Collections in this community

Recent Submissions

  • The contradictory role of febuxostat in ABCG2 expression and potentiating hypericin‐mediated photodynamic therapy in colorectal cancers

    King, A.; Maisey, T.; Harris, E.L.; Poulter, J.A.; Jayne, D.G.; Khot, Ibrahim (2024-04-16)
    Photodynamic Therapy (PDT) is an emerging method to treat colorectal cancers (CRC). Hypericin (HYP) is an effective mediator of PDT and the ABCG2 inhibitor, Febuxostat (FBX) could augment PDT. HT29 and HEK293 cells showed light dependant cytotoxic response to PDT in both 2D and 3D cell models. FBX co-treatment was not found to improve PDT cytotoxicity. Next, ABCG2 protein expression was observed in HT29 but not in HEK293 cells. However, ABCG2 gene expression analysis did not support protein expression results as ABCG2 gene expression results were found to be higher in HEK293 cells. Although HYP treatment was found to significantly reduce ABCG2 gene expression levels in both cell lines, FBX treatment partially restored ABCG2 gene expression. Our findings indicate that FBX co-treatment may not be suitable for augmenting HYP-mediated PDT in CRC but could potentially be useful for other applications.
  • Medicines Shortages Reporting Systems (MSRS): An exploratory review of access and sustainability

    2024
    Background: The efficacy of medicines depends on their accessibility and availability. Dedicated medicine shortage reporting systems (MSRS) have been set up in different countries, either mandatory or voluntary, following the recommendations of the World Health Organisation to ensure these. Objectives: To explore how the Medicine Shortages Reporting System (MSRS) can tackle medicine shortages through improved access and sustainability. Methods: Personnel directly involved in the reporting mechanisms for medicine shortages in eight (8) countries participated in semi-structured interviews. An interview protocol based on the Dynamic Capabilities View and Organisational Information Processing Theory (OIPT) was developed. It contained questions related to participant's views on the process involved in MSRS and how it was used to tackle shortages. Data were thematically analysed. Results: Three core elements were identified to influence MSRS's ability to tackle shortages and ensure sustainability; (1) the ability to identify what information requirements the reporting system needs, (2) identify information processing capabilities, and (3) the ability to match requirements and information processing capabilities through a dynamic capability decision-making process. The dynamic decision-making process involves reiteratively sensing shortages by understanding and validating information received. Conclusion: Building MSRS to tackle shortages for accessibility and sustainability is a systemic process that entails understanding the various elements and processes of MSRS. It includes defining medicine shortages, reconfiguring resources, defining accessibility and ensuring the system's sustainability. Our study provides insights into MSRS developed for mitigating medicine shortages and provides a framework for a sustainable MSRS. The findings extend the literature on medicine shortage management by identifying the various elements required to set up an MSRS. It also provides practical implications for countries that seek to establish MSRS to mitigate medicine shortages. Further studies could extend the number of participating countries to provide a clearer picture of the MSRS and how it can reduce medicine shortages.
  • The Use of MM/QM calculations of 13C chemical shifts in the analysis of Edaravone tautomers

    2022-09
    The 13C NMR chemical shifts of the three Edaravone tautomers (keto, enol, and amine) were calculated using a combined molecular mechanics (Pcmod 9.1/MMFF94) and ab initio (GIAO (B3LYP/DFT, 6–31 + G(d)) model. This method gave such good agreement with experiment that the assignment of the complex spectrum of Edaravone in solution, which is a mixture of the three tautomers could be made. This has been attempted previously by various methods with diverse results. In CDCl3 solution, the observed spectra show only one form, the keto tautomer, and this is also the case with acetonitrile solvent. Acetone solvent reacts with Edavarone in the NMR tube. In the other solvents studied, methanol, pyridine, DMSO, trifluoroethanol (TFE), there is a mixture of the tautomers with populations which vary with the solvent. The application of the shift predictions allows the assignment of the 13C spectra to the three tautomers and from this the proportions of the tautomers in the solution. The results at times differ significantly from previous studies, and this is discussed.
  • Evaluating team-based learning in a foundation training pathway for trainee pharmacists

