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Article: Ultra-High Dose Rate (FLASH) Radiotherapy: Silver Bullet or Fool's Gold?

Wilson, Joseph D / Hammond, Ester M / Higgins, Geoff S / Petersson, Kristoffer

2020 Volume 9, Page(s) 1563

Abstract: Radiotherapy is a cornerstone of both curative and palliative cancer care. However, radiotherapy is severely limited by radiation-induced toxicities. If these toxicities could be reduced, a greater dose of radiation could be given therefore facilitating ... ...

Abstract	Radiotherapy is a cornerstone of both curative and palliative cancer care. However, radiotherapy is severely limited by radiation-induced toxicities. If these toxicities could be reduced, a greater dose of radiation could be given therefore facilitating a better tumor response. Initial pre-clinical studies have shown that irradiation at dose rates far exceeding those currently used in clinical contexts reduce radiation-induced toxicities whilst maintaining an equivalent tumor response. This is known as the FLASH effect. To date, a single patient has been subjected to FLASH radiotherapy for the treatment of subcutaneous T-cell lymphoma resulting in complete response and minimal toxicities. The mechanism responsible for reduced tissue toxicity following FLASH radiotherapy is yet to be elucidated, but the most prominent hypothesis so far proposed is that acute oxygen depletion occurs within the irradiated tissue. This review examines the tissue response to FLASH radiotherapy, critically evaluates the evidence supporting hypotheses surrounding the biological basis of the FLASH effect, and considers the potential for FLASH radiotherapy to be translated into clinical contexts.
Language	English
Publishing date	2020-01-17
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2019.01563
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Corrigendum: Ultra-High Dose Rate (FLASH) Radiotherapy: Silver Bullet or Fool's Gold?

Wilson, Joseph D / Hammond, Ester M / Higgins, Geoff S / Petersson, Kristoffer

Frontiers in oncology

2020 Volume 10, Page(s) 210

Abstract: This corrects the article DOI: 10.3389/fonc.2019.01563.]. ...

Abstract	[This corrects the article DOI: 10.3389/fonc.2019.01563.].
Language	English
Publishing date	2020-02-25
Publishing country	Switzerland
Document type	Published Erratum
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2020.00210
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Evaluation of QuantiFERON SARS-CoV-2 interferon-γ release assay following SARS-CoV-2 infection and vaccination.

Johnson, Síle A / Phillips, Eloise / Adele, Sandra / Longet, Stephanie / Malone, Tom / Mason, Chris / Stafford, Lizzie / Jamsen, Anni / Gardiner, Siobhan / Deeks, Alexandra / Neo, Janice / Blurton, Emily J / White, Jemima / Ali, Muhammed / Kronsteiner, Barbara / Wilson, Joseph D / Skelly, Dónal T / Jeffery, Katie / Conlon, Christopher P /

Goulder, Philip / Consortium, Pitch / Carroll, Miles / Barnes, Eleanor / Klenerman, Paul / Dunachie, Susanna J

Clinical and experimental immunology

2023 Volume 212, Issue 3, Page(s) 249–261

Abstract: T cells are important in preventing severe disease from SARS-CoV-2, but scalable and field-adaptable alternatives to expert T-cell assays are needed. The interferon-gamma release assay QuantiFERON platform was developed to detect T-cell responses to SARS- ...

