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2. An integrated single cell and spatial transcriptomic map of human white adipose tissue

Author

Massier, Lucas, Jalkanen, Jutta, Elmastas, Merve, Zhong, Jiawei, Wang, Tongtong, Nono Nankam, Pamela A., Frendo-Cumbo, Scott, Bäckdahl, Jesper, Subramanian, Narmadha, Sekine, Takuya, Kerr, Alastair G., Tseng, Ben T. P., Laurencikiene, Jurga, Buggert, Marcus, Lourda, Magda, Kublickiene, Karolina, Bhalla, Nayanika, Andersson, Alma, Valsesia, Armand, Astrup, Arne, Blaak, Ellen E., Ståhl, Patrik L., Viguerie, Nathalie, Langin, Dominique, Wolfrum, Christian, Blüher, Matthias, Rydén, Mikael, and Mejhert, Niklas

Published
2023
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4. Lineage Plasticity in SCLC Generates Non-Neuroendocrine Cells Primed for Vasculogenic Mimicry

Author

Pearsall, Sarah M., Williamson, Stuart C., Humphrey, Sam, Hughes, Ellyn, Morgan, Derrick, García Marqués, Fernando J., Awanis, Griselda, Carroll, Rebecca, Burks, Laura, Shue, Yan Ting, Bermudez, Abel, Frese, Kristopher K., Galvin, Melanie, Carter, Mathew, Priest, Lynsey, Kerr, Alastair, Zhou, Cong, Oliver, Trudy G., Humphries, Jonathan D., Humphries, Martin J., Blackhall, Fiona, Cannell, Ian G., Pitteri, Sharon J., Hannon, Gregory J., Sage, Julien, Dive, Caroline, and Simpson, Kathryn L.

Published
2023
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5. cfDNA methylome profiling for detection and subtyping of small cell lung cancers

Author

Chemi, Francesca, Pearce, Simon P., Clipson, Alexandra, Hill, Steven M., Conway, Alicia-Marie, Richardson, Sophie A., Kamieniecka, Katarzyna, Caeser, Rebecca, White, Daniel J., Mohan, Sumitra, Foy, Victoria, Simpson, Kathryn L., Galvin, Melanie, Frese, Kristopher K., Priest, Lynsey, Egger, Jacklynn, Kerr, Alastair, Massion, Pierre P., Poirier, John T., Brady, Gerard, Blackhall, Fiona, Rothwell, Dominic G., Rudin, Charles M., and Dive, Caroline

Published
2022
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11. Functional Characterisation of the ATOH1 Molecular Subtype Indicates a Pro-Metastatic Role in Small Cell Lung Cancer

Author

Catozzi, Alessia, primary, Peiris-Pagès, Maria, additional, Humphrey, Sam, additional, Revill, Mitchell, additional, Morgan, Derrick, additional, Roebuck, Jordan, additional, Chen, Yitao, additional, Davies-Williams, Bethan, additional, Lallo, Alice, additional, Galvin, Melanie, additional, Pearce, Simon P, additional, Kerr, Alastair, additional, Priest, Lynsey, additional, Foy, Victoria, additional, Carter, Mathew, additional, Caeser, Rebecca, additional, Chan, Joseph, additional, Rudin, Charles M., additional, Blackhall, Fiona, additional, Frese, Kristopher K, additional, Dive, Caroline, additional, and Simpson, Kathryn L, additional

Published
2024
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12. Photoallergic Contact Dermatitis

Author

Ferguson, James, Kerr, Alastair C., John, Swen Malte, editor, Johansen, Jeanne Duus, editor, Rustemeyer, Thomas, editor, Elsner, Peter, editor, and Maibach, Howard I., editor

Published
2020
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13. Novel molecular therapies for the treatment of familial hypercholesterolaemia

Author

Kerr, Alastair, Channon, Keith, and Wade-Martins, Richard

Subjects
616.3
Abstract

Familial hypercholesterolaemia (FH) is an autosomal dominant genetic disorder characterised by elevated levels of plasma low density lipoprotein (LDL) cholesterol. Loss-of-function mutations in the Low-Density Lipoprotein Receptor (LDLR) gene are responsible for ~85% of all FH cases. Heterozygous FH (HeFH) affects 1 in 200-500 individuals world-wide, while homozygous FH (HoFH) has a prevalence of one in a 160000-1000000. Elevated levels of LDL-cholesterol in the blood lead to an accelerated development of atherosclerosis and progression to coronary heart disease. The work presented in this thesis investigates two novel molecular therapies for the treatment of FH. A small molecule approach for the treatment of HeFH and a non-viral gene therapy for the treatment of HoFH. Small molecule: Through a compound screen, we identified a series of small molecules able to upregulate the LDLR at nanomolar potencies, via a mechanism distinct from statins. We then went on to elucidate the mechanism of action as inhibitors of squalene synthase and demonstrated, that when used in combination with statins, these compounds give a much greater increase in LDLR expression than can be achieved with statins alone. By carrying out extensive structure-activity relationship studies we improved the potency and pharmacokinetics of our lead compound and demonstrated in vivo efficacy. Non-viral gene therapy: We have previously generated mini-gene vectors carrying the human LDLR cDNA, driven by 10 kb of genomic DNA from the native human LDLR locus, encompassing the promoter region. To further enhance LDLR transgene expression, a miRNA, targeting Hmgcr (miR82) was cloned into the same vector, generating a combinatorial RNAi-LDLR vector. In vivo, we show the RNAi-LDLR vector is able to significantly reduce total and LDL-cholesterol in Ldlr-/- mice fed a high cholesterol diet twelve weeks post-delivery. The LDL-cholesterol lowering resulted in reduced atherosclerosis in the RNAi-LDLR vector treated mice. Here we demonstrate for the first time, that an episomal non-viral vector is able to significantly reduce LDL-cholesterol and slow the progression of atherosclerosis in a mouse model of FH.

Published
2016

14. CUPiD: A cfDNA methylation-based tissue-of-origin classifier for Cancers of Unknown Primary

Author

Rothwell, Dominic, primary, Conway, Alicia-Marie, additional, Pearce, Simon, additional, Clipson, Alexandra, additional, Hill, Steven, additional, Chemi, Francesca, additional, Slane-Tan, Daniel, additional, Ferdous, Saba, additional, Hoss, A S Md Mukarram, additional, Kamieniecka, Katarzyna, additional, White, Daniel, additional, Mitchell, Claire, additional, Kerr, Alastair, additional, Krebs, Matthew, additional, Brady, Ged, additional, Dive, Caroline, additional, and Cook, Natalie, additional

Published
2023
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15. Soluble guanylate cyclase signalling mediates etoposide resistance in progressing small cell lung cancer

Author

Schenk, Maximilian W., Humphrey, Sam, Hossain, A. S. Md Mukarram, Revill, Mitchell, Pearsall, Sarah, Lallo, Alice, Brown, Stewart, Bratt, Samuel, Galvin, Melanie, Descamps, Tine, Zhou, Cong, Pearce, Simon P., Priest, Lynsey, Greenhalgh, Michelle, Chaturvedi, Anshuman, Kerr, Alastair, Blackhall, Fiona, Dive, Caroline, and Frese, Kristopher K.

