An Immune Gene Expression Signature Associated With Development of Human Hepatocellular Carcinoma Identifies Mice That Respond to Chemopreventive Agents

Cirrhosis and chronic inflammation precede development of hepatocellular carcinoma (HCC) in approximately 80% of cases. We investigated immune-related gene expression patterns in liver tissues surrounding early-stage HCCs and chemopreventive agents that might alter these patterns to prevent liver tumorigenesis.We analyzed gene expression profiles of non-tumor liver tissues from 392 patients with early-stage HCC (training set, n=167 and validation set, n=225) and liver tissue from patients with cirrhosis without HCC (n=216, controls) to identify changes in expression of genes that regulate the immune response that could contribute to hepatocarcinogenesis. We defined 172 genes as markers for this deregulated immune response, which we called the immune-mediated cancer field (ICF). We analyzed the expression data of liver tissues from 216 patients with cirrhosis without HCC and investigated the association between this gene expression signature and development of HCC and outcomes of patients (median follow-up 10 years). Human liver tissues were also analyzed by histology. C57BL/6J mice were given a single injection of N-nitrosodiethylamine followed by weekly doses of carbon tetrachloride to induce liver fibrosis and tumorigenesis. Mice were then given orally the multiple tyrosine inhibitor nintedanib or vehicle (controls); liver tissues were collected and histology, transcriptome, and protein analyses were performed. We also analyzed transcriptomes of liver tissues collected from mice on a choline-deficient high-fat diet, which developed chronic liver inflammation and tumors, given orally aspirin and clopidogrel or the anti-inflammatory agent sulindac vs mice on a chow (control) diet.We found the ICF gene expression pattern in 50% of liver tissues from patients with cirrhosis without HCC and in 60% of non-tumor liver tissues from patients with early-stage HCC. The liver tissues with the ICF gene expression pattern had 3 different features: increased numbers of effector T cells; increased expression of genes that suppress the immune response and activation of transforming growth factor beta signaling; or expression of genes that promote inflammation and activation of interferon gamma signaling. Patients with cirrhosis and liver tissues with the immunosuppressive profile (10% of cases) had a higher risk of HCC (hazard ratio, 2.41; 95% 1.21-4.80). Mice with chemically-induced fibrosis or diet-induced steatohepatitis given nintedanib or aspirin and clopidogrel downregulated the ICF gene expression pattern in liver and developed fewer and smaller tumors than mice given vehicle.We identified an immune-related gene expression pattern in liver tissues of patients with early-stage HCC, called the ICF, that associates with risk of HCC development in patients with cirrhosis. Administration of nintedanib or aspirin and clopidogrel to mice with chronic liver inflammation caused loss of this gene expression pattern and developed fewer and smaller liver tumors. Agents that alter immune regulatory gene expression patterns associated with carcinogenesis might be tested as chemopreventive agents in patients with cirrhosis

Tumour initiating cells and IGF/FGF signalling contribute to sorafenib resistance in hepatocellular carcinoma

Objective: Sorafenib is effective in hepatocellular carcinoma (HCC), but patients ultimately present disease progression. Molecular mechanisms underlying acquired resistance are still unknown. Herein, we characterise the role of tumour-initiating cells (T-ICs) and signalling pathways involved in sorafenib resistance. Design: HCC xenograft mice treated with sorafenib (n=22) were explored for responsiveness (n=5) and acquired resistance (n=17). Mechanism of acquired resistance were assessed by: (1) role of T-ICs by in vitro sphere formation and in vivo tumourigenesis assays using NOD/SCID mice, (2) activation of alternative signalling pathways and (3) efficacy of anti-FGF and anti-IGF drugs in experimental models. Gene expression (microarray, quantitative real-time PCR (qRT-PCR)) and protein analyses (immunohistochemistry, western blot) were conducted. A novel gene signature of sorafenib resistance was generated and tested in two independent cohorts. Results: Sorafenib-acquired resistant tumours showed significant enrichment of T-ICs (164 cells needed to create a tumour) versus sorafenib-sensitive tumours (13 400 cells) and non-treated tumours (1292 cells), p<0.001. Tumours with sorafenib-acquired resistance were enriched with insulin-like growth factor (IGF) and fibroblast growth factor (FGF) signalling cascades (false discovery rate (FDR)<0.05). In vitro, cells derived from sorafenib-acquired resistant tumours and two sorafenib-resistant HCC cell lines were responsive to IGF or FGF inhibition. In vivo, FGF blockade delayed tumour growth and improved survival in sorafenib-resistant tumours. A sorafenib-resistance 175 gene signature was characterised by enrichment of progenitor cell features, aggressive tumorous traits and predicted poor survival in two cohorts (n=442 patients with HCC). Conclusion: Acquired resistance to sorafenib is driven by T-ICs with enrichment of progenitor markers and activation of IGF and FGF signalling. Inhibition of these pathways would benefit a subset of patients after sorafenib progression

