@phdthesis{Unger2020,
  author    = {Unger, Nina},
  title     = {Stability of Tryptophan in Parenteral Amino Acid Solutions: Identification of Degradation Products and Development of HPLC Analysis Methods},
  doi       = {10.25972/OPUS-19982},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-199825},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2020},
  abstract  = {The stability of Trp in pure solutions and in parenteral AA formulations was evaluated with regard to typically used manufacturing processes, storage conditions and primary packaging. Therefore, thorough stability studies on Trp solutions were conducted beforehand. The applied stressing method, i.e. steam sterilization by autoclave, are chemically seen relatively mild but showed to be efficient to induce Trp degradation in the presence of oxygen. Subsequent identification, separation and characterization were challenging due to similar substance properties, numerous stereoisomers and pairs of diastereomers found amongst them. However, the identified o-aminoacetophenone compounds, Kyn and NFK, are associated with photo reactivity and have photo-oxidizing properties. Thus, best possible protection from UV-light, together with strict oxygen expulsion, are the most important criteria to impede Trp degradation after autoclaving. The identification of Trp degradation products was assisted by the compilation of a substance library, which included manifold reported and chemically plausible Trp degradation substances. The substances were classified for priority and their early or late-stage occurrence. The large number of possible substances and stereoisomers was narrowed down with the information retrieved from LC-UV/MS experiments. However, final identification was achieved by the synthesis of proposed substances as references. The following eight substances were characterized as Trp degradation substances: Kyn, NFK and three pairs of diastereomers R,R/R,S DiOia, R,R/R,S Oia and cis/trans PIC. Fig. 33 shows the proposed degradation pathway and demonstrates the close chemical relationship, which may be an explanation for the conversion of some substances into each other during the storage period. The proposed pathway brings together the results of different Trp stability and stressing studies, respectively [89, 94, 97, 98, 103, 133]. To our knowledge, the simultaneous formation of the identified degradation substances has not been reported before and especially not under the stressing conditions applied. The application of a traditional RP-HPLC method was compared to two developed IP-HPLC methods and a RP-HPLC methods using a modified perfluorinated column. Orthogonal analyses methods and especially the combination of UV and MS detection are necessary in order to indicate potentially undetected degradation substances. Main evaluation criteria were the separation performance, analyses time, reproducibility and feasibility. The best results upon assessment of all Trp degradation products, in both; pure Trp solutions and pharmaceutical formulations, were obtained by a traditional RP-HPLC. The optimized method was validated according to ICH guidelines Q2(R1) and meets the criteria of a stability-indicating HPLC-UV method. The validated method has a sufficient separation performance with an adequate selectivity indicating the Trp degradation substances next to each other and next to other AAs in finished pharmaceutical formulations. The detailed knowledge of Trp degradation and the method presented may be transferred practically to the pharmaceutical industry processing Trp-containing products. In general, the findings might contribute to the quality management of such pharmaceutical products during manufacturing and storage. Additionally, the study results provide basic information for the establishment of an impurity consideration following the ICH guidelines Q3B (R2) (impurities in new drug products) for products containing Trp. However, further development of the method applying more sophisticated detectors or more potent HPLC techniques like e.g. UHPLC and the implication of more sensitive (MS) detectors like ToF-MS would be advantageous with regard to economic and practical aspects.},
  subject      = {Stabilit{\"a}t},
  language  = {en}
}
@phdthesis{Promkam2019,
  author    = {Promkam, Ratthaprom},
  title     = {Hybrid Dynamical Systems: Modeling, Stability and Interconnection},
  doi       = {10.25972/OPUS-19099},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-190993},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2019},
  abstract  = {This work deals with a class of nonlinear dynamical systems exhibiting both continuous and discrete dynamics, which is called as hybrid dynamical system. We provide a broader framework of generalized hybrid dynamical systems allowing us to handle issues on modeling, stability and interconnections. Various sufficient stability conditions are proposed by extensions of direct Lyapunov method. We also explicitly show Lyapunov formulations of the nonlinear small-gain theorems for interconnected input-to-state stable hybrid dynamical systems. Applications on modeling and stability of hybrid dynamical systems are given by effective strategies of vaccination programs to control a spread of disease in epidemic systems.},
  subject      = {Dynamical system},
  language  = {en}
}
@phdthesis{Sapozhnikova2018,
  author    = {Sapozhnikova, Kateryna},
  title     = {Robust Stability of Differential Equations with Maximum},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-173945},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2018},
  abstract  = {In this thesis stability and robustness properties of systems of functional differential equations which dynamics depends on the maximum of a solution over a prehistory time interval is studied. Max-operator is analyzed and it is proved that due to its presence such kind of systems are particular case of state dependent delay differential equations with piecewise continuous delay function. They are nonlinear, infinite-dimensional and may reduce to one-dimensional along its solution. Stability analysis with respect to input is accomplished by trajectory estimate and via averaging method. Numerical method is proposed.},
  subject      = {Differentialgleichung},
  language  = {en}
}
@article{WeisSchoenVictoretal.2011,
  author    = {Weis, Eva and Schoen, Holger and Victor, Anja and Spix, Claudia and Ludwig, Marco and Schneider-Raetzke, Brigitte and Kohlschmidt, Nicolai and Bartsch, Oliver and Gerhold-Ay, Aslihan and Boehm, Nils and Grus, Franz and Haaf, Thomas and Galetzka, Danuta},
  title     = {Reduced mRNA and Protein Expression of the Genomic Caretaker RAD9A in Primary Fibroblasts of Individuals with Childhood and Independent Second Cancer},
  series = {PLoS ONE},
  volume    = {6},
  journal   = {PLoS ONE},
  number    = {10},
  doi       = {10.1371/journal.pone.0025750},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-141838},
  pages     = {e25750},
  year      = {2011},
  abstract  = {Background: The etiology of secondary cancer in childhood cancer survivors is largely unclear. Exposure of normal somatic cells to radiation and/or chemotherapy can damage DNA and if not all DNA lesions are properly fixed, the mis-repair may lead to pathological consequences. It is plausible to assume that genetic differences, i.e. in the pathways responsible for cell cycle control and DNA repair, play a critical role in the development of secondary cancer. Methodology/Findings: To identify factors that may influence the susceptibility for second cancer formation, we recruited 20 individuals who survived a childhood malignancy and then developed a second cancer as well as 20 carefully matched control individuals with childhood malignancy but without a second cancer. By antibody microarrays, we screened primary fibroblasts of matched patients for differences in the amount of representative DNA repair-associated proteins. We found constitutively decreased levels of RAD9A and several other DNA repair proteins in two-cancer patients, compared to one-cancer patients. The RAD9A protein level increased in response to DNA damage, however to a lesser extent in the two-cancer patients. Quantification of mRNA expression by real-time RT PCR revealed lower RAD9A mRNA levels in both untreated and 1 Gy gamma-irradiated cells of two-cancer patients. Conclusions/Significance: Collectively, our results support the idea that modulation of RAD9A and other cell cycle arrest and DNA repair proteins contribute to the risk of developing a second malignancy in childhood cancer patients.},
  language  = {en}
}