16 results on '"McCabe, Christopher"'
Search Results
2. Logical Inconsistencies in the Health Years in Total and Equal Value of Life-Years Gained
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Paulden, Mike, Sampson, Chris, O’Mahony, James F., Spackman, Eldon, McCabe, Christopher, Round, Jeff, and Snowsill, Tristan
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- 2024
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3. Terrestrial very-long-baseline atom interferometry: Workshop summary
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Abend, Sven, primary, Allard, Baptiste, additional, Alonso, Iván, additional, Antoniadis, John, additional, Araújo, Henrique, additional, Arduini, Gianluigi, additional, Arnold, Aidan S., additional, Asano, Tobias, additional, Augst, Nadja, additional, Badurina, Leonardo, additional, Balaž, Antun, additional, Banks, Hannah, additional, Barone, Michele, additional, Barsanti, Michele, additional, Bassi, Angelo, additional, Battelier, Baptiste, additional, Baynham, Charles F. A., additional, Beaufils, Quentin, additional, Belić, Aleksandar, additional, Beniwal, Ankit, additional, Bernabeu, Jose, additional, Bertinelli, Francesco, additional, Bertoldi, Andrea, additional, Biswas, Ikbal Ahamed, additional, Blas, Diego, additional, Boegel, Patrick, additional, Bogojević, Aleksandar, additional, Böhm, Jonas, additional, Böhringer, Samuel, additional, Bongs, Kai, additional, Bouyer, Philippe, additional, Brand, Christian, additional, Brimis, Apostolos, additional, Buchmueller, Oliver, additional, Cacciapuoti, Luigi, additional, Calatroni, Sergio, additional, Canuel, Benjamin, additional, Caprini, Chiara, additional, Caramete, Ana, additional, Caramete, Laurentiu, additional, Carlesso, Matteo, additional, Carlton, John, additional, Casariego, Mateo, additional, Charmandaris, Vassilis, additional, Chen, Yu-Ao, additional, Chiofalo, Maria Luisa, additional, Cimbri, Alessia, additional, Coleman, Jonathon, additional, Constantin, Florin Lucian, additional, Contaldi, Carlo R., additional, Cui, Yanou, additional, Ros, Elisa Da, additional, Davies, Gavin, additional, Rosendo, Esther del Pino, additional, Deppner, Christian, additional, Derevianko, Andrei, additional, Rham, Claudia de, additional, Roeck, Albert De, additional, Derr, Daniel, additional, Di Pumpo, Fabio, additional, Djordjevic, Goran S., additional, Döbrich, Babette, additional, Domokos, Peter, additional, Dornan, Peter, additional, Doser, Michael, additional, Drougakis, Giannis, additional, Dunningham, Jacob, additional, Duspayev, Alisher, additional, Easo, Sajan, additional, Eby, Joshua, additional, Efremov, Maxim, additional, Ekelof, Tord, additional, Elertas, Gedminas, additional, Ellis, John, additional, Evans, David, additional, Fadeev, Pavel, additional, Fanì, Mattia, additional, Fassi, Farida, additional, Fattori, Marco, additional, Fayet, Pierre, additional, Felea, Daniel, additional, Feng, Jie, additional, Friedrich, Alexander, additional, Fuchs, Elina, additional, Gaaloul, Naceur, additional, Gao, Dongfeng, additional, Gardner, Susan, additional, Garraway, Barry, additional, Gauguet, Alexandre, additional, Gerlach, Sandra, additional, Gersemann, Matthias, additional, Gibson, Valerie, additional, Giese, Enno, additional, Giudice, Gian F., additional, Glasbrenner, Eric P., additional, Gündoğan, Mustafa, additional, Haehnelt, Martin, additional, Hakulinen, Timo, additional, Hammerer, Klemens, additional, Hanımeli, Ekim T., additional, Harte, Tiffany, additional, Hawkins, Leonie, additional, Hees, Aurelien, additional, Heise, Jaret, additional, Henderson, Victoria A., additional, Herrmann, Sven, additional, Hird, Thomas M., additional, Hogan, Jason M., additional, Holst, Bodil, additional, Holynski, Michael, additional, Hussain, Kamran, additional, Janson, Gregor, additional, Jeglič, Peter, additional, Jelezko, Fedor, additional, Kagan, Michael, additional, Kalliokoski, Matti, additional, Kasevich, Mark, additional, Kehagias, Alex, additional, Kilian, Eva, additional, Koley, Soumen, additional, Konrad, Bernd, additional, Kopp, Joachim, additional, Kornakov, Georgy, additional, Kovachy, Tim, additional, Krutzik, Markus, additional, Kumar, Mukesh, additional, Kumar, Pradeep, additional, Lämmerzahl, Claus, additional, Landsberg, Greg, additional, Langlois, Mehdi, additional, Lanigan, Bryony, additional, Lellouch, Samuel, additional, Leone, Bruno, additional, Poncin-Lafitte, Christophe