Abstract	T cells are important in preventing severe disease from SARS-CoV-2, but scalable and field-adaptable alternatives to expert T-cell assays are needed. The interferon-gamma release assay QuantiFERON platform was developed to detect T-cell responses to SARS-CoV-2 from whole blood with relatively basic equipment and flexibility of processing timelines. Forty-eight participants with different infection and vaccination backgrounds were recruited. Whole blood samples were analysed using the QuantiFERON SARS-CoV-2 assay in parallel with the well-established 'Protective Immunity from T Cells in Healthcare workers' (PITCH) ELISpot, which can evaluate spike-specific T-cell responses. The primary aims of this cross-sectional observational cohort study were to establish if the QuantiFERON SARS-Co-V-2 assay could discern differences between specified groups and to assess the sensitivity of the assay compared with the PITCH ELISpot. The QuantiFERON SARS-CoV-2 distinguished acutely infected individuals (12-21 days post positive PCR) from naïve individuals (P < 0.0001) with 100% sensitivity and specificity for SARS-CoV-2 T cells, whilst the PITCH ELISpot had reduced sensitivity (62.5%) for the acute infection group. Sensitivity with QuantiFERON for previous infection was 12.5% (172-444 days post positive test) and was inferior to the PITCH ELISpot (75%). Although the QuantiFERON assay could discern differences between unvaccinated and vaccinated individuals (55-166 days since second vaccination), the latter also had reduced sensitivity (44.4%) compared to the PITCH ELISpot (66.6%). The QuantiFERON SARS-CoV-2 assay showed potential as a T- cell evaluation tool soon after SARS-CoV-2 infection but has lower sensitivity for use in reliable evaluation of vaccination or more distant infection.
MeSH term(s)	Humans ; SARS-CoV-2 ; COVID-19 ; Cross-Sectional Studies ; Interferon-gamma Release Tests ; Vaccination ; Antibodies, Viral
Chemical Substances	Antibodies, Viral
Language	English
Publishing date	2023-02-20
Publishing country	England
Document type	Observational Study ; Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, Non-U.S. Gov't
ZDB-ID	218531-3
ISSN	1365-2249 ; 0009-9104 ; 0964-2536
ISSN (online)	1365-2249
ISSN	0009-9104 ; 0964-2536
DOI	10.1093/cei/uxad027
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Article ; Online: Pharmacological Inhibition of ATR Can Block Autophagy through an ATR-Independent Mechanism.

Bowler, Elizabeth / Skwarska, Anna / Wilson, Joseph D / Ramachandran, Shaliny / Bolland, Hannah / Easton, Alistair / Ostheimer, Christian / Hwang, Ming-Shih / Leszczynska, Katarzyna B / Conway, Stuart J / Hammond, Ester M

iScience

2020 Volume 23, Issue 11, Page(s) 101668

Abstract: Inhibition of the ATR kinase has emerged as a therapeutically attractive means to target cancer since the development of potent inhibitors, which are now in clinical testing. We investigated a potential link between ATR inhibition and the autophagy ... ...

Abstract	Inhibition of the ATR kinase has emerged as a therapeutically attractive means to target cancer since the development of potent inhibitors, which are now in clinical testing. We investigated a potential link between ATR inhibition and the autophagy process in esophageal cancer cells using four ATR inhibitors including two in clinical testing. The response to pharmacological ATR inhibitors was compared with genetic systems to investigate the ATR dependence of the effects observed. The ATR inhibitor, VX-970, was found to lead to an accumulation of p62 and LC3-II indicative of a blocked autophagy. This increase in p62 occurred post-transcriptionally and in all the cell lines tested. However, our data indicate that the accumulation of p62 occurred in an ATR-independent manner and was instead an off-target response to the ATR inhibitor. This study has important implications for the clinical response to pharmacological ATR inhibition, which in some cases includes the blockage of autophagy.
Language	English
Publishing date	2020-10-14
Publishing country	United States
Document type	Journal Article
ISSN	2589-0042
ISSN (online)	2589-0042
DOI	10.1016/j.isci.2020.101668
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: T cell phenotypes in COVID-19 - a living review.

Hanna, Stephanie J / Codd, Amy S / Gea-Mallorqui, Ester / Scourfield, D Oliver / Richter, Felix C / Ladell, Kristin / Borsa, Mariana / Compeer, Ewoud B / Moon, Owen R / Galloway, Sarah A E / Dimonte, Sandra / Capitani, Lorenzo / Shepherd, Freya R / Wilson, Joseph D / Uhl, Lion F K / Gallimore, Awen M / Milicic, Anita

Oxford open immunology

2020 Volume 2, Issue 1, Page(s) iqaa007

Abstract: COVID-19 is characterized by profound lymphopenia in the peripheral blood, and the remaining T cells display altered phenotypes, characterized by a spectrum of activation and exhaustion. However, antigen-specific T cell responses are emerging as a ... ...

