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Background The use of high quality human biological samples with associated data and their effective life cycle management (biobanking) are increasingly critical to our understanding of the underlying mechanisms of disease and the development of diagnostics. However, despite much progress, the inadequate supply of quality samples and the excessive complexity in the organisation of biobanks is hampering biomedical research. This is partly due to a lack of unified methods and approaches being applied across samples’ life cycle: acquisition, sample processing, storage, provision and use. Organisation Strategic Tissue Repository Alliances Through Unified Methods (STRATUM) is a public-private, 18-month project to provide building blocks for a national biobanking solution that facilitates biomedical research. The project is funded by the private sector and the government, via the Technology Strategy Board. There are six partners: two UK pharmaceutical companies (AstraZeneca, GlaxoSmithKline), a clinical diagnostic SME (Lab21) and the universities of Manchester, Nottingham and Leicester. A Project Steering Committee, with overall oversight of STRATUM has representatives from each partner, the MRC, the Royal College of Pathologists, British In Vitro Diagnostics Association and Patients. Operationally a Project Lead is responsible for the co-ordination and overall delivery of the project with Work Package leads focusing on specific areas. As biobanking is so broad in its application, one of the key factors for the success of STRATUM is to engage with the wide variety of disciplines and groups across both the public and private sectors, which have an interest in or could be impacted by the deliverables. This engagement is essential for the exploitation of STRATUM, from the delivery of the building blocks for biobanking, and thence enable benefits to be delivered across R&D and healthcare in general. As such, all deliverables from STRATUM will be the result of extensive consultation with experts and the public in the relevant areas, which will be enabled by a communication specialist. Aim and Objectives The aim of STRATUM is to facilitate the co-ordination of biobanking to support innovative research, in the UK by addressing the problems defined above. It will increase the effectiveness of sample provision to ensure that UK research institutions, pharmaceutical, biotechnology and diagnostic companies have the ability to access the large numbers of well-characterised samples with data, currently being held in individual collections. It will result in operating to agreed standards and a cost model for sample life cycle management. Ultimately, this approach should enable diagnostic companies, either singly or in partnership with pharmaceutical firms and research institutes, to develop companion diagnostics that are critical to delivering the personalised healthcare agenda. Scope and Deliverables To achieve this, STRATUM aims to define a framework of policy in biobanking, which will focus on governance, access, infrastructure and ethical principles for biobanking. This framework will be based on existing best practice and consensus across the diverse range of stakeholders involved in biobanking. Overall, the project focuses on: assessing public opinion ( biobanking and the use of samples); developing standards (for tissue sample characterisation and life cycle management); creating network requirements (biobank catalogue/directory); exploring financial arrangements (cost model); defining consent templates and enabling engagement (through two-way communication). The scope for individual work packages’ is outlined below: Public Engagement • To investigate the acceptability to donate samples and towards different models of consent for the use of samples, with the general public • To explore the attitudes, including barriers and drivers, within the NHS and biobanking community in collecting tissues samples The outcome of these findings will enable and help define the policy. Policy • To deliver a biobanking policy that provides the framework for governance, infrastructure and standards for human biological sample life cycle management across the UK; thereby enabling processes to be established that amongst other things enable increased visibility of sample collections (and unidentifiable data) with rules of access to facilitate equitable sharing of samples across the value chain and to provide assurance to donors that their samples’ use will be maximised. Sample Life Cycle Management Standards • To deliver standards for the life cycle management of respiratory and generic samples, including derivatives (acquisition, processing, storage, disposal) • To publish the standards with a process for their adoption and maintenance, with metrics for measuring compliance with the standards, to be able to improve sample quality and provide feedback for continuous improvement in HBS life cycle management Register for Samples/Minimum Datasets • To deliver a user requirements document for a system that will enable collections of samples with associated metadata to be registered and viewed via a single, secure, web-based user interface • To evaluate existing and proposed platforms and their operating environments against the user requirements and provide recommendations on how the user requirements can be implemented, defined in the STRATUM Exploitation Plan • To define the minimum datasets i.e. meta data/attributes that describe and characterise collections, donors and samples (respiratory and generic samples) to support the creation of a sample collection inventory (for use as a data in the register) and a histo-library of characterised samples, enabling researchers to identify samples and select them for research, in accordance with the consent • To pilot the recommended datasets for respiratory collections to inform the development of a register Cost Model • To increase understanding of the overall costs associated with biobanking, identify hidden costs, highlight organisational models that work, and explore relationships between key variables (e.g. funding mechanisms and optimal access arrangements). • The analysis aims to make the costs and benefits of coordinating biobanking nationally more explicit, in order to develop an ‘ideal’ cost-model for a national research infrastructure that will be defined in a report that will be taken forward to the exploitation strategy and plan for STRATUM Consent • To define consent templates that are consistent with the outputs of the public engagement and policy If you would like further information about STRATUM, please do not hesitate to contact: Julie Corfield (Areteva) at juliecorfield@areteva.com

Doctoral Training Partnerships: a range of postgraduate training is funded by the Research Councils. For information on current funding routes, see the common terminology at https://www.ukri.org/apply-for-funding/how-we-fund-studentships/. Training grants may be to one organisation or to a consortia of research organisations. This portal will show the lead organisation only.

