Recent Submissions

  • Glycosyl disulfides: importance, synthesis and application to chemical and biological systems

    Ribeiro Morais, Goreti; Falconer, Robert A. (2020)
    The disulfide bond plays an important role in the formation and stabilisation of higher order structures of peptides and proteins, while in recent years interest in this functional group has been extended to carbohydrate chemistry. Rarely found in nature, glycosyl disulfides have attracted significant attention as glycomimetics, with wide biological applications including lectin binding, as key components of dynamic libraries to study carbohydrate structures, the study of metabolic and enzymatic studies, and even as potential drug molecules. This interest has been accompanied and fuelled by the continuous development of new methods to construct the disulfide bond at the anomeric centre. Glycosyl disulfides have also been exploited as versatile intermediates in carbohydrate synthesis, particularly as glycosyl donors. This review focuses on the importance of the disulfide bond in glycobiology and in chemistry, evaluating the different methods available to synthesise glycosyl disulfides. Furthermore, we review the role of glycosyl disulfides as intermediates and/or glycosyl donors for the synthesis of neoglycoproteins and oligosaccharides, before finally considering examples of how this important class of carbohydrates have made an impact in biological and therapeutic contexts.
  • Depth-resolved variations in visibility of retinal nerve fibre bundles across the retina in enface OCT images of healthy eyes.

    Cheloni, Riccardo; Denniss, Jonathan (2020-11)
    Recent developments in optical coherence tomography (OCT) technology enable direct enface visualisation of retinal nerve fibre bundle (RNFB) loss in glaucoma. However, the optimum depth at which to visualise RNFBs across the retina is unknown. We aimed to evaluate the range of depths and optimum depth at which RNFBs can be visualised across the retina in healthy eyes. The central ± 25° retina of 10 healthy eyes from 10 people aged 57–75 years (median 68.5 years) were imaged with spectral domain OCT. Slab images of maximum axial resolution (4 μm) containing depth‐resolved attenuation coefficients were extracted from 0 to 193.5 μm below the inner limiting membrane (ILM). Bundle visibility within 10 regions of a superimposed grid was assessed subjectively by trained optometrists (n = 8), according to written instructions. Anterior and posterior limits of RNFB visibility and depth of best visibility were identified for each grid sector. Effects of retinal location and individual eye on RNFB visibility were explored using linear mixed modelling with likelihood ratio tests. Intraclass correlation coefficient (ICC) was used to measure overall agreement and repeatability of grading. Spearman’s correlation was used to measure correlation between depth range of visible RNFBs and retinal nerve fibre layer thickness (RNFLT). Retinal location and individual eye affected anterior limit of visibility (χ2(9) = 58.6 and 60.5, both p < 0.0001), but none of the differences exceeded instrument resolution, making anterior limit consistent across the retina and different eyes. Greater differences were observed in the posterior limit of visibility across retinal areas (χ2(9) = 1671.1, p < 0.0001) and different eyes (χ2(9) = 88.7, p < 0.0001). Optimal depth for visualisation of RNFBs was around 20 µm below the ILM in most regions. It varied slightly with retinal location (χ2(9) = 58.8, p < 0.0001), but it was not affected by individual eye (χ2(9) = 10.7, p = 0.29). RNFB visibility showed good agreement between graders (ICC 0.89, 95%CI 0.87–0.91), and excellent repeatability (ICC 0.96–0.99). Depth range of visible RNFBs was highly correlated with RNFLT (ρ = 0.9, 95%CI: 0.86–0.95). The range of depths with visible RNFBs varies markedly across the healthy retina, consistently with RNFLT. To extract all RNFB information consistently across the retina, slab properties should account for differences across retinal locations and between individual eyes.
  • Doggerland and the Lost Frontiers Project (2015–2020)

