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1. Multiarm, non-randomised, single-centre feasibility study—investigation of the differential biology between benign and malignant renal masses using advanced magnetic resonance imaging techniques (IBM-Renal): protocol

Author

Thomas J Mitchell, Hao Li, Grant D Stewart, Anne Y Warren, James N Armitage, Ferdia A Gallagher, Mary A McLean, Andrew N Priest, Andrew B Gill, Iosif Mendichovszky, João Duarte, Ines Horvat-Menih, Maria Jesus Zamora-Morales, Marta Wylot, Joshua Kaggie, Alixander S Khan, Matthew J Locke, Sarah J Welsh, and James O Jones

Subjects
Medicine
Abstract

Introduction Localised renal masses are an increasing burden on healthcare due to the rising number of cases. However, conventional imaging cannot reliably distinguish between benign and malignant renal masses, and renal mass biopsies are unable to characterise the entirety of the tumour due to sampling error, which may lead to delayed treatment or overtreatment. There is an unmet clinical need to develop novel imaging techniques to characterise renal masses more accurately. Renal tumours demonstrate characteristic metabolic reprogramming, and novel MRI methods have the potential to detect these metabolic perturbations, which may therefore aid accurate characterisation. Here, we present our study protocol for the investigation of the differential biology of benign and malignant renal masses using advanced MRI techniques (IBM-Renal).Methods and analysis IBM-Renal is a multiarm, single-centre, non-randomised, feasibility study with the aim to provide preliminary evidence for the potential role of the novel MRI techniques to phenotype localised renal lesions. 30 patients with localised renal masses will be recruited to three imaging arms, with 10 patients in each: (1) hyperpolarised [1-13C]-pyruvate MRI, (2) deuterium metabolic imaging (DMI) and (3) sodium MRI. The diagnosis will be made on samples acquired at biopsy or at surgery. The primary objective is the technical development of the novel MRI techniques, with the ultimate aim to understand whether these can identify differences between benign and malignant tumours, while the secondary objectives aim to assess how complementary the techniques are, and if they provide additional information. The exploratory objective is to link imaging findings with clinical data and molecular analyses for the biological validation of the novel MRI techniques.Ethics and dissemination This study was ethically approved (UK REC HRA: 22/EE/0136; current protocol version 2.1 dated 11 August 2022). The plans for dissemination include presentations at conferences, publications in scientific journals, a doctoral thesis and patient and public involvement.Trial registration number NCT06016075.

Published
2024
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2. Complement lectin pathway activation is associated with COVID-19 disease severity, independent of MBL2 genotype subgroups

Author

Lisa Hurler, Ágnes Szilágyi, Federica Mescia, Laura Bergamaschi, Blanka Mező, György Sinkovits, Marienn Réti, Veronika Müller, Zsolt Iványi, János Gál, László Gopcsa, Péter Reményi, Beáta Szathmáry, Botond Lakatos, János Szlávik, Ilona Bobek, Zita Z. Prohászka, Zsolt Förhécz, Dorottya Csuka, Erika Kajdácsi, László Cervenak, Petra Kiszel, Tamás Masszi, István Vályi-Nagy, Reinhard Würzner, Cambridge Institute of Therapeutic Immunology and Infectious Disease-National Institute of Health Research (CITIID-NIHR) COVID BioResource Collaboration, Paul A. Lyons, Erik J. M. Toonen, Zoltán Prohászka, Stephen Baker, John R. Bradley, Patrick F. Chinnery, Daniel J. Cooper, Gordon Dougan, Ian G. Goodfellow, Ravindra K. Gupta, Nathalie Kingston, Paul J. Lehner, Nicholas J. Matheson, Caroline Saunders, Kenneth G. C. Smith, Charlotte Summers, James Thaventhiran, M. Estee Torok, Mark R. Toshner, Michael P. Weekes, Gisele Alvio, Sharon Baker, Areti Bermperi, Karen Brookes, Ashlea Bucke, Jo Calder, Laura Canna, Cherry Crucusio, Isabel Cruz, Rnalie de Jesus, Katie Dempsey, Giovanni Di Stephano, Jason Domingo, Anne Elmer, Julie Harris, Sarah Hewitt, Heather Jones, Sherly Jose, Jane Kennet, Yvonne King, Jenny Kourampa, Emily Li, Caroline McMahon, Anne Meadows, Vivien Mendoza, Criona O’Brien, Charmain Ocaya, Ciro Pascuale, Marlyn Perales, Jane Price, Rebecca Rastall, Carla Ribeiro, Jane Rowlands, Valentina Ruffolo, Hugo Tordesillas, Phoebe Vargas, Bensi Vergese, Laura Watson, Jieniean Worsley, Julie-Ann Zerrudo, Ariana Betancourt, Georgie Bower, Ben Bullman, Chiara Cossetti, Aloka De Sa, Benjamin J. Dunore, Maddie Epping, Stuart Fawke, Stefan Gräf, Richard Grenfell, Andrew Hinch, Josh Hodgson, Christopher Huang, Oisin Huhn, Kelvin Hunter, Isobel Jarvis, Emma Jones, Maša Josipović, Ekaterina Legchenko, Daniel Lewis, Joe Marsden, Jennifer Martin, Francesca Nice, Ciara O’Donnell, Ommar Omarjee, Marianne Perera, Linda Pointon, Nicole Pond, Nathan Richoz, Nika Romashova, Natalia Savoinykh, Rahul Sharma, Joy Shih, Mateusz Strezlecki, Rachel Sutcliffe, Tobias Tilly, Zhen Tong, Carmen Treacy, Lori Turner, Jennifer Wood, Marta Wylot, John Allison, Heather Biggs, Helen Butcher, Daniela Caputo, Debbie Clapham-Riley, Eleanor Dewhurst, Christian Fernandez, Anita Furlong, Barbara Graves, Jennifer Gray, Tasmin Ivers, Emma Le Gresley, Rachel Linger, Mary Kasanicki, Sarah Meloy, Francesca Muldoon, Nigel Ovington, Sofia Papadia, Christopher J. Penkett, Isabel Phelan, Venkatesh Ranganath, Jennifer Sambrook, Katherine Schon, Hannah Stark, Kathleen E. Stirrups, Paul Townsend, Julie von Ziegenweidt, Jennifer Webster, Ali Asaripour, Lucy Mwaura, Caroline Patterson, Gary Polwarth, Katherine Bunclark, Michael Mackay, Alice Michael, Sabrina Rossi, Mayurun Selvan, Sarah Spencer, Cissy Yong, and Petra Polgarova

