31 results on '"Cleaver, R."'
Search Results
2. Multiple endocrine neoplasia type 2A syndrome presenting with corneal nerve thickening.
- Author
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Petrie, I, Cartwright, N Knox, Roberts, H, Kyrodimou, E, Moudiotis, C, Owens, M, Cleaver, R, Smith, J, and Vaidya, B
- Subjects
MEDULLARY thyroid carcinoma ,TUMORS ,CORNEA ,THYROID cancer ,NERVES ,SYNDROMES ,AUTOIMMUNE thyroiditis - Abstract
This article discusses a case study of a 46-year-old woman who presented with corneal nerve thickening (CNT), a characteristic feature of multiple endocrine neoplasia (MEN) type 2B. However, genetic testing revealed that she had a new lineage of MEN2A, which is typically associated with medullary thyroid carcinoma (MTC), phaeochromocytoma, and primary hyperparathyroidism. The article highlights that while CNT is commonly associated with MEN2B, it can also be present in MEN2A, emphasizing the importance of considering both syndromes when CNT is detected. The study also discusses the intrafamilial variation in the presence and degree of CNT in families with MEN2A. [Extracted from the article]
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- 2024
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3. Quantifying prediction of pathogenicity for within-codon concordance (PM5) using 7541 functional classifications of BRCA1 and MSH2 missense variants
- Author
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Loong, Lucy, primary, Cubuk, Cankut, additional, Choi, Subin, additional, Allen, Sophie, additional, Torr, Beth, additional, Garrett, Alice, additional, Loveday, Chey, additional, Durkie, Miranda, additional, Callaway, Alison, additional, Burghel, George J., additional, Drummond, James, additional, Robinson, Rachel, additional, Berry, Ian R., additional, Wallace, Andrew, additional, Eccles, Diana M., additional, Tischkowitz, Marc, additional, Ellard, Sian, additional, Ware, James S., additional, Hanson, Helen, additional, Turnbull, Clare, additional, Samant, S., additional, Lucassen, A., additional, Znaczko, A., additional, Shaw, A., additional, Ansari, A., additional, Kumar, A., additional, Donaldson, A., additional, Murray, A., additional, Ross, A., additional, Taylor-Beadling, A., additional, Taylor, A., additional, Innes, A., additional, Brady, A., additional, Kulkarni, A., additional, Hogg, A.-C., additional, Bowden, A. Ramsay, additional, Hadonou, A., additional, Coad, B., additional, McIldowie, B., additional, Speight, B., additional, DeSouza, B., additional, Mullaney, B., additional, McKenna, C., additional, Brewer, C., additional, Olimpio, C., additional, Clabby, C., additional, Crosby, C., additional, Jenkins, C., additional, Armstrong, C., additional, Bowles, C., additional, Brooks, C., additional, Byrne, C., additional, Maurer, C., additional, Baralle, D., additional, Chubb, D., additional, Stobo, D., additional, Moore, D., additional, O'Sullivan, D., additional, Donnelly, D., additional, Randhawa, D., additional, Halliday, D., additional, Atkinson, E., additional, Baple, E., additional, Rauter, E., additional, Johnston, E., additional, Woodward, E., additional, Maher, E., additional, Sofianopoulou, E., additional, Petrides, E., additional, Lalloo, F., additional, McRonald, F., additional, Pelz, F., additional, Frayling, I., additional, Evans, G., additional, Corbett, G., additional, Rea, G., additional, Clouston, H., additional, Powell, H., additional, Williamson, H., additional, Carley, H., additional, Thomas, H.J.W., additional, Tomlinson, I., additional, Cook, J., additional, Hoyle, J., additional, Tellez, J., additional, Whitworth, J., additional, Williams, J., additional, Murray, J., additional, Campbell, J., additional, Tolmie, J., additional, Field, J., additional, Mason, J., additional, Burn, J., additional, Bruty, J., additional, Callaway, J., additional, Grant, J., additional, Del Rey Jimenez, J., additional, Pagan, J., additional, VanCampen, J., additional, Barwell, J., additional, Monahan, K., additional, Tatton-Brown, K., additional, Ong, K.-R., additional, Murphy, K., additional, Andrews, K., additional, Mokretar, K., additional, Cadoo, K., additional, Smith, K., additional, Baker, K., additional, Brown, K., additional, Reay, K., additional, McKay Bounford, K., additional, Bradshaw, K., additional, Russell, K., additional, Stone, K., additional, Snape, K., additional, Crookes, L., additional, Reed, L., additional, Taggart, L., additional, Yarram, L., additional, Cobbold, L., additional, Walker, L., additional, Hawkes, L., additional, Busby, L., additional, Izatt, L., additional, Kiely, L., additional, Hughes, L., additional, Side, L., additional, Sarkies, L., additional, Greenhalgh, K.