Recent Submissions

  • Towards identifying potent new hits for glioblastoma

    Sherer, Chris; Prabhu, Saurabh; Adams, David; Hayes, Joseph; Rowther, Farzana; Tolaymat, Ibrahim; Warr, Tracy; Snape, Timothy J. (Royal Society of Chemistry, 2018-10-02)
    Glioblastoma is a devastating disease of the brain and is the most common malignant primary brain tumour in adults. The prognosis for patients is very poor with median time of survival after diagnosis measured in months, due in part to the tumours being highly aggressive and often resistant to chemotherapies. Alongside the ongoing research to identify key factors involved in tumour progression in glioblastoma, medicinal chemistry approaches must also be used in order to rapidly establish new and better treatments for brain tumour patients. Using a computational similarity search of the ZINC database, alongside traditional analogue design by medicinal chemistry intuition to improve the breadth of chemical space under consideration, six new hit compounds (14, 16, 18, 19, 20 and 22) were identified possessing low micromolar activity against both established cell lines (U87MG and U251MG) and patient-derived cell cultures (IN1472, IN1528 and IN1760). Each of these scaffolds provides a new platform for future development of a new therapy in this area, with particular promise shown against glioblastoma subtypes that are resistant to conventional chemotherapeutic agents.
  • Genomic and transcriptomic characterisation of undifferentiated pleomorphic sarcoma of bone

    Ali, Naser M.; Niada, Stefania; Brini, Anna T.; Morris, Mark R.; Kurusamy, Sathishkumar; Alholle, Abdullah; Huen, David; Antonescu, Cristina R.; Tirode, Franck; Sumathi, Vaiyapuri; Latif, Farida (Wiley, 2018-10-03)
    Undifferentiated pleomorphic sarcoma of bone (UPSb), is a rare primary bone sarcoma that lacks a specific line of differentiation. There is very little information about the genetic alterations leading to tumourigenesis or malignant transformation. Distinguishing between UPSb and other malignant bone sarcomas, including dedifferentiated chondrosarcoma and osteosarcoma, can be challenging due to overlapping features. To explore the genomic and transcriptomic landscape of UPSb tumours, whole-exome sequencing (WES) and RNA Sequencing (RNA-Seq) were performed on UPSb tumours. All tumours lacked hotspot mutations in IDH1/2 132 or 172 codons, thereby excluding the diagnosis of dedifferentiated chondrosarcoma. Recurrent somatic mutations in TP53 were identified in 4/14 samples (29%). Moreover, recurrent mutations in histone chromatin remodelling genes, including H3F3A, ATRX and DOT1L, were identified in 5/14 samples (36%), highlighting the potential role of deregulated chromatin remodelling pathways in UPSb tumourigenesis. The majority of recurrent mutations in chromatin remodelling genes identified here are reported in COSMIC, including the H3F3A G35 and K36 hotspot residues. Copy number alteration analysis identified gains and losses in genes that have been previously altered in UPSb or UPS of soft tissue. Eight somatic gene fusions were identified by RNA-Seq, two of which, CLTC-VMP1 and FARP1-STK24, were reported previously in multiple cancers. Five gene fusions were genomically characterised. Hierarchical clustering analysis, using RNA-Seq data, distinctly clustered UPSb tumours from osteosarcoma and other sarcomas, thus molecularly distinguishing UPSb from other sarcomas. RNA-Seq expression profiling analysis and quantitative RT-PCR showed an elevated expression in FGF23 which can be a potential molecular biomarker in UPSb. To our knowledge, this study represents the first comprehensive WES and RNA-Seq analysis of UPSb tumours revealing novel protein-coding recurrent gene mutations, gene fusions and identifying a potential UPSb molecular biomarker, thereby broadening the understanding of the pathogenic mechanisms and highlighting the possibility of developing novel targeted therapeutics.
  • 10 Marked differences in the pharmacokinetic and pharmacodynamic profiles of ticagrelor in patients undergoing treatment for ST elevation and non ST elevation myocardial infarction (stemi and nstemi)