    Gaffney, Vincent L.; Allaby, R.; Bates, R.; Bates, M.; Ch'ng, E.; Fitch, Simon; Garwood, P.; Momber, G.; Murgatroyd, Philip; Pallen, M.; et al. (2017-05)
    As this volume, the final monograph of the SPLASHCOS network, was being finalised, the European Research Council agreed to fund a major new project relating to the marine palaeolandscapes of the southern North Sea. Emerging from the earlier work of the North Sea Palaeolandscapes Project (NSPP), the Lost Frontiers project seeks to go beyond the maps generated by that ground-breaking research. Led by researchers in the fields of archaeogeophysics, molecular biology and computer simulation, the project seeks to develop a new paradigm for the study of past environments, ecological change and the transition between hunter gathering societies and farming in North West Europe. Following from earlier work, the project will seek to release the full potential of the available seismic reflectance data sets to generate topographical maps of the whole of early Holocene Doggerland that are as accurate and complete as possible. Using these data, the study will then reconstruct and simulate the emerging palaeoenvironments of Doggerland using conventional palaeoenvironmental data, as well as ancient DNA extracted directly from sediment cores along the routes of two submerged river valleys. Using this base data, the project aims to transform our understanding of the colonisation and development of floral, faunal and human life, to explore the Mesolithic landscapes and to identify incipient Neolithic signals indicating early contact and development within the region of Doggerland.
  • Evaluation of the toxicity of two electron-deficient half-sandwich complexes against human lymphocytes from healthy individuals

    Habas, Khaled S.A.; Soldevila Barreda, Joan J.; Azmanova, Maria; Rafols, Laia; Pitto-Barry, Anaïs; Anderson, Diana; Barry, Nicolas P.E. (2020)
    Electron‐deficient half‐sandwich complexes are a class of under‐studied organometallics with demonstrated potential as metallodrug candidates. The present study investigates the effect of two 16‐electron organoruthenium complexes ([( p‐ cym)Ru(benzene‐1,2‐dithiolato)] ( 1 ) and [( p ‐cym)Ru(maleonitriledithiolate)] ( 2 )) on the cell viability of non‐immortalised human lymphocytes from healthy individuals. The genotoxic effects of 1 and 2 in lymphocytes using the Comet and cytokinesis‐block micronucleus assays is also investigated. Gene expression studies were carried out on a panel of genes involved in apoptosis and DNA damage repair response. Results show that the two 16‐electron complexes do not have significant effect on the cell viability of human lymphocytes from healthy individuals. However, an increase in DNA damage is induced by both compounds, presumably through oxidative stress production.
  • Application of small molecule FPR1 antagonists in the treatment of cancers

    Ahmet, Djevdet S.; Basheer, H.A.; Salem, Anwar; Lu, Di; Aghamohammadi, Amin; Weyerhäuser, P.; Bordiga, A.; Almeniawi, J.; Rashid, S.; Cooper, Patricia A.; et al. (Nature, 2020-10)
    The formylpeptide receptor-1 (FPR1) is a member of the chemotactic GPCR-7TM formyl peptide receptor family, whose principle function is in trafficking of various leukocytes into sites of bacterial infection and inflammation. More recently, FPR1 has been shown to be expressed in different types of cancer and in this context, plays a significant role in their expansion, resistance and recurrence. ICT12035 is a selective and potent (30 nM in calcium mobilisation assay) small molecule FPR1 antagonist. Here, we demonstrate the efficacy of ICT12035, in a number of 2D and 3D proliferation and invasion in vitro assays and an in vivo model. Our results demonstrate that targeting FPR1 by a selective small molecule antagonist, such as ICT12035, can provide a new avenue for the treatment of cancers.
  • Effect of polymerisation by microwave on the physical properties of molecularly imprinted polymers (MIPs) specific for caffeine

    Brahmbhatt, H.A.; Surtees, Alexander P.H.; Tierney, C.; Ige, O.A.; Piletska, E.V.; Swift, Thomas; Turner, N.W. (Royal Society of Chemistry, 2020-08)
    Molecularly Imprinted Polymers (MIPs) are a class of polymeric materials that exhibit highly specific recognition properties towards a chosen target. These “smart materials” offer robustness to work in extreme environmental conditions and cost effectiveness; and have shown themselves capable of the affinities/specificities observed of their biomolecular counterparts. Despite this, in many MIP systems heterogeneity generated in the polymerisation process is known to affect the performance. Microwave reactors have been extensively studied in organic chemistry because they can afford fast and well-controlled reactions, and have been used for polymerisation reactions; however, their use for creating MIPs is limited. Here we report a case study of a model MIP system imprinted for caffeine, using microwave initiation. Experimental parameters such as polymerisation time, temperature and applied microwave power have been investigated and compared with polymers prepared by oven and UV irradiation. MIPs have been characterised by BET, SEM, DSC, TGA, NMR, and HPLC for their physical properties and analyte recognition performance. The results suggest that the performance of these polymers correlates to their physical characteristics. These characteristics were significantly influenced by changes in the experimental polymerisation parameters, and the complexity of the component mixture. A series of trends were observed as each parameter was altered, suggesting that the performance of a generated polymer could be possible to predict. As expected, component selection is shown to be a major factor in the success of an imprint using this method, but this also has a significant effect on the quality of resultant polymers suggesting that only certain types of MIPs can be made using microwave irradiation. This work also indicates that the controlled polymerisation conditions offered by microwave reactors could open a promising future in the development of MIPs with more predictable analyte recognition performance, assuming material selection lends itself to this type of initiation.
  • Model-based integration analysis revealed presence of novel prognostic miRNA targets and important cancer driver genes in triple-negative breast cancers