Abstract	COVID-19 is characterized by profound lymphopenia in the peripheral blood, and the remaining T cells display altered phenotypes, characterized by a spectrum of activation and exhaustion. However, antigen-specific T cell responses are emerging as a crucial mechanism for both clearance of the virus and as the most likely route to long-lasting immune memory that would protect against re-infection. Therefore, T cell responses are also of considerable interest in vaccine development. Furthermore, persistent alterations in T cell subset composition and function post-infection have important implications for patients' long-term immune function. In this review, we examine T cell phenotypes, including those of innate T cells, in both peripheral blood and lungs, and consider how key markers of activation and exhaustion correlate with, and may be able to predict, disease severity. We focus on SARS-CoV-2-specific T cells to elucidate markers that may indicate formation of antigen-specific T cell memory. We also examine peripheral T cell phenotypes in recovery and the likelihood of long-lasting immune disruption. Finally, we discuss T cell phenotypes in the lung as important drivers of both virus clearance and tissue damage. As our knowledge of the adaptive immune response to COVID-19 rapidly evolves, it has become clear that while some areas of the T cell response have been investigated in some detail, others, such as the T cell response in children remain largely unexplored. Therefore, this review will also highlight areas where T cell phenotypes require urgent characterisation.
Language	English
Publishing date	2020-12-29
Publishing country	England
Document type	Journal Article
ISSN	2633-6960
ISSN (online)	2633-6960
DOI	10.1093/oxfimm/iqaa007
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Evolution of long-term vaccine-induced and hybrid immunity in healthcare workers after different COVID-19 vaccine regimens.

Moore, Shona C / Kronsteiner, Barbara / Longet, Stephanie / Adele, Sandra / Deeks, Alexandra S / Liu, Chang / Dejnirattisai, Wanwisa / Reyes, Laura Silva / Meardon, Naomi / Faustini, Sian / Al-Taei, Saly / Tipton, Tom / Hering, Luisa M / Angyal, Adrienn / Brown, Rebecca / Nicols, Alexander R / Dobson, Susan L / Supasa, Piyada / Tuekprakhon, Aekkachai /

Cross, Andrew / Tyerman, Jessica K / Hornsby, Hailey / Grouneva, Irina / Plowright, Megan / Zhang, Peijun / Newman, Thomas A H / Nell, Jeremy M / Abraham, Priyanka / Ali, Mohammad / Malone, Tom / Neale, Isabel / Phillips, Eloise / Wilson, Joseph D / Murray, Sam M / Zewdie, Martha / Shields, Adrian / Horner, Emily C / Booth, Lucy H / Stafford, Lizzie / Bibi, Sagida / Wootton, Daniel G / Mentzer, Alexander J / Conlon, Christopher P / Jeffery, Katie / Matthews, Philippa C / Pollard, Andrew J / Brown, Anthony / Rowland-Jones, Sarah L / Mongkolsapaya, Juthathip / Payne, Rebecca P / Dold, Christina / Lambe, Teresa / Thaventhiran, James E D / Screaton, Gavin / Barnes, Eleanor / Hopkins, Susan / Hall, Victoria / Duncan, Christopher J A / Richter, Alex / Carroll, Miles / de Silva, Thushan I / Klenerman, Paul / Dunachie, Susanna / Turtle, Lance

Med (New York, N.Y.)

2023 Volume 4, Issue 3, Page(s) 191–215.e9

Abstract: Background: Both infection and vaccination, alone or in combination, generate antibody and T cell responses against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the maintenance of such responses-and hence protection from ... ...