Le, additional, Lewicki, Marek, additional, Leykauf, Bastian, additional, Lezeik, Ali, additional, Lombriser, Lucas, additional, Luis Lopez-Gonzalez, J., additional, Lopez Asamar, Elias, additional, Monjaraz, Cristian López, additional, Luciano, Giuseppe Gaetano, additional, Mahmoud, M. A., additional, Maleknejad, Azadeh, additional, Marteau, Jacques, additional, Massonnet, Didier, additional, Mazumdar, Anupam, additional, McCabe, Christopher, additional, Meister, Matthias, additional, Menu, Jonathan, additional, Messineo, Giuseppe, additional, Micalizio, Salvatore, additional, Millington, Peter, additional, Milosevic, Milan, additional, Mitchell, Jeremiah, additional, Montero, Mario, additional, Morley, Gavin W., additional, Müller, Jürgen, additional, ioğlu, Özgür E. Müstecapl, additional, Ni, Wei-Tou, additional, Noller, Johannes, additional, Odžak, Senad, additional, Oi, Daniel K. L., additional, Omar, Yasser, additional, Pahl, Julia, additional, Paling, Sean, additional, Pandey, Saurabh, additional, Pappas, George, additional, Pareek, Vinay, additional, Pasatembou, Elizabeth, additional, Pelucchi, Emanuele, additional, Pereira dos Santos, Franck, additional, Piest, Baptist, additional, Pikovski, Igor, additional, Pilaftsis, Apostolos, additional, Plunkett, Robert, additional, Poggiani, Rosa, additional, Prevedelli, Marco, additional, Puputti, Julia, additional, Veettil, Vishnupriya Puthiya, additional, Quenby, John, additional, Rafelski, Johann, additional, Rajendran, Surjeet, additional, Rasel, Ernst M., additional, Sfar, Haifa Rejeb, additional, Reynaud, Serge, additional, Richaud, Andrea, additional, Rodzinka, Tangui, additional, Roura, Albert, additional, Rudolph, Jan, additional, Sabulsky, Dylan O., additional, Safronova, Marianna S., additional, Santamaria, Luigi, additional, Schilling, Manuel, additional, Schkolnik, Vladimir, additional, Schleich, Wolfgang P., additional, Schlippert, Dennis, additional, Schneider, Ulrich, additional, Schreck, Florian, additional, Schubert, Christian, additional, Schwersenz, Nico, additional, Semakin, Aleksei, additional, Sergijenko, Olga, additional, Shao, Lijing, additional, Shipsey, Ian, additional, Singh, Rajeev, additional, Smerzi, Augusto, additional, Sopuerta, Carlos F., additional, Spallicci, Alessandro D. A. M., additional, Stefanescu, Petruta, additional, Stergioulas, Nikolaos, additional, Ströhle, Jannik, additional, Struckmann, Christian, additional, Tentindo, Silvia, additional, Throssell, Henry, additional, Tino, Guglielmo M., additional, Tinsley, Jonathan N., additional, Tintareanu Mircea, Ovidiu, additional, Tkalčec, Kimberly, additional, Tolley, Andrew. J., additional, Tornatore, Vincenza, additional, Torres-Orjuela, Alejandro, additional, Treutlein, Philipp, additional, Trombettoni, Andrea, additional, Tsai, Yu-Dai, additional, Ufrecht, Christian, additional, Ulmer, Stefan, additional, Valuch, Daniel, additional, Vaskonen, Ville, additional, Vázquez-Aceves, Verónica, additional, Vitanov, Nikolay V., additional, Vogt, Christian, additional, Klitzing, Wolf von, additional, Vukics, András, additional, Walser, Reinhold, additional, Wang, Jin, additional, Warburton, Niels, additional, Webber-Date, Alexander, additional, Wenzlawski, André, additional, Werner, Michael, additional, Williams, Jason, additional, Windpassinger, Patrick, additional, Wolf, Peter, additional, Woerner, Lisa, additional, Xuereb, André, additional, Yahia, Mohamed E., additional, Cruzeiro, Emmanuel Zambrini, additional, Zarei, Moslem, additional, Zhan, Mingsheng, additional, Zhou, Lin, additional, Zupan, Jure, additional, and Zupanič, Erik, additional
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- 2024
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4. Supplementary Information 1 from Combined Vorinostat and Chloroquine Inhibit Sodium–Iodide Symporter Endocytosis and Enhance Radionuclide Uptake In Vivo
