34 results on '"Hopcroft, Lisa E. M."'
Search Results
2. Leukaemia exposure alters the transcriptional profile and function of BCR::ABL1 negative macrophages in the bone marrow niche
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Dawson, Amy, Zarou, Martha M., Prasad, Bodhayan, Bittencourt-Silvestre, Joana, Zerbst, Désirée, Himonas, Ekaterini, Hsieh, Ya-Ching, van Loon, Isabel, Blanco, Giovanny Rodriguez, Ianniciello, Angela, Kerekes, Zsombor, Krishnan, Vaidehi, Agarwal, Puneet, Almasoudi, Hassan, McCluskey, Laura, Hopcroft, Lisa E. M., Scott, Mary T., Baquero, Pablo, Dunn, Karen, Vetrie, David, Copland, Mhairi, Bhatia, Ravi, Coffelt, Seth B., Tiong, Ong Sin, Wheadon, Helen, Zanivan, Sara, Kirschner, Kristina, and Helgason, G. Vignir
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- 2024
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3. Incidence of diabetes after SARS-CoV-2 infection in England and the implications of COVID-19 vaccination: a retrospective cohort study of 16 million people
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Al Arab, Marwa, Almaghrabi, Fatima, Andrews, Colm, Badrick, Ellena, Baz, Sarah, Beckford, Chelsea, Berman, Samantha, Bolton, Tom, Booth, Charlotte, Bowyer, Ruth, Boyd, Andy, Bridger-Staatz, Charis, Brophy, Sinead, Campbell, Archie, Campbell, Kirsteen C, Carnemolla, Alisia, Carpentieri, Jd, Cezard, Genevieve, Chaturvedi, Nishi, Cheetham, Nathan, Costello, Ruth, Cowling, Thomas, Crane, Matthew, Cuitun Coronado, Jose Ignacio, Curtis, Helen, Denaxas, Spiros, Denholm, Rachel, Di Gessa, Giorgio, Dobson, Richard, Douglas, Ian, Evans, Katharine M, Fang, Chao, Ferreira, Vanessa, Finnigan, Lucy, Fisher, Louis, Flaig, Robin, Folarin, Amos, Forbes, Harriet, Foster, Diane, Fox, Laura, Freydin, Maxim, Garcia, Paz, Gibson, Andy, Glen, Fiona, Goldacre, Ben, Goncalves Soares, Ana, Greaves, Felix, Green, Amelia, Green, Mark, Green, Michael, Griffith, Gareth, Hamill Howes, Lee, Hamilton, Olivia, Herbet, Annie, Herrett, Emily, Hopcroft, Lisa, Horne, Elsie, Hou, Bo, Hughes, Alun, Hulme, William, Huntley, Lizzie, Ip, Samantha, Jacques, Wels, Jezzard, Peter, Jones, Louise, Kanagaratnam, Arun, Karthikeyan Suseeladevi, Arun, Katikireddi, Vittal, Kellas, John, Kennedy, Jonathan I, Kibble, Milla, Knight, Rochelle, Knueppel, Anika, Kopasker, Daniel, Kromydas, Theocharis, Kwong, Alex, Langan, Sinead, Lemanska, Agnieszka, Lukaschuk, Elena, Mackenna, Brain, Macleod, John, Maddock, Jane, Mahalingasivam, Viyaasan, Mansfield, Kathryn, McArdle, Fintan, McCartney, Daniel, McEachan, Rosie, McElroy, Eoin, McLachlan, Stela, Mitchell, Ruth, Moltrecht, Bettina, Morley, Jess, Nab, Linda, Neubauer, Stefan, Nigrelli, Lidia, North, Teri, Northstone, Kate, Oakley, Jacqui, Palmer, Tom, Park, Chloe, Parker, Michael, Parsons, Sam, Patalay, Praveetha, Patel, Kishan, Perez-Reche, Francisco, Piechnik, Stefan, Piehlmaier, Dominik, Ploubidis, George, Rafeti, Elena, Raman, Betty, Ranjan, Yatharth, Rapala, Alicja, Rhead, Rebecca, Roberts, Amy, Sampri, Alexia, Sanders, Zeena-Britt, Santorelli, Gillian, Saunders, Laura C, Shah, Anoop, Shah, Syed Ahmar, Sharp, Steve, Shaw, Richard, Sheard, Laura, Sheikh, Aziz, Silverwood, Richard, Smeeth, Liam, Smith, Stephen, Stafford, Jean, Steptoe, Andrew, Sterne, Jonathan, Steves, Claire, Stewart, Callum, Taylor, Kurt, Tazare, John, Teece, Lucy, Thomas, Richard, Thompson, Ellen, Tilling, Kate, Timpson, Nicholas, Tomlinson, Laurie, Toms, Renin, Tunnicliffe, Elizabeth, Turner, Emma L, Walker, Alex, Walker, Venexia, Walter, Scott, Wang, Kevin, Wei, Yinghui, Whitehorn, Rebecca, Wielgoszewska, Bozena, Wild, James M, Willan, Kathryn, Willans, Robert, Williams, Dylan, Wong, Andrew, Wood, Angela, Woodward, Hannah, Wright, John, Yang, Tiffany, Zaninotto, Paola, Zheng, Bang, Zhu, Jingmin, Eastwood, Sophie, Horne, Elsie M F, Massey, Jon, Hopcroft, Lisa E M, Cuitun Coronado, Jose, Davy, Simon, Dillingham, Iain, Morton, Caroline, and Sterne, Jonathan A C
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- 2024
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4. Neonatal and maternal outcomes following SARS-CoV-2 infection and COVID-19 vaccination: a population-based matched cohort study
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Lindsay, Laura, Calvert, Clara, Shi, Ting, Carruthers, Jade, Denny, Cheryl, Donaghy, Jack, Hopcroft, Lisa E. M., Hopkins, Leanne, Goulding, Anna, McLaughlin, Terry, Moore, Emily, Taylor, Bob, Bhaskaran, Krishnan, Katikireddi, Srinivasa Vittal, McCabe, Ronan, McCowan, Colin, Simpson, Colin R., Robertson, Chris, Sheikh, Aziz, Wood, Rachael, and Stock, Sarah J.
