Now showing items 61-80 of 2619

    • A rapid approach to the digital documentation of Bradford's rich industrial heritage

      Moore, Joseph; Gaffney, Christopher F.; Sparrow, Thomas; Irving, H.; Ali, S.; Middleton, R.; Campbell, S.; Ackroyd, J.; Walker, A.; Simpson, S.; et al. (Springer Nature, 2022-04)
      The industrial heritage for the City of Bradford Metropolitan District is of international significance, with the city formerly being the centre of the world’s worsted trade during the nineteenth century. The intensification of textile production during the industrial revolution resulted in exponential growth of all aspects of the city, the legacy seen in the townscape heritage of the city today. The structures from this period have played a key role in defining the city’s identity. Since the decline of the textile industry the fabric of many of these buildings from the city’s golden age are under threat and at high risk of loss due to weathering, vandalism and fire. Given the varied nature and condition of these structures, a rapid approach has been applied that complements initiatives in train with Bradford Council to regenerate the ‘Top of Town’; that are reflective of Historic England’s ‘Engines of Prosperity’ report into the regeneration of Industrial Heritage; and with the Management of Saltaire World Heritage site. This chapter focuses on the digital documentation of a conservation area which is highly vulnerable, producing a dataset to aid conservation, management, interpretation and promotion of Bradford’s rich heritage.
    • Digital refit analysis of anthropogenically fragmented equine bone from the Schoningen 13 II-4 Deposits, Germany

      Holland, Andrew D.; Hutson, J.M.; Villaluenga, A.; Sparrow, Thomas; Murgatroyd, Andrew; García-Moreno, A.; Turner, E.; Evans, Adrian A.; Gaudzinski-Windheuser, S.; Wilson, Andrew S. (Springer Nature, 2022-04)
      Excavation of the Schöningen lignite mine in Germany produced the earliest examples of hunting spears to date, and a large assemblage of anthropogenically fragmented faunal remains deposited in anaerobic lacustrine silt sediments during the Middle Pleistocene. The exceptional preservation of the assemblage makes the site of prime importance to our understanding of the behavioural, social and economic patterns of hominins in the Lower Palaeolithic of the Middle Pleistocene in Europe. This chapter describes the digital refitting analysis, part of the AHRC-funded Fragmented Heritage project, undertaken to address the logistical challenge posed by manually comparing individual bone fragments within the assemblage to identify refitting sequences. This logistical refit challenge uses the Schöningen assemblage to investigate the effectiveness of a digital refit approach to the analysis of large faunal assemblages. We describe the process from digitisation of the bone fragments by macro structured light scanning, digital segmentation of refitting surfaces, and digital comparison of the refitting and non-refitting surfaces to produce statistical matches. We discuss how taphonomic data can be visualised from the analysis and can be used to inform interpretation of the taphonomic histories of these faunal remains and the human behaviours associated with the formation of this unique assemblage.
    • Getting the measure of brochs: using survey records old and new to investigate Shetland's Iron Age archaeology

      Sou, Li Z.; Bond, Julie M.; Dockrill, Stephen J.; Hepher, J.; Rawlinson, A.; Sparrow, Thomas; Turner, V.; Wilson, L.; Wilson, Andrew S. (Springer Nature, 2022-04)
      Brochs are monumental Iron Age (c.400–200 BC) drystone towers or roundhouses. They are only found in Scotland, particularly the Atlantic north and west. Whilst the structural layout of brochs has long been debated, few measured surveys have been conducted. Three significant broch sites form the tentative World Heritage site of “Mousa, Old Scatness and Jarlshof: the Zenith of Iron Age Shetland” (UNESCO in Mousa, Old Scatness and Jarlshof: the zenith of Iron Age Shetland, UNESCO (2019) Mousa, Old Scatness and Jarlshof: the zenith of Iron Age Shetland. Accessed 9 Aug 2019). All three sites have undergone new surveys as part of a collaborative doctoral partnership research project. This chapter presents a diachronic perspective using digital documentation techniques to detect stone displacement and weathering at the site of Old Scatness using historic imagery, including photographs from the Old Scatness excavations (1995–2006) and regular condition monitoring undertaken by Shetland Amenity Trust to undertake retrospective digital structure-from-motion (SfM) photogrammetry. Whilst point clouds and 3D meshes were successfully generated from low-resolution digital images, analogue film transparencies without metadata could not produce accurate geospatial data without manually trying to extant reference data. It was possible to detect displacements in stonework over time by comparing two meshes together and measuring the distances between vertex point pairs. The reliability and accuracy of these results were dependent on how well pairs of meshes could be aligned.
    • Visualising animal hard tissues

