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2. Liver injury after SARS-CoV-2 vaccination: Features of immune-mediated hepatitis, role of corticosteroid therapy and outcome

Author

Efe, C, Kulkarni, A, Terziroli Beretta-Piccoli, B, Magro, B, Friedrich Stattermayer, A, Cengiz, M, Clayton-Chubb, D, Lammert, C, Bernsmeier, C, Gul, O, la Tijera, F, Anders, M, Lytvyak, E, Akin, M, Purnak, T, Liberal, R, Peralta, M, Ebik, B, Duman, S, Demir, N, Balaban, Y, Urzua, A, Contreras, F, Venturelli, M, Bilgic, Y, Medina, A, Girala, M, Gunsar, F, Londono, M, Androutsakos, T, Kisch, A, Yurci, A, Guzelbult, F, Cagin, Y, Avci, E, Guzelbulut, M, Dindar-Demiray, E, Harputluoglu, M, Kumar, R, Satapathy, S, Mendizabal, M, Silva, M, Fagiuoli, S, Roberts, S, Soylu, N, Idilman, R, Yoshida, E, Montano-Loza, A, Dalekos, G, Ridruejo, E, Schiano, T, Wahlin, S, Efe C., Kulkarni A. V., Terziroli Beretta-Piccoli B., Magro B., Friedrich Stattermayer A., Cengiz M., Clayton-Chubb D., Lammert C., Bernsmeier C., Gul O., la Tijera F. H. -D., Anders M., Lytvyak E., Akin M., Purnak T., Liberal R., Peralta M., Ebik B., Duman S., Demir N., Balaban Y., Urzua A., Contreras F., Venturelli M. G., Bilgic Y., Medina A., Girala M., Gunsar F., Londono M. -C., Androutsakos T., Kisch A., Yurci A., Guzelbult F., Cagin Y. F., Avci E., Guzelbulut M., Dindar-Demiray E. K., Harputluoglu M., Kumar R., Satapathy S. K., Mendizabal M., Silva M., Fagiuoli S., Roberts S. K., Soylu N. K., Idilman R., Yoshida E. M., Montano-Loza A. J., Dalekos G. N., Ridruejo E., Schiano T. D., Wahlin S., Efe, C, Kulkarni, A, Terziroli Beretta-Piccoli, B, Magro, B, Friedrich Stattermayer, A, Cengiz, M, Clayton-Chubb, D, Lammert, C, Bernsmeier, C, Gul, O, la Tijera, F, Anders, M, Lytvyak, E, Akin, M, Purnak, T, Liberal, R, Peralta, M, Ebik, B, Duman, S, Demir, N, Balaban, Y, Urzua, A, Contreras, F, Venturelli, M, Bilgic, Y, Medina, A, Girala, M, Gunsar, F, Londono, M, Androutsakos, T, Kisch, A, Yurci, A, Guzelbult, F, Cagin, Y, Avci, E, Guzelbulut, M, Dindar-Demiray, E, Harputluoglu, M, Kumar, R, Satapathy, S, Mendizabal, M, Silva, M, Fagiuoli, S, Roberts, S, Soylu, N, Idilman, R, Yoshida, E, Montano-Loza, A, Dalekos, G, Ridruejo, E, Schiano, T, Wahlin, S, Efe C., Kulkarni A. V., Terziroli Beretta-Piccoli B., Magro B., Friedrich Stattermayer A., Cengiz M., Clayton-Chubb D., Lammert C., Bernsmeier C., Gul O., la Tijera F. H. -D., Anders M., Lytvyak E., Akin M., Purnak T., Liberal R., Peralta M., Ebik B., Duman S., Demir N., Balaban Y., Urzua A., Contreras F., Venturelli M. G., Bilgic Y., Medina A., Girala M., Gunsar F., Londono M. -C., Androutsakos T., Kisch A., Yurci A., Guzelbult F., Cagin Y. F., Avci E., Guzelbulut M., Dindar-Demiray E. K., Harputluoglu M., Kumar R., Satapathy S. K., Mendizabal M., Silva M., Fagiuoli S., Roberts S. K., Soylu N. K., Idilman R., Yoshida E. M., Montano-Loza A. J., Dalekos G. N., Ridruejo E., Schiano T. D., and Wahlin S.

Abstract

Background and Aims: A few case reports of autoimmune hepatitis–like liver injury have been reported after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination. We evaluated clinical features, treatment response and outcomes of liver injury following SARS-CoV-2 vaccination in a large case series. Approach and Results: We collected data from cases in 18 countries. The type of liver injury was assessed with the R-value. The study population was categorized according to features of immune-mediated hepatitis (positive autoantibodies and elevated immunoglobulin G levels) and corticosteroid therapy for the liver injury. We identified 87 patients (63%, female), median age 48 (range: 18–79) years at presentation. Liver injury was diagnosed a median 15 (range: 3–65) days after vaccination. Fifty-one cases (59%) were attributed to the Pfizer-BioNTech (BNT162b2) vaccine, 20 (23%) cases to the Oxford-AstraZeneca (ChAdOX1 nCoV-19) vaccine and 16 (18%) cases to the Moderna (mRNA-1273) vaccine. The liver injury was predominantly hepatocellular (84%) and 57% of patients showed features of immune-mediated hepatitis. Corticosteroids were given to 46 (53%) patients, more often for grade 3–4 liver injury than for grade 1–2 liver injury (88.9% vs. 43.5%, p = 0.001) and more often for patients with than without immune-mediated hepatitis (71.1% vs. 38.2%, p = 0.003). All patients showed resolution of liver injury except for one man (1.1%) who developed liver failure and underwent liver transplantation. Steroid therapy was withdrawn during the observation period in 12 (26%) patients after complete biochemical resolution. None had a relapse during follow-up. Conclusions: SARS-CoV-2 vaccination can be associated with liver injury. Corticosteroid therapy may be beneficial in those with immune-mediated features or severe hepatitis. Outcome was generally favorable, but vaccine-associated liver injury led to fulminant liver failure in one patient.

