Immune checkpoint inhibitors in renal cell carcinoma

The immune system has long been known to play a critical role in the body's defence against cancer, and there have been multiple attempts to harness it for therapeutic gain. Renal cancer was, historically, one of a small number of tumour types where immune manipulation had been shown to be effective. The current generation of immune checkpoint inhibitors are rapidly entering into routine clinical practice in the management of a number of tumour types, including renal cancer, where one drug, nivolumab, an anti-programmed death-1 (PD-1) monoclonal antibody (mAb), is licensed for patients who have progressed on prior systemic treatment. Ongoing trials aim to maximize the benefits that can be gained from this new class of drug by exploring optimal timing in the natural course of the disease as well as combinations with other checkpoint inhibitors and drugs from different classes

Joyful expressions in infancy : cross-species comparisons

Joyful expressions of one-year-old infants were studied in naturalistic contexts in infants’ home environments. Chimpanzee infants (n = 7) and human infants from the Cameroon Nso community (n = 8) were studied in their own right and in comparison. Similar methodologies and the development of a single coding scheme allowed direct comparisons between the groups. The research aims to contribute to knowledge about 1) emotion socialisation; 2) the whole-body expression of emotions in infancy; 3) the evolutionary heritage of emotions; and 4) the functions of joyful emotions. Playful behaviours were analysed for play type, infant joy (facial, motor, and vocal1), play partners and their engagement, and matching of infant joy by play partners. The first study (Chapter 4) describes the play contexts of chimpanzee infants from two settings (Chester Zoo, UK, and Primate Research Institute (PRI), Japan), as there was little published quantitative data specific to one-year-old chimpanzees. Play contexts were similar across settings though the proportion of time spent in the different types of social play varied with more rough-and-tumble play at Chester Zoo (larger group, juveniles present) and more tickling by mothers at PRI. The second study (Chapter 5) describes the joyful expressions of chimpanzee infants. Facial and motor joy occurred at similar rates overall though the rate of facial joy was skewed towards social contact and tickling play to a greater degree than motor joy. Mothers elicited a particularly high rate of infant joy (often during tickling) but peers matched a greater proportion of infant joy (often during contact play). The third study (Chapter 6) describes the joyful. Vocal joy was analysed for human sample only expressions of human infants. Facial, motor, and vocal joy occurred at similar rates overall though rates of facial joy and vocal joy were skewed towards social communicative and rhythmic play to a greater degree than was motor joy. Play partners matched a greater proportion of infant joy during social communicative and rhythmic play and social object exchange than during other types of social play. The fourth study (Chapter 7) compares the joyful expressions of chimpanzee infants and human infants. The rate of facial joy was equivalent in both groups despite differences in the contexts of play, underlining the importance of joy to infant development in both species. Differences were evident in the rate of motor joy (higher in the human sample) and in matching of infant joy (marginally higher in the human sample, variation by play partners). The general discussion highlights key findings in relation to the socialisation of joy (e.g. the high rates of joy during play contexts which support social cohesion, the different roles of mothers and peers/older children in eliciting and responding to infant joy) and the whole body expression of joy (the distinctive patterns of facial, motor and vocal joy across social and solitary play contexts). Findings are discussed in relation to theories about the functions of joy.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Investigating the linkage between Trypanosoma brucei pleomorphism and antigen switch frequency