    Zaka, M.; Sutton, Chris W.; Peng, Y.; Konur, Savas (2020-03)
    Background: miRNAs (microRNAs) play a key role in triple-negative breast cancer (TNBC) progression, and its heterogeneity at the expression, pathological and clinical levels. Stratification of breast cancer subtypes on the basis of genomics and transcriptomics profiling, along with the known biomarkers’ receptor status, has revealed the existence of subgroups known to have diverse clinical outcomes. Recently, several studies have analysed expression profiles of matched mRNA and miRNA to investigate the underlying heterogeneity of TNBC and the potential role of miRNA as a biomarker within cancers. However, the miRNA-mRNA regulatory network within TNBC has yet to be understood. Results and Findings: We performed model-based integrated analysis of miRNA and mRNA expression profiles on breast cancer, primarily focusing on triple-negative, to identify subtype-specific signatures involved in oncogenic pathways and their potential role in patient survival outcome. Using univariate and multivariate Cox analysis, we identified 25 unique miRNAs associated with the prognosis of overall survival (OS) and distant metastases-free survival (DMFS) with “risky” and “protective” outcomes. The association of these prognostic miRNAs with subtype-specific mRNA genes was established to investigate their potential regulatory role in the canonical pathways using anti-correlation analysis. The analysis showed that miRNAs contribute to the positive regulation of known breast cancer driver genes as well as the activation of respective oncogenic pathway during disease formation. Further analysis on the “risk associated” miRNAs group revealed significant regulation of critical pathways such as cell growth, voltage-gated ion channel function, ion transport and cell-to-cell signalling. Conclusion: The study findings provide new insights into the potential role of miRNAs in TNBC disease progression through the activation of key oncogenic pathways. The results showed previously unreported subtype-specific prognostic miRNAs associated with clinical outcome that may be used for further clinical evaluation.
  • Synthesis, characterisation, and in vitro anticancer activity of catalytically active indole-based half-sandwich complexes

    Soldevila-Barreda, Joan J.; Fawibe, K.B.; Azmanova, Maria; Rafols, Laia; Pitto-Barry, Anaïs; Eke, U.B.; Barry, Nicolas P.E. (2020-10-03)
    The synthesis, characterisation and evaluation of the in vitro cytotoxicity of four indole-based half-sandwich metal complexes towards two ovarian cancer cell lines (A2780 and A2780cisR) and one normal prostate cell line (PNT2) are presented herein. Although capable of inducing catalytic oxidation of NADH and able to reduce NAD+ with high turnover frequencies, in cells and in the presence of sodium formate, these complexes also strongly interact with biomolecules such as glutathione. This work highlights that efficient out-of-cells catalytic activity might lead to higher reactivity towards biomolecules, thus inhibiting the in-cells catalytic processes.
  • MicroRNAs and Cancer

    Maher, S.G.; Bibby, B.A.S.; Moody, Hannah L.; Reid, G. (2015)
    MicroRNAs are a relatively new class of small, noncoding RNA species that represent a cornerstone of cell biology, with diverse roles ranging from embryonic development to aging. miRNAs function to regulate posttranscriptional gene expression, are critical to the normal function of cells, and as such are frequently dysregulated during disease processes. In this chapter, we discuss the biogenesis and mechanism of action of miRNA and their role in cancer initiation, promotion, and progression. In addition, we discuss the most recently identified dual roles of miRNA in epigenetic gene regulation; how they are both regulators and regulated. Finally, we discuss the emerging roles of miRNA as epigenetic anti-cancer therapeutics, the current research examining inhibition of oncogenic miRNAs, and studies now establishing the potential of replacing lost, tumor-suppressive miRNA.
  • MicroRNA-31 Regulates Chemosensitivity in Malignant Pleural Mesothelioma

