Assessment of Low-Dose Radiotoxicity in Microorganisms and Higher Organisms

This work was dedicated to quantify and distinguish the radio- and chemitoxic effects of environmentally relevant low doses of uranium on the metabolism of microorganisms and multicellular organisms by a modern and highly sensitive microcalorimetry. In such low-dose regime, lethality is low or absent. Therefore, quantitative assays based on survival curves cannot be employed, particularly for multicellular organisms. Even in the case of microbial growth, where individual cells may be killed by particle radiation, classical toxicity assessments based on colony counting are not only extremely time-consuming but also highly error-prone. Therefore, measuring the metabolic activity of the organism under such kinds of conditions would give an extremely valuable quantitative measure of viability that is based on life cell monitoring, rather than determining lethality at higher doses and extrapolating it to the low dose regime. The basic concept is simple as it relies on the metabolic heat produced by an organism during development, growth or replication as an inevitable byproduct of all biochemical processes. A metabolic effect in this concept is defined as a change in heat production over time in the presence of a stressor, such as a heavy metal. This approach appeared to be particular versatile for the low dose regime. Thus, the thesis attempted in this case to measure the enthalpy production of a bacterial population as a whole to derive novel toxicity concepts. In the following chapters, an introduction about the properties of ionizing radiation will be briefly presented, in addition to a review about the isothermal calorimetry and its application in studying the bacterial growth. Later in chapter 2, the effect of uranium on the metabolic activity of three different bacterial strains isolated form a uranium mining waste pile together with a reference strain that is genetically related to them will be investigated. Due to the lack of published dedicated calibration techniques for the interpretation of heat production of bacterial cells under the conditions of calorimetric recordings, additional experiments, thorough investigations of the effects of experimental conditions, have been carried out in order to guide the interpretation of calorimetric results. In chapter 3, the differentiation between chemi- and radiotoxicity of uranium has been addressed by isotope exchange, which was a key effort in this thesis as it opens new experimental approaches in radioecology. In chapter 4, through investigating the role of the tripeptide glutathione (GSH) in detoxifying uranium, it will be shown to which degree the intrinsically unspecific signal provided by metabolic heat can be related to highly specific metabolic pathways of an organism, when combined with genetic engineering. The demonstration of gaining molecule-specific information by life metabolic monitoring was another experimental challenge of this thesis and provides proof of principle that can be extended to many organisms. Finally in chapter 5, an attempt has been undertaken to establish a minimal food chain, in order to study the effects of the exposure of a multicellular organism to uranium through its diet

Radiation Response Biomarkers for Individualised Cancer Treatments

Personalised medicine is the next step in healthcare, especially when applied to genetically diverse diseases such as cancers. Naturally, a host of methods need to evolve alongside this, in order to allow the practice and implementation of individual treatment regimens. One of the major tasks for the development of personalised treatment of cancer is the identification and validation of a comprehensive, robust, and reliable panel of biomarkers that guide the clinicians to provide the best treatment to patients. This is indeed important with regards to radiotherapy; not only do biomarkers allow for the assessment of treatability, tumour response, and the radiosensitivity of healthy tissue of the treated patient. Furthermore, biomarkers should allow for the evaluation of the risks of developing adverse late effects as a result of radiotherapy such as second cancers and non-cancer effects, for example cardiovascular injury and cataract formation. Knowledge of all of these factors would allow for the development of a tailored radiation therapy regime. This Special Issue of the Journal of Personalised Medicine covers the topic of Radiation Response Biomarkers in the context of individualised cancer treatments, and offers an insight into some of the further evolution of radiation response biomarkers, their usefulness in guiding clinicians, and their application in radiation therapy

Identification of predictors of patient survival with TSPAN8 as a mediator of tumor aggressiveness in clear cell renal cell carcinoma

With the help of a patient-derived clear cell renal cell carcinoma (ccRCC) model system previously established in our laboratory, which recapitulates the heterogeneity of the originating tumor, we were able to study ccRCC on a functional level. In five rounds and in four biological replicates of an in vivo selection, we transplanted lung metastases of orthotopically transplanted tumor cells into the renal capsules of NOD scid gamma (NSG) mice. The tumor was enriched for cells with increased growth and higher metastatic potential compared to the initial heterogeneous population. Comparative gene expression analysis revealed candidate genes associated with enhanced malignant growth and metastasis. Least absolute shrinkage and selection operator (LASSO) regression identified a gene signature that can robustly predict cancer specific patient survival. The prognostic power of our signature was additionally verified in independent patient cohorts suggesting that this approach leverages efficient stratification of patients into distinctive risk groups. Intra- and intertumor heterogeneity remains a clinical challenge as estimated survival rates could vary substantially when comparing different tumor regions. Tetraspanin-8 (TSPAN8) was identified as one of the hallmark genes in the generated ccRCC signature and is known to alter cellular signaling. Therefore, we hypothesized that TSPAN8 contributes to tumor aggressiveness and thus to growth and metastasis of ccRCC. In fact, in knockdown and overexpression xenografts experiments, we could confirm an essential role for tumor aggressiveness in vivo suggesting that TSPAN8 is an attractive target for treatment of clear cell renal cell carcinoma

Institute for Transuranium Elements Activity Report 2002.

Abstract not availableJRC.E-Institute for Transuranium Elements (Karlsruhe

New Aspects of Cancer Stem Cell Biology

The cancer stem cell (CSC) paradigm represents one of the most prominent breakthroughs of the last decades in tumor biology. CSCs are that subpopulation within a tumor that can survive conventional therapies and as a consequence are able to fuel tumor recurrence. Nevertheless, the biological characteristics of CSCs and even their existence, remain the main topic among tumor biologists debates. The difficulty in achieving a better definition of CSC biology may actually be explained by the plasticity of such a cell subpopulation. Indeed, the emerging view is that CSCs represent a dynamic “state” of tumor cells that can acquire stemness-related properties under specific circumstances, rather than referring to a well-defined group of cells. Regardless of their origin, it is clear that designing novel antitumor treatments based on the eradication of CSCs will only be possible upon unraveling the biological mechanisms that underlie their pathogenic role in tumor progression and therapy resistance. The Special Issue on “New aspects of cancer stem cell biology: implications for innovative therapies” aims at highlighting recent insights into CSC features that can make them an attractive target for novel therapeutic strategies

Radiopharmaceuticals

Radiopharmaceuticals - Current Research for Better Diagnosis and Therapy discusses the importance of radiopharmaceuticals and their environmental, pharmaceutical, diagnostic, therapeutic, and research applications. Chapters address such topics as the fundamentals of radiopharmaceutical chemistry and preparation, fabrication, materials manipulation, and characterization of radiopharmaceuticals, applications of radiopharmaceuticals in preclinical studies, radiopharmaceuticals in modern cancer therapy, and new trends in preparation, biodistribution, and pharmacokinetics of radiopharmaceuticals in diagnosis and research