Optimisation of immune effector function within the tumour microenvironment

Cancer represents a leading of cause of death in the developed world, inflicting tremendous suffering and plundering billions from health budgets. The traditional treatment approaches of surgery, radiotherapy and chemotherapy have achieved little in terms of cure for this deadly disease. Instead, life is prolonged for many, with dubious quality of life, only for disease to reappear with the inevitable fatal outcome. “Blue sky” thinking is required to tackle this disease and improve outcomes. The realisation and acceptance of the intrinsic role of the immune system in cancer pathogenesis, pathophysiology and treatment represented such a “blue sky” thought. Moreover, the embracement of immunotherapy, the concept of targeting immune cells rather than the tumour cells themselves, represents a paradigm shift in the approach to cancer therapy. The harnessing of immunotherapy demands radical and innovative therapeutic endeavours – endeavours such as gene and cell therapies and RNA interference, which two decades ago existed as mere concepts. This thesis straddles the frontiers of fundamental tumour immunobiology and novel therapeutic discovery, design and delivery. The work undertaken focused on two distinct immune cell populations known to undermine the immune response to cancer – suppressive T cells and macrophages. Novel RNAi mediators were designed, validated and incorporated into clinically relevant gene therapy vectors – involving a traditional lentiviral vector approach, and a novel bacterial vector strategy. Chapter 2 deals with the design of novel RNAi mediators against FOXP3 – a crucial regulator of the immunosuppressive regulatory T cell population. Two mediators were tested and validated. The superior mediator was taken forward as part of work in chapter 3. Chapter 3 deals with transposing the RNA sequence from chapter 2 into a DNA-based construct and subsequent incorporation into a lentiviral-based vector system. The lentiviral vector was shown to mediate gene delivery in vitro and functional RNAi was achieved against FOXP3. Proof of gene delivery was further confirmed in vivo in tumour-bearing animals. Chapter 4 focuses on a different immune cell population – tumour-associated macrophages. Non-invasive bacteria were explored as a specific means of delivering gene therapy to this phagocytic cell type. Proof of delivery was shown in vitro and in vivo. Moreover, in vivo delivery of a gene by this method achieved the desired immune response in terms of cytokine profile. Overall, the data presented here advance exploration within the field of cancer immunotherapy, introduce novel delivery and therapeutic strategies, and demonstrate pre-clinically the potential for such novel anti-cancer therapies.

Does attendance affect grade? An analysis of first year economics students in Ireland

This paper examines the relationship between attendance and grade, controlling for other factors, in first year economics courses in University College Cork. Determinants of both class attendance and grade are specified and estimated. We find that attendance is low, at least by comparison with US evidence. Hours worked and travel time are among the factors affecting class attendance. Class attendance, and especially tutorial attendance has a positive and diminishing marginal effect on grade, while hours worked in a part-time job have a significant negative effect on grade.

The role of synchronization in digital communications using chaos - Part II: Chaotic modulation and chaotic synchronization.

For pt. I see ibid., vol. 44, p. 927-36 (1997). In a digital communications system, data are transmitted from one location to another by mapping bit sequences to symbols, and symbols to sample functions of analog waveforms. The analog waveform passes through a bandlimited (possibly time-varying) analog channel, where the signal is distorted and noise is added. In a conventional system the analog sample functions sent through the channel are weighted sums of one or more sinusoids; in a chaotic communications system the sample functions are segments of chaotic waveforms. At the receiver, the symbol may be recovered by means of coherent detection, where all possible sample functions are known, or by noncoherent detection, where one or more characteristics of the sample functions are estimated. In a coherent receiver, synchronization is the most commonly used technique for recovering the sample functions from the received waveform. These sample functions are then used as reference signals for a correlator. Synchronization-based coherent receivers have advantages over noncoherent receivers in terms of noise performance, bandwidth efficiency (in narrow-band systems) and/or data rate (in chaotic systems). These advantages are lost if synchronization cannot be maintained, for example, under poor propagation conditions. In these circumstances, communication without synchronization may be preferable. The theory of conventional telecommunications is extended to chaotic communications, chaotic modulation techniques and receiver configurations are surveyed, and chaotic synchronization schemes are described

Athletic groin pain (part 2): a prospective cohort study on the biomechanical evaluation of change of direction identifies three clusters of movement patterns

Background: Athletic groin pain (AGP) is prevalent in sports involving repeated accelerations, decelerations, kicking and change-of-direction movements. Clinical and radiological examinations lack the ability to assess pathomechanics of AGP, but three-dimensional biomechanical movement analysis may be an important innovation. Aim: The primary aim was to describe and analyse movements used by patients with AGP during a maximum effort change-of-direction task. The secondary aim was to determine if specific anatomical diagnoses were related to a distinct movement strategy. Methods: 322 athletes with a current symptom of chronic AGP participated. Structured and standardised clinical assessments and radiological examinations were performed on all participants. Additionally, each participant performed multiple repetitions of a planned maximum effort change-of-direction task during which whole body kinematics were recorded. Kinematic and kinetic data were examined using continuous waveform analysis techniques in combination with a subgroup design that used gap statistic and hierarchical clustering. Results: Three subgroups (clusters) were identified. Kinematic and kinetic measures of the clusters differed strongly in patterns observed in thorax, pelvis, hip, knee and ankle. Cluster 1 (40%) was characterised by increased ankle eversion, external rotation and knee internal rotation and greater knee work. Cluster 2 (15%) was characterised by increased hip flexion, pelvis contralateral drop, thorax tilt and increased hip work. Cluster 3 (45%) was characterised by high ankle dorsiflexion, thorax contralateral drop, ankle work and prolonged ground contact time. No correlation was observed between movement clusters and clinically palpated location of the participant's pain. Conclusions: We identified three distinct movement strategies among athletes with long-standing groin pain during a maximum effort change-of-direction task. These movement strategies were not related to clinical assessment findings but highlighted targets for rehabilitation in response to possible propagative mechanisms. Trial registration number NCT02437942, pre results.

Public policies and work integration social enterprises: the challenges of institutionalism in a neoliberal era.

One particular field of Social Enterprise – WISEs or Work Integration Social Enterprises – has become increasingly recognised as being emblematic of the dynamics of social enterprises and now constitutes a major sphere of their activity globally. From their early roots, focusing on providing productive activity for the blind and those with other physical and/or intellectual disabilities, WISEs are pioneers in promoting the integration of excluded persons through a productive activity. In recent decades, WISEs have incrementally evolved as a tool for implementing national and regional labour market policies. The papers in this special edition explore how populations of WISEs in different country contexts have emerged, and in some instances, shifted in their identities over time in relation to changing national or regional public policies. This special issue is part of the ICSEM project, a worldwide research project aiming to identify, analyze and compare social enterprise models across countries, regions and fields. The special issue features five country specific analyses from the first stage of the ICSEM project where researchers focusing on WISEs examined the policy environment surrounding WISEs and the heterogeneity of the organizational WISE models that have emerged in different contexts: Ireland, the United States, Japan, Austria and Switzerland.