    Moody, Hannah L.; Lind, M.; Maher, S.G. (2017-09-15)
    Malignant pleural mesothelioma (MPM) is associated with an extremely poor prognosis, and most patients initially are or rapidly become unresponsive to platinum-based chemotherapy. MicroRNA-31 (miR-31) is encoded on a genomic fragile site, 9p21.3, which is reportedly lost in many MPM tumors. Based on previous findings in a variety of other cancers, we hypothesized that miR-31 alters chemosensitivity and that miR-31 reconstitution may influence sensitivity to chemotherapeutics in MPM. Reintroduction of miR-31 into miR-31 null NCI-H2452 cells significantly enhanced clonogenic resistance to cisplatin and carboplatin. Although miR-31 re-expression increased chemoresistance, paradoxically, a higher relative intracellular accumulation of platinum was detected. This was coupled to a significantly decreased intranuclear concentration of platinum. Linked with a downregulation of OCT1, a bipotential transcriptional regulator with multiple miR-31 target binding sites, we subsequently identified an indirect miR-31-mediated upregulation of ABCB9, a transporter associated with drug accumulation in lysosomes, and increased uptake of platinum to lysosomes. However, when overexpressed directly, ABCB9 promoted cellular chemosensitivity, suggesting that miR-31 promotes chemoresistance largely via an ABCB9-independent mechanism. Overall, our data suggest that miR-31 loss from MPM tumors promotes chemosensitivity and may be prognostically beneficial in the context of therapeutic sensitivity.
  • Faster visual reaction times in elite athletes are not linked to better gaze stability

    Barrett, Brendan T.; Cruickshank, A.G.; Flavell, J.C.; Bennett, S.J.; Buckley, John G.; Harris, J.M.; Scally, Andy J. (2020-08)
    The issue of whether visually-mediated, simple reaction time (VRT) is faster in elite athletes is contentious. Here, we examined if and how VRT is afected by gaze stability in groups of international cricketers (16 females, 28 males), professional rugby-league players (21 males), and non-sporting controls (20 females, 30 males). VRT was recorded via a button-press response to the sudden appearance of a stimulus (circular target—diameter 0.8°), that was presented centrally, or 7.5° to the left or right of fxation. The incidence and timing of saccades and blinks occurring from 450 ms before stimulus onset to 225 ms after onset were measured to quantify gaze stability. Our results show that (1) cricketers have faster VRT than controls; (2) blinks and, in particular, saccades are associated with slower VRT regardless of the level of sporting ability; (3) elite female cricketers had steadier gaze (fewer saccades and blinks) compared to female controls; (4) when we accounted for the presence of blinks and saccades, our group comparisons of VRT were virtually unchanged. The stability of gaze is not a factor that explains the difference between elite and control groups in VRT. Thus we conclude that better gaze stability cannot explain faster VRT in elite sports players.
  • Structural Basis for Mechanical Anisotropy in Polymorphs of Caffeine-Glutaric Acid Cocrystal

    Mishra, M.K.; Mishra, K.; Narayan, Aditya N.; Reddy, C.M.; Vangala, Venu R. (American Chemical Society, 2020-10-07)
    Insights into structure–mechanical property correlations in molecular and multicomponent crystals have recently attracted significant attention owing to their practical applications in the pharmaceutical and specialty fine chemicals manufacturing. In this contribution, we systematically examine the mechanical properties of dimorphic forms, Forms I and II of 1:1 caffeine-glutaric acid cocrystal on multiple faces using nanoindentation to fully understand their mechanical anisotropy and mechanical stability under applied load. Higher hardness, H, and elastic modulus, E, of stable Form II has been rationalized based on its corrugated layers, higher interlayer energy, lower interlayer separation, and presence of more intermolecular interactions in the crystal structure compared to metastable Form I. Our results show that mechanical anisotropy in both polymorphs arises due to the difference in orientation of the same 2D structural features, namely the number of possible slip systems, and strength of the intermolecular interactions with respect to the indentation direction. The mechanical properties results suggest that 1:1 caffeine-glutaric acid cocrystal, metastable form (Form I) could be a suitable candidate with desired tablet performance to that of stable Form II. The overall, it demonstrates that the multiple faces of nanoindentation is critical to determine mechanical anisotropy and structure- mechanical property correlation. Further, the structural-mechanical property correlations aids in the selection of the best solid phase for macroscopic pharmaceutical formulation.
  • The RAC1 target NCKAP1 plays a crucial role in progression of BRAF/PTEN -driven melanoma in mice