      O'Connor, Sonia A.; Sparrow, Thomas; Holland, Andrew D.; Kershaw, Rachael; Brown, Emma L.; Janaway, Robert C.; Ugail, Hassan; Wilson, Andrew S. (Springer Nature, 2022-04)
      This chapter summarises AHRC/EPSRC Science and Heritage Programme-funded research to develop a digital resource to disseminate knowledge of the identification of osseous and keratinous animal hard tissues. The choice of materials in the manufacture of individual artefacts or classes of objects can make a major contribution to understanding their cultural significance and questions of provenance or authenticity. This resource builds on understanding gained through a Fellowship to O’Connor in developing, evaluating and validating identification criteria for these materials in raw, worked and decayed states. The resource concentrates on the non-destructive visual methods of particular relevance to the examination of artworks, historic and archaeological artefacts. The chapter highlights the potential of various visualisation methods and digital technologies to capture and combine 2D images and 3D models and guide the viewer through the multi-scalar visual cues of each material to a reliable identification. By accessing a range of collections, the project has produced a comprehensive and accessible resource, disseminating these findings more widely than could be achieved by a physical reference collection. This resource supports the identification of cultural heritage objects for conservation scientists and heritage professionals and informs the fight against the illegal hunting and trafficking of rare and endangered species.
    • Curious Travellers: Using web-scraped and crowd-sourced imagery in support of heritage under threat

      Wilson, Andrew S.; Gaffney, Vincent L.; Gaffney, Christopher F.; Ch'ng, E.; Bates, R.; Ichumbaki, E.B.; Sears, G.; Sparrow, Thomas; Murgatroyd, Andrew; Faber, Edward; et al. (Springer, 2022-04)
      Designed as a pragmatic approach that anticipates change to cultural heritage, this chapter discusses responses that encompass records for tangible cultural heritage (monuments, sites and landscapes) and the narratives that see the impact upon them. The Curious Travellers project provides a mechanism for digitally documenting heritage sites that have been destroyed or are under immediate threat from unsympathetic development, neglect, natural disasters, conflict and cultural vandalism. The project created and tested data-mining and crowd-sourced workflows that enable the accurate digital documentation and 3D visualisation of buildings, archaeological sites, monuments and heritage at risk. When combined with donated content, image data are used to recreate 3D models of endangered and lost monuments and heritage sites using a combination of open-source and proprietary methods. These models are queried against contextual information, helping to place and interrogate structures with relevant site and landscape data for the surrounding environment. Geospatial records such as aerial imagery and 3D mobile mapping laser scan data serve as a framework for adding new content and testing accuracy. In preserving time-event records, image metadata offers important information on visitor habits and conservation pressures, which can be used to inform measures for site management.
    • Zirconium-based MOFs and their biodegradable polymer composites for controlled and sustainable delivery of herbicides

      Mahmoud, L.A.M.; Telford, Richard; Livesey, T.C.; Katsikogianni, Maria G.; Kelly, Adrian L.; Terry, L.R.; Ting, V.P.; Nayak, Sanjit (2022-07-29)
      Adsorption and controlled release of agrochemicals has been studied widely using different nanomaterials and a variety of formulations. However, the potential for application of high surface-area metal-organic frameworks (MOFs) for the controlled release of agrochemicals has not been thoroughly explored. Herein, we report controlled and sustainable release of a widely used herbicide (2-methyl-4-chlorophenoxyacetic acid, MCPA) via incorporation in a range of zirconium-based MOFs and their biodegradable polymer composites. Three Zr-based MOFs, viz., UiO-66, UiO-66-NH2, and UiO-67 were loaded with MCPA either postsynthetically or in situ during synthesis of the MOFs. The MCPA-loaded MOFs were then incorporated into a biodegradable polycaprolactone (PCL) composite membrane. All three MOFs and their PCL composites were thoroughly characterized using FT-IR, TGA, SEM, PXRD, BET, and mass spectrometry. Release of MCPA from each of these MOFs and their PCL composites was then studied in both distilled water and in ethanol for up to 72 h using HPLC. The best performance for MCPA release was observed for the postsynthetically loaded MOFs, with PS-MCPA@UiO-66-NH2 showing the highest MCPA concentrations in ethanol and water of 0.056 and 0.037 mg/mL, respectively. Enhanced release of MCPA was observed in distilled water when the MOFs were incorporated in PCL. The concentrations of herbicides in the release studies provide us with a range of inhibitory concentrations that can be utilized depending on the crop, making this class of composite materials a promising new route for future agricultural applications.
    • Generation and Use of Functional Hydrogels That Can Rapidly Sample Infected Surfaces