African trypanosome infections are characterised by antigenic variation to avoid host immunity and by the production of transmission stages to promote disease spread. Laboratory-adapted (‘monomorphic’) lines of Trypanosoma brucei are reported to switch their expressed VSG antigenic coat at a much lower frequency than ‘pleomorphic’ populations recently transmitted through tsetse flies. These laboratory-adapted parasites also lose the capacity to differentiate into transmission competent ‘stumpy forms’. It is unclear if the reduced rate of antigenic variation is directly coupled to the loss of pleomorphism or whether the processes, although co-selected by multiple passage, are independent. To address whether monomorphism caused a concomitant change in the frequency of antigenic variation, an ‘inducible monomorphism’ model was exploited. This exploited pleomorphic RNAi cell lines that would inducibly silence genes required for stumpy formation. This provided a tool to switch pleomorphism ‘on’ or ‘off’ inducibly, without long term passage. Thereafter, two approaches were used to ask if the induction of monomorphism directly influenced antigenic variation: in vitro flow cytometry-based VSG switch assays, and VSGseq, a targeted sequencing approach. These assays demonstrated that the induction of monomorphism did not reduce VSG switch rate nor generate a reduction in expressed VSG diversity, or change the expressed VSG subset. To extend this analysis further, the prolonged in vitro passage of a pleomorphic cell line was used to select isogenic monomorphic populations with reduced capacity to generate stumpy forms. These selected monomorphs cells did not exhibit a reduction in VSG switch rate compared to the parental pleomorphic population, thus corroborating the observations with the induced monomorphic cells. To understand the loss of pleomorphism in the selected cells, an ‘evolve and resequence’ approach and RNAseq analysis was adopted. Interestingly, the ‘selected monomorphs’ were depleted of transcripts whose expression was associated with the stumpy and insect forms of the parasite. Particularly, a number of CCCH zinc finger proteins, such as ZC3H20, were significantly downregulated. These RNA-binding proteins could represent novel regulators of slender to stumpy differentiation. Overall our results demonstrate that T. brucei antigen switch frequency and pleomorphism can be uncoupled, and provide new insight into the molecular control of stumpy formation

Novel strategies to prevent and treat experimental pneumococcal disease

With over 90 different serotypes of Streptococcus pneumoniae unevenly distributed around the world, current vaccine formulations vary significantly in their ability to protect against invasive pneumococcal disease (IPD). The adult pneumococcal vaccine is composed of capsular polysaccharide from 23 of the most prevalent disease causing serotypes. Purely polysaccharide vaccines are unable to protect those most at risk; infants under the age of two. This has led to the development of a paediatric conjugate vaccine, composed of capsular polysaccharide from seven of the most common disease causing serotypes, each chemically conjugated to a carrier protein. Although efficacious at protecting the target age group from disease caused by homologous serotypes, it fails to protect against the non-vaccine serotypes. Serotype specific vaccination is a short-term solution to pneumococcal disease. As the most common serotypes are eradicated by vaccination, previously less common serotypes fill the vacant niche and cause serotype replacement disease. A solution to this problem would be the development of pneumococcal vaccines containing antigens that elicit non-serotype specific protection. Pneumolysin, the pore-forming toxin produced by S. pneumoniae, may play a role in future pneumococcal vaccine. It is a major virulence factor produced by all invasive isolates and has previously been demonstrated to confer non- serotype specific protection. In this thesis, pneumolysin retained the ability to bind to cell membranes and form pores even when other antigens were fused genetically to the N terminus. Pneumolysin performed as a highly immunogenic mucosal adjuvant, with substantial mucosal and systemic immune responses to the fused antigen, when nanograms quantities when applied to the mucosal surface of the nasopharynx. A fusion between pneumococcal surface adhesin A (PsaA) and pneumolysin (PLY) was created to investigate potential protection conferred by the antigen specific response. Vaccination of Balb/c and MF1 mice with PsaAPLY conferred no protection against challenge with virulent S. pneumoniae TIGR4. The toxicity of pneumolysin is problematic and existing pneumolysin mutants possess residual cytotoxicity. By ablating the toxicity of pneumolysin with formalin it permits its use in parental vaccines. The pneumococcal histidinetriad proteins (Pht) are a recently identified family of surface exposed proteins that have homologues in other Streptococcus species and are therefore novel potential vaccine candidates. In vivo models of disease require the sacrifice of a large number of animals at time points to investigate the impact of vaccine or pharmaceuticals on disease progression. Real-time photonic imaging of bioluminescent bacteria offers significant advantages over conventional methods for monitoring and combating bacterial disease in animals. Not only does this approach reduce the time and costs associated with such experiments, but also it considerably reduces the number of animals used. Furthermore, because bioluminescent imaging allows the same group of animals to be monitored over time, animal-to-animal variations are overcome by including the zero time point as an internal control. Models of pneumococcal pneumonia were established in MF1 mice. Newly established bioluminescent models were then used to investigate the impact of vaccination with the paediatric pneumococcal conjugate vaccine as proof of principle