    2024
    A new programme incorporating online study days delivered using team-based learning (TBL) for hospital-based trainee pharmacists (TPs) in the North of England was created. To our knowledge, TBL has not previously been used in educational programmes for TPs designed to supplement their workplace learning. The project aimed to investigate the experiences of TPs learning using online TBL by exploring their perceptions on their engagement, learning, and satisfaction with TBL. Data were collected using online anonymous surveys at the end of four online TBL study days. A bespoke survey consisted of 5-point or 4-point Likert scale and two free text questions. TBL Student Assessment Instrument (SAI), a validated survey, was used to assess TPs' acceptance of TBL. Survey data was summarized descriptively, and free text comments analysed using thematic analysis. TPs developed accountability to their team, remained engaged with TBL delivery online and stated a preference for and satisfaction with this method. TPs valued opportunities to apply their knowledge in challenging scenarios and learn from discussions with their peers, the larger group, and facilitators. TBL was also perceived to be an engaging approach to learning and helped to maintain their interest with the teaching material. However, TPs struggled to engage with pre-work outside of the class due to competing work priorities. This study shows that online TBL was well accepted by TPs and can be successfully used to deliver education to large cohorts of learners. The model developed shows potential for scalability to larger numbers of learners.
  • MaDDOSY (Mass Determination Diffusion Ordered Spectroscopy) using an 80 MHz bench top NMR for the rapid determination of polymer and macromolecular molecular weight

    2024
    Measurement of molecular weight is an integral part of macromolecular and polymer characterization which usually has limitations. Herein, we present the use of a bench-top 80 MHz NMR spectrometer for diffusion-ordered spectroscopy as a practical and rapid approach for the determination of molecular weight/size using a novel solvent and polymer-independent universal calibration.
  • In situ monitoring of competitive coformer exchange reaction by 1H MAS Solid-state NMR

    Hareendran, C.; Alsirawan, B.; Paradkar, Anant R; Ajithku, T.G.am (2024-03)
    In a competitive coformer exchange reaction, a recent topic of interest in pharmaceutical research, the coformer in a pharmaceutical cocrystal is exchanged with another coformer which is expected to form a cocrystal that is more stable. There will be a competition between coformers to form the most stable product through formation of hydrogen bonds. Thus, to monitor each and every step of such reactions, employing a very sensitive technique is crucial. 1H nuclear magnetic resonance (NMR) is a very powerful technique that is very sensitive to the hydrogen bond interactions. In this study, an in situ monitoring of a coformer exchange reaction is carried out by 1H magic angle spinning (MAS) solid-state NMR (SSNMR) at a spinning frequency of 60 KHz. The changes in caffeine maleic acid cocrystals on addition of glutaric acid, and caffeine glutaric cocrystal on addition of maleic acid were monitored. In all the reactions, it has been observed that caffeine glutaric acid Form I is formed. When glutaric acid was added to 2:1 caffeine maleic acid, the formation of metastable 1:1 caffeine glutaric acid Form I was observed, at the start of the experiment, indicating that the centrifugal pressure is enough for the formation. The difference in the end product of the reactions with similar reaction pathway of 1:1 and 2:1 reactant stoichiometry indicate that a complete replacement of maleic acid has only occurred only in the 1:1 stoichiometry of the reactants. The polymorphic transition of caffeine glutaric acid Form II to Form I at higher temperature was crucial reason which triggers the exchange of glutaric acid with maleic acid in the reaction of caffeine glutaric acid and maleic acid. Based on these results, new reaction pathways in competitive coformer exchange reactions could be distinguished, and the remarkable role of stoichiometry, polymorphism, temperature and centrifugal pressure could be established.
  • Assembling Wellbeing in Archaeological Teaching and Learning

