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1. Deletion of Apoptosis Inhibitor F1L in Vaccinia Virus Increases Safety and Oncolysis for Cancer Therapy

Author

Adrian Pelin, Johann Foloppe, Julia Petryk, Ragunath Singaravelu, Marian Hussein, Florian Gossart, Victoria A. Jennings, Lawton J. Stubbert, Madison Foster, Christopher Storbeck, Antonio Postigo, Elena Scut, Brian Laight, Michael Way, Philippe Erbs, Fabrice Le Boeuf, and John C. Bell

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Vaccinia virus (VACV) possesses a great safety record as a smallpox vaccine and has been intensively used as an oncolytic virus against various types of cancer over the past decade. Different strategies were developed to make VACV safe and selective to cancer cells. Leading clinical candidates, such as Pexa-Vec, are attenuated through deletion of the viral thymidine kinase (TK) gene, which limits virus growth to replicate in cancer tissue. However, tumors are not the only tissues whose metabolic activity can overcome the lack of viral TK. In this study, we sought to further increase the tumor-specific replication and oncolytic potential of Copenhagen strain VACV ΔTK. We show that deletion of the anti-apoptosis viral gene F1L not only increases the safety of the Copenhagen ΔTK virus but also improves its oncolytic activity in an aggressive glioblastoma model. The additional loss of F1L does not affect VACV replication capacity, yet its ability to induce cancer cell death is significantly increased. Our results also indicate that cell death induced by the Copenhagen ΔTK/F1L mutant releases more immunogenic signals, as indicated by increased levels of IL-1β production. A cytotoxicity screen in an NCI-60 panel shows that the ΔTK/F1L virus induces faster tumor cell death in different cancer types. Most importantly, we show that, compared to the TK-deleted virus, the ΔTK/F1L virus is attenuated in human normal cells and causes fewer pox lesions in murine models. Collectively, our findings describe a new oncolytic vaccinia deletion strain that improves safety and increases tumor cell killing.

Published
2019
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2. The Contribution of Transactivation Subdomains 1 and 2 to p53-Induced Gene Expression Is Heterogeneous But Not Subdomain-Specific

Author

Jennifer M. Smith, Lawton J. Stubbert, Jeffrey D. Hamill, and Bruce C. McKay

Subjects
p53, gene expression, microarray, transcription factor, apoptosis, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Two adjacent regions within the transactivation domain of p53 are sufficient to support sequence-specific transactivation when fused to a heterologous DNA binding domain. It has been hypothesized that these two subdomains of p53 may contribute to the expression of distinct p53-responsive genes. Here we have used oligonucleotide microarrays to identify transcripts induced by variants of p53 with point mutations within subdomains 1, 2, or 1 and 2 (QS1, QS2, QS1/QS2, respectively). The expression of 254 transcripts was increased in response to wild-type p53 expression but most of these transcripts were poorly induced by these variants of p53. Strikingly, a number of known p53regulated transcripts including TNFRSF10B, BAX, BTG2, POLH were increased to wild-type levels by p53QS1 and p53QS2 but not p53QS1/QS2, indicating that either sub domain 1 or 2 is sufficient for p53-dependent expression of a small subset of p53-responsive genes. Unexpectedly, there was no evidence for p53QS1- or p53QS2-specific gene expression. Taken together, we found heterogeneity in the requirement for transactivation subdomains 1 and 2 of p53 without any subdomain-specific contribution to p53-induced gene expression.

Published
2007
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6. Investigation of the cir multi-gene family of Plasmodium chabaudi

Author

Lawton, J. C.

