Author: "Nye E" / Publication Year Range: Last 10 years - Searchworks@Jio Institute Digital Library Search Results

Your search keyword '"Nye E"' showing total 92 results

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92 results on '"Nye E"'

1. A disease-associated gene desert directs macrophage inflammation through ETS2

Author: Stankey, C. T., Bourges, C., Haag, L. M., Turner-Stokes, T., Piedade, A. P., Palmer-Jones, C., Papa, I., Silva dos Santos, M., Zhang, Q., Cameron, A. J., Legrini, A., Zhang, T., Wood, C. S., New, F. N., Randzavola, L. O., Speidel, L., Brown, A. C., Hall, A., Saffioti, F., Parkes, E. C., Edwards, W., Direskeneli, H., Grayson, P. C., Jiang, L., Merkel, P. A., Saruhan-Direskeneli, G., Sawalha, A. H., Tombetti, E., Quaglia, A., Thorburn, D., Knight, J. C., Rochford, A. P., Murray, C. D., Divakar, P., Green, M., Nye, E., MacRae, J. I., Jamieson, N. B., Skoglund, P., Cader, M. Z., Wallace, C., Thomas, D. C., and Lee, J. C.
Published: 2024
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2. UK multicentre real-world data of the use of cyclin-dependent kinase 4/6 inhibitors in metastatic breast cancer

Author: Gullick, G., Owen, C.N., Watkins, W.J., Cook, S., Helbrow, J., Reed, H., Squires, R., Park, S., Weir, E., Aquilina, F., Webber, N., Nye, E., Atkinson, C., Blair, C., Halstead, A., Daniels, E., Alves, A., Chew, S., Thomas, W., Spensley, S., Beresford, M., Bowen, R., and Robinson, T.
Published: 2024
Full Text: View/download PDF

3. Mixed responses to targeted therapy driven by chromosomal instability through p53 dysfunction and genome doubling

Author: Hobor, S, Al Bakir, M, Hiley, C, Skrzypski, M, Frankell, A, Bakker, B, Watkins, T, Markovets, A, Dry, J, Brown, A, van der Aart, J, van den Bos, H, Spierings, D, Oukrif, D, Novelli, M, Chakrabarti, T, Rabinowitz, A, Ait Hassou, L, Litiere, S, Kerr, D, Tan, L, Kelly, G, Moore, D, Renshaw, M, Venkatesan, S, Hill, W, Huebner, A, Martinez-Ruiz, C, Black, J, Wu, W, Angelova, M, Mcgranahan, N, Downward, J, Chmielecki, J, Barrett, C, Litchfield, K, Chew, S, Blakely, C, de Bruin, E, Foijer, F, Vousden, K, Bivona, T, Lester, J, Bajaj, A, Nakas, A, Sodha-Ramdeen, A, Tufail, M, Scotland, M, Boyles, R, Rathinam, S, Wilson, C, Marrone, D, Dulloo, S, Fennell, D, Matharu, G, Shaw, J, Boleti, E, Cheyne, H, Khalil, M, Richardson, S, Cruickshank, T, Price, G, Kerr, K, Benafif, S, French, J, Gilbert, K, Naidu, B, Patel, A, Osman, A, Enstone, C, Langman, G, Shackleford, H, Djearaman, M, Kadiri, S, Middleton, G, Leek, A, Hodgkinson, J, Totton, N, Montero, A, Smith, E, Fontaine, E, Granato, F, Paiva-Correia, A, Novasio, J, Rammohan, K, Joseph, L, Bishop, P, Shah, R, Moss, S, Joshi, V, Crosbie, P, Brown, K, Carter, M, Chaturvedi, A, Oliveira, P, Lindsay, C, Blackhall, F, Krebs, M, Summers, Y, Clipson, A, Tugwood, J, Kerr, A, Rothwell, D, Dive, C, Aerts, H, Schwarz, R, Kaufmann, T, Wilson, G, Rosenthal, R, Van Loo, P, Birkbak, N, Szallasi, Z, Kisistok, J, Sokac, M, Salgado, R, Diossy, M, Demeulemeester, J, Bunkum, A, Dwornik, A, Magness, A, Rowan, A, Karamani, A, Toncheva, A, Chain, B, Castignani, C, Bailey, C, Abbosh, C, Puttick, C, Weeden, C, Lee, C, Richard, C, Naceur-Lombardelli, C, Pearce, D, Karagianni, D, Biswas, D, Levi, D, Larose Cadieux, E, Lim, E, Colliver, E, Nye, E, Galvez-Cancino, F, Gimeno-Valiente, F, Kassiotis, G, Stavrou, G, Mastrokalos, G, Lowe, H, Matos, I, Noorani, I, Goldman, J, Reading, J, Rane, J, Nicod, J, Hartley, J, Peggs, K, Enfield, K, Selvaraju, K, Thol, K, Ng, K, Chen, K, Dijkstra, K, Grigoriadis, K, Thakkar, K, Ensell, L, Shah, M, Litovchenko, M, Jamal-Hanjani, M, Werner Sunderland, M, Huska, M, Hill, M, Dietzen, M, Leung, M, Escudero, M, Tanic, M, Sivakumar, M, Chervova, O, Lucas, O, Pich, O, Al-Sawaf, O, Prymas, P, Hobson, P, Pawlik, P, Stone, R, Bentham, R, Vendramin, R, Saghafinia, S, Gamble, S, Veeriah, S, Ung, S, Quezada, S, Vanloo, S, Hessey, S, Ward, S, Harries, S, Boeing, S, Beck, S, Bola, S, Karasaki, T, Denner, T, Marafioti, T, Jones, T, Spanswick, V, Barbe, V, Lu, W, Liu, W, Wu, Y, Naito, Y, Ramsden, Z, Veiga, C, Royle, G, Collins-Fekete, C, Fraioli, F, Ashford, P, Forster, M, Lee, S, Borg, E, Falzon, M, Papadatos-Pastos, D, Wilson, J, Ahmad, T, Procter, A, Ahmed, A, Taylor, M, Nair, A, Lawrence, D, Patrini, D, Navani, N, Thakrar, R, Janes, S, Martinoni Hoogenboom, E, Monk, F, Holding, J, Choudhary, J, Bhakhri, K, Scarci, M, Gorman, P, Khiroya, R, Stephens, R, Wong, Y, Kaplar, Z, Bandula, S, Hackshaw, A, Hacker, A, Sharp, A, Smith, S, Kaur Dhanda, H, Pilotti, C, Leslie, R, Grapa, A, Zhang, H, Abduljabbar, K, Pan, X, Yuan, Y, Chuter, D, Mackenzie, M, Chee, S, Alzetani, A, Cave, J, Richards, J, De Sousa, P, Jordan, S, Rice, A, Raubenheimer, H, Bhayani, H, Ambrose, L, Devaraj, A, Chavan, H, Begum, S, Buderi, S, Kaniu, D, Malima, M, Booth, S, Nicholson, A, Fernandes, N, Shah, P, Proli, C, Hewish, M, Danson, S, Shackcloth, M, Robinson, L, Russell, P, Blyth, K, Kidd, A, Dick, C, Le Quesne, J, Kirk, A, Asif, M, Bilancia, R, Kostoulas, N, Thomas, M, Hynds, R, Kanu, N, Zaccaria, S, Gronroos, E, Swanton, C, Hobor S., Al Bakir M., Hiley C. T., Skrzypski M., Frankell A. M., Bakker B., Watkins T. B. K., Markovets A., Dry J. R., Brown A. P., van der Aart J., van den Bos H., Spierings D., Oukrif D., Novelli M., Chakrabarti T., Rabinowitz A. H., Ait Hassou L., Litiere S., Kerr D. L., Tan L., Kelly G., Moore D. A., Renshaw M. J., Venkatesan S., Hill W., Huebner A., Martinez-Ruiz C., Black J. R. M., Wu W., Angelova M., McGranahan N., Downward J., Chmielecki J., Barrett C., Litchfield K., Chew S. K., Blakely C. M., de Bruin E. C., Foijer F., Vousden K. H., Bivona T. G., Lester J. F., Bajaj A., Nakas A., Sodha-Ramdeen A., Tufail M., Scotland M., Boyles R., Rathinam S., Wilson C., Marrone D., Dulloo S., Fennell D. A., Matharu G., Shaw J. A., Boleti E., Cheyne H., Khalil M., Richardson S., Cruickshank T., Price G., Kerr K. M., Benafif S., French J., Gilbert K., Naidu B., Patel A. J., Osman A., Enstone C., Langman G., Shackleford H., Djearaman M., Kadiri S., Middleton G., Leek A., Hodgkinson J. D., Totton N., Montero A., Smith E., Fontaine E., Granato F., Paiva-Correia A., Novasio J., Rammohan K., Joseph L., Bishop P., Shah R., Moss S., Joshi V., Crosbie P. A. J., Brown K. D., Carter M., Chaturvedi A., Oliveira P., Lindsay C. R., Blackhall F. H., Krebs M. G., Summers Y., Clipson A., Tugwood J., Kerr A., Rothwell D. G., Dive C., Aerts H. J. W. L., Schwarz R. F., Kaufmann T. L., Wilson G. A., Rosenthal R., Van Loo P., Birkbak N. J., Szallasi Z., Kisistok J., Sokac M., Salgado R., Diossy M., Demeulemeester J., Bunkum A., Dwornik A., Magness A., Rowan A. J., Karamani A., Toncheva A., Chain B., Castignani C., Bailey C., Abbosh C., Puttick C., Weeden C. E., Lee C., Richard C., Naceur-Lombardelli C., Pearce D. R., Karagianni D., Biswas D., Levi D., Larose Cadieux E., Lim E. L., Colliver E., Nye E., Galvez-Cancino F., Gimeno-Valiente F., Kassiotis G., Stavrou G., Mastrokalos G. -T., Lowe H. L., Matos I. G., Noorani I., Goldman J., Reading J. L., Rane J. K., Nicod J., Hartley J. A., Peggs K. S., Enfield K. S. S., Selvaraju K., Thol K., Ng K. W., Chen K., Dijkstra K., Grigoriadis K., Thakkar K., Ensell L., Shah M., Litovchenko M., Jamal-Hanjani M., Werner Sunderland M., Huska M. R., Hill M. S., Dietzen M., Leung M. M., Escudero M., Tanic M., Sivakumar M., Chervova O., Lucas O., Pich O., Al-Sawaf O., Prymas P., Hobson P., Pawlik P., Stone R. K., Bentham R., Vendramin R., Saghafinia S., Gamble S., Veeriah S., Ung S. K. A., Quezada S. A., Vanloo S., Hessey S., Ward S., Harries S., Boeing S., Beck S., Bola S. K., Karasaki T., Denner T., Marafioti T., Jones T. P., Spanswick V., Barbe V., Lu W. -T., Liu W. K., Wu Y., Naito Y., Ramsden Z., Veiga C., Royle G., Collins-Fekete C. -A., Fraioli F., Ashford P., Forster M. D., Lee S. M., Borg E., Falzon M., Papadatos-Pastos D., Wilson J., Ahmad T., Procter A. J., Ahmed A., Taylor M. N., Nair A., Lawrence D., Patrini D., Navani N., Thakrar R. M., Janes S. M., Martinoni Hoogenboom E., Monk F., Holding J. W., Choudhary J., Bhakhri K., Scarci M., Gorman P., Khiroya R., Stephens R. C. M., Wong Y. N. S., Kaplar Z., Bandula S., Hackshaw A., Hacker A. -M., Sharp A., Smith S., Kaur Dhanda H., Pilotti C., Leslie R., Grapa A., Zhang H., AbdulJabbar K., Pan X., Yuan Y., Chuter D., MacKenzie M., Chee S., Alzetani A., Cave J., Richards J., Lim E., De Sousa P., Jordan S., Rice A., Raubenheimer H., Bhayani H., Ambrose L., Devaraj A., Chavan H., Begum S., Buderi S. I., Kaniu D., Malima M., Booth S., Nicholson A. G., Fernandes N., Shah P., Proli C., Hewish M., Danson S., Shackcloth M. J., Robinson L., Russell P., Blyth K. G., Kidd A., Dick C., Le Quesne J., Kirk A., Asif M., Bilancia R., Kostoulas N., Thomas M., Hynds R. E., Kanu N., Zaccaria S., Gronroos E., Swanton C., Hobor, S, Al Bakir, M, Hiley, C, Skrzypski, M, Frankell, A, Bakker, B, Watkins, T, Markovets, A, Dry, J, Brown, A, van der Aart, J, van den Bos, H, Spierings, D, Oukrif, D, Novelli, M, Chakrabarti, T, Rabinowitz, A, Ait Hassou, L, Litiere, S, Kerr, D, Tan, L, Kelly, G, Moore, D, Renshaw, M, Venkatesan, S, Hill, W, Huebner, A, Martinez-Ruiz, C, Black, J, Wu, W, Angelova, M, Mcgranahan, N, Downward, J, Chmielecki, J, Barrett, C, Litchfield, K, Chew, S, Blakely, C, de Bruin, E, Foijer, F, Vousden, K, Bivona, T, Lester, J, Bajaj, A, Nakas, A, Sodha-Ramdeen, A, Tufail, M, Scotland, M, Boyles, R, Rathinam, S, Wilson, C, Marrone, D, Dulloo, S, Fennell, D, Matharu, G, Shaw, J, Boleti, E, Cheyne, H, Khalil, M, Richardson, S, Cruickshank, T, Price, G, Kerr, K, Benafif, S, French, J, Gilbert, K, Naidu, B, Patel, A, Osman, A, Enstone, C, Langman, G, Shackleford, H, Djearaman, M, Kadiri, S, Middleton, G, Leek, A, Hodgkinson, J, Totton, N, Montero, A, Smith, E, Fontaine, E, Granato, F, Paiva-Correia, A, Novasio, J, Rammohan, K, Joseph, L, Bishop, P, Shah, R, Moss, S, Joshi, V, Crosbie, P, Brown, K, Carter, M, Chaturvedi, A, Oliveira, P, Lindsay, C, Blackhall, F, Krebs, M, Summers, Y, Clipson, A, Tugwood, J, Kerr, A, Rothwell, D, Dive, C, Aerts, H, Schwarz, R, Kaufmann, T, Wilson, G, Rosenthal, R, Van Loo, P, Birkbak, N, Szallasi, Z, Kisistok, J, Sokac, M, Salgado, R, Diossy, M, Demeulemeester, J, Bunkum, A, Dwornik, A, Magness, A, Rowan, A, Karamani, A, Toncheva, A, Chain, B, Castignani, C, Bailey, C, Abbosh, C, Puttick, C, Weeden, C, Lee, C, Richard, C, Naceur-Lombardelli, C, Pearce, D, Karagianni, D, Biswas, D, Levi, D, Larose Cadieux, E, Lim, E, Colliver, E, Nye, E, Galvez-Cancino, F, Gimeno-Valiente, F, Kassiotis, G, Stavrou, G, Mastrokalos, G, Lowe, H, Matos, I, Noorani, I, Goldman, J, Reading, J, Rane, J, Nicod, J, Hartley, J, Peggs, K, Enfield, K, Selvaraju, K, Thol, K, Ng, K, Chen, K, Dijkstra, K, Grigoriadis, K, Thakkar, K, Ensell, L, Shah, M, Litovchenko, M, Jamal-Hanjani, M, Werner Sunderland, M, Huska, M, Hill, M, Dietzen, M, Leung, M, Escudero, M, Tanic, M, Sivakumar, M, Chervova, O, Lucas, O, Pich, O, Al-Sawaf, O, Prymas, P, Hobson, P, Pawlik, P, Stone, R, Bentham, R, Vendramin, R, Saghafinia, S, Gamble, S, Veeriah, S, Ung, S, Quezada, S, Vanloo, S, Hessey, S, Ward, S, Harries, S, Boeing, S, Beck, S, Bola, S, Karasaki, T, Denner, T, Marafioti, T, Jones, T, Spanswick, V, Barbe, V, Lu, W, Liu, W, Wu, Y, Naito, Y, Ramsden, Z, Veiga, C, Royle, G, Collins-Fekete, C, Fraioli, F, Ashford, P, Forster, M, Lee, S, Borg, E, Falzon, M, Papadatos-Pastos, D, Wilson, J, Ahmad, T, Procter, A, Ahmed, A, Taylor, M, Nair, A, Lawrence, D, Patrini, D, Navani, N, Thakrar, R, Janes, S, Martinoni Hoogenboom, E, Monk, F, Holding, J, Choudhary, J, Bhakhri, K, Scarci, M, Gorman, P, Khiroya, R, Stephens, R, Wong, Y, Kaplar, Z, Bandula, S, Hackshaw, A, Hacker, A, Sharp, A, Smith, S, Kaur Dhanda, H, Pilotti, C, Leslie, R, Grapa, A, Zhang, H, Abduljabbar, K, Pan, X, Yuan, Y, Chuter, D, Mackenzie, M, Chee, S, Alzetani, A, Cave, J, Richards, J, De Sousa, P, Jordan, S, Rice, A, Raubenheimer, H, Bhayani, H, Ambrose, L, Devaraj, A, Chavan, H, Begum, S, Buderi, S, Kaniu, D, Malima, M, Booth, S, Nicholson, A, Fernandes, N, Shah, P, Proli, C, Hewish, M, Danson, S, Shackcloth, M, Robinson, L, Russell, P, Blyth, K, Kidd, A, Dick, C, Le Quesne, J, Kirk, A, Asif, M, Bilancia, R, Kostoulas, N, Thomas, M, Hynds, R, Kanu, N, Zaccaria, S, Gronroos, E, Swanton, C, Hobor S., Al Bakir M., Hiley C. T., Skrzypski M., Frankell A. M., Bakker B., Watkins T. B. K., Markovets A., Dry J. R., Brown A. P., van der Aart J., van den Bos H., Spierings D., Oukrif D., Novelli M., Chakrabarti T., Rabinowitz A. H., Ait Hassou L., Litiere S., Kerr D. L., Tan L., Kelly G., Moore D. A., Renshaw M. J., Venkatesan S., Hill W., Huebner A., Martinez-Ruiz C., Black J. R. M., Wu W., Angelova M., McGranahan N., Downward J., Chmielecki J., Barrett C., Litchfield K., Chew S. K., Blakely C. M., de Bruin E. C., Foijer F., Vousden K. H., Bivona T. G., Lester J. F., Bajaj A., Nakas A., Sodha-Ramdeen A., Tufail M., Scotland M., Boyles R., Rathinam S., Wilson C., Marrone D., Dulloo S., Fennell D. A., Matharu G., Shaw J. A., Boleti E., Cheyne H., Khalil M., Richardson S., Cruickshank T., Price G., Kerr K. M., Benafif S., French J., Gilbert K., Naidu B., Patel A. J., Osman A., Enstone C., Langman G., Shackleford H., Djearaman M., Kadiri S., Middleton G., Leek A., Hodgkinson J. D., Totton N., Montero A., Smith E., Fontaine E., Granato F., Paiva-Correia A., Novasio J., Rammohan K., Joseph L., Bishop P., Shah R., Moss S., Joshi V., Crosbie P. A. J., Brown K. D., Carter M., Chaturvedi A., Oliveira P., Lindsay C. R., Blackhall F. H., Krebs M. G., Summers Y., Clipson A., Tugwood J., Kerr A., Rothwell D. G., Dive C., Aerts H. J. W. L., Schwarz R. F., Kaufmann T. L., Wilson G. A., Rosenthal R., Van Loo P., Birkbak N. J., Szallasi Z., Kisistok J., Sokac M., Salgado R., Diossy M., Demeulemeester J., Bunkum A., Dwornik A., Magness A., Rowan A. J., Karamani A., Toncheva A., Chain B., Castignani C., Bailey C., Abbosh C., Puttick C., Weeden C. E., Lee C., Richard C., Naceur-Lombardelli C., Pearce D. R., Karagianni D., Biswas D., Levi D., Larose Cadieux E., Lim E. L., Colliver E., Nye E., Galvez-Cancino F., Gimeno-Valiente F., Kassiotis G., Stavrou G., Mastrokalos G. -T., Lowe H. L., Matos I. G., Noorani I., Goldman J., Reading J. L., Rane J. K., Nicod J., Hartley J. A., Peggs K. S., Enfield K. S. S., Selvaraju K., Thol K., Ng K. W., Chen K., Dijkstra K., Grigoriadis K., Thakkar K., Ensell L., Shah M., Litovchenko M., Jamal-Hanjani M., Werner Sunderland M., Huska M. R., Hill M. S., Dietzen M., Leung M. M., Escudero M., Tanic M., Sivakumar M., Chervova O., Lucas O., Pich O., Al-Sawaf O., Prymas P., Hobson P., Pawlik P., Stone R. K., Bentham R., Vendramin R., Saghafinia S., Gamble S., Veeriah S., Ung S. K. A., Quezada S. A., Vanloo S., Hessey S., Ward S., Harries S., Boeing S., Beck S., Bola S. K., Karasaki T., Denner T., Marafioti T., Jones T. P., Spanswick V., Barbe V., Lu W. -T., Liu W. K., Wu Y., Naito Y., Ramsden Z., Veiga C., Royle G., Collins-Fekete C. -A., Fraioli F., Ashford P., Forster M. D., Lee S. M., Borg E., Falzon M., Papadatos-Pastos D., Wilson J., Ahmad T., Procter A. J., Ahmed A., Taylor M. N., Nair A., Lawrence D., Patrini D., Navani N., Thakrar R. M., Janes S. M., Martinoni Hoogenboom E., Monk F., Holding J. W., Choudhary J., Bhakhri K., Scarci M., Gorman P., Khiroya R., Stephens R. C. M., Wong Y. N. S., Kaplar Z., Bandula S., Hackshaw A., Hacker A. -M., Sharp A., Smith S., Kaur Dhanda H., Pilotti C., Leslie R., Grapa A., Zhang H., AbdulJabbar K., Pan X., Yuan Y., Chuter D., MacKenzie M., Chee S., Alzetani A., Cave J., Richards J., Lim E., De Sousa P., Jordan S., Rice A., Raubenheimer H., Bhayani H., Ambrose L., Devaraj A., Chavan H., Begum S., Buderi S. I., Kaniu D., Malima M., Booth S., Nicholson A. G., Fernandes N., Shah P., Proli C., Hewish M., Danson S., Shackcloth M. J., Robinson L., Russell P., Blyth K. G., Kidd A., Dick C., Le Quesne J., Kirk A., Asif M., Bilancia R., Kostoulas N., Thomas M., Hynds R. E., Kanu N., Zaccaria S., Gronroos E., and Swanton C.
Abstract: The phenomenon of mixed/heterogenous treatment responses to cancer therapies within an individual patient presents a challenging clinical scenario. Furthermore, the molecular basis of mixed intra-patient tumor responses remains unclear. Here, we show that patients with metastatic lung adenocarcinoma harbouring co-mutations of EGFR and TP53, are more likely to have mixed intra-patient tumor responses to EGFR tyrosine kinase inhibition (TKI), compared to those with an EGFR mutation alone. The combined presence of whole genome doubling (WGD) and TP53 co-mutations leads to increased genome instability and genomic copy number aberrations in genes implicated in EGFR TKI resistance. Using mouse models and an in vitro isogenic p53-mutant model system, we provide evidence that WGD provides diverse routes to drug resistance by increasing the probability of acquiring copy-number gains or losses relative to non-WGD cells. These data provide a molecular basis for mixed tumor responses to targeted therapy, within an individual patient, with implications for therapeutic strategies.
Published: 2024

