Inhibitors of the Fanconi Anaemia pathway as potential antitumour agents for ovarian cancer

The Fanconi anaemia (FA) pathway is an important mechanism for cellular DNA damage repair, which functions to remove toxic DNA interstrand crosslinks. This is particularly relevant in the context of ovarian and other cancers which rely extensively on interstrand cross-link generating platinum chemotherapy as standard of care treatment. These cancers often respond well to initial treatment, but reoccur with resistant disease and upregulation of DNA damage repair pathways. The FA pathway is therefore of great interest as a target for therapies that aim to improve the efficacy of platinum chemotherapies, and reverse tumour resistance to these. In this review, we discuss recent advances in understanding the mechanism of interstrand cross-link repair by the FA pathway, and the potential of the component parts as targets for therapeutic agents. We then focus on the current state of play of inhibitor development, covering both the characterisation of broad spectrum inhibitors and high throughput screening approaches to identify novel small molecule inhibitors. We also consider synthetic lethality between the FA pathway and other DNA damage repair pathways as a therapeutic approach

The case for internalising externalities in a sustainable rail asset base

Although the concept of sustainability and Sustainable development has tended to be mostly associated with the management of natural resources and the consequent environmental impact, the most accepted definition draws together its social, economic and environmental dimensions. The rail industry, as provider of a low carbon transport system, is well placed to have a significant role to play in promoting an environmental, economic and social balance that can be sustained and afforded for the foreseeable future. The paper suggests that a more comprehensive perspective on the scope of a sustainable intervention in rail infrastructure assets is needed, arguing that the necessary whole life evaluation process should include an additional positive externality: the uplift in knowledge, skill and expertise that comes about as a result of participation in projects and programmes. The inclusion of this benefit would provide a more accurate representation of value to support investment decision making and strengthen the case for a broader funding base. And that the demonstration of the correlation between participation in projects and programmes and the consequent uplift in skill, knowledge and expertise could be used to shift the emphasis in rail project planning

Towards a shift of values in rail infrastructure project evaluation

The rail industry, despite its iconic value and status as a key economic infrastructure, faces significant challenges today: An ageing, historically underinvested system has had to accommodate an unprecedented increase in demand with limited financial resources at its disposal. Now, following the Covid pandemic the same historically underinvested infrastructure has had to address the reality of an unprecedented reduction. In order to meet these polarised challenges, brought sharply into focus by its imminent restructuring (initiated by the recent White Paper) it needs more than ever, to harness the positive socio-economic impact of its interventions on its key resource: its human potential. In this work the author argues that the value of enhanced skill, knowledge and expertise derived from projects should be recognised and incorporated into more meaningful evaluations of project viability and sustainability. The argument draws on the notions of sustainability, the nature of the asset base and a more comprehensive whole life evaluation to inform and make this case. It has been supported through the use of surveys and interviews, within the context of case studies, in order to represent the nature of the relationship between participation in projects and the enhancement of expertise. The findings describe both a strong relationship (80% agreement and strong agreement) between project participation and expertise enhancement as well as providing indications of some of its key qualities. Adding support to the assertion that there is a necessary and contributory causal relationship between project participation and the enhancement of the expertise of the participants. The Interviews, based on grounded theory, also provide further insights through the identification and distillation of themes which emerge as integral to this process and are consistent with the concepts drawn out from the notion of a sustainable intervention in rail assets. Supported by these findings the author concludes that the value derived from harnessing the potential of its key resource in this way needs greater recognition and to be incorporated into a more comprehensive calibration of project value. A more comprehensive form of whole life evaluation, which made greater accommodation of externalities, while at the same time recognising that rather than being an external attribute of asset value, the enhancement of skill, knowledge and expertise is, in fact, intrinsic to it. A recognition requiring a significant shift of emphasis in the realm of project evaluation and governance in order to ensure its rightful place in the effective incorporation and deployment of asset valu

An educational framework for a post-capitalist world? A review of the 2021 report from UNESCO's International Commission of the Futures of Education

