146 results on '"Hillman, KM"'
Search Results
2. Non-coding RNAs underlie genetic predisposition to breast cancer
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Moradi Marjaneh, M, Beesley, J, O'Mara, TA, Mukhopadhyay, P, Koufariotis, LT, Kazakoff, S, Hussein, N, Fachal, L, Bartonicek, N, Hillman, KM, Kaufmann, S, Sivakumaran, H, Smart, CE, McCart Reed, AE, Ferguson, K, Saunus, JM, Lakhani, SR, Barnes, DR, Antoniou, AC, Dinger, ME, Waddell, N, Easton, DF, Dunning, AM, Chenevix-Trench, G, Edwards, SL, French, JD, Moradi Marjaneh, M, Beesley, J, O'Mara, TA, Mukhopadhyay, P, Koufariotis, LT, Kazakoff, S, Hussein, N, Fachal, L, Bartonicek, N, Hillman, KM, Kaufmann, S, Sivakumaran, H, Smart, CE, McCart Reed, AE, Ferguson, K, Saunus, JM, Lakhani, SR, Barnes, DR, Antoniou, AC, Dinger, ME, Waddell, N, Easton, DF, Dunning, AM, Chenevix-Trench, G, Edwards, SL, and French, JD
- Abstract
Background: Genetic variants identified through genome-wide association studies (GWAS) are predominantly non-coding and typically attributed to altered regulatory elements such as enhancers and promoters. However, the contribution of non-coding RNAs to complex traits is not clear. Results: Using targeted RNA sequencing, we systematically annotated multi-exonic non-coding RNA (mencRNA) genes transcribed from 1.5-Mb intervals surrounding 139 breast cancer GWAS signals and assessed their contribution to breast cancer risk. We identify more than 4000 mencRNA genes and show their expression distinguishes normal breast tissue from tumors and different breast cancer subtypes. Importantly, breast cancer risk variants, identified through genetic fine-mapping, are significantly enriched in mencRNA exons, but not the promoters or introns. eQTL analyses identify mencRNAs whose expression is associated with risk variants. Furthermore, chromatin interaction data identify hundreds of mencRNA promoters that loop to regions that contain breast cancer risk variants. Conclusions: We have compiled the largest catalog of breast cancer-associated mencRNAs to date and provide evidence that modulation of mencRNAs by GWAS variants may provide an alternative mechanism underlying complex traits.
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- 2020
3. Publisher Correction: Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation.
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Ghoussaini, M, Edwards, SL, Michailidou, K, Nord, S, Cowper-Sal Lari, R, Desai, K, Kar, S, Hillman, KM, Kaufmann, S, Glubb, DM, Beesley, J, Dennis, J, Bolla, MK, Wang, Q, Dicks, E, Guo, Q, Schmidt, MK, Shah, M, Luben, R, Brown, J, Czene, K, Darabi, H, Eriksson, M, Klevebring, D, Bojesen, SE, Nordestgaard, BG, Nielsen, SF, Flyger, H, Lambrechts, D, Thienpont, B, Neven, P, Wildiers, H, Broeks, A, Van't Veer, LJ, Rutgers, EJT, Couch, FJ, Olson, JE, Hallberg, E, Vachon, C, Chang-Claude, J, Rudolph, A, Seibold, P, Flesch-Janys, D, Peto, J, Dos-Santos-Silva, I, Gibson, L, Nevanlinna, H, Muranen, TA, Aittomäki, K, Blomqvist, C, Hall, P, Li, J, Liu, J, Humphreys, K, Kang, D, Choi, J-Y, Park, SK, Noh, D-Y, Matsuo, K, Ito, H, Iwata, H, Yatabe, Y, Guénel, P, Truong, T, Menegaux, F, Sanchez, M, Burwinkel, B, Marme, F, Schneeweiss, A, Sohn, C, Wu, AH, Tseng, C-C, Van Den Berg, D, Stram, DO, Benitez, J, Pilar Zamora, M, Perez, JIA, Menéndez, P, Shu, X-O, Lu, W, Gao, Y-T, Cai, Q, Cox, A, Cross, SS, Reed, MWR, Andrulis, IL, Knight, JA, Glendon, G, Tchatchou, S, Sawyer, EJ, Tomlinson, I, Kerin, MJ, Miller, N, Haiman, CA, Henderson, BE, Schumacher, F, Le Marchand, L, Lindblom, A, Margolin, S, Teo, SH, Yip, CH, Lee, DSC, Wong, TY, Hooning, MJ, Martens, JWM, Collée, JM, van Deurzen, CHM, Hopper, JL, Southey, MC, Tsimiklis, H, Kapuscinski, MK, Shen, C-Y, Wu, P-E, Yu, J-C, Chen, S-T, Alnæs, GG, Borresen-Dale, A-L, Giles, GG, Milne, RL, McLean, C, Muir, K, Lophatananon, A, Stewart-Brown, S, Siriwanarangsan, P, Hartman, M, Miao, H, Buhari, SABS, Teo, YY, Fasching, PA, Haeberle, L, Ekici, AB, Beckmann, MW, Brenner, H, Dieffenbach, AK, Arndt, V, Stegmaier, C, Swerdlow, A, Ashworth, A, Orr, N, Schoemaker, MJ, García-Closas, M, Figueroa, J, Chanock, SJ, Lissowska, J, Simard, J, Goldberg, MS, Labrèche, F, Dumont, M, Winqvist, R, Pylkäs, K, Jukkola-Vuorinen, A, Brauch, H, Brüning, T, Koto, Y-D, Radice, P, Peterlongo, P, Bonanni, B, Volorio, S, Dörk, T, Bogdanova, NV, Helbig, S, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, JM, Devilee, P, Tollenaar, RAEM, Seynaeve, C, Van Asperen, CJ, Jakubowska, A, Lubinski, J, Jaworska-Bieniek, K, Durda, K, Slager, S, Toland, AE, Ambrosone, CB, Yannoukakos, D, Sangrajrang, S, Gaborieau, V, Brennan, P, McKay, J, Hamann, U, Torres, D, Zheng, W, Long, J, Anton-Culver, H, Neuhausen, SL, Luccarini, C, Baynes, C, Ahmed, S, Maranian, M, Healey, CS, González-Neira, A, Pita, G, Rosario Alonso, M, Álvarez, N, Herrero, D, Tessier, DC, Vincent, D, Bacot, F, de Santiago, I, Carroll, J, Caldas, C, Brown, MA, Lupien, M, Kristensen, VN, Pharoah, PDP, Chenevix-Trench, G, French, JD, Easton, DF, Dunning, AM, Ghoussaini, M, Edwards, SL, Michailidou, K, Nord, S, Cowper-Sal Lari, R, Desai, K, Kar, S, Hillman, KM, Kaufmann, S, Glubb, DM, Beesley, J, Dennis, J, Bolla, MK, Wang, Q, Dicks, E, Guo, Q, Schmidt, MK, Shah, M, Luben, R, Brown, J, Czene, K, Darabi, H, Eriksson, M, Klevebring, D, Bojesen, SE, Nordestgaard, BG, Nielsen, SF, Flyger, H, Lambrechts, D, Thienpont, B, Neven, P, Wildiers, H, Broeks, A, Van't Veer, LJ, Rutgers, EJT, Couch, FJ, Olson, JE, Hallberg, E, Vachon, C, Chang-Claude, J, Rudolph, A, Seibold, P, Flesch-Janys, D, Peto, J, Dos-Santos-Silva, I, Gibson, L, Nevanlinna, H, Muranen, TA, Aittomäki, K, Blomqvist, C, Hall, P, Li, J, Liu, J, Humphreys, K, Kang, D, Choi, J-Y, Park, SK, Noh, D-Y, Matsuo, K, Ito, H, Iwata, H, Yatabe, Y, Guénel, P, Truong, T, Menegaux, F, Sanchez, M, Burwinkel, B, Marme, F, Schneeweiss, A, Sohn, C, Wu, AH, Tseng, C-C, Van Den Berg, D, Stram, DO, Benitez, J, Pilar Zamora, M, Perez, JIA, Menéndez, P, Shu, X-O, Lu, W, Gao, Y-T, Cai, Q, Cox, A, Cross, SS, Reed, MWR, Andrulis, IL, Knight, JA, Glendon, G, Tchatchou, S, Sawyer, EJ, Tomlinson, I, Kerin, MJ, Miller, N, Haiman, CA, Henderson, BE, Schumacher, F, Le Marchand, L, Lindblom, A, Margolin, S, Teo, SH, Yip, CH, Lee, DSC, Wong, TY, Hooning, MJ, Martens, JWM, Collée, JM, van Deurzen, CHM, Hopper, JL, Southey, MC, Tsimiklis, H, Kapuscinski, MK, Shen, C-Y, Wu, P-E, Yu, J-C, Chen, S-T, Alnæs, GG, Borresen-Dale, A-L, Giles, GG, Milne, RL, McLean, C, Muir, K, Lophatananon, A, Stewart-Brown, S, Siriwanarangsan, P, Hartman, M, Miao, H, Buhari, SABS, Teo, YY, Fasching, PA, Haeberle, L, Ekici, AB, Beckmann, MW, Brenner, H, Dieffenbach, AK, Arndt, V, Stegmaier, C, Swerdlow, A, Ashworth, A, Orr, N, Schoemaker, MJ, García-Closas, M, Figueroa, J, Chanock, SJ, Lissowska, J, Simard, J, Goldberg, MS, Labrèche, F, Dumont, M, Winqvist, R, Pylkäs, K, Jukkola-Vuorinen, A, Brauch, H, Brüning, T, Koto, Y-D, Radice, P, Peterlongo, P, Bonanni, B, Volorio, S, Dörk, T, Bogdanova, NV, Helbig, S, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, JM, Devilee, P, Tollenaar, RAEM, Seynaeve, C, Van Asperen, CJ, Jakubowska, A, Lubinski, J, Jaworska-Bieniek, K, Durda, K, Slager, S, Toland, AE, Ambrosone, CB, Yannoukakos, D, Sangrajrang, S, Gaborieau, V, Brennan, P, McKay, J, Hamann, U, Torres, D, Zheng, W, Long, J, Anton-Culver, H, Neuhausen, SL, Luccarini, C, Baynes, C, Ahmed, S, Maranian, M, Healey, CS, González-Neira, A, Pita, G, Rosario Alonso, M, Álvarez, N, Herrero, D, Tessier, DC, Vincent, D, Bacot, F, de Santiago, I, Carroll, J, Caldas, C, Brown, MA, Lupien, M, Kristensen, VN, Pharoah, PDP, Chenevix-Trench, G, French, JD, Easton, DF, and Dunning, AM
- Abstract
This corrects the article DOI: 10.1038/ncomms5999.
- Published
- 2018
4. STANDING Collaboration: A study protocol for developing clinical standards
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Wiles, LK, Hibbert, PD, Stephens, JH, Coiera, E, Westbrook, J, Braithwaite, J, Day, RO, Hillman, KM, Runciman, WB, Wiles, LK, Hibbert, PD, Stephens, JH, Coiera, E, Westbrook, J, Braithwaite, J, Day, RO, Hillman, KM, and Runciman, WB
- Abstract
© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. Introduction Despite widespread availability of clinical practice guidelines (CPGs), considerable gaps continue between the care that is recommended ('appropriate care') and the care provided. Problems with current CPGs are commonly cited as barriers to providing 'appropriate care'. Our study aims to develop and test an alternative method to keep CPGs accessible and up to date. This method aims to mitigate existing problems by using a single process to develop clinical standards (embodied in clinical indicators) collaboratively with researchers, healthcare professionals, patients and consumers. A transparent and inclusive online curated (purpose-designed, custom-built, wiki-Type) system will use an ongoing and iterative documentation process to facilitate synthesis of up-To-date information and make available its provenance. All participants are required to declare conflicts of interest. This protocol describes three phases: engagement of relevant stakeholders; design of a process to develop clinical standards (embodied in indicators) for 'appropriate care' for common medical conditions; and evaluation of our processes, products and feasibility. Methods and analysis A modified e-Delphi process will be used to gain consensus on 'appropriate care' for a range of common medical conditions. Clinical standards and indicators will be developed through searches of national and international guidelines, and formulated with explicit criteria for inclusion, exclusion, time frame and setting. Healthcare professionals and consumers will review the indicators via the wiki-based modified e-Delphi process. Reviewers will declare conflicts of interest which will be recorded and managed according to an established protocol. The provenance of all indicators and suggestions included or excluded will be logged from indicator inception to finalisation. A mixed-methods
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- 2017
5. Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170
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Dunning, AM, Michailidou, K, Kuchenbaecker, KB, Thompson, D, French, JD, Beesley, J, Healey, CS, Kar, S, Pooley, KA, Lopez-Knowles, E, Dicks, E, Barrowdale, D, Sinnott-Armstrong, NA, Sallari, RC, Hillman, KM, Kaufmann, S, Sivakumaran, H, Marjaneh, MM, Lee, JS, Hills, M, Jarosz, M, Drury, S, Canisius, S, KBolla, M, Dennis, J, Wang, Q, LHopper, J, Southey, MC, Broeks, A, Schmidt, MK, Lophatananon, A, Muir, K, Beckmann, MW, Fasching, PA, Dos-Santos-Silva, I, Peto, J, Sawyer, EJ, Tomlinson, I, Burwinkel, B, Marme, F, Guénel, P, Truong, T, Bojesen, SE, Flyger, H, Gonzlez-Neira, A, Perez, JIA, Anton-Culver, H, Eunjung, L, Arndt, V, Brenner, H, Meindl, A, Schmutzler, RK, Brauch, H, Hamann, U, Aittomki, K, Blomqvist, C, Ito, H, Matsuo, K, Bogdanova, N, Dörk, T, Lindblom, A, Margolin, S, Kosma, VM, Mannermaa, A, Tseng, CC, Wu, AH, Lambrechts, D, Wildiers, H, Chang-Claude, J, Rudolph, A, Peterlongo, P, Radice, P, EOlson, J, GGiles, G, and Milne, RL
- Abstract
© 2016 Nature America, Inc. We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor α) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER + or ER -) and human ERBB2 (HER2 + or HER2 -) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER - tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression.
