43 research outputs found
Stereotypes and human rights law
The scope of the book includes different stereotyping grounds – such as race, gender, and disability. Moreover, this book examines stereotyping approaches across a broad range of supranational human rights monitoring bodies, including the United Nations human rights treaty system as well as the regional systems that are most developed when it comes to addressing stereotypes: the Council of Europe and the inter-American system
Increased PXR and Suppressed T-Cell Signaling Are Associated With Malignant Degeneration of Barrett's Esophagus
Background and Aims: Barrett's esophagus (BE) is the precursor lesion for esophageal adenocarcinoma (EAC). To detect EAC in early stage, patients with BE undergo endoscopic surveillance. Surveillance cohorts largely consist of nondysplastic BE (NDBE) patients with a low annual progression risk (<0.5%). Predictive biomarkers for malignant progression of NDBE could improve efficacy of surveillance. Biomarker research has mostly focused on aberrant protein expression on BE epithelial cells. Moreover, insight in cell signaling driving malignant transformation is unknown. This study uses a data-driven approach to analyze tumor-stroma interaction in NDBE which progressed to high-grade dysplasia or EAC. Methods: In this case-control study, we performed RNA sequencing analysis on index NDBE biopsies from 6 patients who, during long-term follow-up, progressed and 7 who did not progress to high-grade dysplasia/EAC. For control samples, squamous and duodenum tissues from BE patients were analyzed. For validation, we used quantitative PCR. Results: Significant differences in BE transcriptomic profiles between progressors and nonprogressors were found by principal component and differential expression analyses. Ingenuity pathway analysis indicated that 8 cell signaling pathways were significantly upregulated in the progressors, and 14 pathways were significantly downregulated. The most interesting finding was the upregulation of the xenobiotic metabolism pregnane X receptor signaling pathway in the progressor cohort, while of the downregulated pathways in progressors, several were related to the immune system. Conclusion: These novel transcriptomic insights are fundamental for developing (chemo-)preventive therapies. These could be therapies, which protect against toxins, including biles, responsible for pregnane X receptor activation or which enhance protective immune mechanisms. The identified RNA markers are promising biomarkers for improving risk stratification in surveillance programs.</p
Hybrid optimization method with general switching strategy for parameter estimation
This article is available from: http://www.biomedcentral.com/1752-0509/2/26[Background] Modeling and simulation of cellular signaling and metabolic pathways as networks of
biochemical reactions yields sets of non-linear ordinary differential equations. These models usually
depend on several parameters and initial conditions. If these parameters are unknown, results from
simulation studies can be misleading. Such a scenario can be avoided by fitting the model to
experimental data before analyzing the system. This involves parameter estimation which is usually
performed by minimizing a cost function which quantifies the difference between model predictions
and measurements. Mathematically, this is formulated as a non-linear optimization problem which
often results to be multi-modal (non-convex), rendering local optimization methods detrimental.[Results] In this work we propose a new hybrid global method, based on the combination of an
evolutionary search strategy with a local multiple-shooting approach, which offers a reliable and
efficient alternative for the solution of large scale parameter estimation problems.[Conclusion] The presented new hybrid strategy offers two main advantages over previous
approaches: First, it is equipped with a switching strategy which allows the systematic
determination of the transition from the local to global search. This avoids computationally
expensive tests in advance. Second, using multiple-shooting as the local search procedure reduces
the multi-modality of the non-linear optimization problem significantly. Because multiple-shooting
avoids possible spurious solutions in the vicinity of the global optimum it often outperforms the
frequently used initial value approach (single-shooting). Thereby, the use of multiple-shooting yields
an enhanced robustness of the hybrid approach.This work was supported by the European Community as part of the FP6
COSBICS Project (STREP FP6-512060), the German Federal Ministry of
Education and Research, BMBF-project FRISYS (grant 0313921) and Xunta
de Galicia (PGIDIT05PXIC40201PM).Peer reviewe