4. The artificial intelligence-based model ANORAK improves histopathological grading of lung adenocarcinoma

Author: Pan, X, Abduljabbar, K, Coelho-Lima, J, Grapa, A, Zhang, H, Cheung, A, Baena, J, Karasaki, T, Wilson, C, Sereno, M, Veeriah, S, Aitken, S, Hackshaw, A, Nicholson, A, Jamal-Hanjani, M, Le Quesne, J, Janes, S, Hacker, A, Sharp, A, Smith, S, Dhanda, H, Chan, K, Pilotti, C, Leslie, R, Chuter, D, Mackenzie, M, Chee, S, Alzetani, A, Lim, E, De Sousa, P, Jordan, S, Rice, A, Raubenheimer, H, Bhayani, H, Ambrose, L, Devaraj, A, Chavan, H, Begum, S, Buderi, S, Kaniu, D, Malima, M, Booth, S, Fernandes, N, Shah, P, Proli, C, Hewish, M, Danson, S, Shackcloth, M, Robinson, L, Russell, P, Blyth, K, Kidd, A, Kirk, A, Asif, M, Bilancia, R, Kostoulas, N, Thomas, M, Dick, C, Lester, J, Bajaj, A, Nakas, A, Sodha-Ramdeen, A, Tufail, M, Scotland, M, Boyles, R, Rathinam, S, Fennell, D, Marrone, D, Dulloo, S, Matharu, G, Shaw, J, Riley, J, Primrose, L, Boleti, E, Cheyne, H, Khalil, M, Richardson, S, Cruickshank, T, Price, G, Kerr, K, Benafif, S, Papadatos-Pastos, D, Wilson, J, Ahmad, T, French, J, Gilbert, K, Naidu, B, Patel, A, Osman, A, Lacson, C, Langman, G, Shackleford, H, Djearaman, M, Kadiri, S, Middleton, G, Leek, A, Hodgkinson, J, Totten, N, Montero, A, Smith, E, Fontaine, E, Granato, F, Novasio, J, Rammohan, K, Joseph, L, Bishop, P, Shah, R, Moss, S, Joshi, V, Crosbie, P, Paiva-Correia, A, Chaturvedi, A, Priest, L, Oliveira, P, Gomes, F, Brown, K, Carter, M, Lindsay, C, Blackhall, F, Krebs, M, Summers, Y, Clipson, A, Tugwood, J, Kerr, A, Rothwell, D, Dive, C, Aerts, H, Schwarz, R, Kaufmann, T, Van Loo, P, Wilson, G, Rosenthal, R, Rowan, A, Bailey, C, Lee, C, Colliver, E, Enfield, K, Hill, M, Angelova, M, Pich, O, Leung, M, Frankell, A, Hiley, C, Zhai, H, Bakir, M, Birkbak, N, Lucas, O, Huebner, A, Puttick, C, Grigoriadis, K, Dietzen, M, Biswas, D, Athanasopoulou, F, Ward, S, Demeulemeester, J, Castignani, C, Cadieux, E, Kisistok, J, Sokac, M, Szallasi, Z, Diossy, M, Salgado, R, Stewart, A, Magness, A, Weeden, C, Levi, D, Gronroos, E, Noorani, I, Goldman, J, Escudero, M, Hobson, P, Vendramin, R, Boeing, S, Denner, T, Barbe, V, Lu, W, Hill, W, Naito, Y, Ramsden, Z, Kassiotis, G, Dwornik, A, Karamani, A, Chain, B, Pearce, D, Karagianni, D, Galvez-Cancino, F, Stavrou, G, Mastrokalos, G, Lowe, H, Matos, I, Reading, J, Hartley, J, Selvaraju, K, Chen, K, Ensell, L, Shah, M, Litovchenko, M, Chervova, O, Pawlik, P, Hynds, R, Gamble, S, Ung, S, Bola, S, Spanswick, V, Wu, Y, Al-Sawaf, O, Jones, T, Beck, S, Tanic, M, Marafioti, T, Borg, E, Falzon, M, Khiroya, R, Toncheva, A, Abbosh, C, Richard, C, Naceur-Lombardelli, C, Gimeno-Valiente, F, Thakkar, K, Sunderland, M, Sivakumar, M, Kanu, N, Prymas, P, Saghafinia, S, Vanloo, S, Lam, J, Liu, W, Bunkum, A, Hessey, S, Zaccaria, S, Martinez-Ruiz, C, Black, J, Thol, K, Bentham, R, Litchfield, K, Mcgranahan, N, Quezada, S, Forster, M, Lee, S, Herrero, J, Nye, E, Stone, R, Nicod, J, Rane, J, Peggs, K, Ng, K, Dijkstra, K, Huska, M, Hoogenboom, E, Monk, F, Holding, J, Choudhary, J, Bhakhri, K, Scarci, M, Gorman, P, Stephens, R, Wong, Y, Kaplar, Z, Bandula, S, Watkins, T, Veiga, C, Royle, G, Collins-Fekete, C, Fraioli, F, Ashford, P, Procter, A, Ahmed, A, Taylor, M, Nair, A, Lawrence, D, Patrini, D, Navani, N, Thakrar, R, Swanton, C, Yuan, Y, Moore, D, Pan X., AbdulJabbar K., Coelho-Lima J., Grapa A. -I., Zhang H., Cheung A. H. K., Baena J., Karasaki T., Wilson C. R., Sereno M., Veeriah S., Aitken S. J., Hackshaw A., Nicholson A. G., Jamal-Hanjani M., Le Quesne J., Janes S. M., Hacker A. -M., Sharp A., Smith S., Dhanda H. K., Chan K., Pilotti C., Leslie R., Chuter D., MacKenzie M., Chee S., Alzetani A., Lim E., De Sousa P., Jordan S., Rice A., Raubenheimer H., Bhayani H., Ambrose L., Devaraj A., Chavan H., Begum S., Buderi S. I., Kaniu D., Malima M., Booth S., Fernandes N., Shah P., Proli C., Hewish M., Danson S., Shackcloth M. J., Robinson L., Russell P., Blyth K. G., Kidd A., Kirk A., Asif M., Bilancia R., Kostoulas N., Thomas M., Dick C., Lester J. F., Bajaj A., Nakas A., Sodha-Ramdeen A., Tufail M., Scotland M., Boyles R., Rathinam S., Fennell D. A., Wilson C., Marrone D., Dulloo S., Matharu G., Shaw J. A., Riley J., Primrose L., Boleti E., Cheyne H., Khalil M., Richardson S., Cruickshank T., Price G., Kerr K. M., Benafif S., Papadatos-Pastos D., Wilson J., Ahmad T., French J., Gilbert K., Naidu B., Patel A. J., Osman A., Lacson C., Langman G., Shackleford H., Djearaman M., Kadiri S., Middleton G., Leek A., Hodgkinson J. D., Totten N., Montero A., Smith E., Fontaine E., Granato F., Novasio J., Rammohan K., Joseph L., Bishop P., Shah R., Moss S., Joshi V., Crosbie P., Paiva-Correia A., Chaturvedi A., Priest L., Oliveira P., Gomes F., Brown K., Carter M., Lindsay C. R., Blackhall F. H., Krebs M. G., Summers Y., Clipson A., Tugwood J., Kerr A., Rothwell D. G., Dive C., Aerts H. J. W. L., Schwarz R. F., Kaufmann T. L., Van Loo P., Wilson G. A., Rosenthal R., Rowan A., Bailey C., Lee C., Colliver E., Enfield K. S. S., Hill M. S., Angelova M., Pich O., Leung M., Frankell A. M., Hiley C. T., Lim E. L., Zhai H., Bakir M. A., Birkbak N. J., Lucas O., Huebner A., Puttick C., Grigoriadis K., Dietzen M., Biswas D., Athanasopoulou F., Ward S., Demeulemeester J., Castignani C., Cadieux E. L., Kisistok J., Sokac M., Szallasi Z., Diossy M., Salgado R., Stewart A., Magness A., Weeden C. E., Levi D., Gronroos E., Noorani I., Goldman J., Escudero M., Hobson P., Vendramin R., Boeing S., Denner T., Barbe V., Lu W. -T., Hill W., Naito Y., Ramsden Z., Kassiotis G., Dwornik A., Karamani A., Chain B., Pearce D. R., Karagianni D., Galvez-Cancino F., Stavrou G., Mastrokalos G., Lowe H. L., Matos I. G., Reading J. L., Hartley J. A., Selvaraju K., Chen K., Ensell L., Shah M., Litovchenko M., Chervova O., Pawlik P., Hynds R. E., Gamble S., Ung S. K. A., Bola S. K., Spanswick V., Wu Y., Al-Sawaf O., Jones T. P., Beck S., Tanic M., Marafioti T., Borg E., Falzon M., Khiroya R., Toncheva A., Abbosh C., Richard C., Naceur-Lombardelli C., Gimeno-Valiente F., Thakkar K., Sunderland M. W., Sivakumar M., Kanu N., Prymas P., Saghafinia S., Vanloo S., Lam J. M., Liu W. K., Bunkum A., Hessey S., Zaccaria S., Martinez-Ruiz C., Black J. R. M., Thol K., Bentham R., Litchfield K., McGranahan N., Quezada S. A., Forster M. D., Lee S. M., Herrero J., Nye E., Stone R. K., Nicod J., Rane J. K., Peggs K. S., Ng K. W., Dijkstra K., Huska M. R., Hoogenboom E. M., Monk F., Holding J. W., Choudhary J., Bhakhri K., Scarci M., Gorman P., Stephens R. C. M., Wong Y. N. S., Kaplar Z., Bandula S., Watkins T. B. K., Veiga C., Royle G., Collins-Fekete C. -A., Fraioli F., Ashford P., Procter A. J., Ahmed A., Taylor M. N., Nair A., Lawrence D., Patrini D., Navani N., Thakrar R. M., Swanton C., Yuan Y., Moore D. A., Pan, X, Abduljabbar, K, Coelho-Lima, J, Grapa, A, Zhang, H, Cheung, A, Baena, J, Karasaki, T, Wilson, C, Sereno, M, Veeriah, S, Aitken, S, Hackshaw, A, Nicholson, A, Jamal-Hanjani, M, Le Quesne, J, Janes, S, Hacker, A, Sharp, A, Smith, S, Dhanda, H, Chan, K, Pilotti, C, Leslie, R, Chuter, D, Mackenzie, M, Chee, S, Alzetani, A, Lim, E, De Sousa, P, Jordan, S, Rice, A, Raubenheimer, H, Bhayani, H, Ambrose, L, Devaraj, A, Chavan, H, Begum, S, Buderi, S, Kaniu, D, Malima, M, Booth, S, Fernandes, N, Shah, P, Proli, C, Hewish, M, Danson, S, Shackcloth, M, Robinson, L, Russell, P, Blyth, K, Kidd, A, Kirk, A, Asif, M, Bilancia, R, Kostoulas, N, Thomas, M, Dick, C, Lester, J, Bajaj, A, Nakas, A, Sodha-Ramdeen, A, Tufail, M, Scotland, M, Boyles, R, Rathinam, S, Fennell, D, Marrone, D, Dulloo, S, Matharu, G, Shaw, J, Riley, J, Primrose, L, Boleti, E, Cheyne, H, Khalil, M, Richardson, S, Cruickshank, T, Price, G, Kerr, K, Benafif, S, Papadatos-Pastos, D, Wilson, J, Ahmad, T, French, J, Gilbert, K, Naidu, B, Patel, A, Osman, A, Lacson, C, Langman, G, Shackleford, H, Djearaman, M, Kadiri, S, Middleton, G, Leek, A, Hodgkinson, J, Totten, N, Montero, A, Smith, E, Fontaine, E, Granato, F, Novasio, J, Rammohan, K, Joseph, L, Bishop, P, Shah, R, Moss, S, Joshi, V, Crosbie, P, Paiva-Correia, A, Chaturvedi, A, Priest, L, Oliveira, P, Gomes, F, Brown, K, Carter, M, Lindsay, C, Blackhall, F, Krebs, M, Summers, Y, Clipson, A, Tugwood, J, Kerr, A, Rothwell, D, Dive, C, Aerts, H, Schwarz, R, Kaufmann, T, Van Loo, P, Wilson, G, Rosenthal, R, Rowan, A, Bailey, C, Lee, C, Colliver, E, Enfield, K, Hill, M, Angelova, M, Pich, O, Leung, M, Frankell, A, Hiley, C, Zhai, H, Bakir, M, Birkbak, N, Lucas, O, Huebner, A, Puttick, C, Grigoriadis, K, Dietzen, M, Biswas, D, Athanasopoulou, F, Ward, S, Demeulemeester, J, Castignani, C, Cadieux, E, Kisistok, J, Sokac, M, Szallasi, Z, Diossy, M, Salgado, R, Stewart, A, Magness, A, Weeden, C, Levi, D, Gronroos, E, Noorani, I, Goldman, J, Escudero, M, Hobson, P, Vendramin, R, Boeing, S, Denner, T, Barbe, V, Lu, W, Hill, W, Naito, Y, Ramsden, Z, Kassiotis, G, Dwornik, A, Karamani, A, Chain, B, Pearce, D, Karagianni, D, Galvez-Cancino, F, Stavrou, G, Mastrokalos, G, Lowe, H, Matos, I, Reading, J, Hartley, J, Selvaraju, K, Chen, K, Ensell, L, Shah, M, Litovchenko, M, Chervova, O, Pawlik, P, Hynds, R, Gamble, S, Ung, S, Bola, S, Spanswick, V, Wu, Y, Al-Sawaf, O, Jones, T, Beck, S, Tanic, M, Marafioti, T, Borg, E, Falzon, M, Khiroya, R, Toncheva, A, Abbosh, C, Richard, C, Naceur-Lombardelli, C, Gimeno-Valiente, F, Thakkar, K, Sunderland, M, Sivakumar, M, Kanu, N, Prymas, P, Saghafinia, S, Vanloo, S, Lam, J, Liu, W, Bunkum, A, Hessey, S, Zaccaria, S, Martinez-Ruiz, C, Black, J, Thol, K, Bentham, R, Litchfield, K, Mcgranahan, N, Quezada, S, Forster, M, Lee, S, Herrero, J, Nye, E, Stone, R, Nicod, J, Rane, J, Peggs, K, Ng, K, Dijkstra, K, Huska, M, Hoogenboom, E, Monk, F, Holding, J, Choudhary, J, Bhakhri, K, Scarci, M, Gorman, P, Stephens, R, Wong, Y, Kaplar, Z, Bandula, S, Watkins, T, Veiga, C, Royle, G, Collins-Fekete, C, Fraioli, F, Ashford, P, Procter, A, Ahmed, A, Taylor, M, Nair, A, Lawrence, D, Patrini, D, Navani, N, Thakrar, R, Swanton, C, Yuan, Y, Moore, D, Pan X., AbdulJabbar K., Coelho-Lima J., Grapa A. -I., Zhang H., Cheung A. H. K., Baena J., Karasaki T., Wilson C. R., Sereno M., Veeriah S., Aitken S. J., Hackshaw A., Nicholson A. G., Jamal-Hanjani M., Le Quesne J., Janes S. M., Hacker A. -M., Sharp A., Smith S., Dhanda H. K., Chan K., Pilotti C., Leslie R., Chuter D., MacKenzie M., Chee S., Alzetani A., Lim E., De Sousa P., Jordan S., Rice A., Raubenheimer H., Bhayani H., Ambrose L., Devaraj A., Chavan H., Begum S., Buderi S. I., Kaniu D., Malima M., Booth S., Fernandes N., Shah P., Proli C., Hewish M., Danson S., Shackcloth M. J., Robinson L., Russell P., Blyth K. G., Kidd A., Kirk A., Asif M., Bilancia R., Kostoulas N., Thomas M., Dick C., Lester J. F., Bajaj A., Nakas A., Sodha-Ramdeen A., Tufail M., Scotland M., Boyles R., Rathinam S., Fennell D. A., Wilson C., Marrone D., Dulloo S., Matharu G., Shaw J. A., Riley J., Primrose L., Boleti E., Cheyne H., Khalil M., Richardson S., Cruickshank T., Price G., Kerr K. M., Benafif S., Papadatos-Pastos D., Wilson J., Ahmad T., French J., Gilbert K., Naidu B., Patel A. J., Osman A., Lacson C., Langman G., Shackleford H., Djearaman M., Kadiri S., Middleton G., Leek A., Hodgkinson J. D., Totten N., Montero A., Smith E., Fontaine E., Granato F., Novasio J., Rammohan K., Joseph L., Bishop P., Shah R., Moss S., Joshi V., Crosbie P., Paiva-Correia A., Chaturvedi A., Priest L., Oliveira P., Gomes F., Brown K., Carter M., Lindsay C. R., Blackhall F. H., Krebs M. G., Summers Y., Clipson A., Tugwood J., Kerr A., Rothwell D. G., Dive C., Aerts H. J. W. L., Schwarz R. F., Kaufmann T. L., Van Loo P., Wilson G. A., Rosenthal R., Rowan A., Bailey C., Lee C., Colliver E., Enfield K. S. S., Hill M. S., Angelova M., Pich O., Leung M., Frankell A. M., Hiley C. T., Lim E. L., Zhai H., Bakir M. A., Birkbak N. J., Lucas O., Huebner A., Puttick C., Grigoriadis K., Dietzen M., Biswas D., Athanasopoulou F., Ward S., Demeulemeester J., Castignani C., Cadieux E. L., Kisistok J., Sokac M., Szallasi Z., Diossy M., Salgado R., Stewart A., Magness A., Weeden C. E., Levi D., Gronroos E., Noorani I., Goldman J., Escudero M., Hobson P., Vendramin R., Boeing S., Denner T., Barbe V., Lu W. -T., Hill W., Naito Y., Ramsden Z., Kassiotis G., Dwornik A., Karamani A., Chain B., Pearce D. R., Karagianni D., Galvez-Cancino F., Stavrou G., Mastrokalos G., Lowe H. L., Matos I. G., Reading J. L., Hartley J. A., Selvaraju K., Chen K., Ensell L., Shah M., Litovchenko M., Chervova O., Pawlik P., Hynds R. E., Gamble S., Ung S. K. A., Bola S. K., Spanswick V., Wu Y., Al-Sawaf O., Jones T. P., Beck S., Tanic M., Marafioti T., Borg E., Falzon M., Khiroya R., Toncheva A., Abbosh C., Richard C., Naceur-Lombardelli C., Gimeno-Valiente F., Thakkar K., Sunderland M. W., Sivakumar M., Kanu N., Prymas P., Saghafinia S., Vanloo S., Lam J. M., Liu W. K., Bunkum A., Hessey S., Zaccaria S., Martinez-Ruiz C., Black J. R. M., Thol K., Bentham R., Litchfield K., McGranahan N., Quezada S. A., Forster M. D., Lee S. M., Herrero J., Nye E., Stone R. K., Nicod J., Rane J. K., Peggs K. S., Ng K. W., Dijkstra K., Huska M. R., Hoogenboom E. M., Monk F., Holding J. W., Choudhary J., Bhakhri K., Scarci M., Gorman P., Stephens R. C. M., Wong Y. N. S., Kaplar Z., Bandula S., Watkins T. B. K., Veiga C., Royle G., Collins-Fekete C. -A., Fraioli F., Ashford P., Procter A. J., Ahmed A., Taylor M. N., Nair A., Lawrence D., Patrini D., Navani N., Thakrar R. M., Swanton C., Yuan Y., and Moore D. A.
Abstract: The introduction of the International Association for the Study of Lung Cancer grading system has furthered interest in histopathological grading for risk stratification in lung adenocarcinoma. Complex morphology and high intratumoral heterogeneity present challenges to pathologists, prompting the development of artificial intelligence (AI) methods. Here we developed ANORAK (pyrAmid pooliNg crOss stReam Attention networK), encoding multiresolution inputs with an attention mechanism, to delineate growth patterns from hematoxylin and eosin-stained slides. In 1,372 lung adenocarcinomas across four independent cohorts, AI-based grading was prognostic of disease-free survival, and further assisted pathologists by consistently improving prognostication in stage I tumors. Tumors with discrepant patterns between AI and pathologists had notably higher intratumoral heterogeneity. Furthermore, ANORAK facilitates the morphological and spatial assessment of the acinar pattern, capturing acinus variations with pattern transition. Collectively, our AI method enabled the precision quantification and morphology investigation of growth patterns, reflecting intratumoral histological transitions in lung adenocarcinoma.
Published: 2024

5. Solid as a rock, flexible as water? Effectiveness of a school-based intervention addressing students' intrapersonal and interpersonal domains

Author: Mertens, E.C.A., Deković, M., Van Londen, M., Nye, E., and Reitz, E.
Published: 2022
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6. γδ T cells compose a developmentally regulated intrauterine population and protect against vaginal candidiasis

Author: Monin, L., Ushakov, D. S., Arnesen, H., Bah, N., Jandke, A., Muñoz-Ruiz, M., Carvalho, J., Joseph, S., Almeida, B. C., Green, M. J., Nye, E., Hatano, S., Yoshikai, Y., Curtis, M., Carlsen, H., Steinhoff, U., Boysen, P., and Hayday, A.
Published: 2020
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7. Body composition and lung cancer-associated cachexia in TRACERx

Author: Al-Sawaf, O, Weiss, J, Skrzypski, M, Lam, J, Karasaki, T, Zambrana, F, Kidd, A, Frankell, A, Watkins, T, Martinez-Ruiz, C, Puttick, C, Black, J, Huebner, A, Bakir, M, Sokac, M, Collins, S, Veeriah, S, Magno, N, Naceur-Lombardelli, C, Prymas, P, Toncheva, A, Ward, S, Jayanth, N, Salgado, R, Bridge, C, Christiani, D, Mak, R, Bay, C, Rosenthal, M, Sattar, N, Welsh, P, Liu, Y, Perrimon, N, Popuri, K, Beg, M, Mcgranahan, N, Hackshaw, A, Breen, D, O'Rahilly, S, Birkbak, N, Aerts, H, Lester, J, Bajaj, A, Nakas, A, Sodha-Ramdeen, A, Ang, K, Tufail, M, Chowdhry, M, Scotland, M, Boyles, R, Rathinam, S, Wilson, C, Marrone, D, Dulloo, S, Fennell, D, Matharu, G, Shaw, J, Riley, J, Primrose, L, Boleti, E, Cheyne, H, Khalil, M, Richardson, S, Cruickshank, T, Price, G, Kerr, K, Benafif, S, Gilbert, K, Naidu, B, Patel, A, Osman, A, Lacson, C, Langman, G, Shackleford, H, Djearaman, M, Kadiri, S, Middleton, G, Leek, A, Hodgkinson, J, Totten, N, Montero, A, Smith, E, Fontaine, E, Granato, F, Doran, H, Novasio, J, Rammohan, K, Joseph, L, Bishop, P, Shah, R, Moss, S, Joshi, V, Crosbie, P, Gomes, F, Brown, K, Carter, M, Chaturvedi, A, Priest, L, Oliveira, P, Lindsay, C, Blackhall, F, Krebs, M, Summers, Y, Clipson, A, Tugwood, J, Kerr, A, Rothwell, D, Kilgour, E, Dive, C, Schwarz, R, Kaufmann, T, Wilson, G, Rosenthal, R, Van Loo, P, Szallasi, Z, Kisistok, J, Diossy, M, Demeulemeester, J, Bunkum, A, Stewart, A, Magness, A, Rowan, A, Karamani, A, Chain, B, Campbell, B, Castignani, C, Bailey, C, Abbosh, C, Weeden, C, Lee, C, Richard, C, Hiley, C, Moore, D, Pearce, D, Karagianni, D, Biswas, D, Levi, D, Hoxha, E, Cadieux, E, Lim, E, Colliver, E, Nye, E, Gronroos, E, Galvez-Cancino, F, Athanasopoulou, F, Gimeno-Valiente, F, Kassiotis, G, Stavrou, G, Mastrokalos, G, Zhai, H, Lowe, H, Matos, I, Goldman, J, Reading, J, Herrero, J, Rane, J, Nicod, J, Hartley, J, Peggs, K, Enfield, K, Selvaraju, K, Thol, K, Litchfield, K, Ng, K, Chen, K, Dijkstra, K, Grigoriadis, K, Thakkar, K, Ensell, L, Shah, M, Duran, M, Litovchenko, M, Sunderland, M, Hill, M, Dietzen, M, Leung, M, Escudero, M, Angelova, M, Tanic, M, Sivakumar, M, Kanu, N, Chervova, O, Lucas, O, Pich, O, Hobson, P, Pawlik, P, Stone, R, Bentham, R, Hynds, R, Vendramin, R, Saghafinia, S, Lopez, S, Gamble, S, Ung, S, Quezada, S, Vanloo, S, Zaccaria, S, Hessey, S, Boeing, S, Beck, S, Bola, S, Denner, T, Marafioti, T, Mourikis, T, Spanswick, V, Barbe, V, Lu, W, Hill, W, Liu, W, Wu, Y, Naito, Y, Ramsden, Z, Veiga, C, Royle, G, Collins-Fekete, C, Fraioli, F, Ashford, P, Clark, T, Forster, M, Lee, S, Borg, E, Falzon, M, Papadatos-Pastos, D, Wilson, J, Ahmad, T, Procter, A, Ahmed, A, Taylor, M, Nair, A, Lawrence, D, Patrini, D, Navani, N, Thakrar, R, Janes, S, Hoogenboom, E, Monk, F, Holding, J, Choudhary, J, Bhakhri, K, Scarci, M, Hayward, M, Panagiotopoulos, N, Gorman, P, Khiroya, R, Stephens, R, Wong, Y, Bandula, S, Sharp, A, Smith, S, Gower, N, Dhanda, H, Chan, K, Pilotti, C, Leslie, R, Grapa, A, Zhang, H, Abduljabbar, K, Pan, X, Yuan, Y, Chuter, D, Mackenzie, M, Chee, S, Alzetani, A, Cave, J, Scarlett, L, Richards, J, Ingram, P, Austin, S, De Sousa, P, Jordan, S, Rice, A, Raubenheimer, H, Bhayani, H, Ambrose, L, Devaraj, A, Chavan, H, Begum, S, Buderi, S, Kaniu, D, Malima, M, Booth, S, Nicholson, A, Fernandes, N, Shah, P, Proli, C, Hewish, M, Danson, S, Shackcloth, M, Robinson, L, Russell, P, Blyth, K, Dick, C, Le Quesne, J, Kirk, A, Asif, M, Bilancia, R, Kostoulas, N, Thomas, M, Jamal-Hanjani, M, Swanton, C, Al-Sawaf O., Weiss J., Skrzypski M., Lam J. M., Karasaki T., Zambrana F., Kidd A. C., Frankell A. M., Watkins T. B. K., Martinez-Ruiz C., Puttick C., Black J. R. M., Huebner A., Bakir M. A., Sokac M., Collins S., Veeriah S., Magno N., Naceur-Lombardelli C., Prymas P., Toncheva A., Ward S., Jayanth N., Salgado R., Bridge C. P., Christiani D. C., Mak R. H., Bay C., Rosenthal M., Sattar N., Welsh P., Liu Y., Perrimon N., Popuri K., Beg M. F., McGranahan N., Hackshaw A., Breen D. M., O'Rahilly S., Birkbak N. J., Aerts H. J. W. L., Aerts H. J., Lester J. F., Bajaj A., Nakas A., Sodha-Ramdeen A., Ang K., Tufail M., Chowdhry M. F., Scotland M., Boyles R., Rathinam S., Wilson C., Marrone D., Dulloo S., Fennell D. A., Matharu G., Shaw J. A., Riley J., Primrose L., Boleti E., Cheyne H., Khalil M., Richardson S., Cruickshank T., Price G., Kerr K. M., Benafif S., Gilbert K., Naidu B., Patel A. J., Osman A., Lacson C., Langman G., Shackleford H., Djearaman M., Kadiri S., Middleton G., Leek A., Hodgkinson J. D., Totten N., Montero A., Smith E., Fontaine E., Granato F., Doran H., Novasio J., Rammohan K., Joseph L., Bishop P., Shah R., Moss S., Joshi V., Crosbie P., Gomes F., Brown K., Carter M., Chaturvedi A., Priest L., Oliveira P., Lindsay C. R., Blackhall F. H., Krebs M. G., Summers Y., Clipson A., Tugwood J., Kerr A., Rothwell D. G., Kilgour E., Dive C., Schwarz R. F., Kaufmann T. L., Wilson G. A., Rosenthal R., Van Loo P., Szallasi Z., Kisistok J., Diossy M., Demeulemeester J., Bunkum A., Stewart A., Magness A., Rowan A., Karamani A., Chain B., Campbell B. B., Castignani C., Bailey C., Abbosh C., Weeden C. E., Lee C., Richard C., Hiley C. T., Moore D. A., Pearce D. R., Karagianni D., Biswas D., Levi D., Hoxha E., Cadieux E. L., Lim E. L., Colliver E., Nye E., Gronroos E., Galvez-Cancino F., Athanasopoulou F., Gimeno-Valiente F., Kassiotis G., Stavrou G., Mastrokalos G., Zhai H., Lowe H. L., Matos I. G., Goldman J., Reading J. L., Herrero J., Rane J. K., Nicod J., Hartley J. A., Peggs K. S., Enfield K. S. S., Selvaraju K., Thol K., Litchfield K., Ng K. W., Chen K., Dijkstra K., Grigoriadis K., Thakkar K., Ensell L., Shah M., Duran M. V., Litovchenko M., Sunderland M. W., Hill M. S., Dietzen M., Leung M., Escudero M., Angelova M., Tanic M., Sivakumar M., Kanu N., Chervova O., Lucas O., Pich O., Hobson P., Pawlik P., Stone R. K., Bentham R., Hynds R. E., Vendramin R., Saghafinia S., Lopez S., Gamble S., Ung S. K. A., Quezada S. A., Vanloo S., Zaccaria S., Hessey S., Boeing S., Beck S., Bola S. K., Denner T., Marafioti T., Mourikis T. P., Spanswick V., Barbe V., Lu W. -T., Hill W., Liu W. K., Wu Y., Naito Y., Ramsden Z., Veiga C., Royle G., Collins-Fekete C. -A., Fraioli F., Ashford P., Clark T., Forster M. D., Lee S. M., Borg E., Falzon M., Papadatos-Pastos D., Wilson J., Ahmad T., Procter A. J., Ahmed A., Taylor M. N., Nair A., Lawrence D., Patrini D., Navani N., Thakrar R. M., Janes S. M., Hoogenboom E. M., Monk F., Holding J. W., Choudhary J., Bhakhri K., Scarci M., Hayward M., Panagiotopoulos N., Gorman P., Khiroya R., Stephens R. C., Wong Y. N. S., Bandula S., Sharp A., Smith S., Gower N., Dhanda H. K., Chan K., Pilotti C., Leslie R., Grapa A., Zhang H., AbdulJabbar K., Pan X., Yuan Y., Chuter D., MacKenzie M., Chee S., Alzetani A., Cave J., Scarlett L., Richards J., Ingram P., Austin S., Lim E., De Sousa P., Jordan S., Rice A., Raubenheimer H., Bhayani H., Ambrose L., Devaraj A., Chavan H., Begum S., Buderi S. I., Kaniu D., Malima M., Booth S., Nicholson A. G., Fernandes N., Shah P., Proli C., Hewish M., Danson S., Shackcloth M. J., Robinson L., Russell P., Blyth K. G., Dick C., Le Quesne J., Kirk A., Asif M., Bilancia R., Kostoulas N., Thomas M., Jamal-Hanjani M., Swanton C., Al-Sawaf, O, Weiss, J, Skrzypski, M, Lam, J, Karasaki, T, Zambrana, F, Kidd, A, Frankell, A, Watkins, T, Martinez-Ruiz, C, Puttick, C, Black, J, Huebner, A, Bakir, M, Sokac, M, Collins, S, Veeriah, S, Magno, N, Naceur-Lombardelli, C, Prymas, P, Toncheva, A, Ward, S, Jayanth, N, Salgado, R, Bridge, C, Christiani, D, Mak, R, Bay, C, Rosenthal, M, Sattar, N, Welsh, P, Liu, Y, Perrimon, N, Popuri, K, Beg, M, Mcgranahan, N, Hackshaw, A, Breen, D, O'Rahilly, S, Birkbak, N, Aerts, H, Lester, J, Bajaj, A, Nakas, A, Sodha-Ramdeen, A, Ang, K, Tufail, M, Chowdhry, M, Scotland, M, Boyles, R, Rathinam, S, Wilson, C, Marrone, D, Dulloo, S, Fennell, D, Matharu, G, Shaw, J, Riley, J, Primrose, L, Boleti, E, Cheyne, H, Khalil, M, Richardson, S, Cruickshank, T, Price, G, Kerr, K, Benafif, S, Gilbert, K, Naidu, B, Patel, A, Osman, A, Lacson, C, Langman, G, Shackleford, H, Djearaman, M, Kadiri, S, Middleton, G, Leek, A, Hodgkinson, J, Totten, N, Montero, A, Smith, E, Fontaine, E, Granato, F, Doran, H, Novasio, J, Rammohan, K, Joseph, L, Bishop, P, Shah, R, Moss, S, Joshi, V, Crosbie, P, Gomes, F, Brown, K, Carter, M, Chaturvedi, A, Priest, L, Oliveira, P, Lindsay, C, Blackhall, F, Krebs, M, Summers, Y, Clipson, A, Tugwood, J, Kerr, A, Rothwell, D, Kilgour, E, Dive, C, Schwarz, R, Kaufmann, T, Wilson, G, Rosenthal, R, Van Loo, P, Szallasi, Z, Kisistok, J, Diossy, M, Demeulemeester, J, Bunkum, A, Stewart, A, Magness, A, Rowan, A, Karamani, A, Chain, B, Campbell, B, Castignani, C, Bailey, C, Abbosh, C, Weeden, C, Lee, C, Richard, C, Hiley, C, Moore, D, Pearce, D, Karagianni, D, Biswas, D, Levi, D, Hoxha, E, Cadieux, E, Lim, E, Colliver, E, Nye, E, Gronroos, E, Galvez-Cancino, F, Athanasopoulou, F, Gimeno-Valiente, F, Kassiotis, G, Stavrou, G, Mastrokalos, G, Zhai, H, Lowe, H, Matos, I, Goldman, J, Reading, J, Herrero, J, Rane, J, Nicod, J, Hartley, J, Peggs, K, Enfield, K, Selvaraju, K, Thol, K, Litchfield, K, Ng, K, Chen, K, Dijkstra, K, Grigoriadis, K, Thakkar, K, Ensell, L, Shah, M, Duran, M, Litovchenko, M, Sunderland, M, Hill, M, Dietzen, M, Leung, M, Escudero, M, Angelova, M, Tanic, M, Sivakumar, M, Kanu, N, Chervova, O, Lucas, O, Pich, O, Hobson, P, Pawlik, P, Stone, R, Bentham, R, Hynds, R, Vendramin, R, Saghafinia, S, Lopez, S, Gamble, S, Ung, S, Quezada, S, Vanloo, S, Zaccaria, S, Hessey, S, Boeing, S, Beck, S, Bola, S, Denner, T, Marafioti, T, Mourikis, T, Spanswick, V, Barbe, V, Lu, W, Hill, W, Liu, W, Wu, Y, Naito, Y, Ramsden, Z, Veiga, C, Royle, G, Collins-Fekete, C, Fraioli, F, Ashford, P, Clark, T, Forster, M, Lee, S, Borg, E, Falzon, M, Papadatos-Pastos, D, Wilson, J, Ahmad, T, Procter, A, Ahmed, A, Taylor, M, Nair, A, Lawrence, D, Patrini, D, Navani, N, Thakrar, R, Janes, S, Hoogenboom, E, Monk, F, Holding, J, Choudhary, J, Bhakhri, K, Scarci, M, Hayward, M, Panagiotopoulos, N, Gorman, P, Khiroya, R, Stephens, R, Wong, Y, Bandula, S, Sharp, A, Smith, S, Gower, N, Dhanda, H, Chan, K, Pilotti, C, Leslie, R, Grapa, A, Zhang, H, Abduljabbar, K, Pan, X, Yuan, Y, Chuter, D, Mackenzie, M, Chee, S, Alzetani, A, Cave, J, Scarlett, L, Richards, J, Ingram, P, Austin, S, De Sousa, P, Jordan, S, Rice, A, Raubenheimer, H, Bhayani, H, Ambrose, L, Devaraj, A, Chavan, H, Begum, S, Buderi, S, Kaniu, D, Malima, M, Booth, S, Nicholson, A, Fernandes, N, Shah, P, Proli, C, Hewish, M, Danson, S, Shackcloth, M, Robinson, L, Russell, P, Blyth, K, Dick, C, Le Quesne, J, Kirk, A, Asif, M, Bilancia, R, Kostoulas, N, Thomas, M, Jamal-Hanjani, M, Swanton, C, Al-Sawaf O., Weiss J., Skrzypski M., Lam J. M., Karasaki T., Zambrana F., Kidd A. C., Frankell A. M., Watkins T. B. K., Martinez-Ruiz C., Puttick C., Black J. R. M., Huebner A., Bakir M. A., Sokac M., Collins S., Veeriah S., Magno N., Naceur-Lombardelli C., Prymas P., Toncheva A., Ward S., Jayanth N., Salgado R., Bridge C. P., Christiani D. C., Mak R. H., Bay C., Rosenthal M., Sattar N., Welsh P., Liu Y., Perrimon N., Popuri K., Beg M. F., McGranahan N., Hackshaw A., Breen D. M., O'Rahilly S., Birkbak N. J., Aerts H. J. W. L., Aerts H. J., Lester J. F., Bajaj A., Nakas A., Sodha-Ramdeen A., Ang K., Tufail M., Chowdhry M. F., Scotland M., Boyles R., Rathinam S., Wilson C., Marrone D., Dulloo S., Fennell D. A., Matharu G., Shaw J. A., Riley J., Primrose L., Boleti E., Cheyne H., Khalil M., Richardson S., Cruickshank T., Price G., Kerr K. M., Benafif S., Gilbert K., Naidu B., Patel A. J., Osman A., Lacson C., Langman G., Shackleford H., Djearaman M., Kadiri S., Middleton G., Leek A., Hodgkinson J. D., Totten N., Montero A., Smith E., Fontaine E., Granato F., Doran H., Novasio J., Rammohan K., Joseph L., Bishop P., Shah R., Moss S., Joshi V., Crosbie P., Gomes F., Brown K., Carter M., Chaturvedi A., Priest L., Oliveira P., Lindsay C. R., Blackhall F. H., Krebs M. G., Summers Y., Clipson A., Tugwood J., Kerr A., Rothwell D. G., Kilgour E., Dive C., Schwarz R. F., Kaufmann T. L., Wilson G. A., Rosenthal R., Van Loo P., Szallasi Z., Kisistok J., Diossy M., Demeulemeester J., Bunkum A., Stewart A., Magness A., Rowan A., Karamani A., Chain B., Campbell B. B., Castignani C., Bailey C., Abbosh C., Weeden C. E., Lee C., Richard C., Hiley C. T., Moore D. A., Pearce D. R., Karagianni D., Biswas D., Levi D., Hoxha E., Cadieux E. L., Lim E. L., Colliver E., Nye E., Gronroos E., Galvez-Cancino F., Athanasopoulou F., Gimeno-Valiente F., Kassiotis G., Stavrou G., Mastrokalos G., Zhai H., Lowe H. L., Matos I. G., Goldman J., Reading J. L., Herrero J., Rane J. K., Nicod J., Hartley J. A., Peggs K. S., Enfield K. S. S., Selvaraju K., Thol K., Litchfield K., Ng K. W., Chen K., Dijkstra K., Grigoriadis K., Thakkar K., Ensell L., Shah M., Duran M. V., Litovchenko M., Sunderland M. W., Hill M. S., Dietzen M., Leung M., Escudero M., Angelova M., Tanic M., Sivakumar M., Kanu N., Chervova O., Lucas O., Pich O., Hobson P., Pawlik P., Stone R. K., Bentham R., Hynds R. E., Vendramin R., Saghafinia S., Lopez S., Gamble S., Ung S. K. A., Quezada S. A., Vanloo S., Zaccaria S., Hessey S., Boeing S., Beck S., Bola S. K., Denner T., Marafioti T., Mourikis T. P., Spanswick V., Barbe V., Lu W. -T., Hill W., Liu W. K., Wu Y., Naito Y., Ramsden Z., Veiga C., Royle G., Collins-Fekete C. -A., Fraioli F., Ashford P., Clark T., Forster M. D., Lee S. M., Borg E., Falzon M., Papadatos-Pastos D., Wilson J., Ahmad T., Procter A. J., Ahmed A., Taylor M. N., Nair A., Lawrence D., Patrini D., Navani N., Thakrar R. M., Janes S. M., Hoogenboom E. M., Monk F., Holding J. W., Choudhary J., Bhakhri K., Scarci M., Hayward M., Panagiotopoulos N., Gorman P., Khiroya R., Stephens R. C., Wong Y. N. S., Bandula S., Sharp A., Smith S., Gower N., Dhanda H. K., Chan K., Pilotti C., Leslie R., Grapa A., Zhang H., AbdulJabbar K., Pan X., Yuan Y., Chuter D., MacKenzie M., Chee S., Alzetani A., Cave J., Scarlett L., Richards J., Ingram P., Austin S., Lim E., De Sousa P., Jordan S., Rice A., Raubenheimer H., Bhayani H., Ambrose L., Devaraj A., Chavan H., Begum S., Buderi S. I., Kaniu D., Malima M., Booth S., Nicholson A. G., Fernandes N., Shah P., Proli C., Hewish M., Danson S., Shackcloth M. J., Robinson L., Russell P., Blyth K. G., Dick C., Le Quesne J., Kirk A., Asif M., Bilancia R., Kostoulas N., Thomas M., Jamal-Hanjani M., and Swanton C.
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.
Published: 2023