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- 2023
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5. A population-based matched cohort study of major congenital anomalies following COVID-19 vaccination and SARS-CoV-2 infection
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Calvert, Clara, Carruthers, Jade, Denny, Cheryl, Donaghy, Jack, Hopcroft, Lisa E. M., Hopkins, Leanne, Goulding, Anna, Lindsay, Laura, McLaughlin, Terry, Moore, Emily, Taylor, Bob, Loane, Maria, Dolk, Helen, Morris, Joan, Auyeung, Bonnie, Bhaskaran, Krishnan, Gibbons, Cheryl L., Katikireddi, Srinivasa Vittal, O’Leary, Maureen, McAllister, David, Shi, Ting, Simpson, Colin R., Robertson, Chris, Sheikh, Aziz, Stock, Sarah J., and Wood, Rachael
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- 2023
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- View/download PDF
6. Aromatase inhibition plus/minus Src inhibitor saracatinib (AZD0530) in advanced breast cancer therapy (ARISTACAT): a randomised phase II study
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Oswald, Ailsa J., Symeonides, Stefan N., Wheatley, Duncan, Chan, Stephen, Brunt, Adrian Murray, McAdam, Karen, Schmid, Peter, Waters, Simon, Poole, Christopher, Twelves, Chris, Perren, Timothy, Bartlett, John, Piper, Tammy, Chisholm, Eve Macdonald, Welsh, Michelle, Hill, Robert, Hopcroft, Lisa E. M., Barrett-Lee, Peter, and Cameron, David A.
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- 2023
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7. A Phase II study of neoadjuvant axitinib for reducing the extent of venous tumour thrombus in clear cell renal cell cancer with venous invasion (NAXIVA)
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Stewart, Grant D., Welsh, Sarah J., Ursprung, Stephan, Gallagher, Ferdia A., Jones, James O., Shields, Jacqui, Smith, Christopher G., Mitchell, Thomas J., Warren, Anne Y., Bex, Axel, Boleti, Ekaterini, Carruthers, Jade, Eisen, Tim, Fife, Kate, Hamid, Abdel, Laird, Alexander, Leung, Steve, Malik, Jahangeer, Mendichovszky, Iosif A., Mumtaz, Faiz, Oades, Grenville, Priest, Andrew N., Riddick, Antony C. P., Venugopal, Balaji, Welsh, Michelle, Riddle, Kathleen, Hopcroft, Lisa E. M., and Jones, Robert J.
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- 2022
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8. Pregnancy outcomes after SARS-CoV-2 infection in periods dominated by delta and omicron variants in Scotland: a population-based cohort study
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Stock, Sarah J, Moore, Emily, Calvert, Clara, Carruthers, Jade, Denny, Cheryl, Donaghy, Jack, Hillman, Sam, Hopcroft, Lisa E M, Hopkins, Leanne, Goulding, Anna, Lindsay, Laura, McLaughlin, Terry, Taylor, Bob, Auyeung, Bonnie, Katikireddi, Srinivasa Vittal, McCowan, Colin, Ritchie, Lewis D, Rudan, Igor, Simpson, Colin R, Robertson, Chris, Sheikh, Aziz, and Wood, Rachael
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- 2022
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9. SARS-CoV-2 infection and COVID-19 vaccination rates in pregnant women in Scotland
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Stock, Sarah J., Carruthers, Jade, Calvert, Clara, Denny, Cheryl, Donaghy, Jack, Goulding, Anna, Hopcroft, Lisa E. M., Hopkins, Leanne, McLaughlin, Terry, Pan, Jiafeng, Shi, Ting, Taylor, Bob, Agrawal, Utkarsh, Auyeung, Bonnie, Katikireddi, Srinivasa Vittal, McCowan, Colin, Murray, Josie, Simpson, Colin R., Robertson, Chris, Vasileiou, Eleftheria, Sheikh, Aziz, and Wood, Rachael
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- 2022
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10. A population-based matched cohort study of early pregnancy outcomes following COVID-19 vaccination and SARS-CoV-2 infection
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Calvert, Clara, Carruthers, Jade, Denny, Cheryl, Donaghy, Jack, Hillman, Sam, Hopcroft, Lisa E. M., Hopkins, Leanne, Goulding, Anna, Lindsay, Laura, McLaughlin, Terry, Moore, Emily, Pan, Jiafeng, Taylor, Bob, Almaghrabi, Fatima, Auyeung, Bonnie, Bhaskaran, Krishnan, Gibbons, Cheryl L., Katikireddi, Srinivasa Vittal, McCowan, Colin, Murray, Josie, O’Leary, Maureen, Ritchie, Lewis D., Shah, Syed Ahmar, Simpson, Colin R., Robertson, Chris, Sheikh, Aziz, Stock, Sarah J., and Wood, Rachael
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- 2022
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11. Incidence of diabetes after SARS-CoV-2 infection in England and the implications of COVID-19 vaccination: a retrospective cohort study of 16 million people
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Taylor, Kurt, Eastwood, Sophie, Walker, Venexia, Cezard, Genevieve, Knight, Rochelle, Al Arab, Marwa, Wei, Yinghui, Horne, Elsie M F, Teece, Lucy, Forbes, Harriet, Walker, Alex, Fisher, Louis, Massey, Jon, Hopcroft, Lisa E M, Palmer, Tom, Cuitun Coronado, Jose, Ip, Samantha, Davy, Simon, Dillingham, Iain, Morton, Caroline, Greaves, Felix, Macleod, John, Goldacre, Ben, Wood, Angela, Chaturvedi, Nishi, Sterne, Jonathan A C, Denholm, Rachel, Al Arab, Marwa, Almaghrabi, Fatima, Andrews, Colm, Badrick, Ellena, Baz, Sarah, Beckford, Chelsea, Berman, Samantha, Bolton, Tom, Booth, Charlotte, Bowyer, Ruth, Boyd, Andy, Bridger-Staatz, Charis, Brophy, Sinead, Campbell, Archie, Campbell, Kirsteen C, Carnemolla, Alisia, Carpentieri, Jd, Cezard, Genevieve, Chaturvedi, Nishi, Cheetham, Nathan, Costello, Ruth, Cowling, Thomas, Crane, Matthew, Cuitun Coronado, Jose Ignacio, Curtis, Helen, Denaxas, Spiros, Denholm, Rachel, Di Gessa, Giorgio, Dobson, Richard, Douglas, Ian, Evans, Katharine M, Fang, Chao, Ferreira, Vanessa, Finnigan, Lucy, Fisher, Louis, Flaig, Robin, Folarin, Amos, Forbes, Harriet, Foster, Diane, Fox, Laura, Freydin, Maxim, Garcia, Paz, Gibson, Andy, Glen, Fiona, Goldacre, Ben, Goncalves