Published
2021
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16. Convergent genes shape budding yeast pericentromeres

Author

Paldi, Flora, Alver, Bonnie, Robertson, Daniel, Schalbetter, Stephanie A., Kerr, Alastair, Kelly, David A., and Baxter, Jonathan

Subjects
Centromeres -- Structure -- Physiological aspects -- Genetic aspects, Brewer's yeast -- Genetic aspects -- Physiological aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

The three-dimensional architecture of the genome governs its maintenance, expression and transmission. The cohesin protein complex organizes the genome by topologically linking distant loci, and is highly enriched in specialized chromosomal domains surrounding centromeres, called pericentromeres.sup.1-6. Here we report the three-dimensional structure of pericentromeres in budding yeast (Saccharomyces cerevisiae) and establish the relationship between genome organization and function. We find that convergent genes mark pericentromere borders and, together with core centromeres, define their structure and function by positioning cohesin. Centromeres load cohesin, and convergent genes at pericentromere borders trap it. Each side of the pericentromere is organized into a looped conformation, with border convergent genes at the base. Microtubule attachment extends a single pericentromere loop, size-limited by convergent genes at its borders. Reorienting genes at borders into a tandem configuration repositions cohesin, enlarges the pericentromere and impairs chromosome biorientation during mitosis. Thus, the linear arrangement of transcriptional units together with targeted cohesin loading shapes pericentromeres into a structure that is competent for chromosome segregation. Our results reveal the architecture of the chromosomal region within which kinetochores are embedded, as well as the restructuring caused by microtubule attachment. Furthermore, we establish a direct, causal relationship between the three-dimensional genome organization of a specific chromosomal domain and cellular function. The three-dimensional structure of pericentromeres in budding yeast is defined by convergent genes, which mark pericentromere borders and trap cohesin complexes loaded at centromeres, generating an architecture that allows correct chromosome segregation., Author(s): Flora Paldi [sup.1] , Bonnie Alver [sup.1] , Daniel Robertson [sup.1] , Stephanie A. Schalbetter [sup.2] , Alastair Kerr [sup.1] , David A. Kelly [sup.1] , Jonathan Baxter [sup.2] [...]

Published
2020
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17. A biobank of small cell lung cancer CDX models elucidates inter- and intratumoral phenotypic heterogeneity

Author

Simpson, Kathryn L., Stoney, Ruth, Frese, Kristopher K., Simms, Nicole, Rowe, William, Pearce, Simon P., Humphrey, Sam, Booth, Laura, Morgan, Derrick, Dynowski, Marek, Trapani, Francesca, Catozzi, Alessia, Revill, Mitchell, Helps, Thomas, Galvin, Melanie, Girard, Luc, Nonaka, Daisuke, Carter, Louise, Krebs, Matthew G., Cook, Natalie, Carter, Mathew, Priest, Lynsey, Kerr, Alastair, Gazdar, Adi F., Blackhall, Fiona, and Dive, Caroline

Published
2020
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18. Identical sets of methylated and nonmethylated genes in Ciona intestinalis sperm and muscle cells

Author

Suzuki, Miho M, Yoshinari, Akiko, Obara, Madoka, Takuno, Shohei, Shigenobu, Shuji, Sasakura, Yasunori, Kerr, Alastair RW, Webb, Shaun, Bird, Adrian, and Nakayama, Atsuo

Abstract

Abstract Background The discovery of gene body methylation, which refers to DNA methylation within gene coding region, suggests an as yet unknown role of DNA methylation at actively transcribed genes. In invertebrates, gene bodies are the primary targets of DNA methylation, and only a subset of expressed genes is modified. Results Here we investigate the tissue variability of both the global levels and distribution of 5-methylcytosine (5mC) in the sea squirt Ciona intestinalis. We find that global 5mC content of early developmental embryos is high, but is strikingly reduced in body wall tissues. We chose sperm and adult muscle cells, with high and reduced levels of global 5mC respectively, for genome-wide analysis of 5mC targets. By means of CXXC-affinity purification followed by deep sequencing (CAP-seq), and genome-wide bisulfite sequencing (BS-seq), we designated body-methylated and unmethylated genes in each tissue. Surprisingly, body-methylated and unmethylated gene groups are identical in the sperm and muscle cells. Our analysis of microarray expression data shows that gene body methylation is associated with broad expression throughout development. Moreover, transgenic analysis reveals contrasting gene body methylation at an identical gene-promoter combination when integrated at different genomic sites. Conclusions We conclude that gene body methylation is not a direct regulator of tissue specific gene expression in C. intestinalis. Our findings reveal constant targeting of gene body methylation irrespective of cell type, and they emphasize a correlation between gene body methylation and ubiquitously expressed genes. Our transgenic experiments suggest that the promoter does not determine the methylation status of the associated gene body.

Published
2013

21. Photoallergic contact dermatitis in Europe

Author

Kerr, Alastair and Ibbotson, Sally

Subjects
616.5, Photoallergic contact dermatitis, Sunscreens, Topical NSAIDs, Photopatch testing
Abstract

Photoallergic contact dermatitis (PACD) is a clinical problem that has often been poorly understood and neglected by dermatologists over recent years. This can be partly attributed to its investigation by photopatch testing (PPT) falling between the expertise of photobiologists and contact dermatitis clinicians. One result of this situation was that no European Baseline PPT series had been agreed on. To redress this, the European multi centre photopatch test study (EMCPPTS) was conceived to provide up to date information on which photoallergens are of greatest clinical relevance. Its conduct and results form the core research project of this thesis. To enable the EMCPPTS to proceed and its results to be viewed in a wider context, the other Chapters of this thesis explore important related aspects of PACD and PPT in Europe. The introduction examines the nature of PACD and PPT and reviews current photoallergens. Then, the investigation of the two photoallergens carprofen and chlorproethazine by PPT is recounted. These studies highlight deficiencies within the current European regulatory system for preventing photoallergens from reaching the marketplace, as well as providing templates for the investigation of new photoallergens in the human environment. This is followed by a pilot PPT study which provides new information on the optimum non-irritating concentration of the 19 ultraviolet sunscreen absorbers to be used in the EMCPPTS. The issue of attempting to determine the photoallergenic potential of the EMCPPTS agents with respect to exposure patterns is addressed by conducting a sunscreen survey in the UK. The EMCPPTS itself is then detailed, as well as the difficulties that can be encountered when conducting a large clinical study of this nature. The results from the EMCPPTS and other presented studies were shown to be of importance in deciding upon a new European Baseline PPT series. The process involved in deciding this series, as well as its content are described before overall conclusions and possible future studies in the domain of PACD and PPT are discussed.

Published
2012

23. Strategy selection in mental arithmetic problem solving : a case for adaptive, not automatic selection

Author

McKenzie-Kerr, Alastair

Subjects
153.4
Abstract

The present thesis examined the processes responsible for strategy selection in problem-solving tasks. Despite the salience of this mechanism there has been a dearth in empirical research in the paradigm. Existing accounts, primarily modelled upon simulations of data sets, propose that strategies are not selected per se, but problems are solved by an automatic attempt to retrieve a solution (the Automaticity account Logan, 1988 2002). Contrary to this account four studies presented in the first empirical series demonstrated that predicted retrieve/calculate selections could be made rapidly (within 850 ms) and accurately. This indicated that problem-solving comprises two dissociable phases, selection then solution. Selection was found to be sensitive to the familiarity of a problem and also specific problem features supporting an account in which selection may be determined by the type of problem and the context in which the problem is solved (the Adaptive account Reder & Ritter, 1992 Siegler & Araya, 2005). Elucidating the mechanisms responsible for these effects, in the second empirical series, three issues representative of real-world problem-solving episodes were examined. When multiple cues to selection were available, the interplay between the cues either served to inhibit the effects of both cues, or facilitated the effect of one cue at the expense of the other. Problem familiarity effects were attributed to implicit procedures as these effects were apparently un-reliant upon conscious processes (Reder & Ritter, 1992 Schunn et al, 1997). However, the feature identification process, rather than the selection mechanism itself, was found to be reliant upon consciously directed processes (Siegler & Araya, 2005). The findings from these studies were used to evaluate existing accounts of strategy selection, and reflecting limitations in these models, candidate mechanisms are proposed to account for the key effects revealed in this thesis.

