Cancer is a major cause of morbidity and mortality affecting populations in all countries and all regions. Breast cancer (BC) is the second leading cause of cancer death among women in the UK. Although the overall survival of BC has been significantly improved due to systemic therapy in early BC, the treatment of advanced/metastatic BC remains a major challenge. The main limitation of therapeutic failure is the de novo and acquired resistance of BC cells to conventional anticancer drugs. Cancer stem cells (CSCs) have been thought to be responsible for the chemoresistance. My study demonstrated that mammospheres manifested CSC characteristics and are highly resistant to several first line anti-BC drugs. This may be due to the hypoxia in the centre of the spheres. Transfection of BC cells with NFκB p65 induces CSC characters and chemoresistance. Therefore hypoxia-induced activation of NFκB could lead to escape of CSCs from apoptosis and regenerate the tumour after conventional chemotherapy. In clinic, the relapsed cancer is commonly pan-resistant to various drugs. Development of CSCs-targeting drug will be significantly important in clinic for cancer patients. Disulfiram (DS) is a commercially available anti-alcoholism drug with strong cytotoxicity in a wide range of cancer types and has a reversing II effect on chemoresistance. In this study, the anticancer efficacy of DS on cancer cell lines and CSCs was investigated. DS was highly cytotoxic to BC cell lines in vitro in a copper (Cu)-dependent manner. CI-isobologram analysis demonstrated a synergistic effect between DS/Cu and paclitaxel (PAC) in BC cell lines. DS/Cu induces reactive oxygen species (ROS), activates JNK and p38 pathways and simultaneously inhibits NFκB activity in BC cell lines. DS/Cu may trigger intrinsic apoptotic pathway via modulation of the Bcl2 family. The in vitro clonogenicity and sphere-forming ability of BC cell lines were inhibited by DS/Cu. The common stem cell markers such as aldehyde dehydrogenase (ALDH) and CD24-/CD44+ as well as Nanog, Sox2, and Oct4 were also suppressed. In PAC resistant cell line, DS abolished CSC characters and completely reversed PAC resistance. Lipo-DS blocked NFκB activation and specifically targeted CSCs in vitro. Lipo-DS also targeted CSC population in vivo and showed very strong anticancer efficacy. This study elucidated the role of NFB in bridging hypoxia with CSC-related chemoresistance. It also investigated the fundamental anticancer mechanisms of DS. The results derived from this study indicate that further study may be able to translate DS into cancer therapeutics in the future.

Sammanfattning Syftet med föreliggande studie är att undersöka skolpersonals uppfattningar och upplevelser kring likabehandlingsarbetet och utbildningar med Friendsprogrammet under det första året programmet implementerats. Vidare ämnar studien undersöka skolpersonalens tolkning av Friendsprogrammets vision avseende att utmana normer. Data samlades in genom fyra kvalitativa semistrukturerade intervjuer med skolpersonal på en skola i ett litet samhälle utanför en mellanstor kommun i Sverige. Resultatet visade att skolan inte börjat med det aktiva likabehandlingsarbetet genom Friendsprogrammet. Detta utifrån negativa kontextuella förutsättningar som lett till att likabehandlingsarbetet bortprioriteras, såsom personalbrist, hög personalomsättning och otydligt ledarskap. Dock identifierades även positiva kontextuella förutsättningar som en stark personalgrupp och engagerad personal vilket tyder på att programmet kan implementeras i viss utsträckning. En slutsats som dras är att Friendsprogrammet i sin utveckling av programmet bör ha en ökad flexibilitet i sitt förhållningssätt. En överblick kring skolans kontextuella förutsättningar kan ge en mer fördjupad förståelse för skolans möjligheter kring likabehandlingsarbete. Studien är av relevans för att belysa hur Friendsprogrammet tas emot och implementeras i skolor - och därigenom skapa förutsättningar för att i slutändan utvärdera programmets effekt på mobbningsfrekvensen.

In May 2002 the National Institute for Clinical Excellence (NICE) made the recommendation that all pregnant women with an RhD negative blood type should be offered routine antenatal anti-D immunoglobulin (Ig) prophylaxis (RAADP). Midwives were the key professional group who would be involved in administration of anti-D Ig and yet they had little input to formation of policy and contributed little to the evidence base that informs policy and practice. A midwifery perspective is however important and relevant, and forms the basis of this work. The thesis comprises three distinct, but related, pieces of research: a survey conducted in 2005 to determine implementation of RAADP at UK maternity units; secondary analysis of anti-D Ig errors involving midwives that were reported to the Serious Hazards of Transfusion (SHOT) scheme in 2007/8; and focus group interviews conducted in 2010 to explore midwives’ views on issues that impact the care provided for women with an RhD negative blood type. The aim of the RAADP survey was to establish current {2005} policy in the United Kingdom in relation to the NICE recommendation for RAADP (NICE, 2002). The survey formed the foundation on which to build the thesis by determining that by 2005 RAADP had become an integral aspect of maternity care within the UK. However it also found that there were significant variations within local policies and among the information that was provided to pregnant women and healthcare professionals. The aim of the survey was to determine implementation of policy and not to explain findings, raising important questions which were used to inform the subsequent research. The second piece of research was secondary analysis of existing anti-D Ig error reports collated by SHOT. The analysis was unique in that it included only those errors involving midwives. The findings highlight both individual and organisational impact on errors, building on the findings of the RAADP survey. The research identified proximal errors, trigger events and fallible practices providing a framework within which the common pathways to error involving anti-D Ig can be understood. This will allow midwives to better understand and improve the care they provide. This piece of research also raised further questions about midwifery practice and those questions informed the focus group research. The focus group research aimed to consolidate the findings of the previous research by gaining direct input from midwives. Two focus group interviews were held, with clinical midwives as participants. The research found that the midwives and the organisations within which they worked provided care in line with policy and procedure at the apparent expense of a woman centred approach. This appeared to be linked to the midwives’ understanding of their responsibility, accountability and the education and information that underpinned the care they provided. The other important finding from the focus group research was that the midwives regarded RAADP as a less important intervention than they did anti-D Ig given following a potentially sensitising event (PSE) during pregnancy or given following delivery. When considered as a whole body of work, this research provides unique and valuable insight to midwifery involvement in the care of women with an RhD negative blood type. The research highlights the challenge of achieving government objectives for individualised, woman centred care within the present framework of clinical governance and evidence based care. In doing so it also raises questions about how individual midwives and the midwifery profession have engaged with medical colleagues and policy makers to maintain a midwifery context to the care they provide. Although the research findings relate to care provided for women with an RhD negative blood type the findings are pertinent to other aspects midwifery practice, particularly those originating within the medical profession that are now a routine part of midwifery care.