Subjects
616
Abstract

The pir genes comprise the largest multi-gene family in Plasmodium, with members found in P. vivax, P. knowlesi and rodent malaria species. Despite their almost universal presence, little is known about the functions of the PIR proteins. To investigate the role PIR proteins play during the erythrocytic stages of infection, the P. chabaudi model was chosen, where this gene family is termed cir. 198 cir genes were identified in the P. chabaudi genome, 86% of which clustered to form two major sub-families on the basis of sequence similarity. Quantitative RT-PCR and Illumina RNA sequencing were used to investigate cir transcription during P. chabaudi infection. Both methods detected many cir genes transcribed at low levels, as shown previously for other pirs. Three of the transcribed cir genes were selected for recombinant protein expression in the yeast Pichia pastoris: PCHAS_000100, PCHAS_070130 and PCHAS_040110. Soluble PCHAS_000100 was used for measurements of CIR secondary structure. Conserved and sub-family specific peptides were also synthesized. Antibodies present in the sera of P. chabaudi immune mice recognized all CIR proteins and peptides. Polyclonal antibodies were used to determine CIR localization by confocal microscopy and flow cytometry. Whilst most CIRs were located within the parasites, some CIRs were also found on the infected erythrocyte surface of mature trophozoites. In addition, CIRs were detected at the apical end of merozoites. These results imply that CIR proteins are exposed to the immune system during P. chabaudi infection and are antigenic, yet immunization with most CIR proteins and peptides did not protect mice from P. chabaudi infection. Upon P. chabaudi challenge of mice immunized with CIR sub-family specific reagents, increased levels of cir transcripts belonging to the other major sub-family were detected. This may explain why few differences in parasitaemia were observed. The exception was observed during P. chabaudi challenge of mice immunized with PCHAS_000100, which were able to clear parasitaemia earlier than controls.

Published
2012

7. TPACK in times of Emergency Remote Teaching: Status of Newly-Hired Public School Teachers

Author

Lawton J. Dy

Subjects
General Medicine
Abstract

This study aimed to evaluate the status of newly-hired public school teachers in terms of their TPACK Components and Emergency Remote Teaching (ERT) as indicated in their e-learning readiness, perceived effectiveness, attitude, satisfaction, and anxiety. Quantitative research particularly the correlational research design was employed in this study. Thirty-four(34) purposefully selected newly hired public school teachers were the participants of the study. Results showed that among the TPACK components, those that have technology integration were among the areas where teacher-participants need major improvement. Their ERT Readiness scores showed 55.5% of the teacher-participants scored low in e-Learning Readiness, 55.9% scored moderately in perceived effectiveness, 73.5% were neutral in terms of attitude towards ERT, 58.8% moderately satisfied with ERT implementation, and 61.8% showed no anxiety. Findings showed a moderately positive and significant correlation between perceived effectiveness and attitude (r=.56, p

Published
2022

9. Ecosystem Effects of Biodiversity Manipulations in European Grasslands

Author

Spehn, E. M., Hector, A., Joshi, J., Scherer-Lorenzen, M., Schmid, B., Bazeley-White, E., Beierkuhnlein, C., Caldeira, M. C., Diemer, M., Dimitrakopoulos, P. G., Finn, J. A., Freitas, H., Giller, P. S., Good, J., Harris, R., Högberg, P., Huss-Danell, K., Jumpponen, A., Koricheva, J., Leadley, P. W., Loreau, M., Minns, A., Mulder, C. P. H., O'Donovan, G., Otway, S. J., Pereira, J. S., Pfisterer, A. B., Prinz, A., Read, D. J., Terry, A. C., Troumbis, A. Y., Woodward, F. I., Yachi, S., and Lawton, J. H.

Published
2005

12. Impacts of Soil Faunal Community Composition on Model Grassland Ecosystems

Author

Bradford, M. A., Jones, T. H., Bardgett, R. D., Black, H. I. J., Boag, B., Bonkowski, M., Cook, R., Eggers, T., Gange, A. C., Grayston, S. J., Kandeler, E., McCaig, A. E., Newington, J. E., Prosser, J. I., Setälä, H., Staddon, P. L., Tordoff, G. M., Tscherko, D., and Lawton, J. H.

Published
2002

15. Dedication

Author

Glaser, Joel S., primary, Schatz, Norman J., additional, Smith, Lawton J., additional, Lessell, Simmons, additional, and Rizzo, Joseph F., additional

Published
2019
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17. Plant Diversity and Productivity Experiments in European Grasslands

Author

Hector, A., Schmid, B., Beierkuhnlein, C., Caldeira, M. C., Diemer, M., Dimitrakopoulos, P. G., Finn, J. A., Freitas, H., Giller, P. S., Good, J., Harris, R., Högberg, P., Huss-Danell, K., Joshi, J., Jumpponen, A., Körner, C., Leadley, P. W., Loreau, M., Minns, A., Mulder, C. P. H., O'Donovan, G., Otway, S. J., Pereira, J. S., Prinz, A., Read, D. J., Scherer-Lorenzen, M., Schulze, E. D., Siamantziouras, A. S. D., Spehn, E. M., Terry, A. C., Troumbis, A. Y., Woodward, F. I., Yachi, S., and Lawton, J. H.