Published
2007

24. Data from Loss of Tet1-Associated 5-Hydroxymethylcytosine Is Concomitant with Aberrant Promoter Hypermethylation in Liver Cancer

Author

Thomson, John P., primary, Ottaviano, Raffaele, primary, Unterberger, Elif B., primary, Lempiäinen, Harri, primary, Muller, Arne, primary, Terranova, Remi, primary, Illingworth, Robert S., primary, Webb, Shaun, primary, Kerr, Alastair R.W., primary, Lyall, Marcus J., primary, Drake, Amanda J., primary, Wolf, C. Roland, primary, Moggs, Jonathan G., primary, Schwarz, Michael, primary, and Meehan, Richard R., primary

Published
2023
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25. Supplementary Figures from Loss of Tet1-Associated 5-Hydroxymethylcytosine Is Concomitant with Aberrant Promoter Hypermethylation in Liver Cancer

Author

Thomson, John P., primary, Ottaviano, Raffaele, primary, Unterberger, Elif B., primary, Lempiäinen, Harri, primary, Muller, Arne, primary, Terranova, Remi, primary, Illingworth, Robert S., primary, Webb, Shaun, primary, Kerr, Alastair R.W., primary, Lyall, Marcus J., primary, Drake, Amanda J., primary, Wolf, C. Roland, primary, Moggs, Jonathan G., primary, Schwarz, Michael, primary, and Meehan, Richard R., primary

Published
2023
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26. Supplementary Materials and Methods from Loss of Tet1-Associated 5-Hydroxymethylcytosine Is Concomitant with Aberrant Promoter Hypermethylation in Liver Cancer

Author

Thomson, John P., primary, Ottaviano, Raffaele, primary, Unterberger, Elif B., primary, Lempiäinen, Harri, primary, Muller, Arne, primary, Terranova, Remi, primary, Illingworth, Robert S., primary, Webb, Shaun, primary, Kerr, Alastair R.W., primary, Lyall, Marcus J., primary, Drake, Amanda J., primary, Wolf, C. Roland, primary, Moggs, Jonathan G., primary, Schwarz, Michael, primary, and Meehan, Richard R., primary

Published
2023
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27. SUPPLEMENTARY TABLE S1. from Loss of Tet1-Associated 5-Hydroxymethylcytosine Is Concomitant with Aberrant Promoter Hypermethylation in Liver Cancer

Author

Thomson, John P., primary, Ottaviano, Raffaele, primary, Unterberger, Elif B., primary, Lempiäinen, Harri, primary, Muller, Arne, primary, Terranova, Remi, primary, Illingworth, Robert S., primary, Webb, Shaun, primary, Kerr, Alastair R.W., primary, Lyall, Marcus J., primary, Drake, Amanda J., primary, Wolf, C. Roland, primary, Moggs, Jonathan G., primary, Schwarz, Michael, primary, and Meehan, Richard R., primary

Published
2023
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28. SUPPLEMENTARYTABLE S2 from Loss of Tet1-Associated 5-Hydroxymethylcytosine Is Concomitant with Aberrant Promoter Hypermethylation in Liver Cancer

Author

Thomson, John P., primary, Ottaviano, Raffaele, primary, Unterberger, Elif B., primary, Lempiäinen, Harri, primary, Muller, Arne, primary, Terranova, Remi, primary, Illingworth, Robert S., primary, Webb, Shaun, primary, Kerr, Alastair R.W., primary, Lyall, Marcus J., primary, Drake, Amanda J., primary, Wolf, C. Roland, primary, Moggs, Jonathan G., primary, Schwarz, Michael, primary, and Meehan, Richard R., primary

Published
2023
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30. Body composition and lung cancer-associated cachexia in TRACERx

Author

Al-Sawaf, Othman, Weiss, Jakob, Skrzypski, Marcin, Lam, Jie Min, Karasaki, Takahiro, Zambrana, Francisco, Kidd, Andrew C, Frankell, Alexander M, Watkins, Thomas BK, Martinez-Ruiz, Carlos, Puttick, Clare, Black, James RM, Huebner, Ariana, Al Bakir, Maise, Sokac, Mateo, Collins, Susie, Veeriah, Selvaraju, Magno, Neil, Naceur-Lombardelli, Cristina, Prymas, Paulina, Toncheva, Antonia, Ward, Sophia, Jayanth, Nick, Salgado, Roberto, Bridge, Christopher P, Christiani, David C, Mak, Raymond H, Bay, Camden, Rosenthal, Michael, Sattar, Naveed, Welsh, Paul, Liu, Ying, Perrimon, Norbert, Popuri, Karteek, Beg, Mirza Faisal, McGranahan, Nicholas, Hackshaw, Allan, Breen, Danna M, O'Rahilly, Stephen, Birkbak, Nicolai J, Aerts, Hugo JWL, Jamal-Hanjani, Mariam, Swanton, Charles, Lester, Jason F, Bajaj, Amrita, Nakas, Apostolos, Sodha-Ramdeen, Azmina, Ang, Keng, Tufail, Mohamad, Chowdhry, Mohammed Fiyaz, Scotland, Molly, Boyles, Rebecca, Rathinam, Sridhar, Wilson, Claire, Marrone, Domenic, Dulloo, Sean, Fennell, Dean A, Matharu, Gurdeep, Shaw, Jacqui A, Riley, Joan, Primrose, Lindsay, Boleti, Ekaterini, Cheyne, Heather, Khalil, Mohammed, Richardson, Shirley, Cruickshank, Tracey, Price, Gillian, Kerr, Keith M, Benafif, Sarah, Gilbert, Kayleigh, Naidu, Babu, Patel, Akshay J, Osman, Aya, Lacson, Christer, Langman, Gerald, Shackleford, Helen, Djearaman, Madava, Kadiri, Salma, Middleton, Gary, Leek, Angela, Hodgkinson, Jack Davies, Totten, Nicola, Montero, Angeles, Smith, Elaine, Fontaine, Eustace, Granato, Felice, Doran, Helen, Novasio, Juliette, Rammohan, Kendadai, Joseph, Leena, Bishop, Paul, Shah, Rajesh, Moss, Stuart, Joshi, Vijay, Crosbie, Philip, Gomes, Fabio, Brown, Kate, Carter, Mathew, Chaturvedi, Anshuman, Priest, Lynsey, Oliveira, Pedro, Lindsay, Colin R, Blackhall, Fiona H, Krebs, Matthew G, Summers, Yvonne, Clipson, Alexandra, Tugwood, Jonathan, Kerr, Alastair, Rothwell, Dominic G, Kilgour, Elaine, Dive, Caroline, Schwarz, Roland F, Kaufmann, Tom L, Wilson, Gareth A, Rosenthal, Rachel, Van Loo, Peter, Szallasi, Zoltan, Kisistok, Judit, Diossy, Miklos, Demeulemeester, Jonas, Bunkum, Abigail, Stewart, Aengus, Magness, Alastair, Rowan, Andrew, Karamani, Angeliki, Chain, Benny, Campbell, Brittany B, Castignani, Carla, Bailey, Chris, Abbosh, Christopher, Weeden, Clare E, Lee, Claudia, Richard, Corentin, Hiley, Crispin T, Moore, David A, Pearce, David R, Karagianni, Despoina, Biswas, Dhruva, Levi, Dina, Hoxha, Elena, Cadieux, Elizabeth Larose, Lim, Emilia L, Colliver, Emma, Nye, Emma, Gronroos, Eva, Galvez-Cancino, Felip, Athanasopoulou, Foteini, Gimeno-Valiente, Francisco, Kassiotis, George, Stavrou, Georgia, Mastrokalos, Gerasimos, Zhai, Haoran, Lowe, Helen L, Matos, Ignacio Garcia, Goldman, Jacki, Reading, James L, Herrero, Javier, Rane, Jayant K, Nicod, Jerome, Hartley, John A, Peggs, Karl S, Enfield, Katey SS, Selvaraju, Kayalvizhi, Thol, Kerstin, Litchfield, Kevin, Ng, Kevin W, Chen, Kezhong, Dijkstra, Krijn, Grigoriadis, Kristiana, Thakkar, Krupa, Ensell, Leah, Shah, Mansi, Duran, Marcos Vasquez, Litovchenko, Maria, Sunderland, Mariana Werner, Hill, Mark S, Dietzen, Michelle, Leung, Michelle, Escudero, Mickael, Angelova, Mihaela, Tanic, Miljana, Sivakumar, Monica, Kanu, Nnennaya, Chervova, Olga, Lucas, Olivia, Pich, Oriol, Hobson, Philip, Pawlik, Piotr, Stone, Richard Kevin, Bentham, Robert, Hynds, Robert E, Vendramin, Roberto, Saghafinia, Sadegh, Lopez, Saioa, Gamble, Samuel, Ung, Seng Kuong Anakin, Quezada, Sergio A, Vanloo, Sharon, Zaccaria, Simone, Hessey, Sonya, Boeing, Stefan, Beck, Stephan, Bola, Supreet Kaur, Denner, Tamara, Marafioti, Teresa, Mourikis, Thanos P, Spanswick, Victoria, Barbe, Vittorio, Lu, Wei-Ting, Hill, William, Liu, Wing Kin, Wu, Yin, Naito, Yutaka, Ramsden, Zoe, Veiga, Catarina, Royle, Gary, Collins-Fekete, Charles-Antoine, Fraioli, Francesco, Ashford, Paul, Clark, Tristan, Forster, Martin D, Lee, Siow Ming, Borg, Elaine, Falzon, Mary, Papadatos-Pastos, Dionysis, Wilson, James, Ahmad, Tanya, Procter, Alexander James, Ahmed, Asia, Taylor, Magali N, Nair, Arjun, Lawrence, David, Patrini, Davide, Navani, Neal, Thakrar, Ricky M, Janes, Sam M, Hoogenboom, Emilie Martinoni, Monk, Fleur, Holding, James W, Choudhary, Junaid, Bhakhri, Kunal, Scarci, Marco, Hayward, Martin, Panagiotopoulos, Nikolaos, Gorman, Pat, Khiroya, Reena, Stephens, Robert CM, Wong, Yien Ning Sophia, Bandula, Steve, Sharp, Abigail, Smith, Sean, Gower, Nicole, Dhanda, Harjot Kaur, Chan, Kitty, Pilotti, Camilla, Leslie, Rachel, Grapa, Anca, Zhang, Hanyun, AbdulJabbar, Khalid, Pan, Xiaoxi, Yuan, Yinyin, Chuter, David, MacKenzie, Mairead, Chee, Serena, Alzetani, Aiman, Cave, Judith, Scarlett, Lydia, Richards, Jennifer, Ingram, Papawadee, Austin, Silvia, Lim, Eric, De Sousa, Paulo, Jordan, Simon, Rice, Alexandra, Raubenheimer, Hilgardt, Bhayani, Harshil, Ambrose, Lyn, Devaraj, Anand, Chavan, Hema, Begum, Sofina, Buderi, Silviu, Kaniu, Daniel, Malima, Mpho, Booth, Sarah, Nicholson, Andrew G, Fernandes, Nadia, Shah, Pratibha, Proli, Chiara, Hewish, Madeleine, Danson, Sarah, Shackcloth, Michael J, Robinson, Lily, Russell, Peter, Blyth, Kevin G, Dick, Craig, Le Quesne, John, Kirk, Alan, Asif, Mo, Bilancia, Rocco, Kostoulas, Nikos, and Thomas, Mathew