-L., additional, Shanmugasundaram, M., additional, Duff, M., additional, Bartlett, M., additional, Watson, M., additional, Owens, M., additional, Bradford, M., additional, Huxley, M., additional, Slean, M., additional, Ryten, M., additional, Smith, M., additional, Ahmed, M., additional, Roberts, N., additional, O'Brien, C., additional, Middleton, O., additional, Tarpey, P., additional, Logan, P., additional, Dean, P., additional, May, P., additional, Brace, P., additional, Tredwell, R., additional, Harrison, R., additional, Hart, R., additional, Kirk, R., additional, Martin, R., additional, Nyanhete, R., additional, Wright, R., additional, Davidson, R., additional, Cleaver, R., additional, Talukdar, S., additional, Butler, S., additional, Sampson, J., additional, Ribeiro, S., additional, Dell, S., additional, Mackenzie, S., additional, Hegarty, S., additional, Albaba, S., additional, McKee, S., additional, Palmer-Smith, S., additional, Heggarty, S., additional, MacParland, S., additional, Greville-Heygate, S., additional, Daniels, S., additional, Prapa, S., additional, Abbs, S., additional, Tennant, S., additional, Hardy, S., additional, MacMahon, S., additional, McVeigh, T., additional, Foo, T., additional, Bedenham, T., additional, Cranston, T., additional, McDevitt, T., additional, Clowes, V., additional, Tripathi, V., additional, McConnell, V., additional, Woodwaer, N., additional, Wallis, Y., additional, Kemp, Z., additional, Mullan, G., additional, Pierson, L., additional, Rainey, L., additional, Joyce, C., additional, Timbs, A., additional, Reuther, A.-M., additional, Frugtniet, B., additional, Husher, C., additional, Lawn, C., additional, Corbett, C., additional, Nocera-Jijon, D., additional, Reay, D., additional, Cross, E., additional, Ryan, F., additional, Lindsay, H., additional, Oliver, J., additional, Dring, J., additional, Spiers, J., additional, Harper, J., additional, Ciucias, K., additional, Connolly, L., additional, Tsang, M., additional, Brown, R., additional, Shepherd, S., additional, Begum, S., additional, Tadiso, T., additional, Linton-Willoughby, T., additional, Heppell, H., additional, Sahan, K., additional, Worrillow, L., additional, Allen, Z., additional, Barlett, M., additional, Watt, C., additional, and Hegarty, M., additional
- Published
- 2022
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4. Instabilities of surface gravity waves
- Author
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Cleaver, R. P.
- Subjects
551.46 ,Oceanography - Published
- 1981
5. Quantifying prediction of pathogenicity for within-codon concordance (PM5) using 7541 functional classifications of BRCA1and MSH2missense variants
- Author
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Loong, Lucy, Cubuk, Cankut, Choi, Subin, Allen, Sophie, Torr, Beth, Garrett, Alice, Loveday, Chey, Durkie, Miranda, Callaway, Alison, Burghel, George J., Drummond, James, Robinson, Rachel, Berry, Ian R., Wallace, Andrew, Eccles, Diana M., Tischkowitz, Marc, Ellard, Sian, Ware, James S., Hanson, Helen, Turnbull, Clare, Samant, S., Lucassen, A., Znaczko, A., Shaw, A., Ansari, A., Kumar, A., Donaldson, A., Murray, A., Ross, A., Taylor-Beadling, A., Taylor, A., Innes, A., Brady, A., Kulkarni, A., Hogg, A.-C., Bowden, A. Ramsay, Hadonou, A., Coad, B., McIldowie, B., Speight, B., DeSouza, B., Mullaney, B., McKenna, C., Brewer, C., Olimpio, C., Clabby, C., Crosby, C., Jenkins, C., Armstrong, C., Bowles, C., Brooks, C., Byrne, C., Maurer, C., Baralle, D., Chubb, D., Stobo, D., Moore, D., O'Sullivan, D., Donnelly, D., Randhawa, D., Halliday, D., Atkinson, E., Baple, E., Rauter, E., Johnston, E., Woodward, E., Maher, E., Sofianopoulou, E., Petrides, E., Lalloo, F., McRonald, F., Pelz, F., Frayling, I., Evans, G., Corbett, G., Rea, G., Clouston, H., Powell, H., Williamson, H., Carley, H., Thomas, H.J.W., Tomlinson, I., Cook, J., Hoyle, J., Tellez, J., Whitworth, J., Williams, J., Murray, J., Campbell, J., Tolmie, J., Field, J., Mason, J., Burn, J., Bruty, J., Callaway, J., Grant, J., Del Rey Jimenez, J., Pagan, J., VanCampen, J., Barwell, J., Monahan, K., Tatton-Brown, K., Ong, K.-R., Murphy, K., Andrews, K., Mokretar, K., Cadoo, K., Smith, K., Baker, K., Brown, K., Reay, K., McKay Bounford, K., Bradshaw, K., Russell, K., Stone, K., Snape, K., Crookes, L., Reed, L., Taggart, L., Yarram, L., Cobbold, L., Walker, L., Walker, L., Hawkes, L., Busby, L., Izatt, L., Kiely, L., Hughes, L., Side, L., Sarkies, L., Greenhalgh, K.-L., Shanmugasundaram, M., Duff, M., Bartlett, M., Watson, M., Owens, M., Bradford, M., Huxley, M., Slean, M., Ryten, M., Smith, M., Ahmed, M., Roberts, N., O'Brien, C., Middleton, O., Tarpey, P., Logan, P., Dean, P., May, P., Brace, P., Tredwell, R., Harrison, R., Hart, R., Kirk, R., Martin, R., Nyanhete, R., Wright, R., Martin, R., Davidson, R., Cleaver, R., Talukdar, S., Butler, S., Sampson, J., Ribeiro, S., Dell, S., Mackenzie, S., Hegarty, S., Albaba, S., McKee, S., Palmer-Smith, S., Heggarty, S., MacParland, S., Greville-Heygate, S., Daniels, S., Prapa, S., Abbs, S., Tennant, S., Hardy, S., MacMahon, S., McVeigh, T., Foo, T., Bedenham, T., Cranston, T., McDevitt, T., Clowes, V., Tripathi, V., McConnell, V., Woodwaer, N., Wallis, Y., Kemp, Z., Mullan, G., Pierson, L., Rainey, L., Joyce, C., Timbs, A., Reuther, A.-M., Frugtniet, B., DeSouza, B., Husher, C., Lawn, C., Corbett, C., Nocera-Jijon, D., Reay, D., Cross, E., Ryan, F., Lindsay, H., Oliver, J., Dring, J., Spiers, J., Harper, J., Ciucias, K., Connolly, L., Tsang, M., Brown, R., Shepherd, S., Begum, S., Daniels, S., Tadiso, T., Linton-Willoughby, T., Heppell, H., Sahan, K., Worrillow, L., Allen, Z., Barlett, M., Watt, C., and Hegarty, M.