Published
1999

21. Data from Re-engineering Vesicular Stomatitis Virus to Abrogate Neurotoxicity, Circumvent Humoral Immunity, and Enhance Oncolytic Potency

Author

Muik, Alexander, primary, Stubbert, Lawton J., primary, Jahedi, Roza Z., primary, Geiβ, Yvonne, primary, Kimpel, Janine, primary, Dold, Catherine, primary, Tober, Reinhard, primary, Volk, Andreas, primary, Klein, Sabine, primary, Dietrich, Ursula, primary, Yadollahi, Beta, primary, Falls, Theresa, primary, Miletic, Hrvoje, primary, Stojdl, David, primary, Bell, John C., primary, and von Laer, Dorothee, primary

Published
2023
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22. Supplementary Figures 1 - 7 from Re-engineering Vesicular Stomatitis Virus to Abrogate Neurotoxicity, Circumvent Humoral Immunity, and Enhance Oncolytic Potency

Author

Muik, Alexander, primary, Stubbert, Lawton J., primary, Jahedi, Roza Z., primary, Geiβ, Yvonne, primary, Kimpel, Janine, primary, Dold, Catherine, primary, Tober, Reinhard, primary, Volk, Andreas, primary, Klein, Sabine, primary, Dietrich, Ursula, primary, Yadollahi, Beta, primary, Falls, Theresa, primary, Miletic, Hrvoje, primary, Stojdl, David, primary, Bell, John C., primary, and von Laer, Dorothee, primary

Published
2023
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28. Expert systematic review on the choice of conduits for coronary artery bypass grafting: endorsed by the European Association for Cardio-Thoracic Surgery (EACTS) and The Society of Thoracic Surgeons (STS).

Author

Gaudino, M, Bakaeen, FG, Sandner, S, Aldea, GS, Arai, H, Chikwe, J, Firestone, S, Fremes, SE, Gomes, WJ, Bong-Kim, K, Kisson, K, Kurlansky, P, Lawton, J, Navia, D, Puskas, JD, Ruel, M, Sabik, JF, Schwann, TA, Taggart, DP, Tatoulis, J, Wyler von Ballmoos, M, Gaudino, M, Bakaeen, FG, Sandner, S, Aldea, GS, Arai, H, Chikwe, J, Firestone, S, Fremes, SE, Gomes, WJ, Bong-Kim, K, Kisson, K, Kurlansky, P, Lawton, J, Navia, D, Puskas, JD, Ruel, M, Sabik, JF, Schwann, TA, Taggart, DP, Tatoulis, J, and Wyler von Ballmoos, M

Published
2023

30. Supplementary Figures 1 - 7 from Re-engineering Vesicular Stomatitis Virus to Abrogate Neurotoxicity, Circumvent Humoral Immunity, and Enhance Oncolytic Potency

Author

Dorothee von Laer, John C. Bell, David Stojdl, Hrvoje Miletic, Theresa Falls, Beta Yadollahi, Ursula Dietrich, Sabine Klein, Andreas Volk, Reinhard Tober, Catherine Dold, Janine Kimpel, Yvonne Geiβ, Roza Z. Jahedi, Lawton J. Stubbert, and Alexander Muik

Abstract

PDF file - 6330KB, Schematic representation of the recombinant vesicular stomatitis virus (VSV) genomes and its replication potential (S1). rVSV(GP) administration i.c. is associated with marginal inflammation (S2). rVSV(GP) tissue distribution after systemic application is almost consistent with rVSV (S3). rVSV(GP) is comparable to rVSV with regard to its in vitro antitumour efficacy (S4). Replication fitness of rVSV(GP) vs. rVSV in glioma cells (S5). Intratumoural virus administration in s.c. G62 human glioblastoma xenografts leads to productive infection and massive viral burst (S6). U87rfp tumour relapse was not due to OV therapy resistance (S7).

Published
2023

31. Adolescents' Views about a Proposed Rewards Intervention to Promote Healthy Food Choice in Secondary School Canteens

Author

McEvoy, C. T., Lawton, J., Kee, F., Young, I. S., Woodside, J. V., McBratney, J., and McKinley, M. C.