Subjects
Male, Proteomics, Cachexia, Lung Neoplasms, Antigens, Neoplasm, Carcinoma, Non-Small-Cell Lung, Body Weight, Body Composition, Humans, Neoplasm Recurrence, Local, Muscle, Skeletal, Neoplasm Proteins
Abstract

Cancer-associated cachexia (CAC) is a major contributor to morbidity and mortality in individuals with non-small cell lung cancer. Key features of CAC include alterations in body composition and body weight. Here, we explore the association between body composition and body weight with survival and delineate potential biological processes and mediators that contribute to the development of CAC. Computed tomography-based body composition analysis of 651 individuals in the TRACERx (TRAcking non-small cell lung Cancer Evolution through therapy (Rx)) study suggested that individuals in the bottom 20th percentile of the distribution of skeletal muscle or adipose tissue area at the time of lung cancer diagnosis, had significantly shorter lung cancer-specific survival and overall survival. This finding was validated in 420 individuals in the independent Boston Lung Cancer Study. Individuals classified as having developed CAC according to one or more features at relapse encompassing loss of adipose or muscle tissue, or body mass index-adjusted weight loss were found to have distinct tumor genomic and transcriptomic profiles compared with individuals who did not develop such features. Primary non-small cell lung cancers from individuals who developed CAC were characterized by enrichment of inflammatory signaling and epithelial-mesenchymal transitional pathways, and differentially expressed genes upregulated in these tumors included cancer-testis antigen MAGEA6 and matrix metalloproteinases, such as ADAMTS3. In an exploratory proteomic analysis of circulating putative mediators of cachexia performed in a subset of 110 individuals from TRACERx, a significant association between circulating GDF15 and loss of body weight, skeletal muscle and adipose tissue was identified at relapse, supporting the potential therapeutic relevance of targeting GDF15 in the management of CAC. ispartof: NATURE MEDICINE vol:29 issue:4 ispartof: location:United States status: Published online