- Abstract
Conditions and thresholds applied for evidence weighting of within-codon concordance (PM5) for pathogenicity vary widely between laboratories and expert groups. Because of the sparseness of available clinical classifications, there is little evidence for variation in practice.
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- 2022
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6. THE BADGES OF THE IRISH FREE STATE ARMY
- Author
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Cleaver, R. D. M.
- Published
- 1937
7. Risk Evaluation at Natural Gas Compressor Stations and Above Ground Installations
- Author
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Cleaver, R. P., primary, Maycock, K., additional, Halford, A. R., additional, Potts, S. J., additional, McCollum, D. J., additional, Sadd, A. W. T., additional, and Acton, M. R., additional
- Published
- 2012
- Full Text
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8. Experimental study on hydrogen explosions in a full-scale hydrogen filling station model
- Author
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TANAKA, T, primary, AZUMA, T, additional, EVANS, J, additional, CRONIN, P, additional, JOHNSON, D, additional, and CLEAVER, R, additional
- Published
- 2007
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9. A model for the initial stages following the rupture of a natural gas transmission pipeline.
- Author
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Cleaver, R. P. and Halford, A. R.
- Subjects
- *
NATURAL gas pipeline failures , *GAS pipeline companies , *EMISSIONS (Air pollution) , *HAZARDS , *PIPELINES , *MATHEMATICAL models - Abstract
Experience shows that, despite the best efforts of the pipeline industry worldwide, pipelines do fail and release their contents to the atmosphere. In the case of below-ground pipelines transmitting natural gas, there is a chance that the release will be ignited, posing a significant hazard to any people in the vicinity. Mindful of this hazard, an international group of gas companies have collaborated over a period of many years on research projects aimed at developing an understanding of how these releases may arise (failure causes), how often they might occur (failure frequency), what type of releases might be produced (failure modes) and what type of behaviour might be produced for each of these modes of release (consequence analysis). This paper has been prepared to describe the mathematical models that have been developed on behalf of this group to assess the initial transient period following the rupture of a buried natural gas transmission pipeline assuming the release ignites immediately. It gives details of the equations used by the different models and it refers to some of the experimental data that has been used in the development of the models. A comparison of the model with the experimental data is provided. This demonstrates that the early stages could have a significant impact when evaluating the harm that could be caused. This provides a justification for developing the models rather than using a simpler alternative that does not take the initial highly transient period into account. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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10. Modeling the Effects of Pipeline Fires and the Response of People in Large Buildings
- Author
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Cleaver, R. P., primary, Acton, M. R., additional, and Halford, A. R., additional
- Published
- 2006
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11. Methods for Assessing Risks at Above Ground Installations
- Author
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Acton, M. R., primary, Baldwin, P. J., additional, Cleaver, R. P., additional, and McCollum, D. J., additional
- Published
- 2004
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12. Learning nonlinear functions with MLPs and SRNs.
- Author
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Cleaver, R. and Venayagamoorthy, G.K.
- Published
- 2009
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13. Learning functions generated by randomly initialized MLPs and SRNs.
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Cleaver, R. and Venayagamoorthy, G.K.
- Published
- 2009
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14. Right hemisphere white matter non-verbal deficits and depression in adolescents and young adults in a psychiatric population
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Cleaver, R. L., primary and Whitman, D., additional
- Published
- 1997
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15. Crest instabilities of gravity waves. Part 2. Matching and asymptotic analysis
- Author
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Longuet-Higgins, Michael S., primary, Cleaver, R. P., additional, and Fox, M. J. H., additional
- Published
- 1994
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16. Crest instabilities of gravity waves. Part 1. The almost-highest wave
- Author
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Longuet-Higgins, Michael S., primary and Cleaver, R. P., additional
- Published
- 1994
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17. Accidental generation of gas clouds on offshore process installations
- Author
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Cleaver, R. Philip, primary, Humphreys, Carol E., additional, and Robinson, Clive G., additional
- Published
- 1994
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18. The vortex created by mass transfer between layers of a rotating fluid.
