Diversity of US participants in AstraZeneca-sponsored clinical trials.

BACKGROUND: To develop medicines that are safe and efficacious to all patients, clinical trials must enroll appropriate target populations, but imbalances related to race, ethnicity and sex have been reported. A comprehensive analysis and improvement in understanding representativeness of patient enrollment in industry-sponsored trials are key public health needs. METHODS: We assessed race/ethnicity and sex representation in AstraZeneca (AZ)-sponsored clinical trials in the United States (US) from 2010 to 2022, compared with the 2019 US Census. RESULTS: In total, 246 trials representing 95,372 patients with complete race/ethnicity and sex records were analyzed. The proportions of different race/ethnicity subgroups in AZ-sponsored clinical trials and the US Census were similar (White: 69.5% vs 60.1%, Black or African American: 13.3% vs 12.5%, Asian: 1.8% vs 5.8%, Hispanic: 14.4% vs 18.5%). We also observed parity in the proportions of males and females between AZ clinical trials and US Census (males: 52.4% vs 49.2%, females: 47.6% vs 50.8%). Comparisons of four distinct therapy areas within AZ (Respiratory and Immunology [R&I]; Cardiovascular, Renal, and Metabolism [CVRM]; Solid Tumors; and Hematological Malignancies), including by trial phases, revealed greater variability, with proportions observed above and below US Census levels. CONCLUSION: This analysis provides the first detailed insights into the representativeness of AZ trials. Overall, the proportions of different race/ethnicity and sex subgroups in AZ-sponsored clinical trials were broadly aligned with the US Census. We outline some of AZ's planned health equity initiatives that are intended to continue to improve equitable patient enrollment.

Longitudinal trends of peripheral blood counts in polycythaemia vera and essential thrombocythemia patients in the UK.

There is sparse evidence of how well haematological targets are met in practice for essential thrombocythemia (ET) and polycythaemia vera (PV) patients. Patient data was collected between 2008 and 2020 from two UK NHS Trusts for ET and PV patients. Longitudinal changes in peripheral blood counts, including the proportion of patients meeting peripheral blood count remission, was modelled. Relative risk of cardiovascular-related events for patients achieving remission within 3-months was estimated. A total of 620 ET and 429 PV patients were analysed. For high-risk patients, haematological parameters decreased in the first months of observation then stabilised within normal reference ranges until year 5. Total time spent in peripheral blood count remission was 39.2% for ET and 29.1% for PV. A lower proportion of ET patients reached target platelet counts (48.3%) compared to WBC (79.1%), whilst PV patients were less likely to reach target haematocrit levels (56.9%) compared to platelets (77.3%) or WBC (74.6%). There was no statistically significant association between reaching target blood counts within 3-months and cardiovascular risk. Complete haematological remission remains a challenging target in managing PV and ET, however this study was unable to show statistically-significant evidence that this was associated with increased risk of cardiovascular events.

Directly imaging the localisation and photosensitization properties of the pan-mTOR inhibitor, AZD2014, in living cancer cells.

The range of cellular functions the mechanistic target of rapamycin (mTOR) protein performs makes it an attractive drug target for cancer therapy. However, the cellular localisation and mode of action of second generation inhibitors of mTOR is poorly understood despite the level of attention there is in targeting the mTOR protein. We have therefore studied the properties of the pan-mTOR inhibitor AZD2014, an ideal candidate to study because it is naturally fluorescent, characterising its photochemical properties in solution phase (DMSO, PBS and BSA) and within living cells, where it localises within both the nucleus and the cytoplasm but with different excited state lifetimes of 4.8 (+/- 0.5) and 3.9 (+/- 0.4) ns respectively. We measure the uptake of the inhibitor AZD2014 (7 µM) in monolayer HEK293 cells occurring with a half-life of 1 min but observe complex behaviour for 3D spheroids with the core of the spheroid showing a slower uptake and a slow biphasic behaviour at longer times. From a cellular perspective using fluorescence lifetime imaging microscopy AZD2014 was found to interact directly with GFP-tagged mTORC1 proteins including the downstream target, S6K1. We observe light sensitive behaviour of the cells containing AZD2014 which leads to cell death, in both monolayer and spheroids cells, demonstrating the potential of AZD2014 to act as a possible photodynamic drug under both single photon and multiphoton excitation and discuss its use as a photosensitizer. We also briefly characterise another pan-mTOR inhibitor, INK128.

TRACKING DOWN ALPHA-PARTICLES: THE DESIGN, CHARACTERISATION AND TESTING OF A SHALLOW-ANGLED ALPHA-PARTICLE IRRADIATOR.

Human exposure to α-particles from radon and other radionuclides is associated with carcinogenesis, but if well controlled and targeted to cancer cells, α-particles may be used in radiotherapy. Thus, it is important to understand the biological effects of α-particles to predict cancer risk and optimise radiotherapy. To enable studies of α-particles in cells, we developed and characterised an α-particle automated irradiation rig that allows exposures at a shallow angle (70° to the normal) of cell monolayers in a 30 mm diameter dish to complement standard perpendicular irradiations. The measured incident energy of the α-particles was 3.3 ± 0.5 MeV (LET in water = 120 keV µm-1), with a maximum incident dose rate of 1.28 ± 0.02 Gy min-1, which for a 5 µm cell monolayer corresponds to a mean dose rate of 1.57 ± 0.02 Gy min-1 and a mean LET in water of 154 keV µm-1. The feasibility of resolving radiation-induced DNA double-strand breaks (DSB) foci along the track of α-particles was demonstrated using immunofluorescent labelling with γH2AX and 53BP1 in normal MRC-5 human lung cells.

Super-Resolution Nanoscopy Imaging Applied to DNA Double-Strand Breaks.

Genomic deoxyribonucleic acid (DNA) is continuously being damaged by endogenous processes such as metabolism or by exogenous events such as radiation. The specific phosphorylation of histone H2AX on serine residue 139, described as γ-H2AX, is an excellent indicator or marker of DNA double-strand breaks (DSBs). The yield of γ-H2AX (foci) is shown to have some correlation with the dose of radiation or other DSB-causing agents. However, there is some discrepancy in the DNA DSB foci yield among imaging and other methods such as gel electrophoresis. Super-resolution imaging techniques are now becoming widely used as essential tools in biology and medicine, after a slow uptake of their development almost two decades ago. Here we compare several super-resolution techniques used to image and determine the amount and spatial distribution of γ-H2AX foci formation after X-ray irradiation: stimulated emission depletion (STED), ground-state depletion microscopy followed by individual molecule return (GSDIM), structured illumination microscopy (SIM), as well as an improved confocal, Airyscan and HyVolution 2. We show that by using these super-resolution imaging techniques with as low as 30-nm resolution, each focus may be further resolved, thus increasing the number of foci per radiation dose compared to standard microscopy. Furthermore, the DNA repair proteins 53BP1 (after low-LET irradiations) and Ku70/Ku80 (from laser microbeam irradiation) do not always yield a significantly increased number of foci when imaged by the super-resolution techniques, suggesting that γ-H2AX, 53PB1 and Ku70/80 repair proteins do not fully co-localize on the units of higher order chromatin structure.