Published
2023

31. The evolution of non-small cell lung cancer metastases in TRACERx

Author

Al Bakir, Maise, Huebner, Ariana, Martinez-Ruiz, Carlos, Grigoriadis, Kristiana, Watkins, Thomas BK, Pich, Oriol, Moore, David A, Veeriah, Selvaraju, Ward, Sophia, Laycock, Joanne, Johnson, Diana, Rowan, Andrew, Razaq, Maryam, Akther, Mita, Naceur-Lombardelli, Cristina, Prymas, Paulina, Toncheva, Antonia, Hessey, Sonya, Dietzen, Michelle, Colliver, Emma, Frankell, Alexander, Bunkum, Abigail, Lim, Emilia L, Karasaki, Takahiro, Abbosh, Christopher, Hiley, Crispin T, Hill, Mark S, Cook, Daniel E, Wilson, Gareth A, Salgado, Roberto, Nye, Emma, Stone, Richard Kevin, Fennell, Dean A, Price, Gillian, Kerr, Keith M, Naidu, Babu, Middleton, Gary, Summers, Yvonne, Lindsay, Colin R, Blackhall, Fiona H, Cave, Judith, Blyth, Kevin G, Nair, Arjun, Ahmed, Asia, Taylor, Magali N, Procter, Alexander James, Falzon, Mary, Lawrence, David, Navani, Neal, Thakrar, Ricky M, Janes, Sam M, Papadatos-Pastos, Dionysis, Forster, Martin D, Lee, Siow Ming, Ahmad, Tanya, Quezada, Sergio, Peggs, Karl S, Van Loo, Peter, Dive, Caroline, Hackshaw, Allan, Birkbak, Nicolai J, Zaccaria, Simone, Jamal-Hanjani, Mariam, McGranahan, Nicholas, Swanton, Charles, Lester, Jason F, Bajaj, Amrita, Nakas, Apostolos, Sodha-Ramdeen, Azmina, Ang, Keng, Tufail, Mohamad, Chowdhry, Mohammed Fiyaz, Scotland, Molly, Boyles, Rebecca, Rathinam, Sridhar, Wilson, Claire, Marrone, Domenic, Dulloo, Sean, Matharu, Gurdeep, Shaw, Jacqui A, Riley, Joan, Primrose, Lindsay, Boleti, Ekaterini, Cheyne, Heather, Khalil, Mohammed, Richardson, Shirley, Cruickshank, Tracey, Benafif, Sarah, Gilbert, Kayleigh, Patel, Akshay J, Osman, Aya, Lacson, Christer, Langman, Gerald, Shackleford, Helen, Djearaman, Madava, Kadiri, Salma, Leek, Angela, Hodgkinson, Jack Davies, Totten, Nicola, Montero, Angeles, Smith, Elaine, Fontaine, Eustace, Granato, Felice, Doran, Helen, Novasio, Juliette, Rammohan, Kendadai, Joseph, Leena, Bishop, Paul, Shah, Rajesh, Moss, Stuart, Joshi, Vijay, Crosbie, Philip, Gomes, Fabio, Brown, Kate, Carter, Mathew, Chaturvedi, Anshuman, Priest, Lynsey, Oliveira, Pedro, Krebs, Matthew G, Clipson, Alexandra, Tugwood, Jonathan, Kerr, Alastair, Rothwell, Dominic G, Kilgour, Elaine, Aerts, Hugo JWL, Schwarz, Roland F, Kaufmann, Tom L, Rosenthal, Rachel, Szallasi, Zoltan, Kisistok, Judit, Sokac, Mateo, Diossy, Miklos, Demeulemeester, Jonas, Stewart, Aengus, Magness, Alastair, Karamani, Angeliki, Chain, Benny, Campbell, Brittany B, Castignani, Carla, Bailey, Chris, Puttick, Clare, Weeden, Clare E, Lee, Claudia, Richard, Corentin, Pearce, David R, Karagianni, Despoina, Biswas, Dhruva, Levi, Dina, Hoxha, Elena, Larose Cadieux, Elizabeth, Gronroos, Eva, Galvez-Cancino, Felip, Athanasopoulou, Foteini, Gimeno-Valiente, Francisco, Kassiotis, George, Stavrou, Georgia, Mastrokalos, Gerasimos, Zhai, Haoran, Lowe, Helen L, Matos, Ignacio, Goldman, Jacki, Reading, James L, Black, James RM, Herrero, Javier, Rane, Jayant K, Nicod, Jerome, Lam, Jie Min, Hartley, John A, Enfield, Katey SS, Selvaraju, Kayalvizhi, Thol, Kerstin, Litchfield, Kevin, Ng, Kevin W, Chen, Kezhong, Dijkstra, Krijn, Thakkar, Krupa, Ensell, Leah, Shah, Mansi, Vasquez, Marcos, Litovchenko, Maria, Werner Sunderland, Mariana, Leung, Michelle, Escudero, Mickael, Angelova, Mihaela, Tanic, Miljana, Sivakumar, Monica, Kanu, Nnennaya, Chervova, Olga, Lucas, Olivia, Al-Sawaf, Othman, Hobson, Philip, Pawlik, Piotr, Bentham, Robert, Hynds, Robert E, Vendramin, Roberto, Saghafinia, Sadegh, Lopez, Saioa, Gamble, Samuel, Ung, Seng Kuong Anakin, Vanloo, Sharon, Boeing, Stefan, Beck, Stephan, Bola, Supreet Kaur, Denner, Tamara, Marafioti, Teresa, Mourikis, Thanos P, Spanswick, Victoria, Barbe, Vittorio, Lu, Wei-Ting, Hill, William, Liu, Wing Kin, Wu, Yin, Naito, Yutaka, Ramsden, Zoe, Veiga, Catarina, Royle, Gary, Collins-Fekete, Charles-Antoine, Fraioli, Francesco, Ashford, Paul, Clark, Tristan, Borg, Elaine, Wilson, James, Patrini, Davide, Martinoni Hoogenboom, Emilie, Monk, Fleur, Holding, James W, Choudhary, Junaid, Bhakhri, Kunal, Scarci, Marco, Hayward, Martin, Panagiotopoulos, Nikolaos, Gorman, Pat, Khiroya, Reena, Stephens, Robert CM, Wong, Yien Ning Sophia, Bandula, Steve, Sharp, Abigail, Smith, Sean, Gower, Nicole, Dhanda, Harjot Kaur, Chan, Kitty, Pilotti, Camilla, Leslie, Rachel, Grapa, Anca, Zhang, Hanyun, AbdulJabbar, Khalid, Pan, Xiaoxi, Yuan, Yinyin, Chuter, David, MacKenzie, Mairead, Chee, Serena, Alzetani, Aiman, Scarlett, Lydia, Richards, Jennifer, Ingram, Papawadee, Austin, Silvia, Lim, Eric, De Sousa, Paulo, Jordan, Simon, Rice, Alexandra, Raubenheimer, Hilgardt, Bhayani, Harshil, Ambrose, Lyn, Devaraj, Anand, Chavan, Hema, Begum, Sofina, Buderi, Silviu, Kaniu, Daniel, Malima, Mpho, Booth, Sarah, Nicholson, Andrew G, Fernandes, Nadia, Shah, Pratibha, Proli, Chiara, Hewish, Madeleine, Danson, Sarah, Shackcloth, Michael J, Robinson, Lily, Russell, Peter, Dick, Craig, Le Quesne, John, Kirk, Alan, Asif, Mo, Bilancia, Rocco, Kostoulas, Nikos, and Thomas, Mathew

Subjects
Clonal Evolution, Cohort Studies, Evolution, Molecular, Lung Neoplasms, Carcinoma, Non-Small-Cell Lung, Disease Progression, Humans, Neoplasm Metastasis, Neoplasm Recurrence, Local, Clone Cells
Abstract

Metastatic disease is responsible for the majority of cancer-related deaths1. We report the longitudinal evolutionary analysis of 126 non-small cell lung cancer (NSCLC) tumours from 421 prospectively recruited patients in TRACERx who developed metastatic disease, compared with a control cohort of 144 non-metastatic tumours. In 25% of cases, metastases diverged early, before the last clonal sweep in the primary tumour, and early divergence was enriched for patients who were smokers at the time of initial diagnosis. Simulations suggested that early metastatic divergence more frequently occurred at smaller tumour diameters (less than 8 mm). Single-region primary tumour sampling resulted in 83% of late divergence cases being misclassified as early, highlighting the importance of extensive primary tumour sampling. Polyclonal dissemination, which was associated with extrathoracic disease recurrence, was found in 32% of cases. Primary lymph node disease contributed to metastatic relapse in less than 20% of cases, representing a hallmark of metastatic potential rather than a route to subsequent recurrences/disease progression. Metastasis-seeding subclones exhibited subclonal expansions within primary tumours, probably reflecting positive selection. Our findings highlight the importance of selection in metastatic clone evolution within untreated primary tumours, the distinction between monoclonal versus polyclonal seeding in dictating site of recurrence, the limitations of current radiological screening approaches for early diverging tumours and the need to develop strategies to target metastasis-seeding subclones before relapse. ispartof: NATURE vol:616 issue:7957 ispartof: location:England status: Published online