- Author
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Gill, A. E., Smith, J. M., Cleaver, R. P., Hide, R., and Jonas, P. R.
- Published
- 1979
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19. Right hemisphere, white-matter learning disabilities associated with depression in an adolescent and young adult psychiatric population.
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Cleaver, R L and Whitman, R D
- Published
- 1998
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20. AN AUTOMATIC RADIO TRIANGULATION SYSTEM.
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CLEAVER, R. F., SOTHCOTT, P., and ROBINSON, F. J.
- Published
- 1960
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21. Simplicity itself.
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Dacey, P M and Cleaver, R A
- Published
- 1996
22. The psychosocial impact of prostate cancer screening for BRCA1 and BRCA2 carriers.
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Bancroft EK, Page EC, Brook MN, Pope J, Thomas S, Myhill K, Helfand BT, Talaty P, Ong KR, Douglas E, Cook J, Rosario DJ, Salinas M, Buys SS, Anson J, Davidson R, Longmuir M, Side L, Eccles DM, Tischkowitz M, Taylor A, Cruellas M, Ballestero EP, Cleaver R, Varughese M, Barwell J, LeButt M, Greenhalgh L, Hart R, Azzabi A, Jobson I, Cogley L, Evans DG, Rothwell J, Taylor N, Hogben M, Saya S, Eeles RA, and Aaronson NK
- Subjects
- Humans, Male, Middle Aged, Aged, Quality of Life, Genes, BRCA1, Surveys and Questionnaires, Genes, BRCA2, Heterozygote, Anxiety etiology, Longitudinal Studies, Prostatic Neoplasms psychology, Prostatic Neoplasms genetics, Prostatic Neoplasms diagnosis, Genetic Predisposition to Disease psychology, Early Detection of Cancer psychology
- Abstract
Objectives: To report the long-term outcomes from a longitudinal psychosocial study that forms part of the 'Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted Screening in men at higher genetic risk and controls' (IMPACT) study. The IMPACT study is a multi-national study of targeted prostate cancer (PrCa) screening in individuals with a known germline pathogenic variant (GPV) in either the BReast CAncer gene 1 (BRCA1) or the BReast CAncer gene 2 (BRCA2)., Subjects and Methods: Participants enrolled in the IMPACT study were invited to complete a psychosocial questionnaire prior to each annual screening visit for a minimum of 5 years. The questionnaire included questions on sociodemographics and the following measures: Hospital Anxiety and Depression Scale, Impact of Event Scale, 36-item Short-Form Health Survey, Memorial Anxiety Scale for PrCa, Cancer Worry Scale, risk perception and knowledge., Results: A total of 760 participants completed questionnaires: 207 participants with GPV in BRCA1, 265 with GPV in BRCA2 and 288 controls (non-carriers from families with a known GPV). We found no evidence of clinically concerning levels of general or cancer-specific distress or poor health-related quality of life in the cohort as a whole. Individuals in the control group had significantly less worry about PrCa compared with the carriers; however, all mean scores were low and within reported general population norms, where available. BRCA2 carriers with previously high prostate-specific antigen (PSA) levels experience a small but significant increase in PrCa anxiety (P = 0.01) and PSA-specific anxiety (P < 0.001). Cancer risk perceptions reflected information provided during genetic counselling and participants had good levels of knowledge, although this declined over time., Conclusion: This is the first study to report the longitudinal psychosocial impact of a targeted PrCa screening programme for BRCA1 and BRCA2 carriers. The results reassure that an annual PSA-based screening programme does not have an adverse impact on psychosocial health or health-related quality of life in these higher-risk individuals. These results are important as more PrCa screening is targeted to higher-risk groups., (© 2024 The Author(s). BJU International published by John Wiley & Sons Ltd on behalf of BJU International.)
- Published
- 2024
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23. Multiple endocrine neoplasia type 2A syndrome presenting with corneal nerve thickening.
- Author
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Petrie I, Knox Cartwright N, Roberts H, Kyrodimou E, Moudiotis C, Owens M, Cleaver R, Smith J, and Vaidya B
- Subjects
- Humans, Cornea diagnostic imaging, Multiple Endocrine Neoplasia Type 2a complications, Multiple Endocrine Neoplasia Type 2a diagnosis, Thyroid Neoplasms
- Published
- 2024
- Full Text
- View/download PDF
24. UK consensus recommendations for clinical management of cancer risk for women with germline pathogenic variants in cancer predisposition genes: RAD51C , RAD51D , BRIP1 and PALB2 .
