Antiplatelet therapy with clopidogrel is widely used in patients with coronary artery disease, but the recent development of the new P2Y12 receptor antagonists prasugrel and ticagrelor will increase treatment options. An overview of systematic reviews was performed to summarize available evidence on clopidogrel. Current data on prasugrel and ticagrelor were identified by a systematic review and used for an indirect treatment comparison (ITC) of the drugs against each other and versus placebo in the absence of head-to-head clinical trials. Adjusted indirect comparison according to Bucher, Bayesian methods for mixed treatment comparisons using Winbugs, and generalized linear mixed models using SAS were employed for ITC, yielding almost identical results: prasugrel was favored regarding stent thrombosis and ticagrelor regarding major bleeding. However, substantial differences in trial design were identified, demanding caution when interpreting these results. On the basis of the obtained results, a randomized controlled trial was designed within the gap of current evidence.

Thesis advisor: Welkin E. Johnson / Tetherin/BST2 is an interferon-inducible antiviral factor that restricts the egress of numerous enveloped viruses including HIV-1. Consequently, many viruses have evolved mechanisms to actively or passively evade restriction by tetherin. Most studies conducted to date focused on the tetherin-evasion mechanism of complex retroviruses like HIV and SIV, which encode accessory proteins like Vpu and Nef respectively to counteract tetherin-mediated restriction. However, there is a wide gap in knowledge in understanding how simple retroviruses (that includes alpharetroviruses, some betaretroviruses and gammaretroviruses) that lack obvious accessory proteins like HIV-1 Vpu and SIV-Nef, evade restriction by tetherin. In this dissertation, I have established that Simian retrovirus type-3, a prototypical type-D betaretrovirus, isolated from Asian macaques, is restricted by human tetherin but not by rhesus macaque tetherin. This differential sensitivity indicated that SRV-3 has a mechanism to evade tetherin-mediated restriction. I have identified the SRV-3 envelope (Env) glycoprotein as the viral determinant of tetherin antagonism, and have also found that SRV-3 envelope expression in-trans was sufficient to rescue a heterologous virus from tetherin. SRV-3 Env resulted in cell-surface down-modulation of rhesus tetherin, and this mechanism of tetherin-antagonism is independent of the SRV-3 Env trafficking pathway. The target specificity of SRV-3 Env overlapped a stretch of five residues (G14DIWK18) in the rhesus tetherin cytoplasmic tail that are absent from human tetherin. Additionally, I was able to show that SRV-3 Env physically interacts with rhesus tetherin by targeting the G14DIWK18 motif. SRV-3 belongs to a large supergroup of retroviruses, called the RDR Interference Supergroup. Due to this reason, I screened additional RDR envelope glycoproteins for their ability to antagonize a panel of tetherin homologs. All the RDR envelopes tested were sensitive to human tetherin but exhibited anti-tetherin activity when tested against a panel of tetherin homologs from squirrel monkey, baboon, dog and cat. I also found that several non-RDR gammaretroviral envelope glycoproteins also have anti-tetherin function. Thus, tetherin-antagonism is not just restricted to the envelope glycoproteins of retroviruses in the RDR interference supergroups but extends to other non-RDR gammaretroviruses as well. To my knowledge, this is the first characterization of gamma-type envelopes as tetherin antagonists. Thus, in the absence of a dedicated tetherin antagonist, many simple retroviruses in the beta- and gammaretrovirus genera may evade tetherin-mediated restriction through neo-functionalization of their envelope glycoproteins. We speculate that the evolutionary success of the gamma-type envelope may be due, at least in part, to this anti-tetherin function. / Thesis (PhD) — Boston College, 2018. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Biology.

