Senior Recital:Rachel Devitt, Soprano Nancy Pounds, Piano

Kemp Recital Hall Saturday Evening November 20, 1999 7:00 P.M

Interrogating the relationship between the tumour microenvironment and its infiltrating immune cells in ovarian cancer

Ovarian cancer (OC) is the sixth most common cancer amongst women, with approximately 7,500 new cases diagnosed each year in the United Kingdom. The complex ovarian tumour microenvironment is poorly understood, while the nature and role of tumour-infiltrating NK cells in OC progression remains unclear. To analyse the cell type contexture of OC tissue, two single cell sequencing techniques were performed on omental tumour biopsies from patients with advanced OC. The scRNAseq analysis focused on portraying an immunogenic tumour microenvironment and determined the characteristics of a dysfunctional NK cell population, implying NK reactivation upon chemotherapy exposure. In contrast, scATACseq data identified significant epithelial tumour cell heterogeneity and demonstrated an increase in chromatin accessibility for oncogenes and transcription factors related to cancer stem cells following chemotherapy treatment. Utilising a large prospective cohort of OC patient samples, the phenotype and function of NK cells in peripheral blood, primary ovarian tumour and metastatic omental tumour was explored. Flow cytometric analysis has revealed that peripheral blood NK cells are activated in OC, while NK cell inhibition occurs following tumour infiltration. Results have shown the adaptations to NK cell receptors in advancing disease and the specific inhibitory NK features associated with poor patient outcomes. The OC NK cells demonstrated a reduced ability to proliferate and expand upon exposure to cells lacking HLA and secreted fewer cytokines than the non-cancerous control samples. Instead, the OC NK cells were highly cytotoxic towards K-562 cells and primary ovarian tumours. Interestingly, the NK cell cytotoxicity to primary ovarian tumours was dependent on the activation receptor, DNAM-1. The significance of DNAM-1 in the tumour-immune response was demonstrated, identifying it as a possible biomarker that can be used as a target for NK-mediated immunotherapy

Under expression of the Sonic Hedgehog receptor, Patched1 (PTCH1), is associated with an increased risk of local recurrence in squamous cell carcinoma of the vulva arising on a background of Lichen Sclerosus

OBJECTIVE:Dysregulation of the Hedgehog (Hh) pathway has been described in a variety of cancers, including cervical cancer, a disease which shares a common aetiology with vulval squamous cell carcinoma (VSCC). Here, we investigate a large number of primary VSCC cases for evidence of Hedgehog pathway activation and examine the implications of pathway activity on clinical outcomes in a cohort of patients with primary VSCC. METHODS:Archival histology blocks containing VSCC and histologically normal adjacent epithelium were retrieved from a cohort of 91 patients who underwent treatment for primary VSCC. Immunohistochemistry staining was undertaken to assess for the expression of key Hh pathway components (SHH, PTCH1, GLI1). A competing risks statistical model was used to evaluate the implications of the levels of key Hh pathway components on clinical outcomes. RESULTS:We show that 92% of primary VSCC cases over-expressed one or more components of the Hh signalling pathway when compared to the adjacent normal epithelium. While expression of SHH and GLI1 did not correlate with any clinicopathological criteria, over- or under-expression of PTCH1 was associated with a reduced or increased risk of developing a local disease recurrence, respectively. In VSCC arising on a background of Lichen Sclerosus, the risk of local recurrence was potentiated in cases where PTCH1 was under-expressed. CONCLUSIONS:Our findings reveal, for the first time, that the Hh pathway is activated in VSCC and that PTCH1 expression can be used as a biomarker to stratify patients and inform clinicians of the risk of their local recurrence, particularly in cases of VSCC associated with LS

A novel retinoblastoma therapy from genomic and epigenetic analyses.

Retinoblastoma is an aggressive childhood cancer of the developing retina that is initiated by the biallelic loss of RB1. Tumours progress very quickly following RB1 inactivation but the underlying mechanism is not known. Here we show that the retinoblastoma genome is stable, but that multiple cancer pathways can be epigenetically deregulated. To identify the mutations that cooperate with RB1 loss, we performed whole-genome sequencing of retinoblastomas. The overall mutational rate was very low; RB1 was the only known cancer gene mutated. We then evaluated the role of RB1 in genome stability and considered non-genetic mechanisms of cancer pathway deregulation. For example, the proto-oncogene SYK is upregulated in retinoblastoma and is required for tumour cell survival. Targeting SYK with a small-molecule inhibitor induced retinoblastoma tumour cell death in vitro and in vivo. Thus, retinoblastomas may develop quickly as a result of the epigenetic deregulation of key cancer pathways as a direct or indirect result of RB1 loss

A graphic elicitation technique to represent patient rights.