    2022
    Wellbeing is a growing concern for educators and students alike and is especially significant in the light of the Covid-19 pandemic, which has brought the importance of wellbeing into sharp focus. Elsewhere, the authors (Cobb and Croucher) have written about a new pedagogic approach they have developed, specifically related to archaeology, although applicable across higher education. In this approach, they draw on relational theories and archaeology's “material turn” to focus on “Inclusive Learning Assemblages”. They explore the material and social assemblages that students encounter, both in different learning contexts and outwith learning, arguing that if we foreground learning assemblages, then student diversity and the student learning experience will be enhanced. In this paper, the authors take a step further by exploring the value of this approach for student wellbeing. They argue that taking an assemblage approach to teaching and learning in archaeology, and foregrounding diversity, actively improves student wellbeing too. This paper brings into dialogue mental health issues, with the diversity of student experiences, and the broad material engagements of an archaeology degree, in order to suggest a series of concrete steps that practitioners can implement to enhance student wellbeing.
  • Daily Negotiations with Materiality: Re–Assembling Halaf Ornamentation

    Belcher, E.; Croucher, Karina (2023-11)
    In this paper we consider the making, daily use and deposition of ornaments in the Halaf period. We seek to move beyond rigid ‘craft production’ interpretive frameworks intersecting symbolism, complexity and social inequality. Instead, we seek different ways of knowing prehistoric ornaments, through their materiality, assemblage and visuality as evidence of ambiguous mutable person-object relationships and experiences. Making and decoration of/with ornaments offers insights into social concepts of embodiment, personhood, identity and belonging, and should be interpreted as having ambiguous, multiple uses and meanings. Using six case studies of ornament types from excavated assemblages, we critically examine existing methods of small finds’ presentation and suggest more dynamic ways of artefact analysis, interpretation and publication. We present this interpretative model as a methodology applicable broadly to small find studies in all archaeological contexts. In our analysis we re-orient towards considering assemblages of dynamic communities of makers, users and identities embedded in these objects’ life histories.
  • Dying 2 Talk: Generating a more compassion community for young people

    Booth, J.; Croucher, Karina; Walters, Elizabeth R.; Sutton-Butler, Aoife; Booth-Boniface, E.; Coe, Mia (2023-12)
    People in the Global North often have a problem talking about — and processing — the inevitability of death. This can be because death and care of the dying has been professionalised, with encounters of death within our families and communities no longer being ‘normal and routine’ (Kellehear 2005). Young people are particularly excluded from these conversations, with implications for future mental health and wellbeing (Ainsley-Green 2017). Working in Wolverhampton and Bradford, the Dying 2 Talk (D2T) project aimed to build young people’s future resilience around this challenging topic. We recruited over 20 young people as project ambassadors to co-produce resources that would encourage talk about death, dying and bereavement. The resources were used as the basis of ‘Festivals of the Dead’ which were taken to schools to engage wider audiences of young people (aged 11 +). The project aimed to use alternative ‘ways in’ to open discussion, beginning with archaeology, and ultimately using gaming, dance, creative writing and other creative outputs to facilitate discussion, encourage compassionate relationships and build resilience. The resources succeeded in engaging young people from ages 11–19 years, facilitating a comfortable and supportive environment for these vital conversations. Project evaluations and observations revealed that the Festivals, and the activities co-created by the young ambassadors helped to facilitate spontaneous conversations about death, dying and bereavement amongst young people by providing a comfortable and supportive environment. The project was funded by the Arts and Humanities Research Council (AH/V008609/1), building on a pilot project funded by the Higher Education Innovation Fund at the University of Bradford.
  • Etiquette in the context of death and dying: Communication and conversation

    2024
    Death, bereavement, and grief are experiences suffused with conflict and disenfranchisement. Intricately connected is ‘etiquette’ – the sense of ‘should’ ‘must’ ‘right’ ‘wrong’ ‘appropriate’ and ‘inappropriate’ individuals feel in death and bereavement situations. This paper is the first of two answering the question, ‘where does etiquette arise in death and bereavement situations and what does this ‘look like?’’ The theme The etiquette of communication and conversation is described, highlighting the importance of early communication for resolving conflict, what is considered ‘appropriate’ communication and support, and the social values underpinning these. Data highlighted how the CBT concept of ‘shoulding and musting’ manifests in death and bereavement situations, gave insight into etiquette’s role in disenfranchising grief through shaping conversations, and offered suggestions for bereavement support. Though the term ‘etiquette’ may be misleading out of context, the concept resonated with the bereaved community and provided language to discuss the nuances of their experiences.
  • A proteomic investigation to discover candidate proteins involved in novel mechanisms of 5-fluorouracil resistance in colorectal cancer

