatinib for median 1.3 years (IQR 1.3-5.3 years). Reservoir size and composition in PBMCs from these individuals was analyzed in comparison with HIV-infected individuals on triple ART regimen and undetectable viremia. The frequency of latently infected cells was reduced more than 5-fold in these individuals. The reactivation of proviruses from these cells was reduced more than 4-fold and, upon activation, SAMHD1 phosphorylation was reduced 40-fold. Plasma levels of the homeostatic cytokine IL-7 and CD4 effector subpopulations TEM and TEMRA in peripheral blood were also reduced. Therefore, treatment of HIV-infected individuals with dasatinib as adjuvant of ART could disturb the reservoir reactivation and reseeding, which might have a beneficial impact to reduce its size.Publication Cytotoxic cell populations developed during treatment with tyrosine kinase inhibitors protect autologous CD4+ T cells from HIV-1 infection(Elsevier, 2020-12) Vigon-Hernandez, Lorena; Rodríguez-Mora, Sara; Luna, Alejandro; Sandonis-Martin, Virginia; Mateos, Elena; Bautista, Guiomar; Steegmann, Juan Luis; Climent, Núria; Plana, Montserrat; Perez-Romero, Pilar; De Ory, Fernando de; Alcamí, José; García-Gutiérrez, Valentín; Planelles, Vicente; Lopez-Huertas, Maria Rosa; Coiras, Mayte; Ministerio de Economía y Competitividad (España); Red de Investigación Cooperativa en Investigación en Sida (España); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); National Institutes of Health (Estados Unidos)Tyrosine kinase inhibitors (TKIs) are successfully used in clinic to treat chronic myeloid leukemia (CML). Our group previously described that CD4+ T cells from patients with CML on treatment with TKIs such as dasatinib were resistant to HIV-1 infection ex vivo. The main mechanism for this antiviral activity was primarily based on the inhibition of SAMHD1 phosphorylation, which preserves the activity against HIV-1 of this innate immune factor. Approximately 50% CML patients who achieved a deep molecular response (DMR) may safely withdraw TKI treatment without molecular recurrence. Therefore, it has been speculated that TKIs may induce a potent antileukemic response that is maintained in most patients even one year after treatment interruption (TI). Subsequent to in vitro T-cell activation, we observed that SAMHD1 was phosphorylated in CD4+ T cells from CML patients who withdrew TKI treatment more than one year earlier, which indicated that these cells were now susceptible to HIV-1 infection. Importantly, these patients were seronegative for HIV-1 and seropositive for cytomegalovirus (CMV), but without CMV viremia. Although activated CD4+ T cells from CML patients on TI were apparently permissive to HIV-1 infection ex vivo, the frequency of proviral integration was reduced more than 12-fold on average when these cells were infected ex vivo in comparison with cells isolated from untreated, healthy donors. This reduced susceptibility to infection could be related to an enhanced NK-dependent cytotoxic activity, which was increased 8-fold on average when CD4+ T cells were infected ex vivo with HIV-1 in the presence of autologous NK cells. Enhanced cytotoxic activity was also observed in CD8 + T cells from these patients, which showed 8-fold increased expression of TCRγδ and more than 18-fold increased production of IFNγ upon activation with CMV peptides. In conclusion, treatment with TKIs induced a potent antileukemic response that may also have antiviral effects against HIV-1 and CMV, suggesting that transient use of TKIs in HIV-infected patients could develop a sustained antiviral response that would potentially interfere with HIV-1 reservoir dynamics.Publication The Transcription Factor FEZF1, a Direct Target of EWSR1-FLI1 in Ewing Sarcoma Cells, Regulates the Expression of Neural-Specific Genes(Multidisciplinary Digital Publishing Institute (MDPI), 2021-11-12) Garcia-Garcia, Laura; Fernández-Tabanera, Enrique; Cervera Mayor, Saint Thomas; Melero-Fernández de Mera, Raquel María; Josa, Santiago; Gonzalez-Gonzalez, Laura; Rodriguez-Martin, Carlos; Grünewald, Thomas G P; Alonso, Javier; Instituto de Salud Carlos III; Asociación Pablo Ugarte contra el cáncer infantil; Candela Ribera. Asociación contra el sarcoma de Ewing; Asociación Todos somos Iván; Centro de Investigación Biomedica en Red - CIBER; Fundación la Sonrisa de Alex para la investigación y el tratamiento del sarcoma de EwingEwing sarcoma is a rare pediatric tumor characterized by chromosomal translocations that give rise to aberrant chimeric transcription factors (e.g., EWSR1-FLI1). EWSR1-FLI1 promotes a specific cellular transcriptional program. Therefore, the study of EWSR1-FLI1 target genes is important to identify critical pathways involved in Ewing sarcoma tumorigenesis. In this work, we focused on the transcription factors regulated by EWSR1-FLI1 in Ewing sarcoma. Transcriptomic analysis of the Ewing sarcoma cell line A673 indicated that one of the genes more strongly upregulated by