RESUMO
Cell cycle progression is orchestrated by E2F factors. We previously reported that in ETS-driven cancers of the bone and prostate, activating E2F3 cooperates with ETS on target promoters. The mechanism of target co-regulation remained unknown. Using RNAi and time-resolved chromatin-immunoprecipitation in Ewing sarcoma we report replacement of E2F3/pRB by constitutively expressed repressive E2F4/p130 complexes on target genes upon EWS-FLI1 modulation. Using mathematical modeling we interrogated four alternative explanatory models for the observed EWS-FLI1/E2F3 cooperation based on longitudinal E2F target and regulating transcription factor expression analysis. Bayesian model selection revealed the formation of a synergistic complex between EWS-FLI1 and E2F3 as the by far most likely mechanism explaining the observed kinetics of E2F target induction. Consequently we propose that aberrant cell cycle activation in Ewing sarcoma is due to the de-repression of E2F targets as a consequence of transcriptional induction and physical recruitment of E2F3 by EWS-FLI1 replacing E2F4 on their target promoters.
Assuntos
Fator de Transcrição E2F3/metabolismo , Fator de Transcrição E2F4/metabolismo , Regulação Neoplásica da Expressão Gênica , Proteínas de Fusão Oncogênica/metabolismo , Proteína Proto-Oncogênica c-fli-1/metabolismo , Proteína EWS de Ligação a RNA/metabolismo , Algoritmos , Teorema de Bayes , Ciclo Celular/genética , Linhagem Celular Tumoral , Imunoprecipitação da Cromatina , Fator de Transcrição E2F3/genética , Fator de Transcrição E2F4/genética , Humanos , Immunoblotting , Modelos Genéticos , Proteínas de Fusão Oncogênica/genética , Regiões Promotoras Genéticas/genética , Ligação Proteica , Proteína Proto-Oncogênica c-fli-1/genética , Interferência de RNA , Proteína EWS de Ligação a RNA/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sarcoma de Ewing/genética , Sarcoma de Ewing/metabolismo , Sarcoma de Ewing/patologiaRESUMO
SUMMARY: We present a new C implementation of an advanced Markov chain Monte Carlo (MCMC) method for the sampling of ordinary differential equation (ode) model parameters. The software mcmc_clib uses the simplified manifold Metropolis-adjusted Langevin algorithm (SMMALA), which is locally adaptive; it uses the parameter manifold's geometry (the Fisher information) to make efficient moves. This adaptation does not diminish with MC length, which is highly advantageous compared with adaptive Metropolis techniques when the parameters have large correlations and/or posteriors substantially differ from multivariate Gaussians. The software is standalone (not a toolbox), though dependencies include the GNU scientific library and sundials libraries for ode integration and sensitivity analysis. AVAILABILITY AND IMPLEMENTATION: The source code and binary files are freely available for download at http://a-kramer.github.io/mcmc_clib/. This also includes example files and data. A detailed documentation, an example model and user manual are provided with the software. CONTACT: andrei.kramer@ist.uni-stuttgart.de.
Assuntos
Algoritmos , Cadeias de Markov , Modelos Estatísticos , Método de Monte Carlo , SoftwareRESUMO
The development of an intra-abdominal bile collection (biloma) is an infrequent complication of laparoscopic cholecystectomy (LC). These bilomas develop in the subhepatic space most often secondary to iatrogenic injury of the extrahepatic ducts. We present a case of hepatic subcapsular biloma following LC and we discuss its etiology and management. Early diagnosis is crucial and percutaneous drainage under CT guidance should be employed to resolve this complication.
RESUMO
Bayesian analysis for Markov jump processes (MJPs) is a non-trivial and challenging problem. Although exact inference is theoretically possible, it is computationally demanding, thus its applicability is limited to a small class of problems. In this paper, we describe the application of Riemann manifold Markov chain Monte Carlo (MCMC) methods using an approximation to the likelihood of the MJP that is valid when the system modelled is near its thermodynamic limit. The proposed approach is both statistically and computationally efficient whereas the convergence rate and mixing of the chains allow for fast MCMC inference. The methodology is evaluated using numerical simulations on two problems from chemical kinetics and one from systems biology.
Assuntos
Algoritmos , Teorema de Bayes , Modelos Lineares , Cadeias de Markov , Modelos Biológicos , Modelos Químicos , Método de Monte Carlo , Simulação por ComputadorRESUMO
The main criterion for abdominal aortic aneurysm (AAA) repair is an AAA diameter >/=5.5 cm. However, some AAAs rupture when they are smaller. Size alone may therefore not be a sufficient criterion to determine rupture risk. Fluorodeoxyglucose (FDG) uptake is increased in the presence of inflammation and it was suggested that this may be a better predictor of rupture risk than AAA size. Furthermore, increased FDG uptake following endovascular AAA repair may be an indirect predictor of continuous AAA sac enlargement due to the presence of an endoleak (even if this is not detected by imaging modalities) and/or increased AAA rupture risk. The role of FDG uptake needs to be explored further in the management of AAAs.
RESUMO
Lower extremity venous ulcers comprise a complex medical and social issue. The conservative and/or surgical management of venous ulcers is often inadequate. In addition, the psychosocial aspect of the disease is often overlooked and most often undertreated. Common symptoms such as pain, low self-esteem and patient isolation are usually not recognized and therefore not adequately managed.This mini-review summarizes the current data on the management of lower extremity venous ulcers and their impact on the quality of life of these patients.