It has long been known that oxygen has the potential to be toxic to biologic systems and that this toxicity is not due to oxygen itself, but due to the production of oxygen radicals. One of these potentially toxic radicals, superoxide (O₂⁻) can be generated as a result of ionizing radiation, and if not adequately removed can proceed to cause cell damage. Superoxide dismutase (SOD) is one of the key enzymes involved in the defence against oxygen toxicity. SOD activity can be inhibited by diethyldithiocarbamate (DOC), a powerful copper chelator. If inhibition of SOD by DOC increases the lifetime and effectiveness of radiation induced O₂⁻, it follows that the potential exists for DOC to enhance the effect of radiation. DOC is however also a thiol compound, and thus may act as a radioprotector by modifying tissue oxygenation status or by free radical scavenging. This study has concerned itself primarily with the inhibition of superoxide dismutase by diethyldithiocarbamate in order to sensitize tumours to ionizing radiation. The use of DOC as an inhibitor of SOD has however meant that any sensitization resulting from SOD inhibition could be masked by a radioprotective effect by DOC. The inhibition of SOD by DDC was confirmed in a murine rhabdomyosarcoma, and it was shown that this inhibition can be maintained for up to twenty-four hours after DDC administration. It was hypothesised that there was a potential for the radioprotective effect of DDC to be overcome, if the levels of DDC were low enough at the time of irradiation. Indeed, if DDC was removed from the growth medium of B16 mouse melanoma cells in culture prior to irradiation, a significant sensitization was demonstrated. It was shown that DDC could act as both a radiosensitizer and as a radioprotector in the same experiment. The dominant action of DDC was found to be dependent on the time allowed between DDC administration and irradiation. If this time was approximately 4 hours, it was possible to show a radiosensitizing effect by means of a tumour growth delay assay. This time modulation effect of DOC was shown in larger tumours, rather than smaller tumours, which could indicate that tumour oxygenation is an important criterion in determining the response to radiation of DOC treated cells. It was shown that B16 mouse melanoma cells exposed to 43°C after DDC pre-treatment were sensitized to thermal damage. This work suggests that some caution should be exercised when DDC is put forward as either a radiosensitizer or a radioprotector in the clinic, but that DDC may have potential as a thermosensitizer.

The high rate of relapse often seen in breast cancer patients has been suggested to be the result of a small subset of chemotherapy-resistant cancer stem cells (CSCs), believed to be responsible for initiating tumor formation. These CSCs possess the capability to self-renew and give rise to a hierarchy of cells which makes up the bulk of a tumor. Neurotransmitters have been suggested to influence CSC self-renewal and proliferation capabilities, and antagonists of neurotransmission pathways have been implicated as possible treatment methods for chemo-resistant tumors. Using nicotinic acetylcholine receptor (nAChR) antagonists in sphere-forming assays, we have identified a very promising candidate compound: MG624. We found this compound to have a high selectivity for sphere-forming cells over non-sphere-forming cells in vitro, in a dose-dependent relationship, across a panel of cell lines as well as in patient-derived xenograft cells. This was validated in two ex vivo assays, where tumor formation was significantly delayed in mice injected with MG624-treated HCC1954 cells at both the IC50 and IC90 of the compound, indicating that MG624 does indeed target functional BTICs. MG624 was also found to synergize with both taxotere and doxorubicin chemotherapies in vitro, and shrink tumors in NOD/SCID mice when combined with taxotere in vivo. MG624 in combination with taxotere was found to induce apoptosis, and prevent cells from entering into the M-phase of the cell cycle. Interestingly, MG624 was found to eliminate intratumoral fibroblasts in combination with taxotere, despite taxotere being found to recruit fibroblasts to the tumor site when used on its own. Most importantly, the combination of MG624 and taxotere was found to significantly delay tumor progression/relapse in mice, indicating that MG624 may be an excellent candidate compound to one day be combined with chemotherapy to provide durable remission to breast cancer patients. / Thesis / Master of Science (MSc)

Invasion and metastasis of cancer is the leading cause of increased mortality. In addition, haematological malignancies (leukaemia and lymphoma) are a significant cause of morbidity and mortality in both children and adults. Therefore, new treatments which will inhibit cancer progression are required. Integrin adhesion receptors, particularly the RGD-binding integrin subfamily comprising αvβ3, αvβ5, αvβ6, αvβ8, αllbβ3, α5β1, α8β1 and αvβ1 are related to progress and spread of cancer and poor prognosis. Because of the importance of integrin biology in the regulation of cancer dissemination, the integrin receptors are being utilised as targets to regulate cancer progression. The goal of this study was to develop a dual αvβ3/ αIIbβ3 expressing model for testing integrin antagonists. Expression of αv, αIIb, and β3 integrin subunits was characterised using immunofluorescence and flow cytometry in a panel of cell lines. After characterising the expression of αv, αIIb and β3 integrin subunits in inducible and natural expression models (K562 and MCF-7 cells respectively), functional tests for cellular adhesion, detachment and migration were determined. Phorbol 12-myristate 13-acetate (PMA)-treated K562 cells showed increased adhesion on fibrinogen compared to untreated cells. Adhesion of cancer cells (K562 ± PMA and MCF-7) to fibrinogen was inhibited and detachment was induced by the known β3 antagonists, cRGDfV and GR104453. Migration of cancer cells (K562 without PMA and MCF-7) was inhibited by combination of the known β3 antagonists. A panel of 12 novel small molecules developed in the ICT was investigated for cytotoxicity and activity in the validated function assays. ICT9055 was the most potent antagonist in inhibition of cell adhesion, migration, and inducing cell detachment. The data presented in this thesis had selected models and assays for evaluating small molecule integrin antagonists and identified ICT9055 as a promising molecule to develop for further preclinical evaluation. / The Libyan Embassy; Omer Al Mukhtar University, Faculty of Medical Technology, Derna, Libya.