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- 2016
6. A Common Variant at the 14q32 Endometrial Cancer Risk Locus Activates AKT1 through YY1 Binding
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Painter, JN, Kaufmann, S, O'Mara, TA, Hillman, KM, Sivakumaran, H, Darabi, H, Cheng, TH, Pearson, J, Kazakoff, S, Waddell, N, Hoivik, EA, Goode, EL, Scott, RJ, Tomlinson, I, Dunning, AM, Easton, DF, French, JD, Salvesen, HB, Pollock, PM, Thompson, DJ, Spurdle, AB, Edwards, SL, Dunning, Alison [0000-0001-6651-7166], Easton, Douglas [0000-0003-2444-3247], Thompson, Deborah [0000-0003-1465-5799], and Apollo - University of Cambridge Repository
- Subjects
Chromosomes, Human, Pair 14 ,Genotype ,Polymorphism, Single Nucleotide ,Article ,Endometrial Neoplasms ,Phosphatidylinositol 3-Kinases ,Genetic Loci ,Risk Factors ,Uterine Neoplasms ,Genetics ,Humans ,Genetics(clinical) ,Female ,Genetic Predisposition to Disease ,Proto-Oncogene Proteins c-akt ,YY1 Transcription Factor ,Genome-Wide Association Study ,Protein Binding ,Signal Transduction - Abstract
A recent meta-analysis of multiple genome-wide association and follow-up endometrial cancer case-control datasets identified a novel genetic risk locus for this disease at chromosome 14q32.33. To prioritize the functional SNP(s) and target gene(s) at this locus, we employed an in silico fine-mapping approach using genotyped and imputed SNP data for 6,608 endometrial cancer cases and 37,925 controls of European ancestry. Association and functional analyses provide evidence that the best candidate causal SNP is rs2494737. Multiple experimental analyses show that SNP rs2494737 maps to a silencer element located within AKT1, a member of the PI3K/AKT/MTOR intracellular signaling pathway activated in endometrial tumors. The rs2494737 risk A allele creates a YY1 transcription factor-binding site and abrogates the silencer activity in luciferase assays, an effect mimicked by transfection of YY1 siRNA. Our findings suggest YY1 is a positive regulator of AKT1, mediating the stimulatory effects of rs2494737 increasing endometrial cancer risk. Identification of an endometrial cancer risk allele within a member of the PI3K/AKT signaling pathway, more commonly activated in tumors by somatic alterations, raises the possibility that well tolerated inhibitors targeting this pathway could be candidates for evaluation as chemopreventive agents in individuals at high risk of developing endometrial cancer.
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- 2016
7. Evidence that the 5p12 Variant rs10941679 Confers Susceptibility to Estrogen-Receptor-Positive Breast Cancer through FGF10 and MRPS30 Regulation
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Ghoussaini, M, French, JD, Michailidou, K, Nord, S, Beesley, J, Canisus, S, Hillman, KM, Kaufmann, S, Sivakumaran, H, Marjaneh, M M, Lee, JS, Dennis, J, Bolla, MK, Wang, Q, Dicks, E, Milne, RL, Hopper, JL, Southey, MC, Schmidt, MK (Marjanka), Broeks, A, Muir, K, Lophatananon, A, Fasching, PA, Beckmann, MW, Fletcher, O, Johnson, N, Sawyer, EJ, Tomlinson, I, Burwinkel, B, Marme, F, Guenel, P, Truong, T, Bojesen, SE, Flyger, H, Benitez, J, Gonzalez-Neira, A, Alonso, R, Pita, G, Neuhausen, SL, Anton-Culver, H, Brenner, H, Arndt, V, Meindl, A, Schmutzler, RK, Brauch, H, Hamann, U, Tessier, DC, Vincent, D, Nevanlinna, H, Khan, Salima, Matsuo, K, Ito, H, Dork, T, Bogdanova, NV, Lindblom, A, Margolin, S, Mannermaa, A, Kosma, VM, Wu, AH, van den Berg, D, Lambrechts, D, Floris, G, Chang-Claude, J, Rudolph, A, Radice, P, Barile, M, Couch, FJ, Hallberg, E, Giles, GG, Haiman, CA, Le Marchand, L, Goldberg, MS, Teo, SH, Yip, CH, Borresen-Dale, AL, Zheng, W, Cai, QY, Winqvist, R, Pylkas, K, Andrulis, IL, Devilee, P, Tollenaar, RAEM, Garcia-Closas, M, Figueroa, J, Hall, P, Czene, K, Brand, JS, Darabi, H, Eriksson, M, Hooning, Maartje, Koppert, Linetta, Li, JM, Shu, XO, Zheng, Y, Cox, A, Cross, SS, Shah, M, Rhenius, V, Choi, JY, Kang, D, Hartman, M, Chia, KS, Kabisch, M, Torres, D, Luccarini, C, Conroy, D M, Jakubowska, A, Lubinski, J, Sangrajrang, S, Brennan, P, Olswold, C, Slager, S, Shen, CY, Hou, MF, Swerdlow, A, Schoemaker, MJ, Simard, J, Pharoah, PDP, Kristensen, V, Chenevix-Trench, G, Easton, DF, Dunning, AM, Edwards, SL, Ghoussaini, M, French, JD, Michailidou, K, Nord, S, Beesley, J, Canisus, S, Hillman, KM, Kaufmann, S, Sivakumaran, H, Marjaneh, M M, Lee, JS, Dennis, J, Bolla, MK, Wang, Q, Dicks, E, Milne, RL, Hopper, JL, Southey, MC, Schmidt, MK (Marjanka), Broeks, A, Muir, K, Lophatananon, A, Fasching, PA, Beckmann, MW, Fletcher, O, Johnson, N, Sawyer, EJ, Tomlinson, I, Burwinkel, B, Marme, F, Guenel, P, Truong, T, Bojesen, SE, Flyger, H, Benitez, J, Gonzalez-Neira, A, Alonso, R, Pita, G, Neuhausen, SL, Anton-Culver, H, Brenner, H, Arndt, V, Meindl, A, Schmutzler, RK, Brauch, H, Hamann, U, Tessier, DC, Vincent, D, Nevanlinna, H, Khan, Salima, Matsuo, K, Ito, H, Dork, T, Bogdanova, NV, Lindblom, A, Margolin, S, Mannermaa, A, Kosma, VM, Wu, AH, van den Berg, D, Lambrechts, D, Floris, G, Chang-Claude, J, Rudolph, A, Radice, P, Barile, M, Couch, FJ, Hallberg, E, Giles, GG, Haiman, CA, Le Marchand, L, Goldberg, MS, Teo, SH, Yip, CH, Borresen-Dale, AL, Zheng, W, Cai, QY, Winqvist, R, Pylkas, K, Andrulis, IL, Devilee, P, Tollenaar, RAEM, Garcia-Closas, M, Figueroa, J, Hall, P, Czene, K, Brand, JS, Darabi, H, Eriksson, M, Hooning, Maartje, Koppert, Linetta, Li, JM, Shu, XO, Zheng, Y, Cox, A, Cross, SS, Shah, M, Rhenius, V, Choi, JY, Kang, D, Hartman, M, Chia, KS, Kabisch, M, Torres, D, Luccarini, C, Conroy, D M, Jakubowska, A, Lubinski, J, Sangrajrang, S, Brennan, P, Olswold, C, Slager, S, Shen, CY, Hou, MF, Swerdlow, A, Schoemaker, MJ, Simard, J, Pharoah, PDP, Kristensen, V, Chenevix-Trench, G, Easton, DF, Dunning, AM, and Edwards, SL
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- 2016
8. Implementing a palliative approach in the intensive care unit: An oxymoron or a realistic possibility?
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Athari, F, Davidson, PM, Hillman, KM, Phillips, J, Athari, F, Davidson, PM, Hillman, KM, and Phillips, J
- Abstract
© 2016 MA Healthcare Ltd. Providing a palliative approach in an ICU is not an oxymoron and is within our reach today. Implementing a palliative approach will better ensure the needs of older patients and their families are met. Investing in developing the palliative care capabilities of ICUs and implementing appropriate policies that support the delivery of best evidence-based palliative care, will help ICU clinicians move seamlessly from implementing intensive therapies focusing on cure to palliation and relief of symptoms and care of families.
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- 2016
9. Cardiopulmonary arrest and mortality trends, and their association with rapid response system expansion
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Chen, J, Hillman, KM, Chen, J, and Hillman, KM
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- 2015
10. The ten barriers to appropriate management of patients at the end of their life
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Hillman, KM, Cardona-Morrell, M, Hillman, KM, and Cardona-Morrell, M
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- 2015
11. Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk
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Painter, JN, O'Mara, TA, Batra, J, Cheng, T, Lose, FA, Dennis, J, Michailidou, K, Tyrer, JP, Ahmed, S, Ferguson, K, Healey, CS, Kaufmann, S, Hillman, KM, Walpole, C, Moya, L, Pollock, P, Jones, A, Howarth, K, Martin, L, Gorman, M, Hodgson, S, Magdalena Echeverry De Polanco, M, Sans, M, Carracedo, A, Castellvi-Bel, S, Rojas-Martinez, A, Santos, E, Teixeira, MR, Carvajal-Carmona, L, Shu, X-O, Long, J, Zheng, W, Xiang, Y-B, Montgomery, GW, Webb, PM, Scott, RJ, McEvoy, M, Attia, J, Holliday, E, Martin, NG, Nyholt, DR, Henders, AK, Fasching, PA, Hein, A, Beckmann, MW, Renner, SP, Doerk, T, Hillemanns, P, Duerst, M, Runnebaum, I, Lambrechts, D, Coenegrachts, L, Schrauwen, S, Amant, F, Winterhoff, B, Dowdy, SC, Goode, EL, Teoman, A, Salvesen, HB, Trovik, J, Njolstad, TS, Werner, HMJ, Ashton, K, Proietto, T, Otton, G, Tzortzatos, G, Mints, M, Tham, E, Hall, P, Czene, K, Liu, J, Li, J, Hopper, JL, Southey, MC, Ekici, AB, Ruebner, M, Johnson, N, Peto, J, Burwinkel, B, Marme, F, Brenner, H, Dieffenbach, AK, Meindl, A, Brauch, H, Lindblom, A, Depreeuw, J, Moisse, M, Chang-Claude, J, Rudolph, A, Couch, FJ, Olson, JE, Giles, GG, Bruinsma, F, Cunningham, JM, Fridley, BL, Borresen-Dale, A-L, Kristensen, VN, Cox, A, Swerdlow, AJ, Orr, N, Bolla, MK, Wang, Q, Weber, RP, Chen, Z, Shah, M, French, JD, Pharoah, PDP, Dunning, AM, Tomlinson, I, Easton, DF, Edwards, SL, Thompson, DJ, Spurdle, AB, Painter, JN, O'Mara, TA, Batra, J, Cheng, T, Lose, FA, Dennis, J, Michailidou, K, Tyrer, JP, Ahmed, S, Ferguson, K, Healey, CS, Kaufmann, S, Hillman, KM, Walpole, C, Moya, L, Pollock, P, Jones, A, Howarth, K, Martin, L, Gorman, M, Hodgson, S, Magdalena Echeverry De Polanco, M, Sans, M, Carracedo, A, Castellvi-Bel, S, Rojas-Martinez, A, Santos, E, Teixeira, MR, Carvajal-Carmona, L, Shu, X-O, Long, J, Zheng, W, Xiang, Y-B, Montgomery, GW, Webb, PM, Scott, RJ, McEvoy, M, Attia, J, Holliday, E, Martin, NG, Nyholt, DR, Henders, AK, Fasching, PA, Hein, A, Beckmann, MW, Renner, SP, Doerk, T, Hillemanns, P, Duerst, M, Runnebaum, I, Lambrechts, D, Coenegrachts, L, Schrauwen, S, Amant, F, Winterhoff, B, Dowdy, SC, Goode, EL, Teoman, A, Salvesen, HB, Trovik, J, Njolstad, TS, Werner, HMJ, Ashton, K, Proietto, T, Otton, G, Tzortzatos, G, Mints, M, Tham, E, Hall, P, Czene, K, Liu, J, Li, J, Hopper, JL, Southey, MC, Ekici, AB, Ruebner, M, Johnson, N, Peto, J, Burwinkel, B, Marme, F, Brenner, H, Dieffenbach, AK, Meindl, A, Brauch, H, Lindblom, A, Depreeuw, J, Moisse, M, Chang-Claude, J, Rudolph, A, Couch, FJ, Olson, JE, Giles, GG, Bruinsma, F, Cunningham, JM, Fridley, BL, Borresen-Dale, A-L, Kristensen, VN, Cox, A, Swerdlow, AJ, Orr, N, Bolla, MK, Wang, Q, Weber, RP, Chen, Z, Shah, M, French, JD, Pharoah, PDP, Dunning, AM, Tomlinson, I, Easton, DF, Edwards, SL, Thompson, DJ, and Spurdle, AB
- Abstract
Common variants in the hepatocyte nuclear factor 1 homeobox B (HNF1B) gene are associated with the risk of Type II diabetes and multiple cancers. Evidence to date indicates that cancer risk may be mediated via genetic or epigenetic effects on HNF1B gene expression. We previously found single-nucleotide polymorphisms (SNPs) at the HNF1B locus to be associated with endometrial cancer, and now report extensive fine-mapping and in silico and laboratory analyses of this locus. Analysis of 1184 genotyped and imputed SNPs in 6608 Caucasian cases and 37 925 controls, and 895 Asian cases and 1968 controls, revealed the best signal of association for SNP rs11263763 (P = 8.4 × 10(-14), odds ratio = 0.86, 95% confidence interval = 0.82-0.89), located within HNF1B intron 1. Haplotype analysis and conditional analyses provide no evidence of further independent endometrial cancer risk variants at this locus. SNP rs11263763 genotype was associated with HNF1B mRNA expression but not with HNF1B methylation in endometrial tumor samples from The Cancer Genome Atlas. Genetic analyses prioritized rs11263763 and four other SNPs in high-to-moderate linkage disequilibrium as the most likely causal SNPs. Three of these SNPs map to the extended HNF1B promoter based on chromatin marks extending from the minimal promoter region. Reporter assays demonstrated that this extended region reduces activity in combination with the minimal HNF1B promoter, and that the minor alleles of rs11263763 or rs8064454 are associated with decreased HNF1B promoter activity. Our findings provide evidence for a single signal associated with endometrial cancer risk at the HNF1B locus, and that risk is likely mediated via altered HNF1B gene expression.