    Swaminathan, Karthic; Campbell, A.; Papalazarou, V.; Jaber-Hijazi, F.; Nixon, C.; McGhee, E.; Strathdee, D.; Sansom, O.J.; Machesky, L.M. (2020)
    BRAF V600E is the most common driver mutation in human cutaneous melanoma and is frequently accompanied by loss of the tumor suppressing phosphatase PTEN. Recent evidence suggests a co-operative role for RAC1 activity in BRAF V600E -driven melanoma progression and drug resistance. However, the underlying molecular mechanisms and the role of RAC1 downstream targets are not well explored. Here, we examine the role of the NCKAP1 subunit of the pentameric cytoskeletal SCAR/WAVE complex, a major downstream target of RAC1, in a mouse model of melanoma driven by BRAF V600E; PTEN loss. The SCAR/WAVE complex is the major driver of lamellipodia formation and cell migration downstream of RAC1 and depends on NCKAP1 for its integrity. Targeted deletion of Nckap1 in the melanocyte lineage delayed tumor onset and progression of a mutant Braf ; Pten loss driven melanoma mouse model. Nckap1 depleted tumors displayed fibrotic stroma with increased collagen deposition concomitant with enhanced immune infiltration. Nckap1 loss slowed proliferation and tumor growth, highlighting a role in cell cycle progression. Altogether, we propose that NCKAP1-orchestrated actin polymerization is essential for tumor progression and maintenance of tumor tissue integrity in a mutant Braf ; Pten loss driven mouse model for melanoma.
  • Effect of Education on Myopia: Evidence from the United Kingdom ROSLA 1972 Reform

    Plotnikov, D.; Williams, C.; Atan, D.; Davies, N.M.; Ghorbani Mojarrad, Neema; Guggenheim, J.A. (2020-09-04)
    Cross-sectional and longitudinal studies have consistently reported an association between education and myopia. However, conventional observational studies are at risk of bias due to confounding by factors such as socioeconomic position and parental educational attainment. The current study aimed to estimate the causal effect of education on refractive error using regression discontinuity analysis. Methods: Regression discontinuity analysis was applied to assess the influence on refractive error of the raising of the school leaving age (ROSLA) from 15 to 16 years introduced in England and Wales in 1972. For comparison, a conventional ordinary least squares (OLS) analysis was performed. The analysis sample comprised 21,548 UK Biobank participants born in a nine-year interval centered on September 1957, the date of birth of those first affected by ROSLA. Results: In OLS analysis, the ROSLA 1972 reform was associated with a −0.29 D (95% confidence interval [CI]: −0.36 to −0.21, P < 0.001) more negative refractive error. In other words, the refractive error of the study sample became more negative by −0.29 D during the transition from a minimum school leaving age of 15 to 16 years of age. Regression discontinuity analysis estimated the causal effect of the ROSLA 1972 reform on refractive error as −0.77 D (95% CI: −1.53 to −0.02, P = 0.04). Conclusions: Additional compulsory schooling due to the ROSLA 1972 reform was associated with a more negative refractive error, providing additional support for a causal relationship between education and myopia.
  • Initial resistance to companion drugs should not be considered an exclusion criterion for the multidrug-resistant tuberculosis shorter treatment regimen

