Deregulation of TGF-β Family Ligands in Cancer

The study of signalling dynamics is important for understanding how signalling pathways operate in health and disease. Previous work within the lab investigated how cells respond to TGF-β family ligands over time, in terms of pathway activity. Cells treated with TGF-β reach maximal signal induction at one hour which rapidly attenuates to a low-level steady state despite sustained ligand exposure. Additionally, cells become unresponsive to fresh ligand. This suggests that in diseases, including cancer, where there are sustained levels of pathway activity, another ligand may be responsible for signal propagation or there is re-wiring of mechanisms underlying TGF-β signalling dynamics. Further work in the lab demonstrated that reduced expression of components of the ESCRT machinery led to sustained pathway activity in cells exposed to TGF-β. Furthermore, it was shown that CAFs, a cell type in the tumour stroma, produce functional Activin ligand, which may also be responsible for sustained pathway activation. The work in this thesis aimed to investigate whether these two distinct possibilities could explain the sustained TGF-β family pathway activity observed in disease states by answering two questions: 1. Does compromised ESCRT signalling lead to enhanced TGF-β-mediated output? 2. Is CAF-sourced Activin responsible for pathway signal and output, previously ascribed to TGF-? I have demonstrated that compromised ESCRT function leads to an enhanced TGF-β-mediated epithelial-mesenchymal transition through elevated PSMAD signalling. I have also shown that CAFs from the MMTV-PyMT mouse model of breast cancer produce Activin, that is critical for their contractility whilst affecting their proteome and transcriptome. Furthermore, I have developed in vivo experiments to determine the role of CAF-sourced Activin during tumourigenesis

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication

The enemy within? : Armenians, Jews, the Military Crises of 1915 and the Genocidal Origins of the 'Minorities Question

This chapter identifies two simultaneous First World War military crises, the one Ottoman, the other Russian, with major consequences in the way post-war nation-states began “seeing” minorities and resorting to genocidal action against them. Russian Jews and Ottoman Armenians were largely held responsible for the near-military disasters of 1915 in each case leading to mass communal deportations. While genocide was avoided in the former case, realised in the latter, both sequences acted as “military” models for how “new” states might eliminate unwanted groups through ethnic cleansing. While an alarmed international community responded with a 1919 commitment to minorities’ protection this same community’s imprimatur to mass compulsory population exchange at the 1923 Treaty of Lausanne rather suggests a post-war acceptance of programmes of violent state homogenisation