- Published
- 2015
12. Fine-Scale Mapping of the 5q11.2 Breast Cancer Locus Reveals at Least Three Independent Risk Variants Regulating MAP3K1
- Author
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Glubb, DM, Maranian, MJ, Michailidou, K, Pooley, KA, Meyer, KB, Kar, S, Carlebur, S, O'Reilly, M, Betts, JA, Hillman, KM, Kaufmann, S, Beesley, J, Canisius, S, Hopper, JL, Southey, MC, Tsimiklis, H, Apicella, C, Schmidt, MK (Marjanka), Broeks, A, Hogervorst, FB, van der Schoot, CE, Muir, K, Lophatananon, A, Stewart-Brown, S, Siriwanarangsan, P, Fasching, PA, Ruebner, M, Ekici, AB, Beckmann, MW, Peto, J, dos-Santos-Silva, I, Fletcher, O, Johnson, N, Pharoah, PDP, Bolla, MK, Wang, Q (Qing), Dennis, J, Sawyer, EJ, Tomlinson, I, Kerin, MJ, Miller, N, Burwinkel, B, Marme, F, Yang, RX, Surowy, H, Guenel, P, Truong, T, Menegaux, F, Sanchez, M, Bojesen, SE, Nordestgaard, BG, Nielsen, SF, Flyger, H, Gonzelez-Neira, A, Benitez, J, Zamora, MP, Perez, JIA, Anton-Culver, H, Neuhausen, SL, Brenner, H, Dieffenbach, AK, Arndt, V, Stegmaier, C, Meindl, A, Schmutzler, RK, Brauch, H, Ko, YD, Bruning, T, Nevanlinna, H, Muranen, TA, Aittomaki, K, Blomqvist, C, Matsuo, K, Ito, H, Iwata, H, Tanaka, H, Dork, T, Bogdanova, NV, Helbig, S, Lindblom, A, Margolin, S, Mannermaa, A, Kataja, V, Kosma, VM, Hartikainen, JM, Wu, AH, Tseng, CC, van den Berg, D, Stram, DO, Lambrechts, D, Zhao, H (Hui), Weltens, C, van Limbergen, E, Chang-Claude, J, Flesch-Janys, D, Rudolph, A, Seibold, P, Radice, P, Peterlongo, P, Barile, M, Capra, F, Couch, FJ, Olson, JE, Hallberg, E, Vachon, C, Giles, GG, Milne, RL, McLean, C, Haiman, CA, Henderson, BE, Schumacher, F, Le Marchand, L, Simard, J, Goldberg, MS, Labreche, F, Dumont, M, Teo, SH, Yip, CH, See, MH, Cornes, B, Cheng, CY (Ching-Yu), Ikram, Kamran, Kristensen, V, Zheng, W, Halverson, SL, Shrubsole, M, Long, J, Winqvist, R, Pylkas, K, Jukkola-Vuorinen, A, Kauppila, S, Andrulis, IL, Knight, JA, Glendon, G, Tchatchou, S, Devilee, P, Tollenaar, RAEM, Seynaeve, Caroline, van Asperen, CJ, Garcia-Closas, M, Figueroa, J, Chanock, SJ, Lissowska, J, Czene, K, Klevebring, D, Darabi, H, Eriksson, M, Hooning, Maartje, Hollestelle, Antoinette, Martens, John, Collee, Margriet, Hall, P, Li, JM, Humphreys, K, Shu, XO, Lu, W, Gao, YT, Cai, H, Cox, A, Cross, SS, Reed, MWR, Blot, W, Signorello, LB, Cai, QY, Shah, M, Ghoussaini, M, Kang, D, Choi, JY, Park, SK, Noh, DY, Hartman, M, Miao, H, Lim, WY, Tang, A, Hamann, U, Torres, D, Jakubowska, A, Lubinski, J, Jaworska, K, Durda, K, Sangrajrang, S, Gaborieau, V, Brennan, P, Mckay, J, Olswold, C, Slager, S, Toland, AE, Yannoukakos, D, Shen, CY, Wu, PE, Yu, JC, Hou, MF, Swerdlow, A, Ashworth, A, Orr, N, Jones, M, Pita, G, Alonso, MR, Alvarez, N, Herrero, D, Tessier, DC, Vincent, D, Bacot, F, Luccarini, C, Baynes, C, Ahmed, S (Shahana), Healey, CS, Brown, MA, Ponder, BAJ, Chenevix-Trench, G, Thompson, DJ, Edwards, SL, Easton, DF, Dunning, AM, French, JD, Glubb, DM, Maranian, MJ, Michailidou, K, Pooley, KA, Meyer, KB, Kar, S, Carlebur, S, O'Reilly, M, Betts, JA, Hillman, KM, Kaufmann, S, Beesley, J, Canisius, S, Hopper, JL, Southey, MC, Tsimiklis, H, Apicella, C, Schmidt, MK (Marjanka), Broeks, A, Hogervorst, FB, van der Schoot, CE, Muir, K, Lophatananon, A, Stewart-Brown, S, Siriwanarangsan, P, Fasching, PA, Ruebner, M, Ekici, AB, Beckmann, MW, Peto, J, dos-Santos-Silva, I, Fletcher, O, Johnson, N, Pharoah, PDP, Bolla, MK, Wang, Q (Qing), Dennis, J, Sawyer, EJ, Tomlinson, I, Kerin, MJ, Miller, N, Burwinkel, B, Marme, F, Yang, RX, Surowy, H, Guenel, P, Truong, T, Menegaux, F, Sanchez, M, Bojesen, SE, Nordestgaard, BG, Nielsen, SF, Flyger, H, Gonzelez-Neira, A, Benitez, J, Zamora, MP, Perez, JIA, Anton-Culver, H, Neuhausen, SL, Brenner, H, Dieffenbach, AK, Arndt, V, Stegmaier, C, Meindl, A, Schmutzler, RK, Brauch, H, Ko, YD, Bruning, T, Nevanlinna, H, Muranen, TA, Aittomaki, K, Blomqvist, C, Matsuo, K, Ito, H, Iwata, H, Tanaka, H, Dork, T, Bogdanova, NV, Helbig, S, Lindblom, A, Margolin, S, Mannermaa, A, Kataja, V, Kosma, VM, Hartikainen, JM, Wu, AH, Tseng, CC, van den Berg, D, Stram, DO, Lambrechts, D, Zhao, H (Hui), Weltens, C, van Limbergen, E, Chang-Claude, J, Flesch-Janys, D, Rudolph, A, Seibold, P, Radice, P, Peterlongo, P, Barile, M, Capra, F, Couch, FJ, Olson, JE, Hallberg, E, Vachon, C, Giles, GG, Milne, RL, McLean, C, Haiman, CA, Henderson, BE, Schumacher, F, Le Marchand, L, Simard, J, Goldberg, MS, Labreche, F, Dumont, M, Teo, SH, Yip, CH, See, MH, Cornes, B, Cheng, CY (Ching-Yu), Ikram, Kamran, Kristensen, V, Zheng, W, Halverson, SL, Shrubsole, M, Long, J, Winqvist, R, Pylkas, K, Jukkola-Vuorinen, A, Kauppila, S, Andrulis, IL, Knight, JA, Glendon, G, Tchatchou, S, Devilee, P, Tollenaar, RAEM, Seynaeve, Caroline, van Asperen, CJ, Garcia-Closas, M, Figueroa, J, Chanock, SJ, Lissowska, J, Czene, K, Klevebring, D, Darabi, H, Eriksson, M, Hooning, Maartje, Hollestelle, Antoinette, Martens, John, Collee, Margriet, Hall, P, Li, JM, Humphreys, K, Shu, XO, Lu, W, Gao, YT, Cai, H, Cox, A, Cross, SS, Reed, MWR, Blot, W, Signorello, LB, Cai, QY, Shah, M, Ghoussaini, M, Kang, D, Choi, JY, Park, SK, Noh, DY, Hartman, M, Miao, H, Lim, WY, Tang, A, Hamann, U, Torres, D, Jakubowska, A, Lubinski, J, Jaworska, K, Durda, K, Sangrajrang, S, Gaborieau, V, Brennan, P, Mckay, J, Olswold, C, Slager, S, Toland, AE, Yannoukakos, D, Shen, CY, Wu, PE, Yu, JC, Hou, MF, Swerdlow, A, Ashworth, A, Orr, N, Jones, M, Pita, G, Alonso, MR, Alvarez, N, Herrero, D, Tessier, DC, Vincent, D, Bacot, F, Luccarini, C, Baynes, C, Ahmed, S (Shahana), Healey, CS, Brown, MA, Ponder, BAJ, Chenevix-Trench, G, Thompson, DJ, Edwards, SL, Easton, DF, Dunning, AM, and French, JD
- Abstract
Genome-wide association studies (GWASs) have revealed SNP rs889312 on 5q11.2 to be associated with breast cancer risk in women of European ancestry. In an attempt to identify the biologically relevant variants, we analyzed 909 genetic variants across 5q11.2 in 103,991 breast cancer individuals and control individuals from 52 studies in the Breast Cancer Association Consortium. Multiple logistic regression analyses identified three independent risk signals: the strongest associations were with 15 correlated variants (iCHAV1), where the minor allele of the best candidate, rs62355902, associated with significantly increased risks of both estrogen-receptor-positive (ER-: odds ratio [OR] = 1.24, 95% confidence interval [CI] = 1.21-1.27, p(trend) = 5.7 3 10(-44)) and estrogen-receptor-negative (ER-: OR = 1.10, 95% CI = 1.05-1.15, p(trend) = 3.0 x 10(-4)) tumors. After adjustment for rs62355902, we found evidence of association of a further 173 variants (iCHAV2) containing three subsets with a range of effects (the strongest was rs113317823 [p(cond) = 1.61 x 10(-5)]) and five variants composing iCHAV3 (lead rs11949391; ER-: OR = 0.90, 95% CI = 0.87-0.93, p(cond) = 1.4 x 10(-4)). Twenty-six percent of the prioritized candidate variants coincided with four putative regulatory elements that interact with the MAP3K1 promoter through chromatin looping and affect MAP3K1 promoter activity. Functional analysis indicated that the cancer risk alleles of four candidates (rs74345699 and rs62355900 [iCHAV1], rs16886397 [iCHAV2a], and rs17432750 [iCHAV3]) increased MAP3K1 transcriptional activity. Chromatin immunoprecipitation analysis revealed diminished GATA3 binding to the minor (cancer-protective) allele of rs17432750, indicating a mechanism for its action. We propose that the cancer risk alleles act to increase MAP3K1 expression in vivo and might promote breast cancer cell survival.
- Published
- 2015
13. A review of the nursing role in central venous cannulation: Implications for practice policy and research
- Author
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Alexandrou, E, Spencer, TR, Frost, SA, Parr, MJA, Davidson, PM, and Hillman, KM
- Subjects
Catheterization, Central Venous ,Humans ,Nursing ,Nurse's Role ,Catheterization - Abstract
Aims and objectives: The aim of this article is to review published studies about central vein cannulation to identify implications for policy, practice and research in an advanced practice nursing role. Design: Modified integrative literature review. Methods: Searches of the electronic databases: Cumulative Index of Nursing and Allied Health Literature (CINAHL); Medline, Embase, and the World Wide Web were undertaken using MeSH key words. Hand searching for relevant articles was also undertaken. All studies relating to the nurses role inserting central venous cannulae in adult populations met the search criteria and were reviewed by three authors using a critical appraisal tool. Results: Ten studies met the inclusion criteria for the review, all reported data were from the UK. There were disparate models of service delivery and study populations and the studies were predominantly non experimental in design. The results of this review need to be considered within the methodological caveats associated with this approach. The studies identified did not demonstrate differences in rates of adverse events between a specialist nurse and a medical officer. Conclusions: There were only a small number of studies found in the literature review and the limited availability of clinical outcome data precluded formal analysis from being generated. Relevance to clinical practice: Central vein cannulation is potentially an emerging practice area with important considerations for policy practice and research. Training specialist nurses to provide such a service may facilitate standardising of practice and improving surveillance of lines, and possibly improve the training and accreditation process for CVC insertions for junior medical officers. For this to occur, there is a need to undertake well-conducted clinical studies to clearly document the value and efficacy of this advanced practice nursing role. © 2009 Blackwell Publishing Ltd.