Subjects
mannose binding lectin (MBL), MBL2 genotypes, COVID-19, severe acute respiratory coronavirus 2 (SARS-CoV-2), lectin pathway activation, lectin pathway of complement, Immunologic diseases. Allergy, RC581-607
Abstract

IntroductionWhile complement is a contributor to disease severity in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, all three complement pathways might be activated by the virus. Lectin pathway activation occurs through different pattern recognition molecules, including mannan binding lectin (MBL), a protein shown to interact with SARS-CoV-2 proteins. However, the exact role of lectin pathway activation and its key pattern recognition molecule MBL in COVID-19 is still not fully understood.MethodsWe therefore investigated activation of the lectin pathway in two independent cohorts of SARS-CoV-2 infected patients, while also analysing MBL protein levels and potential effects of the six major single nucleotide polymorphisms (SNPs) found in the MBL2 gene on COVID-19 severity and outcome.ResultsWe show that the lectin pathway is activated in acute COVID-19, indicated by the correlation between complement activation product levels of the MASP-1/C1-INH complex (p=0.0011) and C4d (p

Published
2023
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3. Distinction of early complement classical and lectin pathway activation via quantification of C1s/C1-INH and MASP-1/C1-INH complexes using novel ELISAs

Author

Lisa Hurler, Erik J. M. Toonen, Erika Kajdácsi, Bregje van Bree, Ricardo J. M. G. E. Brandwijk, Wieke de Bruin, Paul A. Lyons, Laura Bergamaschi, Cambridge Institute of Therapeutic Immunology and Infectious Disease-National Institute of Health Research (CITIID-NIHR) COVID BioResource Collaboration, György Sinkovits, László Cervenak, Reinhard Würzner, Zoltán Prohászka, Stephen Baker, John R. Bradley, Patrick F. Chinnery, Daniel J. Cooper, Gordon Dougan, Ian G. Goodfellow, Ravindra K. Gupta, Nathalie Kingston, Paul J. Lehner, Nicholas J. Matheson, Caroline Saunders, Kenneth G. C. Smith, Charlotte Summers, James Thaventhiran, M. Estee Torok, Mark R. Toshner, Michael P. Weekes, Gisele Alvio, Sharon Baker, Areti Bermperi, Karen Brookes, Ashlea Bucke, Jo Calder, Laura Canna, Cherry Crucusio, Isabel Cruz, Rnalie de Jesus, Katie Dempsey, Giovanni Di Stephano, Jason Domingo, Anne Elmer, Julie Harris, Sarah Hewitt, Heather Jones, Sherly Jose, Jane Kennet, Yvonne King, Jenny Kourampa, Emily Li, Caroline McMahon, Anne Meadows, Vivien Mendoza, Criona O’Brien, Charmain Ocaya, Ciro Pascuale, Marlyn Perales, Jane Price, Rebecca Rastall, Carla Ribeiro, Jane Rowlands, Valentina Ruffolo, Hugo Tordesillas, Phoebe Vargas, Bensi Vergese, Laura Watson, Jieniean Worsley, Julie-Ann Zerrudo, Ariana Betancourt, Georgie Bower, Ben Bullman, Chiara Cossetti, Aloka De Sa, Benjamin J. Dunore, Maddie Epping, Stuart Fawke, Stefan Gräf, Richard Grenfell, Andrew Hinch, Josh Hodgson, Christopher Huang, Oisin Huhn, Kelvin Hunter, Isobel Jarvis, Emma Jones, Maša Josipović, Ekaterina Legchenko, Daniel Lewis, Joe Marsden, Jennifer Martin, Federica Mescia, Francesca Nice, Ciara O’Donnell, Ommar Omarjee, Marianne Perera, Linda Pointon, Nicole Pond, Nathan Richoz, Nika Romashova, Natalia