8. Evolutionary characterization of lung adenocarcinoma morphology in TRACERx

Author: Karasaki, T, Moore, D, Veeriah, S, Naceur-Lombardelli, C, Toncheva, A, Magno, N, Ward, S, Bakir, M, Watkins, T, Grigoriadis, K, Huebner, A, Hill, M, Frankell, A, Abbosh, C, Puttick, C, Zhai, H, Gimeno-Valiente, F, Saghafinia, S, Kanu, N, Dietzen, M, Pich, O, Lim, E, Martinez-Ruiz, C, Black, J, Biswas, D, Campbell, B, Lee, C, Colliver, E, Enfield, K, Hessey, S, Hiley, C, Zaccaria, S, Litchfield, K, Birkbak, N, Cadieux, E, Demeulemeester, J, Van Loo, P, Adusumilli, P, Tan, K, Cheema, W, Sanchez-Vega, F, Jones, D, Rekhtman, N, Travis, W, Hackshaw, A, Marafioti, T, Salgado, R, Le Quesne, J, Nicholson, A, Lester, J, Bajaj, A, Nakas, A, Sodha-Ramdeen, A, Ang, K, Tufail, M, Chowdhry, M, Scotland, M, Boyles, R, Rathinam, S, Wilson, C, Marrone, D, Dulloo, S, Fennell, D, Matharu, G, Shaw, J, Riley, J, Primrose, L, Boleti, E, Cheyne, H, Khalil, M, Richardson, S, Cruickshank, T, Price, G, Kerr, K, Benafif, S, Gilbert, K, Naidu, B, Patel, A, Osman, A, Lacson, C, Langman, G, Shackleford, H, Djearaman, M, Kadiri, S, Middleton, G, Leek, A, Hodgkinson, J, Totten, N, Montero, A, Smith, E, Fontaine, E, Granato, F, Doran, H, Novasio, J, Rammohan, K, Joseph, L, Bishop, P, Shah, R, Moss, S, Joshi, V, Crosbie, P, Gomes, F, Brown, K, Carter, M, Chaturvedi, A, Priest, L, Oliveira, P, Lindsay, C, Blackhall, F, Krebs, M, Summers, Y, Clipson, A, Tugwood, J, Kerr, A, Rothwell, D, Kilgour, E, Dive, C, Aerts, H, Schwarz, R, Kaufmann, T, Wilson, G, Rosenthal, R, Szallasi, Z, Kisistok, J, Sokac, M, Diossy, M, Bunkum, A, Stewart, A, Magness, A, Rowan, A, Karamani, A, Chain, B, Castignani, C, Bailey, C, Weeden, C, Richard, C, Pearce, D, Karagianni, D, Levi, D, Hoxha, E, Nye, E, Gronroos, E, Galvez-Cancino, F, Athanasopoulou, F, Kassiotis, G, Stavrou, G, Mastrokalos, G, Lowe, H, Matos, I, Goldman, J, Reading, J, Herrero, J, Rane, J, Nicod, J, Lam, J, Hartley, J, Peggs, K, Selvaraju, K, Thol, K, Ng, K, Chen, K, Dijkstra, K, Thakkar, K, Ensell, L, Shah, M, Duran, M, Litovchenko, M, Sunderland, M, Leung, M, Escudero, M, Angelova, M, Tanic, M, Sivakumar, M, Chervova, O, Lucas, O, Al-Sawaf, O, Prymas, P, Hobson, P, Pawlik, P, Stone, R, Bentham, R, Hynds, R, Vendramin, R, Lopez, S, Gamble, S, Ung, S, Quezada, S, Vanloo, S, Boeing, S, Beck, S, Bola, S, Denner, T, Mourikis, T, Spanswick, V, Barbe, V, Lu, W, Hill, W, Liu, W, Wu, Y, Naito, Y, Ramsden, Z, Veiga, C, Royle, G, Collins-Fekete, C, Fraioli, F, Ashford, P, Clark, T, Forster, M, Lee, S, Borg, E, Falzon, M, Papadatos-Pastos, D, Wilson, J, Ahmad, T, Procter, A, Ahmed, A, Taylor, M, Nair, A, Lawrence, D, Patrini, D, Navani, N, Thakrar, R, Janes, S, Hoogenboom, E, Monk, F, Holding, J, Choudhary, J, Bhakhri, K, Scarci, M, Hayward, M, Panagiotopoulos, N, Gorman, P, Khiroya, R, Stephens, R, Wong, Y, Bandula, S, Sharp, A, Smith, S, Gower, N, Dhanda, H, Chan, K, Pilotti, C, Leslie, R, Grapa, A, Zhang, H, Abduljabbar, K, Pan, X, Yuan, Y, Chuter, D, Mackenzie, M, Chee, S, Alzetani, A, Cave, J, Scarlett, L, Richards, J, Ingram, P, Austin, S, De Sousa, P, Jordan, S, Rice, A, Raubenheimer, H, Bhayani, H, Ambrose, L, Devaraj, A, Chavan, H, Begum, S, Buderi, S, Kaniu, D, Malima, M, Booth, S, Fernandes, N, Shah, P, Proli, C, Hewish, M, Danson, S, Shackcloth, M, Robinson, L, Russell, P, Blyth, K, Dick, C, Kirk, A, Asif, M, Bilancia, R, Kostoulas, N, Thomas, M, Mcgranahan, N, Swanton, C, Jamal-Hanjani, M, Karasaki T., Moore D. A., Veeriah S., Naceur-Lombardelli C., Toncheva A., Magno N., Ward S., Bakir M. A., Watkins T. B. K., Grigoriadis K., Huebner A., Hill M. S., Frankell A. M., Abbosh C., Puttick C., Zhai H., Gimeno-Valiente F., Saghafinia S., Kanu N., Dietzen M., Pich O., Lim E. L., Martinez-Ruiz C., Black J. R. M., Biswas D., Campbell B. B., Lee C., Colliver E., Enfield K. S. S., Hessey S., Hiley C. T., Zaccaria S., Litchfield K., Birkbak N. J., Cadieux E. L., Demeulemeester J., Van Loo P., Adusumilli P. S., Tan K. S., Cheema W., Sanchez-Vega F., Jones D. R., Rekhtman N., Travis W. D., Hackshaw A., Marafioti T., Salgado R., Le Quesne J., Nicholson A. G., Lester J. F., Bajaj A., Nakas A., Sodha-Ramdeen A., Ang K., Tufail M., Chowdhry M. F., Scotland M., Boyles R., Rathinam S., Wilson C., Marrone D., Dulloo S., Fennell D. A., Matharu G., Shaw J. A., Riley J., Primrose L., Boleti E., Cheyne H., Khalil M., Richardson S., Cruickshank T., Price G., Kerr K. M., Benafif S., Gilbert K., Naidu B., Patel A. J., Osman A., Lacson C., Langman G., Shackleford H., Djearaman M., Kadiri S., Middleton G., Leek A., Hodgkinson J. D., Totten N., Montero A., Smith E., Fontaine E., Granato F., Doran H., Novasio J., Rammohan K., Joseph L., Bishop P., Shah R., Moss S., Joshi V., Crosbie P., Gomes F., Brown K., Carter M., Chaturvedi A., Priest L., Oliveira P., Lindsay C. R., Blackhall F. H., Krebs M. G., Summers Y., Clipson A., Tugwood J., Kerr A., Rothwell D. G., Kilgour E., Dive C., Aerts H. J. W. L., Schwarz R. F., Kaufmann T. L., Wilson G. A., Rosenthal R., Szallasi Z., Kisistok J., Sokac M., Diossy M., Bunkum A., Stewart A., Magness A., Rowan A., Karamani A., Chain B., Castignani C., Bailey C., Weeden C. E., Richard C., Pearce D. R., Karagianni D., Levi D., Hoxha E., Nye E., Gronroos E., Galvez-Cancino F., Athanasopoulou F., Kassiotis G., Stavrou G., Mastrokalos G., Lowe H. L., Matos I. G., Goldman J., Reading J. L., Herrero J., Rane J. K., Nicod J., Lam J. M., Hartley J. A., Peggs K. S., Selvaraju K., Thol K., Ng K. W., Chen K., Dijkstra K., Thakkar K., Ensell L., Shah M., Duran M. V., Litovchenko M., Sunderland M. W., Leung M., Escudero M., Angelova M., Tanic M., Sivakumar M., Chervova O., Lucas O., Al-Sawaf O., Prymas P., Hobson P., Pawlik P., Stone R. K., Bentham R., Hynds R. E., Vendramin R., Lopez S., Gamble S., Ung S. K. A., Quezada S. A., Vanloo S., Boeing S., Beck S., Bola S. K., Denner T., Mourikis T. P., Spanswick V., Barbe V., Lu W. -T., Hill W., Liu W. K., Wu Y., Naito Y., Ramsden Z., Veiga C., Royle G., Collins-Fekete C. -A., Fraioli F., Ashford P., Clark T., Forster M. D., Lee S. M., Borg E., Falzon M., Papadatos-Pastos D., Wilson J., Ahmad T., Procter A. J., Ahmed A., Taylor M. N., Nair A., Lawrence D., Patrini D., Navani N., Thakrar R. M., Janes S. M., Hoogenboom E. M., Monk F., Holding J. W., Choudhary J., Bhakhri K., Scarci M., Hayward M., Panagiotopoulos N., Gorman P., Khiroya R., Stephens R. C., Wong Y. N. S., Bandula S., Sharp A., Smith S., Gower N., Dhanda H. K., Chan K., Pilotti C., Leslie R., Grapa A., Zhang H., AbdulJabbar K., Pan X., Yuan Y., Chuter D., MacKenzie M., Chee S., Alzetani A., Cave J., Scarlett L., Richards J., Ingram P., Austin S., Lim E., De Sousa P., Jordan S., Rice A., Raubenheimer H., Bhayani H., Ambrose L., Devaraj A., Chavan H., Begum S., Buderi S. I., Kaniu D., Malima M., Booth S., Fernandes N., Shah P., Proli C., Hewish M., Danson S., Shackcloth M. J., Robinson L., Russell P., Blyth K. G., Dick C., Kirk A., Asif M., Bilancia R., Kostoulas N., Thomas M., McGranahan N., Swanton C., Jamal-Hanjani M., Karasaki, T, Moore, D, Veeriah, S, Naceur-Lombardelli, C, Toncheva, A, Magno, N, Ward, S, Bakir, M, Watkins, T, Grigoriadis, K, Huebner, A, Hill, M, Frankell, A, Abbosh, C, Puttick, C, Zhai, H, Gimeno-Valiente, F, Saghafinia, S, Kanu, N, Dietzen, M, Pich, O, Lim, E, Martinez-Ruiz, C, Black, J, Biswas, D, Campbell, B, Lee, C, Colliver, E, Enfield, K, Hessey, S, Hiley, C, Zaccaria, S, Litchfield, K, Birkbak, N, Cadieux, E, Demeulemeester, J, Van Loo, P, Adusumilli, P, Tan, K, Cheema, W, Sanchez-Vega, F, Jones, D, Rekhtman, N, Travis, W, Hackshaw, A, Marafioti, T, Salgado, R, Le Quesne, J, Nicholson, A, Lester, J, Bajaj, A, Nakas, A, Sodha-Ramdeen, A, Ang, K, Tufail, M, Chowdhry, M, Scotland, M, Boyles, R, Rathinam, S, Wilson, C, Marrone, D, Dulloo, S, Fennell, D, Matharu, G, Shaw, J, Riley, J, Primrose, L, Boleti, E, Cheyne, H, Khalil, M, Richardson, S, Cruickshank, T, Price, G, Kerr, K, Benafif, S, Gilbert, K, Naidu, B, Patel, A, Osman, A, Lacson, C, Langman, G, Shackleford, H, Djearaman, M, Kadiri, S, Middleton, G, Leek, A, Hodgkinson, J, Totten, N, Montero, A, Smith, E, Fontaine, E, Granato, F, Doran, H, Novasio, J, Rammohan, K, Joseph, L, Bishop, P, Shah, R, Moss, S, Joshi, V, Crosbie, P, Gomes, F, Brown, K, Carter, M, Chaturvedi, A, Priest, L, Oliveira, P, Lindsay, C, Blackhall, F, Krebs, M, Summers, Y, Clipson, A, Tugwood, J, Kerr, A, Rothwell, D, Kilgour, E, Dive, C, Aerts, H, Schwarz, R, Kaufmann, T, Wilson, G, Rosenthal, R, Szallasi, Z, Kisistok, J, Sokac, M, Diossy, M, Bunkum, A, Stewart, A, Magness, A, Rowan, A, Karamani, A, Chain, B, Castignani, C, Bailey, C, Weeden, C, Richard, C, Pearce, D, Karagianni, D, Levi, D, Hoxha, E, Nye, E, Gronroos, E, Galvez-Cancino, F, Athanasopoulou, F, Kassiotis, G, Stavrou, G, Mastrokalos, G, Lowe, H, Matos, I, Goldman, J, Reading, J, Herrero, J, Rane, J, Nicod, J, Lam, J, Hartley, J, Peggs, K, Selvaraju, K, Thol, K, Ng, K, Chen, K, Dijkstra, K, Thakkar, K, Ensell, L, Shah, M, Duran, M, Litovchenko, M, Sunderland, M, Leung, M, Escudero, M, Angelova, M, Tanic, M, Sivakumar, M, Chervova, O, Lucas, O, Al-Sawaf, O, Prymas, P, Hobson, P, Pawlik, P, Stone, R, Bentham, R, Hynds, R, Vendramin, R, Lopez, S, Gamble, S, Ung, S, Quezada, S, Vanloo, S, Boeing, S, Beck, S, Bola, S, Denner, T, Mourikis, T, Spanswick, V, Barbe, V, Lu, W, Hill, W, Liu, W, Wu, Y, Naito, Y, Ramsden, Z, Veiga, C, Royle, G, Collins-Fekete, C, Fraioli, F, Ashford, P, Clark, T, Forster, M, Lee, S, Borg, E, Falzon, M, Papadatos-Pastos, D, Wilson, J, Ahmad, T, Procter, A, Ahmed, A, Taylor, M, Nair, A, Lawrence, D, Patrini, D, Navani, N, Thakrar, R, Janes, S, Hoogenboom, E, Monk, F, Holding, J, Choudhary, J, Bhakhri, K, Scarci, M, Hayward, M, Panagiotopoulos, N, Gorman, P, Khiroya, R, Stephens, R, Wong, Y, Bandula, S, Sharp, A, Smith, S, Gower, N, Dhanda, H, Chan, K, Pilotti, C, Leslie, R, Grapa, A, Zhang, H, Abduljabbar, K, Pan, X, Yuan, Y, Chuter, D, Mackenzie, M, Chee, S, Alzetani, A, Cave, J, Scarlett, L, Richards, J, Ingram, P, Austin, S, De Sousa, P, Jordan, S, Rice, A, Raubenheimer, H, Bhayani, H, Ambrose, L, Devaraj, A, Chavan, H, Begum, S, Buderi, S, Kaniu, D, Malima, M, Booth, S, Fernandes, N, Shah, P, Proli, C, Hewish, M, Danson, S, Shackcloth, M, Robinson, L, Russell, P, Blyth, K, Dick, C, Kirk, A, Asif, M, Bilancia, R, Kostoulas, N, Thomas, M, Mcgranahan, N, Swanton, C, Jamal-Hanjani, M, Karasaki T., Moore D. A., Veeriah S., Naceur-Lombardelli C., Toncheva A., Magno N., Ward S., Bakir M. A., Watkins T. B. K., Grigoriadis K., Huebner A., Hill M. S., Frankell A. M., Abbosh C., Puttick C., Zhai H., Gimeno-Valiente F., Saghafinia S., Kanu N., Dietzen M., Pich O., Lim E. L., Martinez-Ruiz C., Black J. R. M., Biswas D., Campbell B. B., Lee C., Colliver E., Enfield K. S. S., Hessey S., Hiley C. T., Zaccaria S., Litchfield K., Birkbak N. J., Cadieux E. L., Demeulemeester J., Van Loo P., Adusumilli P. S., Tan K. S., Cheema W., Sanchez-Vega F., Jones D. R., Rekhtman N., Travis W. D., Hackshaw A., Marafioti T., Salgado R., Le Quesne J., Nicholson A. G., Lester J. F., Bajaj A., Nakas A., Sodha-Ramdeen A., Ang K., Tufail M., Chowdhry M. F., Scotland M., Boyles R., Rathinam S., Wilson C., Marrone D., Dulloo S., Fennell D. A., Matharu G., Shaw J. A., Riley J., Primrose L., Boleti E., Cheyne H., Khalil M., Richardson S., Cruickshank T., Price G., Kerr K. M., Benafif S., Gilbert K., Naidu B., Patel A. J., Osman A., Lacson C., Langman G., Shackleford H., Djearaman M., Kadiri S., Middleton G., Leek A., Hodgkinson J. D., Totten N., Montero A., Smith E., Fontaine E., Granato F., Doran H., Novasio J., Rammohan K., Joseph L., Bishop P., Shah R., Moss S., Joshi V., Crosbie P., Gomes F., Brown K., Carter M., Chaturvedi A., Priest L., Oliveira P., Lindsay C. R., Blackhall F. H., Krebs M. G., Summers Y., Clipson A., Tugwood J., Kerr A., Rothwell D. G., Kilgour E., Dive C., Aerts H. J. W. L., Schwarz R. F., Kaufmann T. L., Wilson G. A., Rosenthal R., Szallasi Z., Kisistok J., Sokac M., Diossy M., Bunkum A., Stewart A., Magness A., Rowan A., Karamani A., Chain B., Castignani C., Bailey C., Weeden C. E., Richard C., Pearce D. R., Karagianni D., Levi D., Hoxha E., Nye E., Gronroos E., Galvez-Cancino F., Athanasopoulou F., Kassiotis G., Stavrou G., Mastrokalos G., Lowe H. L., Matos I. G., Goldman J., Reading J. L., Herrero J., Rane J. K., Nicod J., Lam J. M., Hartley J. A., Peggs K. S., Selvaraju K., Thol K., Ng K. W., Chen K., Dijkstra K., Thakkar K., Ensell L., Shah M., Duran M. V., Litovchenko M., Sunderland M. W., Leung M., Escudero M., Angelova M., Tanic M., Sivakumar M., Chervova O., Lucas O., Al-Sawaf O., Prymas P., Hobson P., Pawlik P., Stone R. K., Bentham R., Hynds R. E., Vendramin R., Lopez S., Gamble S., Ung S. K. A., Quezada S. A., Vanloo S., Boeing S., Beck S., Bola S. K., Denner T., Mourikis T. P., Spanswick V., Barbe V., Lu W. -T., Hill W., Liu W. K., Wu Y., Naito Y., Ramsden Z., Veiga C., Royle G., Collins-Fekete C. -A., Fraioli F., Ashford P., Clark T., Forster M. D., Lee S. M., Borg E., Falzon M., Papadatos-Pastos D., Wilson J., Ahmad T., Procter A. J., Ahmed A., Taylor M. N., Nair A., Lawrence D., Patrini D., Navani N., Thakrar R. M., Janes S. M., Hoogenboom E. M., Monk F., Holding J. W., Choudhary J., Bhakhri K., Scarci M., Hayward M., Panagiotopoulos N., Gorman P., Khiroya R., Stephens R. C., Wong Y. N. S., Bandula S., Sharp A., Smith S., Gower N., Dhanda H. K., Chan K., Pilotti C., Leslie R., Grapa A., Zhang H., AbdulJabbar K., Pan X., Yuan Y., Chuter D., MacKenzie M., Chee S., Alzetani A., Cave J., Scarlett L., Richards J., Ingram P., Austin S., Lim E., De Sousa P., Jordan S., Rice A., Raubenheimer H., Bhayani H., Ambrose L., Devaraj A., Chavan H., Begum S., Buderi S. I., Kaniu D., Malima M., Booth S., Fernandes N., Shah P., Proli C., Hewish M., Danson S., Shackcloth M. J., Robinson L., Russell P., Blyth K. G., Dick C., Kirk A., Asif M., Bilancia R., Kostoulas N., Thomas M., McGranahan N., Swanton C., and Jamal-Hanjani M.
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.
Published: 2023

9. Genomic–transcriptomic evolution in lung cancer and metastasis

Author: Martinez-Ruiz, C, Black, J, Puttick, C, Hill, M, Demeulemeester, J, Larose Cadieux, E, Thol, K, Jones, T, Veeriah, S, Naceur-Lombardelli, C, Toncheva, A, Prymas, P, Rowan, A, Ward, S, Cubitt, L, Athanasopoulou, F, Pich, O, Karasaki, T, Moore, D, Salgado, R, Colliver, E, Castignani, C, Dietzen, M, Huebner, A, Al Bakir, M, Tanic, M, Watkins, T, Lim, E, Al-Rashed, A, Lang, D, Clements, J, Cook, D, Rosenthal, R, Wilson, G, Frankell, A, de Carne Trecesson, S, East, P, Kanu, N, Litchfield, K, Birkbak, N, Hackshaw, A, Beck, S, Van Loo, P, Jamal-Hanjani, M, Mcgranahan, N, Swanton, C, Bakir, M, Lester, J, Bajaj, A, Nakas, A, Sodha-Ramdeen, A, Ang, K, Tufail, M, Chowdhry, M, Scotland, M, Boyles, R, Rathinam, S, Wilson, C, Marrone, D, Dulloo, S, Fennell, D, Matharu, G, Shaw, J, Riley, J, Primrose, L, Boleti, E, Cheyne, H, Khalil, M, Richardson, S, Cruickshank, T, Price, G, Kerr, K, Benafif, S, Gilbert, K, Naidu, B, Patel, A, Osman, A, Lacson, C, Langman, G, Shackleford, H, Djearaman, M, Kadiri, S, Middleton, G, Leek, A, Hodgkinson, J, Totten, N, Montero, A, Smith, E, Fontaine, E, Granato, F, Doran, H, Novasio, J, Rammohan, K, Joseph, L, Bishop, P, Shah, R, Moss, S, Joshi, V, Crosbie, P, Gomes, F, Brown, K, Carter, M, Chaturvedi, A, Priest, L, Oliveira, P, Lindsay, C, Blackhall, F, Krebs, M, Summers, Y, Clipson, A, Tugwood, J, Kerr, A, Rothwell, D, Kilgour, E, Dive, C, Aerts, H, Schwarz, R, Kaufmann, T, Szallasi, Z, Kisistok, J, Sokac, M, Diossy, M, Bunkum, A, Stewart, A, Magness, A, Karamani, A, Chain, B, Campbell, B, Bailey, C, Abbosh, C, Weeden, C, Lee, C, Richard, C, Hiley, C, Pearce, D, Karagianni, D, Biswas, D, Levi, D, Hoxha, E, Nye, E, Gronroos, E, Galvez-Cancino, F, Gimeno-Valiente, F, Kassiotis, G, Stavrou, G, Mastrokalos, G, Zhai, H, Lowe, H, Matos, I, Goldman, J, Reading, J, Herrero, J, Rane, J, Nicod, J, Lam, J, Hartley, J, Peggs, K, Enfield, K, Selvaraju, K, Ng, K, Chen, K, Dijkstra, K, Grigoriadis, K, Thakkar, K, Ensell, L, Shah, M, Duran, M, Litovchenko, M, Sunderland, M, Leung, M, Escudero, M, Angelova, M, Sivakumar, M, Chervova, O, Lucas, O, Al-Sawaf, O, Hobson, P, Pawlik, P, Stone, R, Bentham, R, Hynds, R, Vendramin, R, Saghafinia, S, Lopez, S, Gamble, S, Ung, S, Quezada, S, Vanloo, S, Zaccaria, S, Hessey, S, Boeing, S, Bola, S, Denner, T, Marafioti, T, Mourikis, T, Spanswick, V, Barbe, V, Lu, W, Hill, W, Liu, W, Wu, Y, Naito, Y, Ramsden, Z, Veiga, C, Royle, G, Collins-Fekete, C, Fraioli, F, Ashford, P, Clark, T, Forster, M, Lee, S, Borg, E, Falzon, M, Papadatos-Pastos, D, Wilson, J, Ahmad, T, Procter, A, Ahmed, A, Taylor, M, Nair, A, Lawrence, D, Patrini, D, Navani, N, Thakrar, R, Janes, S, Hoogenboom, E, Monk, F, Holding, J, Choudhary, J, Bhakhri, K, Scarci, M, Hayward, M, Panagiotopoulos, N, Gorman, P, Khiroya, R, Stephens, R, Wong, Y, Bandula, S, Sharp, A, Smith, S, Gower, N, Dhanda, H, Chan, K, Pilotti, C, Leslie, R, Grapa, A, Zhang, H, Abduljabbar, K, Pan, X, Yuan, Y, Chuter, D, Mackenzie, M, Chee, S, Alzetani, A, Cave, J, Scarlett, L, Richards, J, Ingram, P, Austin, S, De Sousa, P, Jordan, S, Rice, A, Raubenheimer, H, Bhayani, H, Ambrose, L, Devaraj, A, Chavan, H, Begum, S, Buderi, S, Kaniu, D, Malima, M, Booth, S, Nicholson, A, Fernandes, N, Shah, P, Proli, C, Hewish, M, Danson, S, Shackcloth, M, Robinson, L, Russell, P, Blyth, K, Dick, C, Le Quesne, J, Kirk, A, Asif, M, Bilancia, R, Kostoulas, N, Thomas, M, Martinez-Ruiz C., Black J. R. M., Puttick C., Hill M. S., Demeulemeester J., Larose Cadieux E., Thol K., Jones T. P., Veeriah S., Naceur-Lombardelli C., Toncheva A., Prymas P., Rowan A., Ward S., Cubitt L., Athanasopoulou F., Pich O., Karasaki T., Moore D. A., Salgado R., Colliver E., Castignani C., Dietzen M., Huebner A., Al Bakir M., Tanic M., Watkins T. B. K., Lim E. L., Al-Rashed A. M., Lang D., Clements J., Cook D. E., Rosenthal R., Wilson G. A., Frankell A. M., de Carne Trecesson S., East P., Kanu N., Litchfield K., Birkbak N. J., Hackshaw A., Beck S., Van Loo P., Jamal-Hanjani M., McGranahan N., Swanton C., Bakir M. A., Lester J. F., Bajaj A., Nakas A., Sodha-Ramdeen A., Ang K., Tufail M., Chowdhry M. F., Scotland M., Boyles R., Rathinam S., Wilson C., Marrone D., Dulloo S., Fennell D. A., Matharu G., Shaw J. A., Riley J., Primrose L., Boleti E., Cheyne H., Khalil M., Richardson S., Cruickshank T., Price G., Kerr K. M., Benafif S., Gilbert K., Naidu B., Patel A. J., Osman A., Lacson C., Langman G., Shackleford H., Djearaman M., Kadiri S., Middleton G., Leek A., Hodgkinson J. D., Totten N., Montero A., Smith E., Fontaine E., Granato F., Doran H., Novasio J., Rammohan K., Joseph L., Bishop P., Shah R., Moss S., Joshi V., Crosbie P., Gomes F., Brown K., Carter M., Chaturvedi A., Priest L., Oliveira P., Lindsay C. R., Blackhall F. H., Krebs M. G., Summers Y., Clipson A., Tugwood J., Kerr A., Rothwell D. G., Kilgour E., Dive C., Aerts H. J. W. L., Schwarz R. F., Kaufmann T. L., Szallasi Z., Kisistok J., Sokac M., Diossy M., Bunkum A., Stewart A., Magness A., Karamani A., Chain B., Campbell B. B., Bailey C., Abbosh C., Weeden C. E., Lee C., Richard C., Hiley C. T., Pearce D. R., Karagianni D., Biswas D., Levi D., Hoxha E., Nye E., Gronroos E., Galvez-Cancino F., Gimeno-Valiente F., Kassiotis G., Stavrou G., Mastrokalos G., Zhai H., Lowe H. L., Matos I. G., Goldman J., Reading J. L., Herrero J., Rane J. K., Nicod J., Lam J. M., Hartley J. A., Peggs K. S., Enfield K. S. S., Selvaraju K., Ng K. W., Chen K., Dijkstra K., Grigoriadis K., Thakkar K., Ensell L., Shah M., Duran M. V., Litovchenko M., Sunderland M. W., Leung M., Escudero M., Angelova M., Sivakumar M., Chervova O., Lucas O., Al-Sawaf O., Hobson P., Pawlik P., Stone R. K., Bentham R., Hynds R. E., Vendramin R., Saghafinia S., Lopez S., Gamble S., Ung S. K. A., Quezada S. A., Vanloo S., Zaccaria S., Hessey S., Boeing S., Bola S. K., Denner T., Marafioti T., Mourikis T. P., Spanswick V., Barbe V., Lu W. -T., Hill W., Liu W. K., Wu Y., Naito Y., Ramsden Z., Veiga C., Royle G., Collins-Fekete C. -A., Fraioli F., Ashford P., Clark T., Forster M. D., Lee S. M., Borg E., Falzon M., Papadatos-Pastos D., Wilson J., Ahmad T., Procter A. J., Ahmed A., Taylor M. N., Nair A., Lawrence D., Patrini D., Navani N., Thakrar R. M., Janes S. M., Hoogenboom E. M., Monk F., Holding J. W., Choudhary J., Bhakhri K., Scarci M., Hayward M., Panagiotopoulos N., Gorman P., Khiroya R., Stephens R. C. M., Wong Y. N. S., Bandula S., Sharp A., Smith S., Gower N., Dhanda H. K., Chan K., Pilotti C., Leslie R., Grapa A., Zhang H., AbdulJabbar K., Pan X., Yuan Y., Chuter D., MacKenzie M., Chee S., Alzetani A., Cave J., Scarlett L., Richards J., Ingram P., Austin S., Lim E., De Sousa P., Jordan S., Rice A., Raubenheimer H., Bhayani H., Ambrose L., Devaraj A., Chavan H., Begum S., Buderi S. I., Kaniu D., Malima M., Booth S., Nicholson A. G., Fernandes N., Shah P., Proli C., Hewish M., Danson S., Shackcloth M. J., Robinson L., Russell P., Blyth K. G., Dick C., Le Quesne J., Kirk A., Asif M., Bilancia R., Kostoulas N., Thomas M., Martinez-Ruiz, C, Black, J, Puttick, C, Hill, M, Demeulemeester, J, Larose Cadieux, E, Thol, K, Jones, T, Veeriah, S, Naceur-Lombardelli, C, Toncheva, A, Prymas, P, Rowan, A, Ward, S, Cubitt, L, Athanasopoulou, F, Pich, O, Karasaki, T, Moore, D, Salgado, R, Colliver, E, Castignani, C, Dietzen, M, Huebner, A, Al Bakir, M, Tanic, M, Watkins, T, Lim, E, Al-Rashed, A, Lang, D, Clements, J, Cook, D, Rosenthal, R, Wilson, G, Frankell, A, de Carne Trecesson, S, East, P, Kanu, N, Litchfield, K, Birkbak, N, Hackshaw, A, Beck, S, Van Loo, P, Jamal-Hanjani, M, Mcgranahan, N, Swanton, C, Bakir, M, Lester, J, Bajaj, A, Nakas, A, Sodha-Ramdeen, A, Ang, K, Tufail, M, Chowdhry, M, Scotland, M, Boyles, R, Rathinam, S, Wilson, C, Marrone, D, Dulloo, S, Fennell, D, Matharu, G, Shaw, J, Riley, J, Primrose, L, Boleti, E, Cheyne, H, Khalil, M, Richardson, S, Cruickshank, T, Price, G, Kerr, K, Benafif, S, Gilbert, K, Naidu, B, Patel, A, Osman, A, Lacson, C, Langman, G, Shackleford, H, Djearaman, M, Kadiri, S, Middleton, G, Leek, A, Hodgkinson, J, Totten, N, Montero, A, Smith, E, Fontaine, E, Granato, F, Doran, H, Novasio, J, Rammohan, K, Joseph, L, Bishop, P, Shah, R, Moss, S, Joshi, V, Crosbie, P, Gomes, F, Brown, K, Carter, M, Chaturvedi, A, Priest, L, Oliveira, P, Lindsay, C, Blackhall, F, Krebs, M, Summers, Y, Clipson, A, Tugwood, J, Kerr, A, Rothwell, D, Kilgour, E, Dive, C, Aerts, H, Schwarz, R, Kaufmann, T, Szallasi, Z, Kisistok, J, Sokac, M, Diossy, M, Bunkum, A, Stewart, A, Magness, A, Karamani, A, Chain, B, Campbell, B, Bailey, C, Abbosh, C, Weeden, C, Lee, C, Richard, C, Hiley, C, Pearce, D, Karagianni, D, Biswas, D, Levi, D, Hoxha, E, Nye, E, Gronroos, E, Galvez-Cancino, F, Gimeno-Valiente, F, Kassiotis, G, Stavrou, G, Mastrokalos, G, Zhai, H, Lowe, H, Matos, I, Goldman, J, Reading, J, Herrero, J, Rane, J, Nicod, J, Lam, J, Hartley, J, Peggs, K, Enfield, K, Selvaraju, K, Ng, K, Chen, K, Dijkstra, K, Grigoriadis, K, Thakkar, K, Ensell, L, Shah, M, Duran, M, Litovchenko, M, Sunderland, M, Leung, M, Escudero, M, Angelova, M, Sivakumar, M, Chervova, O, Lucas, O, Al-Sawaf, O, Hobson, P, Pawlik, P, Stone, R, Bentham, R, Hynds, R, Vendramin, R, Saghafinia, S, Lopez, S, Gamble, S, Ung, S, Quezada, S, Vanloo, S, Zaccaria, S, Hessey, S, Boeing, S, Bola, S, Denner, T, Marafioti, T, Mourikis, T, Spanswick, V, Barbe, V, Lu, W, Hill, W, Liu, W, Wu, Y, Naito, Y, Ramsden, Z, Veiga, C, Royle, G, Collins-Fekete, C, Fraioli, F, Ashford, P, Clark, T, Forster, M, Lee, S, Borg, E, Falzon, M, Papadatos-Pastos, D, Wilson, J, Ahmad, T, Procter, A, Ahmed, A, Taylor, M, Nair, A, Lawrence, D, Patrini, D, Navani, N, Thakrar, R, Janes, S, Hoogenboom, E, Monk, F, Holding, J, Choudhary, J, Bhakhri, K, Scarci, M, Hayward, M, Panagiotopoulos, N, Gorman, P, Khiroya, R, Stephens, R, Wong, Y, Bandula, S, Sharp, A, Smith, S, Gower, N, Dhanda, H, Chan, K, Pilotti, C, Leslie, R, Grapa, A, Zhang, H, Abduljabbar, K, Pan, X, Yuan, Y, Chuter, D, Mackenzie, M, Chee, S, Alzetani, A, Cave, J, Scarlett, L, Richards, J, Ingram, P, Austin, S, De Sousa, P, Jordan, S, Rice, A, Raubenheimer, H, Bhayani, H, Ambrose, L, Devaraj, A, Chavan, H, Begum, S, Buderi, S, Kaniu, D, Malima, M, Booth, S, Nicholson, A, Fernandes, N, Shah, P, Proli, C, Hewish, M, Danson, S, Shackcloth, M, Robinson, L, Russell, P, Blyth, K, Dick, C, Le Quesne, J, Kirk, A, Asif, M, Bilancia, R, Kostoulas, N, Thomas, M, Martinez-Ruiz C., Black J. R. M., Puttick C., Hill M. S., Demeulemeester J., Larose Cadieux E., Thol K., Jones T. P., Veeriah S., Naceur-Lombardelli C., Toncheva A., Prymas P., Rowan A., Ward S., Cubitt L., Athanasopoulou F., Pich O., Karasaki T., Moore D. A., Salgado R., Colliver E., Castignani C., Dietzen M., Huebner A., Al Bakir M., Tanic M., Watkins T. B. K., Lim E. L., Al-Rashed A. M., Lang D., Clements J., Cook D. E., Rosenthal R., Wilson G. A., Frankell A. M., de Carne Trecesson S., East P., Kanu N., Litchfield K., Birkbak N. J., Hackshaw A., Beck S., Van Loo P., Jamal-Hanjani M., McGranahan N., Swanton C., Bakir M. A., Lester J. F., Bajaj A., Nakas A., Sodha-Ramdeen A., Ang K., Tufail M., Chowdhry M. F., Scotland M., Boyles R., Rathinam S., Wilson C., Marrone D., Dulloo S., Fennell D. A., Matharu G., Shaw J. A., Riley J., Primrose L., Boleti E., Cheyne H., Khalil M., Richardson S., Cruickshank T., Price G., Kerr K. M., Benafif S., Gilbert K., Naidu B., Patel A. J., Osman A., Lacson C., Langman G., Shackleford H., Djearaman M., Kadiri S., Middleton G., Leek A., Hodgkinson J. D., Totten N., Montero A., Smith E., Fontaine E., Granato F., Doran H., Novasio J., Rammohan K., Joseph L., Bishop P., Shah R., Moss S., Joshi V., Crosbie P., Gomes F., Brown K., Carter M., Chaturvedi A., Priest L., Oliveira P., Lindsay C. R., Blackhall F. H., Krebs M. G., Summers Y., Clipson A., Tugwood J., Kerr A., Rothwell D. G., Kilgour E., Dive C., Aerts H. J. W. L., Schwarz R. F., Kaufmann T. L., Szallasi Z., Kisistok J., Sokac M., Diossy M., Bunkum A., Stewart A., Magness A., Karamani A., Chain B., Campbell B. B., Bailey C., Abbosh C., Weeden C. E., Lee C., Richard C., Hiley C. T., Pearce D. R., Karagianni D., Biswas D., Levi D., Hoxha E., Nye E., Gronroos E., Galvez-Cancino F., Gimeno-Valiente F., Kassiotis G., Stavrou G., Mastrokalos G., Zhai H., Lowe H. L., Matos I. G., Goldman J., Reading J. L., Herrero J., Rane J. K., Nicod J., Lam J. M., Hartley J. A., Peggs K. S., Enfield K. S. S., Selvaraju K., Ng K. W., Chen K., Dijkstra K., Grigoriadis K., Thakkar K., Ensell L., Shah M., Duran M. V., Litovchenko M., Sunderland M. W., Leung M., Escudero M., Angelova M., Sivakumar M., Chervova O., Lucas O., Al-Sawaf O., Hobson P., Pawlik P., Stone R. K., Bentham R., Hynds R. E., Vendramin R., Saghafinia S., Lopez S., Gamble S., Ung S. K. A., Quezada S. A., Vanloo S., Zaccaria S., Hessey S., Boeing S., Bola S. K., Denner T., Marafioti T., Mourikis T. P., Spanswick V., Barbe V., Lu W. -T., Hill W., Liu W. K., Wu Y., Naito Y., Ramsden Z., Veiga C., Royle G., Collins-Fekete C. -A., Fraioli F., Ashford P., Clark T., Forster M. D., Lee S. M., Borg E., Falzon M., Papadatos-Pastos D., Wilson J., Ahmad T., Procter A. J., Ahmed A., Taylor M. N., Nair A., Lawrence D., Patrini D., Navani N., Thakrar R. M., Janes S. M., Hoogenboom E. M., Monk F., Holding J. W., Choudhary J., Bhakhri K., Scarci M., Hayward M., Panagiotopoulos N., Gorman P., Khiroya R., Stephens R. C. M., Wong Y. N. S., Bandula S., Sharp A., Smith S., Gower N., Dhanda H. K., Chan K., Pilotti C., Leslie R., Grapa A., Zhang H., AbdulJabbar K., Pan X., Yuan Y., Chuter D., MacKenzie M., Chee S., Alzetani A., Cave J., Scarlett L., Richards J., Ingram P., Austin S., Lim E., De Sousa P., Jordan S., Rice A., Raubenheimer H., Bhayani H., Ambrose L., Devaraj A., Chavan H., Begum S., Buderi S. I., Kaniu D., Malima M., Booth S., Nicholson A. G., Fernandes N., Shah P., Proli C., Hewish M., Danson S., Shackcloth M. J., Robinson L., Russell P., Blyth K. G., Dick C., Le Quesne J., Kirk A., Asif M., Bilancia R., Kostoulas N., and Thomas M.
Abstract: Intratumour heterogeneity (ITH) fuels lung cancer evolution, which leads to immune evasion and resistance to therapy1. Here, using paired whole-exome and RNA sequencing data, we investigate intratumour transcriptomic diversity in 354 non-small cell lung cancer tumours from 347 out of the first 421 patients prospectively recruited into the TRACERx study2,3. Analyses of 947 tumour regions, representing both primary and metastatic disease, alongside 96 tumour-adjacent normal tissue samples implicate the transcriptome as a major source of phenotypic variation. Gene expression levels and ITH relate to patterns of positive and negative selection during tumour evolution. We observe frequent copy number-independent allele-specific expression that is linked to epigenomic dysfunction. Allele-specific expression can also result in genomic–transcriptomic parallel evolution, which converges on cancer gene disruption. We extract signatures of RNA single-base substitutions and link their aetiology to the activity of the RNA-editing enzymes ADAR and APOBEC3A, thereby revealing otherwise undetected ongoing APOBEC activity in tumours. Characterizing the transcriptomes of primary–metastatic tumour pairs, we combine multiple machine-learning approaches that leverage genomic and transcriptomic variables to link metastasis-seeding potential to the evolutionary context of mutations and increased proliferation within primary tumour regions. These results highlight the interplay between the genome and transcriptome in influencing ITH, lung cancer evolution and metastasis.
Published: 2023