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Read, Martin L., primary, Brookes, Katie, primary, Zha, Ling, primary, Manivannan, Selvambigai, primary, Kim, Jana, primary, Kocbiyik, Merve, primary, Fletcher, Alice, primary, Gorvin, Caroline M., primary, Firth, George, primary, Fruhwirth, Gilbert O., primary, Nicola, Juan P., primary, Jhiang, Sissy, primary, Ringel, Matthew D., primary, Campbell, Moray J., primary, Sunassee, Kavitha, primary, Blower, Philip J., primary, Boelaert, Kristien, primary, Nieto, Hannah R., primary, Smith, Vicki E., primary, and McCabe, Christopher J., primary
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- 2024
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5. Data from Combined Vorinostat and Chloroquine Inhibit Sodium–Iodide Symporter Endocytosis and Enhance Radionuclide Uptake In Vivo
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Read, Martin L., primary, Brookes, Katie, primary, Zha, Ling, primary, Manivannan, Selvambigai, primary, Kim, Jana, primary, Kocbiyik, Merve, primary, Fletcher, Alice, primary, Gorvin, Caroline M., primary, Firth, George, primary, Fruhwirth, Gilbert O., primary, Nicola, Juan P., primary, Jhiang, Sissy, primary, Ringel, Matthew D., primary, Campbell, Moray J., primary, Sunassee, Kavitha, primary, Blower, Philip J., primary, Boelaert, Kristien, primary, Nieto, Hannah R., primary, Smith, Vicki E., primary, and McCabe, Christopher J., primary
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- 2024
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6. Supplementary Figure S10 from Combined Vorinostat and Chloroquine Inhibit Sodium–Iodide Symporter Endocytosis and Enhance Radionuclide Uptake In Vivo
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Read, Martin L., primary, Brookes, Katie, primary, Zha, Ling, primary, Manivannan, Selvambigai, primary, Kim, Jana, primary, Kocbiyik, Merve, primary, Fletcher, Alice, primary, Gorvin, Caroline M., primary, Firth, George, primary, Fruhwirth, Gilbert O., primary, Nicola, Juan P., primary, Jhiang, Sissy, primary, Ringel, Matthew D., primary, Campbell, Moray J., primary, Sunassee, Kavitha, primary, Blower, Philip J., primary, Boelaert, Kristien, primary, Nieto, Hannah R., primary, Smith, Vicki E., primary, and McCabe, Christopher J., primary
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- 2024
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7. Supplementary Table S2 from Combined Vorinostat and Chloroquine Inhibit Sodium–Iodide Symporter Endocytosis and Enhance Radionuclide Uptake In Vivo
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Read, Martin L., primary, Brookes, Katie, primary, Zha, Ling, primary, Manivannan, Selvambigai, primary, Kim, Jana, primary, Kocbiyik, Merve, primary, Fletcher, Alice, primary, Gorvin, Caroline M., primary, Firth, George, primary, Fruhwirth, Gilbert O., primary, Nicola, Juan P., primary, Jhiang, Sissy, primary, Ringel, Matthew D., primary, Campbell, Moray J., primary, Sunassee, Kavitha, primary, Blower, Philip J., primary, Boelaert, Kristien, primary, Nieto, Hannah R., primary, Smith, Vicki E., primary, and McCabe, Christopher J., primary
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- 2024
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8. Decision Makers Should Avoid the Health Years in Total (HYT) Approach: A Response to Dr Basu
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Paulden, Mike, primary, Sampson, Chris, additional, O’Mahony, James F., additional, Spackman, Eldon, additional, McCabe, Christopher, additional, Round, Jeff, additional, and Snowsill, Tristan, additional
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- 2024
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9. Long-read sequencing for fast and robust identification of correct genome-edited alleles: PCR-based and Cas9 capture methods