    2024-02
    One of the main obstacles to therapeutic success in colorectal cancer (CRC) is the development of acquired resistance to treatment with drugs such as 5-fluorouracil (5-FU). Whilst some resistance mechanisms are well known, it is clear from the stasis in therapy success rate that much is still unknown. Here, a proteomics approach is taken towards identification of candidate proteins using 5-FU-resistant sublines of human CRC cell lines generated in house. Using a multiplexed stable isotope labelling with amino acids in cell culture (SILAC) strategy, 5-FU-resistant and equivalently passaged sensitive cell lines were compared to parent cell lines by growing in Heavy medium with 2D liquid chromatography and Orbitrap Fusion™ Tribrid™ Mass Spectrometry analysis. Among 3003 commonly quantified proteins, six (CD44, APP, NAGLU, CORO7, AGR2, PLSCR1) were found up-regulated, and six (VPS45, RBMS2, RIOK1, RAP1GDS1, POLR3D, CD55) down-regulated. A total of 11 of the 12 proteins have a known association with drug resistance mechanisms or role in CRC oncogenesis. Validation through immunodetection techniques confirmed high expression of CD44 and CD63, two known drug resistance mediators with elevated proteomics expression results. The information revealed by the sensitivity of this method warrants it as an important tool for elaborating the complexity of acquired drug resistance in CRC.
  • Oncology Activity

    2015-01-15
    The development of therapeutics to treat cancer is conceptually more difficult than for nonlife-threatening diseases for several reasons, including its complex pathophysiological nature, the molecular individuality of each tumor, and the robustness and predictability of preclinical models toward determining efficacy and safety. A major limitation to development of a “blockbuster” therapeutic strategy is the infinite combination of cellular and molecular perturbations and associated heterogeneity of causative genetic factors driving disease progression. Although challenging, the diversity of drug targets, coupled with the lethality of the disease, has encouraged studies of a vast array of approaches and opportunities for disease treatment over the years.
  • Apigenin cocrystals: from computational pre-screening to physicochemical property characterisation

    Makadia, J.; Seaton, Colin C.; Li, M. (2023-05)
    Apigenin (4′,5,7-trihydroxyflavone, APG) has many potential therapeutic benefits; however, its poor aqueous solubility has limited its clinical applications. In this work, a large scale cocrystal screening has been conducted, aiming to discover potential APG cocrystals for enhancement of its solubility and dissolution rate. In order to reduce the number of the experimental screening tests, three computational prescreening tools, i.e., molecular complementarity (MC), hydrogen bond propensity (HBP), and hydrogen bond energy (HBE), were used to provide an initial selection of 47 coformer candidates, leading to the discovery of seven APG cocrystals. Among them, six APG cocrystal structures have been determined by successful growth of single crystals, i.e., apigenin-carbamazepine hydrate 1:1:1 cocrystal, apigenin-1,2-di(pyridin-4-yl)ethane hydrate 1:1:1 cocrystal, apigenin-valerolactam 1:2 cocrystal, apigenin-(dl) proline 1:2 cocrystal, apigenin-(d) proline/(l) proline 1:1 cocrystal. All of the APG cocrystals showed improved dissolution performances with the potential to be formulated into drug products.
  • Cherries with different geographical origins regulate neuroprotection in a photoperiod-dependent manner in F344 rats

    2024-01
    The photoperiod is the main environmental cue that drives seasonal adaptive responses in reproduction, behavior, and metabolism in seasonal animals. Increasing evidence suggests that (poly)phenols contained in fruits can also modulate seasonal rhythms. (Poly)phenol-rich diets are associated with an improvement in cognitive function and neuroprotection due to their anti-inflammatory and antioxidative properties. However, it is unknown whether cherries affect neuroprotection in a photoperiod-dependent manner. To test this, F344 rats were exposed to L6 (6 h light/day), L12 (12 h light/day) and L18 (18 h light/day) photoperiods and fed a standard chow diet supplemented with either a control, lyophilized cherry 1 or cherry 2 with distinctive phenolic hallmarks. Physiological parameters (body weight, eating pattern index (EPI), testosterone, T4/T3) and hypothalamic key genes (Dio2, Dio3, Raldh1 and Ghrh) were strongly regulated by the photoperiod and/or fruit consumption. Importantly, we show for the first time that neurotrophs (Bdnf, Sod1 and Gpx1) in the hippocampus are also regulated by the photoperiod. Furthermore, the consumption of cherry 2, which was richer in total flavonols, but not cherry 1, which was richer in total anthocyanins and flavanols, enhanced neuroprotection in the hippocampus. Our results show that the seasonal consumption of cherry with a specific phenolic composition plays an important role in the hippocampal activation of neuroprotection in a photoperiod-dependent manner.
  • High-fat diet effects on contractile performance of isolated mouse soleus and extensor digitorum longus when supplemented with high dose vitamin D