10. Tracking early lung cancer metastatic dissemination in TRACERx using ctDNA

Author: Abbosh, C, Frankell, A, Harrison, T, Kisistok, J, Garnett, A, Johnson, L, Veeriah, S, Moreau, M, Chesh, A, Chaunzwa, T, Weiss, J, Schroeder, M, Ward, S, Grigoriadis, K, Shahpurwalla, A, Litchfield, K, Puttick, C, Biswas, D, Karasaki, T, Black, J, Martinez-Ruiz, C, Bakir, M, Pich, O, Watkins, T, Lim, E, Huebner, A, Moore, D, Godin-Heymann, N, L'Hernault, A, Bye, H, Odell, A, Roberts, P, Gomes, F, Patel, A, Manzano, E, Hiley, C, Carey, N, Riley, J, Cook, D, Hodgson, D, Stetson, D, Barrett, J, Kortlever, R, Evan, G, Hackshaw, A, Daber, R, Shaw, J, Aerts, H, Licon, A, Stahl, J, Jamal-Hanjani, M, Lester, J, Bajaj, A, Nakas, A, Sodha-Ramdeen, A, Ang, K, Tufail, M, Chowdhry, M, Scotland, M, Boyles, R, Rathinam, S, Wilson, C, Marrone, D, Dulloo, S, Fennell, D, Matharu, G, Primrose, L, Boleti, E, Cheyne, H, Khalil, M, Richardson, S, Cruickshank, T, Price, G, Kerr, K, Benafif, S, Gilbert, K, Naidu, B, Osman, A, Lacson, C, Langman, G, Shackleford, H, Djearaman, M, Kadiri, S, Middleton, G, Leek, A, Hodgkinson, J, Totten, N, Montero, A, Smith, E, Fontaine, E, Granato, F, Doran, H, Novasio, J, Rammohan, K, Joseph, L, Bishop, P, Shah, R, Moss, S, Joshi, V, Crosbie, P, Brown, K, Carter, M, Chaturvedi, A, Priest, L, Oliveira, P, Lindsay, C, Blackhall, F, Krebs, M, Summers, Y, Clipson, A, Tugwood, J, Kerr, A, Rothwell, D, Kilgour, E, Dive, C, Schwarz, R, Kaufmann, T, Wilson, G, Rosenthal, R, Van Loo, P, Szallasi, Z, Sokac, M, Salgado, R, Diossy, M, Demeulemeester, J, Bunkum, A, Stewart, A, Magness, A, Rowan, A, Karamani, A, Toncheva, A, Chain, B, Campbell, B, Castignani, C, Bailey, C, Weeden, C, Lee, C, Richard, C, Naceur-Lombardelli, C, Pearce, D, Karagianni, D, Levi, D, Hoxha, E, Larose Cadieux, E, Colliver, E, Nye, E, Gronroos, E, Galvez-Cancino, F, Athanasopoulou, F, Gimeno-Valiente, F, Kassiotis, G, Stavrou, G, Mastrokalos, G, Zhai, H, Lowe, H, Matos, I, Goldman, J, Reading, J, Herrero, J, Rane, J, Nicod, J, Lam, J, Hartley, J, Peggs, K, Enfield, K, Selvaraju, K, Thol, K, Ng, K, Chen, K, Dijkstra, K, Thakkar, K, Ensell, L, Shah, M, Vasquez, M, Litovchenko, M, Werner Sunderland, M, Hill, M, Dietzen, M, Leung, M, Escudero, M, Angelova, M, Tanic, M, Sivakumar, M, Kanu, N, Chervova, O, Lucas, O, Al-Sawaf, O, Prymas, P, Hobson, P, Pawlik, P, Stone, R, Bentham, R, Hynds, R, Vendramin, R, Saghafinia, S, Lopez, S, Gamble, S, Ung, S, Quezada, S, Vanloo, S, Zaccaria, S, Hessey, S, Boeing, S, Beck, S, Bola, S, Denner, T, Marafioti, T, Mourikis, T, Spanswick, V, Barbe, V, Lu, W, Hill, W, Liu, W, Wu, Y, Naito, Y, Ramsden, Z, Veiga, C, Royle, G, Collins-Fekete, C, Fraioli, F, Ashford, P, Clark, T, Forster, M, Lee, S, Borg, E, Falzon, M, Papadatos-Pastos, D, Wilson, J, Ahmad, T, Procter, A, Ahmed, A, Taylor, M, Nair, A, Lawrence, D, Patrini, D, Navani, N, Thakrar, R, Janes, S, Martinoni Hoogenboom, E, Monk, F, Holding, J, Choudhary, J, Bhakhri, K, Scarci, M, Hayward, M, Panagiotopoulos, N, Gorman, P, Khiroya, R, Stephens, R, Wong, Y, Bandula, S, Sharp, A, Smith, S, Gower, N, Dhanda, H, Chan, K, Pilotti, C, Leslie, R, Grapa, A, Zhang, H, Abduljabbar, K, Pan, X, Yuan, Y, Chuter, D, Mackenzie, M, Chee, S, Alzetani, A, Cave, J, Scarlett, L, Richards, J, Ingram, P, Austin, S, De Sousa, P, Jordan, S, Rice, A, Raubenheimer, H, Bhayani, H, Ambrose, L, Devaraj, A, Chavan, H, Begum, S, Buderi, S, Kaniu, D, Malima, M, Booth, S, Nicholson, A, Fernandes, N, Shah, P, Proli, C, Hewish, M, Danson, S, Shackcloth, M, Robinson, L, Russell, P, Blyth, K, Dick, C, Le Quesne, J, Kirk, A, Asif, M, Bilancia, R, Kostoulas, N, Thomas, M, Birkbak, N, Mcgranahan, N, Swanton, C, Abbosh C., Frankell A. M., Harrison T., Kisistok J., Garnett A., Johnson L., Veeriah S., Moreau M., Chesh A., Chaunzwa T. L., Weiss J., Schroeder M. R., Ward S., Grigoriadis K., Shahpurwalla A., Litchfield K., Puttick C., Biswas D., Karasaki T., Black J. R. M., Martinez-Ruiz C., Bakir M. A., Pich O., Watkins T. B. K., Lim E. L., Huebner A., Moore D. A., Godin-Heymann N., L'Hernault A., Bye H., Odell A., Roberts P., Gomes F., Patel A. J., Manzano E., Hiley C. T., Carey N., Riley J., Cook D. E., Hodgson D., Stetson D., Barrett J. C., Kortlever R. M., Evan G. I., Hackshaw A., Daber R. D., Shaw J. A., Aerts H. J. W. L., Licon A., Stahl J., Jamal-Hanjani M., Lester J. F., Bajaj A., Nakas A., Sodha-Ramdeen A., Ang K., Tufail M., Chowdhry M. F., Scotland M., Boyles R., Rathinam S., Wilson C., Marrone D., Dulloo S., Fennell D. A., Matharu G., Primrose L., Boleti E., Cheyne H., Khalil M., Richardson S., Cruickshank T., Price G., Kerr K. M., Benafif S., Gilbert K., Naidu B., Osman A., Lacson C., Langman G., Shackleford H., Djearaman M., Kadiri S., Middleton G., Leek A., Hodgkinson J. D., Totten N., Montero A., Smith E., Fontaine E., Granato F., Doran H., Novasio J., Rammohan K., Joseph L., Bishop P., Shah R., Moss S., Joshi V., Crosbie P., Brown K., Carter M., Chaturvedi A., Priest L., Oliveira P., Lindsay C. R., Blackhall F. H., Krebs M. G., Summers Y., Clipson A., Tugwood J., Kerr A., Rothwell D. G., Kilgour E., Dive C., Schwarz R. F., Kaufmann T. L., Wilson G. A., Rosenthal R., Van Loo P., Szallasi Z., Sokac M., Salgado R., Diossy M., Demeulemeester J., Bunkum A., Stewart A., Magness A., Rowan A., Karamani A., Toncheva A., Chain B., Campbell B. B., Castignani C., Bailey C., Weeden C. E., Lee C., Richard C., Naceur-Lombardelli C., Pearce D. R., Karagianni D., Levi D., Hoxha E., Larose Cadieux E., Colliver E., Nye E., Gronroos E., Galvez-Cancino F., Athanasopoulou F., Gimeno-Valiente F., Kassiotis G., Stavrou G., Mastrokalos G., Zhai H., Lowe H. L., Matos I., Goldman J., Reading J. L., Herrero J., Rane J. K., Nicod J., Lam J. M., Hartley J. A., Peggs K. S., Enfield K. S. S., Selvaraju K., Thol K., Ng K. W., Chen K., Dijkstra K., Thakkar K., Ensell L., Shah M., Vasquez M., Litovchenko M., Werner Sunderland M., Hill M. S., Dietzen M., Leung M., Escudero M., Angelova M., Tanic M., Sivakumar M., Kanu N., Chervova O., Lucas O., Al-Sawaf O., Prymas P., Hobson P., Pawlik P., Stone R. K., Bentham R., Hynds R. E., Vendramin R., Saghafinia S., Lopez S., Gamble S., Ung S. K. A., Quezada S. A., Vanloo S., Zaccaria S., Hessey S., Boeing S., Beck S., Bola S. K., Denner T., Marafioti T., Mourikis T. P., Spanswick V., Barbe V., Lu W. -T., Hill W., Liu W. K., Wu Y., Naito Y., Ramsden Z., Veiga C., Royle G., Collins-Fekete C. -A., Fraioli F., Ashford P., Clark T., Forster M. D., Lee S. M., Borg E., Falzon M., Papadatos-Pastos D., Wilson J., Ahmad T., Procter A. J., Ahmed A., Taylor M. N., Nair A., Lawrence D., Patrini D., Navani N., Thakrar R. M., Janes S. M., Martinoni Hoogenboom E., Monk F., Holding J. W., Choudhary J., Bhakhri K., Scarci M., Hayward M., Panagiotopoulos N., Gorman P., Khiroya R., Stephens R. C., Wong Y. N. S., Bandula S., Sharp A., Smith S., Gower N., Dhanda H. K., Chan K., Pilotti C., Leslie R., Grapa A., Zhang H., AbdulJabbar K., Pan X., Yuan Y., Chuter D., MacKenzie M., Chee S., Alzetani A., Cave J., Scarlett L., Richards J., Ingram P., Austin S., Lim E., De Sousa P., Jordan S., Rice A., Raubenheimer H., Bhayani H., Ambrose L., Devaraj A., Chavan H., Begum S., Buderi S. I., Kaniu D., Malima M., Booth S., Nicholson A. G., Fernandes N., Shah P., Proli C., Hewish M., Danson S., Shackcloth M. J., Robinson L., Russell P., Blyth K. G., Dick C., Le Quesne J., Kirk A., Asif M., Bilancia R., Kostoulas N., Thomas M., Birkbak N. J., McGranahan N., Swanton C., Abbosh, C, Frankell, A, Harrison, T, Kisistok, J, Garnett, A, Johnson, L, Veeriah, S, Moreau, M, Chesh, A, Chaunzwa, T, Weiss, J, Schroeder, M, Ward, S, Grigoriadis, K, Shahpurwalla, A, Litchfield, K, Puttick, C, Biswas, D, Karasaki, T, Black, J, Martinez-Ruiz, C, Bakir, M, Pich, O, Watkins, T, Lim, E, Huebner, A, Moore, D, Godin-Heymann, N, L'Hernault, A, Bye, H, Odell, A, Roberts, P, Gomes, F, Patel, A, Manzano, E, Hiley, C, Carey, N, Riley, J, Cook, D, Hodgson, D, Stetson, D, Barrett, J, Kortlever, R, Evan, G, Hackshaw, A, Daber, R, Shaw, J, Aerts, H, Licon, A, Stahl, J, Jamal-Hanjani, M, Lester, J, Bajaj, A, Nakas, A, Sodha-Ramdeen, A, Ang, K, Tufail, M, Chowdhry, M, Scotland, M, Boyles, R, Rathinam, S, Wilson, C, Marrone, D, Dulloo, S, Fennell, D, Matharu, G, Primrose, L, Boleti, E, Cheyne, H, Khalil, M, Richardson, S, Cruickshank, T, Price, G, Kerr, K, Benafif, S, Gilbert, K, Naidu, B, Osman, A, Lacson, C, Langman, G, Shackleford, H, Djearaman, M, Kadiri, S, Middleton, G, Leek, A, Hodgkinson, J, Totten, N, Montero, A, Smith, E, Fontaine, E, Granato, F, Doran, H, Novasio, J, Rammohan, K, Joseph, L, Bishop, P, Shah, R, Moss, S, Joshi, V, Crosbie, P, Brown, K, Carter, M, Chaturvedi, A, Priest, L, Oliveira, P, Lindsay, C, Blackhall, F, Krebs, M, Summers, Y, Clipson, A, Tugwood, J, Kerr, A, Rothwell, D, Kilgour, E, Dive, C, Schwarz, R, Kaufmann, T, Wilson, G, Rosenthal, R, Van Loo, P, Szallasi, Z, Sokac, M, Salgado, R, Diossy, M, Demeulemeester, J, Bunkum, A, Stewart, A, Magness, A, Rowan, A, Karamani, A, Toncheva, A, Chain, B, Campbell, B, Castignani, C, Bailey, C, Weeden, C, Lee, C, Richard, C, Naceur-Lombardelli, C, Pearce, D, Karagianni, D, Levi, D, Hoxha, E, Larose Cadieux, E, Colliver, E, Nye, E, Gronroos, E, Galvez-Cancino, F, Athanasopoulou, F, Gimeno-Valiente, F, Kassiotis, G, Stavrou, G, Mastrokalos, G, Zhai, H, Lowe, H, Matos, I, Goldman, J, Reading, J, Herrero, J, Rane, J, Nicod, J, Lam, J, Hartley, J, Peggs, K, Enfield, K, Selvaraju, K, Thol, K, Ng, K, Chen, K, Dijkstra, K, Thakkar, K, Ensell, L, Shah, M, Vasquez, M, Litovchenko, M, Werner Sunderland, M, Hill, M, Dietzen, M, Leung, M, Escudero, M, Angelova, M, Tanic, M, Sivakumar, M, Kanu, N, Chervova, O, Lucas, O, Al-Sawaf, O, Prymas, P, Hobson, P, Pawlik, P, Stone, R, Bentham, R, Hynds, R, Vendramin, R, Saghafinia, S, Lopez, S, Gamble, S, Ung, S, Quezada, S, Vanloo, S, Zaccaria, S, Hessey, S, Boeing, S, Beck, S, Bola, S, Denner, T, Marafioti, T, Mourikis, T, Spanswick, V, Barbe, V, Lu, W, Hill, W, Liu, W, Wu, Y, Naito, Y, Ramsden, Z, Veiga, C, Royle, G, Collins-Fekete, C, Fraioli, F, Ashford, P, Clark, T, Forster, M, Lee, S, Borg, E, Falzon, M, Papadatos-Pastos, D, Wilson, J, Ahmad, T, Procter, A, Ahmed, A, Taylor, M, Nair, A, Lawrence, D, Patrini, D, Navani, N, Thakrar, R, Janes, S, Martinoni Hoogenboom, E, Monk, F, Holding, J, Choudhary, J, Bhakhri, K, Scarci, M, Hayward, M, Panagiotopoulos, N, Gorman, P, Khiroya, R, Stephens, R, Wong, Y, Bandula, S, Sharp, A, Smith, S, Gower, N, Dhanda, H, Chan, K, Pilotti, C, Leslie, R, Grapa, A, Zhang, H, Abduljabbar, K, Pan, X, Yuan, Y, Chuter, D, Mackenzie, M, Chee, S, Alzetani, A, Cave, J, Scarlett, L, Richards, J, Ingram, P, Austin, S, De Sousa, P, Jordan, S, Rice, A, Raubenheimer, H, Bhayani, H, Ambrose, L, Devaraj, A, Chavan, H, Begum, S, Buderi, S, Kaniu, D, Malima, M, Booth, S, Nicholson, A, Fernandes, N, Shah, P, Proli, C, Hewish, M, Danson, S, Shackcloth, M, Robinson, L, Russell, P, Blyth, K, Dick, C, Le Quesne, J, Kirk, A, Asif, M, Bilancia, R, Kostoulas, N, Thomas, M, Birkbak, N, Mcgranahan, N, Swanton, C, Abbosh C., Frankell A. M., Harrison T., Kisistok J., Garnett A., Johnson L., Veeriah S., Moreau M., Chesh A., Chaunzwa T. L., Weiss J., Schroeder M. R., Ward S., Grigoriadis K., Shahpurwalla A., Litchfield K., Puttick C., Biswas D., Karasaki T., Black J. R. M., Martinez-Ruiz C., Bakir M. A., Pich O., Watkins T. B. K., Lim E. L., Huebner A., Moore D. A., Godin-Heymann N., L'Hernault A., Bye H., Odell A., Roberts P., Gomes F., Patel A. J., Manzano E., Hiley C. T., Carey N., Riley J., Cook D. E., Hodgson D., Stetson D., Barrett J. C., Kortlever R. M., Evan G. I., Hackshaw A., Daber R. D., Shaw J. A., Aerts H. J. W. L., Licon A., Stahl J., Jamal-Hanjani M., Lester J. F., Bajaj A., Nakas A., Sodha-Ramdeen A., Ang K., Tufail M., Chowdhry M. F., Scotland M., Boyles R., Rathinam S., Wilson C., Marrone D., Dulloo S., Fennell D. A., Matharu G., Primrose L., Boleti E., Cheyne H., Khalil M., Richardson S., Cruickshank T., Price G., Kerr K. M., Benafif S., Gilbert K., Naidu B., Osman A., Lacson C., Langman G., Shackleford H., Djearaman M., Kadiri S., Middleton G., Leek A., Hodgkinson J. D., Totten N., Montero A., Smith E., Fontaine E., Granato F., Doran H., Novasio J., Rammohan K., Joseph L., Bishop P., Shah R., Moss S., Joshi V., Crosbie P., Brown K., Carter M., Chaturvedi A., Priest L., Oliveira P., Lindsay C. R., Blackhall F. H., Krebs M. G., Summers Y., Clipson A., Tugwood J., Kerr A., Rothwell D. G., Kilgour E., Dive C., Schwarz R. F., Kaufmann T. L., Wilson G. A., Rosenthal R., Van Loo P., Szallasi Z., Sokac M., Salgado R., Diossy M., Demeulemeester J., Bunkum A., Stewart A., Magness A., Rowan A., Karamani A., Toncheva A., Chain B., Campbell B. B., Castignani C., Bailey C., Weeden C. E., Lee C., Richard C., Naceur-Lombardelli C., Pearce D. R., Karagianni D., Levi D., Hoxha E., Larose Cadieux E., Colliver E., Nye E., Gronroos E., Galvez-Cancino F., Athanasopoulou F., Gimeno-Valiente F., Kassiotis G., Stavrou G., Mastrokalos G., Zhai H., Lowe H. L., Matos I., Goldman J., Reading J. L., Herrero J., Rane J. K., Nicod J., Lam J. M., Hartley J. A., Peggs K. S., Enfield K. S. S., Selvaraju K., Thol K., Ng K. W., Chen K., Dijkstra K., Thakkar K., Ensell L., Shah M., Vasquez M., Litovchenko M., Werner Sunderland M., Hill M. S., Dietzen M., Leung M., Escudero M., Angelova M., Tanic M., Sivakumar M., Kanu N., Chervova O., Lucas O., Al-Sawaf O., Prymas P., Hobson P., Pawlik P., Stone R. K., Bentham R., Hynds R. E., Vendramin R., Saghafinia S., Lopez S., Gamble S., Ung S. K. A., Quezada S. A., Vanloo S., Zaccaria S., Hessey S., Boeing S., Beck S., Bola S. K., Denner T., Marafioti T., Mourikis T. P., Spanswick V., Barbe V., Lu W. -T., Hill W., Liu W. K., Wu Y., Naito Y., Ramsden Z., Veiga C., Royle G., Collins-Fekete C. -A., Fraioli F., Ashford P., Clark T., Forster M. D., Lee S. M., Borg E., Falzon M., Papadatos-Pastos D., Wilson J., Ahmad T., Procter A. J., Ahmed A., Taylor M. N., Nair A., Lawrence D., Patrini D., Navani N., Thakrar R. M., Janes S. M., Martinoni Hoogenboom E., Monk F., Holding J. W., Choudhary J., Bhakhri K., Scarci M., Hayward M., Panagiotopoulos N., Gorman P., Khiroya R., Stephens R. C., Wong Y. N. S., Bandula S., Sharp A., Smith S., Gower N., Dhanda H. K., Chan K., Pilotti C., Leslie R., Grapa A., Zhang H., AbdulJabbar K., Pan X., Yuan Y., Chuter D., MacKenzie M., Chee S., Alzetani A., Cave J., Scarlett L., Richards J., Ingram P., Austin S., Lim E., De Sousa P., Jordan S., Rice A., Raubenheimer H., Bhayani H., Ambrose L., Devaraj A., Chavan H., Begum S., Buderi S. I., Kaniu D., Malima M., Booth S., Nicholson A. G., Fernandes N., Shah P., Proli C., Hewish M., Danson S., Shackcloth M. J., Robinson L., Russell P., Blyth K. G., Dick C., Le Quesne J., Kirk A., Asif M., Bilancia R., Kostoulas N., Thomas M., Birkbak N. J., McGranahan N., and Swanton C.
Abstract: Circulating tumour DNA (ctDNA) can be used to detect and profile residual tumour cells persisting after curative intent therapy1. The study of large patient cohorts incorporating longitudinal plasma sampling and extended follow-up is required to determine the role of ctDNA as a phylogenetic biomarker of relapse in early-stage non-small-cell lung cancer (NSCLC). Here we developed ctDNA methods tracking a median of 200 mutations identified in resected NSCLC tissue across 1,069 plasma samples collected from 197 patients enrolled in the TRACERx study2. A lack of preoperative ctDNA detection distinguished biologically indolent lung adenocarcinoma with good clinical outcome. Postoperative plasma analyses were interpreted within the context of standard-of-care radiological surveillance and administration of cytotoxic adjuvant therapy. Landmark analyses of plasma samples collected within 120 days after surgery revealed ctDNA detection in 25% of patients, including 49% of all patients who experienced clinical relapse; 3 to 6 monthly ctDNA surveillance identified impending disease relapse in an additional 20% of landmark-negative patients. We developed a bioinformatic tool (ECLIPSE) for non-invasive tracking of subclonal architecture at low ctDNA levels. ECLIPSE identified patients with polyclonal metastatic dissemination, which was associated with a poor clinical outcome. By measuring subclone cancer cell fractions in preoperative plasma, we found that subclones seeding future metastases were significantly more expanded compared with non-metastatic subclones. Our findings will support (neo)adjuvant trial advances and provide insights into the process of metastatic dissemination using low-ctDNA-level liquid biopsy.
Published: 2023

