Studies on Ligand Directed Enzyme Prodrug Therapy and Production of Long Acting Protein Therapeutics for Targeted Cancer Treatment

Targeting cancer therapy is one of the powerful tools that has been implemented for cancer treatment. One of the targeted cancer strategies is known as Antibody Directed Enzyme Prodrug Therapy (ADEPT). Three main components in this strategy, enzyme, cancer-specific antibody and a prodrug. The enzyme that has been used so far and reached clinical trials is carboxypeptidase G2 (CPG2) and the antibody chosen depends on the type of cancer to be treated. To overcome the need to conjugate a cancer-specific antibody to CPG2, our work showed that a small known peptide motif "Aspargine-Glycine-Arginine (NGR)" in place of an antibody fused to CPG2 can direct the enzyme to aminopeptidase N (APN ) that is highly expressed tumor. The CPG2 then converts the prodrug into the drug near the cancerous tissue. We called this strategy Ligand-targeted enzyme prodrug therapy (LDEPT). We have successfully demonstrated the ability of our new conjugates to bind specifically to cancer cells and CPG2 to produce the cytotoxic drug to kill the tumor cells. The ADEPT or LDEPT have disadvantages such as immunogenicity over CPG2 that undermine the efficacy of the therapy. We have therefore started the tasks to produce long acting CPG2 new variants. First and for the first time, we produced two CPG2 conjugates using life extenders PEGylation and gene fusion of HSA Our produced CPG2 variants (PEG-CPG2 and HSA-CPG2) showed a longer half-life under physiological conditions in addition to lower ex-vivo immunotoxicity . Second, we produced a long acting peptide-CPG2 that can specifically bind to tumor and has a long half-life, these are single and double fusion of PEG-CPG2-CNGRC. The resulting conjugates; single (CNGRC-CPG2) and double (CNGRC-CPG2-CNGRC) have been found to specifically target and bind APN, which is known to be highly expressed on the surface of tumor cells. In addition, the conjugates generated showed higher stability and significantly reduced ex vivo immunotoxicity. CPG2 in both conjugates has the ability to convert prodrug into a cytotoxic drug to kill the cancer cells. The work presented in this thesis paves the way for further in vivo and clinical studies to improve two of the important cancer targeting strategies, ADEPT and LDEPT

Alternative water management scenarios for Saudi Arabia

Natural Resources;environmental economics

Promoting social change in the Arab Gulf: two case studies of communication programmes in Kuwait and Bahrain

The thesis presents rich empirical analysis of the role of public relations in facilitating participation in social change in the Arab Gulf. The focus is on what public communication approaches are used and how they are regarded from the perspectives of the key social actors. It presents an historical and sociological background of public communication and media in the Arab Gulf. Moreover, it provides in-depth analysis of two empirical case studies in the Arab Gulf: Ghiras, the national drugs prevention programme in Kuwait, and Be Free, the voluntary anti-child abuse programme in Bahrain. This thesis relates the practice of public communication in the Arab Gulf society to Arabic culture and ethics. The thesis uses a qualitative constructivist paradigm to “re-construct” the multiple realities initially constructed by social actors in the cases to provide original insights on the role of public communication and public relations in social change in the Arab Gulf. It presents a new perspective of 'social change' in the two cases that is tied to Islamic ethics. Besides, it re-constructs original Arabic-oriented understanding of 'relational' and 'persuasion' approaches, which differs from the Western paradigm. One of the key contributions of the thesis is its adaptation of relevant Western communication models to the empirical Arab Gulf cases to identify some of the crucial factors of the practice and role of public communication in the Arab Gulf. The unique contribution of this thesis is that it develops a greater understanding of alternative cultural context that might contribute to the adaptations of existing theory and therefore a first step towards new models. It introduces a theoretical framework for other scholars to develop an Arabic public communication ethics theory and to build up a cultural model of the practice of public communication and public relations in the Arab Gulf. The thesis generates key theoretical implications that contribute to the theoretical discussion on the value and role of media, public relations, social marketing, and public communication in the Arab Gulf society at the age of globalisation