Abstract	Background: Both infection and vaccination, alone or in combination, generate antibody and T cell responses against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the maintenance of such responses-and hence protection from disease-requires careful characterization. In a large prospective study of UK healthcare workers (HCWs) (Protective Immunity from T Cells in Healthcare Workers [PITCH], within the larger SARS-CoV-2 Immunity and Reinfection Evaluation [SIREN] study), we previously observed that prior infection strongly affected subsequent cellular and humoral immunity induced after long and short dosing intervals of BNT162b2 (Pfizer/BioNTech) vaccination. Methods: Here, we report longer follow-up of 684 HCWs in this cohort over 6-9 months following two doses of BNT162b2 or AZD1222 (Oxford/AstraZeneca) vaccination and up to 6 months following a subsequent mRNA booster vaccination. Findings: We make three observations: first, the dynamics of humoral and cellular responses differ; binding and neutralizing antibodies declined, whereas T and memory B cell responses were maintained after the second vaccine dose. Second, vaccine boosting restored immunoglobulin (Ig) G levels; broadened neutralizing activity against variants of concern, including Omicron BA.1, BA.2, and BA.5; and boosted T cell responses above the 6-month level after dose 2. Third, prior infection maintained its impact driving larger and broader T cell responses compared with never-infected people, a feature maintained until 6 months after the third dose. Conclusions: Broadly cross-reactive T cell responses are well maintained over time-especially in those with combined vaccine and infection-induced immunity ("hybrid" immunity)-and may contribute to continued protection against severe disease. Funding: Department for Health and Social Care, Medical Research Council.
MeSH term(s)	Humans ; COVID-19 Vaccines ; BNT162 Vaccine ; ChAdOx1 nCoV-19 ; Prospective Studies ; COVID-19 ; SARS-CoV-2 ; Vaccines ; Antibodies, Neutralizing ; Health Personnel ; Immunity, Humoral
Chemical Substances	COVID-19 Vaccines ; BNT162 Vaccine ; ChAdOx1 nCoV-19 (B5S3K2V0G8) ; Vaccines ; Antibodies, Neutralizing
Language	English
Publishing date	2023-02-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
ISSN	2666-6340
ISSN (online)	2666-6340
DOI	10.1016/j.medj.2023.02.004
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Evolution of long-term hybrid immunity in healthcare workers after different COVID-19 vaccination regimens: a longitudinal observational cohort study

Moore, Shona C / Kronsteiner, Barbara / Longet, Stephanie / Adele, Sandra / Deeks, Alexandra S / Liu, Chang / Dejnirattisai, Wanwisa / Silva Reyes, Laura / Meardon, Naomi / Faustini, Sian / Al-Taei, Saly / Tipton, Tom / Hering, Luisa M / Angyal, Adrienn / Brown, Rebecca / Nicols, Alexander R / Dobson, Susan L / Supasa, Piyada / Tuekprakhon, Aekkachai /

Cross, Andrew / Tyerman, Jessica K / Hornsby, Hailey / Grouneva, Irina / Plowright, Megan / Zhang, Peijun / Newman, Thomas A.H. / Nell, Jeremy M. / Abraham, Priyanka / Ali, Mohammad / Malone, Tom / Neale, Isabel / Phillips, Eloise / Wilson, Joseph D. / Shields, Adrian / Horner, Emily C. / Booth, Lucy H. / Stafford, Lizzie / Bibi, Sagida / Wootton, Daniel G. / Mentzer, Alexander J. / Conlon, Christopher P. / Jeffery, Katie / Matthews, Philippa C. / Pollard, Andrew J. / Brown, Anthony / Rowland-Jones, Sarah L. / Mongkolsapaya, Juthathip / Payne, Rebecca P. / Dold, Christina / Lambe, Teresa / Thaventhiran, James E.D. / Screaton, Gavin / Barnes, Eleanor / Hopkins, Susan / Hall, Victoria / Duncan, Christopher JA / Richter, Alex Richter / Carroll, Miles / de Silva, Thushan I. / Klenerman, Paul / Dunachie, Susanna / Turtle, Lance

medRxiv

Abstract: Both infection and vaccination, alone or in combination, generate antibody and T cell responses against SARS–CoV–2. However, the maintenance of such responses – and hence protection from disease – requires careful characterisation. In a large prospective ...