Published
2022

3. Germline MBD4 deficiency causes a multi-tumor predisposition syndrome

Author

Palles, C, West, HD, Chew, E, Galavotti, S, Flensburg, C, Grolleman, JE, Jansen, EAM, Curley, H, Chegwidden, L, Arbe-Barnes, EH, Lander, N, Truscott, R, Pagan, J, Bajel, A, Sherwood, K, Martin, L, Thomas, H, Georgiou, D, Fostira, F, Goldberg, Y, Adams, DJ, van der Biezen, SAM, Christie, M, Clendenning, M, Thomas, LE, Deltas, C, Dimovski, AJ, Dymerska, D, Lubinski, J, Mahmood, K, van der Post, RS, Sanders, M, Weitz, J, Taylor, JC, Turnbull, C, Vreede, L, van Wezel, T, Whalley, C, Arnedo-Pac, C, Caravagna, G, Cross, W, Chubb, D, Frangou, A, Gruber, AJ, Kinnersley, B, Noyvert, B, Church, D, Graham, T, Houlston, R, Lopez-Bigas, N, Sottoriva, A, Wedge, D, Jenkins, MA, Kuiper, RP, Roberts, AW, Cheadle, JP, Ligtenberg, MJL, Hoogerbrugge, N, Koelzer, VH, Rivas, AD, Winship, IM, Ponte, CR, Buchanan, DD, Power, DG, Green, A, Tomlinson, IPM, Sampson, JR, Majewski, IJ, de Voer, RM, Palles, C, West, HD, Chew, E, Galavotti, S, Flensburg, C, Grolleman, JE, Jansen, EAM, Curley, H, Chegwidden, L, Arbe-Barnes, EH, Lander, N, Truscott, R, Pagan, J, Bajel, A, Sherwood, K, Martin, L, Thomas, H, Georgiou, D, Fostira, F, Goldberg, Y, Adams, DJ, van der Biezen, SAM, Christie, M, Clendenning, M, Thomas, LE, Deltas, C, Dimovski, AJ, Dymerska, D, Lubinski, J, Mahmood, K, van der Post, RS, Sanders, M, Weitz, J, Taylor, JC, Turnbull, C, Vreede, L, van Wezel, T, Whalley, C, Arnedo-Pac, C, Caravagna, G, Cross, W, Chubb, D, Frangou, A, Gruber, AJ, Kinnersley, B, Noyvert, B, Church, D, Graham, T, Houlston, R, Lopez-Bigas, N, Sottoriva, A, Wedge, D, Jenkins, MA, Kuiper, RP, Roberts, AW, Cheadle, JP, Ligtenberg, MJL, Hoogerbrugge, N, Koelzer, VH, Rivas, AD, Winship, IM, Ponte, CR, Buchanan, DD, Power, DG, Green, A, Tomlinson, IPM, Sampson, JR, Majewski, IJ, and de Voer, RM

Abstract

We report an autosomal recessive, multi-organ tumor predisposition syndrome, caused by bi-allelic loss-of-function germline variants in the base excision repair (BER) gene MBD4. We identified five individuals with bi-allelic MBD4 variants within four families and these individuals had a personal and/or family history of adenomatous colorectal polyposis, acute myeloid leukemia, and uveal melanoma. MBD4 encodes a glycosylase involved in repair of G:T mismatches resulting from deamination of 5'-methylcytosine. The colorectal adenomas from MBD4-deficient individuals showed a mutator phenotype attributable to mutational signature SBS1, consistent with the function of MBD4. MBD4-deficient polyps harbored somatic mutations in similar driver genes to sporadic colorectal tumors, although AMER1 mutations were more common and KRAS mutations less frequent. Our findings expand the role of BER deficiencies in tumor predisposition. Inclusion of MBD4 in genetic testing for polyposis and multi-tumor phenotypes is warranted to improve disease management.

Published
2022

4. Impact of renaming NAFLD to MAFLD in an Australian regional cohort: Results from a prospective population-based study

Author

Kemp, W, Clayton-Chubb, D, Majeed, A, Glenister, KM, Magliano, DJ, Lubel, J, Bourke, L, Simmons, D, Roberts, SK, Kemp, W, Clayton-Chubb, D, Majeed, A, Glenister, KM, Magliano, DJ, Lubel, J, Bourke, L, Simmons, D, and Roberts, SK

Abstract

BACKGROUND AND AIMS: Clinical and public health implications of the recent redefining of non-alcoholic fatty liver disease (NAFLD) to metabolic-associated fatty liver disease (MAFLD) remain unclear. We sought to determine the prevalence and compare MAFLD with NAFLD in a well-defined cohort. METHODS: A cross-sectional study was conducted in regional Victoria with participants from randomly selected households. Demographic and health-related clinical and laboratory data were obtained. Fatty liver was defined as a fatty liver index ≥ 60 with MAFLD defined according to recent international expert consensus. RESULTS: A total of 722 participants were included. Mean age was 59.3 ± 16 years, and 55.3% were women with a median body mass index of 27.8 kg/m2 . Most (75.2%) participants were overweight or obese. MAFLD was present in 341 participants giving an unadjusted prevalence of 47.2% compared with a NAFLD prevalence of 38.7%. Fifty-nine (17.5%) participants met the criteria of MAFLD but not NAFLD. The increased prevalence of MAFLD in this cohort was primarily driven by dual etiology of fatty liver. All participants classified as NAFLD met the new definition of MAFLD. Compared with NAFLD subjects, participants with MAFLD had higher ALT (26.0 [14.0] U/L vs 30.0 [23] U/L, P = 0.024), but there were no differences in non-invasive markers for steatosis or fibrosis. CONCLUSION: Metabolic-associated fatty liver disease is a highly prevalent condition within this large community cohort. Application of the MAFLD definition increased prevalence of fatty liver disease by including people with dual etiologies of liver disease.

Published
2022

5. Germline MBD4 deficiency causes a multi-tumor predisposition syndrome

Author

Palles, C., West, H.D., Chew, E., Galavotti, S., Flensburg, C., Grolleman, J.E., Jansen, E.A.M., Curley, H., Chegwidden, L., Arbe-Barnes, E.H., Lander, N., Truscott, R., Pagan, J., Bajel, A., Sherwood, K., Martin, L., Thomas, H, Georgiou, D., Fostira, F., Goldberg, Y., Adams, D.J., Biezen, S.A.M. van der, Christie, M., Clendenning, M., Thomas, L.E., Deltas, C., Dimovski, A.J., Dymerska, D., Lubinski, J., Mahmood, K., Post, R.S. van der, Sanders, M., Weitz, J., Taylor, J.C., Turnbull, C., Vreede, L., Wezel, T. van, Whalley, C., Arnedo-Pac, C., Caravagna, G., Cross, W., Chubb, D., Frangou, A., Gruber, A.J., Kinnersley, B., Noyvert, B., Church, D., Graham, T., Houlston, R., Lopez-Bigas, N., Sottoriva, A., Wedge, D., Jenkins, Mark A., Kuiper, R.P., Roberts, A.W., Cheadle, J.P., Ligtenberg, M.J.L., Hoogerbrugge, N., Koelzer, V.H., Rivas, A.D., Winship, I.M., Ponte, C.R., Buchanan, D.D., Power, D.G., Green, A., Tomlinson, I.P., Sampson, J.R., Majewski, I.J., Voer, R.M. de, Palles, C., West, H.D., Chew, E., Galavotti, S., Flensburg, C., Grolleman, J.E., Jansen, E.A.M., Curley, H., Chegwidden, L., Arbe-Barnes, E.H., Lander, N., Truscott, R., Pagan, J., Bajel, A., Sherwood, K., Martin, L., Thomas, H, Georgiou, D., Fostira, F., Goldberg, Y., Adams, D.J., Biezen, S.A.M. van der, Christie, M., Clendenning, M., Thomas, L.E., Deltas, C., Dimovski, A.J., Dymerska, D., Lubinski, J., Mahmood, K., Post, R.S. van der, Sanders, M., Weitz, J., Taylor, J.C., Turnbull, C., Vreede, L., Wezel, T. van, Whalley, C., Arnedo-Pac, C., Caravagna, G., Cross, W., Chubb, D., Frangou, A., Gruber, A.J., Kinnersley, B., Noyvert, B., Church, D., Graham, T., Houlston, R., Lopez-Bigas, N., Sottoriva, A., Wedge, D., Jenkins, Mark A., Kuiper, R.P., Roberts, A.W., Cheadle, J.P., Ligtenberg, M.J.L., Hoogerbrugge, N., Koelzer, V.H., Rivas, A.D., Winship, I.M., Ponte, C.R., Buchanan, D.D., Power, D.G., Green, A., Tomlinson, I.P., Sampson, J.R., Majewski, I.J., and Voer, R.M. de