- Published
- 2010
14. Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation
- Author
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Ghoussaini, M, Edwards, SL, Michailidou, K, Nord, S, Lari, RC-S, Desai, K, Kar, S, Hillman, KM, Kaufmann, S, Glubb, DM, Beesley, J, Dennis, J, Bolla, MK, Wang, Q, Dicks, E, Guo, Q, Schmidt, MK, Shah, M, Luben, R, Brown, J, Czene, K, Darabi, H, Eriksson, M, Klevebring, D, Bojesen, SE, Nordestgaard, BG, Nielsen, SF, Flyger, H, Lambrechts, D, Thienpont, B, Neven, P, Wildiers, H, Broeks, A, Van't Veer, LJ, Rutgers, EJT, Couch, FJ, Olson, JE, Hallberg, E, Vachon, C, Chang-Claude, J, Rudolph, A, Seibold, P, Flesch-Janys, D, Peto, J, dos-Santos-Silva, I, Gibson, L, Nevanlinna, H, Muranen, TA, Aittomaki, K, Blomqvist, C, Hall, P, Li, J, Liu, J, Humphreys, K, Kang, D, Choi, J-Y, Park, SK, Noh, D-Y, Matsuo, K, Ito, H, Iwata, H, Yatabe, Y, Guenel, P, Truong, T, Menegaux, F, Sanchez, M, Burwinkel, B, Marme, F, Schneeweiss, A, Sohn, C, Wu, AH, Tseng, C-C, Van Den Berg, D, Stram, DO, Benitez, J, Pilar Zamora, M, Arias Perez, JI, Menendez, P, Shu, X-O, Lu, W, Gao, Y-T, Cai, Q, Cox, A, Cross, SS, Reed, MWR, Andrulis, IL, Knight, JA, Glendon, G, Tchatchou, S, Sawyer, EJ, Tomlinson, I, Kerin, MJ, Miller, N, Haiman, CA, Henderson, BE, Schumacher, F, Le Marchand, L, Lindblom, A, Margolin, S, Teo, SH, Yip, CH, Lee, DSC, Wong, TY, Hooning, MJ, Martens, JWM, Collee, JM, van Deurzen, CHM, Hopper, JL, Southey, MC, Tsimiklis, H, Kapuscinski, MK, Shen, C-Y, Wu, P-E, Yu, J-C, Chen, S-T, Alnaes, GG, Borresen-Dale, A-L, Giles, GG, Milne, RL, McLean, C, Muir, K, Lophatananon, A, Stewart-Brown, S, Siriwanarangsan, P, Hartman, M, Miao, H, Buhari, SABS, Teo, YY, Fasching, PA, Haeberle, L, Ekici, AB, Beckmann, MW, Brenner, H, Dieffenbach, AK, Arndt, V, Stegmaier, C, Swerdlow, A, Ashworth, A, Orr, N, Schoemaker, MJ, Garcia-Closas, M, Figueroa, J, Chanock, SJ, Lissowska, J, Simard, J, Goldberg, MS, Labreche, F, Dumont, M, Winqvist, R, Pylkas, K, Jukkola-Vuorinen, A, Brauch, H, Bruening, T, Koto, Y-D, Radice, P, Peterlongo, P, Bonanni, B, Volorio, S, Doerk, T, Bogdanova, NV, Helbig, S, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, JM, Devilee, P, Tollenaar, RAEM, Seynaeve, C, Van Asperen, CJ, Jakubowska, A, Lubinski, J, Jaworska-Bieniek, K, Durda, K, Slager, S, Toland, AE, Ambrosone, CB, Yannoukakos, D, Sangrajrang, S, Gaborieau, V, Brennan, P, Mckay, J, Hamann, U, Torres, D, Zheng, W, Long, J, Anton-Culver, H, Neuhausen, SL, Luccarini, C, Baynes, C, Ahmed, S, Maranian, M, Healey, CS, Gonzalez-Neira, A, Pita, G, Alonso, MR, Alvarez, N, Herrero, D, Tessier, DC, Vincent, D, Bacot, F, de Santiago, I, Carroll, J, Caldas, C, Brown, MA, Lupien, M, Kristensen, VN, Pharoah, PDP, Chenevix-Trench, G, French, JD, Easton, DF, Dunning, AM, Ghoussaini, M, Edwards, SL, Michailidou, K, Nord, S, Lari, RC-S, Desai, K, Kar, S, Hillman, KM, Kaufmann, S, Glubb, DM, Beesley, J, Dennis, J, Bolla, MK, Wang, Q, Dicks, E, Guo, Q, Schmidt, MK, Shah, M, Luben, R, Brown, J, Czene, K, Darabi, H, Eriksson, M, Klevebring, D, Bojesen, SE, Nordestgaard, BG, Nielsen, SF, Flyger, H, Lambrechts, D, Thienpont, B, Neven, P, Wildiers, H, Broeks, A, Van't Veer, LJ, Rutgers, EJT, Couch, FJ, Olson, JE, Hallberg, E, Vachon, C, Chang-Claude, J, Rudolph, A, Seibold, P, Flesch-Janys, D, Peto, J, dos-Santos-Silva, I, Gibson, L, Nevanlinna, H, Muranen, TA, Aittomaki, K, Blomqvist, C, Hall, P, Li, J, Liu, J, Humphreys, K, Kang, D, Choi, J-Y, Park, SK, Noh, D-Y, Matsuo, K, Ito, H, Iwata, H, Yatabe, Y, Guenel, P, Truong, T, Menegaux, F, Sanchez, M, Burwinkel, B, Marme, F, Schneeweiss, A, Sohn, C, Wu, AH, Tseng, C-C, Van Den Berg, D, Stram, DO, Benitez, J, Pilar Zamora, M, Arias Perez, JI, Menendez, P, Shu, X-O, Lu, W, Gao, Y-T, Cai, Q, Cox, A, Cross, SS, Reed, MWR, Andrulis, IL, Knight, JA, Glendon, G, Tchatchou, S, Sawyer, EJ, Tomlinson, I, Kerin, MJ, Miller, N, Haiman, CA, Henderson, BE, Schumacher, F, Le Marchand, L, Lindblom, A, Margolin, S, Teo, SH, Yip, CH, Lee, DSC, Wong, TY, Hooning, MJ, Martens, JWM, Collee, JM, van Deurzen, CHM, Hopper, JL, Southey, MC, Tsimiklis, H, Kapuscinski, MK, Shen, C-Y, Wu, P-E, Yu, J-C, Chen, S-T, Alnaes, GG, Borresen-Dale, A-L, Giles, GG, Milne, RL, McLean, C, Muir, K, Lophatananon, A, Stewart-Brown, S, Siriwanarangsan, P, Hartman, M, Miao, H, Buhari, SABS, Teo, YY, Fasching, PA, Haeberle, L, Ekici, AB, Beckmann, MW, Brenner, H, Dieffenbach, AK, Arndt, V, Stegmaier, C, Swerdlow, A, Ashworth, A, Orr, N, Schoemaker, MJ, Garcia-Closas, M, Figueroa, J, Chanock, SJ, Lissowska, J, Simard, J, Goldberg, MS, Labreche, F, Dumont, M, Winqvist, R, Pylkas, K, Jukkola-Vuorinen, A, Brauch, H, Bruening, T, Koto, Y-D, Radice, P, Peterlongo, P, Bonanni, B, Volorio, S, Doerk, T, Bogdanova, NV, Helbig, S, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, JM, Devilee, P, Tollenaar, RAEM, Seynaeve, C, Van Asperen, CJ, Jakubowska, A, Lubinski, J, Jaworska-Bieniek, K, Durda, K, Slager, S, Toland, AE, Ambrosone, CB, Yannoukakos, D, Sangrajrang, S, Gaborieau, V, Brennan, P, Mckay, J, Hamann, U, Torres, D, Zheng, W, Long, J, Anton-Culver, H, Neuhausen, SL, Luccarini, C, Baynes, C, Ahmed, S, Maranian, M, Healey, CS, Gonzalez-Neira, A, Pita, G, Alonso, MR, Alvarez, N, Herrero, D, Tessier, DC, Vincent, D, Bacot, F, de Santiago, I, Carroll, J, Caldas, C, Brown, MA, Lupien, M, Kristensen, VN, Pharoah, PDP, Chenevix-Trench, G, French, JD, Easton, DF, and Dunning, AM
- Abstract
GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs using the 'iCOGS' genotyping array and impute genotypes for a further 1,284 using 1000 Genomes Project data. All but two, strongly correlated SNPs (rs4442975 G/T and rs6721996 G/A) are excluded as candidate causal variants at odds against >100:1. The best functional candidate, rs4442975, is associated with oestrogen receptor positive (ER+) disease with an odds ratio (OR) in Europeans of 0.85 (95% confidence interval=0.84-0.87; P=1.7 × 10(-43)) per t-allele. This SNP flanks a transcriptional enhancer that physically interacts with the promoter of IGFBP5 (encoding insulin-like growth factor-binding protein 5) and displays allele-specific gene expression, FOXA1 binding and chromatin looping. Evidence suggests that the g-allele confers increased breast cancer susceptibility through relative downregulation of IGFBP5, a gene with known roles in breast cell biology.
- Published
- 2014
15. Severity of illness and risk of readmission to intensive care: A meta-analysis
- Author
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Frost, SA, Alexandrou, E, Bogdanovski, T, Salamonson, Y, Davidson, PM, Parr, MJ, and Hillman, KM
- Subjects
Intensive Care Units ,Critical Care ,health care facilities, manpower, and services ,Critical Illness ,Intensive Care ,Humans ,Emergency & Critical Care Medicine ,Patient Readmission ,Severity of Illness Index ,Risk Assessment ,APACHE - Abstract
Background: Almost one in every 10 patients who survive intensive care will be readmitted to the intensive care unit (ICU) during the same hospitalisation. The association between increasing severity of illness (widely calculated in ICU patients) with risk of readmission to ICU has not been systematically summarized. Objective: The meta-analysis was designed to combine information from published studies to assess the relationship between severity of illness in ICU patients and the risk of readmission to ICU during the same hospitalisation. Data sources: Studies were identified by searching MEDLINE (1966 to August 2008), EMBASE (1980-2008), and CINAHL (1982 to August 2008). Review methods: Studies included only adult populations, readmissions to ICU during the same hospitalisation and reports of valid severity of illness index. Results: Eleven studies (totaling 220 000 patients) were included in the meta-analysis. Severity of illness (APACHE II, APACHE III, SAPS and SAPS II) measured at the time of ICU admission or discharge, was higher in patients readmitted to the ICU during the same hospitalisation compared to patients not-readmitted (both p-values < 0.001). The risk of readmission to ICU increased by 43% with each standard deviation increase in severity of illness score (regardless if measured on admission to, or discharge from the ICU) (odds ratio (OR) = 1.43, 95% confidence interval (CI) = 1.3-1.6). Conclusions: A relationship between increasing intensive care severity of illness and risk of readmission to ICU was found. The effect was the same regardless of the time of measurement of severity of illness (at admission to ICU or the time of discharge from ICU). However, further research is required to develop more comprehensive tools to identify patients at risk of readmission to ICU to allow the targeted interventions, such as ICU-outreach to follow-up these patients to minimize adverse events. © 2009 Elsevier Ireland Ltd. All rights reserved.
- Published
- 2009
16. Nurse-led central venous catheter insertion-Procedural characteristics and outcomes of three intensive care based catheter placement services
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Alexandrou, E, Murgo, M, Calabria, E, Spencer, TR, Carpen, H, Brennan, K, Frost, SA, Davidson, PM, Hillman, KM, Alexandrou, E, Murgo, M, Calabria, E, Spencer, TR, Carpen, H, Brennan, K, Frost, SA, Davidson, PM, and Hillman, KM
- Abstract
Background: Nurse-led central venous catheter placement is an emerging clinical role internationally. Procedural characteristics and clinical outcomes is an important consideration in appraisal of such advanced nursing roles. Objectives: To review characteristics and outcomes of three nurse-led central venous catheter insertion services based in intensive care units in New South Wales, Australia. Design: Using data from the Central Line Associated Bacteraemia project in New South Wales intensive care units. Descriptive statistical techniques were used to ascertain comparison rates and proportions. Participants: De-identified outcome data of patients who had a central venous catheter inserted as part of their therapy by one of the four advanced practice nurses working in three separate hospitals in New South Wales. Results: Between March 2007 and June 2009, 760 vascular access devices were placed by the three nurse-led central venous catheter placement services. Hospital A inserted 520 catheters; Hospital C with 164; and Hospital B with 76. Over the study period, insertion outcomes were favourable with only 1 pneumothorax (1%), 1 arterial puncture (1%) and 1 CLAB (1%) being recorded across the three groups. The CLAB rate was lower in comparison to the aggregated CLAB data set [1.3 per 1000 catheters (95% CI. = 0.03-7.3) vs. 7.2 per 1000 catheters (95% CI = 5.9-8.7)]. Conclusion: This study has demonstrated safe patient outcomes with nurse led CVC insertion as compared with published data. Nurses who are formally trained and credentialed to insert CVCs can improve organisational efficiencies. This study adds to emerging data that developing clinical roles that focus on skills, procedural volume and competency can be a viable option in health care facilities. © 2011.