Abstract	Both infection and vaccination, alone or in combination, generate antibody and T cell responses against SARS–CoV–2. However, the maintenance of such responses – and hence protection from disease – requires careful characterisation. In a large prospective study of UK healthcare workers (PITCH, within the larger SIREN study) we previously observed that prior infection impacted strongly on subsequent cellular and humoral immunity induced after long and short dosing intervals of BNT162b2 (Pfizer/BioNTech) vaccination. Here, we report longer follow up of 684 HCWs in this cohort over 6–9 months following two doses of BNT162b2 or AZ1222 (Oxford/AstraZeneca) vaccination and following a subsequent BNT162b2 booster vaccination. We make three important observations: Firstly, the dynamics of humoral and cellular responses differ; binding and neutralising antibodies declined whereas T and B cell responses were better maintained after the second vaccine dose. Secondly, vaccine boosting restored IgG levels to post second dose levels and broadened neutralising activity against variants of concern including omicron BA.1, alongside further boosting of T cell responses. Thirdly, prior infection maintained its impact driving larger T cell responses compared to never infected people, including after the third dose. In conclusion, the maintenance of T cell responses in time and against variants of concern may account for continued protection against severe disease.
Keywords	covid19
Language	English
Publishing date	2022-06-07
Publisher	Cold Spring Harbor Laboratory Press
Document type	Article ; Online
DOI	10.1101/2022.06.06.22275865
Database	COVID19

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Article ; Online: Differential occupational risks to healthcare workers from SARS-CoV-2 observed during a prospective observational study

Eyre, David W / Lumley, Sheila F / O'Donnell, Denise / Campbell, Mark / Sims, Elizabeth / Lawson, Elaine / Warren, Fiona / James, Tim / Cox, Stuart / Howarth, Alison / Doherty, George / Hatch, Stephanie B / Kavanagh, James / Chau, Kevin K / Fowler, Philip W / Swann, Jeremy / Volk, Denis / Yang-Turner, Fan / Stoesser, Nicole /

Matthews, Philippa C / Dudareva, Maria / Davies, Timothy / Shaw, Robert H / Peto, Leon / Downs, Louise O / Vogt, Alexander / Amini, Ali / Young, Bernadette C / Drennan, Philip George / Mentzer, Alexander J / Skelly, Donal T / Karpe, Fredrik / Neville, Matt J / Andersson, Monique / Brent, Andrew J / Jones, Nicola / Martins Ferreira, Lucas / Christott, Thomas / Marsden, Brian D / Hoosdally, Sarah / Cornall, Richard / Crook, Derrick W / Stuart, David I / Screaton, Gavin / Watson, Adam JR / Taylor, Adan / Chetwynd, Alan / Grassam-Rowe, Alexander / Mighiu, Alexandra S / Livingstone, Angus / Killen, Annabel / Rigler, Caitlin / Harries, Callum / East, Cameron / Lee, Charlotte / Mason, Chris JB / Holland, Christian / Thompson, Connor / Hennesey, Conor / Savva, Constantinos / Kim, David S / Harris, Edward WA / McGivern, Euan J / Qian, Evelyn / Rothwell, Evie / Back, Francesca / Kelly, Gabriella / Watson, Gareth / Howgego, Gregory / Chase, Hannah / Danbury, Hannah / Laurenson-Schafer, Hannah / Ward, Harry L / Hendron, Holly / Vorley, Imogen C / Tol, Isabel / Gunnell, James / Ward, Jocelyn LF / Drake, Jonathan / Wilson, Joseph D / Morton, Joshua / Dequaire, Julie / O'Byrne, Katherine / Motohashi, Kenzo / Harper, Kirsty / Ravi, Krupa / Millar, Lancelot J / Peck, Liam J / Oliver, Madeleine / English, Marcus Rex / Kumarendran, Mary / Wedlich, Matthew / Ambler, Olivia / Deal, Oscar T / Sweeney, Owen / Cowie, Philip / Naudé, Rebecca te Water / Young, Rebecca / Freer, Rosie / Scott, Samuel / Sussmes, Samuel / Peters, Sarah / Pattenden, Saxon / Waite, Seren / Johnson, Síle Ann / Kourdov, Stefan / Santos-Paulo, Stephanie / Dimitrov, Stoyan / Kerneis, Sven / Ahmed-Firani, Tariq / King, Thomas B / Ritter, Thomas G / Foord, Thomas H / De Toledo, Zoe / Christie, Thomas / Gergely, Bernadett / Axten, David / Simons, Emma-Jane / Nevard, Heather / Philips, Jane / Szczurkowska, Justyna / Patel, Kaisha / Smit, Kyla / Warren, Laura / Morgan, Lisa / Smith, Lucianne / Robles, Maria / McKnight, Mary / Luciw, Michael / Gates, Michelle / Sande, Nellia / Turford, Rachel / Ray, Roshni / Rughani, Sonam / Mitchell, Tracey / Bellinger, Trisha / Wharton, Vicki / Justice, Anita / Jesuthasan, Gerald / Wareing, Susan / Huda Mohamad Fadzillah, Nurul / Cann, Kathryn / Kirton, Richard / Sutton, Claire / Salvagno, Claudia / DAmato, Gabriella / Pill, Gemma / Butcher, Lisa / Rylance-Knight, Lydia / Tabirao, Merline / Moroney, Ruth / Wright, Sarah / Peto, Timothy EA / Holthof, Bruno / O'Donnell, Anne-Marie / Ebner, Daniel / Conlon, Christopher P / Jeffery, Katie / Walker, Timothy M