No description available.

Submitted in fulfillment of the requirements of the degree of Master of Applied Science in Chemistry, Durban University of Technology, 2015. / Human Serum Albumin (HSA) predominantly found in the blood plasma proteins, acts as a carrier for many drugs. In the present work binding interactions of eight arylpropionate non-steroidal anti-inflammatory drugs (NSAIDs) were studied with Human Serum Albumin HSA using Capillary Electrophoresis (CE) under physiological conditions. The concentration of HSA was kept constant (525 μM) whereas the drug concentrations were varied between 50-300 μM in each case. The Frontal analysis (FA) and Capillary Zone Electrophoresis (CZE) modes of CE were applied together with a mathematical modelling of the experimental results with a view to obtaining pharmacokinetic properties of each drug. The binding order of the drugs to HSA were established with the three methods together with the mathematical approach. Our studies revealed the presence of more than one binding sites for some of the available drugs. Additionally, molecular docking studies were conducted to establish the binding conformations of drugs in the binding pocket of the HSA. A very good correlation between the computed binding energies (docking) and the experimental binding constants were observed throughout this study. The logK values for all eight drugs were ranging from 3.37 - 4.56 for FA, 3.16 – 4.39 for CZE, and 3.48 – 5.30 for computational studies. / M

published_or_final_version / Medicine / Doctoral / Doctor of Philosophy

published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy

published_or_final_version / abstract / Humanities / Master / Master of Philosophy

In the past 15-20 years, advances in antibody engineering have facilitated the generation and isolation of monoclonal antibodies (mAbs) to a wide array of antigens. Consequently, mAbs have become essential therapeutic tools and currently dominate the global protein therapeutics market. The engineering of anti-infective antibodies, however, has proven quite a challenge, despite the fact that antibodies were naturally evolved to fight infections. The identification of suitable antigens, the mode of administration and the high cost associated with the production of antibody therapeutics are some of the major hurdles for the progress of anti-infective antibodies. This dissertation addresses issues concerning the development of anti-infective antibodies against two different pathogens: SARS coronavirus (CoV) and two pathogenic species of Burkholderia bacteria. To investigate the role of affinity in viral neutralization and evolution of escape mutants, we first sought to isolate an antibody with high affinity towards the receptor binding domain (RBD) of SARS-CoV. Following high-throughput screening of a library of random mutants via the APEx display system, we isolated antibodies with affinities in the range of 0.8 nM - 0.1 nM. The affinity was further improved by additional mutagenesis and DNA shuffling, and a high affinity variant (45pM) with ~300-fold improvement over the parental antibody was isolated. Evaluation of these antibodies in an in vitro assay demonstrated that neutralization of wild-type Urbani strain of SARS-CoV correlates well with the affinity of the antibody, with higher affinity leading to greater neutralization. Moreover, the antibody exhibiting the highest affinity could neutralize SARS-CoV escape mutants that evaded neutralization by both parental and lower affinity antibodies. Another important aspect for the development of anti-infective antibodies concerns the identification of suitable antigen targets to be used in the isolation of antibodies. In an effort to develop a high-throughput screening method for the isolation of antibodies to a wide array of antigens, we used a synthetic antibody (Fab) library constructed by a minimalist approach and displayed on the surface of filamentous bacteriophage. The library was screened against antigens from Burkholderia pseudomallei and Burkholderia mallei. After only three rounds of selection and enrichment against five different antigens, we obtained Fabs specific to four of the antigens as confirmed by ELISA. These results not only demonstrate the use of a synthetic antibody library for the isolation of antibodies against infectious pathogens, but also its feasibility, and potential applicability as a high-throughput screen for a variety of antigens. / text

This thesis explores how Anti-Japanese War Drama in Chinese TV becomes a field of negotiation in which the forces of dominant state ideology, liberal market and alternative discourses meet. Focusing how the notion of Chinese nationalism has been constructed in the negotiation, this work examines TV dramas as a homogenizing national project in which market forces and state intervention are no longer at odd with each other. By critically reading representations and narratives of bandits and women in two dramas To Advance towards the Fire and Auntie Duohe, the study points out how dominant nationalist discourses attempt to incorporate the marginalized or disadvantaged group as a consistent part of the nation. However, the anti-Japanese war dramas still allow a space for the alternative discourse to emerge which disturbs the perceived coherence of the nation. / text