    Khan, Nazish; Amoah, Vincent; Cornes, Mike; Martins, Joe; Wrigley, Ben; Khogali, Saib; Nevill, Alan M.; Cotton, James (BMJ Publishing Group, 2018-06-01)
    Introduction Ticagrelor, an orally administered, direct acting, reversible P2Y12 receptor inhibitor, provides faster onset and greater levels of platelet inhibition when compared to clopidogrel. Current data indicates a reduced antiplatelet effect in STEMI. We sought to determine the early pharmacokinetic (PK) and pharmacodynamic (PD) effect of ticagrelor loading doses administered to patients undergoing PCI for STEMI and NSTEMI. Methods This is a single centre non-randomised study. P2Y12 naive patients presenting with STEMI or NSTEMI were considered for inclusion. All patients gave informed consent. Enrolled patients were administered a loading dose of aspirin 300 mg and ticagrelor 180 mg prior to PCI. Blood was sampled at 20 min, coronary balloon time, 1 hour and 4 hours after loading. PD results are expressed as P2Y12 reaction units (PRU) and were assessed using VerifyNow. A PRU>208 indicates a sub-optimal antiplatelet response. PK properties were assessed by measuring plasma concentration of ticagrelor parent compound (T-PC) and active metabolite (T-AM) using liquid chromatography in tandem with mass spectrometry. The lower limits of quantification of T-PC and its active metabolite, AR-C124910XX (T-AM) are 1 ng/ml and 2.5 ng/ml respectively. PRU and plasma concentrations over time were tested between the two groups using 2-way ANOVA. p<0.05 was considered significant. Results 30 patients (15 STEMI/15 NSTEMI) were recruited. Baseline characteristics are described in Table 1.
  • A new waist-to-height ratio predicts abdominal adiposity in adults.

    Nevill, Alan M.; Stewart, Arthur D; Olds, Tim; Duncan, Michael J (Taylor & Francis, 2018-07-25)
    Our aim was to identify the best anthropometric index associated with waist adiposity. The six weight-status indices included body mass index (BMI), waist-to-hip ratio (WHR), waist-to-height ratio (WHTR), and a new waist-by-height
  • The effect of walking on risk factors for cardiovascular disease: an updated systematic review and meta-analysis of randomised control trials.

    Murtagh, Elaine M; Nichols, Linda; Mohammed, Mohammed A; Holder, Roger; Nevill, Alan M.; Murphy, Marie H (Elsevier, 2015-03)
    Objective To conduct a systematic review and meta-analysis of randomised control trials that examined the effect of walking on risk factors for cardiovascular disease.Methods Four electronic databases and reference lists were searched (Jan 1971–June 2012). Two authors identified randomised control trials of interventions ≥ 4 weeks in duration that included at least one group with walking as the only treatment and a no-exercise comparator group. Participants were inactive at baseline. Pooled results were reported as weighted mean treatment effects and 95% confidence intervals using a random effects model. Results 32 articles reported the effects of walking interventions on cardiovascular disease risk factors. Walking increased aerobic capacity (3.04 mL/kg/min, 95% CI 2.48 to 3.60) and reduced systolic (− 3.58 mm Hg, 95% CI − 5.19 to − 1.97) and diastolic (− 1.54 mm Hg, 95% CI − 2.83 to − 0.26) blood pressure, waist circumference (− 1.51 cm, 95% CI − 2.34 to − 0.68), weight (− 1.37 kg, 95% CI − 1.75 to − 1.00), percentage body fat (− 1.22%, 95% CI − 1.70 to − 0.73) and body mass index (− 0.53 kg/m2, 95% CI − 0.72 to − 0.35) but failed to alter blood lipids. Conclusions Walking interventions improve many risk factors for cardiovascular disease. This underscores the central role of walking in physical activity for health promotion.
  • Faster, higher, stronger, older: Relative age effects are most influential during the youngest age grade of track and field athletics in the United Kingdom.