Savoinykh, Rahul Sharma, Joy Shih, Mateusz Strezlecki, Rachel Sutcliffe, Tobias Tilly, Zhen Tong, Carmen Treacy, Lori Turner, Jennifer Wood, Marta Wylot, John Allison, Heather Biggs, Helen Butcher, Daniela Caputo, Debbie Clapham-Riley, Eleanor Dewhurst, Christian Fernandez, Anita Furlong, Barbara Graves, Jennifer Gray, Tasmin Ivers, Emma Le Gresley, Rachel Linger, Mary Kasanicki, Sarah Meloy, Francesca Muldoon, Nigel Ovington, Sofia Papadia, Christopher J. Penkett, Isabel Phelan, Venkatesh Ranganath, Jennifer Sambrook, Katherine Schon, Hannah Stark, Kathleen E. Stirrups, Paul Townsend, Julie von Ziegenweidt, Jennifer Webster, Ali Asaripour, Lucy Mwaura, Caroline Patterson, Gary Polwarth, Katherine Bunclark, Michael Mackay, Alice Michael, Sabrina Rossi, Mayurun Selvan, Sarah Spencer, Cissy Yong, and Petra Polgarova

Subjects
early complement activation, classical pathway activation, lectin pathway activation, C1-INH complexes, assay development and validation, C1s/C1-INH complex, Immunologic diseases. Allergy, RC581-607
Abstract

The most commonly used markers to assess complement activation are split products that are produced through activation of all three pathways and are located downstream of C3. In contrast, C4d derives from the cleavage of C4 and indicates either classical (CP) or lectin pathway (LP) activation. Although C4d is perfectly able to distinguish between CP/LP and alternative pathway (AP) activation, no well-established markers are available to differentiate between early CP and LP activation. Active enzymes of both pathways (C1s/C1r for the CP, MASP-1/MASP-2 for the LP) are regulated by C1 esterase inhibitor (C1-INH) through the formation of covalent complexes. Aim of this study was to develop validated immunoassays detecting C1s/C1-INH and MASP-1/C1-INH complex levels. Measurement of the complexes reveals information about the involvement of the respective pathways in complement-mediated diseases. Two sandwich ELISAs detecting C1s/C1-INH and MASP-1/C1-INH complex were developed and tested thoroughly, and it was investigated whether C1s/C1-INH and MASP-1/C1-INH complexes could serve as markers for either early CP or LP activation. In addition, a reference range for these complexes in healthy adults was defined, and the assays were clinically validated utilizing samples of 414 COVID-19 patients and 96 healthy controls. The immunoassays can reliably measure C1s/C1-INH and MASP-1/C1-INH complex concentrations in EDTA plasma from healthy and diseased individuals. Both complex levels are increased in serum when activated with zymosan, making them suitable markers for early classical and early lectin pathway activation. Furthermore, measurements of C1-INH complexes in 96 healthy adults showed normally distributed C1s/C1-INH complex levels with a physiological concentration of 1846 ± 1060 ng/mL (mean ± 2SD) and right-skewed distribution of MASP-1/C1-INH complex levels with a median concentration of 36.9 (13.18 - 87.89) ng/mL (2.5-97.5 percentile range), while levels of both complexes were increased in COVID-19 patients (p

Published
2022
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4. Levels of soluble complement regulators predict severity of COVID-19 symptoms

