Desemmascarar el càncer: Centenars de malalties, un sol nom

Tothom té una idea més o menys clara del que representa un càncer: un conjunt de cèl·lules que es divideixen sense control. Darrera aquesta imatge simplista s’amaga un dels problemes de salut més complexes i més greus que existeixen. És gràcies als avenços biomèdics dels últims vint anys que finalment estem reconeixent les grans diferències que hi ha entre els tipus de càncers coneguts, un descobriment que resultarà clau per a dissenyar teràpies més efectives en un futur proper

Hesitation about coronavirus vaccines in healthcare professionals and general population in Spain

This study attempts to provide a picture of the hesitancy to vaccination against COVID-19 in Spain during the 2021 spring-autumn vaccination campaign, both in the general population and in healthcare professionals. The participants were recruited using social media such as Facebook and Twitter, in addition to the cooperation of health personnel contacted with the collaboration of medical scientific societies. A cross-sectional study was carried out that included the response of an online questionnaire. The data were collected from April 30 to September 26, 2021. To assess the different associations between variables to be measured, we fit Poisson regression models with robust variance. Responses were obtained from 3,850 adults from the general population group and 502 health professionals. Of the overall sample, 48.6% of participants from the general population were vaccinated against COVID-19, whereas in the healthcare professionals, 94.8% were vaccinated. The prevalence of general population vaccination increased with age, and was higher in women than men. Most participants did not show a preference for any vaccine itself. However, the prevalence of people vaccinated with their preferred vaccine was higher for the ones vaccinated with Pfizer's vaccine. 6.5% of the general population reported being reticent to be vaccinated. People from younger age groups, people with lower educational levels and those who were not from a risk group showed greater reluctance to be vaccinated. No gender differences in reluctancy were found. Health professionals were significantly less likely to refuse vaccination even though they had more doubts about the safety and efficacy of vaccines. On the other hand, younger people, those with a lower level of education and those who were not from a risk group were the most hesitant

PML-II regulates ERK and AKT signal activation and IFNα-induced cell death

Background The requirement of promyelocytic leukaemia protein (PML) in interferon (IFN)-induced cell apoptosis is well-established. However, the exact mechanisms by which the multiple isoforms of PML protein participate in this process remain not well-understood. We previously demonstrated that PML isoform II (PML-II) positively regulates induced gene expression during a type I IFN response and evaluate here how PML-II contributes to IFNα-induced cell death. Methods HeLa cells were transiently depleted of PML-II by siRNA treatment and the response of these cells to treatment with IFNα assessed by molecular assays of mRNA and proteins associated with IFN and apoptosis responses. Results In HeLa cells, death during IFNα stimulation was reduced by prior PML-II depletion. PML-II removal also considerably decreased the induced expression of pro-apoptotic ISGs such as ISG54 (IFIT2), and substantially impaired or prevented expression of PUMA and TRAIL, proteins that are associated with the intrinsic and extrinsic apoptotic pathways respectively. Thirdly, PML-II depletion enhanced ERK and AKT pro-survival signaling activation suggesting that PML-II normally suppresses signaling via these pathways, and that lack of PML-II hence led to greater than normal activation of AKT signaling upon IFNα stimulation and consequently increased resistance to IFNα-induced apoptosis. Conclusions The positive contribution of PML-II to the expression of various IFNα-induced pro-apoptotic proteins and its inhibition of pro-survival signaling together provide a mechanistic explanation for reduced apoptosis under conditions of PML deficiency and may account for at least part of the role of PML as a tumor suppressor gene

Junts a casa! Els dies del coronavirus

Aquest llibre solidari de “L’ Agus i els monstres” és un llibre molt especial generat en un context excepcional. Es tracta d’una novel·la gràfica breu, en format digital, que és el resultat del moment actual i que té un objectiu molt senzill i molt complex alhora: oferir als nens i nenes una reflexió serena sobre la situació que estem vivint arran de la pandèmia de la COVID-19. JUNTS A CASA! Els dies del coronavirus convida els protagonistes (L’Agus, la Lídia i els monstres) i els lectors a aprendre a viure en el confinament i el desconfinament i actuar com a herois ajudant a evitar que la pandèmia segueixi avançant. En definitiva, en paraules del protagonista, l’Agus Pianola: “cadascú s’està a casa seva, però tots anem en el mateix vaixell”.Postprint (published version