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Yes / The integrins are a family of 24 heterodimeric transmembrane cell surface receptors. Involvement in cell attachment to the extracellular matrix, motility, and proliferation identifies integrins as therapeutic targets in cancer and associated conditions; thrombosis, angiogenesis and osteoporosis. The most reported strategy for drug development is synthesis of an agent that is highly selective for a single integrin receptor. However, the ability of cancer cells to change their integrin repertoire in response to drug treatment renders this approach vulnerable to the development of resistance and paradoxical promotion of tumor growth. Here, we review progress towards development of antagonists targeting two or more members of the RGD-binding integrins, notably αvβ3, αvβ5, αvβ6, αvβ8, α5β1, and αIIbβ3, as anticancer therapeutics.

by Lee Chi-Chung. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2001. / Includes bibliographical references (leaves 74-78). / Abstracts in English and Chinese. / Acknowledgment --- p.ii / Table of Contents --- p.iii / Abstract --- p.v / Abstract (Chinese Version) --- p.vi / Abbreviation --- p.vii / Chapter 1. --- Introduction --- p.1 / Chapter 1.1 --- General Background --- p.1 / Chapter 1.1.1 --- Valienamine --- p.2 / Chapter 1.1.2 --- Valienamine Derivatives --- p.4 / Chapter 1.2 --- Mechanistic Aspects of Glycosidase Inhibition --- p.6 / Chapter 1.2.1 --- General Background --- p.6 / Chapter 1.2.2 --- Mechanism of Enzyme Catalyzed Hydrolysis of Glycosides --- p.6 / Chapter 1.2.3 --- Types of Glucosidase Inhibitors --- p.7 / Chapter 1.2.4 --- Inhibition of Glycosidases by Valienamine Derivatives --- p.8 / Chapter 1.3 --- Previous Synthesis of Valienamine --- p.9 / Chapter 1.3.1 --- Enantiospecific Synthesis of Valienamine by Vasella and co-workers --- p.9 / Chapter 1.3.2 --- Enantiospecific Synthesis of Valienamine by Tatsuta and co-workers --- p.10 / Chapter 1.3.3 --- Synthesis of N-Alkyl Derivatives of Valienamine --- p.12 / Chapter 1.4 --- Previous Syntheses of Valienamine-containing Pseudodisaccharides and its Diastereomers --- p.12 / Chapter 1.4.1 --- Epoxide aminolysis --- p.12 / Chapter 1.4.2 --- Condensation of amine with ketone --- p.15 / Chapter 1.4.3 --- Synthesis of pseudoaminodisaccharide by Kapp and co-workers --- p.16 / Chapter 2. --- Results and Discussion --- p.18 / Chapter 2.1 --- General Strategy --- p.18 / Chapter 2.2 --- Syntheses of coupling precursors --- p.20 / Chapter 2.2.1 --- Syntheses of protected valienamine 65 and its 2-epimer80 --- p.20 / Chapter 2.2.1.1 --- Synthesis of Diol68 --- p.20 / Chapter 2.2.1.2 --- Synthesis of Diol67 --- p.21 / Chapter 2.2.1.3 --- Synthesis of protected valienamine 65 and its 2-epimer80 --- p.22 / Chapter 2.2.2 --- Syntheses of 6-deoxyaminosugars 63 and118 --- p.24 / Chapter 2.2.2.1 --- Synthesis of benzyl ether91 --- p.24 / Chapter 2.2.2.2 --- Synthesis of β-diol103 --- p.28 / Chapter 2.2.2.3 --- Synthesis of α-alcohol107 --- p.30 / Chapter 2.2.2.4 --- Synthesis of β-diol113 --- p.31 / Chapter 2.2.2.5 --- Syntheses of amines 63 and118 --- p.33 / Chapter 2.2.3 --- Syntheses of allylic chlorides --- p.34 / Chapter 2.3 --- Syntheses of pseudoaminodissaccharides --- p.36 / Chapter 3. --- Conclusion --- p.42 / Chapter 4. --- Experimental --- p.44 / Chapter 5. --- References --- p.74 / Chapter 6. --- Appendix --- p.79 / List of spectra --- p.79