Der Einfluss von Diabetes auf Erkrankungen der Bauchspeicheldrüse

Die Habilitationsschrift untersucht die Fragestellung, in wie weit Diabetes mellitus ähnliche Stoffwechsellagen unterschiedliche Pathologien der Bauchspeicheldrüse beeinflussen. Die präsentierten Daten belegen, dass Diabetes mellitus Typ I in Mäusen zu einer Aggravierung einer akuten Pankreatitis führt und die Fibrose während des Verlaufs einer chronischen Pankreatitis verstärkt. Des Weiteren belegen die Daten, dass eine dem Diabetes mellitus Typ II ähnliche Stoffwechsellage in Mäusen potentiell präkanzerogene Läsionen im Pankreas stimuliert und auch die Proliferationsrate in Pankreaskarzinomen erhöht

β-Catenin signals regulate cell growth and the balance between progenitor cell expansion and differentiation in the nervous system

Abstractβ-Catenin is an essential component of the canonical Wnt signaling system that controls decisive steps in development. We employed here two conditional β-catenin mutant alleles to alter β-catenin signaling in the central nervous system of mice: one allele to ablate β-catenin and the second allele to express a constitutively active β-catenin. The tissue mass of the spinal cord and brain is reduced after ablation of β-catenin, and the neuronal precursor population is not maintained. In contrast, the spinal cord and brain of mice that express activated β-catenin is much enlarged in mass, and the neuronal precursor population is increased in size. β-Catenin signals are thus essential for the maintenance of proliferation of neuronal progenitors, controlling the size of the progenitor pool, and impinging on the decision of neuronal progenitors to proliferate or to differentiate

Blocking Autophagy in Cancer-Associated Fibroblasts Supports Chemotherapy of Pancreatic Cancer Cells

In this study we evaluated the interaction of pancreatic cancer cells, cancer-associated fibroblasts, and distinct drugs such as α-cyano-4-hydroxycinnamate, metformin, and gemcitabine. We observed that α-cyano-4-hydroxycinnamate as monotherapy or in combination with metformin could significantly induce collagen I deposition within the stromal reaction. Subsequently, we demonstrated that cancer-associated fibroblasts impaired the anti-proliferation efficacy of α-cyano-4-hydroxycinnamate, metformin and gemcitabine. Interestingly, inhibition of autophagy in these fibroblasts can augment the anti-proliferation effect of these chemotherapeutics in vitro and can reduce the tumor weight in a syngeneic pancreatic cancer model. These results suggest that inhibiting autophagy in cancer-associated fibroblasts may contribute to strategies targeting cancer

The Ambivalent Function of YAP in Apoptosis and Cancer

Yes-associated protein, a core regulator of the Hippo-YAP signaling pathway, plays a vital role in inhibiting apoptosis. Thus, several studies and reviews suggest that yes-associated protein is a good target for treating cancer. Unfortunately, more and more evidence demonstrates that this protein is also an essential contributor of p73-mediated apoptosis. This questions the concept that yes-associated protein is always a good target for developing novel anti-cancer drugs. Thus, the aim of this review was to evaluate the clinical relevance of yes-associated protein for cancer pathophysiology. This review also summarized the molecules, processes and drugs, which regulate Hippo-YAP signaling and discusses their effect on apoptosis. In addition, issues are defined, which should be addressed in the future in order to provide a solid basis for targeting the Hippo-YAP signaling pathway in clinical trials

Grading Distress of Different Animal Models for Gastrointestinal Diseases Based on Plasma Corticosterone Kinetics

Comparative studies for evaluating distress in established animal models are still rare. However, this issue is becoming more important as a consequence of worldwide appreciation of animal welfare. One good parameter for evaluating distress is the quantification of corticosterone. We hypothesized that not just the absolute value but also the duration of increased corticosterone concentration in the blood is an important aspect for evaluating animal distress. Therefore, we analyzed plasma corticosterone concentrations 30, 60, 120, and 240 min after induction of pancreatitis by cerulein, liver damage by carbon tetrachloride, liver damage by bile duct ligation, and after orthotopic injection of pancreatic cancer cells. We also evaluated corticosterone kinetics after injection of distinct carrier substances. Compared to phosphate buffered saline, dimethyl sulfoxide leads to dose-dependent higher and longer-lasting circulating corticosterone concentrations. In all disease models, we observed significantly increased corticosterone concentration 30 min after stress induction. However, the corticosterone kinetics differed among the animal models. Both the absolute value of corticosterone concentration and the duration correlated positively with the quantification of animal distress by a score sheet. This suggests that both variables of corticosterone kinetics might provide a solid basis for comparing and grading distress of different animal models

Generalizability, Robustness and Replicability When Evaluating Wellbeing of Laboratory Mice with Various Methods

An essential basis for objectively improving the status of animals during in vivo research is the ability to measure the wellbeing of animals in a reliable and scientific manner. Several non-invasive methods such as assessing body weight, burrowing activity, nesting behavior, a distress score and fecal corticosterone metabolites were evaluated in healthy mice and after three surgical interventions or during the progression of four gastrointestinal diseases. The performance of each method in differentiating between healthy and diseased animals was assessed using receiver operating characteristic curves. The ability to differentiate between these two states differed between distinct surgical interventions and distinct gastrointestinal diseases. Thus, the generalizability of these methods for assessing animal wellbeing was low. However, the robustness of these methods when assessing wellbeing in one gastrointestinal disease was high since the same methods were often capable of differentiating between healthy and diseased animals independent of applied drugs. Moreover, the replicability when assessing two distinct cohorts with an identical surgical intervention was also high. These data suggest that scientists can reach valid conclusions about animal wellbeing when using these methods within one specific animal model. This might be important when optimizing methodological aspects for improving animal wellbeing. The lack of generalizability, however, suggests that comparing animal models by using single methods might lead to incorrect conclusions. Thus, these data support the concept of using a combination of several methods when assessing animal welfare

Investigation of Anti-Tumor Effects of an MLK1 Inhibitor in Prostate and Pancreatic Cancers

It was shown that mixed lineage kinase 1 (MLK1) regulates pancreatic cancer growth; however, its role in prostate cancer remains unclear. We showed that MLK1 is a tumor marker in prostate cancer by analyzing clinical gene expression data and identified a novel MLK1 inhibitor (NSC14465) from the compound library of the National Cancer Institute (NCI) using a MLK1 protein structure. The inhibitory effects of MLK1 were validated by an in vitro kinase assay and by monitoring phosphorylation signaling, and the anti-proliferation function was shown in several prostate and pancreatic cancer cell lines. We also demonstrated anti-tumor ability and prevention of cancer-related weight loss in a syngeneic orthotopic mouse model of pancreatic cancer that mimicked the tumor growth environment in the pancreas. Our results demonstrate that the MLK1 inhibitor is an anti-tumor agent for malignant prostate and pancreatic cancers