Transcriptional role of p53 in interferon-mediated antiviral immunity

Tumor suppressor p53 is activated by several stimuli, including DNA damage and oncogenic stress. Previous studies (Takaoka, A., S. Hayakawa, H. Yanai, D. Stoiber, H. Negishi, H. Kikuchi, S. Sasaki, K. Imai, T. Shibue, K. Honda, and T. Taniguchi. 2003. Nature. 424:516–523) have shown that p53 is also induced in response to viral infections as a downstream transcriptional target of type I interferon (IFN) signaling. Moreover, many viruses, including SV40, human papillomavirus, Kaposi's sarcoma herpesvirus, adenoviruses, and even RNA viruses such as polioviruses, have evolved mechanisms designated to abrogate p53 responses. We describe a novel p53 function in the activation of the IFN pathway. We observed that infected mouse and human cells with functional p53 exhibited markedly decreased viral replication early after infection. This early inhibition of viral replication was mediated both in vitro and in vivo by a p53-dependent enhancement of IFN signaling, specifically the induction of genes containing IFN-stimulated response elements. Of note, p53 also contributed to an increase in IFN release from infected cells. We established that this p53-dependent enhancement of IFN signaling is dependent to a great extent on the ability of p53 to activate the transcription of IFN regulatory factor 9, a central component of the IFN-stimulated gene factor 3 complex. Our results demonstrate that p53 contributes to innate immunity by enhancing IFN-dependent antiviral activity independent of its functions as a proapoptotic and tumor suppressor gene

Characterizing the protein-protein interaction between MDM2 and 14-3-3σ; proof of concept for small molecule stabilization

Mouse Double Minute 2 (MDM2) is a key negative regulator of the tumor suppressor protein p53. MDM2 overexpression occurs in many types of cancer and results in the suppression of WT p53. The 14-3-3 family of adaptor proteins are known to bind MDM2 and the 14-3-3σ isoform controls MDM2 cellular localization and stability to inhibit its activity. Therefore, small molecule stabilization of the 14-3-3σ/MDM2 protein-protein interaction (PPI) is a potential therapeutic strategy for the treatment of cancer. Here, we provide a detailed biophysical and structural characterization of the phosphorylation-dependent interaction between 14-3-3σ and peptides that mimic the 14-3-3 binding motifs within MDM2. The data show that di-phosphorylation of MDM2 at S166 and S186 is essential for high affinity 14-3-3 binding and that the binary complex formed involves one MDM2 di-phosphorylated peptide bound to a dimer of 14-3-3σ. However, the two phosphorylation sites do not simultaneously interact so as to bridge the 14-3-3 dimer in a 'multivalent' fashion. Instead, the two phosphorylated MDM2 motifs 'rock' between the two binding grooves of the dimer, which is unusual in the context of 14-3-3 proteins. In addition, we show that the 14-3-3σ-MDM2 interaction is amenable to small molecule stabilization. The natural product fusicoccin A forms a ternary complex with a 14-3-3σ dimer and an MDM2 di-phosphorylated peptide resulting in the stabilization of the 14-3-3σ/MDM2 PPI. This work serves as a proof-of-concept of the drugability of the 14-3-3/MDM2 PPI and paves the way toward the development of more selective and efficacious small molecule stabilizers.</p

BTK Modulates p53 Activity to Enhance Apoptotic and Senescent Responses

p53 is a tumor suppressor that prevents the emergence of transformed cells by inducing apoptosis or senescence, among other responses. Its functions are regulated tightly by posttranslational modifications. Here we show that Bruton's tyrosine kinase (BTK) is a novel modulator of p53. We found that BTK is induced in response to DNA damage and p53 activation. BTK induction leads to p53 phosphorylation, which constitutes a positive feedback loop that increases p53 protein levels and enhances the transactivation of its target genes in response to stress. Inhibiting BTK reduced both p53-dependent senescence and apoptosis. Further, BTK expression also upregulated DNA damage signals and apoptosis. We conclude that despite being involved in oncogenic signals in blood malignancies, BTK has antineoplastic properties in other contexts, such as the enhancement of p53's tumor suppressor responses. Along with evidence that BTK expression correlates with good prognosis in some epithelial tumors, our findings may encourage a reevaluation of the clinical uses of BTK inhibitors in cancer therapy