EWSR1-FLI1 was FEZF1 (FEZ family zinc finger protein 1), a transcriptional repressor involved in neural cell identity. The functional characterization of FEZF1 was performed in three Ewing sarcoma cell lines (A673, SK-N-MC, SK-ES-1) through an shRNA-directed silencing approach. FEZF1 knockdown inhibited clonogenicity and cell proliferation. Finally, the analysis of the FEZF1-dependent expression profile in A673 cells showed several neural genes regulated by FEZF1 and concomitantly regulated by EWSR1-FLI1. In summary, FEZF1 is transcriptionally regulated by EWSR1-FLI1 in Ewing sarcoma cells and is involved in the regulation of neural-specific genes, which could explain the neural-like phenotype observed in several Ewing sarcoma tumors and cell lines.Publication Therapeutic Potential of EWSR1-FLI1 Inactivation by CRISPR/Cas9 in Ewing Sarcoma(Multidisciplinary Digital Publishing Institute (MDPI), 2021-07-27) Cervera Mayor, Saint Thomas; Rodriguez-Martin, Carlos; Fernández-Tabanera, Enrique; Melero-Fernández de Mera, Raquel María; Morin, Matias; Fernández-Peñalver, Sergio; Iranzo-Martínez, Maria; Amhih-Cardenas, Jorge; Garcia-Garcia, Laura; Gonzalez-Gonzalez, Laura; Moreno-Pelayo, Miguel Angel; Alonso, Javier; Instituto de Salud Carlos III; Asociación Pablo Ugarte contra el cáncer infantil; Candela Ribera. Asociación contra el sarcoma de Ewing; Fundación la Sonrisa de Alex para la investigación y el tratamiento del sarcoma de Ewing; Centro de Investigación Biomedica en Red - CIBER; Comunidad de Madrid (España); Asociación Todos somos IvánEwing sarcoma is an aggressive bone cancer affecting children and young adults. The main molecular hallmark of Ewing sarcoma are chromosomal translocations that produce chimeric oncogenic transcription factors, the most frequent of which is the aberrant transcription factor EWSR1-FLI1. Because this is the principal oncogenic driver of Ewing sarcoma, its inactivation should be the best therapeutic strategy to block tumor growth. In this study, we genetically inactivated EWSR1-FLI1 using CRISPR-Cas9 technology in order to cause permanent gene inactivation. We found that gene editing at the exon 9 of FLI1 was able to block cell proliferation drastically and induce senescence massively in the well-studied Ewing sarcoma cell line A673. In comparison with an extensively used cellular model of EWSR1-FLI1 knockdown (A673/TR/shEF), genetic inactivation was more effective, particularly in its capability to block cell proliferation. In summary, genetic inactivation of EWSR1-FLI1 in A673 Ewing sarcoma cells blocks cell proliferation and induces a senescence phenotype that could be exploited therapeutically. Although efficient and specific in vivo CRISPR-Cas9 editing still presents many challenges today, our data suggest that complete inactivation of EWSR1-FLI1 at the cell level should be considered a therapeutic approach to develop in the future.Publication Sarcoma treatment in the era of molecular medicine.(EMBO Press, 2020) Grünewald, Thomas G P; Alonso, Marta; Avnet, Sofia; Banito, Ana; Burdach, Stefan; Cidre-Aranaz, Florencia; Di Pompo, Gemma; Distel, Martin; Dorado-Garcia, Heathcliff; Garcia-Castro, Javier; Gonzalez-Gonzalez, Laura; Grigoriadis, Agamemnon E; Kasan, Merve; Koelsche, Christian; Krumbholz, Manuela; Lecanda, Fernando; Lemma, Silvia; Longo, Dario L; Madrigal-Esquivel, Claudia; Morales-Molina, Alvaro; Musa, Julian; Ohmura, Shunya; Ory, Benjamin; Pereira-Silva, Miguel; Perut, Francesca; Rodriguez, Rene; Seeling, Carolin; Al Shaaili, Nada; Shaabani, Shabnam; Shiavone, Kristina; Sinha, Snehadri; Tomazou, Eleni M; Trautmann, Marcel; Vela, Maria; Versleijen-Jonkers, Yvonne M H; Visgauss, Julia; Zalacain, Marta; Schober, Sebastian J; Lissat, Andrej; English, William R; Baldini, Nicola; Heymann, DominiqueSarcomas are heterogeneous and clinically challenging soft tissue and bone cancers. Although constituting only 1% of all human malignancies, sarcomas represent the second most common type of solid tumors in children and adolescents and comprise an important group of secondary malignancies. More than 100 histological subtypes have been characterized to date, and many more are being discovered due to molecular profiling. Owing to their mostly aggressive biological behavior, relative rarity, and occurrence at virtually every anatomical site, many sarcoma subtypes are in particular difficult-to-treat categories. Current multimodal treatment concepts combine surgery, polychemotherapy (with/without local hyperthermia), irradiation, immunotherapy, and/or targeted therapeutics. Recent scientific advancements have enabled a more precise molecular characterization of sarcoma subtypes and revealed novel therapeutic targets and prognostic/predictive biomarkers. This review aims at providing a comprehensive overview of the latest advances in the molecular biology of sarcomas and their effects on clinical oncology; it is meant for a broad readership ranging from novices to experts in the field of sarcoma.