Abstract

Contains fulltext : 251996.pdf (Publisher’s version ) (Open Access), We report an autosomal recessive, multi-organ tumor predisposition syndrome, caused by bi-allelic loss-of-function germline variants in the base excision repair (BER) gene MBD4. We identified five individuals with bi-allelic MBD4 variants within four families and these individuals had a personal and/or family history of adenomatous colorectal polyposis, acute myeloid leukemia, and uveal melanoma. MBD4 encodes a glycosylase involved in repair of G:T mismatches resulting from deamination of 5'-methylcytosine. The colorectal adenomas from MBD4-deficient individuals showed a mutator phenotype attributable to mutational signature SBS1, consistent with the function of MBD4. MBD4-deficient polyps harbored somatic mutations in similar driver genes to sporadic colorectal tumors, although AMER1 mutations were more common and KRAS mutations less frequent. Our findings expand the role of BER deficiencies in tumor predisposition. Inclusion of MBD4 in genetic testing for polyposis and multi-tumor phenotypes is warranted to improve disease management.

Published
2022

6. Quantifying prediction of pathogenicity for within-codon concordance (PM5) using 7541 functional classifications of BRCA1 and MSH2 missense variants

Author

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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8. Erratum to ‘Germline-focussed analysis of tumour-only sequencing: recommendations from the ESMO Precision Medicine Working Group’: [Annals of Oncology 30 (2019) 1221–1231]

Author

Mandelker, D., Donoghue, M., Talukdar, S., Bandlamudi, C., Srinivasan, P., Vivek, M., Jezdic, S., Hanson, H., Snape, K., Kulkarni, A., Hawkes, L., Douillard, J.-Y., Wallace, S.E., Rial-Sebbag, E., Meric-Bersntam, F., George, A., Chubb, D., Loveday, C., Ladanyi, M., Berger, M.F., Taylor, B.S., and Turnbull, C.

Published
2021
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9. Thunderstorm asthma in Australia-characteristics of a silent cohort.

Author

Thien F., Clayton-Chubb D., Rangamuwa K., Taylor D., Wadhwa V., Abramson M., Thien F., Clayton-Chubb D., Rangamuwa K., Taylor D., Wadhwa V., and Abramson M.

Abstract

Introduction/Aim: Thunderstorm Asthma is an infrequent global phenomenon which recently struck Melbourne, Australia, leading to 9 deaths and many airways-related hospital presentations. We aimed to identify characteristics of persons symptomatic during the event and not previously known to be at risk. Method(s): Eastern Health is a large health network in Victoria, Australia. An anonymous electronic survey was conducted among its staff and volunteers. Result(s): 515 participants (80% female, n=411) completed the survey. 41% (n=211) had symptoms. 12 sought medical attention. 88% (n=267) of the asymptomatic group were white compared with 71% (n=149) of symptomatic respondents. In symptomatic respondents, a previous asthma diagnosis was reported in 38% (n=81) and a history of hayfever in 73% (n=155). Interestingly, in those without symptoms, 28% (n=85) had previously diagnosed asthma and 35% (n=107) had a hayfever history. In the group of 130 with no history of asthma but who were symptomatic during the event, 69% (n=90) reported previous typical asthma symptom (s). In comparison, 52% (n=106) of the 219 respondents with no past history of asthma and NO event symptoms reported having experienced previous typical asthma symptom(s). In those who reported windborne allergy, 64% experienced symptoms, compared with 37% of those without it. Over 25% had at least one lower respiratory tract symptom. Conclusion(s): Our study provides evidence for a silent large cohort who developed symptoms during the 2016 Melbourne Thunderstorm Asthma event. Although past diagnosis of asthma or asthma symptoms, non-white background, and airborne allergy history were more likely in those with symptoms, a large undiagnosed susceptible population exists.

Published
2019

10. Quantifying prediction of pathogenicity for within-codon concordance (PM5) using 7541 functional classifications of BRCA1and MSH2missense variants

Author

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.

Published
2022
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12. Classification of Variants of Reduced Penetrance in High Penetrance Cancer Susceptibility Genes: Framework for Genetics Clinicians and Clinical Scientists by CanVIG-UK (Cancer Variant Interpretation Group-UK)

