Integrative multi-omics analysis identifies a prognostic miRNA signature and a targetable miR-21-3p/TSC2/ mTOR axis in metastatic pheochromocytoma/ paraganglioma

Artículo escrito por un elevado número de autores, solo se referencian el que aparece en primer lugar y los autores pertenecientes a la UAMPheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors that present variable outcomes. To date, no effective therapies or reliable prognostic markers are available for patients who develop metastatic PPGL (mPPGL). Our aim was to discover robust prognostic markers validated through in vitro models, and define specific therapeutic options according to tumor genomic features. Methods: We analyzed three PPGL miRNome datasets (n=443), validated candidate markers and assessed them in serum samples (n=36) to find a metastatic miRNA signature. An integrative study of miRNome, transcriptome and proteome was performed to find miRNA targets, which were further characterized in vitro. Results: A signature of six miRNAs (miR-21-3p, miR-183-5p, miR-182-5p, miR-96-5p, miR-551b-3p, and miR-202-5p) was associated with metastatic risk and time to progression. A higher expression of five of these miRNAs was also detected in PPGL patients’ liquid biopsies compared with controls. The combined expression of miR-21-3p/miR-183-5p showed the best power to predict metastasis (AUC=0.804, P=4.67·10-18), and was found associated in vitro with pro-metastatic features, such as neuroendocrine-mesenchymal transition phenotype, and increased cell migration rate. A pan-cancer multi-omic integrative study correlated miR-21-3p levels with TSC2 expression, mTOR pathway activation, and a predictive signature for mTOR inhibitor-sensitivity in PPGLs and other cancers. Likewise, we demonstrated in vitro a TSC2 repression and an enhanced rapamycin sensitivity upon miR-21-3p expression. Conclusions: Our findings support the assessment of miR-21-3p/miR-183-5p, in tumors and liquid biopsies, as biomarkers for risk stratification to improve the PPGL patients’ management. We propose miR-21-3p to select mPPGL patients who may benefit from mTOR inhibitorsThis work was supported by the Instituto de Salud Carlos III (ISCIII), Acción Estratégica en Salud, cofounded by FEDER, [grant number PI14/00240, PI17/01796 to M.R., PI15/00783 to A.C], the Paradifference Foundation [no grant number applicable to M.R.], the ANR [ANR-2011-JCJC-00701 MODEOMAPP to AP.G-R], the European Union [FP7/2007-2013 n° 259735, Horizon 2020 n° 633983 to AP.G-R], Epigénétique et Cancer [EPIG201303 METABEPIC to AP.G-R], the the Ligue Nationale contre le Cancer ["Cartes d'Identité des Tumeurs (CIT) program" to AP.G-R], the Institut National du Cancer, the Direction Générale de l’Offre de Soins [PRT-K 2014, COMETE-TACTIC, INCa-DGOS_8663 to AP.G-R], the Deutsche Forschungsgemeinschaft (DFG) [CRC/Transregio 205/1 “The Adrenal: Central Relay in Health and Disease“ to F.B, M.F and G.E], the Rafael del Pino Foundation [Becas de Excelencia Rafael del Pino 2017 to B.C], the Severo Ochoa Excellence Programme [project SEV-2011-0191 to M.C-F], La Caixa Foundation [B004235 to JM.R-R], the Spanish Ministry of Education, Culture and Sport [grant number FPU16/05527 to M.S.], the Site de Recherche Intégré sur le Cancer-SIRIC [CARPEM Project to N.B.] and the AECC Foundation [grant number AIO15152858 to C.M-C

Structured populations with distributed recruitment: from PDE to delay formulation

In this work first we consider a physiologically structured population model with a distributed recruitment process. That is, our model allows newly recruited individuals to enter the population at all possible individual states, in principle. The model can be naturally formulated as a first order partial integro-differential equation, and it has been studied extensively. In particular, it is well-posed on the biologically relevant state space of Lebesgue integrable functions. We also formulate a delayed integral equation (renewal equation) for the distributed birth rate of the population. We aim to illustrate the connection between the partial integro-differential and the delayed integral equation formulation of the model utilising a recent spectral theoretic result. In particular, we consider the equivalence of the steady state problems in the two different formulations, which then leads us to characterise irreducibility of the semigroup governing the linear partial integro-differential equation. Furthermore, using the method of characteristics, we investigate the connection between the time dependent problems. In particular, we prove that any (non-negative) solution of the delayed integral equation determines a (non-negative) solution of the partial differential equation and vice versa. The results obtained for the particular distributed states at birth model then lead us to present some very general results, which establish the equivalence between a general class of partial differential and delay equation, modelling physiologically structured populations.Comment: 28 pages, to appear in Mathematical Methods in the Applied Science

Bifurcacions genériques d'atractors en sistemes de reacció i difusió

In this work we write down in some detail the bifurcation theory of stationary states of reaction-diffusion equations. First, we prove, adapting notes of looss on the Navier-Stokes equations, that under some weak hypothesis a reaction-diffusion equation defines a differentiable dynamical systems in the Sobolev space H2 with some boundary conditions . Then it is proven that a rest point where the infinitessimal generator of the linear part of the system has a spectrum in the left hand plane is stable . We prove then that when , depending on a parameter, a simple eigenvalue crosses to the right hand plane, a bifurcation appears (generically). In the last chapter we propose a model for dune formation, which does not have the pretension of being faithful, but which illustrates how the theory given is usefu