Soares, Ana, Greaves, Felix, Green, Amelia, Green, Mark, Green, Michael, Griffith, Gareth, Hamill Howes, Lee, Hamilton, Olivia, Herbet, Annie, Herrett, Emily, Hopcroft, Lisa, Horne, Elsie, Hou, Bo, Hughes, Alun, Hulme, William, Huntley, Lizzie, Ip, Samantha, Jacques, Wels, Jezzard, Peter, Jones, Louise, Kanagaratnam, Arun, Karthikeyan Suseeladevi, Arun, Katikireddi, Vittal, Kellas, John, Kennedy, Jonathan I, Kibble, Milla, Knight, Rochelle, Knueppel, Anika, Kopasker, Daniel, Kromydas, Theocharis, Kwong, Alex, Langan, Sinead, Lemanska, Agnieszka, Lukaschuk, Elena, Mackenna, Brain, Macleod, John, Maddock, Jane, Mahalingasivam, Viyaasan, Mansfield, Kathryn, McArdle, Fintan, McCartney, Daniel, McEachan, Rosie, McElroy, Eoin, McLachlan, Stela, Mitchell, Ruth, Moltrecht, Bettina, Morley, Jess, Nab, Linda, Neubauer, Stefan, Nigrelli, Lidia, North, Teri, Northstone, Kate, Oakley, Jacqui, Palmer, Tom, Park, Chloe, Parker, Michael, Parsons, Sam, Patalay, Praveetha, Patel, Kishan, Perez-Reche, Francisco, Piechnik, Stefan, Piehlmaier, Dominik, Ploubidis, George, Rafeti, Elena, Raman, Betty, Ranjan, Yatharth, Rapala, Alicja, Rhead, Rebecca, Roberts, Amy, Sampri, Alexia, Sanders, Zeena-Britt, Santorelli, Gillian, Saunders, Laura C, Shah, Anoop, Shah, Syed Ahmar, Sharp, Steve, Shaw, Richard, Sheard, Laura, Sheikh, Aziz, Silverwood, Richard, Smeeth, Liam, Smith, Stephen, Stafford, Jean, Steptoe, Andrew, Sterne, Jonathan, Steves, Claire, Stewart, Callum, Taylor, Kurt, Tazare, John, Teece, Lucy, Thomas, Richard, Thompson, Ellen, Tilling, Kate, Timpson, Nicholas, Tomlinson, Laurie, Toms, Renin, Tunnicliffe, Elizabeth, Turner, Emma L, Walker, Alex, Walker, Venexia, Walter, Scott, Wang, Kevin, Wei, Yinghui, Whitehorn, Rebecca, Wielgoszewska, Bozena, Wild, James M, Willan, Kathryn, Willans, Robert, Williams, Dylan, Wong, Andrew, Wood, Angela, Woodward, Hannah, Wright, John, Yang, Tiffany, Zaninotto, Paola, Zheng, Bang, and Zhu, Jingmin
- Abstract
Some studies have shown that the incidence of type 2 diabetes increases after a diagnosis of COVID-19, although the evidence is not conclusive. However, the effects of the COVID-19 vaccine on this association, or the effect on other diabetes subtypes, are not clear. We aimed to investigate the association between COVID-19 and incidence of type 2, type 1, gestational and non-specific diabetes, and the effect of COVID- 19 vaccination, up to 52 weeks after diagnosis.
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- 2024
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12. Author Correction: SARS-CoV-2 infection and COVID-19 vaccination rates in pregnant women in Scotland
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Stock, Sarah J., Carruthers, Jade, Calvert, Clara, Denny, Cheryl, Donaghy, Jack, Goulding, Anna, Hopcroft, Lisa E. M., Hopkins, Leanne, McLaughlin, Terry, Pan, Jiafeng, Shi, Ting, Taylor, Bob, Agrawal, Utkarsh, Auyeung, Bonnie, Katikireddi, Srinivasa Vittal, McCowan, Colin, Murray, Josie, Simpson, Colin R., Robertson, Chris, Vasileiou, Eleftheria, Sheikh, Aziz, and Wood, Rachael
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- 2022
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13. Lifestyle coaching is feasible in fatigued brain tumor patients: A phase I/feasibility, multi-center, mixed-methods randomized controlled trial
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Rooney, Alasdair G, Hewins, William, Walker, Amie, Mackinnon, Mairi, Withington, Lisa, Robson, Sara, Torrens, Claire, Hopcroft, Lisa E M, Clark, Antony, Anderson, Garry, Bulbeck, Helen, Dunlop, Joanna, Welsh, Michelle, Dyson, Aimee, Emerson, Julie, Cochrane, Carol, Hill, Robert, Carruthers, Jade, Day, Julia, Gillespie, David, Hewitt, Christopher, Molinari, Emanuela, Wells, Mary, Mcbain, Catherine, Chalmers, Anthony J, and Grant, Robin
- Subjects
lifestyle ,coaching ,Medicine (miscellaneous) ,fatigue ,brain tumor ,RCT - Abstract
Background There are no effective treatments for brain tumor-related fatigue. We studied the feasibility of two novel lifestyle coaching interventions in fatigued brain tumor patients. Methods This phase I/feasibility multi-center RCT recruited patients with a clinically stable primary brain tumor and significant fatigue (mean Brief Fatigue Inventory [BFI] score ≥ 4/10). Participants were randomized in a 1–1–1 allocation ratio to: Control (usual care); Health Coaching (“HC”, an eight-week program targeting lifestyle behaviors); or HC plus Activation Coaching (“HC + AC”, further targeting self-efficacy). The primary outcome was feasibility of recruitment and retention. Secondary outcomes were intervention acceptability, which was evaluated via qualitative interview, and safety. Exploratory quantitative outcomes were measured at baseline (T0), post-interventions (T1, 10 weeks), and endpoint (T2, 16 weeks). Results n = 46 fatigued brain tumor patients (T0 BFI mean = 6.8/10) were recruited and 34 were retained to endpoint, establishing feasibility. Engagement with interventions was sustained over time. Qualitative interviews (n = 21) suggested that coaching interventions were broadly acceptable, although mediated by participant outlook and prior lifestyle. Coaching led to significant improvements in fatigue (improvement in BFI versus control at T1: HC=2.2 points [95% CI 0.6, 3.8], HC + AC = 1.8 [0.1, 3.4], Cohen’s d [HC] = 1.9; improvement in FACIT-Fatigue: HC = 4.8 points [−3.7, 13.3]; HC + AC = 12 [3.5, 20.5], d [HC and AC] = 0.9). Coaching also improved depressive and mental health outcomes. Modeling suggested a potential limiting effect of higher baseline depressive symptoms. Conclusions Lifestyle coaching interventions are feasible to deliver to fatigued brain tumor patients. They were manageable, acceptable, and safe, with preliminary evidence of benefit on fatigue and mental health outcomes. Larger trials of efficacy are justified.