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McCabe, Christopher V., primary, Price, Peter D., additional, Codner, Gemma F., additional, Allan, Alasdair J., additional, Caulder, Adam, additional, Christou, Skevoulla, additional, Loeffler, Jorik, additional, Mackenzie, Matthew, additional, Malzer, Elke, additional, Mianné, Joffrey, additional, Nowicki, Krystian J., additional, O’Neill, Edward J., additional, Pike, Fran J., additional, Hutchison, Marie, additional, Petit-Demoulière, Benoit, additional, Stewart, Michelle E., additional, Gates, Hilary, additional, Wells, Sara, additional, Sanderson, Nicholas D., additional, and Teboul, Lydia, additional
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- 2024
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10. Dual agonism of sodium iodide symporter functionin vivo
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Brookes, Katie, primary, Thornton, Caitlin M., additional, Zha, Ling, additional, Kim, Jana, additional, Small, Benjamin, additional, Manivannan, Selvambigai, additional, Nieto, Hannah R., additional, Adcock, Holly, additional, Bottegoni, Giovanni, additional, Cox, Liam R., additional, Kannappan, Vinodh, additional, Wang, Weiguang, additional, Gorvin, Caroline M., additional, Jhiang, Sissy, additional, Ringel, Matthew D., additional, Campbell, Moray J., additional, Sunassee, Kavitha, additional, Blower, Philip J., additional, Boelaert, Kristien, additional, Smith, Vicki E., additional, Read, Martin L., additional, and McCabe, Christopher J., additional
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- 2024
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11. We need to talk about values: a proposed framework for the articulation of normative reasoning in health technology assessment.
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Charlton, Victoria, DiStefano, Michael, Mitchell, Polly, Morrell, Liz, Rand, Leah, Badano, Gabriele, Baker, Rachel, Calnan, Michael, Chalkidou, Kalipso, Culyer, Anthony, Howdon, Daniel, Hughes, Dyfrig, Lomas, James, Max, Catherine, McCabe, Christopher, O'Mahony, James F., Paulden, Mike, Pemberton-Whiteley, Zack, Rid, Annette, and Scuffham, Paul
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TECHNOLOGY assessment ,MEDICAL technology ,VALUES (Ethics) ,PRACTICAL reason ,RESEARCH personnel - Abstract
It is acknowledged that health technology assessment (HTA) is an inherently value-based activity that makes use of normative reasoning alongside empirical evidence. But the language used to conceptualise and articulate HTA's normative aspects is demonstrably unnuanced, imprecise, and inconsistently employed, undermining transparency and preventing proper scrutiny of the rationales on which decisions are based. This paper – developed through a cross-disciplinary collaboration of 24 researchers with expertise in healthcare priority-setting – seeks to address this problem by offering a clear definition of key terms and distinguishing between the types of normative commitment invoked during HTA, thus providing a novel conceptual framework for the articulation of reasoning. Through application to a hypothetical case, it is illustrated how this framework can operate as a practical tool through which HTA practitioners and policymakers can enhance the transparency and coherence of their decision-making, while enabling others to hold them more easily to account. The framework is offered as a starting point for further discussion amongst those with a desire to enhance the legitimacy and fairness of HTA by facilitating practical public reasoning, in which decisions are made on behalf of the public, in public view, through a chain of reasoning that withstands ethical scrutiny. [ABSTRACT FROM AUTHOR]
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- 2024
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12. Author Reply
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Paulden, Mike, Sampson, Chris, O’Mahony, James F., Spackman, Eldon, McCabe, Christopher, Round, Jeff, and Snowsill, Tristan
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- 2024
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13. Temporary treatment cessation compared with continuation of tyrosine kinase inhibitors for adults with renal cancer: the STAR non-inferiority RCT.
