Diss. (sammanfattning) Stockholm : Karol. inst., 2006. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2006. / Härtill 5 uppsatser.

Thesis (Ph. D.)--West Virginia University, 2004. / Title from document title page. Document formatted into pages; contains x, 160 p. : ill. (some col.). Vita. Includes abstract. Includes bibliographical references.

München, Techn. University, Diss., 2005.

Thesis (M.S.)--Miami University, Dept. of Zoology, 2004. / Title from first page of PDF document. Includes bibliographical references (p. 36-47).

Thesis (Ph. D.)--University of Washington, 2007. / Vita. Includes bibliographical references (leaves 117-139).

Doctor of Philosophy / Department of Animal Sciences and Industry / Bradley J. Johnson / We used a total of fifty-nine gilts (BW=137.7 kg) from three different breeding groups were used to assess the effects of feeding L-carnitine during gestation on gilt growth characteristics, gilt and fetal blood metabolites, litter characteristics, and IGF axis components in fetal hepatic and skeletal muscle, maternal uterine and chorioallantois tissues, and porcine embryonic myoblasts collected from fetuses. Experimental treatments were arranged in a 2 × 3 factorial arrangement with main effects of L-carnitine and day of gestation. Gilts were fed a constant feed allowance of 1.75 kg/d and a top-dress containing either 0 or 50 ppm of L-carnitine starting on the first day of breeding through the allotted gestation length (40, 55, or 70). No differences (P > 0.16) were observed for BW or estimated protein or fat mass at any gestation length. Gilts fed L-carnitine tended to have greater (P = 0.10) backfat at d 40 and were numerically heavier at d 70 compared to control gilts. No differences (P > 0.77) were observed in circulating total and free carnitine at breeding, but concentrations increased (P < 0.01) as gestation length increased for the gilts fed L-carnitine compared to those fed the control diet. Fetuses from the gilts fed L-carnitine tended to be heavier (P = 0.06) and fetal circulating IGF-II lower (P = 0.09) at day 70 compared to the fetuses from the control gilts. Insulin-like growth factor-I (IGF-I) mRNA was lower (P = 0.05) in fetal hepatic tissue in fetuses collected from gilts fed supplemental L-carnitine. Insulin-like growth factor binding protein-3 (IGFBP-3; P = 0.05) and IGFBP-5 mRNA increased (P = 0.01) and IGF-I mRNA numerically increased (P = 0.16) in the endometrium of gilts supplemented with L-carnitine. At d 55 or 70 gestation, fetuses were removed for collection of porcine embryonic myoblasts (PEM) from the semitendinosus. There were no treatment differences (P > 0.10) for the expression of IGF-I, IGF-II or IGFBP-5 mRNA levels. However, PEM isolated from fetuses collected from gilts fed L-carnitine had lower (P = 0.08) IGFBP-3 mRNA levels compared to the controls. Myoblasts isolated from fetuses obtained from gilts fed L-carnitine had greater (P = 0.09; 8.8 %) 5.1H11 monoclonal antibody attachment after 72 h in culture. Although not significant (P = 0.20), the total number of PEM in the S phase of the cell cycle was 4.7 % greater in PEM collected from fetuses from gilts fed L-carnitine compared to the controls. This study shows L-carnitine supplementation to gestating gilts has beneficial effects on average fetal weight, due in part to changes in the expression of the IGF axis at the fetal-maternal interface in swine. These changes in the IGF axis play a fundamental role in porcine fetal growth and development due to enhanced proliferation and delayed differentiation of PEM.