11. Antibodies against endogenous retroviruses promote lung cancer immunotherapy

Author: Ng, K, Boumelha, J, Enfield, K, Almagro, J, Cha, H, Pich, O, Karasaki, T, Moore, D, Salgado, R, Sivakumar, M, Young, G, Molina-Arcas, M, de Carne Trecesson, S, Anastasiou, P, Fendler, A, Au, L, Shepherd, S, Martinez-Ruiz, C, Puttick, C, Black, J, Watkins, T, Kim, H, Shim, S, Faulkner, N, Attig, J, Veeriah, S, Magno, N, Ward, S, Frankell, A, Al Bakir, M, Lim, E, Hill, M, Wilson, G, Cook, D, Birkbak, N, Behrens, A, Yousaf, N, Popat, S, Hackshaw, A, Rowan, A, Huebner, A, Campbell, B, Bailey, C, Lee, C, Biswas, D, Colliver, E, Athanasopoulou, F, Zhai, H, Rane, J, Grigoriadis, K, Dietzen, M, Leung, M, Angelova, M, Lucas, O, Al-Sawaf, O, Rosenthal, R, Nicod, J, Bunkum, A, Toncheva, A, Abbosh, C, Richard, C, Naceur-Lombardelli, C, Gimeno-Valiente, F, Lam, J, Thol, K, Thakkar, K, Werner Sunderland, M, Forster, M, Kanu, N, Prymas, P, Bentham, R, Saghafinia, S, Quezada, S, Vanloo, S, Zaccaria, S, Lee, S, Hessey, S, Liu, W, Papadatos-Pastos, D, Wilson, J, Benafif, S, Ahmad, T, Borg, E, Falzon, M, Khiroya, R, Marafioti, T, Sharp, A, Pilotti, C, Dhanda, H, Chan, K, Gower, N, Leslie, R, Smith, S, Nicholson, A, Herrero, J, Castignani, C, Larose Cadieux, E, Demeulemeester, J, Van Loo, P, Peggs, K, Veiga, C, Royle, G, Collins-Fekete, C, Procter, A, Nair, A, Ahmed, A, Taylor, M, Navani, N, Thakrar, R, Lawrence, D, Patrini, D, Nye, E, Stone, R, Chuter, D, Mackenzie, M, Fraioli, F, Ashford, P, Janes, S, Tanic, M, Beck, S, Rice, A, Devaraj, A, Proli, C, Kaniu, D, Bhayani, H, Chavan, H, Raubenheimer, H, Ambrose, L, Malima, M, Fernandes, N, De Sousa, P, Shah, P, Booth, S, Buderi, S, Jordan, S, Begum, S, Boleti, E, Stewart, A, Magness, A, Weeden, C, Levi, D, Gronroos, E, Goldman, J, Escudero, M, Hobson, P, Vendramin, R, Boeing, S, Denner, T, Barbe, V, Lu, W, Hill, W, Naito, Y, Ramsden, Z, Grapa, A, Zhang, H, Abduljabbar, K, Pan, X, Gilbert, K, Karamani, A, Chain, B, Pearce, D, Karagianni, D, Hoxha, E, Galvez-Cancino, F, Stavrou, G, Mastrokalos, G, Lowe, H, Matos, I, Reading, J, Hartley, J, Selvaraju, K, Chen, K, Ensell, L, Shah, M, Vasquez, M, Litovchenko, M, Chervova, O, Pawlik, P, Hynds, R, Lopez, S, Gamble, S, Ung, S, Bola, S, Mourikis, T, Spanswick, V, Wu, Y, Martinoni Hoogenboom, E, Monk, F, Holding, J, Choudhary, J, Bhakhri, K, Scarci, M, Hayward, M, Panagiotopoulos, N, Gorman, P, Stephens, R, Bandula, S, Wong, Y, Clark, T, Cheyne, H, Khalil, M, Richardson, S, Cruickshank, T, Naidu, B, Matharu, G, Shaw, J, Riley, J, Primrose, L, Le Quesne, J, Blyth, K, Kerr, A, Clipson, A, Chaturvedi, A, Dive, C, Rothwell, D, Kilgour, E, Tugwood, J, Priest, L, Oliveira, P, Crosbie, P, Price, G, Cave, J, Kerr, K, Lindsay, C, Blackhall, F, Krebs, M, Summers, Y, Kirk, A, Thomas, M, Asif, M, Kostoulas, N, Bilancia, R, Middleton, G, Shackcloth, M, Leek, A, Hodgkinson, J, Totten, N, Dick, C, Robinson, L, Russell, P, Hewish, M, Danson, S, Lester, J, Gomes, F, Brown, K, Carter, M, Patel, A, Osman, A, Lacson, C, Langman, G, Shackleford, H, Djearaman, M, Kadiri, S, Alzetani, A, Richards, J, Scarlett, L, Ingram, P, Chee, S, Austin, S, Bajaj, A, Nakas, A, Sodha-Ramdeen, A, Fennell, D, Ang, K, Tufail, M, Chowdhry, M, Scotland, M, Boyles, R, Rathinam, S, Wilson, C, Marrone, D, Dulloo, S, Montero, A, Smith, E, Fontaine, E, Granato, F, Doran, H, Novasio, J, Rammohan, K, Joseph, L, Bishop, P, Shah, R, Moss, S, Joshi, V, Aerts, H, Kaufmann, T, Schwarz, R, Kisistok, J, Sokac, M, Diossy, M, Szallasi, Z, Dijkstra, K, Yuan, Y, Byrne, F, Boos, L, Shum, B, Gerard, C, Schmitt, A, Messiou, C, Cunningham, D, Chau, I, Starling, N, Turner, N, Welsh, L, Jones, R, Droney, J, Banerjee, S, Tatham, K, Jhanji, S, Harrington, K, Okines, A, Reid, A, Young, K, Furness, A, Pickering, L, Nicholson, E, Kumar, S, Wilkinson, K, Swerdlow, A, Wilkinson, R, Hiley, C, Litchfield, K, Mcgranahan, N, Jamal-Hanjani, M, Larkin, J, Turajlic, S, Swanton, C, Downward, J, Kassiotis, G, Ng K. W., Boumelha J., Enfield K. S. S., Almagro J., Cha H., Pich O., Karasaki T., Moore D. A., Salgado R., Sivakumar M., Young G., Molina-Arcas M., de Carne Trecesson S., Anastasiou P., Fendler A., Au L., Shepherd S. T. C., Martinez-Ruiz C., Puttick C., Black J. R. M., Watkins T. B. K., Kim H., Shim S., Faulkner N., Attig J., Veeriah S., Magno N., Ward S., Frankell A. M., Al Bakir M., Lim E. L., Hill M. S., Wilson G. A., Cook D. E., Birkbak N. J., Behrens A., Yousaf N., Popat S., Hackshaw A., Rowan A., Huebner A., Campbell B. B., Bailey C., Lee C., Biswas D., Colliver E., Athanasopoulou F., Zhai H., Rane J. K., Grigoriadis K., Dietzen M., Leung M., Angelova M., Lucas O., Al-Sawaf O., Rosenthal R., Nicod J., Bunkum A., Toncheva A., Abbosh C., Richard C., Naceur-Lombardelli C., Gimeno-Valiente F., Lam J. M., Thol K., Thakkar K., Werner Sunderland M., Forster M. D., Kanu N., Prymas P., Bentham R., Saghafinia S., Quezada S. A., Vanloo S., Zaccaria S., Lee S. M., Hessey S., Liu W. K., Papadatos-Pastos D., Wilson J., Benafif S., Ahmad T., Borg E., Falzon M., Khiroya R., Marafioti T., Sharp A., Pilotti C., Dhanda H. K., Chan K., Gower N., Leslie R., Smith S., Nicholson A. G., Lim E., Herrero J., Castignani C., Larose Cadieux E., Demeulemeester J., Van Loo P., Peggs K. S., Veiga C., Royle G., Collins-Fekete C. -A., Procter A. J., Nair A., Ahmed A., Taylor M. N., Navani N., Thakrar R. M., Lawrence D., Patrini D., Nye E., Stone R. K., Chuter D., MacKenzie M., Fraioli F., Ashford P., Janes S. M., Tanic M., Beck S., Rice A., Devaraj A., Proli C., Kaniu D., Bhayani H., Chavan H., Raubenheimer H., Ambrose L., Malima M., Fernandes N., De Sousa P., Shah P., Booth S., Buderi S. I., Jordan S., Begum S., Boleti E., Stewart A., Magness A., Weeden C. E., Levi D., Gronroos E., Goldman J., Escudero M., Hobson P., Vendramin R., Boeing S., Denner T., Barbe V., Lu W. -T., Hill W., Naito Y., Ramsden Z., Grapa A., Zhang H., AbdulJabbar K., Pan X., Gilbert K., Karamani A., Chain B., Pearce D. R., Karagianni D., Hoxha E., Galvez-Cancino F., Stavrou G., Mastrokalos G., Lowe H. L., Matos I., Reading J. L., Hartley J. A., Selvaraju K., Chen K., Ensell L., Shah M., Vasquez M., Litovchenko M., Chervova O., Pawlik P., Hynds R. E., Lopez S., Gamble S., Ung S. K. A., Bola S. K., Mourikis T. P., Spanswick V., Wu Y., Martinoni Hoogenboom E., Monk F., Holding J. W., Choudhary J., Bhakhri K., Scarci M., Hayward M., Panagiotopoulos N., Gorman P., Stephens R. C. M., Bandula S., Wong Y. N. S., Clark T., Cheyne H., Khalil M., Richardson S., Cruickshank T., Naidu B., Matharu G., Shaw J. A., Riley J., Primrose L., Le Quesne J., Blyth K. G., Kerr A., Clipson A., Chaturvedi A., Dive C., Rothwell D. G., Kilgour E., Tugwood J., Priest L., Oliveira P., Crosbie P., Price G., Cave J., Kerr K. M., Lindsay C. R., Blackhall F. H., Krebs M. G., Summers Y., Kirk A., Thomas M., Asif M., Kostoulas N., Bilancia R., Middleton G., Shackcloth M. J., Leek A., Hodgkinson J. D., Totten N., Dick C., Robinson L., Russell P., Hewish M., Danson S., Lester J. F., Gomes F., Brown K., Carter M., Patel A. J., Osman A., Lacson C., Langman G., Shackleford H., Djearaman M., Kadiri S., Alzetani A., Richards J., Scarlett L., Ingram P., Chee S., Austin S., Bajaj A., Nakas A., Sodha-Ramdeen A., Fennell D. A., Ang K., Tufail M., Chowdhry M. F., Scotland M., Boyles R., Rathinam S., Wilson C., Marrone D., Dulloo S., Montero A., Smith E., Fontaine E., Granato F., Doran H., Novasio J., Rammohan K., Joseph L., Bishop P., Shah R., Moss S., Joshi V., Aerts H. J. W. L., Kaufmann T. L., Schwarz R. F., Kisistok J., Sokac M., Diossy M., Szallasi Z., Dijkstra K., Yuan Y., Byrne F., Boos L. A., Shum B., Gerard C. L., Schmitt A. M., Messiou C., Cunningham D., Chau I., Starling N., Turner N., Welsh L., Jones R. L., Droney J., Banerjee S., Tatham K. C., Jhanji S., Harrington K., Okines A., Reid A., Young K., Furness A. J. S., Pickering L., Nicholson E., Kumar S., Wilkinson K. A., Swerdlow A., Wilkinson R. J., Hiley C. T., Litchfield K., McGranahan N., Jamal-Hanjani M., Larkin J., Lee S. -H., Turajlic S., Swanton C., Downward J., Kassiotis G., Ng, K, Boumelha, J, Enfield, K, Almagro, J, Cha, H, Pich, O, Karasaki, T, Moore, D, Salgado, R, Sivakumar, M, Young, G, Molina-Arcas, M, de Carne Trecesson, S, Anastasiou, P, Fendler, A, Au, L, Shepherd, S, Martinez-Ruiz, C, Puttick, C, Black, J, Watkins, T, Kim, H, Shim, S, Faulkner, N, Attig, J, Veeriah, S, Magno, N, Ward, S, Frankell, A, Al Bakir, M, Lim, E, Hill, M, Wilson, G, Cook, D, Birkbak, N, Behrens, A, Yousaf, N, Popat, S, Hackshaw, A, Rowan, A, Huebner, A, Campbell, B, Bailey, C, Lee, C, Biswas, D, Colliver, E, Athanasopoulou, F, Zhai, H, Rane, J, Grigoriadis, K, Dietzen, M, Leung, M, Angelova, M, Lucas, O, Al-Sawaf, O, Rosenthal, R, Nicod, J, Bunkum, A, Toncheva, A, Abbosh, C, Richard, C, Naceur-Lombardelli, C, Gimeno-Valiente, F, Lam, J, Thol, K, Thakkar, K, Werner Sunderland, M, Forster, M, Kanu, N, Prymas, P, Bentham, R, Saghafinia, S, Quezada, S, Vanloo, S, Zaccaria, S, Lee, S, Hessey, S, Liu, W, Papadatos-Pastos, D, Wilson, J, Benafif, S, Ahmad, T, Borg, E, Falzon, M, Khiroya, R, Marafioti, T, Sharp, A, Pilotti, C, Dhanda, H, Chan, K, Gower, N, Leslie, R, Smith, S, Nicholson, A, Herrero, J, Castignani, C, Larose Cadieux, E, Demeulemeester, J, Van Loo, P, Peggs, K, Veiga, C, Royle, G, Collins-Fekete, C, Procter, A, Nair, A, Ahmed, A, Taylor, M, Navani, N, Thakrar, R, Lawrence, D, Patrini, D, Nye, E, Stone, R, Chuter, D, Mackenzie, M, Fraioli, F, Ashford, P, Janes, S, Tanic, M, Beck, S, Rice, A, Devaraj, A, Proli, C, Kaniu, D, Bhayani, H, Chavan, H, Raubenheimer, H, Ambrose, L, Malima, M, Fernandes, N, De Sousa, P, Shah, P, Booth, S, Buderi, S, Jordan, S, Begum, S, Boleti, E, Stewart, A, Magness, A, Weeden, C, Levi, D, Gronroos, E, Goldman, J, Escudero, M, Hobson, P, Vendramin, R, Boeing, S, Denner, T, Barbe, V, Lu, W, Hill, W, Naito, Y, Ramsden, Z, Grapa, A, Zhang, H, Abduljabbar, K, Pan, X, Gilbert, K, Karamani, A, Chain, B, Pearce, D, Karagianni, D, Hoxha, E, Galvez-Cancino, F, Stavrou, G, Mastrokalos, G, Lowe, H, Matos, I, Reading, J, Hartley, J, Selvaraju, K, Chen, K, Ensell, L, Shah, M, Vasquez, M, Litovchenko, M, Chervova, O, Pawlik, P, Hynds, R, Lopez, S, Gamble, S, Ung, S, Bola, S, Mourikis, T, Spanswick, V, Wu, Y, Martinoni Hoogenboom, E, Monk, F, Holding, J, Choudhary, J, Bhakhri, K, Scarci, M, Hayward, M, Panagiotopoulos, N, Gorman, P, Stephens, R, Bandula, S, Wong, Y, Clark, T, Cheyne, H, Khalil, M, Richardson, S, Cruickshank, T, Naidu, B, Matharu, G, Shaw, J, Riley, J, Primrose, L, Le Quesne, J, Blyth, K, Kerr, A, Clipson, A, Chaturvedi, A, Dive, C, Rothwell, D, Kilgour, E, Tugwood, J, Priest, L, Oliveira, P, Crosbie, P, Price, G, Cave, J, Kerr, K, Lindsay, C, Blackhall, F, Krebs, M, Summers, Y, Kirk, A, Thomas, M, Asif, M, Kostoulas, N, Bilancia, R, Middleton, G, Shackcloth, M, Leek, A, Hodgkinson, J, Totten, N, Dick, C, Robinson, L, Russell, P, Hewish, M, Danson, S, Lester, J, Gomes, F, Brown, K, Carter, M, Patel, A, Osman, A, Lacson, C, Langman, G, Shackleford, H, Djearaman, M, Kadiri, S, Alzetani, A, Richards, J, Scarlett, L, Ingram, P, Chee, S, Austin, S, Bajaj, A, Nakas, A, Sodha-Ramdeen, A, Fennell, D, Ang, K, Tufail, M, Chowdhry, M, Scotland, M, Boyles, R, Rathinam, S, Wilson, C, Marrone, D, Dulloo, S, Montero, A, Smith, E, Fontaine, E, Granato, F, Doran, H, Novasio, J, Rammohan, K, Joseph, L, Bishop, P, Shah, R, Moss, S, Joshi, V, Aerts, H, Kaufmann, T, Schwarz, R, Kisistok, J, Sokac, M, Diossy, M, Szallasi, Z, Dijkstra, K, Yuan, Y, Byrne, F, Boos, L, Shum, B, Gerard, C, Schmitt, A, Messiou, C, Cunningham, D, Chau, I, Starling, N, Turner, N, Welsh, L, Jones, R, Droney, J, Banerjee, S, Tatham, K, Jhanji, S, Harrington, K, Okines, A, Reid, A, Young, K, Furness, A, Pickering, L, Nicholson, E, Kumar, S, Wilkinson, K, Swerdlow, A, Wilkinson, R, Hiley, C, Litchfield, K, Mcgranahan, N, Jamal-Hanjani, M, Larkin, J, Turajlic, S, Swanton, C, Downward, J, Kassiotis, G, Ng K. W., Boumelha J., Enfield K. S. S., Almagro J., Cha H., Pich O., Karasaki T., Moore D. A., Salgado R., Sivakumar M., Young G., Molina-Arcas M., de Carne Trecesson S., Anastasiou P., Fendler A., Au L., Shepherd S. T. C., Martinez-Ruiz C., Puttick C., Black J. R. M., Watkins T. B. K., Kim H., Shim S., Faulkner N., Attig J., Veeriah S., Magno N., Ward S., Frankell A. M., Al Bakir M., Lim E. L., Hill M. S., Wilson G. A., Cook D. E., Birkbak N. J., Behrens A., Yousaf N., Popat S., Hackshaw A., Rowan A., Huebner A., Campbell B. B., Bailey C., Lee C., Biswas D., Colliver E., Athanasopoulou F., Zhai H., Rane J. K., Grigoriadis K., Dietzen M., Leung M., Angelova M., Lucas O., Al-Sawaf O., Rosenthal R., Nicod J., Bunkum A., Toncheva A., Abbosh C., Richard C., Naceur-Lombardelli C., Gimeno-Valiente F., Lam J. M., Thol K., Thakkar K., Werner Sunderland M., Forster M. D., Kanu N., Prymas P., Bentham R., Saghafinia S., Quezada S. A., Vanloo S., Zaccaria S., Lee S. M., Hessey S., Liu W. K., Papadatos-Pastos D., Wilson J., Benafif S., Ahmad T., Borg E., Falzon M., Khiroya R., Marafioti T., Sharp A., Pilotti C., Dhanda H. K., Chan K., Gower N., Leslie R., Smith S., Nicholson A. G., Lim E., Herrero J., Castignani C., Larose Cadieux E., Demeulemeester J., Van Loo P., Peggs K. S., Veiga C., Royle G., Collins-Fekete C. -A., Procter A. J., Nair A., Ahmed A., Taylor M. N., Navani N., Thakrar R. M., Lawrence D., Patrini D., Nye E., Stone R. K., Chuter D., MacKenzie M., Fraioli F., Ashford P., Janes S. M., Tanic M., Beck S., Rice A., Devaraj A., Proli C., Kaniu D., Bhayani H., Chavan H., Raubenheimer H., Ambrose L., Malima M., Fernandes N., De Sousa P., Shah P., Booth S., Buderi S. I., Jordan S., Begum S., Boleti E., Stewart A., Magness A., Weeden C. E., Levi D., Gronroos E., Goldman J., Escudero M., Hobson P., Vendramin R., Boeing S., Denner T., Barbe V., Lu W. -T., Hill W., Naito Y., Ramsden Z., Grapa A., Zhang H., AbdulJabbar K., Pan X., Gilbert K., Karamani A., Chain B., Pearce D. R., Karagianni D., Hoxha E., Galvez-Cancino F., Stavrou G., Mastrokalos G., Lowe H. L., Matos I., Reading J. L., Hartley J. A., Selvaraju K., Chen K., Ensell L., Shah M., Vasquez M., Litovchenko M., Chervova O., Pawlik P., Hynds R. E., Lopez S., Gamble S., Ung S. K. A., Bola S. K., Mourikis T. P., Spanswick V., Wu Y., Martinoni Hoogenboom E., Monk F., Holding J. W., Choudhary J., Bhakhri K., Scarci M., Hayward M., Panagiotopoulos N., Gorman P., Stephens R. C. M., Bandula S., Wong Y. N. S., Clark T., Cheyne H., Khalil M., Richardson S., Cruickshank T., Naidu B., Matharu G., Shaw J. A., Riley J., Primrose L., Le Quesne J., Blyth K. G., Kerr A., Clipson A., Chaturvedi A., Dive C., Rothwell D. G., Kilgour E., Tugwood J., Priest L., Oliveira P., Crosbie P., Price G., Cave J., Kerr K. M., Lindsay C. R., Blackhall F. H., Krebs M. G., Summers Y., Kirk A., Thomas M., Asif M., Kostoulas N., Bilancia R., Middleton G., Shackcloth M. J., Leek A., Hodgkinson J. D., Totten N., Dick C., Robinson L., Russell P., Hewish M., Danson S., Lester J. F., Gomes F., Brown K., Carter M., Patel A. J., Osman A., Lacson C., Langman G., Shackleford H., Djearaman M., Kadiri S., Alzetani A., Richards J., Scarlett L., Ingram P., Chee S., Austin S., Bajaj A., Nakas A., Sodha-Ramdeen A., Fennell D. A., Ang K., Tufail M., Chowdhry M. F., Scotland M., Boyles R., Rathinam S., Wilson C., Marrone D., Dulloo S., Montero A., Smith E., Fontaine E., Granato F., Doran H., Novasio J., Rammohan K., Joseph L., Bishop P., Shah R., Moss S., Joshi V., Aerts H. J. W. L., Kaufmann T. L., Schwarz R. F., Kisistok J., Sokac M., Diossy M., Szallasi Z., Dijkstra K., Yuan Y., Byrne F., Boos L. A., Shum B., Gerard C. L., Schmitt A. M., Messiou C., Cunningham D., Chau I., Starling N., Turner N., Welsh L., Jones R. L., Droney J., Banerjee S., Tatham K. C., Jhanji S., Harrington K., Okines A., Reid A., Young K., Furness A. J. S., Pickering L., Nicholson E., Kumar S., Wilkinson K. A., Swerdlow A., Wilkinson R. J., Hiley C. T., Litchfield K., McGranahan N., Jamal-Hanjani M., Larkin J., Lee S. -H., Turajlic S., Swanton C., Downward J., and Kassiotis G.
Abstract: B cells are frequently found in the margins of solid tumours as organized follicles in ectopic lymphoid organs called tertiary lymphoid structures (TLS)1,2. Although TLS have been found to correlate with improved patient survival and response to immune checkpoint blockade (ICB), the underlying mechanisms of this association remain elusive1,2. Here we investigate lung-resident B cell responses in patients from the TRACERx 421 (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy) and other lung cancer cohorts, and in a recently established immunogenic mouse model for lung adenocarcinoma3. We find that both human and mouse lung adenocarcinomas elicit local germinal centre responses and tumour-binding antibodies, and further identify endogenous retrovirus (ERV) envelope glycoproteins as a dominant anti-tumour antibody target. ERV-targeting B cell responses are amplified by ICB in both humans and mice, and by targeted inhibition of KRAS(G12C) in the mouse model. ERV-reactive antibodies exert anti-tumour activity that extends survival in the mouse model, and ERV expression predicts the outcome of ICB in human lung adenocarcinoma. Finally, we find that effective immunotherapy in the mouse model requires CXCL13-dependent TLS formation. Conversely, therapeutic CXCL13 treatment potentiates anti-tumour immunity and synergizes with ICB. Our findings provide a possible mechanistic basis for the association of TLS with immunotherapy response.
Published: 2023

