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Matrix remodeling could be an important mode of action of multipotent mesenchymal stromal cells (MSC) in extracellular matrix (ECM) disease, but knowledge is limited in this respect. As MSC are well-known to adapt their behavior to their environment, we aimed to investigate if their mode of action would change in response to healthy versus pathologically altered ECM. Human MSC-derived ECM was produced under different culture conditions, including standard culture, culture on Matrigel-coated dishes, and stimulation with the pro-fibrotic transforming growth factor-1 (TGF1). The MSC-ECM was decellularized, characterized by histochemistry, and used as MSC culture substrate reflecting different ECM conditions. MSC were cultured on the different ECM substrates or in control conditions for 2 days. Culture on ECM increased the presence of surface molecules with ECM receptor function in the MSC, demonstrating an interaction between MSC and ECM. In MSC cultured on Matrigel-ECM and TGF1-ECM, which displayed a fibrosis-like morphology, gene expression of collagens and decorin, as well as total matrix metalloproteinase (MMP) activity in the supernatant were decreased as compared with control conditions. These results demonstrated that MSC adapt to their ECM environment, which may include pathological adaptations that could compromise therapeutic efficacy.

Die invasiven und metastatischen Eigenschaften vieler Tumore werden mit einer Veränderung im physiologischen Gleichgewicht der Matrix Metalloproteinasen (MMP) und ihrer spezifischen und unspezifischen Inhibitoren in Zusammenhang gebracht. Das Ziel dieser Dissertation war es, die Wirkung von Batimastat, einem synthetischen Inhibitor der MMP, auf hormonabhängige und hormonunabhängige Prostatakarzinomzellinien sowie auf das Tumorwachstum im orthotopen Tumormodell des Dunning Tumor (R3327) zu untersuchen. Methoden: Im Zellkulturversuch wurde die Wirkung verschiedener Konzentrationen von Batimastat untersucht und die Proliferation mit dem MTT Test gemessen. Die Induktion des orthotopen Tumors erfolgte durch Inokulation von MATLyLu Zellen in die Rattenprostata (Dunning Tumor der Copenhagen Ratte). 10 Tiere wurden nach Tumorinduktion täglich mit 30 mg/kg Batimastat durch intraperitoneale Gabe behandelt, 10 weitere Ratten erhielten nur das Vehikel. Zehn Kontrolltiere blieben unbehandelt. Der Effekt auf des lokale Tumorwachstum wurden durch Bestimmung des Tumorgewichtes nach 20 Tagen definiert. Results:Batimastat zeigte eine dosisabhänige Hemmung des Wachstums der Prostatakarzinomzellinien in vitro. Bei 4000 ng/ml kam es zu einer eindeutigen Hemmung des Zellwachstums. Im Tierversuch fand sich nach 20 Tagen in der Kontrollgruppe ein mittleres Tumorgewicht von 18.9 ± 5,4 g, in der Vehikelgruppe von 22.3 ± 4,3 g und in der mit Batimastat behandelten Gruppe von 11.1 ± 2,6 g. Im Vergleich zur Kontroll- und Vehikelgruppe, zeigte sich in der Batimastatgruppe ein signifikant geringeres Tumorgewicht. Zusammenfassung: Batimastat kann das Tumorwachstum in einem Standardtiermodell des Prostatakarzinoms vermindern. Der Dunning Tumor der Copenhagen Ratte ist ein zuverlässiges Tiermodell zur weiteren Untersuchung von synthetischen Inhibitoren der MMP. / Background: Increased concentrations of metalloproteinases are associated with the invasive and metastatic behavior of several human malignant tumors. Normally, enzymatic activity is tightly regulated by nonspecific mechanisms and specific inhibitors. The aim of this dissertation was to determine the potential of a synthetic metallproteinase inhibitor, batimastat, to show its in vitro effect on hormonedependent and hormoneindependent prostate cancer cell lines and its in vivo effect on tumor growth in orthotopic cancer (R3327 Dunning tumor) in rats. Methods: In vitro, a dose response curve of batimastat was generated over 5 days using the MTT assay. Prostate cancer was injected in vivo in male Copenhagen rats by inoculating R3327 Dunning tumor cells (MATLyLu) into the ventral prostatic lobe of 30 rats. Each of 10 rats received batimastat (30 mg / kg / body weight) or vehicle once a day by i.p. application beginning the day of cell inoculation. Ten rats remained untreated. The effect on local tumor growth was evaluated by measuring tumor weights 20 days after tumor cell inoculation. Results: Significant inhibiton of tumor cell proliferation in vitro occurred at 4000 ng / ml batimastat. After orthotopic cell inoculation, tumors grew to mean weights of 18.9 ± 5,4 g in the control group without treatment, to 22.3 ± 4,3 g in the vehicle group, an to 11.1 ± 2,6 g in the treated group. In comparison to the control group and to the vehicle group, tumor weights increased significantly less under treatment with batimastat. Conclusions: Batimastat is able to reduce tumor growth in the standard prostate cancer model. Using this model, activity against cancer progression of future inhibitory agents can be reliably assessed.

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選舉制度的設計與評估，主要有兩方面的考量，一是可治理性；二是分配的比例性。以台灣的情況為例，新選制的選舉結果，理論上政府的運作將趨向穩定；相較之下，在制度替換的過程中，改革者通常只看見舊制度的缺失，舊制度本身所具有的優點－比例性，在改革過程中往往被忽視。本文的研究目的即是重拾對比例性的視野，透過Loosemore-Hanby D指數測量選制改革前後的比例性偏差程度，檢視1992至2008年間比例性偏差數值的變化，並從五個面向－選區規模、席次分配、法定門檻、席次總數、選票結構－解釋比例性偏差發生的原因，發現所有的選制設計皆不利於比例性，導致新選制的比例性偏差與舊制度產生極大的落差。 此外，透過比較其他可能的比例性狀況可以發現，無論是聯立制的模擬或是票源模擬的結果，皆顯示有助於提升小黨的代表性；另一方面，同樣採用並立制的日本，四次的選舉經驗可以做為我國參考的對象，但是由於選舉制度的各項要素不盡相同，也使得兩國選舉結果的比例性和小黨代表性呈現差異性。 最後，混合制固然同時融合了相對多數決制和比例代表制的特性，但是由於制度上選制要素以及非制度上國情與社會狀況的不同，很難期待一個完美的選舉制度出現，因此，我們只能尋求一個理想的選舉制度，且善用混合制所具有的彈性，做出適度的調整。 / Upon the evaluation of an electoral system, the main concerns are the governability and proportionality. In Taiwan’s case, the electoral system of Legislative Yuan altered from SNTV to mixed-member system; however, the reformers invariably accentuated the stability of governance but ignored the semi-proportionality of SNTV. Hence, the result of election in 2008 got unbalance between governability and proportionality. This article tends to measure the degree of disproportionality by Loosemore-Hanby index from 1992 to 2008 and tries to explain how disproportionality occurred from five dimensions－district magnitude, levels of seat allocation, threshold, number of total seats, and ballot structure. In addition, the results could be quite different when it compared with of other situations. According to this paper, the representation of small parties and the degree of proportionality will be enhanced while adopting MMP and redistributing the votes. Moreover, this paper is going to make a comparative study with Japan which have adopted MMM and have experienced four times elections since 1996. Finally, although mixed systems combine some features of both plurality and PR, there is still no perfect electoral system in the world. However, by making good use of flexibility of mixed systems, we might have an “ideal” system which can be regularly updated to suit changing needs and political conditions.