Published
2023

32. The evolution of lung cancer and impact of subclonal selection in TRACERx

Author

Frankell, Alexander M, Dietzen, Michelle, Al Bakir, Maise, Lim, Emilia L, Karasaki, Takahiro, Ward, Sophia, Veeriah, Selvaraju, Colliver, Emma, Huebner, Ariana, Bunkum, Abigail, Hill, Mark S, Grigoriadis, Kristiana, Moore, David A, Black, James RM, Liu, Wing Kin, Thol, Kerstin, Pich, Oriol, Watkins, Thomas BK, Naceur-Lombardelli, Cristina, Cook, Daniel E, Salgado, Roberto, Wilson, Gareth A, Bailey, Chris, Angelova, Mihaela, Bentham, Robert, Martinez-Ruiz, Carlos, Abbosh, Christopher, Nicholson, Andrew G, Le Quesne, John, Biswas, Dhruva, Rosenthal, Rachel, Puttick, Clare, Hessey, Sonya, Lee, Claudia, Prymas, Paulina, Toncheva, Antonia, Smith, Jon, Xing, Wei, Nicod, Jerome, Price, Gillian, Kerr, Keith M, Naidu, Babu, Middleton, Gary, Blyth, Kevin G, Fennell, Dean A, Forster, Martin D, Lee, Siow Ming, Falzon, Mary, Hewish, Madeleine, Shackcloth, Michael J, Lim, Eric, Benafif, Sarah, Russell, Peter, Boleti, Ekaterini, Krebs, Matthew G, Lester, Jason F, Papadatos-Pastos, Dionysis, Ahmad, Tanya, Thakrar, Ricky M, Lawrence, David, Navani, Neal, Janes, Sam M, Dive, Caroline, Blackhall, Fiona H, Summers, Yvonne, Cave, Judith, Marafioti, Teresa, Herrero, Javier, Quezada, Sergio A, Peggs, Karl S, Schwarz, Roland F, Van Loo, Peter, Miedema, Daniel M, Birkbak, Nicolai J, Hiley, Crispin T, Hackshaw, Allan, Zaccaria, Simone, Jamal-Hanjani, Mariam, McGranahan, Nicholas, Swanton, Charles, Bajaj, Amrita, Nakas, Apostolos, Sodha-Ramdeen, Azmina, Ang, Keng, Tufail, Mohamad, Chowdhry, Mohammed Fiyaz, Scotland, Molly, Boyles, Rebecca, Rathinam, Sridhar, Wilson, Claire, Marrone, Domenic, Dulloo, Sean, Matharu, Gurdeep, Shaw, Jacqui A, Riley, Joa, Primrose, Lindsay, Cheyne, Heather, Khalil, Mohammed, Richardson, Shirley, Cruickshank, Tracey, Gilbert, Kayleigh, Patel, Akshay J, Osman, Aya, Lacson, Christer, Langman, Gerald, Shackleford, Helen, Djearaman, Madava, Kadiri, Salma, Leek, Angela, Hodgkinson, Jack Davies, Totten, Nicola, Montero, Angeles, Smith, Elaine, Fontaine, Eustace, Granato, Felice, Doran, Helen, Novasio, Juliette, Rammohan, Kendadai, Joseph, Leena, Bishop, Paul, Shah, Rajesh, Moss, Stuart, Joshi, Vijay, Crosbie, Philip, Gomes, Fabio, Brown, Kate, Carter, Mathew, Chaturvedi, Anshuman, Priest, Lynsey, Oliveira, Pedro, Lindsay, Colin R, Clipson, Alexandra, Tugwood, Jonathan, Kerr, Alastair, Rothwell, Dominic G, Kilgour, Elaine, Aerts, Hugo JWL, Kaufmann, Tom L, Szallasi, Zoltan, Kisistok, Judit, Sokac, Mateo, Diossy, Miklos, Demeulemeester, Jonas, Stewart, Aengus, Magness, Alastair, Rowan, Andrew, Karamani, Angeliki, Chain, Benny, Campbell, Brittany B, Castignani, Carla, Weeden, Clare E, Richard, Corentin, Pearce, David R, Karagianni, Despoina, Levi, Dina, Hoxha, Elena, Larose Cadieux, Elizabeth, Nye, Emma, Gronroos, Eva, Galvez-Cancino, Felip, Athanasopoulou, Foteini, Gimeno-Valiente, Francisco, Kassiotis, George, Stavrou, Georgia, Mastrokalos, Gerasimos, Zhai, Haoran L, Lowe, Helen L, Matos, Ignacio, Goldman, Jacki, Reading, James L, Rane, Jayant K, Lam, Jie Min, Hartley, John A, Enfield, Katey SS, Selvaraju, Kayalvizhi, Litchfield, Kevin, Ng, Kevin W, Chen, Kezhong, Dijkstra, Krijn, Thakkar, Krupa, Ensell, Leah, Shah, Mansi, Vasquez, Marcos, Litovchenko, Maria, Werner Sunderland, Mariana, Leung, Michelle, Escudero, Mickael, Tanic, Miljana, Sivakumar, Monica, Kanu, Nnennaya, Chervova, Olga, Lucas, Olivia, Al-Sawaf, Othman, Hobson, Philip, Pawlik, Piotr, Stone, Richard Kevin, Hynds, Robert E, Vendramin, Roberto, Saghafinia, Sadegh, Lopez, Saioa, Gamble, Samuel, Ung, Seng Kuong Anakin, Vanloo, Sharon, Boeing, Stefan, Beck, Stephan, Bola, Supreet Kaur, Denner, Tamara, Mourikis, Thanos P, Spanswick, Victoria, Barbe, Vittorio, Lu, Wei-Ting, Hill, William, Wu, Yin, Naito, Yutaka, Ramsden, Zoe, Veiga, Catarina, Royle, Gary, Collins-Fekete, Charles-Antoine, Fraioli, Francesco, Ashford, Paul, Clark, Tristan, Borg, Elaine, Wilson, James, Procter, Alexander James, Ahmed, Asia, Taylor, Magali N, Nair, Arjun, Patrini, Davide, Martinoni Hoogenboom, Emilie, Monk, Fleur, Holding, James W, Choudhary, Junaid, Bhakhri, Kunal, Scarci, Marco, Hayward, Martin, Panagiotopoulos, Nikolaos, Gorman, Pat, Khiroya, Reena, Stephens, Robert CM, Wong, Yien Ning Sophia, Bandula, Steve, Sharp, Abigail, Smith, Sean, Gower, Nicole, Dhanda, Harjot Kaur, Chan, Kitty, Pilotti, Camilla, Leslie, Rachel, Grapa, Anca, Zhang, Hanyun, AbdulJabbar, Khalid, Pan, Xiaoxi, Yuan, Yinyin, Chuter, David, MacKenzie, Mairead, Chee, Serena, Alzetani, Aiman, Scarlett, Lydia, Richards, Jennifer, Ingram, Papawadee, Austin, Silvia, De Sousa, Paulo, Jordan, Simon, Rice, Alexandra, Raubenheimer, Hilgardt, Bhayani, Harshil, Ambrose, Lyn, Devaraj, Anand, Chavan, Hema, Begum, Sofina, Buderi, Silviu, Kaniu, Daniel, Malima, Mpho, Booth, Sarah, Fernandes, Nadia, Shah, Pratibha, Proli, Chiara, Danson, Sarah, Robinson, Lily, Dick, Craig, Kirk, Alan, Asif, Mo, Bilancia, Rocco, Kostoulas, Nikos, and Thomas, Mathew

Subjects
Lung Neoplasms, Treatment Outcome, DNA Copy Number Variations, Mutagenesis, Carcinoma, Non-Small-Cell Lung, Mutation, Smoking, Humans, Adenocarcinoma of Lung, Neoplasm Recurrence, Local, Phylogeny
Abstract