El compromís de l’ICM amb la igualtat de gènere en la recerca marina

2 pages, 1 figure[EN] Despite the drive towards equality between women and men in research institutions in recent years and the progress that has been made, there is still a long road ahead. Science is still associated with the male image, and women’s work and contributions are often invisible. Like many other spheres of society, research institutions contribute to the structural re(production) of gender inequalities. Women and men each tend to have more presence in certain scientific fields, with the horizontal segregation that this involves. Furthermore, the “glass ceiling” (the invisible barrier that hinders women’s access to the highest levels of decision-making or responsibility, limiting their professional careers) causes vertical segregation. Staying in research is an obstacle course in which there is a constant trickle of skills and talents, which is exacerbated for women. Moreover, research often seems blind to the gender dimension in its approach, content and analysis. […][ES] A pesar del impulso de la igualdad entre mujeres y hombres en las instituciones de investigación en los últimos años y de los avances logrados, aún queda un largo camino por recorrer. La ciencia constituye todavía un ámbito asociado a la imagen masculina, invisibilizando con frecuencia el trabajo y las aportaciones de las mujeres. Como muchas otras esferas de la sociedad, las instituciones de investigación contribuyen a la re(producción) estructural de les desigualdades de género. Mujeres y hombres tienden a concentrarse en determinados campos científicos con la segregación horizontal que ello implica. Por otra parte, el llamado “techo de cristal” –la barrera invisible que dificulta u obstaculiza el acceso de las mujeres a los niveles más altos de poder, de decisión o de responsabilidad, limitando sus carreras profesionales–, materializa la segregación vertical. La permanencia en la investigación es una carrera de obstáculos en la que se produce un goteo constante de capacidades y talentos, que se agrava para las mujeres. Además, la investigación parece a menudo ciega a la importancia de considerar la dimensión de género en su abordaje, contenido y análisis. […][CAT] Malgrat l’impuls envers la igualtat a les institucions de recerca dels darrers anys i els avenços assolits, encara hi ha un llarg camí per recórrer. La ciència constitueix encara un àmbit associat a la imatge masculina, invisibilitzant sovint el treball i les aportacions de les dones. Com moltes altres esferes de la societat, les institucions de recerca contribueixen a la re(producció) estructural de les desigualtats de gènere. Dones i homes tendeixen a concentrar-se en determinats camps científics amb la segregació horitzontal que això implica. Per altra banda, l’anomenat “sostre de vidre” –la barrera invisible que dificulta o obstaculitza l’accés de les dones als nivells més alts de poder, de decisió o de responsabilitat, encotillant les seves carreres professionals–, materialitza la segregació vertical. La permanència en la recerca és una carrera d’obstacles on es produeix un degoteig constant de capacitats i talents, agreujat entre les dones. A més, la recerca sembla sovint cega a la importància de considerar la dimensió de gènere en el seu abordatge, contingut i anàlisi. […]Peer reviewe

Molecular characterization of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis

Background and aims: Non-alcoholic steatohepatitis (NASH)-related hepatocellular carcinoma (HCC) is increasing globally, but its molecular features are not well defined. We aimed to identify unique molecular traits characterising NASH-HCC compared to other HCC aetiologies. Methods: We collected 80 NASH-HCC and 125 NASH samples from 5 institutions. Expression array (n = 53 NASH-HCC; n = 74 NASH) and whole exome sequencing (n = 52 NASH-HCC) data were compared to HCCs of other aetiologies (n = 184). Three NASH-HCC mouse models were analysed by RNA-seq/expression-array (n = 20). Activin A receptor type 2A (ACVR2A) was silenced in HCC cells and proliferation assessed by colorimetric and colony formation assays. Results: Mutational profiling of NASH-HCC tumours revealed TERT promoter (56%), CTNNB1 (28%), TP53 (18%) and ACVR2A (10%) as the most frequently mutated genes. ACVR2A mutation rates were higher in NASH-HCC than in other HCC aetiologies (10% vs. 3%, p <0.05). In vitro, ACVR2A silencing prompted a significant increase in cell proliferation in HCC cells. We identified a novel mutational signature (MutSig-NASH-HCC) significantly associated with NASH-HCC (16% vs. 2% in viral/alcohol-HCC, p = 0.03). Tumour mutational burden was higher in non-cirrhotic than in cirrhotic NASH-HCCs (1.45 vs. 0.94 mutations/megabase; p <0.0017). Compared to other aetiologies of HCC, NASH-HCCs were enriched in bile and fatty acid signalling, oxidative stress and inflammation, and presented a higher fraction of Wnt/TGF-β proliferation subclass tumours (42% vs. 26%, p = 0.01) and a lower prevalence of the CTNNB1 subclass. Compared to other aetiologies, NASH-HCC showed a significantly higher prevalence of an immunosuppressive cancer field. In 3 murine models of NASH-HCC, key features of human NASH-HCC were preserved. Conclusions: NASH-HCCs display unique molecular features including higher rates of ACVR2A mutations and the presence of a newly identified mutational signature. Lay summary: The prevalence of hepatocellular carcinoma (HCC) associated with non-alcoholic steatohepatitis (NASH) is increasing globally, but its molecular traits are not well characterised. In this study, we uncovered higher rates of ACVR2A mutations (10%) - a potential tumour suppressor - and the presence of a novel mutational signature that characterises NASH-related HCC

Contribution of Genetic Background, Traditional Risk Factors, and HIV-Related Factors to Coronary Artery Disease Events in HIV-Positive Persons

We show in human immunodeficiency virus-positive persons that the coronary artery disease effect of an unfavorable genetic background is comparable to previous studies in the general population, and comparable in size to traditional risk factors and antiretroviral regimens known to increase cardiovascular ris

Evolving trends in the management of acute appendicitis during COVID-19 waves. The ACIE appy II study

Background: In 2020, ACIE Appy study showed that COVID-19 pandemic heavily affected the management of patients with acute appendicitis (AA) worldwide, with an increased rate of non-operative management (NOM) strategies and a trend toward open surgery due to concern of virus transmission by laparoscopy and controversial recommendations on this issue. The aim of this study was to survey again the same group of surgeons to assess if any difference in management attitudes of AA had occurred in the later stages of the outbreak. Methods: From August 15 to September 30, 2021, an online questionnaire was sent to all 709 participants of the ACIE Appy study. The questionnaire included questions on personal protective equipment (PPE), local policies and screening for SARS-CoV-2 infection, NOM, surgical approach and disease presentations in 2021. The results were compared with the results from the previous study. Results: A total of 476 answers were collected (response rate 67.1%). Screening policies were significatively improved with most patients screened regardless of symptoms (89.5% vs. 37.4%) with PCR and antigenic test as the preferred test (74.1% vs. 26.3%). More patients tested positive before surgery and commercial systems were the preferred ones to filter smoke plumes during laparoscopy. Laparoscopic appendicectomy was the first option in the treatment of AA, with a declined use of NOM. Conclusion: Management of AA has improved in the last waves of pandemic. Increased evidence regarding SARS-COV-2 infection along with a timely healthcare systems response has been translated into tailored attitudes and a better care for patients with AA worldwide

1er Encuentro de Comisiones de Igualdad de Centros del CSIC : Informe del encuentro