Abstract

Using rewards may be an effective method to positively influence adolescent eating behaviour, but evidence regarding this approach is limited. The aim of this study was to explore young adolescent views about a proposed reward intervention associated with food choice in school canteens. Focus groups were held in 10 schools located in lower socioeconomic areas within Northern Ireland and involved 90 pupils aged 11-12 years (54 girls, 36 boys). Our findings indicated a high degree of acceptability for a reward scheme but there was major diversity in the type of rewards valued by pupils, largely defined by geographical area and socio-cultural differences. Pupils from rural areas tended to emphasize group-based and longer-term rewards, whereas pupils from urban-city schools tended to suggest individualistic and immediate rewards. The major factors influencing food choice were food price, value for money, taste and visual appearance. Pupils felt that factors outside of their control, such as being assigned to the second lunch sitting placed considerable constraints on their food choice. This research not only indicated a high degree of acceptability for a rewards-based intervention but also highlighted a number of socio-cultural and environmental factors that should be considered by researchers when developing such an intervention.

Published
2014
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34. Cambridge hybrid closed-loop system in very young children with type 1 diabetes reduces caregivers’ fear of hypoglycemia and improves their well-being

Author

de Beaufort, Carine, Schierloh, Ulrike, Thankamony, A., Ware, J., Wilinska, M.E., Fröhlich-Reiterer, E., Kapellen, T.M., Rami-Merhar, Hofer, S.E., Campbell, F.M., Bocchino, L.E., Lawton, J., Rioze, S., Hood, K., Frisch, M., Thiele, A., Allen, J., Boughton, C., Hovorka, R., and Pit-Ten Cate, Ineke

Subjects
Very young children, Endocrinology, metabolism & nutrition [D06] [Human health sciences], Type 1 Diabetes, closed loop insulin delivery, Endocrinologie, métabolisme & nutrition [D06] [Sciences de la santé humaine]
Abstract

Objective To evaluate the impact of CamAPS FX hybrid closed-loop automated insulin delivery (HCL) in very young children with type 1 diabetes (T1D) on caregivers’ well-being, fear of hypoglycemia and sleepiness. Research Design Multinational, open label, randomized crossover study. Children (1-7years) with T1D received treatment for two 4-month periods in random order, comparing HCL with sensor augmented pump (SAP) (control). At baseline and after each treatment period, caregivers were invited to complete WHO-5, Hypoglycemia Fear Survey (HFS) and Epworth Sleepiness Scale (ESS). Results Caregivers of 74 children (mean±SD: age 5±2 years; 42% female, baseline HbA1c 7.3±0.7%) participated. Results revealed significantly lower scores for hypoglycemia fear (p

Published
2022

41. The Influence of the Secondary School Setting on the Food Practices of Young Teenagers from Disadvantaged Backgrounds in Scotland

Author

Wills, W., Backett-Milburn, K., Gregory, S., and Lawton, J.

Abstract

In this paper, we explore the secondary school environment as an important context for understanding young teenagers eating habits and food practices. We draw on data collected during semi-structured interviews with 36 young teenagers (aged 13/14 years) living in disadvantaged circumstances in Scotland. We found that the systems inherent in school had an impact on what, where and when participants ate their lunch. Each school had rules governing use of the school dining hall and participants sometimes chose to leave this environment to buy food outside school premises. Our interviews showed that parents determined how much money young people took to school and, therefore, had some control over their food choices. Participants rarely spoke of giving priority to food and eating during the non-curriculum parts of the school day, preferring to spend time "hanging out" with friends. Eating with friends was sometimes reported as a cause of anxiety, particularly when participants had concerns about body image, appetite or appearance. We suggest that young teenagers dislike for queuing for food, their ability to budget for food at school and their desire to maximize time spent with friends influence food choices; therefore, these are issues which have implications for health education and will be of interest to those responsible for school meal provision.

Published
2005
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47. Nature positive 2030 - evidence report

Author

Brotherton, P., Anderson, H., Galbraith, C., Isaac, D., Lawton, J., Lewis, M., Mainwaring-Evans, T., McGuckin, S., Ormerod, S., Osowska, F., Sizeland, P., Stuart, E., Walmsley, C., Waters, R., and Wilkinson, S.

