SERPINB5 and AKAP12 -- Expression and promoter methylation of metastasis suppressor genes in pancreatic ductal adenocarcinoma

<p>Abstract</p> <p>Background</p> <p>Early metastasis and infiltration are survival limiting characteristics of pancreatic ductal adenocarcinoma (PDAC). Thus, PDAC is likely to harbor alterations in metastasis suppressor genes that may provide novel diagnostic and therapeutic opportunities. This study investigates a panel of metastasis suppressor genes in correlation to PDAC phenotype and examines promoter methylation for regulatory influence on metastasis suppressor gene expression and for its potential as a diagnostic tool.</p> <p>Methods</p> <p>Metastatic and invasive potential of 16 PDAC cell lines were quantified in an orthotopic mouse model and mRNA expression of 11 metastasis suppressor genes determined by quantitative RT-PCR. Analysis for promoter methylation was performed using methylation specific PCR and bisulfite sequencing PCR. Protein expression was determined by Western blot.</p> <p>Results</p> <p>In general, higher metastasis suppressor gene mRNA expression was not consistent with less aggressive phenotypes of PDAC. Instead, mRNA overexpression of several metastasis suppressor genes was found in PDAC cell lines vs. normal pancreatic RNA. Of the investigated metastasis suppressor genes, only higher <it>AKAP12 </it>mRNA expression was correlated with decreased metastasis (P < 0.05) and invasion scores (P < 0.01) while higher <it>SERPINB5 </it>mRNA expression was correlated with increased metastasis scores (P < 0.05). Both genes' promoters showed methylation, but only increased <it>SERPINB5 </it>methylation was associated with loss of mRNA and protein expression (P < 0.05). <it>SERPINB5 </it>methylation was also directly correlated to decreased metastasis scores (P < 0.05).</p> <p>Conclusions</p> <p><it>AKAP12 </it>mRNA expression was correlated to attenuated invasive and metastatic potential and may be associated with less aggressive phenotypes of PDAC while no such evidence was obtained for the remaining metastasis suppressor genes. Increased <it>SERPINB5 </it>mRNA expression was correlated to increased metastasis and mRNA expression was regulated by methylation. Thus, <it>SERPINB5 </it>methylation was directly correlated to metastasis scores and may provide a diagnostic tool for PDAC.</p

Recurrence of primary sclerosing cholangitis after liver transplantation – analysing the European Liver Transplant Registry and beyond

Liver transplantation for primary sclerosing cholangitis (PSC) can be complicated by recurrence of PSC (rPSC). This may compromise graft survival but the effect on patient survival is less clear. We investigated the effect of post-transplant rPSC on graft and patient survival in a large European cohort. Registry data from the European Liver Transplant Registry regarding all first transplants for PSC between 1980 and 2015 were supplemented with detailed data on rPSC from 48 out of 138 contributing transplant centres, involving 1,549 patients. Bayesian proportional hazards models were used to investigate the impact of rPSC and other covariates on patient and graft survival. Recurrence of PSC was diagnosed in 259 patients (16.7%) after a median follow-up of 5.0 years (quantile 2.5%-97.5%: 0.4–18.5), with a significant negative impact on both graft (HR 6.7; 95% CI 4.9–9.1) and patient survival (HR 2.3; 95% CI 1.5–3.3). Patients with rPSC underwent significantly more re-transplants than those without rPSC (OR 3.6, 95% CI 2.7–4.8). PSC recurrence has a negative impact on both graft and patient survival, independent of transplant-related covariates. Recurrence of PSC leads to higher number of re-transplantations and a 33% decrease in 10-year graft survival

Atomistic simulations of the decomposition kinetics in Fe-Cr alloys: Influence of magnetism

International audienceMagnetism plays a crucial role in the thermodynamic and kinetic properties of ferritic alloys. In fact, magnetism increases the solubility limit of Cr in Fe, inducing an asymmetrical phase diagram. Moreover, the phase transition from ferromagnetic to paramagnetic (F/P) iron alloys modifies to a large extent the system response to different environmental conditions by modification of the alloy diffusion properties. Indeed, experimental tracer diffusion coefficients deviate from an Arrhenius law during the F/P magnetic transition, leading to a large increase in the paramagnetic regime compared to the extrapolated value from the ferromagnetic domain. Furthermore, as the Curie temperature decreases with the Cr concentration, this evolution of the diffusion properties affects the decomposition kinetics in different ways depending on the alloy composition. An atomic diffusion model, with pair interactions that depend on the local composition and on temperature, has been developed to take into account this magnetic transition effect. The interaction model has been implemented in an atomistic kinetic Monte Carlo algorithm to study the diffusion coefficients and precipitation kinetics of the Fe Cr alloys. This model has been successfully compared to decomposition kinetic experiments for a wide range of concentrations and temperatures

Modélisation du développement des microstructures en procédé laser sur lit de poudre – Application au superalliage IN718

International audienc

Three-dimensional modeling of solidification grain structures generated by laser powder bed fusion

International audienceGrain structures generated by laser powder bed fusion (L-PBF) of the Ni-based superalloy Inconel 718 (IN718) are studied using Cellular Automaton modelling. A new hybrid methodology is developed to benefit from a full thermohydraulic simulations that predicts the shape of the consolidated track and the temperature field. The advantage is to reach unprecedented sizes of simulation domains while still taking advantage of a full numerical solution of the L-PBF process at the scale of the melt pool. The computed grain structure becomes available in a Representative Elementary Volume (REV) of an Additively Manufactured (AMed) specimen and can be studied statistically considering the distribution of crystallographic orientations and the grain density. The other advantage is the possibility to vary process and material parameters to approach industrial practice. For the first time, the strategy consisting in opposite bidirectional scanning of the powder with an additional 67 • rotation at each new layer is made available. It is compared with the standard opposite bidirectional monoaxial scanning strategy and the opposite bidirectional orthogonal biaxial scanning strategies with two perpendicular axes, all reproducing trends reported in experimental literature. The generation of virtual REVs of AMed microstructures by L-PBF for IN718 opens the way to study new processing parameters and coupling with models for the prediction of metallurgical properties

Multiscale modeling of laser-powder bed fusion additive manufacturing

International audienc

Predicting the columnar-to-equiaxed transition during additive manufacturing of concentrated multicomponent alloys

International audienc

Modélisation des microstructures obtenues en fabrication additive par fusion laser sur lit de poudre d’un alliage base Nickel

International audienc