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Collinson F, Royle KL, Swain J, Ralph C, Maraveyas A, Eisen T, Nathan P, Jones R, Meads D, Min Wah T, Martin A, Bestall J, Kelly-Morland C, Linsley C, Oughton J, Chan K, Theodoulou E, Arias-Pinilla G, Kwan A, Daverede L, Handforth C, Trainor S, Salawu A, McCabe C, Goh V, Buckley D, Hewison J, Gregory W, Selby P, Brown J, and Brown J
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- Humans, Male, Female, Middle Aged, Aged, United Kingdom, Withholding Treatment, Sunitinib therapeutic use, Technology Assessment, Biomedical, Adult, Antineoplastic Agents therapeutic use, Tyrosine Kinase Inhibitors, Kidney Neoplasms drug therapy, Kidney Neoplasms mortality, Carcinoma, Renal Cell drug therapy, Protein Kinase Inhibitors therapeutic use, Quality-Adjusted Life Years
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Background: There is interest in using treatment breaks in oncology, to reduce toxicity without compromising efficacy., Trial Design: A Phase II/III multicentre, open-label, parallel-group, randomised controlled non-inferiority trial assessing treatment breaks in patients with renal cell carcinoma., Methods: Patients with locally advanced or metastatic renal cell carcinoma, starting tyrosine kinase inhibitor as first-line treatment at United Kingdom National Health Service hospitals., Interventions: At trial entry, patients were randomised (1 : 1) to a drug-free interval strategy or a conventional continuation strategy. After 24 weeks of treatment with sunitinib/pazopanib, drug-free interval strategy patients took up a treatment break until disease progression with additional breaks dependent on disease response and patient choice. Conventional continuation strategy patients continued on treatment. Both trial strategies continued until treatment intolerance, disease progression on treatment, withdrawal or death., Objective: To determine if a drug-free interval strategy is non-inferior to a conventional continuation strategy in terms of the co-primary outcomes of overall survival and quality-adjusted life-years., Co-Primary Outcomes: For non-inferiority to be concluded, a margin of ≤ 7.5% in overall survival and ≤ 10% in quality-adjusted life-years was required in both intention-to-treat and per-protocol analyses. This equated to the 95% confidence interval of the estimates being above 0.812 and -0.156, respectively. Quality-adjusted life-years were calculated using the utility index of the EuroQol-5 Dimensions questionnaire., Results: Nine hundred and twenty patients were randomised (461 conventional continuation strategy vs. 459 drug-free interval strategy) from 13 January 2012 to 12 September 2017. Trial treatment and follow-up stopped on 31 December 2020. Four hundred and eighty-eight (53.0%) patients [240 (52.1%) vs. 248 (54.0%)] continued on trial post week 24. The median treatment-break length was 87 days. Nine hundred and nineteen patients were included in the intention-to-treat analysis (461 vs. 458) and 871 patients in the per-protocol analysis (453 vs. 418). For overall survival, non-inferiority was concluded in the intention-to-treat analysis but not in the per-protocol analysis [hazard ratio (95% confidence interval) intention to treat 0.97 (0.83 to 1.12); per-protocol 0.94 (0.80 to 1.09) non-inferiority margin: 95% confidence interval ≥ 0.812, intention to treat: 0.83 > 0.812 non-inferior, per-protocol: 0.80 < 0.812 not non-inferior]. Therefore, a drug-free interval strategy was not concluded to be non-inferior to a conventional continuation strategy in terms of overall survival. For quality-adjusted life-years, non-inferiority was concluded in both the intention-to-treat and per-protocol analyses [marginal effect (95% confidence interval) intention to treat -0.05 (-0.15 to 0.05); per-protocol 0.04 (-0.14 to 0.21) non-inferiority margin: 95% confidence interval ≥ -0.156]. Therefore, a drug-free interval strategy was concluded to be non-inferior to a conventional continuation strategy in terms of quality-adjusted life-years., Limitations: The main limitation of the study is the fewer than expected overall survival events, resulting in lower power for the non-inferiority comparison., Future Work: Future studies should investigate treatment breaks with more contemporary treatments for renal cell carcinoma., Conclusions: Non-inferiority was shown for the quality-adjusted life-year end point but not for overall survival as pre-defined. Nevertheless, despite not meeting the primary end point of non-inferiority as per protocol, the study suggested that a treatment-break strategy may not meaningfully reduce life expectancy, does not reduce quality of life and has economic benefits. Although the treating clinicians' perspectives were not formally collected, the fact that clinicians recruited a large number of patients over a long period suggests support for the study and provides clear evidence that a treatment-break strategy for patients with renal cell carcinoma receiving tyrosine kinase inhibitor therapy is feasible., Trial Registration: This trial is registered as ISRCTN06473203., Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment Programme (NIHR award ref: 09/91/21) and is published in full in Health Technology Assessment ; Vol. 28, No. 45. See the NIHR Funding and Awards website for further award information.