    Kearney, Philip E; Hayes, Philip R; Nevill, Alan M. (Taylor & Francis, 2018-03-07)
    The relative age effect (RAE) is a common phenomenon in youth sport, whereby children born early in the selection year are more likely to experience success and to sustain participation. There is a lack of research investigating variables which influence RAEs within track and field athletics. Such information is vital to guide policies in relation to competition structure, youth development squads and coach education. A database of competition results was analysed to determine the extent to which RAEs were present in track and field athletics in the United Kingdom. Subsequent analyses examined whether age, sex, event and skill level influenced the RAE. Examination of 77,571 records revealed that RAEs were widespread, but most pronounced during Under 13 (U13) competitions; that is, during athletes' first exposure to formal track and field competition. Sex, event and skill level further influenced the existence and magnitude of RAEs at different age grades. Relative age is a key influencing factor within track and field athletics, especially at the youngest age category. Consequently, national governing bodies need to consider what administrative and stakeholder initiatives are necessary to minimise the effects of RAEs on young athletes' early experiences of competition.
  • How Does a Photocatalytic Antimicrobial Coating Affect Environmental Bioburden in Hospitals?

    Reid, Matthew; Whatley, Vanessa; Spooner, Emma; Nevill, Alan M.; Cooper, Michael; Ramsden, Jeremy J; Dancer, Stephanie J (Cambridge University Press, 2018-04)
    BACKGROUND The healthcare environment is recognized as a source for healthcare-acquired infection. Because cleaning practices are often erratic and always intermittent, we hypothesize that continuously antimicrobial surfaces offer superior control of surface bioburden. OBJECTIVE To evaluate the impact of a photocatalytic antimicrobial coating at near-patient, high-touch sites in a hospital ward. SETTING The study took place in 2 acute-care wards in a large acute-care hospital. METHODS A titanium dioxide-based photocatalytic coating was sprayed onto 6 surfaces in a 4-bed bay in a ward and compared under normal illumination against the same surfaces in an untreated ward: right and left bed rails, bed control, bedside locker, overbed table, and bed footboard. Using standardized methods, the overall microbial burden and presence of an indicator pathogen (Staphylococcus aureus) were assessed biweekly for 12 weeks. RESULTS Treated surfaces demonstrated significantly lower microbial burden than control sites, and the difference increased between treated and untreated surfaces during the study. Hygiene failures (>2.5 colony-forming units [CFU]/cm2) increased 2.6% per day for control surfaces (odds ratio [OR], 1.026; 95% confidence interval [CI], 1.009-1.043; P=.003) but declined 2.5% per day for treated surfaces (OR, 0.95; 95% CI, 0.925-0.977; P<.001). We detected no significant difference between coated and control surfaces regarding S. aureus contamination. CONCLUSION Photocatalytic coatings reduced the bioburden of high-risk surfaces in the healthcare environment. Treated surfaces became steadily cleaner, while untreated surfaces accumulated bioburden. This evaluation encourages a larger-scale investigation to ascertain whether the observed environmental amelioration has an effect on healthcare-acquired infection. Infect Control Hosp Epidemiol 2018;39:398-404.
  • 100-m Breaststroke Swimming Performance in Youth Swimmers: The Predictive Value of Anthropometrics.

    Sammoud, Senda; Nevill, Alan M.; Negra, Yassine; Bouguezzi, Raja; Chaabene, Helmi; Hachana, Younés (Human Kinetics, 2018-03-16)
    This study aimed to estimate the optimal body size, limb segment length, and girth or breadth ratios of 100-m breaststroke performance in youth swimmers. In total, 59 swimmers [male: n = 39, age = 11.5 (1.3) y; female: n = 20, age = 12.0 (1.0) y] participated in this study. To identify size/shape characteristics associated with 100-m breaststroke swimming performance, we computed a multiplicative allometric log-linear regression model, which was refined using backward elimination. Results showed that the 100-m breaststroke performance revealed a significant negative association with fat mass and a significant positive association with the segment length ratio (arm ratio = hand length/forearm length) and limb girth ratio (girth ratio = forearm girth/wrist girth). In addition, leg length, biacromial breadth, and biiliocristal breadth revealed significant positive associations with the 100-m breaststroke performance. However, height and body mass did not contribute to the model, suggesting that the advantage of longer levers was limb-specific rather than a general whole-body advantage. In fact, it is only by adopting multiplicative allometric models that the previously mentioned ratios could have been derived. These results highlighted the importance of considering anthropometric characteristics of youth breaststroke swimmers for talent identification and/or athlete monitoring purposes. In addition, these findings may assist orienting swimmers to the appropriate stroke based on their anthropometric characteristics.
  • Cell-Penetrating Peptides