PI 3-kinases (PI3Ks) generate lipids in cell membranes, controlling many biological functions. The PI3K signalling axis is important, amongst others, in immune cell signalling and is one of the most frequently deregulated pathways in cancer. The lipids produced by PI3Ks coordinate the localisation and function of multiple effector proteins, which bind these lipids through specific lipid-binding domains. These include protein kinases of the Ser/Thr and the Tyr kinase families (such as Akt/PKB and Btk, respectively), adaptor proteins (such as Gab2) and regulators of small GTPases (GAPs and GEFs). Thus far, a large focus of PI3K studies has been on the protein kinase Akt/PKB as a downstream target of PI3K, largely because of the availability of phospho-specific antibodies that allow us to monitor the activation of this kinase and its downstream targets in a relatively straightforward manner. Because the majority of published studies focus on this area, this has given rise to the skewed view that the PI3K pathway 'equals' that of Akt/PKB. This is a gross simplification, and indeed, evidence is emerging for the importance of Akt-independent pathways of PI3K signalling. For example, PI3K can be oncogenically mutated and activated in cancer, but this does not necessarily correlate with an activation of Akt/PKB (Cancer Cell 2009:16:21). As mentioned above, Akt-independent PI3K pathways are known but their relative importance is most often not clear. It cannot be excluded that there are additional pathways downstream of PI3K that remain to be uncovered. This is a fundamental science project that aims to discover new signalling pathways of PI3K, with focus on the p110alpha (p110a) isoform of PI3K. For these studies, we will exploit the availability of a new mutant mouse line that we have generated (unpublished), which carries an inducible oncogenic p110a PI3K allele, and cell lines derived thereof. These studies will be complemented by other cell lines and new mutant mice that we have generated, which carry in-activating alleles of p110a and other PI3K isoforms. Other than providing mechanistic insight into a key signalling pathway, this fundamental science project is also anticipated to allow the identification of molecular alterations induced by p110a (oncogenic or wild-type) which can be used as biomarkers for cancer diagnosis and therapy.

This project seeks to understand the physiological basis of cachexia in African trypanosomiasis and its relationship to appetite control and body-weight regulation. African trypanosome infections cause cachexia in livestock and experimental animals. Although increased catabolism triggered by inflammatory cytokines is one factor in this condition, it is certainly not the only one and almost nothing is known about the energetic basis of cachexia in trypanosomiasis raising fundamental questions such as whether infected-hosts undergo suppression of appetite, increased resting metabolic rate, or reduced digestive efficiency. This project will use a mouse model of trypanosome infection and define longitudinal changes in energy budgets in relation to parasitaemia and body-weight. A preliminary study in our lab has already demonstrated that weight loss is directly attributable to anorexia that is most profound during a period lagging about 5 days beyond peak parasitaemia, and from which animals recover without any hyperphagic response. Therefore it appears that cachexia in trypansomiasis involves a loss of appetite. The fact that this inappetance lags beyond peak parasitemia suggests that it is not simply a consequence of malaise, but that the infection is interfering with specific cytokine and endocrine regulatory circuits controlling appetite. Therefore experimental trypanosome infections have the potential to offer new insights into the fundamental physiological mechanisms of appetite regulation. The project will involve three phases. 1. Using a standardised infection-host model, detailed measurements will be made of the components of energy balance including changes in food intake, energy excretion and hence assimilation efficiency, resting metabolic rate, body temperature and physical activity. These will be monitored using a combination of oxymax calorimetry (CLAMS) and vital view (Minimitter Inc) measures of telemetered body temperature and activity. The time course of changes in energy balance will be linked to the record of parasitamaemia. This will allow us to determine the primary disrupted aspects of energy balance that accompany the infection. 2. We will sacrifice mice at various stages in the infection. These will be used to generate tissues that will be used to further explore the mechanisms underpinning the disturbances in energy balance. In particular we will use in situ hybridisation of three key areas in the brain (the hypothalamus, the nucleus accumbens and the brain stem - including the VTA and nucleus of the solitary tract). In these areas we will explore the changes in gene expression of key neuropeptides know to mediate energy balance responses. These will include in the hypothalamus - neuropeptide Y, agouti-regulated protein, Pro-opiomelanocortin, Melanocortin 4 receptor, Suppressor of cytokine signalling 3, Leptin receptor, Orexin A and TNFalpha receptor 1. In the nucleus accumbens we will measure tyrosine hydroxylase and the dopamine receptors (DR1 and DR2) as well as the mu-opioid receptor. In the NTS we will measure leptin receptor and CCK receptors. This will cover aspects of both the hedonic and homeostatic control mechanisms known to control food intake and energy expenditure. 3. The parasite may exert its action through secretions that interact directly with the host regulation system or indirectly affect signalling molecules in the periphery that have the centrally mediated effect. We will use using fractionated conditioned medium in which trypanosomes have been raised inoculated at concentrations adjusted to parasitaemia equivalent load to explore the possibility that the parasite produces compounds that cause the changes characterised under phases 2 and 3. We will characterise these media and plasma from infected mice to identify mediators of anorexia using metabolomics and proteomics. This latter aspect provides the most prospect for novel target discovery.