      Swift, Thomas; Pinnock, A.; Shivshetty, N.; Pownall, David; MacNeil, S.; Douglas, I.; Garg, P.; Rimmer, Stephen (2022-04)
      This paper outlined our method for developing polymer-linked contact lens type materials for rapid detection and differentiation of Gram-positive, Gram-negative bacteria and fungi in infected corneas. It can be applied to both model synthetic or ex-vivo corneal models and has been successfully trialed in an initial efficacy tested animal study. First a hydrogel substrate for the swab material is selected, we have demonstrated selective swabs using a glycerol monomethacrylate hydrogel. Alternatively any commercial material with carboxylic acid functional groups is suitable but risks nonspecific adhesion. This is then functionalised via use of N-hydroxysuccinimide reaction with amine groups on the specified highly branched polymer ligand (either individually gram negative, gram positive or fungal binding polymers or a combination of all three can be employed for desired sensing application). The hydrogel is then cut into swabs suitable for sampling, used, and then the presence of gram positive, game negative and fungi are disclosed by the sequential addition of dyes (fluorescent vancomycin, fluorescein isothiocyanate and calcofluor white). In summary this method presents: Method to produce glycerol monomethacrylate hydrogels to minimize nonspecific binding Methods of attaching pathogen binding highly branched polymers to produce selective hydrogel swabs Method for disclosing bound pathogens to this swab using sequential dye addition
    • Fluorescence spectroscopy analysis of fly ash removal from aqueous systems: adsorption of alginate to silica and alumina

      Eltaboni, F.; Singh, Sehaj; Swanson, L.; Swift, Thomas; Almalki, A.S.A. (2022-07)
      Fly ash is a toxic industrial waste, mainly consisting of silica and alumina particles, that has been found discharged into the environment. It is proposed that alginate, a naturally occurring biopolymer, can bind to these minerals and thus play a role in water purification. The binding forces involved in this process consist of weak interactions, such as van der Waals forces and electrostatic interactions. Although the attachment of alginate to mineral surfaces is mainly governed by its carboxylate groups, hydroxyl moieties could play a role in the interaction between the polymer and minerals. This work aims to use the SiO2 and Al2O3 particles as models for fly ash and to show the use of alginate biopolymers (fluorescently labelled with an aminonaphthaline sulfonate fluorophore (AmNS)) to coagulate them. The addition of simple electrolytes like NaCl and CaCl2 encourages the coiling of the polymer chain at high pH values which has an effect on its capability to bind to the inorganic particles. A combination of fluorescence and ICP-MS demonstrated that alginate has a considerable adsorption affinity for Al2O3, whereas it attracts SiO2 weakly. The adsorption process is pH dependent: strong adsorption was observed at low pH values. The dependence of adsorption on the mineral (Al2O3 and SiO2) concentration was also examined under different pH conditions: the adsorption amount was observed to increase by increasing the solid concentration. Adsorption isotherms obtained at low and high mineral concentrations were found to be Henry in type.
    • USP5 enhances SGTA mediated protein quality control.

