On Pole Assignment and Stabilizability of Neutral Type Systems

In this note we present a systematic approach to the stabilizability problem of linear infinite-dimensional dynamical systems whose infinitesimal generator has an infinite number of instable eigenvalues. We are interested in strong non-exponential stabilizability by a linear feed-back control. The study is based on our recent results on the Riesz basis property and a careful selection of the control laws which preserve this property. The investigation may be applied to wave equations and neutral type delay equations

On the origin of colorectal cancer: Cell competition in the intestine

The epithelial monolayer of intestine is one of the fastest renewing tissues of the human body, a process that is regulated by intestinal stem cells (ISCs) residing in crypt-like structures. These ISCs continuously divide to generate differentiated cells, while simultaneously engaging in ongoing neutral competition with each other for a position within the crypt. Whenever an ISCs acquires a mutation that confers a competitive advantage, the mutant ISC gradually replaces all normal ISCs which results in permanent fixation of a mutation within the crypt and the initiation of colorectal cancer (CRC). This thesis focuses on the competition between normal and mutant ISCs, with specific emphasis on mutations that activate the Wnt pathway such as loss of Apc or activation of Ctnnb1. We reveal that Apc-mutant ISCs act as ‘supercompetitors’ that actively force normal ISCs to differentiate and leave the crypt. Moreover, we demonstrate that boosting the fitness of normal ISCs can inhibit the competitive advantage of Apc-mutant and prevent adenoma formation. These findings are particularly relevant for familial adenomatous polyposis (FAP) patients that carry germline mutations in the APC gene and are predisposed to the development of CRC. Critically, understanding the molecular basis underlying the competition between normal and mutant cells can be used to develop novel chemoprevention strategies for FAP and other heritable cancer syndromes

Serum levels of iCAF-derived osteoglycin predict favorable outcome in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is characterized by abundant stroma, the main cellular constituents of which are cancer-associated fibroblasts (CAFs). Stroma-targeting agents have been proposed to improve the poor outcome of current treatments. However, clinical trials using these agents showed disappointing results. Heterogeneity in the PDAC CAF population was recently delineated demonstrating that both tumor-promoting and tumor-suppressive activities co-exist in the stroma. Here, we aimed to identify biomarkers for the CAF population that contribute to a favorable outcome. RNA-sequencing reads from patient-derived xenografts (PDXs) were mapped to the human and mouse genome to allocate the expression of genes to the tumor or stroma. Survival meta-analysis for stromal genes was performed and applied to human protein atlas data to identify circulating biomarkers. The candidate protein was perturbed in co-cultures and assessed in existing and novel single-cell gene expression analysis from control, pancreatitis, pancreatitis-recovered and PDAC mouse models. Serum levels of the candidate biomarker were measured in two independent cohorts totaling 148 PDAC patients and related them to overall survival. Osteoglycin (OGN) was identified as a candidate serum prognostic marker. Single-cell analysis indicated that Ogn is derived from a subgroup of inflammatory CAFs. Ogn-expressing fibroblasts are distinct from resident healthy pancreatic stellate cells and arise during pancreatitis. Serum OGN levels were prognostic for favorable overall survival in two independent PDAC cohorts (HR = 0.47, P = .042 and HR = 0.53, P = .006). Altogether, we conclude that high circulating OGN levels inform on a previously unrecognized subgroup of CAFs and predict favorable outcomes in resectable PDAC

Jet physics in electron--proton scattering

Hadronic jets in electron–proton collisions at HERA have been used for some considerable time as a tool for tests of the theory of strong interactions, quantum chromodynamics. Using jet final states, basic concepts like the factorisation ansatz for cross-section calculations, the perturbative approach to the cross section and the universality of the proton parton distribution functions can be examined. More concretely, jet measurements provide ready access to the strong coupling of QCD, α s , and to the parton distributions. In this report, an overview of jet results from the HERA experiments H1 and ZEUS and their interpretation is given together with a description of the theoretical foundations of jet physics in electron–proton collisions and of the experimental environment at HERA. Special emphasis is put on extractions of α s values and on the influence of jet data on fits of the proton parton distribution functions. Where useful, the HERA results are also discussed in the light of results from other colliders like LEP, the Tevatron or the LHC. The central message from these studies is that QCD does not only describe most of the measurements very well, but that QCD at HERA has achieved the status of a precision theory. On the other hand it is shown that further understanding of problematic issues relies critically on theoretical progress in the form of improved models or of increased precision in analytical calculations