eLife

2020 Volume 9

Abstract: We conducted voluntary Covid-19 testing programmes for symptomatic and asymptomatic staff at a UK teaching hospital using naso-/oro-pharyngeal PCR testing and immunoassays for IgG antibodies. 1128/10,034 (11.2%) staff had evidence of Covid-19 at some ... ...

Abstract	We conducted voluntary Covid-19 testing programmes for symptomatic and asymptomatic staff at a UK teaching hospital using naso-/oro-pharyngeal PCR testing and immunoassays for IgG antibodies. 1128/10,034 (11.2%) staff had evidence of Covid-19 at some time. Using questionnaire data provided on potential risk-factors, staff with a confirmed household contact were at greatest risk (adjusted odds ratio [aOR] 4.82 [95%CI 3.45–6.72]). Higher rates of Covid-19 were seen in staff working in Covid-19-facing areas (22.6% vs. 8.6% elsewhere) (aOR 2.47 [1.99–3.08]). Controlling for Covid-19-facing status, risks were heterogenous across the hospital, with higher rates in acute medicine (1.52 [1.07–2.16]) and sporadic outbreaks in areas with few or no Covid-19 patients. Covid-19 intensive care unit staff were relatively protected (0.44 [0.28–0.69]), likely by a bundle of PPE-related measures. Positive results were more likely in Black (1.66 [1.25–2.21]) and Asian (1.51 [1.28–1.77]) staff, independent of role or working location, and in porters and cleaners (2.06 [1.34–3.15]).
Keywords	General Biochemistry, Genetics and Molecular Biology ; General Immunology and Microbiology ; General Neuroscience ; General Medicine ; covid19
Language	English
Publisher	eLife Sciences Publications, Ltd
Publishing country	uk
Document type	Article ; Online
ZDB-ID	2687154-3
ISSN	2050-084X
ISSN	2050-084X
DOI	10.7554/elife.60675
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Book ; Online: Author response

Differential occupational risks to healthcare workers from SARS-CoV-2 observed during a prospective observational study

2020

Keywords	covid19
Publisher	eLife Sciences Publications, Ltd
Publishing country	uk
Document type	Book ; Online
DOI	10.7554/elife.60675.sa2
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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