Published
2021

48. Who gains clinical benefit from using insulin pump therapy? A qualitative study of the perceptions and views of health professionals involved in the Relative Effectiveness of Pumps over MDI and Structured Education (REPOSE) trial

Author

Lawton, J., Kirkham, J., Rankin, D., White, D. A., Elliott, J., Jaap, A., Smithson, W. H., Heller, S., Gianfrancesco, Carla, Gordon, Valerie, Greaves, Linda, Hudson, Susan, Naylor, Valerie, Nisbet, Chloe, Taylor, Carolin, Towse, Karen, Baillie, Jane, Brown, Helen, Callaby, Karen, Davenport, Katy, Donald, Sarah, Evans, Mark, Faghahati, Leila, Hartnell, Sara, Housden, Allison, Pabla, Kalbir Kaur, Ward, Candice, Croxon, Nicola, Green, Fiona, Macdonald, Sheena, Mohammed, Muna, Steel, Vicky, Valentine, Katy, Young, Pamela, Boal, Ann, Clerkin, Patsy, Doran, Lynn, Flynn, Joanne, Gibb, Emma, Kennon, Brian, Lindsay, Robert, Peddie, Hilary, Quinn, Bernie, Shepherd, Janice, Carling, Janet, Collins, Ann, Dinning, Laura, Hammond, Peter, Hare, Christine, Lodge, Joyce, Ray, Sutapa, Brown, Debora, Farmer, Jenny, Amiel, Stephanie, Beckwith, Anita, Cox, Alison, Cheyette, Chris, Choudhary, Pratik, East, Linda, Ellul, June, Hunt, Katharine, Rogers, Helen, Shaw, Kimberley, Stothard, Ben, Diamond, Lucy, Aniello, Lindsay, Anderson, Debbie, Cockerell, Kathy, Heaney, Vida, Hutchison, Alison, Zammitt, Nicola, Babington, Gayna, Bird, Gail, Evans, Janet, Gazis, Tasso, Maude, Nicola, Mansell, Peter, Nunnick, Karen, Spick, Dawn, Fenn, Laura, Basarir, Hasan, Bradburn, Mike, Brennan, Alan, Campbell, Michael, Carr, Lucy, Chater, Tim, Cooper, Cindy, Dimairo, Munya, Dixon, Simon, Hackney, Gemma, Lee, Ellen, Papaioannou, Diana, Pemberton, Kirsty, Pollard, Daniel, Thokala, Praveen, Whatley, Emma, Barnard, Katharine, Royle, Pamela, Waugh, Norman, Thompson, Gill, Walker, Sharon, and Cowling, Pauline

Published
2016
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50. Health professionals' views about who would benefit from using a closed-loop system: a qualitative study

Author

Lawton, J, Kimbell, B, Rankin, D, Ashcroft, NL, Varghese, L, Allen, JM, Boughton, CK, Campbell, F, Randell, T, Besser, REJ, Trevelyan, N, Hovorka, R, CLOuD Consortium, Lawton, J [0000-0002-8016-7374], Rankin, D [0000-0002-5835-3402], Boughton, CK [0000-0003-3272-9544], Hovorka, R [0000-0003-2901-461X], and Apollo - University of Cambridge Repository

Subjects
Health Care Rationing, Attitude of Health Personnel, Blood Glucose Self-Monitoring, Patient Selection, Monitoring, Ambulatory, Nurses, Infusion Pumps, Implantable, Diabetes Mellitus, Type 1, Insulin Infusion Systems, Physicians, Humans, Hypoglycemic Agents, Insulin, Qualitative Research, Randomized Controlled Trials as Topic
Abstract

AIM: To explore health professionals' views about who would benefit from using a closed-loop system and who should be prioritized for access to the technology in routine clinical care. METHODS: Health professionals (n = 22) delivering the Closed Loop from Onset in type 1 Diabetes (CLOuD) trial were interviewed after they had ≥ 6 months' experience supporting participants using a closed-loop system. Data were analysed thematically. RESULTS: Interviewees described holding strong assumptions about the types of people who would use the technology effectively prior to the trial. Interviewees described changing their views as a result of observing individuals engaging with the closed-loop system in ways they had not anticipated. This included educated, technologically competent individuals who over-interacted with the system in ways which could compromise glycaemic control. Other individuals, who health professionals assumed would struggle to understand and use the technology, were reported to have benefitted from it because they stood back and allowed the system to operate without interference. Interviewees concluded that individual, family and psychological attributes cannot be used as pre-selection criteria and, ideally, all individuals should be given the chance to try the technology. However, it was recognized that clinical guidelines will be needed to inform difficult decisions about treatment allocation (and withdrawal), with young children and infants being considered priority groups. CONCLUSIONS: To ensure fair and equitable access to closed-loop systems, prejudicial assumptions held by health professionals may need to be addressed. To support their decision-making, clinical guidelines need to be made available in a timely manner.

Published
2020

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