      Hill, J.; Nyathi, Yvonne (2022-07)
      Mislocalised membrane proteins (MLPs) present a risk to the cell due to exposed hydrophobic amino acids which cause MLPs to aggregate. Previous studies identified SGTA as a key component of the machinery that regulates the quality control of MLPs. Overexpression of SGTA promotes deubiqutination of MLPs resulting in their accumulation in cytosolic inclusions, suggesting SGTA acts in collaboration with deubiquitinating enzymes (DUBs) to exert these effects. However, the DUBs that play a role in this process have not been identified. In this study we have identified the ubiquitin specific peptidase 5 (USP5) as a DUB important in regulating the quality control of MLPs. We show that USP5 is in complex with SGTA, and this association is increased in the presence of an MLP. Overexpression of SGTA results in an increase in steady-state levels of MLPs suggesting a delay in proteasomal degradation of substrates. However, our results show that this effect is strongly dependent on the presence of USP5. We find that in the absence of USP5, the ability of SGTA to increase the steady state levels of MLPs is compromised. Moreover, knockdown of USP5 results in a reduction in the steady state levels of MLPs, while overexpression of USP5 increases the steady state levels. Our findings suggest that the interaction of SGTA with USP5 enables specific MLPs to escape proteasomal degradation allowing selective modulation of MLP quality control. These findings progress our understanding of aggregate formation, a hallmark in a range of neurodegenerative diseases and type II diabetes, as well as physiological processes of aggregate clearance.
    • Kinship practices in Early Iron Age southeast Europe: genetic and isotopic analysis of burials from the Dolge njive barrow cemetery, Dolenjska, Slovenia

      Armit, I.; Fischer, C-E.; Koon, Hannah E.C.; Nicholls, Rebecca A.; Olalde, I.; Rohland, N.; Buckberry, Jo; Montgomery, J.; Mason, P.; Cresnar, M.; et al. (2023-04)
      DNA analysis demonstrates that all seven individuals buried in an Early Iron Age barrow at Dolge njive, southeast Slovenia, are close biological relatives. Although group composition does not suggest strict adherence to a patrilineal or matrilineal kinship system, the funerary tradition appears highly gendered, with family links through both the male and female line being important in structuring communities. We explore the implications for our understandings of kinship and funerary practices in Early Iron Age southeast Europe.
    • Experiences of patients with heart failure with medicines at transition intervention: Findings from the process evaluation of the Improving the Safety and Continuity of Medicines management at Transitions of care (ISCOMAT) programme

      Powell, Catherine; Ismail, Hanif; Davis, M.; Taylor, A.; Breen, Liz; Fylan, Beth; Alderson, S.L.; Gale, C.P.; Kellar, Ian; Silcock, Jonathan; et al. (Wiley International, 2022-10)
      Abstract: Background: Medicines are often suboptimally managed for heart failure patients across the transition from hospital to home, potentially leading to poor patient outcomes. The Improving the Safety and Continuity Of Medicines management at Transitions of care programme included: understanding the problems faced by patients and healthcare professionals; developing and co-designing the Medicines at Transitions of care Intervention (MaTI); a cluster randomized controlled trial testing the effectiveness of a complex behavioural MaTI aimed at improving medicines management at the interface between hospitals discharge and community care for patients with heart failure; and a process evaluation. The MaTI included a patient-held My Medicines Toolkit; enhanced communication between the hospital and the patient's community pharmacist and increased engagement of the community pharmacist postdischarge. This paper reports on the patients' experiences of the MaTI and its implementation from the process evaluation. Design: Twenty one-to-one semi-structured patient interviews from six intervention sites were conducted between November 2018 and January 2020. Data were analysed using the Framework method, involving patients as co-analysts. Interview data were triangulated with routine trial data, the Consolidated Framework for Implementation Research and a logic model. Results: Within the hospital setting patients engaged with the toolkit according to whether staff raised awareness of the My Medicines Toolkit's importance and the time and place of its introduction. Patients' engagement with community pharmacy depended on their awareness of the community pharmacist's role, support sources and perceptions of involvement in medicines management. The toolkit's impact on patients' medicines management at home included reassurance during gaps in care, increased knowledge of medicines, enhanced ability to monitor health and seek support and supporting sharing medicines management between formal and informal care networks. Conclusion: Many patients perceived that the MaTI offered them support in their medicines management when transitioning from hospital into the community. Importantly, it can be incorporated into and built upon patients' lived experiences of heart failure. Key to its successful implementation is the quality of engagement of healthcare professionals in introducing the intervention. Patient or Public Contribution: Patients were involved in the study design, as qualitative data co-analysts and as co-authors.
    • Synthesis of orthogonal push-pull chromophores via click reaction of arylynamines