- Published
- 2012
17. Readmission to intensive care: development of a nomogram for individualising risk.
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Frost, SA, Tam, V, Alexandrou, E, Hunt, L, Salamonson, Y, Davidson, PM, Parr, MJA, Hillman, KM, Frost, SA, Tam, V, Alexandrou, E, Hunt, L, Salamonson, Y, Davidson, PM, Parr, MJA, and Hillman, KM
- Abstract
BACKGROUND: Readmission to intensive care during the same hospital stay has been associated with a greater risk of in-hospital mortality and has been suggested as a marker of quality of care. There is lack of published research attempting to develop clinical prediction tools that individualise the risk of readmission to the intensive care unit during the same hospital stay. OBJECTIVE: To develop a prediction model using an inception cohort of patients surviving an initial ICU stay. DESIGN, SETTING AND PARTICIPANTS: The study was conducted at Liverpool Hospital, Sydney. An inception cohort of 14 952 patients aged 15 years or more surviving an initial ICU stay and transferred to general wards in the study hospital between 1 January 1997 and 31 December 2007 was used to develop the model. Binary logistic regression was used to develop the prediction model and a nomogram was derived to individualise the risk of readmission to the ICU during the same hospital stay. MAIN OUTCOME MEASURE: Readmission to the ICU during the same hospital stay. RESULTS: Among members of the study cohort there were 987 readmissions to ICU during the study period. Compared with patients not readmitted to the ICU, patients who were readmitted were more likely to have had ICU stays of at least 7 days (odds ratio [OR], 2.2 [95% CI, 1.85- 2.56]); non-elective initial admission to the ICU (OR, 1.7 [95% CI, 1.44-2.08]); and acute renal failure (OR, 1.6 [95% CI, 0.97-2.47]). Patients admitted to the ICU from the operating theatre or recovery ward had a lower risk of readmission to ICU than those admitted from general wards, the emergency department or other hospitals. The maximum error between observed frequencies and predicted probabilities of readmission to ICU was estimated to be 3%. The area under the receiver operating characteristic curve of the final model was 0.66. CONCLUSION: We have developed a practical clinical tool to individualise the risk of readmission to the ICU during the same hospit
- Published
- 2010
18. Establishing a nurse-led central venous catheter insertion service
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Alexandrou, E, Spencer, T, Frost, SA, Parr, M, Davidson, PM, Hillman, KM, Alexandrou, E, Spencer, T, Frost, SA, Parr, M, Davidson, PM, and Hillman, KM
- Abstract
Background: Health care systems promote care models that deliver both safety and quality. Nurse-led vascular access teams show promise as a model to achieve hospital efficiencies and improve patient outcomes. Objectives: The aim of this paper is to discuss the process of establishing a nurse-led central venous catheter (CVC) insertion service in a university affiliated hospital using a process evaluation method. Method: Archival information, including reports, communications and minutes of departmental meetings were re-viewed. Key stakeholders involved in establishing this nurse-led service at the time were interviewed. Results: A nurse-led CVC insertion service was first established in 1996 and has increased in service provision over 13 years. Initially there was scepticism from some medical practitioners about the feasibility of a nurse performing a traditional medical procedure. The service currently provides central venous access across the hospital including critical care areas. The service places up to 500 catheters per annum. Conclusions: Establishing a nurse-led CVC insertion service has increased organizational efficiencies and provided an infrastructure for support of best practice. The support of senior management and medical practitioners was crucial to the successful implementation of this model of care.
- Published
- 2010
19. Central venous catheter insertion by a clinical nurse consultant or anaesthetic medical staff: a single-centre observational study.
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Yacopetti, N, Alexandrou, E, Spencer, TR, Frost, SA, Davidson, PM, O'Sullivan, G, Hillman, KM, Yacopetti, N, Alexandrou, E, Spencer, TR, Frost, SA, Davidson, PM, O'Sullivan, G, and Hillman, KM
- Abstract
OBJECTIVE: To compare clinical outcomes of elective central venous catheter (CVC) insertions performed by either a clinical nurse consultant (CNC) or anaesthetic medical staff (AMS). DESIGN, SETTING AND PARTICIPANTS: Prospective audit of a convenience sample of consecutive CVC insertions between July 2005 and October 2007 at a metropolitan teaching hospital in Sydney, Australia. The sample included all outpatients and inpatients requiring a CVC for either acute or chronic conditions. MAIN OUTCOME MEASURES: Number of CVC lines inserted; differences between outcomes in the CNC and AMS groups; complications during and after insertion. RESULTS: Over a 28-month period, 245 CVCs were inserted by AMS and 123 by the CNC. The most common indications for CVC placement in both groups were for the treatment of oncology and autoimmune disorders (61%) and for antibiotic therapy (27%). Other indications were parenteral nutrition (2%) and other therapies (10%). There was no significant difference in complications on insertion between the CNC and AMS groups. AMS failed to obtain access in 12 attempted procedures compared with eight by the CNC. The rate of CVCs investigated for infection was twice as high in the AMS group as in the CNC group (19% v 8%). The confirmed catheter-related bloodstream infection (CRBSI) rate was 2.5/1000 catheters in the AMS group and 0.4/1000 catheters in the CNC group (P = 0.04). CONCLUSION: Insertion outcomes were favourable in both the AMS and CNC groups. Infection outcomes differed between groups, with a higher rate of CRBSI in the AMS group.
- Published
- 2010
20. Baseline hospital perforamnce and the impact of medical emergency teams: Modeling vs conventional subgroup analysis
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Chen, J, Flabouris, A, Bellomo, R, Hillman, KM, Finfer, SR, Chen, J, Flabouris, A, Bellomo, R, Hillman, KM, and Finfer, SR
- Published
- 2009
21. The role of the medical emergency team in end-of-life care: a multicenter, prospective, observational study.
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Jones DA, Bagshaw SM, Barrett J, Bellomo R, Bhatia G, Bucknall TK, Casamento AJ, Duke GJ, Gibney N, Hart GK, Hillman KM, Jäderling G, Parmar A, and Parr MJ
- Published
- 2012
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22. Run, don't walk*.
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Hillman KM
- Published
- 2012
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23. Rapid response systems: you won't know there is a problem until you measure it.
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Hillman KM and Hillman, Ken M
- Abstract
The rapid response system concept is one of the first patient-centered and organizational-wide systems aimed at preventing deaths and serious adverse events. It has been strongly argued that we need a benchmark that reflects the care of a deteriorating patient across the organization using a 'score to door time'; that is, the time from the first vital sign abnormality to admission to the ICU. The study by Oglesby and colleagues highlights serious issues, especially delays, which could adversely impact on patient care, and the study proposes that we concentrate more on measuring patient care from a broad perspective. [ABSTRACT FROM AUTHOR]
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- 2011
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24. CRISPR-Cas13d screens identify KILR, a breast cancer risk-associated lncRNA that regulates DNA replication and repair.
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Wang L, Bitar M, Lu X, Jacquelin S, Nair S, Sivakumaran H, Hillman KM, Kaufmann S, Ziegman R, Casciello F, Gowda H, Rosenbluh J, Edwards SL, and French JD
- Subjects
- Humans, Female, Cell Line, Tumor, Gene Expression Regulation, Neoplastic, Genetic Predisposition to Disease, Genome-Wide Association Study, RNA, Long Noncoding genetics, Breast Neoplasms genetics, Breast Neoplasms pathology, Breast Neoplasms metabolism, DNA Replication, CRISPR-Cas Systems, DNA Repair, Cell Proliferation
- Abstract
Background: Long noncoding RNAs (lncRNAs) have surpassed the number of protein-coding genes, yet the majority have no known function. We previously discovered 844 lncRNAs that were genetically linked to breast cancer through genome-wide association studies (GWAS). Here, we show that a subset of these lncRNAs alter breast cancer risk by modulating cell proliferation, and provide evidence that a reduced expression on one lncRNA increases breast cancer risk through aberrant DNA replication and repair., Methods: We performed pooled CRISPR-Cas13d-based knockdown screens in breast cells to identify which of the 844 breast cancer-associated lncRNAs alter cell proliferation. We selected one of the lncRNAs that increased cell proliferation, KILR, for follow-up functional studies. KILR pull-down followed by mass spectrometry was used to identify binding proteins. Knockdown and overexpression studies were performed to assess the mechanism by which KILR regulates proliferation., Results: We show that KILR functions as a tumor suppressor, safeguarding breast cells against uncontrolled proliferation. The half-life of KILR is significantly reduced by the risk haplotype, revealing an alternative mechanism by which variants alter cancer risk. Mechanistically, KILR sequesters RPA1, a subunit of the RPA complex required for DNA replication and repair. Reduced KILR expression promotes breast cancer cell proliferation by increasing the available pool of RPA1 and speed of DNA replication. Conversely, KILR overexpression promotes apoptosis in breast cancer cells, but not normal breast cells., Conclusions: Our results confirm lncRNAs as mediators of breast cancer risk, emphasize the need to annotate noncoding transcripts in relevant cell types when investigating GWAS variants and provide a scalable platform for mapping phenotypes associated with lncRNAs., (© 2024. The Author(s).)
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- 2024
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25. Frailty, delirium and hospital mortality of older adults admitted to intensive care: the Delirium (Deli) in ICU study.
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Sanchez D, Brennan K, Al Sayfe M, Shunker SA, Bogdanoski T, Hedges S, Hou YC, Lynch J, Hunt L, Alexandrou E, Saxena M, Abel S, Lakshmanan R, Bhonagiri D, Parr MJ, Aneman A, Chroinin DN, Hillman KM, and Frost SA
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- Aged, Aged, 80 and over, Delirium complications, Female, Frailty complications, Hospitalization statistics & numerical data, Humans, Intensive Care Units organization & administration, Male, Middle Aged, Delirium mortality, Frailty mortality, Hospital Mortality trends, Intensive Care Units statistics & numerical data
- Abstract
Background: Clinical frailty among older adults admitted to intensive care has been proposed as an important determinant of patient outcomes. Among this group of patients, an acute episode of delirium is also common, but its relationship to frailty and increased risk of mortality has not been extensively explored. Therefore, the aim of this study was to explore the relationship between clinical frailty, delirium and hospital mortality of older adults admitted to intensive care., Methods: This study is part of a Delirium in Intensive Care (Deli) Study. During the initial 6-month baseline period, clinical frailty status on admission to intensive care, among adults aged 50 years or more; acute episodes of delirium; and the outcomes of intensive care and hospital stay were explored., Results: During the 6-month baseline period, 997 patients, aged 50 years or more, were included in this study. The average age was 71 years (IQR, 63-79); 55% were male (n = 537). Among these patients, 39.2% (95% CI 36.1-42.3%, n = 396) had a Clinical Frailty Score (CFS) of 5 or more, and 13.0% (n = 127) had at least one acute episode of delirium. Frail patients were at greater risk of an episode of delirium (17% versus 10%, adjusted rate ratio (
adj RR) = 1.71, 95% confidence interval (CI) 1.20-2.43, p = 0.003), had a longer hospital stay (2.6 days, 95% CI 1-7 days, p = 0.009) and had a higher risk of hospital mortality (19% versus 7%,adj RR = 2.54, 95% CI 1.72-3.75, p < 0.001), when compared to non-frail patients. Patients who were frail and experienced an acute episode of delirium in the intensive care had a 35% rate of hospital mortality versus 10% among non-frail patients who also experienced delirium in the ICU., Conclusion: Frailty and delirium significantly increase the risk of hospital mortality. Therefore, it is important to identify patients who are frail and institute measures to reduce the risk of adverse events in the ICU such as delirium and, importantly, to discuss these issues in an open and empathetic way with the patient and their families.- Published
- 2020
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26. eQTL Colocalization Analyses Identify NTN4 as a Candidate Breast Cancer Risk Gene.
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Beesley J, Sivakumaran H, Moradi Marjaneh M, Shi W, Hillman KM, Kaufmann S, Hussein N, Kar S, Lima LG, Ham S, Möller A, Chenevix-Trench G, Edwards SL, and French JD
- Subjects
- Alleles, Animals, Breast Neoplasms diagnosis, Breast Neoplasms pathology, Cell Line, Tumor, Enhancer Elements, Genetic, Female, Gene Expression Profiling, Genome-Wide Association Study, Genomics methods, Heterografts, Humans, MCF-7 Cells, Mice, Mice, Nude, Neoplasm Proteins metabolism, Netrins metabolism, Phenotype, Quantitative Trait Loci, Risk, Breast Neoplasms genetics, Gene Expression Regulation, Neoplastic, Genetic Predisposition to Disease, Neoplasm Proteins genetics, Netrins genetics
- Abstract
Breast cancer genome-wide association studies (GWASs) have identified 150 genomic risk regions containing more than 13,000 credible causal variants (CCVs). The CCVs are predominantly noncoding and enriched in regulatory elements. However, the genes underlying breast cancer risk associations are largely unknown. Here, we used genetic colocalization analysis to identify loci at which gene expression could potentially explain breast cancer risk phenotypes. Using data from the Breast Cancer Association Consortium (BCAC) and quantitative trait loci (QTL) from the Genotype-Tissue Expression (GTEx) project and The Cancer Genome Project (TCGA), we identify shared genetic relationships and reveal novel associations between cancer phenotypes and effector genes. Seventeen genes, including NTN4, were identified as potential mediators of breast cancer risk. For NTN4, we showed the rs61938093 CCV at this region was located within an enhancer element that physically interacts with the NTN4 promoter, and the risk allele reduced NTN4 promoter activity. Furthermore, knockdown of NTN4 in breast cells increased cell proliferation in vitro and tumor growth in vivo. These data provide evidence linking risk-associated variation to genes that may contribute to breast cancer predisposition., (Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
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27. Implementing value-based health care at scale: the NSW experience.
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Yap SJ, Forero R, Greenfield D, and Hillman KM
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- Delivery of Health Care
- Published
- 2020
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28. Struvite formation associated with the microalgae biofilm matrix of a rotating algal biofilm reactor (RABR) during nutrient removal from municipal wastewater.