Angiogenesis, the process of new vessel formation, appears to be a central mechanism that underlies the development of haemangiomas. Recently, intralesional bleomycin injection was used to treat paediatric haemangiomas with very good results. The purpose of this study was to determine whether there was significant systemic circulatory spill-over of bleomycin in haemangioma patients treated with intralesional bleomycin to determine safety of use. Furthermore, in order to elucidate bleomycin’s mechanism of action in inducing haemangioma regression, this study aimed at determining the effects of bleomycin on aspects of angiogenesis, namely, endothelial cell migration, growth and apoptosis, and comparing these effects with those of drugs previously reported to inhibit various aspects of the angiogenic process (mitomycin C, 2-methoxyestradiol, taxol, vincristine, vinblastine, colchicine, nocodazole and cytochalasin D). Lastly, the effects of bleomycin, mitomycin C, 2-methoxyestradiol, taxol, vincristine, vinblastine, colchicine, nocodazole and cytochalasin D were studied in an animal haemangioma model. A rapid and highly sensitive high performance liquid chromatographic (HPLC) method was developed. Blood samples were collected from four haemangioma patients before and after (over a 24 hour period) intralesional bleomycin (IB) therapy. As a control, blood samples were also collected at identical time intervals from four patients undergoing intravenous (IV) bleomycin chemotherapy for various malignant tumours. The HPLC method was used to quantitate bleomycin fractions in patient samples. The mean bleomycin concentration detected in plasma samples obtained from IB treated patients was 0.00 ìg/ml for both bleomycin A<Sub>2 and B2 over the 24-hour period following therapy. Plasma bleomycin A2 and B2 levels of 360.79 and 158.85 ìg/ml respectively were detected in samples obtained from cancer patients treated with bleomycin IV. These findings indicate that the low levels detected may translate to a significantly lesser risk of pulmonary fibrosis following IBI. The effect of drugs on endothelial cell migration was analyzed by wounding a confluent monolayer of cells and determining the number of cells that had migrated from the wound edge. Endothelial cell growth was determined in cells treated with various drug concentrations while apoptosis was examined using hematoxylin and eosin staining, DNA fragmentation assay and acridine orange staining. The effect of test drugs on in vitro angiogenesis was determined on endothelial cells induced to form capillary-like tubes in collagen gel. Test drugs were then evaluated for antitumour activity in an animal haemangioma model. Data demonstrated that test drugs inhibited endothelial cell migration, with the exception of mitomycin C. All test drugs induced a reduction in the percentage of viable endothelial cell in a dose-dependant manner, and also induced endothelial cell apoptosis. The drugs inhibited angiogenesis in vitro and inhibited tumour development in vivo with varying potency. In general, results from this study indicated that there was negligible systemic spill-over of bleomycin following IB administration in patients with haemangiomas, suggesting a much lesser risk of developing bleomycin-induced pulmonary fibrosis. This study also showed that test drugs inhibited angiogenesis in vitro and haemangioma development in vivo in a mouse model. Taken together, these observations demonstrate that bleomycin may inhibit haemangioma growth by inhibiting angiogenesis. In addition, mitomycin C, 2-methoxyestradiol, taxol, vincristine, vinblastine, colchicine, nocodazole and cytochalasin D may have potential in the treatment of haemangiomas of infancy, and should be investigated further in a murine haemangioma model to determine effective dose schedules. / Thesis (PhD)--University of Pretoria, 2009. / Physiology / unrestricted