Author

Garrett, Alice, Allen, Sophie, Durkie, Miranda, Burghel, George J., Robinson, Rachel, Callaway, Alison, Field, Joanne, Frugtniet, Bethan, Palmer-Smith, Sheila, Grant, Jonathan, Pagan, Judith, McDevitt, Trudi, Rowlands, Charlie F., McVeigh, Terri, Hanson, Helen, Turnbull, Clare, Turnbull, C., Garrett, A., Loong, L., Choi, S., Torr, B., Allen, S., Durkie, M., Callaway, A., Drummond, J., Burghel, G.J., Robinson, R., Berry, I.R., Wallace, A.J., Eccles, D.M., Tischkowitz, M., Ellard, S., Hanson, H., Baple, E., Evans, D.G., Woodward, E., Lalloo, F., 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., Rauter, E., Johnston, E., Maher, E., Sofianopoulou, E., Petrides, E., McRonald, F., Pelz, F., Frayling, I., 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., Watt, C., Hegarty, M., Mitchell, R., Coles, R., Nickless, G., Cojocaru, E., Doal, I., Sava, F., McCarthy, C., Jeeneea, R., Goudie, D., McConachie, M., Botosneanu, S., Kavanaugh, G., Russell, K., Sherlaw, C., Tsoulaki, O., Forde, C., Petley, E., Jones, A.-B., Oprych, K., Pryde, S., Hyder, Z., Elkhateeb, N., Braham, R., Hanington, L., Huntley, C., Irving, R., Sadan, A., Ramos, M., Elliot, C., Wren, D., Lobo, D., McLean, J., May, D., Kearney, L., Campbell, T., Asakura, K., Alwadi, L., O’Shea, R., Gabriel, J., Chiecchio, L., Bowman, P., Sutton, L.A., Walsh, C., Cloke, V., Ucanok, D., Davies, J., Pleasance, B., Maguire, E., Whaite, A., Best, S., Westbury, S., Logan, A., Navarajasegaran, D., Bench, A., Wightman, P., Cartwright, A., Higgs, E., J.Bott, Whitehouse, H., Stevens, J., Martin, D., Dunlop, J., Thomas, S., Sau, C., Farndon, S., Coleman, N., Angelini, P., Duff, M., Massey, H., Rowlands, C., Garcia-Petit, C., Gillespie, K., Alder, A., Middleton, E., Cassidy, C., Orfali, N., Webb, A., Luharia, A., Walker, N., Charlton, J., Andreou, A., Peddie, J., Khan, M., Wilkinson, L., Bezuidenhout, H., Edis, M., Callard, A., Ostrowski, P., Moverley, P., Bean, K., Dunne, A., Moleirinho, A., Waller, S., Cox, K., Greensmith, L., Brittle, A., Gossan, N., Freestone, L., Shak, C., Langford, T., Clinch, Y., Livesey, H., Borland, S., Joshi, A., Wall, K., Whitworth, A., Wilsdon, A., Edgerley, K., Pugh, S., Chrysochoidi, N., Mutch, S., McMullan, C., Johnston, Y., Muraru, M., May, A., Begum, R., Smith, C., Patel, R., Bhatnagar, I., Taylor, A., Brown, D., Willan, J., Taylor, S., Jones, K., Cox, K., Ramsden, C., Taiwo, O., Jaudzemaite, J., Sharmin, R., Young, L., C.O’Dubhshlaine, McSorley, L., Rodriguez, I. Abreu, Lillis, S., Alexopoulos, P., Mortensson, E., Kingham, L., Moore, R., Kosicka-Slawinska, M., Aslam, S., Wells, R., Carter, A., Warren, H., Rolf, E., Reed, H., Pearce, L., Lock, D., Ali, F., Kolozi, A., White, N., Wood, D., and Hayden, C.

Abstract

Current practice is to report and manage likely pathogenic/pathogenic variants in a given cancer susceptibility gene (CSG) as though having equivalent penetrance, despite increasing evidence of inter-variant variability in risk associations. Using existing variant interpretation approaches, largely based on full-penetrance models, variants where reduced penetrance is suspected may be classified inconsistently and/or as variants of uncertain significance (VUS). We aimed to develop a national consensus approach for such variants within the Cancer Variant Interpretation Group UK (CanVIG-UK) multidisciplinary network.

Published
2024
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13. Correspondence: SEMA4A variation and risk of colorectal cancer

Author

Kinnersley, B. (Ben), Chubb, D. (Daniel), Dobbins, S.E. (Sara E.), Frampton, M. (Matthew), Buch, T. (Thorsten), Timofeeva, M.N. (Maria N.), Castellví-Bel, S., Farrington, S.M. (Susan), Försti, A. (Asta), Hampe, J. (Jochen), Hemminki, K. (Kari), Hofstra, R.M.W. (Robert), Northwood, J.B. (John Blackman), Palles, C. (Claire), Pinheiro, M. (Manuela), Ruiz-Ponte, C. (Clara), Schafmayer, C. (Clemens), Teixeira, M.R. (Manuel R.), Westers, H. (Helga), Wezel, T. (Tom) van, Bishop, D.T. (David Timothy), Tomlinson, I. (Ian), Dunlop, M. (Malcolm), Houlston, R. (Richard), Kinnersley, B. (Ben), Chubb, D. (Daniel), Dobbins, S.E. (Sara E.), Frampton, M. (Matthew), Buch, T. (Thorsten), Timofeeva, M.N. (Maria N.), Castellví-Bel, S., Farrington, S.M. (Susan), Försti, A. (Asta), Hampe, J. (Jochen), Hemminki, K. (Kari), Hofstra, R.M.W. (Robert), Northwood, J.B. (John Blackman), Palles, C. (Claire), Pinheiro, M. (Manuela), Ruiz-Ponte, C. (Clara), Schafmayer, C. (Clemens), Teixeira, M.R. (Manuel R.), Westers, H. (Helga), Wezel, T. (Tom) van, Bishop, D.T. (David Timothy), Tomlinson, I. (Ian), Dunlop, M. (Malcolm), and Houlston, R. (Richard)

Published
2016
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14. Correspondence: SEMA4A variation and risk of colorectal cancer

Author

Kinnersley, B, Chubb, D, Dobbins, S E, Frampton, M, Buch, S, Timofeeva, MN, Castellvi-Bel, S, Farrington, SM, Forsti, A, Hampe, J, Hemminki, K, Hofstra, Robert, Northwood, E, Palles, C, Pinheiro, M, Ruiz-Ponte, C, Schafmayer, C, Teixeira, MR, Westers, H, van Wezel, T, Bishop, DT, Tomlinson, I, Dunlop, MG, Houlston, RS, Kinnersley, B, Chubb, D, Dobbins, S E, Frampton, M, Buch, S, Timofeeva, MN, Castellvi-Bel, S, Farrington, SM, Forsti, A, Hampe, J, Hemminki, K, Hofstra, Robert, Northwood, E, Palles, C, Pinheiro, M, Ruiz-Ponte, C, Schafmayer, C, Teixeira, MR, Westers, H, van Wezel, T, Bishop, DT, Tomlinson, I, Dunlop, MG, and Houlston, RS

Published
2016

15. Cardiometabolic effects of genetic upregulation of the interleukin 1 receptor antagonist: a Mendelian randomisation analysis