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Hillman KM and Sims RC
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- Biofilms, Extracellular Polymeric Substance Matrix, Nutrients, Phosphates, Phosphorus, Struvite, Waste Disposal, Fluid, Microalgae, Wastewater
- Abstract
Struvite was observed within the microalgae biofilm matrix of an outdoor, pilot-scale rotating algal biofilm reactor (RABR) designed to remove nitrogen and phosphorus from municipal anaerobic digester filtrate. The bottom layer of cells (2.5-month growth) and two top layers of cells (1-week and 2.5-month growth) were evaluated on east- and west-facing sides of the RABR. Sun orientation and shading effects of upper biofilm layers impacted the species composition and microalgae content of the bottom biofilm layers. Struvite formed within the microalgae biofilm matrix, and a higher struvite content appeared to be correlated with a higher microalgae content. The highest struvite content (expressed as %wt. of total solids) was observed in the east- and west-facing bottom layers of growth and west-facing 1-week growth (5.0%, 4.3%, and 4.1%, respectively). The lowest struvite content was observed in east- and west-facing 2.5-month growth and east-facing 1-week growth (1.1%, 1.5%, and 1.1%, respectively). Despite RABR influent component ion molar ratios with potential for various magnesium and calcium precipitates, microalgae biofilm provided pH and nucleation sites favorable to struvite precipitation. This evaluation is the first in the refereed literature the authors are aware of that reports on the association of struvite formation in the presence of a microalgae biofilm.
- Published
- 2020
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29. Chromatin interactome mapping at 139 independent breast cancer risk signals.
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Beesley J, Sivakumaran H, Moradi Marjaneh M, Lima LG, Hillman KM, Kaufmann S, Tuano N, Hussein N, Ham S, Mukhopadhyay P, Kazakoff S, Lee JS, Michailidou K, Barnes DR, Antoniou AC, Fachal L, Dunning AM, Easton DF, Waddell N, Rosenbluh J, Möller A, Chenevix-Trench G, French JD, and Edwards SL
- Subjects
- Breast Neoplasms metabolism, Cell Line, Tumor, Genome, Human, Genome-Wide Association Study, Humans, Breast Neoplasms genetics, Chromatin metabolism
- Abstract
Background: Genome-wide association studies have identified 196 high confidence independent signals associated with breast cancer susceptibility. Variants within these signals frequently fall in distal regulatory DNA elements that control gene expression., Results: We designed a Capture Hi-C array to enrich for chromatin interactions between the credible causal variants and target genes in six human mammary epithelial and breast cancer cell lines. We show that interacting regions are enriched for open chromatin, histone marks for active enhancers, and transcription factors relevant to breast biology. We exploit this comprehensive resource to identify candidate target genes at 139 independent breast cancer risk signals and explore the functional mechanism underlying altered risk at the 12q24 risk region., Conclusions: Our results demonstrate the power of combining genetics, computational genomics, and molecular studies to rationalize the identification of key variants and candidate target genes at breast cancer GWAS signals.
- Published
- 2020
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30. Non-coding RNAs underlie genetic predisposition to breast cancer.
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Moradi Marjaneh M, Beesley J, O'Mara TA, Mukhopadhyay P, Koufariotis LT, Kazakoff S, Hussein N, Fachal L, Bartonicek N, Hillman KM, Kaufmann S, Sivakumaran H, Smart CE, McCart Reed AE, Ferguson K, Saunus JM, Lakhani SR, Barnes DR, Antoniou AC, Dinger ME, Waddell N, Easton DF, Dunning AM, Chenevix-Trench G, Edwards SL, and French JD
- Subjects
- Genome-Wide Association Study, Humans, Sequence Analysis, RNA, Breast Neoplasms genetics, RNA, Untranslated genetics
- Abstract
Background: Genetic variants identified through genome-wide association studies (GWAS) are predominantly non-coding and typically attributed to altered regulatory elements such as enhancers and promoters. However, the contribution of non-coding RNAs to complex traits is not clear., Results: Using targeted RNA sequencing, we systematically annotated multi-exonic non-coding RNA (mencRNA) genes transcribed from 1.5-Mb intervals surrounding 139 breast cancer GWAS signals and assessed their contribution to breast cancer risk. We identify more than 4000 mencRNA genes and show their expression distinguishes normal breast tissue from tumors and different breast cancer subtypes. Importantly, breast cancer risk variants, identified through genetic fine-mapping, are significantly enriched in mencRNA exons, but not the promoters or introns. eQTL analyses identify mencRNAs whose expression is associated with risk variants. Furthermore, chromatin interaction data identify hundreds of mencRNA promoters that loop to regions that contain breast cancer risk variants., Conclusions: We have compiled the largest catalog of breast cancer-associated mencRNAs to date and provide evidence that modulation of mencRNAs by GWAS variants may provide an alternative mechanism underlying complex traits.
- Published
- 2020
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31. The concept of frailty in intensive care.
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Athari F, Hillman KM, and Frost SA
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- Aged, Aged, 80 and over, Humans, Frailty diagnosis, Geriatric Assessment, Intensive Care Units
- Abstract
Our population is ageing, and this is also reflected in the ageing of the hospital and intensive care population. Along with ageing, there is also an increase in age-related chronic health conditions or comorbidities, which in turn affects the patient's functional state. There is an increasing need to describe a patient's clinical condition in terms of their functional capacity, such as frailty. Frailty is an age-related syndrome which reduces physiological and cognitive reserves. As a result, frailty increases people's vulnerability to insults such as infection and trauma. The concept of frailty also indicates prognosis and levels of health from a patient's perspective rather than simply from the acute reason for admission to the intensive care unit. Understanding the concept of frailty may facilitate our awareness of long-term outcomes after intensive care and being a trigger for considering its prognostic implications and the need to honestly and empathetically begin discussions with patients and their carers and how the patient's own goals of care could be established around this information., (Copyright © 2017 Australian College of Critical Care Nurses Ltd. Published by Elsevier Ltd. All rights reserved.)
- Published
- 2019
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32. Predicting outcome in the seriously ill-A new approach.
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Hillman KM
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- APACHE, Frailty, Health Status, Humans, Intensive Care Units, Critical Illness mortality
- Published
- 2018
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33. Publisher Correction: Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation.
- Author
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Ghoussaini M, Edwards SL, Michailidou K, Nord S, Cowper-Sal Lari R, Desai K, Kar S, Hillman KM, Kaufmann S, Glubb DM, Beesley J, Dennis J, Bolla MK, Wang Q, Dicks E, Guo Q, Schmidt MK, Shah M, Luben R, Brown J, Czene K, Darabi H, Eriksson M, Klevebring D, Bojesen SE, Nordestgaard BG, Nielsen SF, Flyger H, Lambrechts D, Thienpont B, Neven P, Wildiers H, Broeks A, Van't Veer LJ, Rutgers EJT, Couch FJ, Olson JE, Hallberg E, Vachon C, Chang-Claude J, Rudolph A, Seibold P, Flesch-Janys D, Peto J, Dos-Santos-Silva I, Gibson L, Nevanlinna H, Muranen TA, Aittomäki K, Blomqvist C, Hall P, Li J, Liu J, Humphreys K, Kang D, Choi JY, Park SK, Noh DY, Matsuo K, Ito H, Iwata H, Yatabe Y, Guénel P, Truong T, Menegaux F, Sanchez M, Burwinkel B, Marme F, Schneeweiss A, Sohn C, Wu AH, Tseng CC, Van Den Berg D, Stram DO, Benitez J, Pilar Zamora M, Perez JIA, Menéndez P, Shu XO, Lu W, Gao YT, Cai Q, Cox A, Cross SS, Reed MWR, Andrulis IL, Knight JA, Glendon G, Tchatchou S, Sawyer EJ, Tomlinson I, Kerin MJ, Miller N, Haiman CA, Henderson BE, Schumacher F, Le Marchand L, Lindblom A, Margolin S, Teo SH, Yip CH, Lee DSC, Wong TY, Hooning MJ, Martens JWM, Collée JM, van Deurzen CHM, Hopper JL, Southey MC, Tsimiklis H, Kapuscinski MK, Shen CY, Wu PE, Yu JC, Chen ST, Alnæs GG, Borresen-Dale AL, Giles GG, Milne RL, McLean C, Muir K, Lophatananon A, Stewart-Brown S, Siriwanarangsan P, Hartman M, Miao H, Buhari SABS, Teo YY, Fasching PA, Haeberle L, Ekici AB, Beckmann MW, Brenner H, Dieffenbach AK, Arndt V, Stegmaier C, Swerdlow A, Ashworth A, Orr N, Schoemaker MJ, García-Closas M, Figueroa J, Chanock SJ, Lissowska J, Simard J, Goldberg MS, Labrèche F, Dumont M, Winqvist R, Pylkäs K, Jukkola-Vuorinen A, Brauch H, Brüning T, Koto YD, Radice P, Peterlongo P, Bonanni B, Volorio S, Dörk T, Bogdanova NV, Helbig S, Mannermaa A, Kataja V, Kosma VM, Hartikainen JM, Devilee P, Tollenaar RAEM, Seynaeve C, Van Asperen CJ, Jakubowska A, Lubinski J, Jaworska-Bieniek K, Durda K, Slager S, Toland AE, Ambrosone CB, Yannoukakos D, Sangrajrang S, Gaborieau V, Brennan P, McKay J, Hamann U, Torres D, Zheng W, Long J, Anton-Culver H, Neuhausen SL, Luccarini C, Baynes C, Ahmed S, Maranian M, Healey CS, González-Neira A, Pita G, Rosario Alonso M, Álvarez N, Herrero D, Tessier DC, Vincent D, Bacot F, de Santiago I, Carroll J, Caldas C, Brown MA, Lupien M, Kristensen VN, Pharoah PDP, Chenevix-Trench G, French JD, Easton DF, and Dunning AM
- Abstract
This corrects the article DOI: 10.1038/ncomms5999.
- Published
- 2018
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34. Intensive care medicine in 2050: expanding care beyond the intensive care unit.
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Hillman KM and Takala J
- Subjects
- Intensive Care Units trends, Critical Care trends
- Published
- 2018
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35. Expanding the Scope of the Rapid Response System.
- Author
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DeVita M and Hillman KM
- Subjects
- Benchmarking, Humans, Hospital Rapid Response Team organization & administration, Quality Improvement organization & administration
- Published
- 2017
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36. STANDING Collaboration : a study protocol for developing clinical standards.
- Author
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Wiles LK, Hibbert PD, Stephens JH, Coiera E, Westbrook J, Braithwaite J, Day RO, Hillman KM, and Runciman WB
- Subjects
- Delphi Technique, Health Personnel, Humans, Program Evaluation, Qualitative Research, Quality Improvement, Consensus, Delivery of Health Care standards, Practice Guidelines as Topic standards, Research Design standards
- Abstract
Introduction: Despite widespread availability of clinical practice guidelines (CPGs), considerable gaps continue between the care that is recommended ('appropriate care') and the care provided. Problems with current CPGs are commonly cited as barriers to providing 'appropriate care'.Our study aims to develop and test an alternative method to keep CPGs accessible and up to date. This method aims to mitigate existing problems by using a single process to develop clinical standards (embodied in clinical indicators) collaboratively with researchers, healthcare professionals, patients and consumers. A transparent and inclusive online curated (purpose-designed, custom-built, wiki-type) system will use an ongoing and iterative documentation process to facilitate synthesis of up-to-date information and make available its provenance. All participants are required to declare conflicts of interest. This protocol describes three phases: engagement of relevant stakeholders; design of a process to develop clinical standards (embodied in indicators) for 'appropriate care' for common medical conditions; and evaluation of our processes, products and feasibility., Methods and Analysis: A modified e-Delphi process will be used to gain consensus on 'appropriate care' for a range of common medical conditions. Clinical standards and indicators will be developed through searches of national and international guidelines, and formulated with explicit criteria for inclusion, exclusion, time frame and setting. Healthcare professionals and consumers will review the indicators via the wiki-based modified e-Delphi process. Reviewers will declare conflicts of interest which will be recorded and managed according to an established protocol. The provenance of all indicators and suggestions included or excluded will be logged from indicator inception to finalisation. A mixed-methods formative evaluation of our research methodology will be undertaken., Ethics and Dissemination: Human Research Ethics Committee approval has been received from the University of South Australia. We will submit the results of the study to relevant journals and offer national and international presentations., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)
- Published
- 2017
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37. Long Noncoding RNAs CUPID1 and CUPID2 Mediate Breast Cancer Risk at 11q13 by Modulating the Response to DNA Damage.
- Author
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Betts JA, Moradi Marjaneh M, Al-Ejeh F, Lim YC, Shi W, Sivakumaran H, Tropée R, Patch AM, Clark MB, Bartonicek N, Wiegmans AP, Hillman KM, Kaufmann S, Bain AL, Gloss BS, Crawford J, Kazakoff S, Wani S, Wen SW, Day B, Möller A, Cloonan N, Pearson J, Brown MA, Mercer TR, Waddell N, Khanna KK, Dray E, Dinger ME, Edwards SL, and French JD
- Subjects
- Cell Line, Tumor, Chromatin metabolism, DNA Breaks, Double-Stranded, DNA Damage genetics, Enhancer Elements, Genetic genetics, Estrogens metabolism, Female, Gene Expression Regulation, Neoplastic, Genetic Predisposition to Disease genetics, Humans, MCF-7 Cells, Polymorphism, Single Nucleotide genetics, Promoter Regions, Genetic genetics, RNA Interference, RNA, Small Interfering genetics, RNA, Guide, CRISPR-Cas Systems, Breast Neoplasms genetics, Chromosomes, Human, Pair 11 genetics, Cyclin D1 genetics, DNA Repair genetics, RNA, Long Noncoding genetics
- Abstract
Breast cancer risk is strongly associated with an intergenic region on 11q13. We have previously shown that the strongest risk-associated SNPs fall within a distal enhancer that regulates CCND1. Here, we report that, in addition to regulating CCND1, this enhancer regulates two estrogen-regulated long noncoding RNAs, CUPID1 and CUPID2. We provide evidence that the risk-associated SNPs are associated with reduced chromatin looping between the enhancer and the CUPID1 and CUPID2 bidirectional promoter. We further show that CUPID1 and CUPID2 are predominantly expressed in hormone-receptor-positive breast tumors and play a role in modulating pathway choice for the repair of double-strand breaks. These data reveal a mechanism for the involvement of this region in breast cancer., (Copyright © 2017 American Society of Human Genetics. All rights reserved.)