Author

Anna L. Tierney, Wajd Mohammed Alali, Thomas Scott, Karen S. Rees-Unwin, CITIID-NIHR BioResource COVID-19 Collaboration, Simon J. Clark, Richard D. Unwin, Stephen Baker, John Bradley, Patrick Chinnery, Daniel Cooper, Gordon Dougan, Ian Goodfellow, Ravindra Gupta, Nathalie Kingston, Paul J. Lehner, Paul A. Lyons, Nicholas J. Matheson, Caroline Saunders, Kenneth G. C. Smith, Charlotte Summers, James Thaventhiran, M. Estee Torok, Mark R. Toshner, Michael P. Weekes, Gisele Alvio, Sharon Baker, Areti Bermperi, Karen Brookes, Ashlea Bucke, Jo Calder, Laura Canna, Cherry Crucusio, Isabel Cruz, Ranalie de Jesus, Katie Dempsey, Giovanni Di Stephano, Jason Domingo, Anne Elmer, Julie Harris, Sarah Hewitt, Heather Jones, Sherly Jose, Jane Kennet, Yvonne King, Jenny Kourampa, Emily Li, Caroline McMahon, Anne Meadows, Vivien Mendoza, Criona O’Brien, Charmain Ocaya, Ciro Pasquale, Marlyn Perales, Jane Price, Rebecca Rastall, Carla Ribeiro, Jane Rowlands, Valentina Ruffolo, Hugo Tordesillas, Phoebe Vargas, Bensi Vergese, Laura Watson, Jieniean Worsley, Julie-Ann Zerrudo, Laura Bergamashi, Ariana Betancourt, Georgie Bower, Ben Bullman, Chiara Cossetti, Aloka De Sa, Benjamin J. Dunmore, Maddie Epping, Stuart Fawke, Stefan Gräf, Richard Grenfell, Andrew Hinch, Josh Hodgson, Christopher Huang, Oisin Huhn, Kelvin Hunter, Isobel Jarvis, Emma Jones, Maša Josipović, Ekaterina Legchenko, Daniel Lewis, Joe Marsden, Jennifer Martin, Federica Mescia, Ciara O’Donnell, Ommar Omarjee, Marianne Perera, Linda Pointon, Nicole Pond, Nathan Richoz, Nika Romashova, Natalia Savoinykh, Rahul Sharma, Joy Shih, Mateusz Strezlecki, Rachel Sutcliffe, Tobias Tilly, Zhen Tong, Carmen Treacy, Lori Turner, Jennifer Wood, Marta Wylot, John Allison, Heather Biggs, John R. Bradley, Helen Butcher, Daniela Caputo, Matt Chandler, Debbie Clapham-Riley, Eleanor Dewhurst, Christian Fernandez, Anita Furlong, Barbara Graves, Jennifer Gray, Sabine Hein, Tasmin Ivers, Emma Le Gresley, Rachel Linger, Mary Kasanicki, Rebecca King, Sarah Meloy, Alexei Moulton, Francesca Muldoon, Nigel Ovington, Sofia Papadia, Christopher J. Penkett, Isabel Phelan, Venkatesh Ranganath, Roxana Paraschiv, Abigail Sage, Jennifer Sambrook, Ingrid Scholtes, Katherine Schon, Hannah Stark, Kathleen E. Stirrups, Paul Townsend, Neil Walker, Jennifer Webster, Mayurun Selvan, Petra Polgarova, Sarah L. Caddy, Laura G. Caller, Yasmin Chaudhry, Martin D. Curran, Theresa Feltwell, Stewart Fuller, Iliana Georgana, Grant Hall, William L. Hamilton, Myra Hosmillo, Charlotte J. Houldcroft, Rhys Izuagbe, Aminu S. Jahun, Fahad A. Khokhar, Anna G. Kovalenko, Luke W. Meredith, Surendra Parmar, Malte L. Pinckert, Anna Yakovleva, Emily C. Horner, Lucy Booth, Alexander Ferreira, Rebecca Boston, Robert Hughes, Juan Carlos Yam Puc, Nonantzin Beristain-Covarrubias, Maria Rust, Thevinya Gurugama, Lihinya Gurugama, Thomas Mulroney, Sarah Spencer, Zhaleh Hosseini, and Kate Williamson

Subjects
COVID-19, SARS-CoV-2, complement, factor H, factor H-related proteins, biomarkers, Immunologic diseases. Allergy, RC581-607
Abstract

The SARS-CoV-2 virus continues to cause significant morbidity and mortality worldwide from COVID-19. One of the major challenges of patient management is the broad range of symptoms observed. While the majority of individuals experience relatively mild disease, a significant minority of patients require hospitalisation, with COVID-19 still proving fatal for some. As such, there remains a desperate need to better understand what drives this severe disease, both in terms of the underlying biology, but also to potentially predict at diagnosis which patients are likely to require further interventions, thus enabling better outcomes for both patients and healthcare systems. Several lines of evidence have pointed to dysregulation of the complement cascade as a major factor in severe COVID-19 outcomes. How this is underpinned mechanistically is not known. Here, we have focussed on the role of the soluble complement regulators Complement Factor H (FH), its splice variant Factor H-like 1 (FHL-1) and five Factor H-Related proteins (FHR1-5). Using a targeted mass spectrometry approach, we quantified these proteins in a cohort of 188 plasma samples from controls and SARS-CoV-2 patients taken at diagnosis. This analysis revealed significant elevations in all FHR proteins, but not FH, in patients with more severe disease, particularly FHR2 and FHR5 (FHR2: 1.97-fold, p