- Published
- 2022
14. Trends, variation, and clinical characteristics of recipients of antiviral drugs and neutralising monoclonal antibodies for covid-19 in community settings: retrospective, descriptive cohort study of 23.4 million people in OpenSAFELY
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Green, Amelia C A, primary, Curtis, Helen J, additional, Higgins, Rose, additional, Nab, Linda, additional, Mahalingasivam, Viyaasan, additional, Smith, Rebecca M, additional, Mehrkar, Amir, additional, Inglesby, Peter, additional, Drysdale, Henry, additional, DeVito, Nicholas J, additional, Croker, Richard, additional, Rentsch, Christopher T, additional, Bhaskaran, Krishnan, additional, Tazare, John, additional, Zheng, Bang, additional, Andrews, Colm D, additional, Bacon, Sebastian C J, additional, Davy, Simon, additional, Dillingham, Iain, additional, Evans, David, additional, Fisher, Louis, additional, Hickman, George, additional, Hopcroft, Lisa E M, additional, Hulme, William J, additional, Massey, Jon, additional, MacDonald, Orla, additional, Morley, Jessica, additional, Morton, Caroline E, additional, Park, Robin Y, additional, Walker, Alex J, additional, Ward, Tom, additional, Wiedemann, Milan, additional, Bates, Christopher, additional, Cockburn, Jonathan, additional, Parry, John, additional, Hester, Frank, additional, Harper, Sam, additional, Douglas, Ian J, additional, Evans, Stephen J W, additional, Goldacre, Ben, additional, Tomlinson, Laurie A, additional, and MacKenna, Brian, additional
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- 2023
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15. Identifying Patterns of Clinical Interest in Clinicians’ Treatment Preferences: Hypothesis-free Data Science Approach to Prioritizing Prescribing Outliers for Clinical Review
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MacKenna, Brian, primary, Curtis, Helen J, additional, Hopcroft, Lisa E M, additional, Walker, Alex J, additional, Croker, Richard, additional, Macdonald, Orla, additional, Evans, Stephen J W, additional, Inglesby, Peter, additional, Evans, David, additional, Morley, Jessica, additional, Bacon, Sebastian C J, additional, and Goldacre, Ben, additional
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- 2022
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16. Pregnancy outcomes following SARS-CoV-2 infection in Delta and Omicron dominant periods in Scotland: A population-based cohort study
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Stock, Sarah J, Moore, Emily, Calvert, Clara, Carruthers, Jade, Denny, Cheryl, Donaghy, Jack, Hillman, Sam, Hopcroft, Lisa E M, Hopkins, Leanne, Goulding, Anna, Lindsay, Laura, McLaughlin, Terry, Taylor, Bob, Auyeung, Bonnie, Katikireddi, Srinivasa Vittal, McCowan, Colin, Ritchie, Lewis D, Rudan, Igor, Simpson, Colin R, Robertson, Chris, Sheikh, Aziz, and Wood, Rachael
- Subjects
Cohort Studies ,Pregnancy Complications, Infectious/epidemiology ,COVID-19 Vaccines ,Premature Birth/epidemiology ,Pregnancy ,SARS-CoV-2 ,Stillbirth/epidemiology ,Infant, Newborn ,COVID-19 ,Humans ,Female ,Pregnancy Outcome/epidemiology - Abstract
BACKGROUND: Evidence suggests that the SARS-CoV-2 omicron (B.1·1.529) is associated with lower risks of adverse outcomes than the delta (B.1.617.2) variant among the general population. However, little is known about outcomes after omicron infection in pregnancy. We aimed to assess and compare short-term pregnancy outcomes after SARS-CoV-2 delta and omicron infection in pregnancy.METHODS: We did a national population-based cohort study of women who had SARS-CoV-2 infection in pregnancy between May 17, 2021, and Jan 31, 2022. The primary maternal outcome was admission to critical care within 21 days of infection or death within 28 days of date of infection. Pregnancy outcomes were preterm birth and stillbirth within 28 days of infection. Neonatal outcomes were death within 28 days of birth, and low Apgar score (FINDINGS: Between May 17, 2021, and Jan 31, 2022, there were 9923 SARS-CoV-2 infections in 9823 pregnancies, in 9817 women in Scotland. Compared with infections in the delta-dominant period, SARS-CoV-2 infections in pregnancy in the omicron-dominant period were associated with lower maternal critical care admission risk (0·3% [13 of 4968] vs 1·8% [89 of 4955]; adjusted odds ratio 0·25, 95% CI 0·14-0·44) and lower preterm birth within 28 days of infection (1·8% [37 of 2048] vs 4·2% [98 of 2338]; 0·57, 95% CI 0·38-0·87). There were no maternal deaths within 28 days of infection. Estimates of low Apgar scores were imprecise due to low numbers (5 [1·2%] of 423 with omicron vs 11 [2·1%] of 528 with delta, adjusted odds ratio 0·72, 0·23-2·32). There were fewer stillbirths in the omicron-dominant period than in the delta-dominant period (4·3 [2 of 462] per 1000 births vs 20·3 [13 of 639] per 1000) and no neonatal deaths during the omicron-dominant period (0 [0 of 460] per 1000 births vs 6·3 [4 of 626] per 1000 births), thus numbers were too small to support adjusted analyses. Rates of neonatal infection were low in births within 28 days of maternal SARS-CoV-2 infection, with 11 cases of neonatal SARS-CoV-2 in the delta-dominant period, and 1 case in the omicron-dominant period. Of the 15 stillbirths, 12 occurred in women who had not received two or more doses of COVID-19 vaccination at the time of SARS-CoV-2 infection in pregnancy. All 12 cases of neonatal SARS-CoV-2 infection occurred in women who had not received two or more doses of vaccine at the time of maternal infection. Findings in sensitivity analyses were similar to those in the main analyses.INTERPRETATION: Pregnant women infected with SARS-CoV-2 were substantially less likely to have a preterm birth or maternal critical care admission during the omicron-dominant period than during the delta-dominant period.FUNDING: Wellcome Trust, Tommy's charity, Medical Research Council, UK Research and Innovation, Health Data Research UK, National Core Studies-Data and Connectivity, Public Health Scotland, Scottish Government Health and Social Care, Scottish Government Chief Scientist Office, National Research Scotland.
- Published
- 2022
17. Eleven key measures for monitoring general practice clinical activity during COVID-19: A retrospective cohort study using 48 million adults’ primary care records in England through OpenSAFELY.
- Author
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Fisher, Louis, Curtis, Helen J., Croker, Richard, Wiedemann, Milan, Speed, Victoria, Wood, Christopher, Brown, Andrew, Hopcroft, Lisa E. M., Higgins, Rose, Massey, Jon, Inglesby, Peter, Morton, Caroline E., Walker, Alex J., Morley, Jessica, Mehrkar, Amir, Bacon, Seb, Hickman, George, Macdonald, Orla, Lewis, Tom, and Wood, Marion
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- 2023
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18. Lifestyle coaching is feasible in fatigued brain tumor patients: A phase I/feasibility, multi-center, mixed-methods randomized controlled trial.