- Author
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Hanson H, Kulkarni A, Loong L, Kavanaugh G, Torr B, Allen S, Ahmed M, Antoniou AC, Cleaver R, Dabir T, Evans DG, Golightly E, Jewell R, Kohut K, Manchanda R, Murray A, Murray J, Ong KR, Rosenthal AN, Woodward ER, Eccles DM, Turnbull C, Tischkowitz M, and Lalloo F
- Subjects
- Female, Humans, Consensus, Germ Cells pathology, Germ-Line Mutation genetics, MutS Homolog 2 Protein genetics, United Kingdom, Breast Neoplasms genetics, Breast Neoplasms pathology, DNA-Binding Proteins genetics, Fanconi Anemia Complementation Group N Protein genetics, Genetic Predisposition to Disease genetics, Ovarian Neoplasms genetics
- Abstract
Germline pathogenic variants (GPVs) in the cancer predisposition genes BRCA1 , BRCA2 , MLH1 , MSH2 , MSH6 , BRIP1 , PALB2 , RAD51D and RAD51C are identified in approximately 15% of patients with ovarian cancer (OC). While there are clear guidelines around clinical management of cancer risk in patients with GPV in BRCA1 , BRCA2 , MLH1 , MSH2 and MSH6 , there are few guidelines on how to manage the more moderate OC risk in patients with GPV in BRIP1 , PALB2 , RAD51D and RAD51C , with clinical questions about appropriateness and timing of risk-reducing gynaecological surgery. Furthermore, while recognition of RAD51C and R AD51D as OC predisposition genes has been established for several years, an association with breast cancer (BC) has only more recently been described and clinical management of this risk has been unclear. With expansion of genetic testing of these genes to all patients with non-mucinous OC, new data on BC risk and improved estimates of OC risk, the UK Cancer Genetics Group and CanGene-CanVar project convened a 2-day meeting to reach a national consensus on clinical management of BRIP1 , PALB2 , RAD51D and RAD51C carriers in clinical practice. In this paper, we present a summary of the processes used to reach and agree on a consensus, as well as the key recommendations from the meeting., Competing Interests: Competing interests: HH received honoraria from AstraZeneca for advisory roles. CT received honoraria from AstraZeneca and Roche for advisory roles, which were donated in full to charity (https://tukongote.com/, registration number 11511580, charity number 1186151). RM declares research funding from Barts & the London Charity, Rosetrees Trust, GSK, Eve Appeal, CRUK and Yorkshire Cancer Research outside this work; and honorarium for advisory board membership from AstraZeneca/MSD/GSK/EGL. DME was in receipt of research funding from AstraZeneca. ANR had prior consultancy arrangements with Abcodia and Everything Genetic. ACA was listed as a creator of BOADICEA, which was licensed by Cambridge Enterprise for commercial purposes., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)
- Published
- 2023
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25. A systematic review of licensed weight-loss medications in treating antipsychotic-induced weight gain and obesity in schizophrenia and psychosis.
- Author
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Lee K, Abraham S, and Cleaver R
- Subjects
- Bupropion adverse effects, Humans, Liraglutide adverse effects, Naltrexone therapeutic use, Obesity chemically induced, Obesity drug therapy, Weight Gain, Antipsychotic Agents adverse effects, Psychotic Disorders drug therapy, Schizophrenia drug therapy
- Abstract
Background: Schizophrenia and antipsychotic use are associated with clinically significant weight gain and subsequent increased mortality. Despite weight loss medications (WLMs) licensed by regulatory bodies (FDA, EMA, and MHRA) being available, current psychiatric guidelines recommend off-label alternatives, which differ from non-psychiatric guidelines for obesity., Objective: Evaluate the efficacy of licensed WLMs on treating antipsychotic-induced weight gain (AIWG) and obesity in schizophrenia and psychosis (OSP)., Method: A literature search was conducted using Medline, EMBASE, PsycINFO and Cochrane Library online databases for human studies using licensed WLMs to treat AIWG and OSP., Results: Three RCTs (two liraglutide, one naltrexone-bupropion), one unpublished open-label trial (naltrexone-bupropion), and seven observational studies (five liraglutide, one semaglutide, one multiple WLMs) were identified. Results for liraglutide showed statistically significant improvement in weight, BMI, waist circumference, HbA1c, cholesterol, and LDL readings on meta-analysis. Evidence was mixed for naltrexone-bupropion with no detailed studies conducted for setmelanotide, or stimulants., Conclusion: Evidence is strongest for liraglutide compared to other licensed WLMs. The findings, particularly the inclusion of human trial data, provide evidence for liraglutide use in treating AIWG and OSP, which would better align psychiatric practice with non-psychiatric practices around obesity. The findings also identify continued literature gaps regarding other licensed WLMs., Competing Interests: Declaration of Competing Interest There were no conflicts of interest for any of the authors involved in the review., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
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26. Diagnostic RET genetic testing in 1,058 index patients: A UK centre perspective.