Published
2022
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5. Combined Point-of-Care Nucleic Acid and Antibody Testing for SARS-CoV-2 following Emergence of D614G Spike Variant

Author

Petra Mlcochova, Dami Collier, Allyson Ritchie, Sonny M. Assennato, Myra Hosmillo, Neha Goel, Bo Meng, Krishna Chatterjee, Vivien Mendoza, Nigel Temperton, Leo Kiss, Leo C. James, Katarzyna A. Ciazynska, Xiaoli Xiong, John A.G. Briggs, James A. Nathan, Federica Mescia, Laura Bergamaschi, Hongyi Zhang, Petros Barmpounakis, Nikos Demeris, Richard Skells, Paul A. Lyons, John Bradley, Steven Baker, Jean Pierre Allain, Kenneth G.C. Smith, Rachel Bousfield, Michael Wilson, Dominic Sparkes, Glenn Amoroso, Effrosyni Gkrania-Klotsas, Susie Hardwick, Adrian Boyle, Ian Goodfellow, Ravindra K. Gupta, Stephen Baker, Gordon Dougan, Ravi Gupta, Paul J. Lehner, Paul Lyons, Nicholas J. Matheson, Mark Toshner, Michael P. Weekes, Nick Brown, Martin Curran, Surendra Palmar, David Enoch, Daniel Chapman, Ashley Shaw, Sherly Jose, Areti Bermperi, Julie Ann Zerrudo, Evgenia Kourampa, Laura Watson, Jieniean Worsley, Caroline Saunders, Ranalie de Jesus, Jason Domingo, Ciro Pasquale, Bensi Vergese, Phoebe Vargas, Marivic Fabiculana, Marlyn Perales, Lee Mynott, Elizabeth Blake, Amy Bates, Anne-Laure Vallier, Alexandra Williams, David Phillips, Edmund Chiu, Alex Overhill, Nicola Ramenatte, Jamal Sipple, Steven Frost, Helena Knock, Richard Hardy, Emily Foster, Fiona Davidson, Viona Rundell, Purity Bundi, Richmond Abeseabe, Sarah Clark, Isabel Vicente, Anne Elmer, Carla Ribeiro, Jenny Kourampa, Jane Kennet, Jane Rowlands, Anne Meadows, Criona O’Brien, Rebecca Rastall, Cherry Crucusio, Sarah Hewitt, Jane Price, Jo Calder, Laura Canna, Ashlea Bucke, Hugo Tordesillas, Julie Harris, Valentina Ruffolo, Barbara Graves, Helen Butcher, Daniela Caputo, Emma Le Gresley, Benjamin J. Dunmore, Jennifer Martin, Ekaterina Legchenko, Carmen Treacy, Christopher Huang, Jennifer Wood, Rachel Sutcliffe, Josh Hodgson, Joy Shih, Stefan Graf, Zhen Tong, Tobias Tilly, Ciara O’Donnell, Kelvin Hunter, Linda Pointon, Nicole Pond, Marta Wylot, Emma Jones, Stuart Fawke, Ben Bullman, Lori Turner, Isobel Jarvis, Ommar Omarjee, Aloka De Sa, Joe Marsden, Ariana Betancourt, Marianne Perera, Maddie Epping, Nathan Richoz, Georgie Bower, Rahul Sharma, Francesca Nice, Oisin Huhn, Natalia Savoinykh Yarkoni, Nika Romashova, Daniel Lewis, Andrew Hinch, Chiara Cossetti, Mateusz Strezlecki, Richard Grenfell, Hannah Stark, Neil Walker, Kathy Stirrups, Nigel Ovington, Eleanor Dewhust, Emily Li, Sofia Papadia, Nathalie Kingston, Andrew Lever, Estee Torok, William Hamilton, Grant Hall, Aminu Jahun, Yasmin Chaudhry, Malte Pinckert, Iliana Georgana, Anna Yakovleva, Laura Caller, Sarah Caddy, Theresa Feltwell, Fahad Khokhar, Luke Meredith, Charlotte Holdcroft, and Surendra Parmar

Subjects
SARS-CoV-2, COVID-19, rapid diagnoses, point of care testing, D614G, Medicine (General), R5-920
Abstract

Summary: Rapid COVID-19 diagnosis in the hospital is essential, although this is complicated by 30%–50% of nose/throat swabs being negative by SARS-CoV-2 nucleic acid amplification testing (NAAT). Furthermore, the D614G spike mutant dominates the pandemic and it is unclear how serological tests designed to detect anti-spike antibodies perform against this variant. We assess the diagnostic accuracy of combined rapid antibody point of care (POC) and nucleic acid assays for suspected COVID-19 disease due to either wild-type or the D614G spike mutant SARS-CoV-2. The overall detection rate for COVID-19 is 79.2% (95% CI 57.8–92.9) by rapid NAAT alone. The combined point of care antibody test and rapid NAAT is not affected by D614G and results in very high sensitivity for COVID-19 diagnosis with very high specificity.