- Author
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Rooney, Alasdair G, Hewins, William, Walker, Amie, Mackinnon, Mairi, Withington, Lisa, Robson, Sara, Torrens, Claire, Hopcroft, Lisa E M, Clark, Antony, Anderson, Garry, Bulbeck, Helen, Dunlop, Joanna, Welsh, Michelle, Dyson, Aimee, Emerson, Julie, Cochrane, Carol, Hill, Robert, Carruthers, Jade, Day, Julia, and Gillespie, David
- Subjects
BRAIN tumors ,RANDOMIZED controlled trials ,PATIENT Activation Measure ,MENTAL fatigue ,FATIGUE (Physiology) ,HEALTH coaches - Abstract
Background There are no effective treatments for brain tumor-related fatigue. We studied the feasibility of two novel lifestyle coaching interventions in fatigued brain tumor patients. Methods This phase I/feasibility multi-center RCT recruited patients with a clinically stable primary brain tumor and significant fatigue (mean Brief Fatigue Inventory [BFI] score ≥ 4/10). Participants were randomized in a 1–1–1 allocation ratio to: Control (usual care); Health Coaching ("HC", an eight-week program targeting lifestyle behaviors); or HC plus Activation Coaching ("HC + AC", further targeting self-efficacy). The primary outcome was feasibility of recruitment and retention. Secondary outcomes were intervention acceptability, which was evaluated via qualitative interview, and safety. Exploratory quantitative outcomes were measured at baseline (T0), post-interventions (T1, 10 weeks), and endpoint (T2, 16 weeks). Results n = 46 fatigued brain tumor patients (T0 BFI mean = 6.8/10) were recruited and 34 were retained to endpoint, establishing feasibility. Engagement with interventions was sustained over time. Qualitative interviews (n = 21) suggested that coaching interventions were broadly acceptable, although mediated by participant outlook and prior lifestyle. Coaching led to significant improvements in fatigue (improvement in BFI versus control at T1: HC=2.2 points [95% CI 0.6, 3.8], HC + AC = 1.8 [0.1, 3.4], Cohen's d [HC] = 1.9; improvement in FACIT-Fatigue: HC = 4.8 points [−3.7, 13.3]; HC + AC = 12 [3.5, 20.5], d [HC and AC] = 0.9). Coaching also improved depressive and mental health outcomes. Modeling suggested a potential limiting effect of higher baseline depressive symptoms. Conclusions Lifestyle coaching interventions are feasible to deliver to fatigued brain tumor patients. They were manageable, acceptable, and safe, with preliminary evidence of benefit on fatigue and mental health outcomes. Larger trials of efficacy are justified. [ABSTRACT FROM AUTHOR]
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- 2023
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19. Changes in English medication safety indicators throughout the COVID-19 pandemic: a federated analysis of 57 million patients’ primary care records in situ using OpenSAFELY
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Fisher, Louis, primary, Hopcroft, Lisa E. M., additional, Rodgers, Sarah, additional, Barrett, James, additional, Oliver, Kerry, additional, Avery, Anthony J., additional, Evans, Dai, additional, Curtis, Helen, additional, Croker, Richard, additional, Macdonald, Orla, additional, Morley, Jessica, additional, Mehrkar, Amir, additional, Bacon, Seb, additional, Davy, Simon, additional, Dillingham, Iain, additional, Evans, David, additional, Hickman, George, additional, Inglesby, Peter, additional, Morton, Caroline E., additional, Smith, Becky, additional, Ward, Tom, additional, Hulme, William, additional, Green, Amelia, additional, Massey, Jon, additional, Walker, Alex J., additional, Bates, Chris, additional, Cockburn, Jonathan, additional, Parry, John, additional, Hester, Frank, additional, Harper, Sam, additional, O’Hanlon, Shaun, additional, Eavis, Alex, additional, Jarvis, Richard, additional, Avramov, Dima, additional, Griffiths, Paul, additional, Fowles, Aaron, additional, Parkes, Nasreen, additional, Goldacre, Ben, additional, and MacKenna, Brian, additional
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- 2022
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20. Cohort Profile: The COVID-19 in Pregnancy in Scotland (COPS) dynamic cohort of pregnant women to assess effects of viral and vaccine exposures on pregnancy
- Author
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Stock, Sarah J, primary, Carruthers, Jade, additional, Denny, Cheryl, additional, Donaghy, Jack, additional, Goulding, Anna, additional, Hopcroft, Lisa E M, additional, Hopkins, Leanne, additional, Mulholland, Rachel, additional, Agrawal, Utkarsh, additional, Auyeung, Bonnie, additional, Katikireddi, Srinivasa Vittal, additional, McCowan, Colin, additional, Murray, Josie, additional, Robertson, Chris, additional, Sheikh, Aziz, additional, Shi, Ting, additional, Simpson, Colin R, additional, Vasileiou, Eleftheria, additional, and Wood, Rachael, additional
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- 2022
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21. Dual targeting of p53 and c-MYC selectively eliminates leukaemic stem cells
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Abraham, Sheela A., Hopcroft, Lisa E. M., Carrick, Emma, Drotar, Mark E., Dunn, Karen, Williamson, Andrew J. K., Korfi, Koorosh, Baquero, Pablo, Park, Laura E., Scott, Mary T., Pellicano, Francesca, Pierce, Andrew, Copland, Mhairi, Nourse, Craig, Grimmond, Sean M., Vetrie, David, Whetton, Anthony D., and Holyoake, Tessa L.
- Published
- 2016
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22. Tyrosine Kinase Inhibitor Independent Gene Expression Signature in CML Offers New Targets for LSPC Eradication Therapy.
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Gómez-Castañeda, Eduardo, Hopcroft, Lisa E. M., Rogers, Simon, Munje, Chinmay, Bittencourt-Silvestre, Joana, Copland, Mhairi, Vetrie, David, Holyoake, Tessa, and Jørgensen, Heather G.