- Author
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Fussey JM, Smith JA, Cleaver R, Bowles C, Ellard S, Vaidya B, and Owens M
- Subjects
- Genetic Testing, Germ-Line Mutation, Humans, Proto-Oncogene Mas, Proto-Oncogene Proteins c-ret genetics, Retrospective Studies, United Kingdom, Adrenal Gland Neoplasms, Multiple Endocrine Neoplasia Type 2a diagnosis, Multiple Endocrine Neoplasia Type 2a genetics, Thyroid Neoplasms diagnosis, Thyroid Neoplasms genetics
- Abstract
Objective: Diagnostic germline RET analysis is offered to all patients with a diagnosis of medullary thyroid carcinoma (MTC), or other conditions associated with multiple endocrine neoplasia type 2 (MEN2) in the United Kingdom. Here, we report the experience of a single centre's germline RET analysis over a 21-year period., Design: Retrospective case-note review., Patients: All index patients referred to the Exeter Genomics Laboratory for diagnostic germline RET analysis between 1997 and 2018, and unaffected family members, undergoing predictive testing., Measurements: The rate and nature of pathogenic variant detection were recorded, as well as the indication for testing., Results: 1,058 index patients and 551 unaffected family members were tested. The overall rate of pathogenic variant detection was 10.2% amongst index patients and 29% amongst unaffected family members. The commonest indication was isolated MTC, and amongst the 690 patients with isolated MTC, 68 (9.9%) were found to harbour a RET pathogenic variant. Of those with presumed sporadic MTC, 8.5% were found to harbour germline RET pathogenic variants, compared with 36.4% of those with a family history of MEN2-associated conditions. Pathogenic variants were identified in 3.6% and 0% of patients with isolated phaeochromocytoma and primary hyperparathyroidism, respectively., Conclusions: Although the detection rate of RET germline pathogenic variants in patients with presumed sporadic MTC was significant, the overall detection rate in those with MTC was lower than expected in this series. Advances in RET analysis in response to reports of new variants over the last two decades are likely to have improved the pick-up rate in recent years., (© 2021 John Wiley & Sons Ltd.)
- Published
- 2021
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27. Hereditary Leiomyomatosis and Renal Cell Cancer: Clinical, Molecular, and Screening Features in a Cohort of 185 Affected Individuals.
- Author
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Forde C, Lim DHK, Alwan Y, Burghel G, Butland L, Cleaver R, Dixit A, Evans DG, Hanson H, Lalloo F, Oliveira P, Vialard L, Wallis Y, Maher ER, and Woodward ER
- Subjects
- Adolescent, Adult, Aged, Carcinoma, Renal Cell genetics, Carcinoma, Renal Cell mortality, Carcinoma, Renal Cell therapy, DNA Mutational Analysis, Early Detection of Cancer statistics & numerical data, Female, Follow-Up Studies, Genetic Testing statistics & numerical data, Humans, Kidney diagnostic imaging, Kidney Neoplasms genetics, Kidney Neoplasms mortality, Kidney Neoplasms therapy, Leiomyomatosis epidemiology, Leiomyomatosis genetics, Leiomyomatosis therapy, Magnetic Resonance Imaging, Male, Medical History Taking, Middle Aged, Molecular Epidemiology, Mutation, Neoplasm Staging, Neoplastic Syndromes, Hereditary epidemiology, Neoplastic Syndromes, Hereditary genetics, Neoplastic Syndromes, Hereditary therapy, Prognosis, Skin Neoplasms epidemiology, Skin Neoplasms genetics, Skin Neoplasms therapy, United Kingdom epidemiology, Uterine Neoplasms epidemiology, Uterine Neoplasms genetics, Uterine Neoplasms therapy, Young Adult, Carcinoma, Renal Cell diagnosis, Early Detection of Cancer methods, Fumarate Hydratase genetics, Kidney Neoplasms diagnosis, Leiomyomatosis complications, Neoplastic Syndromes, Hereditary complications, Skin Neoplasms complications, Uterine Neoplasms complications
- Abstract
Background: Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a tumour predisposition syndrome characterised by predisposition to cutaneous and uterine leiomyomata and renal cell carcinoma (RCC)., Objective: To define the clinical findings, molecular genetics, and prognosis in a cohort of 69 families with a fumarate hydratase (FH) pathogenic variant and/or clinical features of HLRCC., Design, Setting, and Participants: Clinical and molecular findings were obtained for 185 individuals from 69 families from four UK regional genetics clinics., Outcome Measurements and Statistical Analysis: Ages at confirmed diagnoses, last dates of follow-up, and molecular results were attained for probands and relatives. To study the effect of potential ascertainment bias, phenotypes of probands and their affected relatives were compared., Results and Limitations: A germline FH variant (19 novel and 21 known, >50% missense variants) was identified in 68/69 probands and 90 relatives. Cutaneous leiomyomata occurred in 90/185 (48.6%) individuals (mean age 45.9 yr) and uterine leiomyomata in 33/107 (30.8%) females (mean age 35.0 yr). Of 185 individuals, 23 (12.4%) had a confirmed renal tumour, and histopathology where known (n = 18) was variable: seven clear cell RCCs, nine papillary RCCs (six of type 2), one collecting duct tumour, and one tumour with oncocytic cystic morphology. Mean age at symptomatic RCC diagnosis was 44.0 yr and median survival was 21.0 mo. Eighty-one individuals underwent 187 renal imaging surveillance scans; three stage 1 RCCs were detected. Mean survival of individuals diagnosed with stage 1/2 RCC was significantly longer than those diagnosed with stage 3/4 RCC (p = 0.0004)., Conclusions: Management of HLRCC is challenging as RCC occurs in a minority of cases but is highly aggressive. This large multicentre series has identified novel features and evidence that renal screening in HLRCC detects early-stage RCCs., Patient Summary: We show that hereditary leiomyomatosis and renal cell cancer is associated with a 21% lifetime risk of renal cell carcinoma (RCC; 95% confidence interval 8.2-37.1), and renal imaging screening detects early-stage RCC., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2020
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28. Novel truncating mutations in CTNND1 cause a dominant craniofacial and cardiac syndrome.