    Shelley, S.P.; James, Rob S.; Eustace, S.J.; Eyre, E.L.J.; Tallis, J. (2024-02)
    Evidence suggests vitamin D3 (VD) supplementation can reduce accumulation of adipose tissue and inflammation and promote myogenesis in obese individuals, and thus could mitigate obesity-induced reductions in skeletal muscle (SkM) contractility. However, this is yet to be directly investigated. This study, using the work-loop technique, examined effects of VD (cholecalciferol) supplementation on isolated SkM contractility. Female mice (n = 37) consumed standard low-fat diet (SLD) or high-fat diet (HFD), with or without VD (20,000 IU/kg-1 ) for 12 weeks. Soleus and EDL (n = 8-10 per muscle per group) were isolated and absolute and normalized (to muscle size and body mass) isometric force and power output (PO) were measured, and fatigue resistance determined. Absolute and normalized isometric force and PO of soleus were unaffected by diet (P > 0.087). However, PO normalized to body mass was reduced in HFD groups (P  0.588). HFD reduced EDL isometric stress (P = 0.048) and absolute and normalized PO (P  0.493). Cumulative work during fatiguing contractions was lower in HFD groups (P  0.060). This study uniquely demonstrated that high-dose VD had limited effects on SkM contractility and did not offset demonstrated adverse effects of HFD. However, small and moderate effect sizes suggest improvement in EDL muscle performance and animal morphology in HFD VD groups. Given effect sizes observed, coupled with proposed inverted U-shaped dose-effect curve, future investigations are needed to determine dose/duration specific responses to VD, which may culminate in improved function of HFD SkM. NEW FINDINGS: What is the central question of this study? Can vitamin D supplementation alleviate detrimental effects of high-fat diet (HFD) consumption on contractile performance of isolated skeletal muscles? What is the main finding and its importance? The present study is the first to examine the synergistic effects of HFD consumption and vitamin D supplementation on the contractile performance of isolated skeletal muscle. These findings suggest high dose vitamin D has limited effects on force, power or fatigue resistance of isolated mouse soleus and extensor digitorum longus.
  • Evaluating the irritant factors of silicone and hydrocolloid skin contact adhesives using trans-epidermal water loss, protein stripping, erythema, and ease of removal

    Dyson, Edward; Sikkink, Stephen; Nocita, Davide; Twigg, Peter C.; Westgate, Gillian E.; Swift, Thomas (2024-01)
    A composite silicone skin adhesive material was designed to improve its water vapor permeability to offer advantages to wearer comfort compared to existing skin adhesive dressings available (including perforated silicone and hydrocolloid products). The chemical and mechanical properties of this novel dressing were analyzed to show that it has a high creep compliance, offering anisotropic elasticity that is likely to place less stress on the skin. A participant study was carried out in which 31 participants wore a novel silicone skin adhesive (Sil2) and a hydrocolloid competitor and were monitored for physiological response to the dressings. Trans-epidermal water loss (TEWL) was measured pre- and postwear to determine impairment of skin barrier function. Sil2 exhibited a higher vapor permeability than the hydrocolloid dressings during wear. Peel strength measurements and dye counter staining of the removed dressings showed that the hydrocolloid had a higher adhesion to the participants’ skin, resulting in a greater removal of proteins from the stratum corneum and a higher pain rating from participants on removal. Once the dressings were removed, TEWL of the participants skin beneath the Sil2 was close to normal in comparison to the hydrocolloid dressings that showed an increase in skin TEWL, indicating that the skin had been highly occluded. Analysis of the skin immediately after removal showed a higher incidence of erythema following application of hydrocolloid dressings (>60%) compared to Sil2, (
  • Germ cell determination and the developmental origin of germ cell tumors