The title of this recent report from UNESCO published in 2021 is, Reimagining our futures together: A new social contract for education (UNESCO, 2021). The report is the third of its kind commissioned by UNESCO, since its foundation in November 1945. The first of these was the Faure Commission report in 1972, Learning to Be: The World of Education Today and Tomorrow (UNESCO, 1972) followed by the Delour’s report in 1996, titled Learning: The Treasure Within (UNESCO, 1996). This most recent report has been prepared by the International Commission on the Futures of Education, led by Her Excellency Madame Sahle-Work Zewde, President of the Federal democratic Republic of Ethiopia. The consultation process took place over a two-year period, involving over one million participants, and also involved the commissioning of a series of working papers. The report goes beyond the timescale of the 2016 report, Education 2030: Incheon Declaration and Framework for Action for the implementation of Sustainable Development Goal 4: Ensure inclusive and equitable quality education and promote lifelong learning opportunities for all (UNESCO, 2016) and looks to 2050 with the aim of being able to anticipate and shape both nearer and more distant futures

Apparent Activation Energies Associated with Protein Dynamics on Hydrophobic and Hydrophilic Surfaces

AbstractWith the use of single-molecule total internal reflection fluorescence microscopy (TIRFM), the dynamics of bovine serum albumin (BSA) and human fibrinogen (Fg) at low concentrations were observed at the solid-aqueous interface as a function of temperature on hydrophobic trimethylsilane (TMS) and hydrophilic fused silica (FS) surfaces. Multiple dynamic modes and populations were observed and characterized by their surface residence times and squared-displacement distributions (surface diffusion). Characteristic desorption and diffusion rates for each population/mode were generally found to increase with temperature, and apparent activation energies were determined from Arrhenius analyses. The apparent activation energies of desorption and diffusion were typically higher on FS than on TMS surfaces, suggesting that protein desorption and mobility were hindered on hydrophilic surfaces due to favorable protein-surface and solvent-surface interactions. The diffusion of BSA on TMS appeared to be activationless for several populations, whereas diffusion on FS always exhibited an apparent activation energy. All activation energies were small in absolute terms (generally only a few kBT), suggesting that most adsorbed protein molecules are weakly bound and move and desorb readily under ambient conditions

Towards a shift of values in rail infrastructure project evaluation

The rail industry, despite its iconic value and status as a key economic infrastructure, faces significant challenges today: An ageing, historically underinvested system has had to accommodate an unprecedented increase in demand with limited financial resources at its disposal. Now, following the Covid pandemic the same historically underinvested infrastructure has had to address the reality of an unprecedented reduction. In order to meet these polarised challenges, brought sharply into focus by its imminent restructuring (initiated by the recent White Paper) it needs more than ever, to harness the positive socio-economic impact of its interventions on its key resource: its human potential. In this work the author argues that the value of enhanced skill, knowledge and expertise derived from projects should be recognised and incorporated into more meaningful evaluations of project viability and sustainability. The argument draws on the notions of sustainability, the nature of the asset base and a more comprehensive whole life evaluation to inform and make this case. It has been supported through the use of surveys and interviews, within the context of case studies, in order to represent the nature of the relationship between participation in projects and the enhancement of expertise. The findings describe both a strong relationship (80% agreement and strong agreement) between project participation and expertise enhancement as well as providing indications of some of its key qualities. Adding support to the assertion that there is a necessary and contributory causal relationship between project participation and the enhancement of the expertise of the participants. The Interviews, based on grounded theory, also provide further insights through the identification and distillation of themes which emerge as integral to this process and are consistent with the concepts drawn out from the notion of a sustainable intervention in rail assets. Supported by these findings the author concludes that the value derived from harnessing the potential of its key resource in this way needs greater recognition and to be incorporated into a more comprehensive calibration of project value. A more comprehensive form of whole life evaluation, which made greater accommodation of externalities, while at the same time recognising that rather than being an external attribute of asset value, the enhancement of skill, knowledge and expertise is, in fact, intrinsic to it. A recognition requiring a significant shift of emphasis in the realm of project evaluation and governance in order to ensure its rightful place in the effective incorporation and deployment of asset valu