    Lempens, P.; Decroo, T.; Aung, K.J.M.; Hossain, M.A.; Rigouts, L.; Meehan, Conor J.; Van Deun, A.; de Jong, B.C. (2020-08)
    We investigated whether companion drug resistance was associated with adverse outcome of the shorter MDR-TB regimen in Bangladesh, after adjusting for fluoroquinolone resistance. MDR/RR-TB patients registered for treatment with a standardized gatifloxacin-based shorter MDR-TB regimen were selected for the study. Drug resistance was determined using the proportion method, gatifloxacin and isoniazid minimum inhibitory concentration testing for selected isolates, and whole genome sequencing. Low-level and high-level fluoroquinolone resistance were the most important predictors of adverse outcomes, with pyrazinamide resistance having a significant yet lower impact. In patients with fluoroquinolone-/second-line injectable-susceptible TB, non-eligibility to the shorter MDR-TB regimen (initial resistance to either pyrazinamide, ethionamide, or ethambutol) was not associated with adverse outcome (aOR 1.01; 95%CI 0.4-2.8). Kanamycin resistance was uncommon (1.3%). Increasing levels of resistance to isoniazid predicted treatment failure, also in a subgroup of patients with high-level fluoroquinolone-resistant TB. Our results suggest that resistance to companion drugs of the shorter MDR-TB regimen, except kanamycin resistance, is of no clinical importance as long as fluoroquinolone susceptibility is preserved. Hence, contrary to current WHO guidelines, exclusions to the standard regimen are justified only in the case of fluoroquinolone, and possibly kanamycin resistance.
  • Preclinical Anticancer Activity of an Electron-Deficient Organoruthenium(II) Complex

    Soldevila-Barreda, Joan J.; Azmanova, Maria; Pitto-Barry, Anaïs; Cooper, Patricia A.; Shnyder, Steven D.; Barry, Nicolas P.E. (2020-06-04)
    Ruthenium compounds have been shown to be promising alternatives to platinum(II) drugs. However, their clinical success depends on achieving mechanisms of action that overcome Pt-resistance mechanisms. Electron-deficient organoruthenium complexes are an understudied class of compounds that exhibit unusual reactivity in solution and might offer novel anticancer mechanisms of action. Here, we evaluate the in vitro and in vivo anticancer properties of the electron-deficient organoruthenium complex [(p-cymene)Ru(maleonitriledithiolate)]. This compound is found to be highly cytotoxic: 5 to 60 times more potent than cisplatin towards ovarian (A2780 and A2780cisR), colon (HCT116 p53+/+ and HCT116 p53−/−), and non-small cell lung H460 cancer cell lines. It shows no cross-resistance and is equally cytotoxic to both A2780 and A2780cisR cell lines. Furthermore, unlike cisplatin, the remarkable in vitro antiproliferative activity of this compound appears to be p53-independent. In vivo evaluation in the hollow-fibre assay across a panel of cancer cell types and subcutaneous H460 non-small cell lung cancer xenograft model hints at the activity of the complex. Although the impressive in vitro data are not fully corroborated by the in vivo follow-up, this work is the first preclinical study of electron-deficient half-sandwich complexes and highlights their promise as anticancer drug candidates.
  • Ultrasound-triggered therapeutic microbubbles enhance the efficacy of cytotoxic drugs by increasing circulation and tumour drug accumulation and limiting bioavailability and toxicity in normal tissues

    Ingram, N.; McVeigh, L.E.; Abou-Saleh, R.H.; Maynard, J.; Peyman, S.A.; McLaughlan, J.R.; Fairclough, M.; Marston, G.; Valleley, E.M.A.; Jimenez-Macias, J.L.; et al. (2020)
    Most cancer patients receive chemotherapy at some stage of their treatment which makes improving the efficacy of cytotoxic drugs an ongoing and important goal. Despite large numbers of potent anti-cancer agents being developed, a major obstacle to clinical translation remains the inability to deliver therapeutic doses to a tumor without causing intolerable side effects. To address this problem, there has been intense interest in nanoformulations and targeted delivery to improve cancer outcomes. The aim of this work was to demonstrate how vascular endothelial growth factor receptor 2 (VEGFR2)-targeted, ultrasound-triggered delivery with therapeutic microbubbles (thMBs) could improve the therapeutic range of cytotoxic drugs. Methods: Using a microfluidic microbubble production platform, we generated thMBs comprising VEGFR2-targeted microbubbles with attached liposomal payloads for localised ultrasound-triggered delivery of irinotecan and SN38 in mouse models of colorectal cancer. Intravenous injection into tumor-bearing mice was used to examine targeting efficiency and tumor pharmacodynamics. High-frequency ultrasound and bioluminescent imaging were used to visualise microbubbles in real-time. Tandem mass spectrometry (LC-MS/MS) was used to quantitate intratumoral drug delivery and tissue biodistribution. Finally, 89Zr PET radiotracing was used to compare biodistribution and tumor accumulation of ultrasound-triggered SN38 thMBs with VEGFR2 targeted SN38 liposomes alone. Results: ThMBs specifically bound VEGFR2 in vitro and significantly improved tumor responses to low dose irinotecan and SN38 in human colorectal cancer xenografts. An ultrasound trigger was essential to achieve the selective effects of thMBs as without it, thMBs failed to extend intratumoral drug delivery or demonstrate enhanced tumor responses. Sensitive LC-MS/MS quantification of drugs and their metabolites demonstrated that thMBs extended drug exposure in tumors but limited exposure in healthy tissues, not exposed to ultrasound, by persistent encapsulation of drug prior to elimination. 89Zr PET radiotracing showed that the percentage injected dose in tumors achieved with thMBs was twice that of VEGFR2-targeted SN38 liposomes alone. Conclusions: thMBs provide a generic platform for the targeted, ultrasound-triggered delivery of cytotoxic drugs by enhancing tumor responses to low dose drug delivery via combined effects on circulation, tumor drug accumulation and exposure and altered metabolism in normal tissues.
  • Dig! Arts Access Project: Finding Inspiration in the Park