- Subjects
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IN vitro studies , *DRUG efficacy , *CHRONIC myeloid leukemia , *LEUKEMIA , *AMINOGLYCOSIDES , *GENE expression , *PROTEIN-tyrosine kinase inhibitors , *CYCLOSPORINE , *TREATMENT effectiveness , *CELLULAR signal transduction , *STEM cells , *PHARMACODYNAMICS , *EVALUATION - Abstract
Simple Summary: Chronic myeloid leukaemia (CML) is initiated by a group of cancer cells called leukaemia stem cells (LSC). These LSC can survive current tyrosine kinase inhibitor (TKI) treatments and, upon treatment withdrawal, are able to re-initiate the disease. Thus, eradicating the LSC would likely cure CML. In this study, we have identified a number of genes whose expression is different between LSC and their healthy counterparts (haematopoietic stem cells) but are not affected by TKI treatment. We hypothesised that these genes may be potential therapeutic targets against LSC and used two different drugs, gemtuzumab–ozogamicin and cyclosporine A, to treat CML in vitro. We found that both drugs have a stronger effect on CML cells than on healthy cells. Therefore, we propose that the list of genes we identified could represent a novel source of therapeutic targets against CML. Tyrosine kinase inhibitors (TKI) have revolutionised the treatment of CML. However, TKI do not eliminate the leukaemia stem cells (LSC), which can re-initiate the disease. Thus, finding new therapeutic targets in CML LSC is key to finding a curative treatment. Using microarray datasets, we defined a list of 227 genes that were differentially expressed in CML LSC compared to the healthy controls but were not affected by TKI in vitro. Two of them, CD33 and PPIF, are targeted by gemtuzumab–ozogamicin and cyclosporin A, respectively. We treated CML and the control CD34+ cells with either drug with or without imatinib to investigate the therapeutic potential of the TKI-independent gene expression programme. Cyclosporine A, in combination with imatinib, reduced the number of CML CFC compared with non-CML controls, but only at supra-therapeutic concentrations. Gemtuzumab–ozogamicin showed an EC50 of 146 ng/mL, below the plasma peak concentration of 630 ng/mL observed in the AML patients and below the EC50 of 3247 ng/mL observed in the non-CML cells. Interestingly, gemtuzumab–ozogamicin seems to promote cell cycle progression in CML CD34+ cells and demonstrated activation of the RUNX1 pathway in an RNAseq experiment. This suggests that targeting the TKI-independent genes in CML LSC could be exploited for the development of new therapies in CML. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
23. Predictive response-relevant clustering of expression data provides insights into disease processes
- Author
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Hopcroft, Lisa E. M., McBride, Martin W., Harris, Keith J., Sampson, Amanda K., McClure, John D., Graham, Delyth, Young, Graham, Holyoake, Tessa L., Girolami, Mark A., and Dominiczak, Anna F.
- Published
- 2010
- Full Text
- View/download PDF
24. Targeting BCR-ABL-Independent TKI resistance in chronic myeloid leukemia by mTOR and autophagy inhibition
- Author
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Mitchell, Rebecca, Hopcroft, Lisa E M, Baquero, Pablo, Allan, Elaine K, Hewit, Kay, James, Daniel, Hamilton, Graham, Mukhopadhyay, Arunima, O'Prey, Jim, Hair, Alan, Melo, Junia V, Chan, Edmond, Ryan, Kevin M, Maguer-Satta, Véronique, Druker, Brian J, Clark, Richard E, Mitra, Subir, Herzyk, Pawel, Nicolini, Franck E, Salomoni, Paolo, and Helgason, G Vignir
- Subjects
RC0254 - Abstract
Background: Imatinib and second-generation tyrosine kinase inhibitors (TKIs) nilotinib and dasatinib have statistically significantly improved the life expectancy of chronic myeloid leukemia (CML) patients; however, resistance to TKIs remains a major clinical challenge. Although ponatinib, a third-generation TKI, improves outcomes for patients with BCR-ABL-dependent mechanisms of resistance, including the T315I mutation, a proportion of patients may have or develop BCR-ABL-independent resistance and fail ponatinib treatment. By modeling ponatinib resistance and testing samples from these CML patients, it is hoped that an alternative drug target can be identified and inhibited with a novel compound. Methods: Two CML cell lines with acquired BCR-ABL-independent resistance were generated following culture in ponatinib. RNA sequencing and gene ontology (GO) enrichment were used to detect aberrant transcriptional response in ponatinib-resistant cells. A validated oncogene drug library was used to identify US Food and Drug Administration-approved drugs with activity against TKI-resistant cells. Validation was performed using bone marrow (BM)-derived cells from TKI-resistant patients (n = 4) and a human xenograft mouse model (n = 4-6 mice per group). All statistical tests were two-sided. Results: We show that ponatinib-resistant CML cells can acquire BCR-ABL-independent resistance mediated through alternative activation of mTOR. Following transcriptomic analysis and drug screening, we highlight mTOR inhibition as an alternative therapeutic approach in TKI-resistant CML cells. Additionally, we show that catalytic mTOR inhibitors induce autophagy and demonstrate that genetic or pharmacological inhibition of autophagy sensitizes ponatinib-resistant CML cells to death induced by mTOR inhibition in vitro (% number of colonies of control[SD], NVP-BEZ235 vs NVP-BEZ235+HCQ: 45.0[17.9]% vs 24.0[8.4]%, P = .002) and in vivo (median survival of NVP-BEZ235- vs NVP-BEZ235+HCQ-treated mice: 38.5 days vs 47.0 days, P = .04). Conclusion: Combined mTOR and autophagy inhibition may provide an attractive approach to target BCR-ABL-independent mechanism of resistance.
- Published
- 2017
25. hsa-mir183/EGR1–mediated regulation of E2F1 is required for CML stem/progenitor cell survival
- Author
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Pellicano, Francesca, primary, Park, Laura, additional, Hopcroft, Lisa E. M., additional, Shah, Mansi M., additional, Jackson, Lorna, additional, Scott, Mary T., additional, Clarke, Cassie J., additional, Sinclair, Amy, additional, Abraham, Sheela A., additional, Hair, Alan, additional, Helgason, G. Vignir, additional, Aspinall-O’Dea, Mark, additional, Bhatia, Ravi, additional, Leone, Gustavo, additional, Kranc, Kamil R., additional, Whetton, Anthony D., additional, and Holyoake, Tessa L., additional
- Published
- 2018
- Full Text
- View/download PDF
26. CML cells actively evade host immune surveillance through cytokine-mediated downregulation of MHC-II expression
- Author
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Tarafdar, Anuradha, primary, Hopcroft, Lisa E. M., additional, Gallipoli, Paolo, additional, Pellicano, Francesca, additional, Cassels, Jennifer, additional, Hair, Alan, additional, Korfi, Koorosh, additional, Jørgensen, Heather G., additional, Vetrie, David, additional, Holyoake, Tessa L., additional, and Michie, Alison M., additional
- Published
- 2017
- Full Text
- View/download PDF
27. CXCR2 and CXCL4 regulate survival and self-renewal of hematopoietic stem/progenitor cells
- Author
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Sinclair, Amy, primary, Park, Laura, additional, Shah, Mansi, additional, Drotar, Mark, additional, Calaminus, Simon, additional, Hopcroft, Lisa E. M., additional, Kinstrie, Ross, additional, Guitart, Amelie V., additional, Dunn, Karen, additional, Abraham, Sheela A., additional, Sansom, Owen, additional, Michie, Alison M., additional, Machesky, Laura, additional, Kranc, Kamil R., additional, Graham, Gerard J., additional, Pellicano, Francesca, additional, and Holyoake, Tessa L., additional
