12508 research outputs found
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Issues of Governance and Culture in the FATA Of Pakistan: Examining the Sources of Insecurity and Extremism
No full textThe full text will be available at the end of the embargo period: 5th Sept 202
Gender Equality in Local Content Policies
No full textYesHistorically, the oil and gas sector has played a significant role in the economic development. Beyond being an important source of energy for industrialisation and other development goals, revenue from oi and gas exports have provided much needed funding for critical sectors in resource rich countries. However, the benefits of oil and gas developments have not been equitably distributed. Local content laws were introduced by resource rich countries to maximise the benefits of resource extraction and production processes for the local population and businesses. Recognising that host communities bear an inordinate burden of the negative externalities associated resource exploitation, local content laws offer an opportunity for mitigating adverse impacts and maximising the wider benefits accruing from the energy sector at the local level. Though women are still often disproportionately impacted by the negative externalities from the oil and gas sector and excluded from employment and decision-making, most local content provisions do not sufficiently address the gender issues. This chapter explores the state of gender equality in Africa’s oil and gas sector and makes recommendations for strengthening women’s inclusion in the sector through local content laws provisions. The chapter also considers main legal approaches for mainstreaming gender equality in local content laws vis-à-vis the trends in the energy sector across the continent.The full-text of this book chapter will be released for public view at the end of the publisher embargo on 1 Mar 2027
Self-Congruity Theory: An Investigation of the Pro-Environmental Tourist Behaviours. An Application and Extension of Self-Congruity Theory of the Eco-Tourism Destinations in Pakistan and UK
No full textThe full text will be available at the end of the embargo: 10th April 202
Synthesis and biological evaluation of MMP-activated anti-cancer prodrugs
No full textThe full text will be available at the end of the embargo period: 28th March 202
Pharmacological evaluation of the inhibition of polysialyltransferases as a therapeutic strategy in cancer. Characterisation of models for evaluating polysialic acid as a potential therapeutic target and pharmacological assessment of novel polysialyltransferase inhibitors
Full text linkNeuroblastoma is a highly metastatic and invasive tumour with poor
prognosis. Despite recent advances in the treatment of neuroblastoma,
mortality is still high due to uncontrolled metastatic disease, and novel
therapeutic approaches for the treatment of neuroblastoma are therefore
desperately needed.
A potential novel approach for therapy of neuroblastoma relates to the
polysialic acid decoration of the neural cell adhesion molecule (PSANCAM). PSA-NCAM is selectively re-expressed in a number of tumours
including neuroblastoma, where it is thought to modulate tumour
dissemination. Expression is strongly associated with poor clinical
prognosis and an aggressive tumour phenotype. Inhibition of the
enzymes responsible for synthesis of PSA, the polysialyltransferases
(polySTs) presents a novel and selective therapeutic opportunity.
The aims of the studies described in this thesis are to evaluate PSANCAM expression and function in neuroblastoma, and to develop and
utilise cell-based models to pharmacologically investigate novel polyST
inhibitors.
PSA-NCAM was seen to be highly expressed in neuroblastoma clinical
specimens and associated with phenotypes of tumour aggressiveness. A
screening panel consisting of cell lines with a range of PSA-NCAM
expression types was established and utilised to develop assays for
pharmacologically assessing novel polyST inhibitors. Using cytidine
monophosphate (CMP), a naturally-occurring inhibitor of polySTs, the
robustness of the assays was confirmed before progression to evaluate
novel molecules. From 16 compounds identified in an in vitro screen of
polyST inhibition, three promising polyST inhibitors were identified.
These promising polyST inhibitors modulated PSA-NCAM expression on
the tumour cell surface and led to a significant reduction in cell migration.
Therefore the work presented in this thesis suggests that targeting
polySTs is a promising novel therapeutic strategy for neuroblastoma and
further research in this area is warranted.Mu'tah University and Jordan Armed Forces, Hashemite Kingdom of Jordan.The full text will be available at the end of the extended embargo period: 5th March 202
Design, Synthesis and Preclinical Evaluation of MT1-MMP Targeted Methotrexate Prodrugs for the Treatment Of Osteosarcoma
No full textBone Cancer Research TrustThe full text will be available at the end of the embargo: 6th October 202
Self-Congruity Theory: An Investigation of the Pro-Environmental Tourist Behaviours. An Application and Extension of Self-Congruity Theory of the Eco-Tourism Destinations in Pakistan and UK
No full textThe full text will be available at the end of the embargo: 10th April 202
Synthesis and pharmacological evaluation of novel anti-tumour prodrugs. Synthesis and pharmacological investigations into novel MMP-activated peptide-based prodrugs of methotrexate as potential cancer therapeutics
No full textMethotrexate (MTX) is an antimetabolite anticancer agent that is used in treatment of multiple cancers, such as acute lymphoblastic leukaemia and osteosarcoma. A lack of selective tumour toxicity is one of the major problems associated with MTX chemotherapy, especially when given at high doses, as in high dose MTX (HDMTX) therapy. MTX causes various toxicity problems including life-threatening nephrotoxicity, haematological toxicity and neurotoxicity. Overcoming this toxicity is of great importance and has been attempted in various ways, not least via the design of prodrugs.
The concept of tumour protease, and specifically matrix metalloproteinase (MMP), activated prodrugs was the focus of the work described in this thesis. This concept relies upon attachment of an MMP-sensitive peptide sequence to a specific site in a drug structure, so as to inactive it. The activity of the parent drug is restored once it is activated by the MMPs in the tumour microenvironment. In this work, different MMP-sensitive peptide sequences linked to MTX were synthesised, resulting in 63 MTX prodrugs.
The MMP-mediated activation of these conjugates in tumour tissues (specifically HT1080 homogenates) ex vivo was assessed and the results were compared to the activation of these conjugates in various normal tissues specifically liver, kidney and lung. Specific criteria were established for the selection of promising conjugates for more detailed study. From 7 promising compounds, compound 75 was identified as the lead prodrug, demonstrating selective MMP activation, as indicated by inhibition of its activation by broad spectrum MMP inhibitor ilomastat.
The pharmacokinetics of compound 75 was studied in tumour (HT1080) xenograft-bearing mice and the results were compared to those obtained from administration of equimolar doses of conventional MTX. Compound 75 led to enhanced tumour concentrations of MTX, with reduced exposure to normal tissues in vivo compared to conventional MTX therapy. Furthermore, the efficacy of equimolar doses of compound 75 and directly dosed MTX in reduction of HT1080 volume were compared. Superior antitumour activity was observed with compound 75 compared to MTX treatment.
Compound 75 is the first example of an MMP-activated prodrug to be reported with enhanced therapeutic index, as evidenced by a full in vivo pharmacokinetic analysis and normal tissue metabolism data.
The data presented in thesis support the concept of MMP-activated prodrug development, and form a strong foundation upon which to develop a clinically-useful MTX prodrug, with the potential to enhance efficacy and reduce toxicity to the patient.Libyan governmentThe full text will be available after the extended embargo: 5th March 202
Design, synthesis and in vitro biological evaluation of potential polysialyltransferase (ST8SiaII) inhibitors
No full textThe full text will be available at the end of the embargo period: 5th March 202
Synthesis and Chemistry of Novel Aryl Sulfonamides and Initial Studies of Their Biological Activity
No full textThe full text will be available at the end of the embargo: 21st Jan 202