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- 2024
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14. Interventions on gender equity in the workplace: a scoping review.
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Tricco AC, Parker A, Khan PA, Nincic V, Robson R, MacDonald H, Warren R, Cleary O, Zibrowski E, Baxter N, Burns KEA, Coyle D, Ndjaboue R, Clark JP, Langlois EV, Ahmed SB, Witteman HO, Graham ID, El-Adhami W, Skidmore B, Légaré F, Curran J, Hawker G, Watt J, Bourgeault IL, Leigh JP, Lawford K, Aiken A, McCabe C, Shepperd S, Pattani R, Leon N, Lundine J, Adisso ÉL, Ono S, Rabeneck L, and Straus SE
- Abstract
Background: Various studies have demonstrated gender disparities in workplace settings and the need for further intervention. This study identifies and examines evidence from randomized controlled trials (RCTs) on interventions examining gender equity in workplace or volunteer settings. An additional aim was to determine whether interventions considered intersection of gender and other variables, including PROGRESS-Plus equity variables (e.g., race/ethnicity)., Methods: Scoping review conducted using the JBI guide. Literature was searched in MEDLINE, Embase, PsycINFO, CINAHL, Web of Science, ERIC, Index to Legal Periodicals and Books, PAIS Index, Policy Index File, and the Canadian Business & Current Affairs Database from inception to May 9, 2022, with an updated search on October 17, 2022. Results were reported using Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension to scoping reviews (PRISMA-ScR), Sex and Gender Equity in Research (SAGER) guidance, Strengthening the Integration of Intersectionality Theory in Health Inequality Analysis (SIITHIA) checklist, and Guidance for Reporting Involvement of Patients and the Public (GRIPP) version 2 checklist. All employment or volunteer sectors settings were included. Included interventions were designed to promote workplace gender equity that targeted: (a) individuals, (b) organizations, or (c) systems. Any comparator was eligible. Outcomes measures included any gender equity related outcome, whether it was measuring intervention effectiveness (as defined by included studies) or implementation. Data analyses were descriptive in nature. As recommended in the JBI guide to scoping reviews, only high-level content analysis was conducted to categorize the interventions, which were reported using a previously published framework., Results: We screened 8855 citations, 803 grey literature sources, and 663 full-text articles, resulting in 24 unique RCTs and one companion report that met inclusion criteria. Most studies (91.7%) failed to report how they established sex or gender. Twenty-three of 24 (95.8%) studies reported at least one PROGRESS-Plus variable: typically sex or gender or occupation. Two RCTs (8.3%) identified a non-binary gender identity. None of the RCTs reported on relationships between gender and other characteristics (e.g., disability, age, etc.). We identified 24 gender equity promoting interventions in the workplace that were evaluated and categorized into one or more of the following themes: (i) quantifying gender impacts; (ii) behavioural or systemic changes; (iii) career flexibility; (iv) increased visibility, recognition, and representation; (v) creating opportunities for development, mentorship, and sponsorship; and (vi) financial support. Of these interventions, 20/24 (83.3%) had positive conclusion statements for their primary outcomes (e.g., improved academic productivity, increased self-esteem) across heterogeneous outcomes., Conclusions: There is a paucity of literature on interventions to promote workplace gender equity. While some interventions elicited positive conclusions across a variety of outcomes, standardized outcome measures considering specific contexts and cultures are required. Few PROGRESS-Plus items were reported. Non-binary gender identities and issues related to intersectionality were not adequately considered. Future research should provide consistent and contemporary definitions of gender and sex., Trial Registration: Open Science Framework https://osf.io/x8yae ., (© 2024. The Author(s).)
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- 2024
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15. Combined Vorinostat and Chloroquine Inhibit Sodium-Iodide Symporter Endocytosis and Enhance Radionuclide Uptake In Vivo.