1er Encuentro de Comisiones de Igualdad de Centros del CSIC, 10 de diciembre 2020.-- 14 pages, 4 annexesEl 1er Encuentro de las Comisiones de Igualdad de los centros del CSIC, celebrado el pasado 10 de diciembre de 2020 (en formato virtual a consecuencia de la pandemia COVID-19) fue impulsado por el Institut de Ciències del Mar (ICM) en coordinación con la Comisión Delegada de Igualdad y la Comisión de Mujeres y Ciencia del CSIC, en el marco del proyecto europeode género: Leading Towards Sustainable Gender Equality Plans in research performing organisations (LeTSGEPs). El Encuentro se planteó conun triple objetivo: a) la presentación oficial del proyecto europeo de género LeTSGEPs en el que el ICM participa como socio; b) el impulso de la creación de la Red de Comisiones de Igualdad de los Centros del CSIC; y c) la provisión de un espacio reflexión en torno a los mecanismos de coordinación entre la Comisión Delegada de Igualdad del CSIC y las Comisiones de Igualdad de los Institutos, Centros y Unidades (en adelante, ICUs), así como la articulación del Plan de Igualdad del CSIC con los Planes de los ICUs del CSIC a partir de la experiencia del ICM (en el anexo 1 se puede consultar la agenda de la jornada)LeTSGEPs Leading Towards Sustainable Gender Equality Plans in research performing organisations. This project received funding from the European Union's Horitzon 2020 Research and Innovation program under Grant Agreement nº 873072Peer reviewe

Informe de resultados de la encuesta “El impacto del confinamiento en la corresponsabilidad: conciliación y teletrabajo”

40 pages, 34 graphics, 2 postersEl presente documento recoge las principales conclusiones extraídas a partir de la encuesta del “Impacto del confinamiento”, elaborada desde el Grupo de 1 Trabajo de Igualdad del ICM, durante el periodo en que la población se encontraba en Estado de Alarma debido a la crisis sanitaria provocada por la pandemia del COVID-19, concretamente del 15 al 31 de mayo del 2020. La encuesta, abierta a todo el personal del CMIMA, centro que incluye personal de la UTM y del ICM, fue diseñada en base a otra encuesta elaborada por la Comisión de Igualdad del centro IDAEA del CSIC, pero adaptada a las circunstancias y características del centro, modificando las preguntas pertinentes para abarcar un mayor número de diversidades y situaciones personales que puedan darse. Además, se añadieron nuevas preguntas, con el interés de disponer de más indicadores de opinión y percepción. En este sentido, cabe puntualizar que la mencionada encuesta no tiene un marcado perfil sociológico, y junto a otros elementos metodológicamente desacertados, el presente análisis puede verse perjudicado. Esta cuestión se aborda en un anexo específico. Aun así, destacamos positivamente la realización del presente estudio, el cual es la primera vez que tiene lugar a nivel del centro. Uno de los objetivos futuros será la comparación de los resultados con los centros IDAEA, CEAB, CABD y IPLBN que, adaptándola a sus propias características, han realizado una encuesta similar. El principal objetivo de la encuesta es disponer de los indicadores de percepción y opinión sobre los diferentes ámbitos relacionados con la afectación en el reparto de roles de género durante el confinamiento de la población provocada por la pandemia del COVID-19, en las diferentes unidades familiares, así como los relacionados con el funcionamiento del teletrabajo. A modo de síntesis, el principal elemento de la investigación se ha centrado en el binomio entre la conciliación y la situación de confinamiento, introduciendo el sesgo de género en el análisis de la corresponsabilidad. [...]Peer reviewe

Aprendizaje basado en problemas (ABP). Estrategia metodológica y organizativa del currículum para la calidad de la enseñanza en los estudios de Magisterio

En las páginas siguientes se presenta una experiencia desarrollada en el marco de un proyecto de innovación docente en la Universidad Autónoma de Madrid titulado Aprendizaje basado en problemas (ABP). Estrategia metodológica y organizativa del currículum para la calidad de la enseñanza en los estudios de Magisterio. En ella un grupo de profesores del Departamento de Didáctica y Teoría de la Educación de la UAM ha ensayado la aplicación de la metodología ABP en la formación de los estudiantes de Magisterio de Educación Infantil y ha tenido la oportunidad de reflexionar sobre los puntos fuertes y las debilidades de la misma