    Howl, John; Jones, Sarah (2015)
    The multi-domain architecture of many human proteins provides a structural basis for the physical maintenance of interactomes, or networks of protein-protein interactions (PPIs), that are so obviously crucial to cellular functions. Moreover, the structural and electrostatic complementarity provided by PPI interfaces, predominantly located on protein surfaces, is a fundamental component of signal transduction events that are known to be compromised in human diseases including many cancers.The pharmacokinetic advantages provided by cell-penetrating peptides (CPPs) are entirely compatible with the development of intrinsically permeable agents capable of modulating intracellular PPIs. Thus, the term bioportide is a useful descriptor of numerous bioactive CPPs that are distinct from the more usual inert CPP vectors. Herein we illustrate a generic strategy, predominantly centered upon the identification of cationic peptides derived from helical protein domains, which offers a reliable platform to identify bioportides capable of modulating intracellular signal transduction events. In addition, we describe robust methodologies to determine the precise intracellular distribution of fluorescent bioportides and present assays routinely employed to screen for the detrimental pharmacodynamic properties often exhibited by both CPPs and bioportides; namely adverse cytotoxicity and the receptor-independent stimulation of mast cell secretion.
  • Long-term quality of life postacute kidney injury in cardiac surgery patients.

    Mishra, Pankaj Kumar; Luckraz, Heyman; Nandi, Jayanta; Nevill, Alan M.; Giri, Ramesh; Panayiotou, Andrew; Nicholas, Johann (Wolters Kluwer, 2018)
    Acute renal failure after cardiac surgery is known to be associated with significant short-term morbidity and mortality. There have as yet been no major reports on long-term quality of life (QOL). This study assessed the impact of acute kidney injury (AKI) and renal replacement therapy (RRT) on long-term survival and QOL after cardiac surgery. The need for long-term RRT is also assessed.
  • Modeling children's development in gross motor coordination reveals key modifiable determinants. An Allometric approach.

    Dos Santos, Marcos André M; Nevill, Alan M.; Buranarugsa, Rojapon; Pereira, Sara; Ferreira Gomes, Thayse Natacha Q; Reyes, Ana; Barnett, Lisa M; Maia, José António R (Wiley, 2018-01-24)
    Children change their body size, shape and gross motor coordination (GMC) as they grow. Further, GMC is expected to link to changes in children's body size, physical activity (PA) and physical fitness (PF). The objective was to model GMC changes in children followed longitudinally and to investigate associations between these changes and PA and PF levels. A total of 245 children (122 girls) were observed at 6 years of age and followed annually until 9 years. A sequence of allometric models were fitted, i.e.: 1. body mass, stature and PA; 2. addition of four PF tests; 3. addition of four more PF tests. In Model 1, changes in GMC are non-linear, and body mass (-0.60±0.07, p<0.001) and stature (2.91±0.35, p<0.001) parameter estimates were significant suggesting children with a more linear body size/shape showed higher GMC performances. Girls tend to outperform boys across time, and PA was not associated with GMC changes. Model 2 fitted the data better, and the PF tests (handgrip, standing long jump, 50-yard dash and shuttle-run) were significantly linked to GMC change. In Model 3, adding the remaining PF tests did not change the order of any factors importance. The greatest GMC changes were achieved by children whose body size/shape has an ectomorphic dominance across the years. Considering that leaner and physically fitter children tended to be more coordinated, physical education should also focus on PF development in components related to muscular strength, speed, agility and aerobic capacity, along with nutritional education to reduce fat mass.
  • Major adverse cardiac and cerebrovascular event and patients' quality of life after endoscopic vein harvesting as compared with open vein harvest (MAQEH): a pilot study.