- Author
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Alharatani R, Ververi A, Beleza-Meireles A, Ji W, Mis E, Patterson QT, Griffin JN, Bhujel N, Chang CA, Dixit A, Konstantino M, Healy C, Hannan S, Neo N, Cash A, Li D, Bhoj E, Zackai EH, Cleaver R, Baralle D, McEntagart M, Newbury-Ecob R, Scott R, Hurst JA, Au PYB, Hosey MT, Khokha M, Marciano DK, Lakhani SA, and Liu KJ
- Subjects
- Adolescent, Adult, Animals, Anodontia diagnostic imaging, Anodontia genetics, Anodontia physiopathology, Child, Child, Preschool, Cleft Lip diagnostic imaging, Cleft Lip physiopathology, Cleft Palate diagnostic imaging, Cleft Palate physiopathology, Craniofacial Abnormalities diagnostic imaging, Craniofacial Abnormalities physiopathology, Disease Models, Animal, Ectropion diagnostic imaging, Ectropion physiopathology, Female, Genetic Predisposition to Disease, Heart Defects, Congenital diagnostic imaging, Heart Defects, Congenital physiopathology, Humans, Male, Mice, Tooth Abnormalities diagnostic imaging, Tooth Abnormalities physiopathology, Xenopus, Young Adult, Delta Catenin, Catenins genetics, Cleft Lip genetics, Cleft Palate genetics, Craniofacial Abnormalities genetics, Ectropion genetics, Heart Defects, Congenital genetics, Tooth Abnormalities genetics
- Abstract
CTNND1 encodes the p120-catenin (p120) protein, which has a wide range of functions, including the maintenance of cell-cell junctions, regulation of the epithelial-mesenchymal transition and transcriptional signalling. Due to advances in next-generation sequencing, CTNND1 has been implicated in human diseases including cleft palate and blepharocheilodontic (BCD) syndrome albeit only recently. In this study, we identify eight novel protein-truncating variants, six de novo, in 13 participants from nine families presenting with craniofacial dysmorphisms including cleft palate and hypodontia, as well as congenital cardiac anomalies, limb dysmorphologies and neurodevelopmental disorders. Using conditional deletions in mice as well as CRISPR/Cas9 approaches to target CTNND1 in Xenopus, we identified a subset of phenotypes that can be linked to p120-catenin in epithelial integrity and turnover, and additional phenotypes that suggest mesenchymal roles of CTNND1. We propose that CTNND1 variants have a wider developmental role than previously described and that variations in this gene underlie not only cleft palate and BCD but may be expanded to a broader velocardiofacial-like syndrome., (© The Author(s) 2020. Published by Oxford University Press.)
- Published
- 2020
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29. Expanding the phenotype of the X-linked BCOR microphthalmia syndromes.
- Author
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Ragge N, Isidor B, Bitoun P, Odent S, Giurgea I, Cogné B, Deb W, Vincent M, Le Gall J, Morton J, Lim D, Le Meur G, Zazo Seco C, Zafeiropoulou D, Bax D, Zwijnenburg P, Arteche A, Swafiri ST, Cleaver R, McEntagart M, Kini U, Newman W, Ayuso C, Corton M, Herenger Y, Jeanne M, Calvas P, and Chassaing N
- Subjects
- Adolescent, Adult, Cataract genetics, Child, Preschool, Eye Abnormalities genetics, Female, Genetic Variation genetics, Heterozygote, Humans, Infant, Male, Phenotype, Syndrome, X Chromosome Inactivation genetics, Young Adult, Abnormalities, Multiple genetics, Cataract congenital, Chromosomes, Human, X genetics, Genes, X-Linked genetics, Heart Septal Defects genetics, Microphthalmos genetics, Proto-Oncogene Proteins genetics, Repressor Proteins genetics
- Abstract
Two distinct syndromes arise from pathogenic variants in the X-linked gene BCOR (BCL-6 corepressor): oculofaciocardiodental (OFCD) syndrome, which affects females, and a severe microphthalmia ('Lenz'-type) syndrome affecting males. OFCD is an X-linked dominant syndrome caused by a variety of BCOR null mutations. As it manifests only in females, it is presumed to be lethal in males. The severe male X-linked recessive microphthalmia syndrome ('Lenz') usually includes developmental delay in addition to the eye findings and is caused by hypomorphic BCOR variants, mainly by a specific missense variant c.254C > T, p.(Pro85Leu). Here, we detail 16 new cases (11 females with 4 additional, genetically confirmed, affected female relatives; 5 male cases each with unaffected carrier mothers). We describe new variants and broaden the phenotypic description for OFCD to include neuropathy, muscle hypotonia, pituitary underdevelopment, brain atrophy, lipoma and the first description of childhood lymphoma in an OFCD case. Our male X-linked recessive cases show significant new phenotypes: developmental delay (without eye anomalies) in two affected half-brothers with a novel BCOR variant, and one male with high myopia, megalophthalmos, posterior embryotoxon, developmental delay, and heart and bony anomalies with a previously undescribed BCOR splice site variant. Our female OFCD cases and their affected female relatives showed variable features, but consistently had early onset cataracts. We show that a mosaic carrier mother manifested early cataract and dental anomalies. All female carriers of the male X-linked recessive cases for whom genetic confirmation was available showed skewed X-inactivation and were unaffected. In view of the extended phenotype, we suggest a new term of X-linked BCOR-related syndrome.
