Thesis (Ph.D.)--University of Delaware, 2006. / Principal faculty advisor: Kristi L. Kiick, Dept. of Materials Science & Engineering. Includes bibliographical references.

by Daron Adam Fincham. / Bibliography: leaves [84-99] / Thesis (M.Phil.) -- Chinese University of Hong Kong, 1983

Thesis (Ph. D.)--University of Washington, 2005. / Vita. Includes bibliographical references (leaves 128-142).

DNA double-strand breaks induced by ionizing radiation are often accompanied by ancillary oxidative base damage that may prevent or delay their repair. In order to better define the features that make some DSBs repair-resistant, XLF-dependent nonhomologous end joining of blunt-ended DSB substrates having the oxidatively modified nonplanar base thymine glycol (Tg) at the first (Tg1) , second (Tg2), third (Tg3) or fifth (Tg5) positions from one 3’ terminus was examined in human whole-cell extracts. Tg at the third position had little effect on end-joining even when present on both ends of the break. However, Tg as the terminal or penultimate base was a major barrier to end joining (>10-fold reduction in ligated products) and an absolute barrier when present at both ends. Dideoxy trapping of base excision repair intermediates indicated that Tg was excised from Tg1, Tg2 and Tg3 largely if not exclusively after DSB ligation. However, Tg was rapidly excised from the Tg5 substrate, resulting in a reduced level of DSB ligation, as well as slow concomitant resection of the opposite strand. XLFL115D mutant completely eliminates ligation of all five substrates and previous X‑ray crystallography shows that XLF binds to XRCC4 via a “leucine lock” motif wherein L115 of XLF slips into a hydrophobic pocket in XRCC4. This makes the XRCC4-XLF interaction a good target to develop peptide inhibitors in order to radiosensitize breast tumor cells that are dependent on NHEJ to repair their DSBs after ionizing radiation exposure. Using mRNA display, we created a diverse library of 870 billion unique peptide sequences. After seven rounds of in vitro selection, the eluted fusions were cloned and sequenced. The results showed homology of sequences of five main families. We have selected representative peptides from those families (Pep 7.1-7.5), and several were chemically synthesized. However, none of these significantly inhibited XLF-dependent end joining in whole-cell extracts. Overall, the results suggest that promoting ligation of DSBs with proximal base damage may be an important function of XLF, but that Tg can still be a major impediment to repair, being relatively resistant to both trimming and ligation. The effectiveness of XLF-XLRCC4 inhibitors in blocking nonhomologous end joining remains to be determined.

Background. Growth-arrest specific 6 (gas6) is a novel vitamin-K dependent protein whose role in venous thromboembolism was recently characterized in murine models. Gas6 is suggested to be a prothrombotic protein capable of mediating thrombus stability. However, the association between gas6 and venous thromboembolism has yet to be elucidated in humans. The present work aims to delineate the existence of such an association in humans and propose a mechanism by which gas6 expression is related to venous thromboembolic disease. / Methods. To analyze the association between gas6 and venous thromboembolism, a highly specific ELISA method was used to measure plasma gas6 levels in 306 patients with a history of deep-vein thrombosis (DVT) and 89 control volunteers. Medication history, comorbid conditions and DVT characteristics were documented for the purposes of statistical analyses. Median gas6 levels were compared between the subgroups, and prevalence rate ratios were calculated. Human umbilical vein endothelial cells were used to measure the effect of gas6 treatment on the expression of various mediators of coagulation. Murine thrombosis models were developed to serve as in vivo models for thrombosis. / Results. The median levels of gas6 were 28.21 ng/ml in patients compared to 26.15 ng/ml in controls (p=0.01). After adjustment for age, sex, comorbidity and medications, DVT patients had a PRR of 2.5 (95% CI 1.36 to 4.61, p=0.003) compared with controls. Within the DVT subgroup, median gas6 levels were significantly higher in those with cancer-associated (vs. unprovoked or secondary) DVT (p<0.001) and in those with more extensive DVT (p=0.037), while levels were significantly lower in those taking warfarin (vs. no warfarin) (p=0.03). Preliminary results with endothelial cell cultures are inconclusive with regards to the effect of gas6 on endothelium derived mediators of coagulation. / Conclusions. Elevated plasma gas6 is associated with venous thromboembolism. The etiology of the clot influences detected levels of gas6, with the highest levels seen in cancer-patients. Furthermore, increasing clot burden correlates with elevated levels of gas6. A mechanistic explanation for how gas6 modulates this association is in its preliminary stages, and is worth pursuing.

Thesis (Ph. D.)--Cornell University, August, 2008. / Vita. Includes bibliographical references (leaves 126-141).

No description available.

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 6 uppsatser.

Ling, Yick Hin. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2013. / Includes bibliographical references (leaves 72-77). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts also in Chinese.

Diss. (sammanfattning) Umeå : University, 2005. / Härtill 5 uppsatser. På omsl. felaktigt: N.S. 954.