- Published
- 2016
- Full Text
- View/download PDF
28. Targeting BCR-ABL-Independent TKI Resistance in Chronic Myeloid Leukemia by mTOR and Autophagy Inhibition.
- Author
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Mitchell, Rebecca, Hopcroft, Lisa E. M., Baquero, Pablo, Allan, Elaine K., Hewit, Kay, James, Daniel, Hamilton, Graham, Mukhopadhyay, Arunima, O'Prey, Jim, Hair, Alan, Melo, Junia V., Chan, Edmond, Ryan, Kevin M., Maguer-Satta, Véronique, Druker, Brian J., Clark, Richard E., Mitra, Subir, Herzyk, Pawel, Nicolini, Franck E., and Salomoni, Paolo
- Subjects
- *
DRUG therapy , *IMATINIB , *CHRONIC myeloid leukemia , *DRUG resistance , *AUTOPHAGY , *MTOR inhibitors , *PATIENTS , *ANTINEOPLASTIC agents , *ANIMAL experimentation , *CELL lines , *COMPARATIVE studies , *DRUG resistance in cancer cells , *HETEROCYCLIC compounds , *IMIDAZOLES , *RESEARCH methodology , *MEDICAL cooperation , *MICE , *PROTEINS , *QUINOLINE , *RESEARCH , *EVALUATION research , *PROTEIN kinase inhibitors , *CHEMICAL inhibitors - Abstract
Background: Imatinib and second-generation tyrosine kinase inhibitors (TKIs) nilotinib and dasatinib have statistically significantly improved the life expectancy of chronic myeloid leukemia (CML) patients; however, resistance to TKIs remains a major clinical challenge. Although ponatinib, a third-generation TKI, improves outcomes for patients with BCR-ABL-dependent mechanisms of resistance, including the T315I mutation, a proportion of patients may have or develop BCR-ABL-independent resistance and fail ponatinib treatment. By modeling ponatinib resistance and testing samples from these CML patients, it is hoped that an alternative drug target can be identified and inhibited with a novel compound.Methods: Two CML cell lines with acquired BCR-ABL-independent resistance were generated following culture in ponatinib. RNA sequencing and gene ontology (GO) enrichment were used to detect aberrant transcriptional response in ponatinib-resistant cells. A validated oncogene drug library was used to identify US Food and Drug Administration-approved drugs with activity against TKI-resistant cells. Validation was performed using bone marrow (BM)-derived cells from TKI-resistant patients (n = 4) and a human xenograft mouse model (n = 4-6 mice per group). All statistical tests were two-sided.Results: We show that ponatinib-resistant CML cells can acquire BCR-ABL-independent resistance mediated through alternative activation of mTOR. Following transcriptomic analysis and drug screening, we highlight mTOR inhibition as an alternative therapeutic approach in TKI-resistant CML cells. Additionally, we show that catalytic mTOR inhibitors induce autophagy and demonstrate that genetic or pharmacological inhibition of autophagy sensitizes ponatinib-resistant CML cells to death induced by mTOR inhibition in vitro (% number of colonies of control[SD], NVP-BEZ235 vs NVP-BEZ235+HCQ: 45.0[17.9]% vs 24.0[8.4]%, P = .002) and in vivo (median survival of NVP-BEZ235- vs NVP-BEZ235+HCQ-treated mice: 38.5 days vs 47.0 days, P = .04).Conclusion: Combined mTOR and autophagy inhibition may provide an attractive approach to target BCR-ABL-independent mechanism of resistance. [ABSTRACT FROM AUTHOR]- Published
- 2018
- Full Text
- View/download PDF
29. Bayesian inference for model selection: an application to aberrant signalling pathways in chronic myeloid leukaemia
- Author
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Hopcroft, Lisa E. M., primary, Calderhead, Ben, additional, Gallipoli, Paolo, additional, Holyoake, Tessa L., additional, and Girolami, Mark A., additional
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- View/download PDF
30. The Antiproliferative Activity of Kinase Inhibitors in Chronic Myeloid Leukemia Cells Is Mediated by FOXO Transcription Factors
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Pellicano, Francesca, primary, Scott, Mary T., additional, Helgason, G. Vignir, additional, Hopcroft, Lisa E. M., additional, Allan, Elaine K., additional, Aspinall-O’Dea, Mark, additional, Copland, Mhairi, additional, Pierce, Andrew, additional, Huntly, Brian J. P., additional, Whetton, Anthony D., additional, and Holyoake, Tessa L., additional
- Published
- 2014
- Full Text
- View/download PDF
31. Characterization of pathogenic germline mutations in human Protein Kinases.
- Author
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Izarzugaza, Jose M. G., Hopcroft, Lisa E. M., Baresic, Anja, Orengo, Christine A., Martin, Andrew C. R., and Valencia, Alfonso
- Subjects
- *
GENETIC mutation , *GENETICS , *PROTEIN kinases , *CYCLIN-dependent kinases , *MICROBIAL genetics - Abstract
Background: Protein Kinases are a superfamily of proteins involved in crucial cellular processes such as cell cycle regulation and signal transduction. Accordingly, they play an important role in cancer biology. To contribute to the study of the relation between kinases and disease we compared pathogenic mutations to neutral mutations as an extension to our previous analysis of cancer somatic mutations. First, we analyzed native and mutant proteins in terms of amino acid composition. Secondly, mutations were characterized according to their potential structural effects and finally, we assessed the location of the different classes of polymorphisms with respect to kinaserelevant positions in terms of subfamily specificity, conservation, accessibility and functional sites. Results: Pathogenic Protein Kinase mutations perturb essential aspects of protein function, including disruption of substrate binding and/or effector recognition at family-specific positions. Interestingly these mutations in Protein Kinases display a tendency to avoid structurally relevant positions, what represents a significant difference with respect to the average distribution of pathogenic mutations in other protein families. Conclusions: Disease-associated mutations display sound differences with respect to neutral mutations: several amino acids are specific of each mutation type, different structural properties characterize each class and the distribution of pathogenic mutations within the consensus structure of the Protein Kinase domain is substantially different to that for non-pathogenic mutations. This preferential distribution confirms previous observations about the functional and structural distribution of the controversial cancer driver and passenger somatic mutations and their use as a proxy for the study of the involvement of somatic mutations in cancer development. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF
32. OpenSAFELY: The impact of COVID‐19 on azathioprine, leflunomide and methotrexate monitoring, and factors associated with change in monitoring rate.