Lung cancer is the leading cause of cancer-associated mortality worldwide1. Here we analysed 1,644 tumour regions sampled at surgery or during follow-up from the first 421 patients with non-small cell lung cancer prospectively enrolled into the TRACERx study. This project aims to decipher lung cancer evolution and address the primary study endpoint: determining the relationship between intratumour heterogeneity and clinical outcome. In lung adenocarcinoma, mutations in 22 out of 40 common cancer genes were under significant subclonal selection, including classical tumour initiators such as TP53 and KRAS. We defined evolutionary dependencies between drivers, mutational processes and whole genome doubling (WGD) events. Despite patients having a history of smoking, 8% of lung adenocarcinomas lacked evidence of tobacco-induced mutagenesis. These tumours also had similar detection rates for EGFR mutations and for RET, ROS1, ALK and MET oncogenic isoforms compared with tumours in never-smokers, which suggests that they have a similar aetiology and pathogenesis. Large subclonal expansions were associated with positive subclonal selection. Patients with tumours harbouring recent subclonal expansions, on the terminus of a phylogenetic branch, had significantly shorter disease-free survival. Subclonal WGD was detected in 19% of tumours, and 10% of tumours harboured multiple subclonal WGDs in parallel. Subclonal, but not truncal, WGD was associated with shorter disease-free survival. Copy number heterogeneity was associated with extrathoracic relapse within 1 year after surgery. These data demonstrate the importance of clonal expansion, WGD and copy number instability in determining the timing and patterns of relapse in non-small cell lung cancer and provide a comprehensive clinical cancer evolutionary data resource. ispartof: NATURE vol:616 issue:7957 ispartof: location:England status: Published online

Published
2023

33. Evolutionary characterization of lung adenocarcinoma morphology in TRACERx

Author

Karasaki, Takahiro, Moore, David A, Veeriah, Selvaraju, Naceur-Lombardelli, Cristina, Toncheva, Antonia, Magno, Neil, Ward, Sophia, Al Bakir, Maise, Watkins, Thomas BK, Grigoriadis, Kristiana, Huebner, Ariana, Hill, Mark S, Frankell, Alexander M, Abbosh, Christopher, Puttick, Clare, Zhai, Haoran, Gimeno-Valiente, Francisco, Saghafinia, Sadegh, Kanu, Nnennaya, Dietzen, Michelle, Pich, Oriol, Lim, Emilia L, Martinez-Ruiz, Carlos, Black, James RM, Biswas, Dhruva, Campbell, Brittany B, Lee, Claudia, Colliver, Emma, Enfield, Katey SS, Hessey, Sonya, Hiley, Crispin T, Zaccaria, Simone, Litchfield, Kevin, Birkbak, Nicolai J, Cadieux, Elizabeth Larose, Demeulemeester, Jonas, Van Loo, Peter, Adusumilli, Prasad R, Tan, Kay See, Cheema, Waseem, Sanchez-Vega, Francisco, Jones, David R, Rekhtman, Natasha, Travis, William D, Hackshaw, Allan, Marafioti, Teresa, Salgado, Roberto, Le Quesne, John, Nicholson, Andrew G, McGranahan, Nicholas, Swanton, Charles, Jamal-Hanjani, Mariam, Lester, Jason F, Bajaj, Amrita, Nakas, Apostolos, Sodha-Ramdeen, Azmina, Ang, Keng, Tufail, Mohamad, Chowdhry, Mohammed Fiyaz, Scotland, Molly, Boyles, Rebecca, Rathinam, Sridhar, Wilson, Claire, Marrone, Domenic, Dulloo, Sean, Fennell, Dean A, Matharu, Gurdeep, Shaw, Jacqui A, Riley, Joan, Primrose, Lindsay, Boleti, Ekaterini, Cheyne, Heather, Khalil, Mohammed, Richardson, Shirley, Cruickshank, Tracey, Price, Gillian, Kerr, Keith M, Benafif, Sarah, Gilbert, Kayleigh, Naidu, Babu, Patel, Akshay J, Osman, Aya, Lacson, Christer, Langman, Gerald, Shackleford, Helen, Djearaman, Madava, Kadiri, Salma, Middleton, Gary, Leek, Angela, Hodgkinson, Jack Davies, Totten, Nicola, Montero, Angeles, Smith, Elaine, Fontaine, Eustace, Granato, Felice, Doran, Helen, Novasio, Juliette, Rammohan, Kendadai, Joseph, Leena, Bishop, Paul, Shah, Rajesh, Moss, Stuart, Joshi, Vijay, Crosbie, Philip, Gomes, Fabio, Brown, Kate, Carter, Mathew, Chaturvedi, Anshuman, Priest, Lynsey, Oliveira, Pedro, Lindsay, Colin R, Blackhall, Fiona H, Krebs, Matthew G, Summers, Yvonne, Clipson, Alexandra, Tugwood, Jonathan, Kerr, Alastair, Rothwell, Dominic G, Kilgour, Elaine, Dive, Caroline, Aerts, Hugo JWL, Schwarz, Roland F, Kaufmann, Tom L, Wilson, Gareth A, Rosenthal, Rachel, Szallasi, Zoltan, Kisistok, Judit, Sokac, Mateo, Diossy, Miklos, Bunkum, Abigail, Stewart, Aengus, Magness, Alastair, Rowan, Andrew, Karamani, Angeliki, Chain, Benny, Castignani, Carla, Bailey, Chris, Weeden, Clare E, Richard, Corentin, Pearce, David R, Karagianni, Despoina, Levi, Dina, Hoxha, Elena, Nye, Emma, Gronroos, Eva, Galvez-Cancino, Felip, Athanasopoulou, Foteini, Kassiotis, George, Stavrou, Georgia, Mastrokalos, Gerasimos, Lowe, Helen L, Matos, Ignacio Garcia, Goldman, Jacki, Reading, James L, Herrero, Javier, Rane, Jayant K, Nicod, Jerome, Lam, Jie Min, Hartley, John A, Peggs, Karl S, Selvaraju, Kayalvizhi, Thol, Kerstin, Ng, Kevin W, Chen, Kezhong, Dijkstra, Krijn, Thakkar, Krupa, Ensell, Leah, Shah, Mansi, Duran, Marcos Vasquez, Litovchenko, Maria, Sunderland, Mariana Werner, Leung, Michelle, Escudero, Mickael, Angelova, Mihaela, Tanic, Miljana, Sivakumar, Monica, Chervova, Olga, Lucas, Olivia, Al-Sawaf, Othman, Prymas, Paulina, Hobson, Philip, Pawlik, Piotr, Stone, Richard Kevin, Bentham, Robert, Hynds, Robert E, Vendramin, Roberto, Lopez, Saioa, Gamble, Samuel, Ung, Seng Kuong Anakin, Quezada, Sergio A, Vanloo, Sharon, Boeing, Stefan, Beck, Stephan, Bola, Supreet Kaur, Denner, Tamara, Mourikis, Thanos P, Spanswick, Victoria, Barbe, Vittorio, Lu, Wei-Ting, Hill, William, Liu, Wing Kin, Wu, Yin, Naito, Yutaka, Ramsden, Zoe, Veiga, Catarina, Royle, Gary, Collins-Fekete, Charles-Antoine, Fraioli, Francesco, Ashford, Paul, Clark, Tristan, Forster, Martin D, Lee, Siow Ming, Borg, Elaine, Falzon, Mary, Papadatos-Pastos, Dionysis, Wilson, James, Ahmad, Tanya, Procter, Alexander James, Ahmed, Asia, Taylor, Magali N, Nair, Arjun, Lawrence, David, Patrini, Davide, Navani, Neal, Thakrar, Ricky M, Janes, Sam M, Hoogenboom, Emilie Martinoni, Monk, Fleur, Holding, James W, Choudhary, Junaid, Bhakhri, Kunal, Scarci, Marco, Hayward, Martin, Panagiotopoulos, Nikolaos, Gorman, Pat, Khiroya, Reena, Stephens, Robert CM, Wong, Yien Ning Sophia, Bandula, Steve, Sharp, Abigail, Smith, Sean, Gower, Nicole, Dhanda, Harjot Kaur, Chan, Kitty, Pilotti, Camilla, Leslie, Rachel, Grapa, Anca, Zhang, Hanyun, AbdulJabbar, Khalid, Pan, Xiaoxi, Yuan, Yinyin, Chuter, David, MacKenzie, Mairead, Chee, Serena, Alzetani, Aiman, Cave, Judith, Scarlett, Lydia, Richards, Jennifer, Ingram, Papawadee, Austin, Silvia, Lim, Eric, De Sousa, Paulo, Jordan, Simon, Rice, Alexandra, Raubenheimer, Hilgardt, Bhayani, Harshil, Ambrose, Lyn, Devaraj, Anand, Chavan, Hema, Begum, Sofina, Buderi, Silviu, Kaniu, Daniel, Malima, Mpho, Booth, Sarah, Fernandes, Nadia, Shah, Pratibha, Proli, Chiara, Hewish, Madeleine, Danson, Sarah, Shackcloth, Michael J, Robinson, Lily, Russell, Peter, Blyth, Kevin G, Dick, Craig, Kirk, Alan, Asif, Mo, Bilancia, Rocco, Kostoulas, Nikos, and Thomas, Mathew