Author

Freitag, DF, Butterworth, AS, Willeit, P, Howson, JMM, Burgess, S, Kaptoge, S, Young, R, Ho, WK, Wood, AM, Sweeting, M, Spackman, S, Staley, JR, Ramond, A, Harshfield, E, Nielsen, SF, Grande, P, Lange, LA, Bown, MJ, Jones, GT, Scott, RA, Bevan, S, Porcu, E, Thorleifsson, G, Zeng, LY, Kessler, T, Nikpay, M, Do, R, Zhang, WH, Hopewell, JC, Kleber, M, Delgado, GE, Nelson, CP, Goel, A, Bis, JC, Dehghan, Abbas, Ligthart, Symen, Smith, AV, Qu, LM, van 't Hof, FNG, de Bakker, PIW, Baas, AF, van Rij, A, Tromp, G, Kuivaniemi, H, Ritchie, MD, Verma, SS, Crawford, DC, Malinowski, J, de Andrade, M, Kullo, IJ, Peissig, PL, McCarty, CA, Bottinger, EP, Gottesman, O, Crosslin, DR, Carrell, DS, Rasmussen-Torvik, LJ, Pacheco, JA, Huang, J, Timpson, NJ, Kettunen, J, Ala-Korpela, M, Mitchell, GF, Parsa, A, Wilkinson, IB, Gorski, M, Li, Yunlei, Franceschini, N, Keller, MF, Ganesh, SK, Langefeld, CD, Bruijn, L, Brown, MA, Evans, DM, Baltic, S, Ferreira, MA, Baurecht, H, Weidinger, S, Franke, A, Lubitz, SA, Muller-Nurasyid, M, Felix, Janine, Smith, NL, Sudman, M, Thompson, SD, Zeggini, E, Panoutsopoulou, K, Nalls, MA, Singleton, A, Polychronakos, C, Bradfield, JP, Hakonarson, H, Easton, DF, Thompson, D, Tomlinson, IP, Dunlop, M, Hemminki, K, Morgan, G, Eisen, T, Goldschmidt, H, Allan, JM, Henrion, M, Whiffin, N, Wang, YF, Chubb, D, Houlston, RS, Iles, MM, Bishop, DT, Law, MH, Hayward, NK, Luo, Y, Nejentsev, S, Barbalic, M, Crossman, D, Sanna, S, Soranzo, N, Markus, HS, Wareham, NJ, Rader, DJ, O Reilly, M, Assimes, T, Harris, TB, Hofman, Bert, Franco Duran, OH, Gudnason, V, Tracy, R, Psaty, BM, Farrall, M, Watkins, H, Hall, AS, Samani, NJ, Marz, W, Clarke, R, Collins, R, Kooner, JS, Chambers, JC, Kathiresan, S, McPherson, R, Erdmann, J, Kastrati, A, Schunkert, H, Stefansson, K, Thorsteinsdottir, U, Walston, JD, Tybjaerg-Hansen, A, Alam, DS, Majumder, AA, Di Angelantonio, E, Chowdhury, R, Nordestgaard, BG, Saleheen, D, Thompson, SG, Danesh, J, Freitag, DF, Butterworth, AS, Willeit, P, Howson, JMM, Burgess, S, Kaptoge, S, Young, R, Ho, WK, Wood, AM, Sweeting, M, Spackman, S, Staley, JR, Ramond, A, Harshfield, E, Nielsen, SF, Grande, P, Lange, LA, Bown, MJ, Jones, GT, Scott, RA, Bevan, S, Porcu, E, Thorleifsson, G, Zeng, LY, Kessler, T, Nikpay, M, Do, R, Zhang, WH, Hopewell, JC, Kleber, M, Delgado, GE, Nelson, CP, Goel, A, Bis, JC, Dehghan, Abbas, Ligthart, Symen, Smith, AV, Qu, LM, van 't Hof, FNG, de Bakker, PIW, Baas, AF, van Rij, A, Tromp, G, Kuivaniemi, H, Ritchie, MD, Verma, SS, Crawford, DC, Malinowski, J, de Andrade, M, Kullo, IJ, Peissig, PL, McCarty, CA, Bottinger, EP, Gottesman, O, Crosslin, DR, Carrell, DS, Rasmussen-Torvik, LJ, Pacheco, JA, Huang, J, Timpson, NJ, Kettunen, J, Ala-Korpela, M, Mitchell, GF, Parsa, A, Wilkinson, IB, Gorski, M, Li, Yunlei, Franceschini, N, Keller, MF, Ganesh, SK, Langefeld, CD, Bruijn, L, Brown, MA, Evans, DM, Baltic, S, Ferreira, MA, Baurecht, H, Weidinger, S, Franke, A, Lubitz, SA, Muller-Nurasyid, M, Felix, Janine, Smith, NL, Sudman, M, Thompson, SD, Zeggini, E, Panoutsopoulou, K, Nalls, MA, Singleton, A, Polychronakos, C, Bradfield, JP, Hakonarson, H, Easton, DF, Thompson, D, Tomlinson, IP, Dunlop, M, Hemminki, K, Morgan, G, Eisen, T, Goldschmidt, H, Allan, JM, Henrion, M, Whiffin, N, Wang, YF, Chubb, D, Houlston, RS, Iles, MM, Bishop, DT, Law, MH, Hayward, NK, Luo, Y, Nejentsev, S, Barbalic, M, Crossman, D, Sanna, S, Soranzo, N, Markus, HS, Wareham, NJ, Rader, DJ, O Reilly, M, Assimes, T, Harris, TB, Hofman, Bert, Franco Duran, OH, Gudnason, V, Tracy, R, Psaty, BM, Farrall, M, Watkins, H, Hall, AS, Samani, NJ, Marz, W, Clarke, R, Collins, R, Kooner, JS, Chambers, JC, Kathiresan, S, McPherson, R, Erdmann, J, Kastrati, A, Schunkert, H, Stefansson, K, Thorsteinsdottir, U, Walston, JD, Tybjaerg-Hansen, A, Alam, DS, Majumder, AA, Di Angelantonio, E, Chowdhury, R, Nordestgaard, BG, Saleheen, D, Thompson, SG, and Danesh, J

Abstract

Background To investigate potential cardiovascular and other effects of long-term pharmacological interleukin 1 (IL-1) inhibition, we studied genetic variants that produce inhibition of IL-1, a master regulator of inflammation. Methods We created a genetic score combining the effects of alleles of two common variants (rs6743376 and rs1542176) that are located upstream of IL1RN, the gene encoding the IL-1 receptor antagonist (IL-1Ra; an endogenous inhibitor of both IL-1 alpha and IL-1 beta); both alleles increase soluble IL-1Ra protein concentration. We compared effects on inflammation biomarkers of this genetic score with those of anakinra, the recombinant form of IL-1Ra, which has previously been studied in randomised trials of rheumatoid arthritis and other inflammatory disorders. In primary analyses, we investigated the score in relation to rheumatoid arthritis and four cardiometabolic diseases (type 2 diabetes, coronary heart disease, ischaemic stroke, and abdominal aortic aneurysm; 453 411 total participants). In exploratory analyses, we studied the relation of the score to many disease traits and to 24 other disorders of proposed relevance to IL-1 signalling (746 171 total participants). Findings For each IL1RN minor allele inherited, serum concentrations of IL-1Ra increased by 0.22 SD (95% CI 0.18-0.25; 12.5%; p=9.3 x 10(-33)), concentrations of interleukin 6 decreased by 0.02 SD (-0.04 to -0.01; -1,7%; p=3.5 x 10(-3)), and concentrations of C-reactive protein decreased by 0.03 SD (-0.04 to -0.02; -3.4%; p=7.7 x 10(-14)). We noted the effects of the genetic score on these inflammation biomarkers to be directionally concordant with those of anakinra. The allele count of the genetic score had roughly log-linear, dose-dependent associations with both IL-1Ra concentration and risk of coronary heart disease. For people who carried four IL-1Ra-raising alleles, the odds ratio for coronary heart disease was 1.15 (1.08-1.22; p=1.8 x 10(-6)) compared with people who ca

Published
2015

16. Erratum: Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas (Nature Genetics (2013) 45 (136-144))

Author

Palles, C, Cazier, J-B, Howarth, KM, Domingo, E, Jones, AM, Broderick, P, Kemp, Z, Spain, SL, Almeida, EG, Salguero, I, Sherborne, A, Chubb, D, Carvajal-Carmona, LG, Ma, Y, Kaur, K, Dobbins, S, Barclay, E, Gorman, M, Martin, L, Kovac, MB, Humphray, S, Lucassen, A, Holmes, CC, Bentley, D, Donnelly, P, Taylor, J, Petridis, C, Roylance, R, Sawyer, EJ, Kerr, DJ, Clark, S, Grimes, J, Kearsey, SE, Thomas, HJW, McVean, G, Houlston, RS, and Tomlinson, I

Published
2013

17. Orthodontic thermoformed retainers: a two-arm laboratory study into post-fabrication outcomes.

Author

Doğramacı, E. J., Chubb, D. W. R., and Rossi‐Fedele, G.