    2021-04
    In each generation, the germline is tasked with producing somatic lineages that form the body, and segregating a population of cells for gametogenesis. During animal development, when do cells of the germline irreversibly commit to producing gametes? Integrating findings from diverse species, we conclude that the final commitment of the germline to gametogenesis - the process of germ cell determination - occurs after primordial germ cells (PGCs) colonize the gonads. Combining this understanding with medical findings, we present a model whereby germ cell tumors arise from cells that failed to undertake germ cell determination, regardless of their having colonized the gonads. We propose that the diversity of cell types present in these tumors reflects the broad developmental potential of migratory PGCs.
  • Advancing clinical and translational research in germ cell tumours (GCT): recommendations from the Malignant Germ Cell International Consortium

    2022-11
    Germ cell tumours (GCTs) are a heterogeneous group of rare neoplasms that present in different anatomical sites and across a wide spectrum of patient ages from birth through to adulthood. Once these strata are applied, cohort numbers become modest, hindering inferences regarding management and therapeutic advances. Moreover, patients with GCTs are treated by different medical professionals including paediatric oncologists, neuro-oncologists, medical oncologists, neurosurgeons, gynaecological oncologists, surgeons, and urologists. Silos of care have thus formed, further hampering knowledge dissemination between specialists. Dedicated biobank specimen collection is therefore critical to foster continuous growth in our understanding of similarities and differences by age, gender, and site, particularly for rare cancers such as GCTs. Here, the Malignant Germ Cell International Consortium provides a framework to create a sustainable, global research infrastructure that facilitates acquisition of tissue and liquid biopsies together with matched clinical data sets that reflect the diversity of GCTs. Such an effort would create an invaluable repository of clinical and biological data which can underpin international collaborations that span professional boundaries, translate into clinical practice, and ultimately impact patient outcomes.
  • Effect of myopia management contact lens design on accommodative microfluctuations and eye movements during reading

    Ghorbani Mojarrad, Neema; Hussain, M.; Mankowska, Aleksandra; Mallen, Edward A.H.; Cufflin, Matthew P. (2024-02)
    Background: Soft contact lenses have been developed and licensed for reducing myopia progression. These lenses have different designs, such as extended depth of focus (EDOF) and dual focus (DF). In this prospective, doublemasked, cross-over study, different lens designs were investigated to see whether these had impact on accommodative microfluctuations and eye movements during reading. Methods: Participants were fitted with three lenses in a randomised order; a single vision (SV) design (Omafilcon A2; Proclear), a DF design (Omafilcon A2; MiSight), and an EDOF lens design (Etafilcon A; NaturalVue),. Accommodative microfluctuations were measured at 25 cm for at least 60s in each lens, using a Shin-Nippon SRW-5000 autorefractor adapted to continuously record accommodation at 22Hz. Eye movement data was collected with the Thomson Clinical Eye Tracker incorporating a Tobii Eye bar. Eye movements include fixations per row, fixations per minute, mean regressions per row, total number of regressions, and total rightward saccades. Accommodation data was analysed using power spectrum analysis. Differences between the lenses were compared using a related sample two-way Friedman test. Results: Twenty-three participants (18–29 years) were recruited to take part. The average mean spherical error was − 2.65D ± 1.42DS, with an average age of 23.4 ± 3.5 years. No significant difference for accommodative microfluctuations was found. Significant differences were found for fixations per row (P = 0.03), fixations per minute (P = 0.008), mean regressions per row (P = 0.002), and total number of regressions (P = 0.002), but not total rightward saccades (P = 0.10). Post-hoc analysis indicated the EDOF lens results were significantly different from the other lenses, with more regressive eye movements observed. Conclusions: Regressive saccades appear to increase when wearing EDOF lens designs, which may impact visual comfort. Further studies in children, over a longer period of adaptation are necessary to assess the potential impact of this finding on daily reading activities in children.

View more