- Published
- 2017
- Full Text
- View/download PDF
38. Chlorhexidine bathing and health care-associated infections among adult intensive care patients: a systematic review and meta-analysis.
- Author
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Frost SA, Alogso MC, Metcalfe L, Lynch JM, Hunt L, Sanghavi R, Alexandrou E, and Hillman KM
- Subjects
- Critical Illness epidemiology, Cross Infection diagnosis, Cross Infection epidemiology, Humans, Intensive Care Units trends, Methicillin-Resistant Staphylococcus aureus drug effects, Baths methods, Chlorhexidine administration & dosage, Critical Care methods, Critical Illness therapy, Cross Infection prevention & control, Disinfectants administration & dosage
- Abstract
Background: Health care-associated infections (HAI) have been shown to increase length of stay, the cost of care, and rates of hospital deaths (Kaye and Marchaim, J Am Geriatr Soc 62(2):306-11, 2014; Roberts and Scott, Med Care 48(11):1026-35, 2010; Warren and Quadir, Crit Care Med 34(8):2084-9, 2006; Zimlichman and Henderson, JAMA Intern Med 173(22):2039-46, 2013). Importantly, infections acquired during a hospital stay have been shown to be preventable (Loveday and Wilson, J Hosp Infect 86:S1-70, 2014). In particular, due to more invasive procedures, mechanical ventilation, and critical illness, patients cared for in the intensive care unit (ICU) are at greater risk of HAI and associated poor outcomes. This meta-analysis aims to summarise the effectiveness of chlorhexidine (CHG) bathing, in adult intensive care patients, to reduce infection., Methods: A systematic literature search was undertaken to identify trials assessing the effectiveness of CHG bathing to reduce risk of infection, among adult intensive care patients. Infections included were: bloodstream infections; central line-associated bloodstream infections (CLABSI); catheter-associated urinary tract infections; ventilator-associated pneumonia; methicillin-resistant Staphylococcus aureus (MRSA); vancomycin-resistant Enterococcus; and Clostridium difficile. Summary estimates were calculated as incidence rate ratios (IRRs) and 95% confidence/credible intervals. Variation in study designs was addressed using hierarchical Bayesian random-effects models., Results: Seventeen trials were included in our final analysis: seven of the studies were cluster-randomised crossover trials, and the remaining studies were before-and-after trials. CHG bathing was estimated to reduce the risk of CLABSI by 56% (Bayesian random effects IRR = 0.44 (95% credible interval (CrI), 0.26, 0.75)), and MRSA colonisation and bacteraemia in the ICU by 41% and 36%, respectively (IRR = 0.59 (95% CrI, 0.36, 0.94); and IRR = 0.64 (95% CrI, 0.43, 0.91)). The numbers needed to treat for these specific ICU infections ranged from 360 (CLABSI) to 2780 (MRSA bacteraemia)., Conclusion: This meta-analysis of the effectiveness of CHG bathing to reduce infections among adults in the ICU has found evidence for the benefit of daily bathing with CHG to reduce CLABSI and MRSA infections. However, the effectiveness may be dependent on the underlying baseline risk of these events among the given ICU population. Therefore, CHG bathing appears to be of the most clinical benefit when infection rates are high for a given ICU population.
- Published
- 2016
- Full Text
- View/download PDF
39. Endometriosis risk alleles at 1p36.12 act through inverse regulation of CDC42 and LINC00339.
- Author
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Powell JE, Fung JN, Shakhbazov K, Sapkota Y, Cloonan N, Hemani G, Hillman KM, Kaufmann S, Luong HT, Bowdler L, Painter JN, Holdsworth-Carson SJ, Visscher PM, Dinger ME, Healey M, Nyholt DR, French JD, Edwards SL, Rogers PA, and Montgomery GW
- Subjects
- Case-Control Studies, Chromosomes, Human, Pair 1, Endometriosis blood, Female, Gene Expression, Gene Expression Regulation, Gene Frequency, Genetic Predisposition to Disease genetics, Genome-Wide Association Study, Genotype, Humans, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Quantitative Trait Loci, RNA, Long Noncoding metabolism, Risk Factors, White People genetics, Wnt4 Protein genetics, Wnt4 Protein metabolism, cdc42 GTP-Binding Protein metabolism, Endometriosis genetics, RNA, Long Noncoding genetics, cdc42 GTP-Binding Protein genetics
- Abstract
Genome-wide association studies (GWAS) have identified markers within the WNT4 region on chromosome 1p36.12 showing consistent and strong association with increasing endometriosis risk. Fine mapping using sequence and imputed genotype data has revealed strong candidates for the causal SNPs within these critical regions; however, the molecular pathogenesis of these SNPs is currently unknown. We used gene expression data collected from whole blood from 862 individuals and endometrial tissue from 136 individuals from independent populations of European descent to examine the mechanism underlying endometriosis susceptibility. Association mapping results from 7,090 individuals (2,594 cases and 4,496 controls) supported rs3820282 as the SNP with the strongest association for endometriosis risk (P = 1.84 × 10−5, OR = 1.244 (1.126-1.375)). SNP rs3820282 is a significant eQTL in whole blood decreasing expression of LINC00339 (also known as HSPC157) and increasing expression of CDC42 (P = 2.0 ×10−54 and 4.5x10−4 respectively). The largest effects were for two LINC00339 probes (P = 2.0 ×10−54; 1.0 × 10−34). The eQTL for LINC00339 was also observed in endometrial tissue (P = 2.4 ×10−8) with the same direction of effect for both whole blood and endometrial tissue. There was no evidence for eQTL effects for WNT4. Chromatin conformation capture provides evidence for risk SNPs interacting with the promoters of both LINC00339 and CDC4 and luciferase reporter assays suggest the risk SNP rs12038474 is located in a transcriptional silencer for CDC42 and the risk allele increases expression of CDC42. However, no effect of rs3820282 was observed in the LINC00339 expression in Ishikawa cells. Taken together, our results suggest that SNPs increasing endometriosis risk in this region act through CDC42, but further functional studies are required to rule out inverse regulation of both LINC00339 and CDC42.
- Published
- 2016
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- View/download PDF
40. Evidence that the 5p12 Variant rs10941679 Confers Susceptibility to Estrogen-Receptor-Positive Breast Cancer through FGF10 and MRPS30 Regulation.
- Author
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Ghoussaini M, French JD, Michailidou K, Nord S, Beesley J, Canisus S, Hillman KM, Kaufmann S, Sivakumaran H, Moradi Marjaneh M, Lee JS, Dennis J, Bolla MK, Wang Q, Dicks E, Milne RL, Hopper JL, Southey MC, Schmidt MK, Broeks A, Muir K, Lophatananon A, Fasching PA, Beckmann MW, Fletcher O, Johnson N, Sawyer EJ, Tomlinson I, Burwinkel B, Marme F, Guénel P, Truong T, Bojesen SE, Flyger H, Benitez J, González-Neira A, Alonso MR, Pita G, Neuhausen SL, Anton-Culver H, Brenner H, Arndt V, Meindl A, Schmutzler RK, Brauch H, Hamann U, Tessier DC, Vincent D, Nevanlinna H, Khan S, Matsuo K, Ito H, Dörk T, Bogdanova NV, Lindblom A, Margolin S, Mannermaa A, Kosma VM, Wu AH, Van Den Berg D, Lambrechts D, Floris G, Chang-Claude J, Rudolph A, Radice P, Barile M, Couch FJ, Hallberg E, Giles GG, Haiman CA, Le Marchand L, Goldberg MS, Teo SH, Yip CH, Borresen-Dale AL, Zheng W, Cai Q, Winqvist R, Pylkäs K, Andrulis IL, Devilee P, Tollenaar RA, García-Closas M, Figueroa J, Hall P, Czene K, Brand JS, Darabi H, Eriksson M, Hooning MJ, Koppert LB, Li J, Shu XO, Zheng Y, Cox A, Cross SS, Shah M, Rhenius V, Choi JY, Kang D, Hartman M, Chia KS, Kabisch M, Torres D, Luccarini C, Conroy DM, Jakubowska A, Lubinski J, Sangrajrang S, Brennan P, Olswold C, Slager S, Shen CY, Hou MF, Swerdlow A, Schoemaker MJ, Simard J, Pharoah PD, Kristensen V, Chenevix-Trench G, Easton DF, Dunning AM, and Edwards SL
- Subjects
- Alleles, Case-Control Studies, Cell Line, Tumor, Enhancer Elements, Genetic genetics, Fibroblast Growth Factor 10 metabolism, Haplotypes genetics, Humans, Promoter Regions, Genetic genetics, Quantitative Trait Loci genetics, Receptor, Fibroblast Growth Factor, Type 2 metabolism, Breast Neoplasms genetics, Breast Neoplasms metabolism, Chromosomes, Human, Pair 5 genetics, Fibroblast Growth Factor 10 genetics, Genetic Predisposition to Disease genetics, Polymorphism, Single Nucleotide genetics, Receptors, Estrogen metabolism
- Abstract
Genome-wide association studies (GWASs) have revealed increased breast cancer risk associated with multiple genetic variants at 5p12. Here, we report the fine mapping of this locus using data from 104,660 subjects from 50 case-control studies in the Breast Cancer Association Consortium (BCAC). With data for 3,365 genotyped and imputed SNPs across a 1 Mb region (positions 44,394,495-45,364,167; NCBI build 37), we found evidence for at least three independent signals: the strongest signal, consisting of a single SNP rs10941679, was associated with risk of estrogen-receptor-positive (ER
+ ) breast cancer (per-g allele OR ER+ = 1.15; 95% CI 1.13-1.18; p = 8.35 × 10-30 ). After adjustment for rs10941679, we detected signal 2, consisting of 38 SNPs more strongly associated with ER-negative (ER- ) breast cancer (lead SNP rs6864776: per-a allele OR ER- = 1.10; 95% CI 1.05-1.14; p conditional = 1.44 × 10-12 ), and a single signal 3 SNP (rs200229088: per-t allele OR ER+ = 1.12; 95% CI 1.09-1.15; p conditional = 1.12 × 10-05 ). Expression quantitative trait locus analysis in normal breast tissues and breast tumors showed that the g (risk) allele of rs10941679 was associated with increased expression of FGF10 and MRPS30. Functional assays demonstrated that SNP rs10941679 maps to an enhancer element that physically interacts with the FGF10 and MRPS30 promoter regions in breast cancer cell lines. FGF10 is an oncogene that binds to FGFR2 and is overexpressed in ∼10% of human breast cancers, whereas MRPS30 plays a key role in apoptosis. These data suggest that the strongest signal of association at 5p12 is mediated through coordinated activation of FGF10 and MRPS30, two candidate genes for breast cancer pathogenesis., (Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2016
- Full Text
- View/download PDF
41. Porphyromonas loveana sp. nov., isolated from the oral cavity of Australian marsupials.
- Author
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Bird PS, Trott DJ, Mikkelsen D, Milinovich GJ, Hillman KM, Burrell PC, and Blackall LL
- Subjects
- Animals, Australia, Bacterial Typing Techniques, Base Composition, DNA, Bacterial genetics, DNA, Ribosomal Spacer genetics, Glutamate Dehydrogenase genetics, Pigmentation, Porphyromonas genetics, Porphyromonas isolation & purification, RNA, Ribosomal, 16S genetics, Sequence Analysis, DNA, Marsupialia microbiology, Mouth microbiology, Phylogeny, Porphyromonas classification
- Abstract
An obligatory anaerobic, Gram-stain-negative coccobacillus with black-pigmented colonies was isolated from the oral cavity of selected Australian marsupial species. Phenotypic and molecular criteria showed that this bacterium was a distinct species within the genus Porphyromonas, and was closely related to Porphyromonas gingivalis and Porphyromonas gulae. This putative novel species and P. gulae could be differentiated from P. gingivalis by catalase activity. Further characterization by multi-locus enzyme electrophoresis of glutamate dehydrogenase and malate dehydrogenase enzyme mobility and matrix-assisted laser desorption ionization time-of-flight MS showed that this putative novel species could be differentiated phenotypically from P. gingivalis and P. gulae. Definitive identification by 16S rRNA gene sequencing showed that this bacterium belonged to a unique monophyletic lineage, phylogenetically distinct from P. gingivalis (94.9 % similarity) and P. gulae (95.5 %). This also was supported by 16S-23S rRNA intergenic spacer region and glutamate dehydrogenase gene sequencing. A new species epithet, Porphyromonas loveana sp. nov., is proposed for this bacterium, with DSM 28520T (=NCTC 13658T=UQD444T=MRK101T), isolated from a musky rat kangaroo, as the type strain.
- Published
- 2016
- Full Text
- View/download PDF
42. Implementing a palliative approach in the intensive care unit: an oxymoron or a realistic possibility?
- Author
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Athari F, Davidson PM, Hillman KM, and Phillips J
- Subjects
- Humans, Intensive Care Units, Hospice and Palliative Care Nursing, Inpatients psychology, Palliative Care
- Published
- 2016
- Full Text
- View/download PDF
43. Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170.