Published
2020
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6. SARS-CoV-2 spike N-terminal domain modulates TMPRSS2-dependent viral entry and fusogenicity

Author

Bo Meng, Rawlings Datir, Jinwook Choi, John R. Bradley, Kenneth G.C. Smith, Joo Hyeon Lee, Ravindra K. Gupta, Stephen Baker, Gordon Dougan, Christoph Hess, Nathalie Kingston, Paul J. Lehner, Paul A. Lyons, Nicholas J. Matheson, Willem H. Owehand, Caroline Saunders, Charlotte Summers, James E.D. Thaventhiran, Mark Toshner, Michael P. Weekes, Patrick Maxwell, Ashley Shaw, Ashlea Bucke, Jo Calder, Laura Canna, Jason Domingo, Anne Elmer, Stewart Fuller, Julie Harris, Sarah Hewitt, Jane Kennet, Sherly Jose, Jenny Kourampa, Anne Meadows, Criona O’Brien, Jane Price, Cherry Publico, Rebecca Rastall, Carla Ribeiro, Jane Rowlands, Valentina Ruffolo, Hugo Tordesillas, Ben Bullman, Benjamin J. Dunmore, Stuart Fawke, Stefan Gräf, Josh Hodgson, Christopher Huang, Kelvin Hunter, Emma Jones, Ekaterina Legchenko, Cecilia Matara, Jennifer Martin, Federica Mescia, Ciara O’Donnell, Linda Pointon, Joy Shih, Rachel Sutcliffe, Tobias Tilly, Carmen Treacy, Zhen Tong, Jennifer Wood, Marta Wylot, Ariana Betancourt, Georgie Bower, Chiara Cossetti, Aloka De Sa, Madeline Epping, Nick Gleadall, Richard Grenfell, Andrew Hinch, Sarah Jackson, Isobel Jarvis, Ben Krishna, Francesca Nice, Ommar Omarjee, Marianne Perera, Martin Potts, Nathan Richoz, Veronika Romashova, Luca Stefanucci, Mateusz Strezlecki, Lori Turner, Eckart M.D.D. De Bie, Katherine Bunclark, Masa Josipovic, Michael Mackay, John Allison, Helen Butcher, Daniela Caputo, Debbie Clapham-Riley, Eleanor Dewhurst, Anita Furlong, Barbara Graves, Jennifer Gray, Tasmin Ivers, Emma Le Gresley, Rachel Linger, Sarah Meloy, Francesca Muldoon, Nigel Ovington, Sofia Papadia, Isabel Phelan, Hannah Stark, Kathleen E. Stirrups, Paul Townsend, Neil Walker, Jennifer Webster, Ingrid Scholtes, Sabine Hein, and Rebecca King

Subjects
Organoid, Omicron, SARS-CoV-2, Serine Endopeptidases, CP: Microbiology, COVID-19, spike, Virus Internalization, General Biochemistry, Genetics and Molecular Biology, Spike Glycoprotein, Coronavirus, NTD, Delta, Spike Glycoprotein, Coronavirus, entry, Humans, fusogenicity, TMPRSS2
Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike N-terminal domain (NTD) remains poorly characterized despite enrichment of mutations in this region across variants of concern (VOCs). Here, we examine the contribution of the NTD to infection and cell-cell fusion by constructing chimeric spikes bearing B.1.617 lineage (Delta and Kappa variants) NTDs and generating spike pseudotyped lentivirus. We find that the Delta NTD on a Kappa or wild-type (WT) background increases S1/S2 cleavage efficiency and virus entry, specifically in lung cells and airway organoids, through use of TMPRSS2. Delta exhibits increased cell-cell fusogenicity that could be conferred to WT and Kappa spikes by Delta NTD transfer. However, chimeras of Omicron BA.1 and BA.2 spikes with a Delta NTD do not show more efficient TMPRSS2 use or fusogenicity. We conclude that the NTD allosterically modulates S1/S2 cleavage and spike-mediated functions in a spike context-dependent manner, and allosteric interactions may be lost when combining regions from more distantly related VOCs.