      Huang, S.; Ma, J.; Yi, Y.; Li, M.; Cai, P.; Wu, Na (Anna) (2022-04)
      Herein, we report a catalyst-free ‘click’ reaction: metal-free [2 + 2] cycloaddition–retro-electrocyclisation (CA–RE) of arylynamines with the sluggish acceptor tetracyanoquinodimethane (TCNQ) to provide orthogonal electron-push–pull light-harvesting small molecules: N-heterocyclic dicyanoquinodimethane-substituted methylene malononitriles. Ynamines are reactive alkynes and tend to induce over-reactions with the CA–RE adducts. The reactivity of arylynamines was balanced properly by ensuring the electrondensity of the nitrogen atom was delocalised more over the aromatic rings than the triple bond.
    • New aldo-keto reductase 1C3 (AKR1C3) inhibitors based on the hydroxytriazole scaffold

      Pippione, A.C.; Kilic-Kurt, Z.; Kovachka, S.; Sainas, S.; Rolando, B.; Denasio, E.; Pors, Klaus; Adinolfi, S.; Zonari, D.; Bagnati, R.; et al. (2022-07-05)
      The aldo-keto reductase 1C3 (AKR1C3) enzyme is considered an attractive target in Castration Resistant Prostate Cancer (CRPC) because of its role in the biosynthesis of androgens. Flufenamic acid, a non-selective AKR1C3 inhibitor, has previously been subjected to bioisosteric modulation to give rise to a series of compounds with the hydroxytriazole core. In this work, the hit compound of the previous series has been modulated further, and new, more potent, and selective derivatives have been obtained. The poor solubility of the most active compound (cpd 5) has been improved by substituting the triazole core with an isoxazole heteronucleous, with similar enzymatic activity being retained. Potent AKR1C3 inhibition is translated into antiproliferative effects against the 22RV1 CRPC cellular model, and the in-silico design, synthesis and biological activity of new compounds is described herein. Compounds have also been assayed in combination with two approved antitumor drugs, abiraterone and enzalutamide.
    • Anticancer water-soluble organoruthenium complexes: synthesis and preclinical evaluation

      Pitto-Barry, Anaïs; Azmanova, Maria; Rafols, Laia; Cooper, Patricia A.; Seaton, Colin C.; Shnyder, Steven D. (2022-09)
      The synthesis, characterisation, and evaluation of the in vitro cytotoxicity of five maleonitriledithiolate-based ruthenium metal complexes bearing various phosphine ligands towards two ovarian cancer cell lines (A2780 and A2780cisR), one non-small-cell lung cancer cell line (H460) and one normal prostate cell line (PNT2) are presented herein. These 18-electron complexes were designed with four water-soluble phosphine ligands to increase the water-solubility character of the corresponding electron-deficient ruthenium complex which showed great in vitro promises, and triphenylphosphine for comparison. The complexes with triphenylphosphine-3,3',3''trisulfonic acid and triphenylphosphine present similar cytotoxicity compared to the 16-electron precursor, with equal cytotoxicity to both A2780 and A2780cisR. Hints at the mechanism of action suggest an apoptotic pathway based on ROS production. No toxicity was observed in preliminary in vivo pilot studies for these two complexes in subcutaneous A2780 and A2780cisR xenograft models, with some evidence of tumour growth delay.
    • Controlled bioactive delivery using degradable electroactive polymers

      Ashton, M.D.; Cooper, Patricia A.; Municoy, S.; Desimone, M.F.; Cheneler, D.; Shnyder, Steven D.; Hardy, J.G. (2022-07)
      Biomaterials capable of precisely controlling the delivery of agrochemicals/biologics/drugs/fragrances have significant markets in the agriscience/healthcare industries. Here, we report the development of degradable electroactive polymers and their application for the controlled delivery of a clinically relevant drug (the anti-inflammatory dexamethasone phosphate, DMP). Electroactive copolymers composed of blocks of polycaprolactone (PCL) and naturally occurring electroactive pyrrole oligomers (e.g., bilirubin, biliverdin, and hemin) were prepared and solution-processed to produce films (optionally doped with DMP). A combination of in silico/in vitro/in vivo studies demonstrated the cytocompatibility of the polymers. The release of DMP in response to the application of an electrical stimulus was observed to be enhanced by ca. 10-30% relative to the passive release from nonstimulated samples in vitro. Such stimuli-responsive biomaterials have the potential for integration devices capable of delivering a variety of molecules for technical/medical applications.
    • The impact of industrialization on malignant neoplastic disease of bone in England: a study of medieval and industrial samples