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

Author: Frankell, A, Dietzen, M, Al Bakir, M, Lim, E, Karasaki, T, Ward, S, Veeriah, S, Colliver, E, Huebner, A, Bunkum, A, Hill, M, Grigoriadis, K, Moore, D, Black, J, Liu, W, Thol, K, Pich, O, Watkins, T, Naceur-Lombardelli, C, Cook, D, Salgado, R, Wilson, G, Bailey, C, Angelova, M, Bentham, R, Martinez-Ruiz, C, Abbosh, C, Nicholson, A, Le Quesne, J, Biswas, D, Rosenthal, R, Puttick, C, Hessey, S, Lee, C, Prymas, P, Toncheva, A, Smith, J, Xing, W, Nicod, J, Price, G, Kerr, K, Naidu, B, Middleton, G, Blyth, K, Fennell, D, Forster, M, Lee, S, Falzon, M, Hewish, M, Shackcloth, M, Benafif, S, Russell, P, Boleti, E, Krebs, M, Lester, J, Papadatos-Pastos, D, Ahmad, T, Thakrar, R, Lawrence, D, Navani, N, Janes, S, Dive, C, Blackhall, F, Summers, Y, Cave, J, Marafioti, T, Herrero, J, Quezada, S, Peggs, K, Schwarz, R, Van Loo, P, Miedema, D, Birkbak, N, Hiley, C, Hackshaw, A, Zaccaria, S, Bajaj, A, Nakas, A, Sodha-Ramdeen, A, Ang, K, Tufail, M, Chowdhry, M, Scotland, M, Boyles, R, Rathinam, S, Wilson, C, Marrone, D, Dulloo, S, Matharu, G, Shaw, J, Riley, J, Primrose, L, Cheyne, H, Khalil, M, Richardson, S, Cruickshank, T, Gilbert, K, Patel, A, Osman, A, Lacson, C, Langman, G, Shackleford, H, Djearaman, M, Kadiri, S, Leek, A, Hodgkinson, J, Totten, N, Montero, A, Smith, E, Fontaine, E, Granato, F, Doran, H, Novasio, J, Rammohan, K, Joseph, L, Bishop, P, Shah, R, Moss, S, Joshi, V, Crosbie, P, Gomes, F, Brown, K, Carter, M, Chaturvedi, A, Priest, L, Oliveira, P, Lindsay, C, Clipson, A, Tugwood, J, Kerr, A, Rothwell, D, Kilgour, E, Aerts, H, Kaufmann, T, Szallasi, Z, Kisistok, J, Sokac, M, Diossy, M, Demeulemeester, J, Stewart, A, Magness, A, Rowan, A, Karamani, A, Chain, B, Campbell, B, Castignani, C, Weeden, C, Richard, C, Pearce, D, Karagianni, D, Levi, D, Hoxha, E, Larose Cadieux, E, Nye, E, Gronroos, E, Galvez-Cancino, F, Athanasopoulou, F, Gimeno-Valiente, F, Kassiotis, G, Stavrou, G, Mastrokalos, G, Zhai, H, Lowe, H, Matos, I, Goldman, J, Reading, J, Rane, J, Lam, J, Hartley, J, Enfield, K, Selvaraju, K, Litchfield, K, Ng, K, Chen, K, Dijkstra, K, Thakkar, K, Ensell, L, Shah, M, Vasquez, M, Litovchenko, M, Werner Sunderland, M, Leung, M, Escudero, M, Tanic, M, Sivakumar, M, Kanu, N, Chervova, O, Lucas, O, Al-Sawaf, O, Hobson, P, Pawlik, P, Stone, R, Hynds, R, Vendramin, R, Saghafinia, S, Lopez, S, Gamble, S, Ung, S, Vanloo, S, Boeing, S, Beck, S, Bola, S, Denner, T, Mourikis, T, Spanswick, V, Barbe, V, Lu, W, Hill, W, Wu, Y, Naito, Y, Ramsden, Z, Veiga, C, Royle, G, Collins-Fekete, C, Fraioli, F, Ashford, P, Clark, T, Borg, E, Wilson, J, Procter, A, Ahmed, A, Taylor, M, Nair, A, Patrini, D, Martinoni Hoogenboom, E, Monk, F, Holding, J, Choudhary, J, Bhakhri, K, Scarci, M, Hayward, M, Panagiotopoulos, N, Gorman, P, Khiroya, R, Stephens, R, Wong, Y, Bandula, S, Sharp, A, Smith, S, Gower, N, Dhanda, H, Chan, K, Pilotti, C, Leslie, R, Grapa, A, Zhang, H, Abduljabbar, K, Pan, X, Yuan, Y, Chuter, D, Mackenzie, M, Chee, S, Alzetani, A, Scarlett, L, Richards, J, Ingram, P, Austin, S, De Sousa, P, Jordan, S, Rice, A, Raubenheimer, H, Bhayani, H, Ambrose, L, Devaraj, A, Chavan, H, Begum, S, Buderi, S, Kaniu, D, Malima, M, Booth, S, Fernandes, N, Shah, P, Proli, C, Danson, S, Robinson, L, Dick, C, Kirk, A, Asif, M, Bilancia, R, Kostoulas, N, Thomas, M, Jamal-Hanjani, M, Mcgranahan, N, Swanton, C, Frankell A. M., Dietzen M., Al Bakir M., Lim E. L., Karasaki T., Ward S., Veeriah S., Colliver E., Huebner A., Bunkum A., Hill M. S., Grigoriadis K., Moore D. A., Black J. R. M., Liu W. K., Thol K., Pich O., Watkins T. B. K., Naceur-Lombardelli C., Cook D. E., Salgado R., Wilson G. A., Bailey C., Angelova M., Bentham R., Martinez-Ruiz C., Abbosh C., Nicholson A. G., Le Quesne J., Biswas D., Rosenthal R., Puttick C., Hessey S., Lee C., Prymas P., Toncheva A., Smith J., Xing W., Nicod J., Price G., Kerr K. M., Naidu B., Middleton G., Blyth K. G., Fennell D. A., Forster M. D., Lee S. M., Falzon M., Hewish M., Shackcloth M. J., Lim E., Benafif S., Russell P., Boleti E., Krebs M. G., Lester J. F., Papadatos-Pastos D., Ahmad T., Thakrar R. M., Lawrence D., Navani N., Janes S. M., Dive C., Blackhall F. H., Summers Y., Cave J., Marafioti T., Herrero J., Quezada S. A., Peggs K. S., Schwarz R. F., Van Loo P., Miedema D. M., Birkbak N. J., Hiley C. T., Hackshaw A., Zaccaria S., Bajaj A., Nakas A., Sodha-Ramdeen A., Ang K., Tufail M., Chowdhry M. F., Scotland M., Boyles R., Rathinam S., Wilson C., Marrone D., Dulloo S., Matharu G., Shaw J. A., Riley J., Primrose L., Cheyne H., Khalil M., Richardson S., Cruickshank T., Gilbert K., Patel A. J., Osman A., Lacson C., Langman G., Shackleford H., Djearaman M., Kadiri S., Leek A., Hodgkinson J. D., Totten N., Montero A., Smith E., Fontaine E., Granato F., Doran H., Novasio J., Rammohan K., Joseph L., Bishop P., Shah R., Moss S., Joshi V., Crosbie P., Gomes F., Brown K., Carter M., Chaturvedi A., Priest L., Oliveira P., Lindsay C. R., Clipson A., Tugwood J., Kerr A., Rothwell D. G., Kilgour E., Aerts H. J. W. L., Kaufmann T. L., Szallasi Z., Kisistok J., Sokac M., Diossy M., Demeulemeester J., Stewart A., Magness A., Rowan A., Karamani A., Chain B., Campbell B. B., Castignani C., Weeden C. E., Richard C., Pearce D. R., Karagianni D., Levi D., Hoxha E., Larose Cadieux E., Nye E., Gronroos E., Galvez-Cancino F., Athanasopoulou F., Gimeno-Valiente F., Kassiotis G., Stavrou G., Mastrokalos G., Zhai H., Lowe H. L., Matos I., Goldman J., Reading J. L., Rane J. K., Lam J. M., Hartley J. A., Enfield K. S. S., Selvaraju K., Litchfield K., Ng K. W., Chen K., Dijkstra K., Thakkar K., Ensell L., Shah M., Vasquez M., Litovchenko M., Werner Sunderland M., Leung M., Escudero M., Tanic M., Sivakumar M., Kanu N., Chervova O., Lucas O., Al-Sawaf O., Hobson P., Pawlik P., Stone R. K., Hynds R. E., Vendramin R., Saghafinia S., Lopez S., Gamble S., Ung S. K. A., Vanloo S., Boeing S., Beck S., Bola S. K., Denner T., Mourikis T. P., Spanswick V., Barbe V., Lu W. -T., Hill W., Wu Y., Naito Y., Ramsden Z., Veiga C., Royle G., Collins-Fekete C. -A., Fraioli F., Ashford P., Clark T., Borg E., Wilson J., Procter A. J., Ahmed A., Taylor M. N., Nair A., Patrini D., Martinoni Hoogenboom E., Monk F., Holding J. W., Choudhary J., Bhakhri K., Scarci M., Hayward M., Panagiotopoulos N., Gorman P., Khiroya R., Stephens R. C., Wong Y. N. S., Bandula S., Sharp A., Smith S., Gower N., Dhanda H. K., Chan K., Pilotti C., Leslie R., Grapa A., Zhang H., AbdulJabbar K., Pan X., Yuan Y., Chuter D., MacKenzie M., Chee S., Alzetani A., Scarlett L., Richards J., Ingram P., Austin S., De Sousa P., Jordan S., Rice A., Raubenheimer H., Bhayani H., Ambrose L., Devaraj A., Chavan H., Begum S., Buderi S. I., Kaniu D., Malima M., Booth S., Fernandes N., Shah P., Proli C., Danson S., Robinson L., Dick C., Kirk A., Asif M., Bilancia R., Kostoulas N., Thomas M., Jamal-Hanjani M., McGranahan N., Swanton C., Frankell, A, Dietzen, M, Al Bakir, M, Lim, E, Karasaki, T, Ward, S, Veeriah, S, Colliver, E, Huebner, A, Bunkum, A, Hill, M, Grigoriadis, K, Moore, D, Black, J, Liu, W, Thol, K, Pich, O, Watkins, T, Naceur-Lombardelli, C, Cook, D, Salgado, R, Wilson, G, Bailey, C, Angelova, M, Bentham, R, Martinez-Ruiz, C, Abbosh, C, Nicholson, A, Le Quesne, J, Biswas, D, Rosenthal, R, Puttick, C, Hessey, S, Lee, C, Prymas, P, Toncheva, A, Smith, J, Xing, W, Nicod, J, Price, G, Kerr, K, Naidu, B, Middleton, G, Blyth, K, Fennell, D, Forster, M, Lee, S, Falzon, M, Hewish, M, Shackcloth, M, Benafif, S, Russell, P, Boleti, E, Krebs, M, Lester, J, Papadatos-Pastos, D, Ahmad, T, Thakrar, R, Lawrence, D, Navani, N, Janes, S, Dive, C, Blackhall, F, Summers, Y, Cave, J, Marafioti, T, Herrero, J, Quezada, S, Peggs, K, Schwarz, R, Van Loo, P, Miedema, D, Birkbak, N, Hiley, C, Hackshaw, A, Zaccaria, S, Bajaj, A, Nakas, A, Sodha-Ramdeen, A, Ang, K, Tufail, M, Chowdhry, M, Scotland, M, Boyles, R, Rathinam, S, Wilson, C, Marrone, D, Dulloo, S, Matharu, G, Shaw, J, Riley, J, Primrose, L, Cheyne, H, Khalil, M, Richardson, S, Cruickshank, T, Gilbert, K, Patel, A, Osman, A, Lacson, C, Langman, G, Shackleford, H, Djearaman, M, Kadiri, S, Leek, A, Hodgkinson, J, Totten, N, Montero, A, Smith, E, Fontaine, E, Granato, F, Doran, H, Novasio, J, Rammohan, K, Joseph, L, Bishop, P, Shah, R, Moss, S, Joshi, V, Crosbie, P, Gomes, F, Brown, K, Carter, M, Chaturvedi, A, Priest, L, Oliveira, P, Lindsay, C, Clipson, A, Tugwood, J, Kerr, A, Rothwell, D, Kilgour, E, Aerts, H, Kaufmann, T, Szallasi, Z, Kisistok, J, Sokac, M, Diossy, M, Demeulemeester, J, Stewart, A, Magness, A, Rowan, A, Karamani, A, Chain, B, Campbell, B, Castignani, C, Weeden, C, Richard, C, Pearce, D, Karagianni, D, Levi, D, Hoxha, E, Larose Cadieux, E, Nye, E, Gronroos, E, Galvez-Cancino, F, Athanasopoulou, F, Gimeno-Valiente, F, Kassiotis, G, Stavrou, G, Mastrokalos, G, Zhai, H, Lowe, H, Matos, I, Goldman, J, Reading, J, Rane, J, Lam, J, Hartley, J, Enfield, K, Selvaraju, K, Litchfield, K, Ng, K, Chen, K, Dijkstra, K, Thakkar, K, Ensell, L, Shah, M, Vasquez, M, Litovchenko, M, Werner Sunderland, M, Leung, M, Escudero, M, Tanic, M, Sivakumar, M, Kanu, N, Chervova, O, Lucas, O, Al-Sawaf, O, Hobson, P, Pawlik, P, Stone, R, Hynds, R, Vendramin, R, Saghafinia, S, Lopez, S, Gamble, S, Ung, S, Vanloo, S, Boeing, S, Beck, S, Bola, S, Denner, T, Mourikis, T, Spanswick, V, Barbe, V, Lu, W, Hill, W, Wu, Y, Naito, Y, Ramsden, Z, Veiga, C, Royle, G, Collins-Fekete, C, Fraioli, F, Ashford, P, Clark, T, Borg, E, Wilson, J, Procter, A, Ahmed, A, Taylor, M, Nair, A, Patrini, D, Martinoni Hoogenboom, E, Monk, F, Holding, J, Choudhary, J, Bhakhri, K, Scarci, M, Hayward, M, Panagiotopoulos, N, Gorman, P, Khiroya, R, Stephens, R, Wong, Y, Bandula, S, Sharp, A, Smith, S, Gower, N, Dhanda, H, Chan, K, Pilotti, C, Leslie, R, Grapa, A, Zhang, H, Abduljabbar, K, Pan, X, Yuan, Y, Chuter, D, Mackenzie, M, Chee, S, Alzetani, A, Scarlett, L, Richards, J, Ingram, P, Austin, S, De Sousa, P, Jordan, S, Rice, A, Raubenheimer, H, Bhayani, H, Ambrose, L, Devaraj, A, Chavan, H, Begum, S, Buderi, S, Kaniu, D, Malima, M, Booth, S, Fernandes, N, Shah, P, Proli, C, Danson, S, Robinson, L, Dick, C, Kirk, A, Asif, M, Bilancia, R, Kostoulas, N, Thomas, M, Jamal-Hanjani, M, Mcgranahan, N, Swanton, C, Frankell A. M., Dietzen M., Al Bakir M., Lim E. L., Karasaki T., Ward S., Veeriah S., Colliver E., Huebner A., Bunkum A., Hill M. S., Grigoriadis K., Moore D. A., Black J. R. M., Liu W. K., Thol K., Pich O., Watkins T. B. K., Naceur-Lombardelli C., Cook D. E., Salgado R., Wilson G. A., Bailey C., Angelova M., Bentham R., Martinez-Ruiz C., Abbosh C., Nicholson A. G., Le Quesne J., Biswas D., Rosenthal R., Puttick C., Hessey S., Lee C., Prymas P., Toncheva A., Smith J., Xing W., Nicod J., Price G., Kerr K. M., Naidu B., Middleton G., Blyth K. G., Fennell D. A., Forster M. D., Lee S. M., Falzon M., Hewish M., Shackcloth M. J., Lim E., Benafif S., Russell P., Boleti E., Krebs M. G., Lester J. F., Papadatos-Pastos D., Ahmad T., Thakrar R. M., Lawrence D., Navani N., Janes S. M., Dive C., Blackhall F. H., Summers Y., Cave J., Marafioti T., Herrero J., Quezada S. A., Peggs K. S., Schwarz R. F., Van Loo P., Miedema D. M., Birkbak N. J., Hiley C. T., Hackshaw A., Zaccaria S., Bajaj A., Nakas A., Sodha-Ramdeen A., Ang K., Tufail M., Chowdhry M. F., Scotland M., Boyles R., Rathinam S., Wilson C., Marrone D., Dulloo S., Matharu G., Shaw J. A., Riley J., Primrose L., Cheyne H., Khalil M., Richardson S., Cruickshank T., Gilbert K., Patel A. J., Osman A., Lacson C., Langman G., Shackleford H., Djearaman M., Kadiri S., Leek A., Hodgkinson J. D., Totten N., Montero A., Smith E., Fontaine E., Granato F., Doran H., Novasio J., Rammohan K., Joseph L., Bishop P., Shah R., Moss S., Joshi V., Crosbie P., Gomes F., Brown K., Carter M., Chaturvedi A., Priest L., Oliveira P., Lindsay C. R., Clipson A., Tugwood J., Kerr A., Rothwell D. G., Kilgour E., Aerts H. J. W. L., Kaufmann T. L., Szallasi Z., Kisistok J., Sokac M., Diossy M., Demeulemeester J., Stewart A., Magness A., Rowan A., Karamani A., Chain B., Campbell B. B., Castignani C., Weeden C. E., Richard C., Pearce D. R., Karagianni D., Levi D., Hoxha E., Larose Cadieux E., Nye E., Gronroos E., Galvez-Cancino F., Athanasopoulou F., Gimeno-Valiente F., Kassiotis G., Stavrou G., Mastrokalos G., Zhai H., Lowe H. L., Matos I., Goldman J., Reading J. L., Rane J. K., Lam J. M., Hartley J. A., Enfield K. S. S., Selvaraju K., Litchfield K., Ng K. W., Chen K., Dijkstra K., Thakkar K., Ensell L., Shah M., Vasquez M., Litovchenko M., Werner Sunderland M., Leung M., Escudero M., Tanic M., Sivakumar M., Kanu N., Chervova O., Lucas O., Al-Sawaf O., Hobson P., Pawlik P., Stone R. K., Hynds R. E., Vendramin R., Saghafinia S., Lopez S., Gamble S., Ung S. K. A., Vanloo S., Boeing S., Beck S., Bola S. K., Denner T., Mourikis T. P., Spanswick V., Barbe V., Lu W. -T., Hill W., Wu Y., Naito Y., Ramsden Z., Veiga C., Royle G., Collins-Fekete C. -A., Fraioli F., Ashford P., Clark T., Borg E., Wilson J., Procter A. J., Ahmed A., Taylor M. N., Nair A., Patrini D., Martinoni Hoogenboom E., Monk F., Holding J. W., Choudhary J., Bhakhri K., Scarci M., Hayward M., Panagiotopoulos N., Gorman P., Khiroya R., Stephens R. C., Wong Y. N. S., Bandula S., Sharp A., Smith S., Gower N., Dhanda H. K., Chan K., Pilotti C., Leslie R., Grapa A., Zhang H., AbdulJabbar K., Pan X., Yuan Y., Chuter D., MacKenzie M., Chee S., Alzetani A., Scarlett L., Richards J., Ingram P., Austin S., De Sousa P., Jordan S., Rice A., Raubenheimer H., Bhayani H., Ambrose L., Devaraj A., Chavan H., Begum S., Buderi S. I., Kaniu D., Malima M., Booth S., Fernandes N., Shah P., Proli C., Danson S., Robinson L., Dick C., Kirk A., Asif M., Bilancia R., Kostoulas N., Thomas M., Jamal-Hanjani M., McGranahan N., and Swanton C.
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.
Published: 2023

13. Copy number architectures define treatment-mediated selection of lethal prostate cancer clones

Author: Hasan, A, Cremaschi, P, Wetterskog, D, Jayaram, A, Wong, S, Williams, S, Pasam, A, Trigos, A, Trujillo, B, Grist, E, Friedrich, S, Vainauskas, O, Parry, M, Ismail, M, Devlies, W, Wingate, A, Linch, M, Naceur-Lombardelli, C, Zaccaria, S, Hessey, S, Shiu, K, Bridgewater, J, Hochhauser, D, Forster, M, Lee, S, Ahmad, T, Papadatos-Pastos, D, Janes, S, Van Loo, P, Enfield, K, Mcgranahan, N, Huebner, A, Quezada, S, Beck, S, Parker, P, Enver, T, Hynds, R, Pearce, D, Falzon, M, Proctor, I, Sinclair, R, Lok, C, Rhodes, Z, Moore, D, Marafioti, T, Mitchison, M, Ellery, P, Sivakumar, M, Brandner, S, Rowan, A, Hiley, C, Veeriah, S, Shaw, H, Toncheva, A, Prymas, P, Watkins, T, Bailey, C, Martinez Ruiz, C, Litchfield, K, Al-Bakir, M, Kanu, N, Ward, S, Lim, E, Reading, J, Chain, B, Akay, M, Flanagan, A, Biswas, D, Pich, O, Dietzen, M, Puttick, C, Colliver, E, Magness, A, Angelova, M, Black, J, Lucas, O, Hill, W, Liu, W, Frankell, A, Magno, N, Athanasopoulou, F, Salgado, R, Lee, C, Grigoriadis, K, Al-Sawaf, O, Karasaki, T, Bunkum, A, Noorani, I, Benafif, S, Barbe, V, Bola, S, Leone, G, Alifrangis, C, Mcgovern, U, Thol, K, Gamble, S, Ung, S, Sahwangarrom, T, Marin, C, Pawlik, P, Lam, J, Richard, C, Vendramin, R, Dijkstra, K, Rane, J, Nicod, J, Dwornik, A, Bowles, K, Zaidi, R, Gishen, F, Stone, P, Stirling, C, Turajlic, S, Larkin, J, Pickering, L, Furness, A, Young, K, Drake, W, Edmonds, K, Hunter, N, Mangwende, M, Pearce, K, Grostate, L, Au, L, Spain, L, Shepherd, S, Yan, H, Shum, B, Tippu, Z, Hanley, B, Spencer, C, Emmerich, M, Gerard, C, Schmitt, A, Del Rosario, L, Carlyle, E, Lewis, C, Holt, L, Lucanas, A, O'Flaherty, M, Hazell, S, Mudhar, H, Messiou, C, Latifoltojar, A, Fendler, A, Byrne, F, Pallikonda, H, Lobon, I, Coulton, A, Cattin, A, Deng, D, Feng, H, Yousaf, N, Popat, S, Curtis, O, Milner-Watts, C, Stamp, G, Nye, E, Murra, A, Korteweg, J, Kelly, D, Terry, L, Biano, J, Peat, K, Kelly, K, Grieco, C, Le, M, D'Arienzo, P, Turay, E, Hill, P, Josephs, D, Irshad, S, Spicer, J, Mahadeva, U, Green, A, Stewart, R, Wright, N, Pulman, G, Mitu, R, Phillips-Boyd, S, Enting, D, Rudman, S, Ghosh, S, Karapanagiotou, E, Pintus, E, Tutt, A, Howlett, S, Brenton, J, Caldas, C, Fitzgerald, R, Jimenez-Linan, M, Provenzano, E, Cluroe, A, Paterson, A, Aitken, S, Allinson, K, Stewart, G, Mcdermott, U, Beddowes, E, Maughan, T, Ansorge, O, Campbell, P, Roxburgh, P, Fraser, S, Blyth, K, Le Quesne, J, Krebs, M, Blackhall, F, Summers, Y, Oliveira, P, Ortega-Franco, A, Dive, C, Gomes, F, Carter, M, Dransfield, J, Thomas, A, Fennell, D, Shaw, J, Wilson, C, Marrone, D, Naidu, B, Baijal, S, Tanchel, B, Langman, G, Robinson, A, Collard, M, Cockcroft, P, Ferris, C, Bancroft, H, Kerr, A, Middleton, G, Webb, J, Kadiri, S, Colloby, P, Olisemeke, B, Wilson, R, Shackleford, H, Osman, A, Tomlinson, I, Jogai, S, Holden, S, Fernandes, T, Mcneish, I, Hampton, B, Mckenzie, M, Hackshaw, A, Sharp, A, Chan, K, Farrelly, L, Bridger, H, Leslie, R, Tookman, A, Swanton, C, Jamal-Hanjani, M, Lise, S, Sandhu, S, Attard, G, Hasan A. M. M., Cremaschi P., Wetterskog D., Jayaram A., Wong S. Q., Williams S., Pasam A., Trigos A., Trujillo B., Grist E., Friedrich S., Vainauskas O., Parry M., Ismail M., Devlies W., Wingate A., Linch M., Naceur-Lombardelli C., Zaccaria S., Hessey S., Shiu K. -K., Bridgewater J., Hochhauser D., Forster M., Lee S. -M., Ahmad T., Papadatos-Pastos D., Janes S., Van Loo P., Enfield K., McGranahan N., Huebner A., Quezada S., Beck S., Parker P., Enver T., Hynds R. E., Pearce D. R., Falzon M., Proctor I., Sinclair R., Lok C. -W., Rhodes Z., Moore D., Marafioti T., Mitchison M., Ellery P., Sivakumar M., Brandner S., Rowan A., Hiley C., Veeriah S., Shaw H., Toncheva A., Prymas P., Watkins T. B. K., Bailey C., Martinez Ruiz C., Litchfield K., Al-Bakir M., Kanu N., Ward S., Lim E., Reading J., Chain B., Watkins T., Akay M., Flanagan A., Biswas D., Pich O., Dietzen M., Puttick C., Colliver E., Magness A., Angelova M., Black J., Lucas O., Hill W., Liu W. -K., Frankell A., Magno N., Athanasopoulou F., Salgado R., Lee C., Grigoriadis K., Al-Sawaf O., Karasaki T., Bunkum A., Noorani I., Benafif S., Barbe V., Bola S. K., Leone G., Alifrangis C., McGovern U., Thol K., Gamble S., Ung S. K., Sahwangarrom T., Marin C. P., Wong S., Pawlik P., Lam J. M., Richard C., Vendramin R., Dijkstra K., Rane J., Nicod J., Dwornik A., Bowles K., Zaidi R., Gishen F., Stone P., Stirling C., Turajlic S., Larkin J., Pickering L., Furness A., Young K., Drake W., Edmonds K., Hunter N., Mangwende M., Pearce K., Grostate L., Au L., Spain L., Shepherd S., Yan H., Shum B., Tippu Z., Hanley B., Spencer C., Emmerich M., Gerard C., Schmitt A. M., Del Rosario L., Carlyle E., Lewis C., Holt L., Lucanas A., O'Flaherty M., Hazell S., Mudhar H., Messiou C., Latifoltojar A., Fendler A., Byrne F., Pallikonda H., Lobon I., Coulton A., Cattin A. -L., Deng D., Feng H., Yousaf N., Popat S., Curtis O., Milner-Watts C., Stamp G., Nye E., Murra A., Korteweg J., Kelly D., Terry L., Biano J., Peat K., Kelly K., Grieco C., Le M. L., D'Arienzo P. D., Turay E., Hill P., Josephs D., Irshad S., Spicer J., Mahadeva U., Green A., Stewart R., Wright N., Pulman G., Mitu R., Phillips-Boyd S., Enting D., Rudman S., Ghosh S., Karapanagiotou E., Pintus E., Tutt A., Howlett S., Brenton J., Caldas C., Fitzgerald R., Jimenez-Linan M., Provenzano E., Cluroe A., Paterson A., Aitken S., Allinson K., Stewart G., McDermott U., Beddowes E., Maughan T., Ansorge O., Campbell P., Roxburgh P., Fraser S., Blyth K., Le Quesne J., Krebs M., Blackhall F., Summers Y., Oliveira P., Ortega-Franco A., Dive C., Gomes F., Carter M., Dransfield J., Thomas A., Fennell D., Shaw J., Wilson C., Marrone D., Naidu B., Baijal S., Tanchel B., Langman G., Robinson A., Collard M., Cockcroft P., Ferris C., Bancroft H., Kerr A., Middleton G., Webb J., Kadiri S., Colloby P., Olisemeke B., Wilson R., Shackleford H., Osman A., Tomlinson I., Jogai S., Holden S., Fernandes T., McNeish I., Hampton B., McKenzie M., Hackshaw A., Sharp A., Chan K., Farrelly L., Bridger H., Leslie R., Tookman A., Swanton C., Jamal-Hanjani M., Lise S., Sandhu S., Attard G., Hasan, A, Cremaschi, P, Wetterskog, D, Jayaram, A, Wong, S, Williams, S, Pasam, A, Trigos, A, Trujillo, B, Grist, E, Friedrich, S, Vainauskas, O, Parry, M, Ismail, M, Devlies, W, Wingate, A, Linch, M, Naceur-Lombardelli, C, Zaccaria, S, Hessey, S, Shiu, K, Bridgewater, J, Hochhauser, D, Forster, M, Lee, S, Ahmad, T, Papadatos-Pastos, D, Janes, S, Van Loo, P, Enfield, K, Mcgranahan, N, Huebner, A, Quezada, S, Beck, S, Parker, P, Enver, T, Hynds, R, Pearce, D, Falzon, M, Proctor, I, Sinclair, R, Lok, C, Rhodes, Z, Moore, D, Marafioti, T, Mitchison, M, Ellery, P, Sivakumar, M, Brandner, S, Rowan, A, Hiley, C, Veeriah, S, Shaw, H, Toncheva, A, Prymas, P, Watkins, T, Bailey, C, Martinez Ruiz, C, Litchfield, K, Al-Bakir, M, Kanu, N, Ward, S, Lim, E, Reading, J, Chain, B, Akay, M, Flanagan, A, Biswas, D, Pich, O, Dietzen, M, Puttick, C, Colliver, E, Magness, A, Angelova, M, Black, J, Lucas, O, Hill, W, Liu, W, Frankell, A, Magno, N, Athanasopoulou, F, Salgado, R, Lee, C, Grigoriadis, K, Al-Sawaf, O, Karasaki, T, Bunkum, A, Noorani, I, Benafif, S, Barbe, V, Bola, S, Leone, G, Alifrangis, C, Mcgovern, U, Thol, K, Gamble, S, Ung, S, Sahwangarrom, T, Marin, C, Pawlik, P, Lam, J, Richard, C, Vendramin, R, Dijkstra, K, Rane, J, Nicod, J, Dwornik, A, Bowles, K, Zaidi, R, Gishen, F, Stone, P, Stirling, C, Turajlic, S, Larkin, J, Pickering, L, Furness, A, Young, K, Drake, W, Edmonds, K, Hunter, N, Mangwende, M, Pearce, K, Grostate, L, Au, L, Spain, L, Shepherd, S, Yan, H, Shum, B, Tippu, Z, Hanley, B, Spencer, C, Emmerich, M, Gerard, C, Schmitt, A, Del Rosario, L, Carlyle, E, Lewis, C, Holt, L, Lucanas, A, O'Flaherty, M, Hazell, S, Mudhar, H, Messiou, C, Latifoltojar, A, Fendler, A, Byrne, F, Pallikonda, H, Lobon, I, Coulton, A, Cattin, A, Deng, D, Feng, H, Yousaf, N, Popat, S, Curtis, O, Milner-Watts, C, Stamp, G, Nye, E, Murra, A, Korteweg, J, Kelly, D, Terry, L, Biano, J, Peat, K, Kelly, K, Grieco, C, Le, M, D'Arienzo, P, Turay, E, Hill, P, Josephs, D, Irshad, S, Spicer, J, Mahadeva, U, Green, A, Stewart, R, Wright, N, Pulman, G, Mitu, R, Phillips-Boyd, S, Enting, D, Rudman, S, Ghosh, S, Karapanagiotou, E, Pintus, E, Tutt, A, Howlett, S, Brenton, J, Caldas, C, Fitzgerald, R, Jimenez-Linan, M, Provenzano, E, Cluroe, A, Paterson, A, Aitken, S, Allinson, K, Stewart, G, Mcdermott, U, Beddowes, E, Maughan, T, Ansorge, O, Campbell, P, Roxburgh, P, Fraser, S, Blyth, K, Le Quesne, J, Krebs, M, Blackhall, F, Summers, Y, Oliveira, P, Ortega-Franco, A, Dive, C, Gomes, F, Carter, M, Dransfield, J, Thomas, A, Fennell, D, Shaw, J, Wilson, C, Marrone, D, Naidu, B, Baijal, S, Tanchel, B, Langman, G, Robinson, A, Collard, M, Cockcroft, P, Ferris, C, Bancroft, H, Kerr, A, Middleton, G, Webb, J, Kadiri, S, Colloby, P, Olisemeke, B, Wilson, R, Shackleford, H, Osman, A, Tomlinson, I, Jogai, S, Holden, S, Fernandes, T, Mcneish, I, Hampton, B, Mckenzie, M, Hackshaw, A, Sharp, A, Chan, K, Farrelly, L, Bridger, H, Leslie, R, Tookman, A, Swanton, C, Jamal-Hanjani, M, Lise, S, Sandhu, S, Attard, G, Hasan A. M. M., Cremaschi P., Wetterskog D., Jayaram A., Wong S. Q., Williams S., Pasam A., Trigos A., Trujillo B., Grist E., Friedrich S., Vainauskas O., Parry M., Ismail M., Devlies W., Wingate A., Linch M., Naceur-Lombardelli C., Zaccaria S., Hessey S., Shiu K. -K., Bridgewater J., Hochhauser D., Forster M., Lee S. -M., Ahmad T., Papadatos-Pastos D., Janes S., Van Loo P., Enfield K., McGranahan N., Huebner A., Quezada S., Beck S., Parker P., Enver T., Hynds R. E., Pearce D. R., Falzon M., Proctor I., Sinclair R., Lok C. -W., Rhodes Z., Moore D., Marafioti T., Mitchison M., Ellery P., Sivakumar M., Brandner S., Rowan A., Hiley C., Veeriah S., Shaw H., Toncheva A., Prymas P., Watkins T. B. K., Bailey C., Martinez Ruiz C., Litchfield K., Al-Bakir M., Kanu N., Ward S., Lim E., Reading J., Chain B., Watkins T., Akay M., Flanagan A., Biswas D., Pich O., Dietzen M., Puttick C., Colliver E., Magness A., Angelova M., Black J., Lucas O., Hill W., Liu W. -K., Frankell A., Magno N., Athanasopoulou F., Salgado R., Lee C., Grigoriadis K., Al-Sawaf O., Karasaki T., Bunkum A., Noorani I., Benafif S., Barbe V., Bola S. K., Leone G., Alifrangis C., McGovern U., Thol K., Gamble S., Ung S. K., Sahwangarrom T., Marin C. P., Wong S., Pawlik P., Lam J. M., Richard C., Vendramin R., Dijkstra K., Rane J., Nicod J., Dwornik A., Bowles K., Zaidi R., Gishen F., Stone P., Stirling C., Turajlic S., Larkin J., Pickering L., Furness A., Young K., Drake W., Edmonds K., Hunter N., Mangwende M., Pearce K., Grostate L., Au L., Spain L., Shepherd S., Yan H., Shum B., Tippu Z., Hanley B., Spencer C., Emmerich M., Gerard C., Schmitt A. M., Del Rosario L., Carlyle E., Lewis C., Holt L., Lucanas A., O'Flaherty M., Hazell S., Mudhar H., Messiou C., Latifoltojar A., Fendler A., Byrne F., Pallikonda H., Lobon I., Coulton A., Cattin A. -L., Deng D., Feng H., Yousaf N., Popat S., Curtis O., Milner-Watts C., Stamp G., Nye E., Murra A., Korteweg J., Kelly D., Terry L., Biano J., Peat K., Kelly K., Grieco C., Le M. L., D'Arienzo P. D., Turay E., Hill P., Josephs D., Irshad S., Spicer J., Mahadeva U., Green A., Stewart R., Wright N., Pulman G., Mitu R., Phillips-Boyd S., Enting D., Rudman S., Ghosh S., Karapanagiotou E., Pintus E., Tutt A., Howlett S., Brenton J., Caldas C., Fitzgerald R., Jimenez-Linan M., Provenzano E., Cluroe A., Paterson A., Aitken S., Allinson K., Stewart G., McDermott U., Beddowes E., Maughan T., Ansorge O., Campbell P., Roxburgh P., Fraser S., Blyth K., Le Quesne J., Krebs M., Blackhall F., Summers Y., Oliveira P., Ortega-Franco A., Dive C., Gomes F., Carter M., Dransfield J., Thomas A., Fennell D., Shaw J., Wilson C., Marrone D., Naidu B., Baijal S., Tanchel B., Langman G., Robinson A., Collard M., Cockcroft P., Ferris C., Bancroft H., Kerr A., Middleton G., Webb J., Kadiri S., Colloby P., Olisemeke B., Wilson R., Shackleford H., Osman A., Tomlinson I., Jogai S., Holden S., Fernandes T., McNeish I., Hampton B., McKenzie M., Hackshaw A., Sharp A., Chan K., Farrelly L., Bridger H., Leslie R., Tookman A., Swanton C., Jamal-Hanjani M., Lise S., Sandhu S., and Attard G.
Abstract: Despite initial responses to hormone treatment, metastatic prostate cancer invariably evolves to a lethal state. To characterize the intra-patient evolutionary relationships of metastases that evade treatment, we perform genome-wide copy number profiling and bespoke approaches targeting the androgen receptor (AR) on 167 metastatic regions from 11 organs harvested post-mortem from 10 men who died from prostate cancer. We identify diverse and patient-unique alterations clustering around the AR in metastases from every patient with evidence of independent acquisition of related genomic changes within an individual and, in some patients, the co-existence of AR-neutral clones. Using the genomic boundaries of pan-autosome copy number changes, we confirm a common clone of origin across metastases and diagnostic biopsies, and identified in individual patients, clusters of metastases occupied by dominant clones with diverged autosomal copy number alterations. These autosome-defined clusters are characterized by cluster-specific AR gene architectures, and in two index cases are topologically more congruent than by chance (p-values 3.07 × 10−8 and 6.4 × 10−4). Integration with anatomical sites suggests patterns of spread and points of genomic divergence. Here, we show that copy number boundaries identify treatment-selected clones with putatively distinct lethal trajectories.
Published: 2023

14. Solid as a rock, flexible as water? Effectiveness of a school-based intervention addressing students' intrapersonal and interpersonal domains

Author: Development and Treatment of Psychosocial Problems, Leerstoel Dekovic, Mertens, E.c.a., Deković, M., Van Londen, M., Nye, E., Reitz, E., Development and Treatment of Psychosocial Problems, Leerstoel Dekovic, Mertens, E.c.a., Deković, M., Van Londen, M., Nye, E., and Reitz, E.
Published: 2022

15. 129 Methamphetamine Use and Engagement With Medications for Opioid Use Disorder

Author: Parrish, M., Grinnell, R., Parrish, C., Lovett, K., Long, S., Taga, S., Martin, A., Nye, E., Zatzick, D., and Whiteside, L.
Published: 2024
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16. 422P UK real-world data (RWD) of cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) use in metastatic breast cancer (MBC)

Author: Gullick, G., Owen, C., Cook, S., Helbrow, J., Squires, R., Reed, H.M., Park, S., Weir, E., Aquilina, F., Webber, N., Nye, E., Atkinson, C., Blair, C., Halstead, A., Daniels, E., Alves, A., Chew, S., Thomas, W., Spensley, S., and Robinson, T.
Published: 2023
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17. Health-related quality of life in people with predementia Alzheimer’s disease, mild cognitive impairment or dementia measured with preference-based instruments: a systematic literature review

Author: Landeiro, F, Mughal, S, Walsh, K, Nye, E, Morton, J, Williams, H, Ghinai, I, Castro, Y, Leal, J, Roberts, N, Wace, H, Handels, R, Lecomte, P, Gustavsson, A, Roncancio-Diaz, E, Belger, M, Jhuti, GS, Bouvy, JC, Potashman, MH, Tockhorn-Heidenreich, A, Gray, AM, and consortium, ROADMAP
Subjects: Quality of life, Gerontology, Cognitive Neuroscience, Population, Review, Disease, lcsh:RC346-429, lcsh:RC321-571, s disease, 03 medical and health sciences, 0302 clinical medicine, Quality of life (healthcare), Alzheimer Disease, mental disorders, Humans, Medicine, Dementia, Cognitive Dysfunction, OLDER-PEOPLE, 030212 general & internal medicine, Alzheimer&#8217, education, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, DEMQOL-PROXY-U, lcsh:Neurology. Diseases of the nervous system, UTILITY, education.field_of_study, business.industry, Systematic literature review, medicine.disease, EQ-5D-5L, Systematic review, Caregivers, Neurology, Severe dementia, Respondent, Neurology (clinical), business, Alzheimer’s disease, 030217 neurology & neurosurgery, Geriatric psychiatry
Abstract: Background Obtaining reliable estimates of the health-related quality of life (HR-QoL) of people with predementia Alzheimer’s disease [AD] (preclinical or prodromal AD), mild cognitive impairment (MCI) and dementia is essential for economic evaluations of related health interventions. Aims To provide an overview of which quality of life instruments are being used to assess HR-QoL in people with predementia AD, MCI or dementia; and, to summarise their reported HR-QoL levels at each stage of the disease and by type of respondent. Methods We systematically searched for and reviewed eligible studies published between January 1990 and the end of April 2017 which reported HR-QoL for people with predementia AD, MCI or dementia. We only included instruments which are preference-based, allowing index scores/utility values to be attached to each health state they describe based on preferences obtained from population surveys. Summary results were presented by respondent type (self or proxy), type of instrument, geographical location and, where possible, stage of disease. Health state utility values derived using the EuroQoL 5-Dimensions (EQ-5D) were meta-analysed by pooling reported results across all studies by disease severity (MCI, mild, mild to moderate, moderate, severe dementia, not specified) and by respondent (person with dementia, carer, general public, not specified), using a fixed-effects approach. Results We identified 61 studies which reported HR-QoL for people with MCI or dementia using preference-based instruments, of which 48 used the EQ-5D. Thirty-six studies reported HR-QoL for mild and/or moderate disease severities, and 12 studies reported utility values for MCI. We found systematic differences between self-rated and proxy-rated HR-QoL, with proxy-rated utility valued being significantly lower in more severe disease states. Conclusions A substantial literature now exists quantifying the impact of dementia on HR-QoL using preference-based measures, giving researchers and modellers a firmer basis on which to select appropriate utility values when estimating the effectiveness and cost-effectiveness of interventions in this area. Further research is required on HR-QoL of people with preclinical and prodromal AD and MCI, possible differences by type of dementia, the effects of comorbidities, study setting and the informal caregiver’s own HR-QoL, including any effect of that on their proxy-ratings.
Published: 2020