BACKGROUND: A patient charter is an explicit declaration of the rights of patients within a particular health care setting. In early 2020 the Save the Children Emergency Health Unit deployed to Cox's Bazar Bangladesh to support the establishment of a severe acute respiratory infection isolation and treatment centre as part of the COVID-19 response. We developed a charter of patient rights and had it translated into Bangla and Burmese; however, the charter remained inaccessible to Rohingya and members of the host community with low literacy. METHODS: To both visualise and contextualise the patient charter we undertook a graphic elicitation method involving both the Rohingya and host communities. We carried out two focus group discussions during which we discussed the charter and agreed how best to illustrate the individual rights contained therein. RESULTS: Logistical constraints and infection prevention and control procedures limited our ability to follow up with the original focus group participants and to engage in back-translation as we had planned; however, we were able to elicit rich descriptions of each right. Reflecting on our method we were able to identify several key learnings relating to: 1) our technique for eliciting feedback on the charter verbatim versus a broader discussion of concepts referenced within each right, 2) our decision to include both men and women in the same focus group, 3) our decision to ask focus group participants to describe specific features of each illustration and how this benefited the inclusivity of our illustrations, and 4) the potential of the focus groups to act as a means to introduce the charter to communities. CONCLUSIONS: Though executing our method was operationally challenging we were able to create culturally appropriate illustrations to accompany our patient charter. In contexts of limited literacy it is possible to enable access to critical clinical governance and accountability tools

The dependence of AGN activity on stellar and halo mass in Semi-Analytic Models

AGN feedback is believed to play an important role in shaping a variety of observed galaxy properties, as well as the evolution of their stellar masses and star formation rates. In particular, in the current theoretical paradigm of galaxy formation, AGN feedback is believed to play a crucial role in regulating the levels of activity in galaxies, in relatively massive halos at low redshift. Only in recent years, however, has detailed statistical information on the dependence of galaxy activity on stellar mass, parent halo mass and hierarchy has become available. In this paper, we compare the fractions of galaxies belonging to different activity classes (star-forming, AGN and radio active) with predictions from four different and independently developed semi-analytical models. We adopt empirical relations to convert physical properties into observables (H_alpha emission lines, OIII line strength and radio power). We demonstrate that all models used in this study reproduce the overall distributions of galaxies belonging to different activity classes as a function of stellar mass and halo mass: star forming galaxies and the strongest radio sources are preferentially associated with low-mass and high-mass galaxies/halos respectively. However, model predictions differ from observational measurements in a number of ways. All models used in our study predict that almost every >1.e12 Msun dark matter halo and/or >1.e11 Msun galaxy should host a bright radio source, while only a small fraction of galaxies belong to this class in the data. In addition, radio brightness is expected to depend strongly on the mass of the parent halo mass in the models, while strong and weak radio galaxies are found in similar environments in data. Our results highlight that the distribution of AGN as a function of stellar mass provides one of the most promising discriminants between different gas accretion schemes.Comment: 15 pages; 8 figures; 1 table; updated to match MNRAS accepted versio

Seafood in Food Security: A Call for Bridging the Terrestrial-Aquatic Divide

The contribution of seafood to global food security is being increasingly highlighted in policy. However, the extent to which such claims are supported in the current food security literature is unclear. This review assesses the extent to which seafood is represented in the recent food security literature, both individually and from a food systems perspective, in combination with terrestrially-based production systems. The results demonstrate that seafood remains under-researched compared to the role of terrestrial animal and plant production in food security. Furthermore, seafood and terrestrial production remain siloed, with very few papers addressing the combined contribution or relations between terrestrial and aquatic systems. We conclude that far more attention is needed to the specific and relative role of seafood in global food security and call for the integration of seafood in a wider interdisciplinary approach to global food system research.Additional co-authors: Neil L. Andrew, Gulshan Ara, Gill Banner-Stevens, Ben Belton, Malcolm Beveridge, Jessica R. Bogard, Simon R. Bush, Peter Edwards, Joao G. Ferreira, Angus Garrett, Iain Gatward, Faruk U. Islam, Marian Kjellevold, Froukje Kruijssen, Abullah-Al Mamun, Birgitte Krogh-Poulsen, Belinda Richardson, Nanna Roos, Elin Röös, Tori Spence-McConnell, Sharon K. Suri, Shauntala H. Thilsted, Kim D. Thompson, Michael F. Tlusty, Max F. Troell, Raffaele Vignola, Wenbo Zhan