      Soria, Sabrina; Buckberry, Jo (2022-09)
      Objective: The increasing prevalence of malignant disease has been associated with shifts in environmental, socioeconomic, and lifestyle risk factors as well as increased adult lifespan. We examine the relationship between malignant neoplasms affecting bone, age and industrialization. Materials: Pre-existing skeletal data from 11 medieval (1066-1547, n=8,973) and 14 industrial (1700-1890, n=4,748) cemeteries (N=13,721) from England. Methods: Context number, sex, age-at-death, evidence of skeletal malignancy, and diagnosis were collated. The data were compared using chi square, Kolmogorov-Smirnov tests and logistic regression (α=0.01). Results: There was a statistically significant increase in skeletal malignancy from 0.06% in the medieval sample to 0.36) in the industrial sample (p< 0.001). Age had a strong relationship with malignancy (p = 0.003), sex did not (p = 0.464). Logistic regression revealed that time-period (p < 0.001) was a stronger predictor of skeletal malignancy than age-at-death (p = 0.002). Conclusion: Our results confirm that even with the temporal increase in adult human lifespan the increase of malignant neoplasms of bone between the medieval and industrial time periods is still statistically significant. Significance: The augmented exposure to carcinogens and pollution during the Industrial Revolution had a strong effect on an individual’s susceptibility to developing malignant disease of bone. Limitations: This meta-analysis relies upon previously gathered data and diagnosis from a large number of researchers and did not include radiographic or CT screening. Only malignant neoplasms that affected bone could be included. Suggestions for further research: Increasing excavation and analysis of post-medieval cemeteries will provide more data. Multimethod approaches (radiography, CT, Micro-CT and histology) are encouraged.
    • The Chemerin-CMKLR1 Axis is Functionally important for Central Regulation of Energy Homeostasis

      Yun, Haesung; Dumbell, R.; Hanna, Katie; Bowen, Junior; McLean, Samantha L.; Kantamneni, Sriharsha; Pors, Klaus; Wu, Q-F; Helfer, Gisela (2022-05)
      Chemerin is an adipokine involved in inflammation, adipogenesis, angiogenesis and energy metabolism, and has been hypothesized as a link between obesity and type II diabetes. In humans affected by obesity, chemerin gene expression in peripheral tissues and circulating levels are elevated. In mice, plasma levels of chemerin are upregulated by high-fat feeding and gain and loss of function studies show an association of chemerin with body weight, food intake and glucose homeostasis. Therefore, chemerin is an important blood-borne mediator that, amongst its other functions, controls appetite and body weight. Almost all studies of chemerin to date have focused on its release from adipose tissue and its effects on peripheral tissues with the central effects largely overlooked. To demonstrate a central role of chemerin, we manipulated chemerin signaling in the hypothalamus, a brain region associated with appetite regulation, using pharmacological and genetic manipulation approaches. Firstly, the selective chemerin receptor CMKLR1 antagonist α-NETA was administered i.c.v. to rats to test for an acute physiological effect. Secondly, we designed a short-hairpin-RNA (shRNA) lentivirus construct targeting expression of CMKLR1. This shRNA construct, or a control construct was injected bilaterally into the arcuate nucleus of male Sprague Dawley rats on high-fat diet (45%). After surgery, rats were maintained on high-fat diet for 2 weeks and then switched to chow diet for a further 2 weeks. We found a significant weight loss acutely and inhibition of weight gain chronically. This difference became apparent after diet switch in arcuate nucleus-CMKLR1 knockdown rats. This was not accompanied by a difference in blood glucose levels. Interestingly, appetite-regulating neuropeptides remained unaltered, however, we found a significant reduction of the inflammatory marker TNF-α suggesting reduced expression of CMKLR1 protects from high-fat diet induced neuroinflammation. In white and brown adipose tissue, mRNA expression of chemerin, its receptors and markers of adipogenesis, lipogenesis and brown adipocyte activation remained unchanged confirming that the effects are driven by the brain. Our behavioral analyses suggest that knockdown of CMKLR1 had an impact on object recognition. Our data demonstrate that CMKLR1 is functionally important for the central effects of chemerin on body weight regulation and neuroinflammation.
    • Intermittent PI3Ko inhibition sustains anti-tumor immunity and curbs irAEs