Subjects
ORTHODONTIC retainers, ORTHODONTIC appliances, MICROFABRICATION, POLYPROPYLENE, THERMOFORMING
Abstract

Background: Retainers are commonly used to maintain post-orthodontic occlusion stability. We aimed to determine post-fabrication thickness and thinning rate of thermoformed retainers.Methods: Forty-eight retainers were fabricated from polyethylenterepthalat-glycol copolyester or polypropylene blanks, using vacuum- or pressure-thermoforming. Retainer thickness was measured at multiple locations.Results: Thinning rate had a broad range: the mid-labial incisor region of 1 mm polyethylenterepthalat-glycol copolyester pressure-thermoformed mandibular retainers had the greatest thinning rate (68.25 ± 8.26%) and smallest mean post-fabrication thickness (0.32 ± 0.08 mm). Polyethylenterepthalat-glycol copolyester retainers were 0.11 mm thinner than polypropylene (P=0.0222), and polypropylene retainers were 0.21 mm thicker, when pressure-thermoformed (P<0.0001). The interaction of manufacturing method and material used, and tooth type, explained over a third of the variability in the post-fabrication thickness of these retainers. Maxillary retainers made from 1 mm blanks were 0.04 mm thicker in the incisor region compared with the molar region (P=0.0492).Conclusions: Thermoformed retainers do no thin uniformly against individual teeth and have variable intra- and inter-arch post-fabrication thicknesses. There is no clear benefit in using a specific type of thermoforming machine or material for increasing post-fabrication thickness or reducing thinning rate. Blank thickness and tooth morphology influence these outcomes. [ABSTRACT FROM AUTHOR]

Published
2018
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18. The 7p15.3 (rs4487645) association for multiple myeloma shows strong allele-specific regulation of the MYC-interacting gene CDCA7L in malignant plasma cells

Author

Weinhold, N., primary, Meissner, T., additional, Johnson, D. C., additional, Seckinger, A., additional, Moreaux, J., additional, Forsti, A., additional, Chen, B., additional, Nickel, J., additional, Chubb, D., additional, Rawstron, A. C., additional, Doughty, C., additional, Dahir, N. B., additional, Begum, D. B., additional, Young, K., additional, Walker, B. A., additional, Hoffmann, P., additional, Nothen, M. M., additional, Davies, F. E., additional, Klein, B., additional, Goldschmidt, H., additional, Morgan, G. J., additional, Houlston, R. S., additional, Hose, D., additional, and Hemminki, K., additional

Published
2014
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19. Developmental timing of mutations revealed by whole-genome sequencing of twins with acute lymphoblastic leukemia

Author

Ma, Y, Dobbins, S, Sherborne, A, Chubb, D, Galbiati, M, Cazzaniga, G, Micalizzi, C, Tearle, R, Lloyd, A, Hain, R, Greaves, M, Houlston, R, Ma, Yussanne, Dobbins, Sara E, Sherborne, Amy L, Chubb, Daniel, Galbiati, Marta, Cazzaniga, Giovanni, Micalizzi, Concetta, Tearle, Rick, Lloyd, Amy L, Hain, Richard, Greaves, Mel, Houlston, Richard S, Ma, Y, Dobbins, S, Sherborne, A, Chubb, D, Galbiati, M, Cazzaniga, G, Micalizzi, C, Tearle, R, Lloyd, A, Hain, R, Greaves, M, Houlston, R, Ma, Yussanne, Dobbins, Sara E, Sherborne, Amy L, Chubb, Daniel, Galbiati, Marta, Cazzaniga, Giovanni, Micalizzi, Concetta, Tearle, Rick, Lloyd, Amy L, Hain, Richard, Greaves, Mel, and Houlston, Richard S

Abstract

Acute lymphoblastic leukemia (ALL) is the major pediatric cancer. At diagnosis, the developmental timing of mutations contributing critically to clonal diversification and selection can be buried in the leukemia's covert natural history. Concordance of ALL in monozygotic, monochorionic twins is a consequence of intraplacental spread of an initiated preleukemic clone. Studying monozygotic twins with ALL provides a unique means of uncovering the timeline of mutations contributing to clonal evolution, pre- and postnatally. We sequenced the whole genomes of leukemic cells from two twin pairs with ALL to comprehensively characterize acquired somatic mutations in ALL, elucidating the developmental timing of all genetic lesions. Shared, prenatal, coding-region single-nucleotide variants were limited to the putative initiating lesions. All other nonsynonymous single-nucleotide variants were distinct between tumors and, therefore, secondary and postnatal. These changes occurred in a background of noncoding mutational changes that were almost entirely discordant in twin pairs and likely passenger mutations acquired during leukemic cell proliferation.

Published
2013

20. The silent mutational landscape of infant MLL-AF4 pro-B acute lymphoblastic leukemia

Author

Dobbins, S, Sherborne, A, Ma, Y, Bardini, M, Biondi, A, Cazzaniga, G, Lloyd, A, Chubb, D, Greaves, M, Houlston, R, Dobbins, SE, Sherborne, AL, Ma, YP, BARDINI, MICHELA, BIONDI, ANDREA, CAZZANIGA, GIOVANNI ITALO, Greaves, MF, Houlston, RS, Dobbins, S, Sherborne, A, Ma, Y, Bardini, M, Biondi, A, Cazzaniga, G, Lloyd, A, Chubb, D, Greaves, M, Houlston, R, Dobbins, SE, Sherborne, AL, Ma, YP, BARDINI, MICHELA, BIONDI, ANDREA, CAZZANIGA, GIOVANNI ITALO, Greaves, MF, and Houlston, RS

Abstract

Over 90% of infants (<1-year-old) diagnosed with leukemia have pro-B acute lymphoblastic leukemia (ALL) containing the MLL-AF4 fusion. When compared with other forms of paediatric ALL affecting later B-cell differentiation, MLL-AF4 pro-B is associated with a dismal prognosis with a typical 5-year disease-free survival of <20%. MLL-AF4 may be sufficient on its own for leukemogenesis or the gene-fusion product may alternatively predispose transformed cells to global genetic instability, enhancing the acquisition of additional key mutations. To gain insight into the genomic landscape of infant MLL-AF4 pro-B ALL we performed whole genome sequencing of diagnostic leukemic blasts and matched germline samples from three MLL-AF4 pro-B ALL infants. Our analysis revealed few somatic changes (copy number abnormalities, loss of heterozygosity, or single nucleotide variants), demonstrating that only a very small number of mutations are necessary to generate infant MLL-leukemia. © 2013 Wiley Periodicals, Inc.