In der vorliegenden Arbeit wurde der Einfluss des Fibroblast Growth Factor 9 (FGF-9) auf die Remyelinisierung in einem Modell der Multiplen Sklerose untersucht. Dafür wurde ein Mausmodell benutzt, bei dem es durch Fütterung von Cuprizon zu Oligodendrozytentod und Demyelinisierung kommt sowie nach Absetzen des Kupferchelators zu Remyelinisierung. FGF-9 wurde zum Zeitpunkt des Absetzens des toxischen Futters stereotaktisch in den Balken der Tiere injiziert. Der Fortschritt der Remyelinisierung wurde an zwei Zeitpunkten analysiert, weshalb eine Hälfte der Tiere nach 3 Tagen und die andere Hälfte nach 6 Tagen perfundiert und histologisch untersucht wurde. Die Beeinflussung von Remyelinisierung durch FGF-9 wurde auf 3 Ebenen beurteilt. (1) Die lichtmikroskopische Analyse der Remyelinisierung zeigte keinen Einfluss einer Behandlung mit FGF-9. (2) Auch in der elektronenmikroskopischen Untersuchung zeigte sich keine Beeinflussung der Anzahl remyelinisierter Fasern durch eine FGF-9- Behandlung. (3) Durch die Antikörper-vermittelte Anfärbung und Quantifizierung verschiedener Oligodendroglia-Populationen konnten folgende Beobachtungen gemacht werden: Während fortlaufender Remyelinisierung kam es zu einer Vermehrung von Oligodendrozyten-Vorläuferzellen. Dies zeigte sich an einer signifikant höheren Zahl von NG-2-markierten Zellen in Tieren, die 6 Tage nach Absetzen von Cuprizon untersucht wurden. Außerdem konnte ein Einfluss von FGF-9 auf die Population myelinbildender Zellen nachgewiesen werden. Die Dichte von Zellen, die das Myelinprotein PLP exprimierten, war bei FGF-9-behandelten Präparaten signifikant niedriger. Die Dichte reifer, Nogo-A-exprimierender Zellen war in der FGF-9- behandelten Versuchsgruppe an Tag 6, jedoch nicht an Tag 3 erniedrigt. Dass FGF-9 einen Einfluss auf Oligodendroglia in vitro hat, ist vorbeschrieben. Dabei gibt es jedoch keine übereinstimmende Aussage, ob der Wachstumsfakor proliferationshemmend oder -fördernd auf die Oligodendrogliagenese wirkt. Zudem fehlt der Nachweis, ob dies auch die Remyelinisierung beeinflusst. In dem hier durchgeführten in-vivo-Experiment konnte dieser Schritt ebenfalls nicht nachgewiesen werden. Die Zellzählungen lassen jedoch vermuten, dass FGF-9 einen hemmenden Einfluss auf die Entwicklung von Oligodendrozyten zu myelinbildenen Oligodendrozyten hat. Somit ist FGF-9 ein möglicher Induktor eines Differenzierungsblockes. In der Literatur wird eine solche Hemmung der Ausreifung von Oligodendrozyten als Ursache für die bei MS-Patienten unvollständig ablaufende Remyelinisierung postuliert. Unzureichende Remyelinisierung gilt als Korrelat der nicht vollständigen Kompensation von Behinderungen, die im Verlauf der autoimmunen Entzündungsschübe bei Multipler Sklerose entstehen.

Carvacrol is a phenol monoterpene found in aromatic plants specially in Lamiaceae family, which has been evaluated in an experimental model of breast cancer. However, any proposed mechanism based on its antitumor effect has not been reported. In our previous study, carvacrol showed a protective effect on 7,12-dimethylbenz[α]anthracene- (DMBA-) induced breast cancer in female rats. The main objective in this research was to evaluate by using in silico study the carvacrol on HER2, PI3Kα, mTOR, hERα, PR, and EGFR receptors involved in breast cancer progression by docking analysis, molecular dynamic, and drug-likeness evaluation. A multilevel computational study to evaluate the antitumor potential of carvacrol focusing on the main targets involved in the breast cancer was carried out. The in silico study starts with protein-ligand docking of carvacrol followed by ligand pathway calculations, molecular dynamic simulations, and molecular mechanics energies combined with the Poisson–Boltzmann (MM/PBSA) calculation of the free energy of binding for carvacrol. As result, the in silico study led to the identification of carvacrol with strong binding affinity on mTOR receptor. Additionally, in silico drug-likeness index for carvacrol showed a good predicted therapeutic profile of druggability. Our findings suggest that mTOR signaling pathway could be responsible for its preventive effect in the breast cancer. / Revisión por pares