    Luckraz, Heyman; Cartwright, Carly; Nagarajan, Kumaresan; Kaur, Prabhjeet; Nevill, Alan M. (BMJ, 2018)
    This is a prospective, comparative, pilot and follow-up (2-year postoperatively) study in patients undergoing coronary artery bypass graft surgery where the long saphenous vein was harvested either by the endoscopic vein harvest (EVH) technique or open vein harvest (OVH) technique. Quality of life (QOL) and major adverse cardiac and cerebrovascular events (MACCE) were assessed.
  • Effects of a peer-led Walking In ScHools intervention (the WISH study) on physical activity levels of adolescent girls: a cluster randomised pilot study.

    Carlin, Angela; Murphy, Marie H; Nevill, Alan M.; Gallagher, Alison M (BMC, 2018-01-11)
    School-based interventions may be effective at increasing levels of physical activity (PA) among adolescents; however, there is a paucity of evidence on whether walking can be successfully promoted to increase PA in this age group. This pilot study aimed to assess the effects of a 12-week school-based peer-led brisk walking programme on levels of school-time PA post intervention.
  • South Asian Children Have Increased Body Fat in Comparison to White Children at the Same Body Mass Index.

    Eyre, Emma L J; Duncan, Michael J; Nevill, Alan M. (MDPI, 2017-11-22)
    The ability of body mass index (BMI) to predict excess fat in South Asian children is unknown. This cross-sectional study examines the influence of ethnicity on body fatness in children. Weight status and body fat were determined using BMI, waist circumference (WC), two skinfold sites (SF; triceps and subscapula) and leg-to-leg bioelectrical impedance analysis (BIA; Tanita BF350, Tanita, Tokyo, Japan) in 194 children aged 8.47 ± 0.50 years from Coventry, United Kingdom. Biological maturity was also determined. Analysis of covariance (ANCOVA) identified significant differences between ethnic (p < 0.001) and gender groups' BMI (p = 0.026), with a significant covariate for skinfold (p < 0.001) and bioelectrical impedance (p < 0.001). For a given body fat value, South Asian children and females had a lower BMI value (-1.12 kg/m², p < 0.001 and -0.50 kg/m², p = 0.026, respectively, when adjusted for SF; -1.56 kg/m², p < 0.001 and -0.31 kg/m², p = 0.16, respectively, when adjusted for BIA) compared with white children and boys. The prediction model including ethnicity, gender and BIA explained 80.4% of the variance in BMI. Maturation was not found to be a significant covariate (p > 0.05). To conclude, the findings suggest that BMI cut-points may need to be lowered in South Asian children, and thus age-by-sex-by-ethnicity specific BMI cut-points are needed in children. Further research examining body composition with health parameters in this population is needed.
  • Randomised controlled trial of a home-based physical activity intervention in breast cancer survivors

    Lahart, Ian M.; Metsios, George S.; Nevill, Alan M.; Kitas, George D.; Carmichael, Amtul R. (2016-03-17)
    Background: To improve adherence to physical activity (PA), behavioural support in the form of behavioural change counselling may be necessary. However, limited evidence of the effectiveness of home-based PA combined with counselling in breast cancer patients exists. The aim of this current randomised controlled trial with a parallel group design was to evaluate the effectiveness of a home-based PA intervention on PA levels, anthropometric measures, health-related quality of life (HRQoL), and blood biomarkers in breast cancer survivors. Methods: Eighty post-adjuvant therapy invasive breast cancer patients (age = 53.6 ± 9.4 years; height = 161.2 ± 6.8 cm; mass = 68.7 ± 10.5 kg) were randomly allocated to a 6-month home-based PA intervention or usual care. The intervention group received face-to-face and telephone PA counselling aimed at encouraging the achievement of current recommended PA guidelines. All patients were evaluated for our primary outcome, PA (International PA Questionnaire) and secondary outcomes, mass, BMI, body fat %, HRQoL (Functional assessment of Cancer Therapy-Breast), insulin resistance, triglycerides (TG) and total (TC), high-density lipoprotein (HDL-C) and low-density lipoprotein (LDL-C) cholesterol were assessed at baseline and at 6-months. Results: On the basis of linear mixed-model analyses adjusted for baseline values performed on 40 patients in each group, total, leisure and vigorous PA significantly increased from baseline to post-intervention in the intervention compared to usual care (between-group differences, 578.5 MET-min∙wk−1, p = .024, 382.2 MET-min∙wk−1, p = .010, and 264.1 MET-min∙wk−1, p = .007, respectively). Both body mass and BMI decreased significantly in the intervention compared to usual care (between-group differences, −1.6 kg, p = .040, and −.6 kg/m2, p = .020, respectively). Of the HRQoL variables, FACT-Breast, Trial Outcome Index, functional wellbeing, and breast cancer subscale improved significantly in the PA group compared to the usual care group (between-group differences, 5.1, p= .024; 5.6, p = .001; 1.9 p = .025; and 2.8, p=.007, respectively). Finally, TC and LDL-C was significantly reduced in the PA group compared to the usual care group (between-group differences, −.38 mmol∙L−1, p=.001; and −.3 mmol∙L−1, p=.023, respectively). Conclusions: We found that home-based PA resulted in significant albeit small to moderate improvements in selfreported PA, mass, BMI, breast cancer specific HRQoL, and TC and LDL-C compared with usual care.
  • The use of the RenalGuard system in cardiac surgery with cardiopulmonary bypass: a first in man prospective, observational, feasibility pilot study