Published
2013

25. Analysis of the Gas Particle Radiator (GPR)

Author

Chubb, D. L

Subjects
Spacecraft Propulsion And Power
Abstract

The theoretical performance of a new space radiator concept, the gas particle radiator (GPR), is calculated. The GPR uses a gas containing emitting, submicron particles as the radiating media. A transparent window contains the gas particle mixture around the solid radiator emitting surface. A major advantage of the GPR is that large emissivity (e sub T is greater than or = 0.8) is achieved without the use of emissive coatings. A radiation heat transfer analysis shows that for a modest volume fraction (approx. 10(-4)) of submicron particles and gas thickness (approx. 1 cm) the emissivity, e sub T, is limited by the window transmittance. Besides determining the emissivity, the window is the critical element for making it possible for the GPR to have lower mass than a tube type radiator. The window acts as a bumper to provide meteoroid protection for the radiator wall. The GPR was compared to a proposed titanium wall, potassium heat pipe radiator. For both radiators operating at a power level of 1.01 MW at 775 K it was calculated that the GPR mass was 31 percent lower than the heat pipe radiator.

Published
1986

26. Thermionic photovoltaic energy converter

Author

Chubb, D. L

Subjects
Energy Production And Conversion
Abstract

A thermionic photovoltaic energy conversion device comprises a thermionic diode mounted within a hollow tubular photovoltaic converter. The thermionic diode maintains a cesium discharge for producing excited atoms that emit line radiation in the wavelength region of 850 nm to 890 nm. The photovoltaic converter is a silicon or gallium arsenide photovoltaic cell having bandgap energies in this same wavelength region for optimum cell efficiency.

Published
1985

27. Assessment of disk MHD generators for a base load powerplant

Author

Chubb, D. L, Retallick, F. D, Lu, C. L, Stella, M, Teare, J. D, Loubsky, W. J, Louis, J. F, and Misra, B

Subjects
Energy Production And Conversion
Abstract

Results from a study of the disk MHD generator are presented. Both open and closed cycle disk systems were investigated. Costing of the open cycle disk components (nozzle, channel, diffuser, radiant boiler, magnet and power management) was done. However, no detailed costing was done for the closed cycle systems. Preliminary plant design for the open cycle systems was also completed. Based on the system study results, an economic assessment of the open cycle systems is presented. Costs of the open cycle disk conponents are less than comparable linear generator components. Also, costs of electricity for the open cycle disk systems are competitive with comparable linear systems. Advantages of the disk design simplicity are considered. Improvements in the channel availability or a reduction in the channel lifetime requirement are possible as a result of the disk design.

Published
1981

28. Charge exchange in zinc-neon

Author

Chubb, D. L

Subjects
Nuclear And High-Energy Physics
Abstract

Excitation of the 4d and 5p levels of Zn(+) by charge exchange between Ne(+) and Zn was investigated. From measured electron temperature and line intensity ratios it was concluded that charge exchange is the dominant mechanism for populating the 4d 2D5/2 level of Zn(+). Comparison of Zn-Ne and Zn-Ar results imply the same conclusion. No evidence for charge exchange as the dominant pumping mechanism for the 5p 2P1/2, 5p 2P3/2, or 4d 2D3/2 levels was obtained.

Published
1975

29. Evidence of charge exchange pumping in calcium-xenon system

Author

Chubb, D. L

Subjects
Atomic And Molecular Physics
Abstract

A flowing xenon plasma seeded with calcium was used to investigate the population mechanism for the 5s and 4d levels of Ca(+). From the dependence of certain line intensity ratios on electron temperature it was concluded that charge exchange between Xe(+) and Ca is the predominate mechanism for populating the 5s and 4d levels. Comparison with intensity ratios obtained in Ca-Ar and Ca-Kr imply the same conclusion.

Published
1975
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30. Study of a rare-gas transverse fast discharge

Author

Chubb, D. L and Michels, C. J

Subjects
Plasma Physics
Abstract

An experimental and analytical study of a Blumlein-type transverse fast discharge operating with He and Xe are presented. An electro-optical voltage probe was used to measure the discharge voltage, and the measured voltages were in agreement with the computed voltages. The analytical model was used to predict the dependence of the discharge efficiency for producing metastables and ions on the important plasma and external circuit parameters. In He the ion efficiency is greater than the metastable efficiency, while in Xe it is the opposite; the He ion efficiencies are much larger than in Xe, while Xe metastable efficiencies are much larger than in He. These differences between Xe and He are accounted by the large dissociative recombination rate of Xe compared with He.

Published
1979
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31. Gain measurements of the Ca-Xe charge exchange system

Author

Michels, C. J and Chubb, D. L

Subjects
Lasers And Masers
Abstract

Charge-exchange-pumped Ca(+) was studied for possible positive laser gain at 370.6 and 315.9 nm using an Xe MPD arc as the Xe(+) source. The present paper describes the MPD arc, the calcium injection system, the diagnostics for gain, and spontaneous emission measurements and results. No positive gain measurements were observed. A small Xe-Ca charge exchange cross section compared to He-metal laser systems charge exchange cross sections is the most probable reason why the result was negative.

Published
1978
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32. Population inversion calculations using near resonant charge exchange as a pumping mechanism

Author

Chubb, D. L and Rose, J. R

Subjects
Physics, Atomic, Molecular, And Nuclear
Abstract

Near resonance charge exchange between ions of a large ionization potential gas such as helium or neon and vapors of metals such as zinc, cadmium, selenium, or tellurium has produced laser action in the metal ion gas. The possibility of obtaining population inversions in near resonant charge exchange systems (Xe-Ca, Xe-Mg, Xe-Sr, Xe-Ba, Ar-Mg, N-Ca) was investigated. The analysis is an initial value problem that utilizes rate equations for the densities of relevant levels of the laser gas (Ca, Ba, Mg, or Sr) and an electron energy equation. Electron excitation rates are calculated using the Bohr-Thomson approximation for the cross section. Approximations to experimental values of the electron ionization cross section and the ion-atom charge exchange cross section are used. Preliminary results have been obtained for the Ca-Xe system and show that it is possible to obtain gains greater than 10 to the 14th power/m with inversion times up to 8x10 to the minus 7th power second. A possible charge exchange laser system using a MPD arc plasma accelerator is also described.