The school experience of Malay adolescent with conduct issues

This research is designed to explore how Malay adolescents who have been identified with conduct issues understand their school experiences. This research is a qualitative research, which utilized Interpretative Phenomenological Analysis (IPA) as an analysis method. Ten participants were recruited from a rehabilitation center for young offenders in Malaysia. Each participant completed at least two semi-structured interviews. The interviews were digitally recorded, transcribed, translated and analyzed for content. Through the emerging themes namely subject-oriented, issues pertaining to English as a medium of instruction, the nature of the school, inconsistency between personal interests and what the school has to offer, experiencing teaching and learning issues and individual differences related to school experiences, analysis suggest that participants felt disadvantaged by the school system. They felt that the education policies and school environment were irrelevant and unresponsive to their capabilities, needs, desires and interests. Thus, apart from benefiting people who work closely with these adolescents, this research provides the voice for the participant so that they feel heard

OPTIMA Case Study 4 : Scotland Pilot of The Brilliant Club

The Brilliant Club is an award-winning charity that exists to increase the number of pupils from under-represented background progressing to highly-selective universities. They do this by mobilizing the PhD community to share its academic expertise with state schools. Helen Parker and Adeel Shafi were chosen to be the first PhD researchers to pilot The Brilliant Club in Scotland, at Holyrood and Hyndland Secondary Schools

The self‐reference effect in attention deficit hyperactivity disorder

The self‐memory system depends on the prioritization and capture of self‐relevant information, so may be disrupted by difficulties in attending to, encoding and retrieving self‐relevant information. The current study compares memory for self‐referenced and other‐referenced items in children with ADHD and typically developing comparison groups matched for verbal and chronological age. Children aged 5–14 (N = 90) were presented with everyday objects alongside an own‐face image (self‐reference trials) or an unknown child's image (other‐referenced trials). They were asked whether the child shown would like the object, before completing a surprise source memory test. In a second task, children performed, and watched another person perform, a series of actions before their memory for the actions was tested. A significant self‐reference effect (SRE) was found in the typically developing children (i.e. both verbal and chronological age‐matched comparison groups) for the first task, with significantly better memory for self‐referenced than other‐referenced objects. However, children with ADHD showed no SRE, suggesting a compromised ability to bind information with the cognitive self‐concept. In the second task, all groups showed superior memory for actions carried out by the self, suggesting a preserved enactment effect in ADHD. Implications and applications for the self‐memory system in ADHD are discussed

The familial experiences of Malay adolescents with conduct issues: an interpretative phenomenological analysis IPA

This research explores how Malay adolescents with behavioural issues make sense of their family life experiences. This research utilised Interpretative Phenomenological Analysis (IPA). This research involved eight (8) Malay male participants, aged between 16 and 18 years. The participants who were selected through purposive sampling were recruited from a rehabilitation centre for young offenders in Malaysia. The participants attended at least two semi-structured interview sessions. Each interview session was conducted in Malay, and each session lasted between 50 and 60 minutes. These interviews, which were digitally audiotaped, were then transcribed, checked and verified accordingly, translated from Malay into English, and analysed using the IPA method. The results suggest that the participants understanding of their family lived experiences is constructed reflective to the complex relationship between the traditional Malay cultures, values, beliefs and practices, which are much influenced by Islamic teaching, the emergent new values and worldviews associated with globalisation and modernisation. Through the emerging themes, the participants pictured that the interactions between family members, parents were essential to them. But their interpretation of such interactions had conflicting values with the normality of the local belief and practices, which played roles in their criminal engagement. Thus, it can be understood that these affected adolescents were not necessarily problematic internally, but they just reacted to the changing context around them, especially to their family institution