18. Solid as a rock, flexible as water? Effectiveness of a school-based intervention addressing students' intrapersonal and interpersonal domains

Author: Mertens, E.c.a., Deković, M., Van Londen, M., Nye, E., Reitz, E., Development and Treatment of Psychosocial Problems, Leerstoel Dekovic, Development and Treatment of Psychosocial Problems, and Leerstoel Dekovic
Subjects: Interpersonal domain, Male, School-based intervention, education, Emotions, Water, Intrapersonal domain, Education, Self-Control, Developmental and Educational Psychology, Humans, Learning, Female, Randomized controlled trial (RCT), Child, Students, Components
Abstract: Students following a preparatory vocational education track seem most in need of an intervention stimulating their competencies and preventing the development of problems in the intrapersonal and interpersonal domain. The aim of the present study was to examine, first, whether Rock & Water, a social emotional learning intervention that uses active forms of learning, is effective in improving students' competencies and preventing problems in the intra- and interpersonal domain, and second, whether intervention effects were influenced by the extent to which multiple systems are involved in the intervention. We conducted a randomized controlled trial with a sample of 7th grade students (N = 1299, Mage = 12.38, 54% boys). Students reported on outcomes of the intra- and interpersonal domains using digital questionnaires. The data were analyzed with Latent Growth Curve models. Results showed that the intervention was most effective when only a core team of teachers was involved in the intervention. The intervention improved several proximal outcomes (i.e., self-control and emotional self-regulation) and distal outcomes in students' intrapersonal and interpersonal domains. The intervention effects were strongest, albeit moderate, in the first year of the intervention. These results show that interventions with an active form of learning and implemented by a core team might be promising interventions for prevocational students, although effort should be put in increasing its effectiveness.
Published: 2020

19. Psychological distress among primary school teachers: a comparison with clinical and population samples

Author: Titheradge, D., Hayes, R., Longdon, B., Allen, K., Price, A., Hansford, L., Nye, E., Ukoumunne, O.C., Byford, S., Norwich, B., Fletcher, M., Logan, S., and Ford, T.
Published: 2019
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20. L’importance des acteurs-mimes étrangers pour le ballet romantique français

Author: Nye, E
Published: 2019

21. Intravenous immunoglobulin responsive gastroparesis in a patient with diabetes mellitus.

Author: Renouf D., Nye E., Xu S., Inchley F., Tan C.Y., Renouf D., Nye E., Xu S., Inchley F., and Tan C.Y.
Published: 2019

22. [Accepted Manuscript] Stigma related to targeted school-based mental health interventions: a systematic review of qualitative evidence

Author: Gronholm, P.C., Nye, E., and Michelson, D.
Subjects: education
Abstract: Background School-based mental health services have been advocated to increase access to psychological support for children and adolescents. However, concerns have been raised about the potential stigma associated with selection of students and the visibility of school-based service contact. Methods This review assessed findings from qualitative studies to identify potential stigmatising effects of participation in targeted school-based mental health interventions for students attending primary- or secondary-level education. Eight articles (reflecting seven studies) were identified through electronic database searches (PsycInfo, EMBASE, Medline, CINAHL, ERIC), supplemented by citation and reference searches and expert consultations. Data were synthesised according to established guidelines for thematic synthesis. Results Three overarching themes were identified: “anticipated and experienced stigma”, “consequences of stigma” and “mitigating strategies”. These findings illustrate how pervasively stigma can compromise efforts to increase access to mental health care through targeted school-based provision, but also outline strategies endorsed by students for alleviating the risk and/or impact of stigma. Limitations These findings need to be considered in view of the relative scarcity of surveyed evidence. Furthermore, as all evidence came from high-income and Western countries, the applicability to other contexts is unclear. Conclusions This synthesis reflects the first overview of qualitative evidence regarding stigmatising experiences and concerns associated with students’ engagement with targeted school-based mental health interventions. The findings can inform efforts to mitigate stigma-related barriers to students’ engagement in targeted mental health support, and serve to guide future research in this area.
Published: 2018

23. Measuring quality of life of people with predementia and dementia and their caregivers: a systematic review protocol

Author: Landeiro, F, Walsh, K, Ghinai, I, Mughal, S, Nye, E, Wace, H, Roberts, N, Lecomte, P, Wittenberg, R, Wolstenholme, J, Handels, R, Roncancio-Diaz, E, Potashman, M, Tockhorn-Heidenreich, A, Gray, A, and Group, Roadmap
Subjects: Gerontology, medicine.medical_specialty, Geriatric Medicine, PsycINFO, 03 medical and health sciences, 0302 clinical medicine, Quality of life (healthcare), medicine, Protocol, Dementia, Humans, 030212 general & internal medicine, Prospective Studies, 10. No inequality, Retrospective Studies, Descriptive statistics, business.industry, Public health, systematic literature review, alzheimer’s disease, General Medicine, medicine.disease, 3. Good health, Systematic review, Data extraction, quality of life, Caregivers, utility, business, RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry, CARERS, 030217 neurology & neurosurgery, Medical literature, Systematic Reviews as Topic
Abstract: IntroductionDementia is the fastest growing major cause of disability globally and may have a profound impact on the health-related quality of life (HRQoL) of both the patient with dementia and those who care for them. This review aims to systematically identify and synthesise the measurements of HRQoL for people with, and their caregivers across the full spectrum of, dementia from its preceding stage of predementia to end of life.Methods and analysisA systematic literature review was conducted in Medical Literature Analysis and Retrieval System Online , ExcerptaMedicadataBASE, Cochrane Database of Systematic Reviews , Cochrane Central Register of Controlled Trials, Database of Abstracts of Reviews of Effect, National Health Service Economic Evaluation Database and PsycINFO between January 1990 and the end of April 2017. Two reviewers will independently assess each study for inclusion and disagreements will be resolved by a third reviewer. Data will be extracted using a predefined data extraction form following best practice. Study quality will be assessed with the Effective Public Health Practice Project quality assessment tool. HRQoL measurements will be presented separately for people with dementia and caregivers by instrument used and, when possible, HRQoL will be reported by disease type and stage of the disease. Descriptive statistics of the results will be provided. A narrative synthesis of studies will also be provided discussing differences in HRQoL measurements by instrument used to estimate it, type of dementia and disease severity.Ethics and disseminationThis systematic literature review is exempt from ethics approval because the work is carried out on published documents. The findings of the review will be disseminated in a related peer-reviewed journal and presented at conferences. They will also contribute to the work developed in the Real World Outcomes across the Alzheimer’s disease spectrum for better care: multimodal data access platform (ROADMAP).Trial registration numberCRD42017071416.
Published: 2018

24. Trends in the Use of Permanent Pacemakers in Australia: A Nationwide Study from 2008–2017

Author: Westaway, S., primary, Nye, E., additional, Gallagher, C., additional, Pitman, B., additional, Lau, D., additional, Mahajan, R., additional, Sanders, P., additional, and Wong, C., additional
Published: 2019
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25. Allele-Specific HLA Loss and Immune Escape in Lung Cancer Evolution

Author: McGranahan, N., Rosenthal, R., Hiley, C.T., Rowan, A.J., Watkins, T.B.K., Wilson, G.A., Birkbak, N.J., Veeriah, S., Van Loo, P., Herrero, J., Swanton, C., Jamal-Hanjani, M., Shafi, S., Czyzewska-Khan, J., Johnson, D., Laycock, J., Bosshard-Carter, L., Gorman, P., Hynds, R.E., Wilson, G., Horswell, S., Mitter, R., Escudero, M., Stewart, A., Rowan, A., Xu, H., Turajlic, S., Hiley, C., Abbosh, C., Goldman, J., Stone, R.K., Denner, T., Matthews, N., Elgar, G., Ward, S., Costa, M., Begum, S., Phillimore, B., Chambers, T., Nye, E., Graca, S., Al Bakir, M., Joshi, K., Furness, A., Ben Aissa, A., Wong, Y.N.S., Georgiou, A., Quezada, S., Hartley, J.A., Lowe, H.L., Lawrence, D., Hayward, M., Panagiotopoulos, N., Kolvekar, S., Falzon, M., Borg, E., Marafioti, T., Simeon, C., Hector, G., Smith, A., Aranda, M., Novelli, M., Oukrif, D., Janes, S.M., Thakrar, R., Forster, M., Ahmad, T., Lee, S.M., Papadatos-Pastos, D., Carnell, D., Mendes, R., George, J., Navani, N., Ahmed, A., Taylor, M., Choudhary, J., Summers, Y., Califano, R., Taylor, P., Shah, R., Krysiak, P., Rammohan, K., Fontaine, E., Booton, R., Evison, M., Crosbie, P., Moss, S., and the TRACERx Consortium, .
Abstract: Immune evasion is a hallmark of cancer. Losing the ability to present neoantigens through human leukocyte antigen (HLA) loss may facilitate immune evasion. However, the polymorphic nature of the locus has precluded accurate HLA copy-number analysis. Here, we present loss of heterozygosity in human leukocyte antigen (LOHHLA), a computational tool to determine HLA allele-specific copy number from sequencing data. Using LOHHLA, we find that HLA LOH occurs in 40% of non-small-cell lung cancers (NSCLCs) and is associated with a high subclonal neoantigen burden, APOBEC-mediated mutagenesis, upregulation of cytolytic activity, and PD-L1 positivity. The focal nature of HLA LOH alterations, their subclonal frequencies, enrichment in metastatic sites, and occurrence as parallel events suggests that HLA LOH is an immune escape mechanism that is subject to strong microenvironmental selection pressures later in tumor evolution. Characterizing HLA LOH with LOHHLA refines neoantigen prediction and may have implications for our understanding of resistance mechanisms and immunotherapeutic approaches targeting neoantigens. Video Abstract [Figure presented] Development of the bioinformatics tool LOHHLA allows precise measurement of allele-specific HLA copy number, improves the accuracy in neoantigen prediction, and uncovers insights into how immune escape contributes to tumor evolution in non-small-cell lung cancer.
Published: 2017

26. Classroom behaviour management to support children's social, emotional, and behavioural development

Author: Nye, E and Gardner, F
Subjects: Psychology, Social Intervention, Education
Abstract: Introduction: Children's social, emotional, and behavioural difficulties are associated with reduced academic performance, stressed teacher-child relationships, and other negative academic and life outcomes. The Incredible Years Teacher Classroom Management (IY TCM) programme is one intervention developed to address problematic behaviours via training teachers to use positive and proactive management strategies. The overall aim of this DPhil is to use the Incredible Years Teacher Classroom Management programme as a case study for applying mixed methods at the systematic review level to ascertain what is known about both the programme's effectiveness and how people experience the course, and subsequently to use the systematic review's findings as a springboard (rather than as an end goal) for more exploratory research into 'for whom' the programme might work. Method: Study One is a mixed methods systematic review of IY TCM. It applied multilevel meta-analysis to RCT outcome data and grounded theory meta-synthesis to interview and focus group data on stakeholders' experiences of IY TCM. Quantitative and qualitative findings were cross-synthesised and mapped using an integrative grid. Study Two moves the field forward by filling a gap in the evidence base, as identified in Study One. Semi-structured telephone interviews were conducted with special educational needs coordinators (SENCos) across Devon, exploring the acceptability and appropriateness of expanding IY TCM to the subgroup of children with special educational needs (SEN) in mainstream schools. Data were analysed thematically and mapped onto IY TCM content. Results: In Study One, nine studies reported across 14 papers met inclusion criteria for either quantitative or qualitative strands of this systematic review. Multilevel meta-analysis of RCTs (n=4) indicated that the programme produced teacher- and child-level results in the desired directions. Clear trends across all measured outcomes favoured the intervention group over the treatment-as-usual comparison. Qualitative meta-synthesis (n=5) illuminated a cyclical learning process and broader conceptualisation of teacher and child outcomes than was evident in the quantitative evidence. Notably, RCT data on teacher outcomes were limited to self-reported or observed behaviours, while teachers described other benefits from IY TCM including increased knowledge and emotional well-being. Cross-synthesis of findings from the two review strands highlighted harmony across the RCT and qualitative evidence but also a number of areas in which constructs that were prioritised by one type of research were not integrated into the other. Study Two generated classroom management strategies from SENCos, which aligned closely with strategies taught in IY TCM, indicating that IY TCM would be both acceptable and applicable (if not sufficient) for use when working with children identified with SEN and behavioural difficulties in schools. Discussion: Based on the positive effects of implementing IY TCM despite very few studies to power analyses, the programme appears to offer tangible benefits to both teachers and children. It is possible that results are underestimated due to limited types of outcomes measured and absence of experiential data from additional stakeholders (e.g., parents). Depending on current provision of special educational needs services, schools operating inclusion models are likely to find these strategies beneficial for children identified with SEN, and this subgroup should be explicitly examined in future IY TCM studies.
Published: 2017

27. Phylogenetic ctDNA analysis depicts early stage lung cancer evolution

Author: Abbosh, C, Birkbak, NJ, Wilson, GA, Jamal-Hanjani, M, Constantin, T, Salari, R, Quesne, JL, Moore, DA, Veeriah, S, Rosenthal, R, Marafioti, T, Kirkizlar, E, Watkins, TBK, McGranahan, N, Ward, S, Martinson, L, Riley, J, Fraioli, F, Bakir, MA, GrÖnroos, E, Zambrana, F, Endozo, R, Bi, WL, Fennessy, FM, Sponer, N, Johnson, D, Laycock, J, Shafi, S, Czyzewska-Khan, J, Rowan, A, Chambers, T, Matthews, N, Turajlic, S, Hiley, C, Lee, SM, Forster, MD, Ahmad, T, Falzon, M, Borg, E, Lawrence, D, Hayward, M, Kolvekar, S, Panagiotopoulos, N, Janes, SM, Thakrar, R, Ahmed, A, Blackhall, F, Summers, Y, Hafez, D, Naik, A, Ganguly, A, Kareht, S, Shah, R, Joseph, L, Quinn, AM, Crosbie, P, Naidu, B, Middleton, G, Langman, G, Trotter, S, Nicolson, M, Remmen, H, Kerr, K, Chetty, M, Gomersall, L, Fennell, DA, Nakas, A, Rathinam, S, Anand, G, Khan, S, Russell, P, Ezhil, V, Ismail, B, Irvin-sellers, M, Prakash, V, Lester, JF, Kornaszewska, M, Attanoos, R, Adams, H, Davies, H, Oukrif, D, Akarca, AU, Hartley, JA, Lowe, HL, Lock, S, Iles, N, Bell, H, Ngai, Y, Elgar, G, Szallasi, Z, Schwarz, RF, Herrero, J, Stewart, A, Quezada, SA, Van Loo, P, Dive, C, Lin, CJ, Rabinowitz, M, Aerts, HJWL, Hackshaw, A, Shaw, JA, Zimmermann, BG, Swanton, C, Bosshard-Carter, L, Goh, G, Gorman, P, Murugaesu, N, Hynds, RE, Wilson, G, Horswell, S, Al Bakir, M, Mitter, R, Escudero, M, Xu, H, Goldman, J, Stone, RK, Denner, T, Biggs, J, Costa, M, Begum, S, Phillimore, B, Nye, E, Graca, S, Joshi, K, Furness, A, Aissa, AB, Wong, YNS, Georgiou, A, Quezada, S, Simeon, C, Hector, G, Smith, A, Aranda, M, Novelli, M, Forster, M, Papadatos-Pastos, D, Carnell, D, Mendes, R, George, J, Navani, N, Taylor, M, Choudhary, J, Califano, R, Taylor, P, Krysiak, P, Rammohan, K, Fontaine, E, Booton, R, Evison, M, Moss, S, Idries, F, Bishop, P, Chaturved, A, Marie Quinn, A, Doran, H, leek, A, Harrison, P, Moore, K, Waddington, R, Novasio, J, Rogan, J, Smith, E, Tugwood, J, Brady, G, Rothwell, DG, Chemi, F, Pierce, J, Gulati, S, Bellamy, M, Bancroft, H, Kerr, A, Kadiri, S, Webb, J, Djearaman, M, Fennell, D, Le Quesne, J, Moore, D, Thomas, A, Walter, H, Monteiro, W, Marshall, H, Nelson, L, Bennett, J, Primrose, L, Amadi, A, Palmer, S, Miller, J, Buchan, K, Lester, J, Edwards, A, Morgan, F, Verjee, A, MacKenzie, M, Wilcox, M, Smith, S, Gower, N, Ottensmeier, C, Chee, S, Johnson, B, Alzetani, A, Shaw, E, Lim, E, De Sousa, P, Tavares Barbosa, M, Bowman, A, Jordan, S, Rice, A, Raubenheimer, H, Proli, C, Elena Cufari, M, Ronquillo, JC, Kwayie, A, Bhayani, H, Hamilton, M, Bakar, Y, Mensah, N, Ambrose, L, Devaraj, A, Buderi, S, Finch, J, Azcarate, L, Chavan, H, Green, S, Mashinga, H, Nicholson, AG, Lau, K, Sheaff, M, Schmid, P, Conibear, J, Light, T, Horey, T, Danson, S, Bury, J, Edwards, J, Hill, J, Matthews, S, Kitsanta, Y, Suvarna, K, Fisher, P, Keerio, AD, Shackcloth, M, Gosney, J, Postmus, P, Feeney, S, Asante-Siaw, J, Constatin, T, Zimmermann, B, Dentro, S, Dessimoz, C, Shiu, K-K, Bridgewater, J, Hochauser, D, Beck, S, Parker, P, Walczak, H, Enver, T, Proctor, I, Sinclair, R, Lok, C-W, Mitchison, M, Trevisan, G, Lynch, M, Brandner, S, Gishen, F, Tookman, A, Stone, P, Sterling, C, Larkin, J, Attard, G, Eeles, R, Foster, C, Bova, S, Sottoriva, A, Chowdhury, S, Ashish, C, Spicer, J, Stares, M, Lynch, J, Caldas, C, Brenton, J, Fitzgerald, R, Jimenez-Linan, M, Provenzano, E, Cluroe, A, Stewart, G, Watts, C, Gilbertson, R, McDermott, U, Tavare, S, Maughan, T, Tomlinson, I, Campbell, P, McNeish, I, Biankin, A, Chambers, A, Fraser, S, Oien, K, Krebs, M, Marais, R, Carter, L, Nonaka, D, Dhomen, N, Shaw, J, Baijal, S, Tanchel, B, Collard, M, Cockcroft, P, Taylor, J, Colloby, P, Olisemeke, B, Wilson, R, Harrison, D, Loda, M, Flanagan, A, McKenzie, M, Lederman, J, Sharp, A, and Farrelly, L
Subjects: 0301 basic medicine, Oncology, Lung Neoplasms, IMPACT, Biopsy, DNA Mutational Analysis, Drug resistance, Metastasis, 0302 clinical medicine, Limit of Detection, Carcinoma, Non-Small-Cell Lung, Medicine, Neoplasm Metastasis, Early Detection of Cancer, Multidisciplinary, medicine.diagnostic_test, Phylogenetic tree, DNA, Neoplasm, STATISTICS, 3. Good health, Tumor Burden, Multidisciplinary Sciences, Cell Tracking, PEACE consortium, 030220 oncology & carcinogenesis, Disease Progression, Science & Technology - Other Topics, medicine.medical_specialty, CARCINOMA, Tumour heterogeneity, General Science & Technology, Early detection, Evolution, Molecular, 03 medical and health sciences, Internal medicine, MD Multidisciplinary, Carcinoma, Humans, Cell Lineage, Lung cancer, Postoperative Care, Science & Technology, MUTATIONS, TRACERx consortium, business.industry, CIRCULATING TUMOR DNA, Reproducibility of Results, medicine.disease, R1, NEGATIVE BREAST-CANCER, Clone Cells, 030104 developmental biology, Drug Resistance, Neoplasm, UPTAKE RATIO, Immunology, FDG PET, Neoplasm Recurrence, Local, business, Multiplex Polymerase Chain Reaction
Abstract: The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies.
Published: 2017

28. Fc-Optimized Anti-CD25 Depletes Tumor-Infiltrating Regulatory T Cells and Synergizes with PD-1 Blockade to Eradicate Established Tumors

Author: Arce Vargas, F, Furness, AJS, Solomon, I, Joshi, K, Mekkaoui, L, Lesko, MH, Miranda Rota, E, Dahan, R, Georgiou, A, Sledzinska, A, Ben Aissa, A, Franz, D, Werner Sunderland, M, Wong, YNS, Henry, JY, O'Brien, T, Nicol, D, Challacombe, B, Beers, SA, Spain, L, Wotherspoon, A, Francis, N, Smith, M, Strauss, D, Hayes, A, Soultati, A, Stares, M, Lynch, J, Fotiadis, N, Fernando, A, Hazell, S, Chandra, A, Pickering, L, Rudman, S, Chowdhury, S, Swanton, C, Jamal-Hanjani, M, Veeriah, S, Shafi, S, Czyzewska-Khan, J, Johnson, D, Laycock, J, Bosshard-Carter, L, Goh, G, Rosenthal, R, Gorman, P, Murugaesu, N, Hynds, RE, Wilson, G, Birkbak, NJ, Watkins, TBK, McGranahan, N, Horswell, S, Mitter, R, Escudero, M, Stewart, A, Van Loo, P, Rowan, A, Xu, H, Turajlic, S, Hiley, C, Abbosh, C, Goldman, J, Stone, RK, Denner, T, Matthews, N, Elgar, G, Ward, S, Biggs, J, Costa, M, Begum, S, Phillimore, B, Chambers, T, Nye, E, Graca, S, Al Bakir, M, Hartley, JA, Lowe, HL, Herrero, J, Lawrence, D, Hayward, M, Panagiotopoulos, N, Kolvekar, S, Falzon, M, and Borg, E
Subjects: hemic and immune systems, chemical and pharmacologic phenomena
Abstract: CD25 is expressed at high levels on regulatory T (Treg) cells and was initially proposed as a target for cancer immunotherapy. However, anti-CD25 antibodies have displayed limited activity against established tumors. We demonstrated that CD25 expression is largely restricted to tumor-infiltrating Treg cells in mice and humans. While existing anti-CD25 antibodies were observed to deplete Treg cells in the periphery, upregulation of the inhibitory Fc gamma receptor (FcγR) IIb at the tumor site prevented intra-tumoral Treg cell depletion, which may underlie the lack of anti-tumor activity previously observed in pre-clinical models. Use of an anti-CD25 antibody with enhanced binding to activating FcγRs led to effective depletion of tumor-infiltrating Treg cells, increased effector to Treg cell ratios, and improved control of established tumors. Combination with anti-programmed cell death protein-1 antibodies promoted complete tumor rejection, demonstrating the relevance of CD25 as a therapeutic target and promising substrate for future combination approaches in immune-oncology.
Published: 2017

29. The C-terminus of Apc does not influence intestinal adenoma development or progression

Author: Lewis, A, Davis, H, Deheragoda, M, Pollard, P, Nye, E, Jeffery, R, Segditsas, S, East, P, Poulsom, R, Stamp, G, Wright, N, and Tomlinson, I
Subjects: Adenoma, Adenomatous Polyposis Coli Protein, Blotting, Western, Fluorescent Antibody Technique, Immunohistochemistry, Article, Mice, Mutant Strains, Protein Structure, Tertiary, Mice, Inbred C57BL, Mice, Cell Movement, Intestinal Neoplasms, Disease Progression, Animals, Wnt Signaling Pathway, In Situ Hybridization, Oligonucleotide Array Sequence Analysis, Signal Transduction
Abstract: Adenomatous polyposis coli (APC) mutations are found in most colorectal tumours. These mutations are almost always protein-truncating, deleting both central domains that regulate Wnt signalling and C-terminal domains that interact with the cytoskeleton. The importance of Wnt dysregulation for colorectal tumourigenesis is well characterized. It is, however, unclear whether loss of C-terminal functions contributes to tumourigenesis, although this protein region has been implicated in cellular processes-including polarity, migration, mitosis, and chromosomal instability (CIN)-that have been postulated as critical for the development and progression of intestinal tumours. Since almost all APC mutations in human patients disrupt both central and C-terminal regions, we created a mouse model to test the role of the C-terminus of APC in intestinal tumourigenesis. This mouse (Apc ΔSAMP) carries an internal deletion within Apc that dysregulates Wnt by removing the beta-catenin-binding and SAMP repeats, but leaves the C-terminus intact. We compared Apc ΔSAMP mice with Apc 1322T animals. The latter allele represented the most commonly found human APC mutation and was identical to Apc ΔSAMP except for absence of the entire C-terminus. Apc ΔSAMP mice developed numerous intestinal adenomas indistinguishable in number, location, and dysplasia from those seen in Apc 1322T mice. No carcinomas were found in Apc ΔSAMP or Apc 1322T animals. While similar disruption of the Wnt signalling pathway was observed in tumours from both mice, no evidence of differential C-terminus functions (such as cell migration, CIN, or localization of APC and EB1) was seen. We conclude that the C-terminus of APC does not influence intestinal adenoma development or progression. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley and Sons, Ltd.
Published: 2016

30. Oral rapamycin reduces tumour burden and vascularization in Lkb1(+/-) mice

Author: Robinson, J, Lai, C, Martin, A, Nye, E, Tomlinson, I, and Silver, A
Abstract: Patients with Peutz-Jeghers syndrome (PJS) are affected by hamartomatous intestinal polyposis and increased risk of cancers in multiple organs caused by germline mutations in the tumour suppressor gene LKB1. Murine models that recapitulate aspects of PJS have been created. Here we examine the therapeutic effect of rapamycin, a macrolide with anti-tumourigenic and anti-angiogenic properties, in reducing tumour incidence in a large cohort of Lkb1(+/-) mice. To study the influence of early intervention, the animals were dosed with rapamycin from the age of 8 weeks, well before the onset of polyposis. These mice continued to receive the drug, which was well tolerated, throughout their lives. At sacrifice, we observed a reduction in gastric tumour burden in the rapamycin-treated mice (p = 0.0001) compared with age- and sex-matched controls. Treated animals also have a lower number of polyps per mouse than controls. In the polyps from the treated mice, phosphorylation of ribosomal p70 S6 kinase was maintained, while the phosphorylation of AKT at serine-473 was elevated, suggesting that mTORC1 function is maintained at this dosage. Despite this, a significant reduction in microvessel density was seen in polyps from the rapamycin-treated mice compared to those from the control mice (p = 5 x 10(-5)), suggesting that the anti-angiogenic effect of rapamycin played a role in polyp reduction. Overall, we demonstrated that prolonged oral administration of rapamycin from an early age is effective in lowering tumour burden in the Lkb1(+/-) mice without evident side effects.
Published: 2016

31. Mixed methods systematic review of a teacher classroom management programme: effectiveness and stakeholders' experiences

Author: Nye, E, Melendez-Torres, G, and Gardner, F
Published: 2015

32. Internet sex-seeking is inconsistently linked with sexual risk in men who have sex with men: systematic review of within-subjects comparisons

Author: Melendez-Torres, GJ, Nye, E, and Bonell, C
Subjects: Gynecology, medicine.medical_specialty, business.industry, Gonorrhea, Public Health, Environmental and Occupational Health, medicine.disease, Men who have sex with men, Genital warts, Infectious Diseases, Erectile dysfunction, Health promotion, Acquired immunodeficiency syndrome (AIDS), Epidemiology, Medicine, The Internet, business, Clinical psychology
Abstract: Background Internet sex-seeking has been associated at the person level with sexual risk. However, the most robust method of encounter-level inference to determine associations between internet sex-seeking and sexual risk is to compare encounters against each other. We systematically reviewed within-subjects comparisons of sexual encounters that tested associations between internet sex-seeking and sexual risk in men who have sex with men. Methods: We systematically searched databases on 9 July 2013, then screened records and full-text articles in duplicate and independently. Studies were synthesised narratively. Results: Four studies were included. Although studies were generally of high quality, the findings were inconsistent and did not show clear evidence of a relationship between internet sex-seeking and sexual risk. Conclusions: Further research in internet sex-seeking among men who have sex with men is required, particularly as internet-enabled sexual sociality continues to evolve. Internet-based health promotion may wish to target person-level features instead of encounter-specific characteristics.
Published: 2015