Structural analysis of the pymedeas integrated assessment model

Treballs Finals de Grau de Física, Facultat de Física, Universitat de Barcelona, Curs: 2022, Tutors: Jordi Solé, Joan BechIntegrated assessment models (IAMs) simulate the coupled behaviour of socioeconomic and natural systems and are used to assess climate and energy policies. Here, the inner structure of pymedeas, an open-source IAM, is visualized and analysed using GraphPySD, a new Python package developed for this project. The results of the study allow to better understand the model and open future directions to improve its design, performance, and functionalitie

Study and design of a photovoltaic system on the TR10 building’s roof in the Campus Terrassa of the UPC

The following thesis addresses the study, design, simulation and analysis of a photovoltaic system located on the roof of the TR10 building in the Campus Terrassa of the UPC. The solar radiation and solar geometry are first introduced, and the working principle of a photovoltaic system is explained. A generic photovoltaic system has been studied and the different possible configurations and typologies are presented. The consumption of the specific building has been analysed. The typology, size and components have been chosen according to the logistic conditions, electrical constrains and economical criteria that is presented. A specific photovoltaic system located in Terrassa has been modelled and designed. A 2D and 3D design has been virtually made and the electrical scheme has been designed. The designed system has been simulated and analysed with the PVsyst software. The total production and economical predictions have been calculated, simulated, compared, exposed and analysed. Finally, the conclusions have been exposed and ideas for future studies are suggeste

Blockchain as a chain for humanitarian aid: transforming the lives of refugees

Updated United Nations data shows that 79.5 million people worldwide were forcibly displaced already by the end of 2019. These were already record-setting numbers of refugees and displaced people around the world. Now they face a new unimaginable and threatening emergency: the global health crisis caused by the Covid-19 pandemic and the consequent economic crisis it has generated. Refugees are amongst the most vulnerable group who now are facing also a pandemic of poverty. It is fair to say that 2020 has been one of the toughest years in history. The present year has also been characterized by a succession of catastrophes and natural disasters, which aggravated a world already severally affected by the Covid-19 crisis. Large emergencies and extreme situations demand for coordination, trust and efficiency. We are currently entering a new era of disruptive technology that will revolutionize the industry, and blockchain holds vast promise for a transformation of the humanitarian sector. This thesis explores the use of blockchain technology to improve effectiveness of contemporary humanitarian aid in the field of refugees and displaced people by focusing on two specific use-case opportunities: digital identity management and aid delivery tracking. This dissertation outlines the use cases of blockchain to help mitigate the impact and strain of the refugee crisis for both refugees and host countries alike. The aim is to reflect on the improvements and pitfalls related to the adaptation of this disruptive technology in the field.Dados atualizados das Nações Unidas mostram que 79,5 milhões de pessoas em todo o mundo foram deslocadas à força no final de 2019. Esses já eram números recordes de refugiados e pessoas deslocadas em todo o mundo. Agora eles enfrentam uma nova emergência inimaginável e ameaçadora: a crise de saúde global causada pela pandemia de Covid-19 e a consequente crise econômica que ela gerou. Os refugiados estão entre o grupo mais vulnerável que agora enfrenta também uma pandemia de pobreza. 2020 foi um dos anos mais difíceis da história. O presente ano também se caracterizou por uma sucessão de catástrofes e desastres naturais, que agravaram um mundo já seriamente afetado pela crise da Covid-19. Grandes emergências e situações extremas exigem coordenação, confiança e eficiência. Atualmente, estamos a entrar em uma nova era de tecnologia disruptiva que revolucionará a indústria, e o "blockchain" é uma grande promessa para a transformação do setor humanitário. Esta tese explora o uso da tecnologia blockchain para melhorar a eficácia da ajuda humanitária contemporânea no campo de refugiados e pessoas deslocadas, concentrando-se em duas oportunidades de casos de uso específicos: gerenciamento de identidade digital e rastreamento de entrega de ajuda. Esta dissertação descreve os casos de uso de "blockchain" para ajudar a mitigar o impacto e a tensão da crise de refugiados para refugiados e países anfitriões. O objetivo é refletir sobre as melhorias e armadilhas relacionadas à adaptação dessa tecnologia disruptiva no campo

Un model de dinàmica de poblacions per a l'anèmia aplàstica

L'anèmia aplàstica és una greu malaltia de la sang que consisteix en grans fluctuacions de la quantitat de glòbuls vermells, i en particular, en disminucions dràstiques del nombre d'aquests, sense que se'n vegin però afectades les propietats individuals. La disminució de la quantitat d'hemoglobina en sang és doncs deguda a una disminució del nombre de glòbuls vermells madurs i no a cap problema intrínsec d'aquests ni a la manca de ferro com en d'altres anèmies comunes