Published
2022

7. Potent and Selective Inhibitors of the Epidermal Growth Factor Receptor to Overcome C797S-Mediated Resistance

Author

Darren Cross, Matthew J. Martin, Carine M. Guérot, Nicolas Floc'h, Clare Gregson, Jonathan P. Orme, Michal Bista, Lin Xue, Xu Li, Amar Rahi, Xiliang Zhao, Richard A. Ward, L. Evans, Gail L. Wrigley, Arash Mosallanejad, Tieguang Yao, Claire McWhirter, David J. Hargreaves, Nicola Colclough, Sue Bickerton, Darren Mckerrecher, Peter Barton, Yang Ye, Yi Liu, Marta Wylot, M. Raymond V. Finlay, Xiaoming Kang, Eva M. Lenz, Daniel O'Neill, Verity Talbot, Olivier Lorthioir, and Paul D. Smith

Subjects
Mice, Nude, Antineoplastic Agents, Mice, SCID, medicine.disease_cause, T790M, Organophosphorus Compounds, In vivo, Cell Line, Tumor, Neoplasms, Drug Discovery, medicine, Animals, Humans, Osimertinib, Epidermal growth factor receptor, Lung cancer, Cell potency, Protein Kinase Inhibitors, EGFR inhibitors, Mutation, biology, Chemistry, medicine.disease, Xenograft Model Antitumor Assays, Rats, ErbB Receptors, Pyrimidines, Drug Resistance, Neoplasm, Cancer research, biology.protein, Molecular Medicine, Female
Abstract

The epidermal growth factor receptor (EGFR) harboring activating mutations is a clinically validated target in non-small-cell lung cancer, and a number of inhibitors of the EGFR tyrosine kinase domain, including osimertinib, have been approved for clinical use. Resistance to these therapies has emerged due to a variety of molecular events including the C797S mutation which renders third-generation C797-targeting covalent EGFR inhibitors considerably less potent against the target due to the loss of the key covalent-bond-forming residue. We describe the medicinal chemistry optimization of a biochemically potent but modestly cell-active, reversible EGFR inhibitor starting point with sub-optimal physicochemical properties. These studies culminated in the identification of compound 12 that showed improved cell potency, oral exposure, and in vivo activity in clinically relevant EGFR-mutant-driven disease models, including an Exon19 deletion/T790M/C797S triple-mutant mouse xenograft model.

Published
2021

8. Monitoring apoptosis in intact cells by high-resolution magic angle spinning

Author

Marta, Wylot, David T E, Whittaker, Stephen A C, Wren, John H, Bothwell, Leslie, Hughes, and Julian L, Griffin

Subjects
Diffusion, Cytoplasm, Mice, Viscosity, Proton Magnetic Resonance Spectroscopy, Muscle Fibers, Skeletal, Animals, Metabolomics, Apoptosis, Lipid Droplets, Cisplatin, Cell Line, Etoposide
Abstract

Apoptosis maintains an equilibrium between cell proliferation and cell death. Many diseases, including cancer, develop because of defects in apoptosis. A known metabolic marker of apoptosis is a notable increase in

Published
2020

9. Potent and Selective Inhibitors of MTH1 Probe Its Role in Cancer Cell Survival

Author

Jon Read, Kevin Michael Foote, Johannes Wilhelmus Maria Nissink, Alan Lau, Louise Goodwin, Lisa Wissler, Jason Breed, Benjamin Taylor, Nichola L. Davies, Husam Alwan, James S. Scott, Jason Grant Kettle, Kay Eckersley, D.R Jones, Michal Bista, Marta Wylot, Graeme Walker, Shaun M. Fillery, and Helena Käck

Subjects
Models, Molecular, 0301 basic medicine, Cell Survival, Antineoplastic Agents, Crystallography, X-Ray, Structure-Activity Relationship, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Cell Line, Tumor, Drug Discovery, medicine, Animals, Humans, Cytotoxic T cell, CRISPR, Potency, Nucleotide, RNA, Small Interfering, chemistry.chemical_classification, Cancer, medicine.disease, Phosphoric Monoester Hydrolases, Rats, DNA Repair Enzymes, 030104 developmental biology, Enzyme, chemistry, Biochemistry, 030220 oncology & carcinogenesis, Cancer cell, Molecular Medicine, DNA
Abstract

Recent literature has claimed that inhibition of the enzyme MTH1 can eradicate cancer. MTH1 is one of the "housekeeping" enzymes that are responsible for hydrolyzing damaged nucleotides in cells and thus prevent them from being incorporated into DNA. We have developed orthogonal and chemically distinct tool compounds to those published in the literature to allow us to test the hypothesis that inhibition of MTH1 has wide applicability in the treatment of cancer. Here we present the work that led to the discovery of three structurally different series of MTH1 inhibitors with excellent potency, selectivity, and proven target engagement in cells. None of these compounds elicited the reported cellular phenotype, and additional siRNA and CRISPR experiments further support these observations. Critically, the difference between the responses of our highly selective inhibitors and published tool compounds suggests that the effect reported for the latter may be due to off-target cytotoxic effects. As a result, we conclude that the role of MTH1 in carcinogenesis and utility of its inhibition is yet to be established.

