Biomedical subjects
Publications and source records attributed to Michael Quante.
The main ethical problem of organ transplantation is the shortage of transplantable organs. The substitute strategies currently under discussion endanger frust in transplantion medicine and thereby increase the problem. Thus ethically preferable alternatives to overcome the shortage are suggested.
Immortalization and malignant transformation are important steps in tumor development. The ability to induce these processes from normal human epithelial cells with genetic alterations frequently found in the corresponding human cancer would significantly enhance our understanding of tumor development. Alterations in several key intracellular regulatory pathways (the pRB, p53, and mitogenic signaling pathways and the telomere maintenance system) appear to be sufficient for the neoplastic transformation of normal human cells. Nevertheless, in vitro transformation models to date depend on viral oncogenes, most prominently the simian virus 40 early region, to induce immortalization and malignant transformation of normal human epithelial cells. Here, we demonstrate a transformation model creating oral-esophageal cancer cells by using a limited set of genetic alterations frequently observed in the corresponding human cancer. In a stepwise model, cyclin D1 overexpression and p53 inactivation led to immortalization of oral keratinocytes. Additional ectopic epithelial growth factor receptor overexpression followed by c-myc overexpression as well as consecutive reactivation of telomerase induced by epithelial growth factor receptor sufficed to transform oral epithelial cells, truly recapitulating the development of the corresponding human disease.
Telomerase activity is observed in approximately 90% of human cancer including esophageal squamous cell cancer. Normal somatic cells do not display telomerase activity on a regular basis. The major mechanism to regulate telomerase activity in human cells is the transcriptional control of the catalytic subunit, the human reverse transcriptase gene hTERT. However, the manner in which telomerase activity is regulated during malignant transformation and whether this regulation is influenced by single genetic alterations important in this process are not well understood. In this study we investigated the transcriptional regulation and activity of human telomerase in a cellular model representing important known genetic alterations observed in esophageal cancer. We characterized the respective cells with regard to their telomere biology and telomerase expression, transcriptional regulation using promoter--as well as electrophoretic mobility shift assay--analyses and their promoter methylation status. We could demonstrate that telomerase expression and subsequent activity are differentially regulated in the progression from normal esophageal epithelial cells to genetically defined esophageal cells harboring a specific genetic alteration frequently found in esophageal cancer and compared those changes with esophageal cancer cells. Whereas primary esophageal cells are mainly regulated by Sp1, in cells harboring a genetic alteration as cyclin D1 overexpression other transcription factors like E2F and c-myc as well as promoter methylation influence hTERT transcription. This model demonstrates that the transcriptional regulation of telomerase is influenced by a given genetic alteration important in esophageal cancer, and therefore provides new insight in telomerase regulation during carcinogenesis.
Squamous cancers of the oral cavity and esophagus are common worldwide. A number of environmental factors as well as genetic alterations have been identified. However, the specific combination of genetic events and their interplay with environmental carcinogens are largely un-known. Furthermore, no good animal model existed to study the molecular changes important in the induction and progression of the disease. Here we summarize the efforts made to establish a mouse model of oral-esophageal carcinogenesis. Cyclin D1 overexpressing(L2D1+) mice were generated using an EBV promoter to specifically target the oral cavity and the esophageal squamous epithelium. Besides analyzing different environmental factors, such as nitrosamines and zinc deficiency, cyclin D1 transgenic mice were crossbred with p53-deficient mice. While L2D1+ mice exhibited a phenotype of dysplasia, different combinations of mice result-ed in invasive oral-esophageal cancer. This mouse model provides a well-defined and reproducible model of oral-esophageal cancer that should be useful for testing chemopreventive, diagnostic, and therapeutic strategies.
After presenting the current version of principlism, in the process repudiating a widespread deductivist misinterpretation, a fundamental metaethical disagreement is developed by outlining the deductivistic critique of principlism. Once the grounds for this critique have been understood, the dispute between casuistry, deductivism and principlism can be restructured, and the model of "application" proven to be the central difference. In the concluding section it is argued that principlism is the most attractive position, if the perceptual model of weak intuitionism is made more explicit.
Debates on precedent autonomy and some forms of paternalistic interventions, which are related to questions of personal identity, are analyzed. The discussion is based on the distinction between personal identity as persistence and as biographical identity. It first is shown that categorical objections to advance directives and "Ulysses contracts" are based on false assumptions about personal identity that conflate persistence and biographical identity. Therefore, advance directives and "Ulysses contracts" are ethically acceptable tools for prolonging one's autonomy. The notions of personality and biographical identity are used to analyze the ethically relevant features. Thereby, it is shown that these concepts are operative in and useful for thinking in biomedical ethics. The overall conclusion is that categorical arguments against precedent autonomy or "Ulysses contracts" are based on misleading theories of personal identity and that advance directives are an ethically respectable tool for prolonging individuals' autonomy in cases of dementia and mental illness.