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- 2019
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30. Refining the Primrose syndrome phenotype: A study of five patients with ZBTB20 de novo variants and a review of the literature.
- Author
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Cleaver R, Berg J, Craft E, Foster A, Gibbons RJ, Hobson E, Lachlan K, Naik S, Sampson JR, Sharif S, Smithson S, Parker MJ, and Tatton-Brown K
- Subjects
- Child, Child, Preschool, Facies, Female, Genetic Loci, Genotype, Humans, Magnetic Resonance Imaging, Male, Mutation, Abnormalities, Multiple diagnosis, Abnormalities, Multiple genetics, Calcinosis diagnosis, Calcinosis genetics, Ear Diseases diagnosis, Ear Diseases genetics, Genetic Association Studies, Genetic Predisposition to Disease, Genetic Variation, Intellectual Disability diagnosis, Intellectual Disability genetics, Muscular Atrophy diagnosis, Muscular Atrophy genetics, Nerve Tissue Proteins genetics, Phenotype, Transcription Factors genetics
- Abstract
Primrose syndrome is a rare autosomal dominant condition caused by heterozygous missense variants within ZBTB20. Through an exome sequencing approach (as part of the Deciphering Developmental Disorders [DDD] study) we have identified five unrelated individuals with previously unreported, de novo ZBTB20 pathogenic missense variants. All five missense variants targeted the C2H2 zinc finger domains. This genotype-up approach has allowed further refinement of the Primrose syndrome phenotype. Major characteristics (>90% individuals) include an intellectual disability (most frequently in the moderate range), a recognizable facial appearance and brain MRI abnormalities, particularly abnormalities of the corpus callosum. Other frequent clinical associations (in 50-90% individuals) include sensorineural hearing loss (83%), hypotonia (78%), cryptorchidism in males (75%), macrocephaly (72%), behavioral issues (56%), and dysplastic/hypoplastic nails (57%). Based upon these clinical data we discuss our current management of patients with Primrose syndrome., (© 2019 Wiley Periodicals, Inc.)
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- 2019
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31. Beta-helix model for the filamentous haemagglutinin adhesin of Bordetella pertussis and related bacterial secretory proteins.
- Author
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Kajava AV, Cheng N, Cleaver R, Kessel M, Simon MN, Willery E, Jacob-Dubuisson F, Locht C, and Steven AC
- Subjects
- Adhesins, Bacterial metabolism, Adhesins, Bacterial ultrastructure, Amino Acid Motifs, Amino Acid Sequence, Antigens, Bacterial chemistry, Antigens, Bacterial ultrastructure, Bacterial Vaccines, Hemagglutinins metabolism, Hemagglutinins ultrastructure, Microscopy, Electron, Scanning Transmission, Models, Molecular, Molecular Sequence Data, Molecular Weight, Negative Staining, Protein Structure, Secondary, Protein Structure, Tertiary, Repetitive Sequences, Amino Acid, Sequence Alignment, Sequence Homology, Amino Acid, Shadowing Technique, Histology, Adhesins, Bacterial chemistry, Bordetella pertussis chemistry, Hemagglutinins chemistry, Virulence Factors, Bordetella
- Abstract
Bordetella pertussis establishes infection by attaching to epithelial cells of the respiratory tract. One of its adhesins is filamentous haemagglutinin (FHA), a 500-A-long secreted protein that is rich in beta-structure and contains two regions, R1 and R2, of tandem 19-residue repeats. Two models have been proposed in which the central shaft is (i) a hairpin made up of a pairing of two long antiparallel beta-sheets; or (ii) a beta-helix in which the polypeptide chain is coiled to form three long parallel beta-sheets. We have analysed a truncated variant of FHA by electron microscopy (negative staining, shadowing and scanning transmission electron microscopy of unstained specimens): these observations support the latter model. Further support comes from detailed sequence analysis and molecular modelling studies. We applied a profile search method to the sequences adjacent to and between R1 and R2 and found additional "covert" copies of the same motifs that may be recognized in overt form in the R1 and R2 sequence repeats. Their total number is sufficient to support the tenet of the beta-helix model that the shaft domain--a 350 A rod--should consist of a continuous run of these motifs, apart from loop inserts. The N-terminus, which does not contain such repeats, was found to be weakly homologous to cyclodextrin transferase, a protein of known immunoglobulin-like structure. Drawing on crystal structures of known beta-helical proteins, we developed structural models of the coil motifs putatively formed by the R1 and R2 repeats. Finally, we applied the same profile search method to the sequence database and found several other proteins--all large secreted proteins of bacterial provenance--that have similar repeats and probably also similar structures.
- Published
- 2001
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