Informe del GTM sobre la fatiga pandémica

El Grupo de Trabajo Multidisciplinar (GTM) asesora y apoya al Ministerio de Ciencia e Innovación en materias científicas relacionadas con la COVID-19 y sus consecuencias futuras. El GTM está compuesto por: José M. Ordovás (Presidente), Mariano Esteban, Rocío García-Retamero, Beatriz González LópezValcárcel, Alfonso Gordaliza, Marco Inzitari, Pedro Jordano, Itziar de Lecuona, Laura M. Lechuga, Ramón López de Mántaras, José Molero, Agustín Portela, Diego Puga, José Javier Ramasco, Francisco SánchezMadrid y Alfonso Valencia. Enric Banda actúa como observador, y Maria Sol Serrano Alonso como secretaria. Todos los componentes del GTM colaboran de forma desinteresada con el Ministerio de Ciencia e Innovación. En este informe han colaborado además el Dr. Salvador Macip Maresma (investigador en biomedicina de la Universidad de Leicester y de la Universitat Oberta de Catalunya, y divulgador científico) y la Sra. Anna Cerdà Pifarré, periodista y Directora de Comunicación en Mapa Media, experta en comunicación en el ámbito de salud y social).Después de más de un año desde el inicio de la pandemia de COVID-19, el seguir manteniendo una adherencia adecuada a las medidas de prevención es un gran reto personal y social. En una situación que se mantiene durante tanto tiempo, es complejo renovar constantemente la motivación de una población que ya ha realizado importantes esfuerzos y renuncias, y padece las consecuencias, en muchos casos directas, pero para todos, indirectas (restricciones de movilidad, reducción de las relaciones sociales, impacto económico) de la pandemia. Esta situación es todavía más acusada en un momento como el actual, en el cual se mezclan sentimientos opuestos, de esperanza por la vacunación, y de incertidumbre por las nuevas variantes. La Organización Mundial de la Salud (OMS) utiliza el concepto de fatiga pandémica no relacionándolo con una enfermedad, sino para indicar esta desmotivación emergente para cumplir las medidas preventivas, en la cual influyen aspectos personales (emociones, experiencias, percepciones) así como culturales y sociales. El objetivo último de la OMS, así como de este informe, es proponer estrategias, basadas principalmente en la comunicación, para conseguir un equilibrio entre la aplicación de las medidas protectoras de limitación del riesgo y que la población retome su vida, y, paralelamente, reconocer el esfuerzo y las dificultades de la población. Como valores transversales en la estrategia de comunicación, es necesario mantener siempre la máxima Transparencia, Equidad, Coherencia, Coordinación y Predictibilidad. A nivel práctico es necesario disponer de datos actualizados en relación, por ejemplo, a la adherencia a las medidas y a la percepción de la fatiga, y actualizar constantemente las estrategias de comunicación, que tienen que ser multidisciplinares (por ejemplo involucrando expertos en comunicación al lado de científicos, gobernantes etc.), involucrando a los usuarios, adaptándolas al contexto local, que estará influido por diferentes factores socio-culturales, además de tener velocidades diferentes de la pandemia en función del territorio, y, finalmente, intentar transmitir mensajes relistas pero comunicando desde la esperanza y la positividad y no apelando al miedo y a la imposición. Estos conceptos son tratados en el presente informe, en el cual también se proponen principios y ejemplos concretos para una comunicación efectiva.Peer reviewe

Covid-19: la malinterpretación de los datos de la pandemia daña la confianza del público

Dos cartas publicadas en The Lancet y The Lancet Public Health en los últimos meses defienden la necesidad de evaluar de forma independiente la respuesta española ante la covid-19. Estamos de acuerdo, pero nos gustaría complementarlas con tres puntos que nos acercan a la ciencia abierta. Nos referimos a la confusión terminológica, la calidad de los datos y su disponibilidad