    Giles, M.; Croucher, Karina T. (2019)
    Dig! Arts Access Project brought together excavation with artistic interpretations using collage, painting, drawing and poetry, to engage school learners in the legacy of the Whitworth Park Community Archaeology and History project. Through a series of workshops and site visits with local schools, participants expressed some of the ambiguities felt by urban children about parks. However, by the end of the sessions, they had increased their understanding of the history and heritage of their everyday places and were more confident about visiting parks.
  • Optimised patient information materials and recruitment to a study of behavioural activation in older adults: an embedded study within a trial

    Knapp, P.; Gilbody, S.; Holt, J.; Keding, A.; Mitchell, N.; Raynor, D.K.; Silcock, Jonathan; Torgerson, D. (2020-05-21)
    Printed participant information about randomised controlled trials is often long, technical and difficult to navigate. Improving information materials is possible through optimisation and user-testing, and may impact on participant understanding and rates of recruitment. Methods: A study within a trial (SWAT) was undertaken within the CASPER trial. Potential CASPER participants were randomised to receive either the standard trial information or revised information that had been optimised through information design and user testing. Results: A total of 11,531 patients were randomised in the SWAT. Rates of recruitment to the CASPER trial were 2.0% in the optimised information group and 1.9% in the standard information group (odds ratio 1.027; 95% CI 0.79 to 1.33; p=0.202). Conclusions: Participant information that had been optimised through information design and user testing did not result in any change to rate of recruitment to the host trial. Registration: ISRCTN ID ISRCTN02202951; registered on 3 June 2009.
  • Co-delivery of a RanGTP inhibitory peptide and doxorubicin using dual loaded liposomal carriers to combat chemotherapeutic resistance in breast cancer cells

    Haggag, Y.; Abu Ras, Bayan; El-Tanani, Yahia; Tambuwala, M.M.; McCarron, P.; Isreb, Mohammed; El-Tanani, Mohamed (2020-11)
    Multidrug resistance (MDR) limits the beneficial outcomes of conventional breast cancer chemotherapy. Ras-related nuclear protein (Ran-GTP) plays a key role in these resistance mechanisms, assisting cancer cells to repair damage to DNA. Herein, we investigate the co-delivery of Ran-RCC1 inhibitory peptide (RAN-IP) and doxorubicin (DOX) to breast cancer cells using liposomal nanocarriers. A liposomal delivery system, co-encapsulating DOX, and RAN-IP, was prepared using a thin-film rehydration technique. Dual-loaded liposomes were optimized by systematic modification of formulation variables. Real-Time-Polymerase Chain Reaction was used to determine Ran-GTP mRNA expression. In vitro cell lines were used to evaluate the effect of loaded liposomes on the viability of breast and lung cancer cell lines. In vivo testing was performed on a murine Solid Ehrlich Carcinoma model. RAN-IP reversed the Ran-expression-mediated MDR by inhibiting the Ran DNA damage repair function. Co-administration of RAN-IP enhanced sensitivity of DOX in breast cancer cell lines. Finally, liposome-mediated co-delivery with RAN-IP improved the anti-tumor effect of DOX in tumor-bearing mice when compared to single therapy. This study is the first to show the simultaneous delivery of RAN-IP and DOX using liposomes can be synergistic with DOX and lead to tumor regression in vitro and in vivo.

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