Published
2016
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10. Correction to Discovery of Pyrazolo[1,5-a]pyrimidine B-Cell Lymphoma 6 (BCL6) Binders and Optimization to High Affinity Macrocyclic Inhibitors

Author

William McCoull, Roman D. Abrams, Erica Anderson, Kevin Blades, Peter Barton, Matthew Box, Jonathan Burgess, Kate Byth, Qing Cao, Claudio Chuaqui, Rodrigo J. Carbajo, Tony Cheung, Erin Code, Andrew D. Ferguson, Shaun Fillery, Nathan O. Fuller, Eric Gangl, Ning Gao, Matthew Grist, David Hargreaves, Martin R. Howard, Jun Hu, Paul D. Kemmitt, Jennifer E. Nelson, Nichole O’Connell, D. Bryan Prince, Piotr Raubo, Philip B. Rawlins, Graeme R. Robb, Junjie Shi, Michael J. Waring, David Whittaker, Marta Wylot, and Xiahui Zhu

Subjects
Drug Discovery, Molecular Medicine
Published
2017

11. Discovery of Pyrazolo[1,5-a]pyrimidine B-Cell Lymphoma 6 (BCL6) Binders and Optimization to High Affinity Macrocyclic Inhibitors

Author

Jennifer E. Nelson, Graeme R. Robb, Martin R. Howard, Piotr Raubo, Paul D. Kemmitt, Kevin Blades, Junjie Shi, Tony Cheung, Qing Cao, Peter Barton, Andrew D. Ferguson, D. Bryan Prince, Shaun M. Fillery, Jun Hu, David J. Hargreaves, Roman D. Abrams, Nathan O. Fuller, Claudio Chuaqui, Eric Gangl, Matthew R. Box, Ning Gao, William McCoull, Kate Byth, Michael J. Waring, Jonathan Burgess, Xiahui Zhu, Matthew Grist, Erica Anderson, Nichole O'Connell, Philip B. Rawlins, Marta Wylot, David Whittaker, Rodrigo J. Carbajo, and Erin Code

Subjects
0301 basic medicine, Pyrimidine, Pyridines, 03 medical and health sciences, chemistry.chemical_compound, immune system diseases, hemic and lymphatic diseases, Cell Line, Tumor, Drug Discovery, medicine, Transferase, Potency, Humans, Protein Interaction Maps, B-cell lymphoma, Cell Proliferation, Chemistry, Kinase, medicine.disease, BCL6, Combinatorial chemistry, Lymphoma, Molecular Docking Simulation, 030104 developmental biology, Biochemistry, Cell culture, Drug Design, Proto-Oncogene Proteins c-bcl-6, Molecular Medicine, Pyrazoles, Lymphoma, Large B-Cell, Diffuse
Abstract

Inhibition of the protein-protein interaction between B-cell lymphoma 6 (BCL6) and corepressors has been implicated as a therapeutic target in diffuse large B-cell lymphoma (DLBCL) cancers and profiling of potent and selective BCL6 inhibitors are critical to test this hypothesis. We identified a pyrazolo[1,5-a]pyrimidine series of BCL6 binders from a fragment screen in parallel with a virtual screen. Using structure-based drug design, binding affinity was increased 100000-fold. This involved displacing crystallographic water, forming new ligand-protein interactions and a macrocyclization to favor the bioactive conformation of the ligands. Optimization for slow off-rate constant kinetics was conducted as well as improving selectivity against an off-target kinase, CK2. Potency in a cellular BCL6 assay was further optimized to afford highly selective probe molecules. Only weak antiproliferative effects were observed across a number of DLBCL lines and a multiple myeloma cell line without a clear relationship to BCL6 potency. As a result, we conclude that the BCL6 hypothesis in DLBCL cancer remains unproven.

Published
2017

12. Die Textsorte Glosse in diachronischer Auffassung

Author

Marta Wylot and Universität Łódź, Philologische Fakultät, Lehrstuhl für Deutsche und Angewandte Sprachwissenschaft, 90–236 Łódź, Pomorska 171/173.

Subjects
the column, the text type, the text linguistic, General Medicine
Abstract

The aim of the paper is to describe the column as a type of text. This text type has its roots back in the 19th century France. But at the beginning this text type had a totally different character, different form, aim and features. It was a part of newspaper, where novels, critiques and poems were posted. Nowadays there may occur a problem to define the term ‘column’. Generally it is the text type with a polemical and derisive character, which serves as the entertainment, but sometimes the term ‘column’ still refers to a part of the newspaper. This article defines the term and how this text type has developed through the time.

Published
2015
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