- Author
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Dunning AM, Michailidou K, Kuchenbaecker KB, Thompson D, French JD, Beesley J, Healey CS, Kar S, Pooley KA, Lopez-Knowles E, Dicks E, Barrowdale D, Sinnott-Armstrong NA, Sallari RC, Hillman KM, Kaufmann S, Sivakumaran H, Moradi Marjaneh M, Lee JS, Hills M, Jarosz M, Drury S, Canisius S, Bolla MK, Dennis J, Wang Q, Hopper JL, Southey MC, Broeks A, Schmidt MK, Lophatananon A, Muir K, Beckmann MW, Fasching PA, Dos-Santos-Silva I, Peto J, Sawyer EJ, Tomlinson I, Burwinkel B, Marme F, Guénel P, Truong T, Bojesen SE, Flyger H, González-Neira A, Perez JI, Anton-Culver H, Eunjung L, Arndt V, Brenner H, Meindl A, Schmutzler RK, Brauch H, Hamann U, Aittomäki K, Blomqvist C, Ito H, Matsuo K, Bogdanova N, Dörk T, Lindblom A, Margolin S, Kosma VM, Mannermaa A, Tseng CC, Wu AH, Lambrechts D, Wildiers H, Chang-Claude J, Rudolph A, Peterlongo P, Radice P, Olson JE, Giles GG, Milne RL, Haiman CA, Henderson BE, Goldberg MS, Teo SH, Yip CH, Nord S, Borresen-Dale AL, Kristensen V, Long J, Zheng W, Pylkäs K, Winqvist R, Andrulis IL, Knight JA, Devilee P, Seynaeve C, Figueroa J, Sherman ME, Czene K, Darabi H, Hollestelle A, van den Ouweland AM, Humphreys K, Gao YT, Shu XO, Cox A, Cross SS, Blot W, Cai Q, Ghoussaini M, Perkins BJ, Shah M, Choi JY, Kang D, Lee SC, Hartman M, Kabisch M, Torres D, Jakubowska A, Lubinski J, Brennan P, Sangrajrang S, Ambrosone CB, Toland AE, Shen CY, Wu PE, Orr N, Swerdlow A, McGuffog L, Healey S, Lee A, Kapuscinski M, John EM, Terry MB, Daly MB, Goldgar DE, Buys SS, Janavicius R, Tihomirova L, Tung N, Dorfling CM, van Rensburg EJ, Neuhausen SL, Ejlertsen B, Hansen TV, Osorio A, Benitez J, Rando R, Weitzel JN, Bonanni B, Peissel B, Manoukian S, Papi L, Ottini L, Konstantopoulou I, Apostolou P, Garber J, Rashid MU, Frost D, Izatt L, Ellis S, Godwin AK, Arnold N, Niederacher D, Rhiem K, Bogdanova-Markov N, Sagne C, Stoppa-Lyonnet D, Damiola F, Sinilnikova OM, Mazoyer S, Isaacs C, Claes KB, De Leeneer K, de la Hoya M, Caldes T, Nevanlinna H, Khan S, Mensenkamp AR, Hooning MJ, Rookus MA, Kwong A, Olah E, Diez O, Brunet J, Pujana MA, Gronwald J, Huzarski T, Barkardottir RB, Laframboise R, Soucy P, Montagna M, Agata S, Teixeira MR, Park SK, Lindor N, Couch FJ, Tischkowitz M, Foretova L, Vijai J, Offit K, Singer CF, Rappaport C, Phelan CM, Greene MH, Mai PL, Rennert G, Imyanitov EN, Hulick PJ, Phillips KA, Piedmonte M, Mulligan AM, Glendon G, Bojesen A, Thomassen M, Caligo MA, Yoon SY, Friedman E, Laitman Y, Borg A, von Wachenfeldt A, Ehrencrona H, Rantala J, Olopade OI, Ganz PA, Nussbaum RL, Gayther SA, Nathanson KL, Domchek SM, Arun BK, Mitchell G, Karlan BY, Lester J, Maskarinec G, Woolcott C, Scott C, Stone J, Apicella C, Tamimi R, Luben R, Khaw KT, Helland Å, Haakensen V, Dowsett M, Pharoah PD, Simard J, Hall P, García-Closas M, Vachon C, Chenevix-Trench G, Antoniou AC, Easton DF, and Edwards SL
- Subjects
- Base Sequence, Breast Neoplasms metabolism, Carrier Proteins metabolism, Cell Cycle Proteins metabolism, Estrogen Receptor alpha metabolism, Female, Gene Expression, Gene Expression Regulation, Neoplastic, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Phenotype, Polymorphism, Single Nucleotide, Protein Binding, Risk Factors, Breast Neoplasms genetics, Carrier Proteins genetics, Cell Cycle Proteins genetics, Chromosomes, Human, Pair 6 genetics, Estrogen Receptor alpha genetics
- Abstract
We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor α) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER(+) or ER(-)) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER(-) tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression.
- Published
- 2016
- Full Text
- View/download PDF
44. Germline polymorphisms in an enhancer of PSIP1 are associated with progression-free survival in epithelial ovarian cancer.
- Author
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French JD, Johnatty SE, Lu Y, Beesley J, Gao B, Kalimutho M, Henderson MJ, Russell AJ, Kar S, Chen X, Hillman KM, Kaufmann S, Sivakumaran H, O'Reilly M, Wang C, Korbie DJ, Lambrechts D, Despierre E, Van Nieuwenhuysen E, Lambrechts S, Vergote I, Karlan B, Lester J, Orsulic S, Walsh C, Fasching PA, Beckmann MW, Ekici AB, Hein A, Matsuo K, Hosono S, Pisterer J, Hillemanns P, Nakanishi T, Yatabe Y, Goodman MT, Lurie G, Matsuno RK, Thompson PJ, Pejovic T, Bean Y, Heitz F, Harter P, du Bois A, Schwaab I, Hogdall E, Kjaer SK, Jensen A, Hogdall C, Lundvall L, Engelholm SA, Brown B, Flanagan JM, Metcalf MD, Siddiqui N, Sellers T, Fridley B, Cunningham J, Schildkraut JM, Iversen E, Weber RP, Brennan D, Berchuck A, Pharoah P, Harnett P, Norris MD, Haber M, Goode EL, Lee JS, Khanna KK, Meyer KB, Chenevix-Trench G, deFazio A, Edwards SL, and MacGregor S
- Subjects
- Apoptosis, Biomarkers, Tumor genetics, Cell Proliferation, Chromatin Immunoprecipitation, Cohort Studies, Cystadenocarcinoma, Serous drug therapy, Cystadenocarcinoma, Serous genetics, Cystadenocarcinoma, Serous mortality, Cystadenocarcinoma, Serous pathology, Electrophoretic Mobility Shift Assay, Fallopian Tube Neoplasms drug therapy, Fallopian Tube Neoplasms genetics, Fallopian Tube Neoplasms pathology, Female, Follow-Up Studies, Humans, Ovarian Neoplasms drug therapy, Ovarian Neoplasms genetics, Ovarian Neoplasms pathology, Peritoneal Neoplasms drug therapy, Peritoneal Neoplasms genetics, Peritoneal Neoplasms pathology, Prognosis, RNA, Messenger genetics, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Survival Rate, Tumor Cells, Cultured, Adaptor Proteins, Signal Transducing genetics, Enhancer Elements, Genetic genetics, Fallopian Tube Neoplasms mortality, Germ-Line Mutation genetics, Ovarian Neoplasms mortality, Peritoneal Neoplasms mortality, Polymorphism, Single Nucleotide genetics, Transcription Factors genetics
- Abstract
Women with epithelial ovarian cancer (EOC) are usually treated with platinum/taxane therapy after cytoreductive surgery but there is considerable inter-individual variation in response. To identify germline single-nucleotide polymorphisms (SNPs) that contribute to variations in individual responses to chemotherapy, we carried out a multi-phase genome-wide association study (GWAS) in 1,244 women diagnosed with serous EOC who were treated with the same first-line chemotherapy, carboplatin and paclitaxel. We identified two SNPs (rs7874043 and rs72700653) in TTC39B (best P=7x10-5, HR=1.90, for rs7874043) associated with progression-free survival (PFS). Functional analyses show that both SNPs lie in a putative regulatory element (PRE) that physically interacts with the promoters of PSIP1, CCDC171 and an alternative promoter of TTC39B. The C allele of rs7874043 is associated with poor PFS and showed increased binding of the Sp1 transcription factor, which is critical for chromatin interactions with PSIP1. Silencing of PSIP1 significantly impaired DNA damage-induced Rad51 nuclear foci and reduced cell viability in ovarian cancer lines. PSIP1 (PC4 and SFRS1 Interacting Protein 1) is known to protect cells from stress-induced apoptosis, and high expression is associated with poor PFS in EOC patients. We therefore suggest that the minor allele of rs7874043 confers poor PFS by increasing PSIP1 expression.
- Published
- 2016
- Full Text
- View/download PDF
45. Time to shut down the acute care conveyor belt?
- Author
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Hillman KM, Rubenfeld GD, and Braithwaite J
- Subjects
- Humans, Critical Care methods, Decision Making, Intensive Care Units organization & administration, Terminal Care organization & administration
- Published
- 2015
- Full Text
- View/download PDF
46. Critical Care Sans Frontieré.
- Author
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Hillman KM
- Subjects
- Female, Humans, Male, Heart Arrest mortality, Heart Arrest therapy, Hospital Rapid Response Team organization & administration, Hospital Rapid Response Team statistics & numerical data, Intensive Care Units statistics & numerical data
- Published
- 2015
- Full Text
- View/download PDF
47. Reply to Letter: 'Re: Education for cardiac arrest - Treatment or prevention?'.
- Author
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Smith GB, Welch J, DeVita MA, Hillman KM, and Jones D
- Subjects
- Humans, Advanced Cardiac Life Support education, Cardiopulmonary Resuscitation education, Emergency Medical Services, Heart Arrest prevention & control, Medical Staff, Hospital education
- Published
- 2015
- Full Text
- View/download PDF
48. Reply to Letter: 'Re: Education for cardiac arrest - Prevention and treatment'.
- Author
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Smith GB, Welch J, DeVita MA, Hillman KM, and Jones D
- Subjects
- Humans, Advanced Cardiac Life Support education, Cardiopulmonary Resuscitation education, Emergency Medical Services, Heart Arrest prevention & control, Medical Staff, Hospital education
- Published
- 2015
- Full Text
- View/download PDF
49. The ten barriers to appropriate management of patients at the end of their life.
- Author
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Hillman KM and Cardona-Morrell M
- Subjects
- Humans, Intensive Care Units, Terminal Care standards
- Abstract
The development of ICUs as the final option for seriously ill patients, especially the elderly frail patient at the end of his/her life, has meant that intensivists have increasingly taken on the role of diagnosing the dying. Our society, and even our medical colleagues, do not necessarily understand what we can achieve in ICUs, and even more importantly, what we cannot achieve. The next crucial step for us as individuals, and through our professional bodies, is to engage our society in discussions on our role and encourage debate and discussion, being aware of the controversies that will inevitably result. Birthing in the 1950s was medicalised without discussion with women and their families. In a similar manner, dying has been medicalised in the twenty-first century. It has not been a conspiracy and the use of futile and expensive treatment at the EoL transition is not necessarily anyone's choice. The specialty of intensive care has a particularly important role in facilitating discussions with our society in order to define different ways of managing dying.
- Published
- 2015
- Full Text
- View/download PDF
50. Long-Range Modulation of PAG1 Expression by 8q21 Allergy Risk Variants.
- Author
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Vicente CT, Edwards SL, Hillman KM, Kaufmann S, Mitchell H, Bain L, Glubb DM, Lee JS, French JD, and Ferreira MA
- Subjects
- B-Lymphocytes immunology, Genetic Association Studies, Humans, Hypersensitivity immunology, Linkage Disequilibrium, Luciferases, Lymphocyte Activation genetics, Multivariate Analysis, Nucleic Acid Conformation, Polymorphism, Single Nucleotide genetics, Regulatory Sequences, Nucleic Acid genetics, Adaptor Proteins, Signal Transducing genetics, Chromosomes, Human, Pair 8 genetics, Gene Expression Regulation genetics, Hypersensitivity genetics, Membrane Proteins genetics
- Abstract
The gene(s) whose expression is regulated by allergy risk variants is unknown for many loci identified through genome-wide association studies. Addressing this knowledge gap might point to new therapeutic targets for allergic disease. The aim of this study was to identify the target gene(s) and the functional variant(s) underlying the association between rs7009110 on chromosome 8q21 and allergies. Eight genes are located within 1 Mb of rs7009110. Multivariate association analysis of publicly available exon expression levels from lymphoblastoid cell lines (LCLs) identified a significant association between rs7009110 and the expression of a single gene, PAG1 (p = 0.0017), 732 kb away. Analysis of histone modifications and DNase I hypersensitive sites in LCLs identified four putative regulatory elements (PREs) in the region. Chromosome conformation capture confirmed that two PREs interacted with the PAG1 promoter, one in allele-specific fashion. To determine whether these PREs were functional, LCLs were transfected with PAG1 promoter-driven luciferase reporter constructs. PRE3 acted as a transcriptional enhancer for PAG1 exclusively when it carried the rs2370615:C allergy predisposing allele, a variant in complete linkage disequilibrium with rs7009110. As such, rs2370615, which overlaps RelA transcription factor (TF) binding in LCLs and was found to disrupt Foxo3a binding to PRE3, represents the putative functional variant in this locus. Our studies suggest that the risk-associated allele of rs2370615 predisposes to allergic disease by increasing PAG1 expression, which might promote B cell activation and have a pro-inflammatory effect. Inhibition of PAG1 expression or function might have therapeutic potential for allergic diseases., (Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
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