      Eschweiler, S.; Ramirez-Suastegui, C.; Li, Y.; King, E.; Chudley, L.; Thomas, J.; Wood, O.; von Witzleben, A.; Jeffrey, D.; McCann, K.; et al. (2022-05-26)
      Phosphoinositide 3-kinase δ (PI3Kδ) has a key role in lymphocytes, and inhibitors that target this PI3K have been approved for treatment of B cell malignancies1–3. Although studies in mouse models of solid tumours have demonstrated that PI3Kδ inhibitors (PI3Kδi) can induce anti-tumour immunity4,5, its effect on solid tumours in humans remains unclear. Here we assessed the effects of the PI3Kδi AMG319 in human patients with head and neck cancer in a neoadjuvant, double-blind, placebo-controlled randomized phase II trial (EudraCT no. 2014-004388-20). PI3Kδ inhibition decreased the number of tumour-infiltrating regulatory T (Treg) cells and enhanced the cytotoxic potential of tumour-infiltrating T cells. At the tested doses of AMG319, immune-related adverse events (irAEs) required treatment to be discontinued in 12 out of 21 of patients treated with AMG319, suggestive of systemic effects on Treg cells. Accordingly, in mouse models, PI3Kδi decreased the number of Treg cells systemically and caused colitis. Single-cell RNA-sequencing analysis revealed a PI3Kδi-driven loss of tissue-resident colonic ST2 Treg cells, accompanied by expansion of pathogenic T helper 17 (TH17) and type 17 CD8+ T (TC17) cells, which probably contributed to toxicity; this points towards a specific mode of action for the emergence of irAEs. A modified treatment regimen with intermittent dosing of PI3Kδi in mouse models led to a significant decrease in tumour growth without inducing pathogenic T cells in colonic tissue, indicating that alternative dosing regimens might limit toxicity.
    • Phenotypic differences between microvascular and macrovascular smooth muscle cells and their contribution to coronary microvascular dysfunction

      Riches-Suman, Kirsten (2021-06-11)
      Coronary microvascular dysfunction (CMD) is an under-diagnosed condition characterized by functional alteration of the small coronary arterioles and the cardiac capillary bed. The vessels do not dilate appropriately in response to changes in cardiac oxygen demand, leading to chest pain and symptoms of angina. These blood vessels contain two major cell types: the endothelial cells, which line the blood vessels and detect changes in oxygen demand, and smooth muscle cells (SMC) which respond to these changes by contracting or relaxing to provide an optimal blood supply to the cardiac tissue. Many CMD studies have focused on the endothelial cells as these cells secrete vasorelaxants and vasoconstrictors. However, comparably fewer studies have examined SMC despite their functional role in contracting and relaxing. A variety of health conditions and lifestyle choices, such as diabetes, hypertension and cigarette smoking, can promote the development of both CMD and macrovascular coronary artery disease; a condition where SMC have been studied extensively. This review article will consider the influence of CMD on SMC phenotype. It will discuss the structural, cellular and molecular changes in CMD, and will summarise how co-morbidities can have differing effects on micro- and macro-vascular SMC phenotype and function, which complicates the development of new therapeutic avenues for CMD.
    • Diverse roles of microRNA-145 in regulating smooth muscle (dys)function in health and disease

      Riches-Suman, Kirsten (2021-02-22)
      MicroRNAs are short, non-coding RNAs that target messenger RNAs for degradation. miR-145 is a vascular-enriched microRNA that is important for smooth muscle cell (SMC) differentiation. Under healthy circumstances, SMC exist in a contractile, differentiated phenotype promoted by miR-145. In cases of disease or injury, SMC can undergo reversible dedifferentiation into a synthetic phenotype, accompanied by inhibition of miR-145 expression. Vascular disorders such as atherosclerosis and neointimal hyperplasia are characterised by aberrant phenotypic switching in SMC. This review will summarise the physiological roles of miR-145 in vascular SMC, including the molecular regulation of differentiation, proliferation and migration. Furthermore, it will discuss the different ways in which miR-145 can be dysregulated and the downstream impact this has on the progression of vascular pathologies. Finally, it will discuss whether miR-145 may be suitable for use as a biomarker of vascular disease.