Subjects
TRACERx Consortium
Abstract

Lung adenocarcinomas (LUADs) display a broad histological spectrum from low-grade lepidic tumors through to mid-grade acinar and papillary and high-grade solid, cribriform and micropapillary tumors. How morphology reflects tumor evolution and disease progression is poorly understood. Whole-exome sequencing data generated from 805 primary tumor regions and 121 paired metastatic samples across 248 LUADs from the TRACERx 421 cohort, together with RNA-sequencing data from 463 primary tumor regions, were integrated with detailed whole-tumor and regional histopathological analysis. Tumors with predominantly high-grade patterns showed increased chromosomal complexity, with higher burden of loss of heterozygosity and subclonal somatic copy number alterations. Individual regions in predominantly high-grade pattern tumors exhibited higher proliferation and lower clonal diversity, potentially reflecting large recent subclonal expansions. Co-occurrence of truncal loss of chromosomes 3p and 3q was enriched in predominantly low-/mid-grade tumors, while purely undifferentiated solid-pattern tumors had a higher frequency of truncal arm or focal 3q gains and SMARCA4 gene alterations compared with mixed-pattern tumors with a solid component, suggesting distinct evolutionary trajectories. Clonal evolution analysis revealed that tumors tend to evolve toward higher-grade patterns. The presence of micropapillary pattern and 'tumor spread through air spaces' were associated with intrathoracic recurrence, in contrast to the presence of solid/cribriform patterns, necrosis and preoperative circulating tumor DNA detection, which were associated with extra-thoracic recurrence. These data provide insights into the relationship between LUAD morphology, the underlying evolutionary genomic landscape, and clinical and anatomical relapse risk. ispartof: NATURE MEDICINE vol:29 issue:4 ispartof: location:United States status: Published online

Published
2023

38. Lineage plasticity in SCLC generates non-neuroendocrine cells primed for vasculogenic mimicry

Author

Pearsall, Sarah M, primary, Williamson, Stuart C, additional, García Marqués, Fernando J, additional, Humphrey, Sam, additional, Hughes, Ellyn, additional, Shue, Yan Ting, additional, Bermudez, Abel, additional, Frese, Kristopher K, additional, Galvin, Melanie, additional, Carter, Mathew, additional, Priest, Lynsey, additional, Kerr, Alastair, additional, Zhou, Cong, additional, Oliver, Trudy G., additional, Humphries, Jonathan D, additional, Humphries, Martin J., additional, Blackhall, Fiona, additional, Cannell, Ian G, additional, Pitteri, Sharon J, additional, Hannon, Gregory J, additional, Sage, Julien, additional, Simpson, Kathryn L, additional, and Dive, Caroline, additional

Published
2022
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40. Abstract 6238: Profiling of the circulating cell-free DNA methylome for detection and subtyping of small cell lung cancers

Author

Rothwell, Dominic G., primary, Chemi, Francesca, additional, Pearce, Simon, additional, Clipson, Alex, additional, Hill, Steven, additional, Conway, Alicia Marie, additional, Richardson, Sophie, additional, Murat, Katarzyna, additional, Caeser, Rebecca, additional, Egger, Jacklynn, additional, Poirier, John T., additional, Kerr, Alastair, additional, Blackhall, Fiona, additional, Rudin, Charles M., additional, and Dive, Caroline, additional

Published
2022
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41. Abstract 3098: The first circulating tumor cell-derived explant (CDX) model of a Merkel cell carcinoma

Author

Frizziero, Melissa, primary, Kilgour, Elaine, additional, Simpson, Kathryn L., additional, Rothwell, Dominic, additional, Frese, Kristopher, additional, Galvin, Melanie, additional, Chen, Yitao, additional, Kerr, Alastair, additional, Humphrey, Sam, additional, Hossain, Mukarram, additional, Valle, Juan W., additional, McNamara, Mairéad G., additional, and Dive, Caroline, additional

Published
2022
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42. Abstract 2808: cfDNA multi-omics profiling and tissue of origin predictions in cancers of unknown primary

Author

Conway, Alicia-Marie, primary, Clipson, Alexandra, additional, Chemi, Francesca, additional, Pearce, Simon, additional, Kamieniecka, Katarzyna, additional, Ferdous, Saba, additional, Richardson, Sophie, additional, Kilgour, Elaine, additional, Krebs, Matthew G., additional, Kerr, Alastair, additional, Rothwell, Dominic, additional, Cook, Natalie, additional, and Dive, Caroline, additional

Published
2022
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46. RELATIONSHIP BETWEEN A SEDENTARY LIFESTYLE AND ADIPOSE INSULIN RESISTANCE.

Author

Andersson, Daniel P., Kerr, Alastair G., Dahlman, Ingrid, Rydén, Mikael, and Arner, Peter

Subjects
*INSULIN resistance, *SEDENTARY lifestyles, *FAT cells, *MULTIPLE regression analysis, *INSULIN sensitivity
Abstract

Sedentary people have insulin resistance in skeletal muscle but whether this also occurs in fat cells is unknown and was examined. Insulin inhibition of hydrolysis of triglycerides (antilipolysis) and stimulation of triglyceride formation (lipogenesis) was investigated in subcutaneous fat cells from 204 sedentary and 336 physically active subjects. Insulin responsiveness (maximum hormone effect) and sensitivity (half maximum effective concentration) were determined. In 69 women hyperinsulinemia-induced circulating fatty acid levels were measured. In 128 women adipose gene expression was analyzed. Responsiveness of insulin for antilipolysis (60% inhibition) and lipogenesis (2-fold stimulation) were similar between sedentary and active subjects. Sensitivity for both measures was about 10-fold decreased in sedentary subjects (p<0.01). However, only the association between antilipolysis sensitivity and physical activity remained significant when adjusting for body mass index, age, sex, waist-to-hip ratio, fat cell size and cardiometabolic disorders in multiple regression. Fatty acid levels decreased following hyperinsulinemia but remained higher in sedentary compared to active women (p=0.01). mRNA expression of insulin receptor and its substrates 1 and 2 was decreased in sedentary subjects. In conclusion, while the maximum effect is preserved, the sensitivity to insulin's antilipolytic effect in subcutaneous fat cells is selectively lower in sedentary subjects. [ABSTRACT FROM AUTHOR]

Published
2023
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48. TIAM1-RAC1 promote survival of Small Cell Lung Cancer cells through antagonizing Nur77-induced BCL2 conformational change

Author

Aishwarya Payapilly, Guilbert, Ryan, Descamps, Tine, White, Gavin, Magee, Peter, Zhou, Cong, Kerr, Alastair, Simpson, Kathryn L., Blackhall, Fiona, Dive, Caroline, and Malliri, Angeliki

Abstract

Code and tables used for the paper "TIAM1-RAC1 promote survival of Small Cell Lung Cancer cells through antagonizing Nur77-induced BCL2 conformational change" Key files: AdiGazdar_NE_ass_genes.csv: a list of gene that define NE cells AdiGazdar_non_NE_ass_genes.csv: a list of gene that define non-NE cells NEscoring_czedit.Rmd: R code for data analyse.

Published
2021
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