Genetic Improvement of Software: a Comprehensive Survey

Genetic improvement uses automated search to find improved versions of existing software. We present a comprehensive survey of this nascent field of research with a focus on the core papers in the area published between 1995 and 2015. We identified core publications including empirical studies, 96% of which use evolutionary algorithms (genetic programming in particular). Although we can trace the foundations of genetic improvement back to the origins of computer science itself, our analysis reveals a significant upsurge in activity since 2012. Genetic improvement has resulted in dramatic performance improvements for a diverse set of properties such as execution time, energy and memory consumption, as well as results for fixing and extending existing system functionality. Moreover, we present examples of research work that lies on the boundary between genetic improvement and other areas, such as program transformation, approximate computing, and software repair, with the intention of encouraging further exchange of ideas between researchers in these fields

FANCD2 expression affects platinum response and further characteristics of high grade serous ovarian cancer in cells with different genetic backgrounds

High-grade serous ovarian cancer (HGSOC) is the most prevalent subtype of ovarian cancer and demonstrates 5-year survival of just 40%. One of the major causes of mortality is the development of tumour resistance to platinum-based chemotherapy, which can be modulated by dysregulation of DNA damage repair pathways. We therefore investigated the contribution of the DNA interstrand crosslink repair protein FANCD2 to chemosensitivity in HGSOC. Increased FANCD2 protein expression was observed in some cell line models of platinum resistant HGSOC compared with paired platinum sensitive models. Knockdown of FANCD2 in some cell lines, including the platinum resistant PEO4, led to increased carboplatin sensitivity. Investigation into mechanisms of FANCD2 regulation showed that increased FANCD2 expression in platinum resistant cells coincides with increased expression of mTOR. Treatment with mTOR inhibitors resulted in FANCD2 depletion, suggesting that mTOR can mediate platinum sensitivity via regulation of FANCD2. Tumours from a cohort of HGSOC patients showed varied nuclear and cytoplasmic FANCD2 expression, however this was not significantly associated with clinical characteristics. Knockout of FANCD2 was associated with increased cell migration, which may represent a non-canonical function of cytoplasmic FANCD2. We conclude that upregulation of FANCD2, possibly mediated by mTOR, is a potential mechanism of chemoresistance in HGSOC and modulation of FANCD2 expression can influence platinum sensitivity and other tumour cell characteristics

RFWD3 modulates response to platinum chemotherapy and promotes cancer associated phenotypes in high grade serous ovarian cancer

Background: DNA damage repair is frequently dysregulated in high grade serous ovarian cancer (HGSOC), which can lead to changes in chemosensitivity and other phenotypic differences in tumours. RFWD3, a key component of multiple DNA repair and maintenance pathways, was investigated to characterise its impact in HGSOC.Methods: RFWD3 expression and association with clinical features was assessed using in silico analysis in the TCGA HGSOC dataset, and in a further cohort of HGSOC tumours stained for RFWD3 using immunohistochemistry. RFWD3 expression was modulated in cell lines using siRNA and CRISPR/cas9 gene editing, and cells were characterised using cytotoxicity and proliferation assays, flow cytometry, and live cell microscopy. Results: Expression of RFWD3 RNA and protein varied in HGSOCs. In cell lines, reduction of RFWD3 expression led to increased sensitivity to interstrand crosslinking (ICL) inducing agents mitomycin C and carboplatin. RFWD3 also demonstrated further functionality outside its role in DNA damage repair, with RFWD3 deficient cells displaying cell cycle dysregulation, reduced cellular proliferation and reduced migration. In tumours, low RFWD3 expression was associated with increased tumour mutational burden, and complete response to platinum chemotherapy. Conclusions: RFWD3 expression varies in HGSOCs, which can lead to functional effects at both the cellular and tumour levels.<br/