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Read ML, Brookes K, Zha L, Manivannan S, Kim J, Kocbiyik M, Fletcher A, Gorvin CM, Firth G, Fruhwirth GO, Nicola JP, Jhiang S, Ringel MD, Campbell MJ, Sunassee K, Blower PJ, Boelaert K, Nieto HR, Smith VE, and McCabe CJ
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- Mice, Animals, Humans, Vorinostat pharmacology, Sodium Pertechnetate Tc 99m metabolism, Iodine Radioisotopes therapeutic use, Histone Deacetylase Inhibitors, Cell Line, Tumor, Thyroid Neoplasms diagnostic imaging, Thyroid Neoplasms drug therapy, Thyroid Neoplasms genetics, Symporters genetics, Symporters metabolism
- Abstract
Purpose: Patients with aggressive thyroid cancer are frequently failed by the central therapy of ablative radioiodide (RAI) uptake, due to reduced plasma membrane (PM) localization of the sodium/iodide symporter (NIS). We aimed to understand how NIS is endocytosed away from the PM of human thyroid cancer cells, and whether this was druggable in vivo., Experimental Design: Informed by analysis of endocytic gene expression in patients with aggressive thyroid cancer, we used mutagenesis, NanoBiT interaction assays, cell surface biotinylation assays, RAI uptake, and NanoBRET to understand the mechanisms of NIS endocytosis in transformed cell lines and patient-derived human primary thyroid cells. Systemic drug responses were monitored via 99mTc pertechnetate gamma counting and gene expression in BALB/c mice., Results: We identified an acidic dipeptide within the NIS C-terminus that mediates binding to the σ2 subunit of the Adaptor Protein 2 (AP2) heterotetramer. We discovered that the FDA-approved drug chloroquine (CQ) modulates NIS accumulation at the PM in a functional manner that is AP2 dependent. In vivo, CQ treatment of BALB/c mice significantly enhanced thyroidal uptake of 99mTc pertechnetate in combination with the histone deacetylase (HDAC) inhibitor vorinostat/SAHA, accompanied by increased thyroidal NIS mRNA. Bioinformatic analyses validated the clinical relevance of AP2 genes with disease-free survival in RAI-treated DTC, enabling construction of an AP2 gene-related risk score classifier for predicting recurrence., Conclusions: NIS internalization is specifically druggable in vivo. Our data, therefore, provide new translatable potential for improving RAI therapy using FDA-approved drugs in patients with aggressive thyroid cancer. See related commentary by Lechner and Brent, p. 1220., (©2023 American Association for Cancer Research.)
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- 2024
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16. Epigenetic disruption of the RARγ complex impairs its function to bookmark AR enhancer interactions required for enzalutamide sensitivity in prostate cancer.
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Wani SA, Hussain S, Gray JS, Nayak D, Tang H, Perez LM, Long MD, Siddappa M, McCabe CJ, Sucheston-Campbell LE, Freeman MR, and Campbell MJ
- Abstract
The current study in prostate cancer (PCa) focused on the genomic mechanisms at the cross-roads of pro-differentiation signals and the emergence of lineage plasticity. We explored an understudied cistromic mechanism involving RARγ's ability to govern AR cistrome-transcriptome relationships, including those associated with more aggressive PCa features. The RARγ complex in PCa cell models was enriched for canonical cofactors, as well as proteins involved in RNA processing and bookmarking. Identifying the repertoire of miR-96 bound and regulated gene targets, including those recognition elements marked by m6A, revealed their significant enrichment in the RARγ complex. RARγ significantly enhanced the AR cistrome, particularly in active enhancers and super-enhancers, and overlapped with the binding of bookmarking factors. Furthermore, RARγ expression led to nucleosome-free chromatin enriched with H3K27ac, and significantly enhanced the AR cistrome in G
2 /M cells. RARγ functions also antagonized the transcriptional actions of the lineage master regulator ONECUT2. Similarly, gene programs regulated by either miR-96 or antagonized by RARγ were enriched in alternative lineages and more aggressive PCa phenotypes. Together these findings reveal an under-investigated role for RARγ, modulated by miR-96, to bookmark enhancer sites during mitosis. These sites are required by the AR to promote transcriptional competence, and emphasize luminal differentiation, while antagonizing ONECUT2., Competing Interests: Competing interests The authors certify that they has NO affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript.- Published
- 2024
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