- Author
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Brown, Andrew D., Fisher, Louis, Curtis, Helen J., Wiedemann, Milan, Hulme, William J., Speed, Victoria, Hopcroft, Lisa E. M., Cunningham, Christine, Costello, Ruth E., Galloway, James B., Russell, Mark D., Bechman, Katie, Kurt, Zeyneb, Croker, Richard, Wood, Chris, Walker, Alex J., Schaffer, Andrea L., Bacon, Seb C. J., Mehrkar, Amir, and Hickman, George
- Abstract
Aims Methods Results Conclusion The COVID‐19 pandemic created unprecedented pressure on healthcare services. This study investigates whether disease‐modifying antirheumatic drug (DMARD) safety monitoring was affected during the COVID‐19 pandemic.A population‐based cohort study was conducted using the OpenSAFELY platform to access electronic health record data from 24.2 million patients registered at general practices using TPP's SystmOne software. Patients were included for further analysis if prescribed azathioprine, leflunomide or methotrexate between November 2019 and July 2022. Outcomes were assessed as monthly trends and variation between various sociodemographic and clinical groups for adherence with standard safety monitoring recommendations.An acute increase in the rate of missed monitoring occurred across the study population (+12.4 percentage points) when lockdown measures were implemented in March 2020. This increase was more pronounced for some patient groups (70–79 year‐olds: +13.7 percentage points; females: +12.8 percentage points), regions (North West: +17.0 percentage points), medications (leflunomide: +20.7 percentage points) and monitoring tests (blood pressure: +24.5 percentage points). Missed monitoring rates decreased substantially for all groups by July 2022. Consistent differences were observed in overall missed monitoring rates between several groups throughout the study.DMARD monitoring rates temporarily deteriorated during the COVID‐19 pandemic. Deterioration coincided with the onset of lockdown measures, with monitoring rates recovering rapidly as lockdown measures were eased. Differences observed in monitoring rates between medications, tests, regions and patient groups highlight opportunities to tackle potential inequalities in the provision or uptake of monitoring services. Further research should evaluate the causes of the differences identified between groups. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
33. Epigenetic Reprogramming Sensitizes CML Stem Cells to Combined EZH2 and Tyrosine Kinase Inhibition.
- Author
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Scott MT, Korfi K, Saffrey P, Hopcroft LE, Kinstrie R, Pellicano F, Guenther C, Gallipoli P, Cruz M, Dunn K, Jorgensen HG, Cassels JE, Hamilton A, Crossan A, Sinclair A, Holyoake TL, and Vetrie D
- Subjects
- Animals, Apoptosis drug effects, Cell Line, Tumor, Cellular Reprogramming genetics, Drug Resistance, Neoplasm genetics, Enhancer of Zeste Homolog 2 Protein antagonists & inhibitors, Epigenesis, Genetic drug effects, Hematopoietic Stem Cells drug effects, Hematopoietic Stem Cells pathology, Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive pathology, Mice, Neoplastic Stem Cells metabolism, Neoplastic Stem Cells pathology, Enhancer of Zeste Homolog 2 Protein genetics, Fusion Proteins, bcr-abl genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Protein Kinase Inhibitors administration & dosage
- Abstract
A major obstacle to curing chronic myeloid leukemia (CML) is residual disease maintained by tyrosine kinase inhibitor (TKI)-persistent leukemic stem cells (LSC). These are BCR-ABL1 kinase independent, refractory to apoptosis, and serve as a reservoir to drive relapse or TKI resistance. We demonstrate that Polycomb Repressive Complex 2 is misregulated in chronic phase CML LSCs. This is associated with extensive reprogramming of H3K27me3 targets in LSCs, thus sensitizing them to apoptosis upon treatment with an EZH2-specific inhibitor (EZH2i). EZH2i does not impair normal hematopoietic stem cell survival. Strikingly, treatment of primary CML cells with either EZH2i or TKI alone caused significant upregulation of H3K27me3 targets, and combined treatment further potentiated these effects and resulted in significant loss of LSCs compared to TKI alone, in vitro, and in long-term bone marrow murine xenografts. Our findings point to a promising epigenetic-based therapeutic strategy to more effectively target LSCs in patients with CML receiving TKIs., Significance: In CML, TKI-persistent LSCs remain an obstacle to cure, and approaches to eradicate them remain a significant unmet clinical need. We demonstrate that EZH2 and H3K27me3 reprogramming is important for LSC survival, but renders LSCs sensitive to the combined effects of EZH2i and TKI. This represents a novel approach to more effectively target LSCs in patients receiving TKI treatment. Cancer Discov; 6(11); 1248-57. ©2016 AACR.See related article by Xie et al., p. 1237This article is highlighted in the In This Issue feature, p. 1197., (©2016 American Association for Cancer Research.)
- Published
- 2016
- Full Text
- View/download PDF
34. Compensated pathogenic deviations: analysis of structural effects.
- Author
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Baresić A, Hopcroft LE, Rogers HH, Hurst JM, and Martin AC
- Subjects
- Amino Acid Sequence, Animals, Antithrombin III chemistry, Antithrombin III genetics, Binding Sites, Databases, Protein, Humans, Models, Molecular, Molecular Sequence Data, Protein Binding, Protein Folding, Protein Stability, Reproducibility of Results, Sheep, Disease genetics, Mutation, Missense genetics
- Abstract
Pathogenic deviations (PDs) in humans are disease-causing missense mutations. However, in some cases, these disease-associated residues occur as the wild-type residues in functionally equivalent proteins in other species and these cases are termed 'compensated pathogenic deviations' (CPDs). The lack of pathogenicity in a non-human protein is presumed to be explained in most cases by the presence of compensatory mutations, most commonly within the same protein. Identification of structural features of CPDs and detection of specific compensatory events will help us to understand traversal along fitness landscape valleys in protein evolution. We divided mutations listed in the OMIM (Online Mendelian Inheritance in Man) database into PD and CPD data sets and performed two independent analyses: (i) We searched for potential compensatory mutations spatially close to the CPDs and, (ii) using our SAAPdb database, we examined likely structural effects to try to explain why mutations are pathogenic, comparing PDs and CPDs. Our data sets were obtained from a set of 245 human proteins of known structure and contained a total of 2328 mutations of which 453 (from 85 structures) were seen to be compensated in at least one functionally equivalent protein in another (non-human) species. Structural analysis results confirm previous findings that CPDs are, on average, 'milder' in their likely structural effects than uncompensated PDs and tend to be on the protein surface. We also showed that the residues surrounding the CPD residue in the folded protein are more often mutated than the residues surrounding an uncompensated mutation, supporting the hypothesis that compensation is largely a result of structurally local mutations., (Copyright 2009 Elsevier Ltd. All rights reserved.)
- Published
- 2010
- Full Text
- View/download PDF
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