Published
1972

33. Fully ionized quasi-one dimensional magnetic nozzle flow

Author

Chubb, D. L

Subjects
Physics, Plasma
Abstract

Fully ionized quasi-one dimensional magnetic nozzle flow analysis, including effects of unequal electron and ion temperatures and electron thermal conductivity

Published
1971

34. Laboratory simulation of solar wind - earth interaction

Author

Chubb, D. L

Subjects
Physics, Plasma
Abstract

Measurement of change in plasma potential and magnetic field of hydrogen plasma impinging on magnetic dipole - simulation of solar wind-earth interaction

Published
1969

36. Evidence of charge exchange pumping in calcium-xenon system

Author

Chubb, D. L

Subjects
Physics, Atomic, Molecular, And Nuclear
Abstract

Presented evidence shows that charge exchanges between xenon ions and calcium atoms may produce an inversion between 5s or 4d and 4p energy levels of calcium ions. The dependence of measured intensity ratios on power input to the xenon plasma indicates that charge exchange pumping of the 5s and 4d levels predominates over electron collisional pumping of these levels.

Published
1973

38. Double electrostatic probe for measuring density, temperature, and velocity of a flowing plasma

Author

Chubb, D. L

Subjects
Physics, Plasma
Abstract

A method for obtaining plasma electron temperature and density, as well as the Mach number and flow velocity from the current-voltage characteristic of a flat-faced double probe, is presented. Calculated momentum fluxes of a flowing argon plasma obtained with this probe are compared with experimentally determined momentum fluxes. Reasonable agreement is obtained.

Published
1973

39. Light sources for wavelengths > 2 mu m grown by MBE on InP using a strain relaxed buffer

Author

Krier, A, Chubb, D, Krier, S E, Hopkinson, M, Hill, G, Krier, A, Chubb, D, Krier, S E, Hopkinson, M, and Hill, G

Abstract

Light emitting diodes (LEDs) and lasers operating in the 2 to 3 mu m spectral region at room temperature are been demonstrated. The devices were fabricated from InxGa1-xAs/InAsyP1-y double heterostructures grown on n-type InP (100) substrates by molecular beam epitaxy. A strain relaxed buffer layer which incorporates composition reversals was used to reduce the threading dislocation density and to accommodate the large lattice mismatch (up to 2.7%) between the InP substrate and the device active region. Efficient electroluminescence emission at wavelengths between 2 and 3 mu m was obtained from the LEDs at room temperature, while diode lasers exhibited coherent emission in the range 2-2.6 mu m at temperatures up to 130 K. For one of the LEDs a characteristic absorption was readily observed at 2.7 mu m in the diode electroluminescence emission spectrum, corresponding to strong water vapour absorption in the atmosphere. These devices could easily form the key component of an infrared gas sensor for water vapour detection and monitoring at 2.7 mu m in a variety of different applications.

Published
1998

45. The effect of a high protein diet on leucine and alanine turnover in acid maltase deficiency.

Author

Umpleby, A M, Trend, P S, Chubb, D, Conaglen, J V, Williams, C D, Hesp, R, Scobie, I N, Wiles, C M, Spencer, G, and Sönksen, P H

Subjects
ALANINE, COMPARATIVE studies, GLUCOSE tolerance tests, GLYCOSIDASES, LACTATES, LACTIC acid, LEUCINE, LONGITUDINAL method, RESEARCH methodology, MEDICAL cooperation, DIETARY proteins, RESEARCH, STATISTICAL sampling, EVALUATION research, RANDOMIZED controlled trials, INBORN errors of carbohydrate metabolism
Abstract

Leucine and alanine production rate was measured in 5 patients with acid maltase deficiency in the postabsorptive state, following 6 months on a normal diet with placebo and 6 months on an isocaloric high protein diet (16-22% protein). Whole body leucine production rate, a measure of protein degradation, expressed in terms of lean body mass was significantly greater than in five control subjects. Following the high protein diet, leucine production rate was decreased in four of the five patients but this was not statistically significant. Alanine production rate expressed in terms of lean body mass was significantly greater than in control subjects. After the high protein diet, alanine production rate and concentration were significantly decreased (p less than 0.05). There were no significant improvements in any of the clinically relevant variables measured in these patients. It is possible that a larger increase in protein intake over a longer time period may have a clinical effect. [ABSTRACT FROM AUTHOR]

Published
1989

47. The effect of ketone bodies on leucine and alanine metabolism in dogs

Author

Umpleby, A. M., Chubb, D., Boroujerdi, M. A., and Sonksen, P. H.

Abstract

1. The effect of an infusion of sodium β-hydroxybutyrate on leucine and alanine metabolism was investigated in dogs starved for 12 h. To determine whether the metabolic changes produced by this infusion were due to the resultant alkalaemia the effect of an equimolar infusion of sodium bicarbonate was also studied. 2. The sodium β-hydroxybutyrate infusion reduced alanine concentration as a result of a decrease in alanine production rate and an increase in alanine metabolic clearance rate. The sodium bicarbonate infusion induced a small decrease in alanine concentration which was due to an increased metabolic clearance rate. Alanine production rate showed no change. This demonstrates that the fall in alanine concentration after a sodium β-hydroxybutyrate infusion is due both to a ketone-specific inhibitory effect on alanine production rate and an increased metabolic clearance rate caused by the alkalaemia. 3. Leucine concentration was increased after the ketone infusion due to a small increase in production rate and there was a small increase in the rate of leucine incorporation into protein. Alkalaemia had no effect on leucine concentration or metabolism.

Published
1988
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48. An Overview of the Applicability and Use of Artificial Intelligence Techniques to the Processing of Communications and Noncommunications Signals

Author

ARMY SIGNALS WARFARE LAB VINT HILL FARMS STATION VA, Chubb,D. W. J., ARMY SIGNALS WARFARE LAB VINT HILL FARMS STATION VA, and Chubb,D. W. J.

Abstract

The proliferation of communications and noncommunications signal types throughout the world has created a dense and complex signal environment. Traditional statistical or deterministic signal processing techniques cannot effectively process many of these types of signals. To approach comparable human signal processing performance, artificial intelligence signal processing techniques are being applied within this domain. However, artificial intelligence is not a science but a collection of techniques. Theoretical and practical problems arise when using these techniques. This paper discusses these issues. (Author), This article is from 'Proceedings of the Army Conference on Application of Artificial Intelligence to Battlefield Information Management Held at White Oak, Maryland on April 20, 21, and 22, 1983,' AD-A139 685, p129-133.

Published
1984

50. Common variation at 3p22.1 and 7p15.3 influences multiple myeloma risk

Author

Davies, Fe, Jackson, Gh, Goldschmidt, H., Fo&#776, rsti, A., Hemminki, K., Broderick, P., Walker, Ba, Gregory, Wa, Neben, K., Hoffmann, P., Tomlinson, Ip, Moebus, S., Houlston, Rs, Mu&#776, hleisen, Tw, Chubb, D., Dobbins, Se, Weinhold, N., Olver, B., Child, Ja, Johnson, Dc, Ma, Yp, No&#776, then, Mm, Jauch, A., Lloyd, A., Morgan, Gj, and Ross, Fm

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