History and Sociology of Public Communication in the Arab Gulf

This research aims to fill the vacuum in the literature on the role of public communication campaigns in the Arab Gulf. It provides detailed qualitative data about the history and sociology of media, public communication and public relations in social change in the Arab Gulf societies. The paper aims to frame a historical and sociological background of media and public communication campaigns that aim at promoting social change and development in the Arab Gulf. It contributes to the global picture of the role of public communication in the Arab Gulf culture. The article begins with a background to the concepts of social change, participation, and social responsibility in the Islamic and Arabic culture. Then, it discusses the challenge of modernisation in the Arab Gulf and the rationales for the launch of public communication campaigns. After that, it provides a brief history of media and its role in promoting social change in the Arab Gulf. Finally, the research provides a historical background of social change campaigns in the Arab Gulf. This is achieved by reviewing literature in two linked areas: a review of the national campaigns in the Arab Gulf, and a discussion of the role of voluntary associations in promoting social change in the Arab Gulf societies

An investigative study of the female initial teacher preparation programme in Saudi Arabia in an Islamic context : perceptions of the key participants

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Physiochemical Properties and Environmental Levels of Legacy and Novel Brominated Flame Retardants

Polybrominated diphenyl ethers (PBDEs) and ‘novel’ brominated flame retardants (NBFRs) are synthetic chemicals widely used in consumer products to enhance their ignition resistance. Since in most applications, these chemicals are used additively, they can transfer from such products into the environment. PBDEs have been classified as significant pollutants in the environment. Knowledge of PBDE and NBFR physicochemical properties provides information about their potential environmental fate and behaviour. This chapter highlights the most important physiochemical properties such as molecular weight, vapour pressure, octanol/air partitioning coefficient, octanol/water partition coefficient, water solubility and organic carbon/water partitioning coefficient that influence the distribution pattern of these contaminants in the environment. In addition, this chapter provides an evaluation of the concentrations of these chemicals in various environmental media such as indoor and outdoor air, indoor dust, soil and sediment, sewage sludge, biota and food, and human tissues

ON M- Hollow modules

Let R be associative ring with identity and M is a non- zero unitary left module over R. M is called M- hollow if every maximal submodule of M is small submodule of M. In this paper we study the properties of this kind of modules

Investigations on how the enteropathogenic Escherichia coli (EPEC) EspF effector inhibits PI-3 kinase-dependent phagocytosis

PhD ThesisEnteropathogenic E. coli inhibits phosphoinositide 3 (PI-3) kinase dependent phagocytosis via a Type Three Secretion System (T3SS) that delivers up to twenty effector proteins into target cells. The T3SS components are encoded on the Locus of Enterocyte Effacement (LEE) pathogenicity island alongside genes for a surface protein, Intimin, and seven effectors (Tir, Map, EspF, EspG, EspZ, EspH and EspB; latter also needed to deliver effectors). Inhibiting phagocytosis is linked to EspB, EspH, EspG and EspF activities with inhibitory mechanisms described for all except EspF. The aim of this study was to determine if EspF alone could inhibit phagocytosis and define the inhibitory mechanism. Initial anti-phagocytosis studies, with J774A.1 macrophages, not only confirmed EspF and T3SS-dependent inhibition but suggested a T3SS-independent contribution. Moreover, studies with effectors-deficient EPEC and non-pathogenic E. coli carrying LEE on a plasmid argued for LEE sufficiency. Surprisingly, delivering EspF into macrophages without most (EPEC multi-mutant) or all (via T3SS of another pathogen, Yersinia) other EPEC effectors argued against EspF sufficiency. Interestingly, the data also argued against EspG driving the anti-phagocytosis process but suggested that EspF’s contribution required Map, EspH, Tir, and/or the Intimin activities. Surprisingly, screening EspF/Map/EspH/Tir/Intimin single, double, triple, quadruple and quintuple mutants failed to confirm the critical roles for EspF or EspH that are linked to phenotypic instability and/or indirect contributions. Preliminary investigations on EspF’s involvement revealed possible features and domains required for its efficient expression, secretion and/or inhibiting phagocytosis. Crucially, the screening data provided many hypotheses including Tir and Intimin being able to drive T3SS-dependent anti-phagocytosis, an idea supported by complementation studies. Collectively, this study provides important new insights on EPEC’s ability to inhibit its uptake by J774A.1 macrophages and reveals unknown levels of complexity.Higher Committee for Education Development in Iraq (HCED