    Luckraz, Heyman; Giri, Ramesh; Wrigley, Benmjamin; Hennessy, Anne-Marie; Nicholas, Johann; Nevill, Alan M. (BMJ Publishing Group, 2017-10-10)
    Objectives As proof of concept, this prospective, observational study assessed the feasibility and early clinical outcomes of performing on-pump cardiac surgery with the RenalGuard system. Background Acute kidney injury (AKI) is reported in up to 30% of patients undergoing cardiac surgery and is a recognised independent predictor of both morbidity and mortality. Forced diuresis with the RenalGuard system reduces the incidence of AKI during percutaneous coronary intervention procedures but its use in cardiac surgery has not been explored. Methods Ten consecutive patients who were at risk of developing AKI during cardiac surgery were selected. The RenalGuard system was used to facilitate forced diuresis using weight-adjusted intravenous furosemide while maintaining neutral fluid balance by matched intravenous fluid replacement. This regimen was initiated preoperatively in all patients and continued for 6–12 hours postoperatively. Serum creatinine, electrolytes and need for renal replacement were documented in all patients. Results The RenalGuard system functioned successfully in all patients and facilitated high perioperative urine outputs, even when patients were placed on cardiopulmonary bypass (CPB). There were no incidences of significant (A) electrolyte imbalance, (B) changes in haemoglobin levels or (C) pulmonary oedema. No patients developed AKI within 36 hours of surgery despite one patient developing cardiac tamponade 8 hours postoperatively and one patient developing paralytic ileus. One patient, however, was ‘electively’ haemofiltered on day 2 after developing acute right ventricular failure. The median intensive care stay was 1.5 (1, 5) days. Conclusion The RenalGuard system can be used successfully in patients undergoing cardiac surgery with CPB and may reduce the incidence of AKI in at-risk patients.
  • Exercise training reduces alcohol consumption but does not affect HPA-axis activity in heavy drinkers.

    Georgakouli, Kalliopi; Manthou, Eirini; Georgoulias, Panagiotis; Ziaka, Anastasia; Fatouros, Ioannis G; Mastorakos, Georgios; Koutedakis, Yiannis; Theodorakis, Yannis; Jamurtas, Athanasios Z (Elsevier, 2017-10-01)
    It has been suggested that physical exercise could have potential beneficial effects in substance abusers, which are based on both physiological and psychological theories. Although a few studies have examined the effect of exercise on alcohol intake and fitness in individuals with alcohol use disorders (AUDs), there is a gap in the literature concerning the physiological and biochemical mechanisms that could be affected by physical exercise in this population.
  • A Comparison of Exercise-Induced Muscle Damage Following Maximal Eccentric Contractions in Men and Boys.

    Deli, Chariklia K; Fatouros, Ioannis G; Paschalis, Vassilis; Georgakouli, Kalliopi; Zalavras, Athanasios; Avloniti, Alexandra; Koutedakis, Yiannis; Jamurtas, Athanasios Z (Human Kinetics, 2017-08)
    Research regarding exercise-induced muscle-damage mainly focuses on adults. The present study examined exercise-induced muscle-damage responses in adults compared with children.

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