33. Allele-Specific HLA Loss and Immune Escape in Lung Cancer Evolution

Author: Nicholas McGranahan, Rachel Rosenthal, Crispin T. Hiley, Andrew J. Rowan, Thomas B.K. Watkins, Gareth A. Wilson, Nicolai J. Birkbak, Selvaraju Veeriah, Peter Van Loo, Javier Herrero, Charles Swanton, Mariam Jamal-Hanjani, Seema Shafi, Justyna Czyzewska-Khan, Diana Johnson, Joanne Laycock, Leticia Bosshard-Carter, Pat Gorman, Robert E. Hynds, Gareth Wilson, Stuart Horswell, Richard Mitter, Mickael Escudero, Aengus Stewart, Andrew Rowan, Hang Xu, Samra Turajlic, Crispin Hiley, Christopher Abbosh, Jacki Goldman, Richard Kevin Stone, Tamara Denner, Nik Matthews, Greg Elgar, Sophia Ward, Marta Costa, Sharmin Begum, Ben Phillimore, Tim Chambers, Emma Nye, Sofia Graca, Maise Al Bakir, Kroopa Joshi, Andrew Furness, Assma Ben Aissa, Yien Ning Sophia Wong, Andy Georgiou, Sergio Quezada, John A. Hartley, Helen L. Lowe, David Lawrence, Martin Hayward, Nikolaos Panagiotopoulos, Shyam Kolvekar, Mary Falzon, Elaine Borg, Teresa Marafioti, Celia Simeon, Gemma Hector, Amy Smith, Marie Aranda, Marco Novelli, Dahmane Oukrif, Sam M. Janes, Ricky Thakrar, Martin Forster, Tanya Ahmad, Siow Ming Lee, Dionysis Papadatos-Pastos, Dawn Carnell, Ruheena Mendes, Jeremy George, Neal Navani, Asia Ahmed, Magali Taylor, Junaid Choudhary, Yvonne Summers, Raffaele Califano, Paul Taylor, Rajesh Shah, Piotr Krysiak, Kendadai Rammohan, Eustace Fontaine, Richard Booton, Matthew Evison, Phil Crosbie, Stuart Moss, Faiza Idries, Leena Joseph, Paul Bishop, Anshuman Chaturved, Anne Marie Quinn, Helen Doran, Angela Leek, Phil Harrison, Katrina Moore, Rachael Waddington, Juliette Novasio, Fiona Blackhall, Jane Rogan, Elaine Smith, Caroline Dive, Jonathan Tugwood, Ged Brady, Dominic G. Rothwell, Francesca Chemi, Jackie Pierce, Sakshi Gulati, Babu Naidu, Gerald Langman, Simon Trotter, Mary Bellamy, Hollie Bancroft, Amy Kerr, Salma Kadiri, Joanne Webb, Gary Middleton, Madava Djearaman, Dean Fennell, Jacqui A. Shaw, John Le Quesne, David Moore, Apostolos Nakas, Sridhar Rathinam, William Monteiro, Hilary Marshall, Louise Nelson, Jonathan Bennett, Joan Riley, Lindsay Primrose, Luke Martinson, Girija Anand, Sajid Khan, Anita Amadi, Marianne Nicolson, Keith Kerr, Shirley Palmer, Hardy Remmen, Joy Miller, Keith Buchan, Mahendran Chetty, Lesley Gomersall, Jason Lester, Alison Edwards, Fiona Morgan, Haydn Adams, Helen Davies, Malgorzata Kornaszewska, Richard Attanoos, Sara Lock, Azmina Verjee, Mairead MacKenzie, Maggie Wilcox, Harriet Bell, Allan Hackshaw, Yenting Ngai, Sean Smith, Nicole Gower, Christian Ottensmeier, Serena Chee, Benjamin Johnson, Aiman Alzetani, Emily Shaw, Eric Lim, Paulo De Sousa, Monica Tavares Barbosa, Alex Bowman, Simon Jordan, Alexandra Rice, Hilgardt Raubenheimer, Chiara Proli, Maria Elena Cufari, John Carlo Ronquillo, Angela Kwayie, Harshil Bhayani, Morag Hamilton, Yusura Bakar, Natalie Mensah, Lyn Ambrose, Anand Devaraj, Silviu Buderi, Jonathan Finch, Leire Azcarate, Hema Chavan, Sophie Green, Hillaria Mashinga, Andrew G. Nicholson, Kelvin Lau, Michael Sheaff, Peter Schmid, John Conibear, Veni Ezhil, Babikir Ismail, Melanie Irvin-sellers, Vineet Prakash, Peter Russell, Teresa Light, Tracey Horey, Sarah Danson, Jonathan Bury, John Edwards, Jennifer Hill, Sue Matthews, Yota Kitsanta, Kim Suvarna, Patricia Fisher, Allah Dino Keerio, Michael Shackcloth, John Gosney, Pieter Postmus, Sarah Feeney, Julius Asante-Siaw, Hugo J.W.L. Aerts, Stefan Dentro, Christophe Dessimoz, TRACERx Consortium, Swanton, C., Jamal-Hanjani, M., Veeriah, S., Shafi, S., Czyzewska-Khan, J., Johnson, D., Laycock, J., Bosshard-Carter, L., Rosenthal, R., Gorman, P., Hynds, R.E., Wilson, G., Birkbak, N.J., Watkins, TBK, McGranahan, N., Horswell, S., Mitter, R., Escudero, M., Stewart, A., Van Loo, P., Rowan, A., Xu, H., Turajlic, S., Hiley, C., Abbosh, C., Goldman, J., Stone, R.K., Denner, T., Matthews, N., Elgar, G., Ward, S., Costa, M., Begum, S., Phillimore, B., Chambers, T., Nye, E., Graca, S., Al Bakir, M., Joshi, K., Furness, A., Ben Aissa, A., Wong, YNS, Georgiou, A., Quezada, S., Hartley, J.A., Lowe, H.L., Herrero, J., Lawrence, D., Hayward, M., Panagiotopoulos, N., Kolvekar, S., Falzon, M., Borg, E., Marafioti, T., Simeon, C., Hector, G., Smith, A., Aranda, M., Novelli, M., Oukrif, D., Janes, S.M., Thakrar, R., Forster, M., Ahmad, T., Lee, S.M., Papadatos-Pastos, D., Carnell, D., Mendes, R., George, J., Navani, N., Ahmed, A., Taylor, M., Choudhary, J., Summers, Y., Califano, R., Taylor, P., Shah, R., Krysiak, P., Rammohan, K., Fontaine, E., Booton, R., Evison, M., Crosbie, P., Moss, S., Idries, F., Joseph, L., Bishop, P., Chaturved, A., Quinn, A.M., Doran, H., Leek, A., Harrison, P., Moore, K., Waddington, R., Novasio, J., Blackhall, F., Rogan, J., Smith, E., Dive, C., Tugwood, J., Brady, G., Rothwell, D.G., Chemi, F., Pierce, J., Gulati, S., Naidu, B., Langman, G., Trotter, S., Bellamy, M., Bancroft, H., Kerr, A., Kadiri, S., Webb, J., Middleton, G., Djearaman, M., Fennell, D., Shaw, J.A., Le Quesne, J., Moore, D., Nakas, A., Rathinam, S., Monteiro, W., Marshall, H., Nelson, L., Bennett, J., Riley, J., Primrose, L., Martinson, L., Anand, G., Khan, S., Amadi, A., Nicolson, M., Kerr, K., Palmer, S., Remmen, H., Miller, J., Buchan, K., Chetty, M., Gomersall, L., Lester, J., Edwards, A., Morgan, F., Adams, H., Davies, H., Kornaszewska, M., Attanoos, R., Lock, S., Verjee, A., MacKenzie, M., Wilcox, M., Bell, H., Hackshaw, A., Ngai, Y., Smith, S., Gower, N., Ottensmeier, C., Chee, S., Johnson, B., Alzetani, A., Shaw, E., Lim, E., De Sousa, P., Barbosa, M.T., Bowman, A., Jordan, S., Rice, A., Raubenheimer, H., Proli, C., Cufari, M.E., Ronquillo, J.C., Kwayie, A., Bhayani, H., Hamilton, M., Bakar, Y., Mensah, N., Ambrose, L., Devaraj, A., Buderi, S., Finch, J., Azcarate, L., Chavan, H., Green, S., Mashinga, H., Nicholson, A.G., Lau, K., Sheaff, M., Schmid, P., Conibear, J., Ezhil, V., Ismail, B., Irvin-Sellers, M., Prakash, V., Russell, P., Light, T., Horey, T., Danson, S., Bury, J., Edwards, J., Hill, J., Matthews, S., Kitsanta, Y., Suvarna, K., Fisher, P., Keerio, A.D., Shackcloth, M., Gosney, J., Postmus, P., Feeney, S., Asante-Siaw, J., Aerts, HJWL, Dentro, S., and Dessimoz, C.
Subjects: Male, immune-editing, 0301 basic medicine, DOWN-REGULATION, immune-escape, Lung Neoplasms, Loss of Heterozygosity, Cohort Studies, Loss of heterozygosity, HLA Antigens, Carcinoma, Non-Small-Cell Lung, Chromosome instability, MUTATIONAL PROCESSES, 11 Medical and Health Sciences, Aged, 80 and over, Antigen Presentation, cancer evolution, Manchester Cancer Research Centre, bioinformatics, Middle Aged, 3. Good health, Female, loss of heterozygosity, SENSITIVITY, Life Sciences & Biomedicine, Adult, Biochemistry & Molecular Biology, chromosomal instability, Antigen presentation, Locus (genetics), NEOANTIGENS, Human leukocyte antigen, Biology, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Immune system, copy number, medicine, Humans, Lung cancer, Aged, Science & Technology, ResearchInstitutes_Networks_Beacons/mcrc, CTLA-4 BLOCKADE, Cell Biology, 06 Biological Sciences, medicine.disease, PD-1 BLOCKADE, neoantigen, lung cancer, 030104 developmental biology, Carcinoma, Non-Small-Cell Lung/genetics, Carcinoma, Non-Small-Cell Lung/immunology, Carcinoma, Non-Small-Cell Lung/pathology, Carcinoma, Non-Small-Cell Lung/therapy, HLA Antigens/genetics, HLA Antigens/immunology, Lung Neoplasms/genetics, Lung Neoplasms/immunology, Lung Neoplasms/pathology, Lung Neoplasms/therapy, Mutation, Tumor Escape, heterogeneity, TRACERx Consortium, DISCOVERY, CELLS, Immunology, RESISTANCE, Developmental Biology
Abstract: Immune evasion is a hallmark of cancer. Losing the ability to present neoantigens through human leukocyte antigen (HLA) loss may facilitate immune evasion. However, the polymorphic nature of the locus has precluded accurate HLA copy-number analysis. Here, we present loss of heterozygosity in human leukocyte antigen (LOHHLA), a computational tool to determine HLA allele-specific copy number from sequencing data. Using LOHHLA, we find that HLA LOH occurs in 40% of non-small-cell lung cancers (NSCLCs) and is associated with a high subclonal neoantigen burden, APOBEC-mediated mutagenesis, upregulation of cytolytic activity, and PD-L1 positivity. The focal nature of HLA LOH alterations, their subclonal frequencies, enrichment in metastatic sites, and occurrence as parallel events suggests that HLA LOH is an immune escape mechanism that is subject to strong microenvironmental selection pressures later in tumor evolution. Characterizing HLA LOH with LOHHLA refines neoantigen prediction and may have implications for our understanding of resistance mechanisms and immunotherapeutic approaches targeting neoantigens. VIDEO ABSTRACT.
Published: 2017

34. Extrachromosomal DNA driven oncogene spatial heterogeneity and evolution in glioblastoma.

Author: Noorani I, Haughey M, Luebeck J, Rowan A, Grönroos E, Terenzi F, Wong IT, Kittel J, Bailey C, Weeden C, Bell D, Joo E, Barbe V, Jones MG, Nye E, Green M, Meader L, Norton EJ, Fabian M, Kanu N, Jamal-Hanjani M, Santarius T, Nicoll J, Boche D, Chang HY, Bafna V, Huang W, Mischel PS, Swanton C, and Werner B
Abstract: Oncogene amplification on extrachromosomal DNA (ecDNA) is strongly associated with treatment resistance and shorter survival for patients with cancer, including patients with glioblastoma. The non-chromosomal inheritance of ecDNA during cell division is a major contributor to intratumoral genetic heterogeneity. At present, the spatial dynamics of ecDNA, and the impact on tumor evolutionary trajectories, are not well understood. Here, we investigate the spatial-temporal evolution of ecDNA and its clinical impact by analyzing tumor samples from 94 treatment-naive human IDH -wildtype glioblastoma patients. We developed a spatial-temporal computational model of ecDNA positive tumors ('SPECIES') that integrates whole-genome sequencing, multi-region DNA FISH, and nascent RNAscope, to provide unique insight into the spatial dynamics of ecDNA evolution. Random segregation in combination with positive selection of ecDNAs induce large, predictable spatial patterns of cell-to-cell ecDNA copy number variation that are highly dependent on the oncogene encoded on the circular DNA. EGFR ecDNAs often reach high mean copy number (mean of 50 copies per tumor cell), are under strong positive selection (mean selection coefficient, s > 2) and do not co-amplify other oncogenes on the same ecDNA particles. In contrast, PDGFRA ecDNAs have lower mean copy number (mean of 15 copies per cell), are under weaker positive selection and frequently co-amplify other oncogenes on the same ecDNA. Evolutionary modeling suggests that EGFR ecDNAs often accumulate prior to clonal expansion. EGFR structural variants, including vIII and c-terminal deletions are under strong positive selection, are found exclusively on ecDNA, and are intermixed with wild-type EGFR ecDNAs. Simulations show EGFRvIII ecDNA likely arises after ecDNA formation in a cell with high wild-type EGFR copy number (> 10) before the onset of the most recent clonal expansion. This remains true even in cases of co-selection and co-amplification of multiple oncogenic ecDNA species in a subset of patients. Overall, our results suggest a potential time window in which early ecDNA detection may provide an opportunity for more effective intervention., Highlights: ecDNA is the most common mechanism of focal oncogene amplification in IDH wt glioblastoma. EGFR and its variants on ecDNA are particularly potent, likely arising early in tumor development, providing a strong oncogenic stimulus to drive tumorigenesis. Wild-type and variant EGFR ecDNA heteroplasmy (co-occurrence) is common with EGFR vIII or c-terminal deletions being derived from EGFR wild-type ecDNA prior to the most recent clonal expansion. Tumors with ecDNA amplified EGFR versus PDGFRA exhibit different evolutionary trajectories. SPECIES model can infer spatial evolutionary dynamics of ecDNA in cancer.A delay between ecDNA accumulation and subsequent oncogenic mutation may give a therapeutic window for early intervention.
Published: 2024
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35. Incidence and characterization of polyglucosan bodies in the cerebella of montserrat orioles ( Icterus oberi ).

Author: Spiro S, Pereira M, Bates KA, Jaunmuktane Z, Everest DJ, Stidworthy MF, Denk D, Núñez A, Wrigglesworth E, Theodoulou A, Barbon A, Nye E, Liu Y, Smith AL, and Fiddaman S
Abstract: Polyglucosan bodies are accumulations of insoluble glucose polymers and proteins that form intracytoplasmic inclusions in the brain, large numbers of which can be indicative of neurodegenerative diseases such as Lafora disease. Montserrat orioles ( Icterus oberi ) are an icterid passerine endemic to Montserrat with conservation populations maintained in captivity abroad. We demonstrate that polyglucosan bodies are unusually abundant in the cerebellar molecular and Purkinje cell layers and cerebellar peduncles of captive-bred and wild-caught Montserrat orioles. The bodies are periodic acid-Schiff positive and diastase resistant and label with concanavalin A and for ubiquitin, consistent with those seen in humans. We found no association of the polyglucosan bodies with concurrent neurological lesions or clinical signs, nor with EPM2 A and EPM2B gene mutations associated with Lafora disease. We conclude that an abundance of cerebellar polyglucosan bodies may be a normal finding in aged Montserrat orioles and not a threat to the captive breeding population., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Published: 2024
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36. Vitamin D regulates microbiome-dependent cancer immunity.

Author: Giampazolias E, Pereira da Costa M, Lam KC, Lim KHJ, Cardoso A, Piot C, Chakravarty P, Blasche S, Patel S, Biram A, Castro-Dopico T, Buck MD, Rodrigues RR, Poulsen GJ, Palma-Duran SA, Rogers NC, Koufaki MA, Minutti CM, Wang P, Vdovin A, Frederico B, Childs E, Lee S, Simpson B, Iseppon A, Omenetti S, Kelly G, Goldstone R, Nye E, Suárez-Bonnet A, Priestnall SL, MacRae JI, Zelenay S, Patil KR, Litchfield K, Lee JC, Jess T, Goldszmid RS, and Reis E Sousa C
Subjects: Animals, Female, Humans, Male, Mice, Immunotherapy, Intestinal Mucosa immunology, Intestinal Mucosa microbiology, Intestinal Mucosa metabolism, Mice, Inbred C57BL, Diet, Cell Line, Tumor, Calcifediol administration & dosage, Calcifediol metabolism, Vitamin D-Binding Protein genetics, Vitamin D-Binding Protein metabolism, Bacteroides fragilis metabolism, Gastrointestinal Microbiome drug effects, Immune Checkpoint Inhibitors therapeutic use, Immune Checkpoint Inhibitors pharmacology, Neoplasms immunology, Neoplasms microbiology, Neoplasms therapy, Vitamin D administration & dosage, Vitamin D metabolism
Abstract: A role for vitamin D in immune modulation and in cancer has been suggested. In this work, we report that mice with increased availability of vitamin D display greater immune-dependent resistance to transplantable cancers and augmented responses to checkpoint blockade immunotherapies. Similarly, in humans, vitamin D-induced genes correlate with improved responses to immune checkpoint inhibitor treatment as well as with immunity to cancer and increased overall survival. In mice, resistance is attributable to the activity of vitamin D on intestinal epithelial cells, which alters microbiome composition in favor of Bacteroides fragilis , which positively regulates cancer immunity. Our findings indicate a previously unappreciated connection between vitamin D, microbial commensal communities, and immune responses to cancer. Collectively, they highlight vitamin D levels as a potential determinant of cancer immunity and immunotherapy success.
Published: 2024
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37. Vitamin B 5 supports MYC oncogenic metabolism and tumor progression in breast cancer.

Author: Kreuzaler P, Inglese P, Ghanate A, Gjelaj E, Wu V, Panina Y, Mendez-Lucas A, MacLachlan C, Patani N, Hubert CB, Huang H, Greenidge G, Rueda OM, Taylor AJ, Karali E, Kazanc E, Spicer A, Dexter A, Lin W, Thompson D, Silva Dos Santos M, Calvani E, Legrave N, Ellis JK, Greenwood W, Green M, Nye E, Still E, Barry S, Goodwin RJA, Bruna A, Caldas C, MacRae J, de Carvalho LPS, Poulogiannis G, McMahon G, Takats Z, Bunch J, and Yuneva M
Subjects: Humans, Mice, Animals, Female, Pantothenic Acid, Proto-Oncogene Proteins c-myc genetics, Proto-Oncogene Proteins c-myc metabolism, Transcription Factors metabolism, Vitamins, Breast Neoplasms metabolism
Abstract: Tumors are intrinsically heterogeneous and it is well established that this directs their evolution, hinders their classification and frustrates therapy 1-3 . Consequently, spatially resolved omics-level analyses are gaining traction 4-9 . Despite considerable therapeutic interest, tumor metabolism has been lagging behind this development and there is a paucity of data regarding its spatial organization. To address this shortcoming, we set out to study the local metabolic effects of the oncogene c-MYC, a pleiotropic transcription factor that accumulates with tumor progression and influences metabolism 10,11 . Through correlative mass spectrometry imaging, we show that pantothenic acid (vitamin B 5 ) associates with MYC-high areas within both human and murine mammary tumors, where its conversion to coenzyme A fuels Krebs cycle activity. Mechanistically, we show that this is accomplished by MYC-mediated upregulation of its multivitamin transporter SLC5A6. Notably, we show that SLC5A6 over-expression alone can induce increased cell growth and a shift toward biosynthesis, whereas conversely, dietary restriction of pantothenic acid leads to a reversal of many MYC-mediated metabolic changes and results in hampered tumor growth. Our work thus establishes the availability of vitamins and cofactors as a potential bottleneck in tumor progression, which can be exploited therapeutically. Overall, we show that a spatial understanding of local metabolism facilitates the identification of clinically relevant, tractable metabolic targets., (© 2023. The Author(s).)
Published: 2023
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38. The evolution of non-small cell lung cancer metastases in TRACERx.

Author: Al Bakir M, Huebner A, Martínez-Ruiz C, Grigoriadis K, Watkins TBK, Pich O, Moore DA, Veeriah S, Ward S, Laycock J, Johnson D, Rowan A, Razaq M, Akther M, Naceur-Lombardelli C, Prymas P, Toncheva A, Hessey S, Dietzen M, Colliver E, Frankell AM, Bunkum A, Lim EL, Karasaki T, Abbosh C, Hiley CT, Hill MS, Cook DE, Wilson GA, Salgado R, Nye E, Stone RK, Fennell DA, Price G, Kerr KM, Naidu B, Middleton G, Summers Y, Lindsay CR, Blackhall FH, Cave J, Blyth KG, Nair A, Ahmed A, Taylor MN, Procter AJ, Falzon M, Lawrence D, Navani N, Thakrar RM, Janes SM, Papadatos-Pastos D, Forster MD, Lee SM, Ahmad T, Quezada SA, Peggs KS, Van Loo P, Dive C, Hackshaw A, Birkbak NJ, Zaccaria S, Jamal-Hanjani M, McGranahan N, and Swanton C
Subjects: Humans, Cohort Studies, Disease Progression, Neoplasm Recurrence, Local, Carcinoma, Non-Small-Cell Lung pathology, Clonal Evolution, Clone Cells pathology, Evolution, Molecular, Lung Neoplasms pathology, Neoplasm Metastasis diagnosis, Neoplasm Metastasis pathology
Abstract: Metastatic disease is responsible for the majority of cancer-related deaths 1 . 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., (© 2023. The Author(s).)
Published: 2023
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39. Do cash transfers alleviate common mental disorders in low- and middle-income countries? A systematic review and meta-analysis.

Author: Wollburg C, Steinert JI, Reeves A, and Nye E
Subjects: Child, Adult, Adolescent, Humans, Africa South of the Sahara, Financial Support, Anxiety Disorders, Developing Countries, Poverty
Abstract: A large literature has demonstrated the link between poverty and mental ill-health. Yet, the potential causal effects of poverty alleviation measures on mental disorders are not well-understood. In this systematic review, we summarize the evidence of the effects of a particular kind of poverty alleviation mechanism on mental health: the provision of cash transfers in low- and middle-income countries. We searched eleven databases and websites and assessed over 4,000 studies for eligibility. Randomized controlled trials evaluating the effects of cash transfers on depression, anxiety, and stress were included. All programs targeted adults or adolescents living in poverty. Overall, 17 studies, comprising 26,794 participants in Sub-Saharan Africa, Latin America, and South Asia, met the inclusion criteria of this review. Studies were critically appraised using Cochrane's Risk of Bias tool and publication bias was tested using funnel plots, egger's regression, and sensitivity analyses. The review was registered in PROSPERO (CRD42020186955). Meta-analysis showed that cash transfers significantly reduced depression and anxiety of recipients (dpooled = -0.10; 95%-CI: -0.15, -0.05; p<0.01). However, improvements may not be sustained 2-9 years after program cessation (dpooled = -0.05; 95%-CI: -0.14, 0.04; ns). Meta-regression indicates that impacts were larger for unconditional transfers (dpooled = -0.14; 95%-CI: -0.17, -0.10; p<0.01) than for conditional programs (dpooled = 0.10; 95%-CI: 0.07, 0.13; p<0.01). Effects on stress were insignificant and confidence intervals include both the possibility of meaningful reductions and small increases in stress (dpooled = -0.10; 95%-CI: -0.32, 0.12; ns). Overall, our findings suggest that cash transfers can play a role in alleviating depression and anxiety disorders. Yet, continued financial support may be necessary to enable longer-term improvements. Impacts are comparable in size to the effects of cash transfers on, e.g., children's test scores and child labor. Our findings further raise caution about potential adverse effects of conditionality on mental health, although more evidence is needed to draw robust conclusions., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Wollburg et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
Published: 2023
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40. Risk and Protective Factors for Men's Sexual Violence Against Women at Higher Education Institutions: A Systematic and Meta-Analytic Review of the Longitudinal Evidence.

Author: Steele B, Martin M, Yakubovich A, Humphreys DK, and Nye E
Subjects: Female, Humans, Male, Men, Protective Factors, Risk Factors, Sexual Behavior, Rape prevention & control, Sex Offenses prevention & control
Abstract: Sexual violence among higher education institution (HEI) students is a growing public health concern. To date, there is little evidence on how to effectively prevent sexual violence among this demographic. This study is the first systematic review to meta-analyze all available evidence for risk and protective factors of sexual violence perpetrated by men at HEIs. We searched four electronic databases and multiple gray literature sources. We screened studies using prespecified selection criteria for the sample (HEI students who identify as men), outcome (sexual violence perpetration against peers), and study design (quantitative and longitudinal). Longitudinal studies provide the most rigorous available evidence on risk and protective factors. We identified 16 studies and meta-analyzed eight different risk factors: alcohol consumption, hostility toward women, delinquency, fraternity membership, history of sexual violence perpetration, rape myth acceptance, age at first sex, and peer approval of sexual violence. We deemed included studies to have a varied risk of bias and the overall quality of evidence to range from moderate to high. History of sexual violence perpetration (perpetration prior to entering an HEI) emerged as the strongest predictor of sexual violence perpetration at HEIs, complicating the notion that HEI environments themselves foster a culture of sexual violence. Peer support for sexual violence predicted perpetration while individual rape-supporting beliefs did not. Our findings suggest that interventions targeting peer norms (e.g., bystander interventions) and early sexual violence prevention and consent interventions for high school and elementary school students could be effective in reducing and preventing sexual violence at HEIs.
Published: 2022
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41. USP25 promotes pathological HIF-1-driven metabolic reprogramming and is a potential therapeutic target in pancreatic cancer.

Author: Nelson JK, Thin MZ, Evan T, Howell S, Wu M, Almeida B, Legrave N, Koenis DS, Koifman G, Sugimoto Y, Llorian Sopena M, MacRae J, Nye E, Howell M, Snijders AP, Prachalias A, Zen Y, Sarker D, and Behrens A
Subjects: Animals, Cell Line, Tumor, Glycolysis genetics, Humans, Mice, Tumor Microenvironment genetics, Ubiquitin Thiolesterase genetics, Ubiquitin Thiolesterase metabolism, Carcinoma, Pancreatic Ductal pathology, Pancreatic Neoplasms metabolism
Abstract: Deubiquitylating enzymes (DUBs) play an essential role in targeted protein degradation and represent an emerging therapeutic paradigm in cancer. However, their therapeutic potential in pancreatic ductal adenocarcinoma (PDAC) has not been explored. Here, we develop a DUB discovery pipeline, combining activity-based proteomics with a loss-of-function genetic screen in patient-derived PDAC organoids and murine genetic models. This approach identifies USP25 as a master regulator of PDAC growth and maintenance. Genetic and pharmacological USP25 inhibition results in potent growth impairment in PDAC organoids, while normal pancreatic organoids are insensitive, and causes dramatic regression of patient-derived xenografts. Mechanistically, USP25 deubiquitinates and stabilizes the HIF-1α transcription factor. PDAC is characterized by a severely hypoxic microenvironment, and USP25 depletion abrogates HIF-1α transcriptional activity and impairs glycolysis, inducing PDAC cell death in the tumor hypoxic core. Thus, the USP25/HIF-1α axis is an essential mechanism of metabolic reprogramming and survival in PDAC, which can be therapeutically exploited., (© 2022. The Author(s).)
Published: 2022
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42. Substance Use Disorder Treatment, Perceived Need for Treatment, and Barriers to Treatment Among Parenting Women With Substance Use Disorder in US Rural Counties.

Author: Ali MM, Nye E, and West K
Subjects: Female, Humans, Parenting, United States epidemiology, Rural Population, Substance-Related Disorders epidemiology, Substance-Related Disorders therapy
Abstract: Objective: Higher rates of substance use in rural counties compared to urban counties have been well documented. Low perceived need for treatment among those with substance use disorder (SUD) has also been documented in the literature. However, not much is known about SUD treatment among parenting women in rural counties and the impact of perceived need for treatment in seeking care. Little research has also examined barriers to SUD treatment among parenting women in rural communities., Methods: Using a large nationally representative dataset, the study utilizes multivariable logistic regression models to estimate the differences in utilizing SUD treatment among parenting women with SUD in rural and urban counties in the United States. Role of perceived need for SUD treatment and barriers related to finance, access, and stigma are also examined., Results: Parenting women in rural counties with SUD who perceive a need for treatment have more than 90% lower odds of receiving treatment compared to those in urban counties. In addition, parenting women with SUD in rural counties have more than 50% higher odds of identifying access-related issues such as lack of openings in programs, unavailability of treatment facilities, and lack of transportation as barriers to care compared to parenting women in urban counties., Conclusion: Diagnosis of SUD among parenting women is steadily increasing in rural communities. While many resources in combatting maternal SUD are being utilized, policy and programmatic responses tailored for mothers with SUD in rural communities might help increase utilization of treatment and reduce barriers to treatment., (© 2020 National Rural Health Association.)
Published: 2022
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43. Functional antibody and T cell immunity following SARS-CoV-2 infection, including by variants of concern, in patients with cancer: the CAPTURE study.

Author: Fendler A, Au L, Shepherd STC, Byrne F, Cerrone M, Boos LA, Rzeniewicz K, Gordon W, Shum B, Gerard CL, Ward B, Xie W, Schmitt AM, Joharatnam-Hogan N, Cornish GH, Pule M, Mekkaoui L, Ng KW, Carlyle E, Edmonds K, Rosario LD, Sarker S, Lingard K, Mangwende M, Holt L, Ahmod H, Stone R, Gomes C, Flynn HR, Agua-Doce A, Hobson P, Caidan S, Howell M, Wu M, Goldstone R, Crawford M, Cubitt L, Patel H, Gavrielides M, Nye E, Snijders AP, MacRae JI, Nicod J, Gronthoud F, Shea RL, Messiou C, Cunningham D, Chau I, Starling N, Turner N, Welsh L, van As N, Jones RL, Droney J, Banerjee S, Tatham KC, Jhanji S, O'Brien M, Curtis O, Harrington K, Bhide S, Bazin J, Robinson A, Stephenson C, Slattery T, Khan Y, Tippu Z, Leslie I, Gennatas S, Okines A, Reid A, Young K, Furness AJS, Pickering L, Gandhi S, Gamblin S, Swanton C, Nicholson E, Kumar S, Yousaf N, Wilkinson KA, Swerdlow A, Harvey R, Kassiotis G, Larkin J, Wilkinson RJ, and Turajlic S
Subjects: Adolescent, Adult, Aged, Aged, 80 and over, Antibodies, Neutralizing immunology, Antibodies, Viral immunology, COVID-19 blood, COVID-19 mortality, Female, Follow-Up Studies, Humans, Immunity, Cellular, Male, Middle Aged, Neoplasms blood, Neoplasms immunology, Prospective Studies, SARS-CoV-2 immunology, Spike Glycoprotein, Coronavirus immunology, Young Adult, Antibodies, Neutralizing blood, Antibodies, Viral blood, COVID-19 immunology, Neoplasms complications, T-Lymphocytes immunology
Abstract: Patients with cancer have higher COVID-19 morbidity and mortality. Here we present the prospective CAPTURE study, integrating longitudinal immune profiling with clinical annotation. Of 357 patients with cancer, 118 were SARS-CoV-2 positive, 94 were symptomatic and 2 died of COVID-19. In this cohort, 83% patients had S1-reactive antibodies and 82% had neutralizing antibodies against wild type SARS-CoV-2, whereas neutralizing antibody titers against the Alpha, Beta and Delta variants were substantially reduced. S1-reactive antibody levels decreased in 13% of patients, whereas neutralizing antibody titers remained stable for up to 329 days. Patients also had detectable SARS-CoV-2-specific T cells and CD4 + responses correlating with S1-reactive antibody levels, although patients with hematological malignancies had impaired immune responses that were disease and treatment specific, but presented compensatory cellular responses, further supported by clinical recovery in all but one patient. Overall, these findings advance the understanding of the nature and duration of the immune response to SARS-CoV-2 in patients with cancer., (© 2021. The Author(s).)
Published: 2021
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44. Oxford Understanding Relationships, Sex, Power, Abuse and Consent Experiences (OUR SPACE) cross-sectional survey: a study protocol.

Author: Steele B, Degli Esposti M, Mandeville P, Hamnett G, Nye E, and Humphreys DK
Subjects: Adult, Cross-Sectional Studies, Female, Humans, Informed Consent, Male, Middle Aged, Sexual Behavior, Universities, Gender Identity, Sex Offenses
Abstract: Introduction: Sexual violence among higher education students is a public health concern, threatening the general safety of students, often with significant physical and mental health implications for victims. Establishing the prevalence estimates of sexual violence at higher education institutions (HEIs) is essential for designing and resourcing responses to sexual violence, including monitoring the effectiveness of prevention initiatives and institutional programmes. Yet, to date, there have been no rigorous studies assessing prevalence of sexual violence at HEIs in the UK., Methods and Analysis: Informed by guidance from Universities UK, the University of Oxford administration and the related student advocacy groups working within the University, Oxford Understanding Relationships, Sex, Power, Abuse and Consent Experiences is a cross-sectional survey of all undergraduate and graduate students over the age of 18 enrolled at the University of Oxford, UK. The survey design uses a complete sampling approach and measures adapted from previous campus climate surveys in the USA as well as the Sexual Experiences Survey (USA). The analysis will estimate the prevalence of sexual harassment and sexual violence perpetration and victimisation, and will examine whether ethnicity, gender identity, and sexual orientation are associated with these primary outcomes., Ethics and Dissemination: Ethical approval was obtained by the Social Sciences and Humanities Interdivisional Research Ethics Committee at the University of Oxford which is a subcommittee of the Central University Research Ethics Committee (ref no.: R73805/RE001). The research team will disseminate findings through peer-reviewed journal articles and conference presentations. A report cowritten by authors and stakeholders will be shared with Oxford University students., Competing Interests: Competing interests: PM is the Service Lead for the Sexual Harassment and Violence Support Service at the University of Oxford., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Published: 2021
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45. Acute Wernicke's encephalopathy in a young female after sleeve gastrectomy.

Author: Lee CWJ, Tuck L, Kumar S, and Nye E
Subjects: Female, Gastrectomy adverse effects, Humans, Obesity, Morbid surgery, Wernicke Encephalopathy diagnosis, Wernicke Encephalopathy etiology
Published: 2021
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46. USP28 deletion and small-molecule inhibition destabilizes c-MYC and elicits regression of squamous cell lung carcinoma.

Author: Ruiz EJ, Pinto-Fernandez A, Turnbull AP, Lan L, Charlton TM, Scott HC, Damianou A, Vere G, Riising EM, Da Costa C, Krajewski WW, Guerin D, Kearns JD, Ioannidis S, Katz M, McKinnon C, O'Connell J, Moncaut N, Rosewell I, Nye E, Jones N, Heride C, Gersch M, Wu M, Dinsmore CJ, Hammonds TR, Kim S, Komander D, Urbe S, Clague MJ, Kessler BM, and Behrens A
Subjects: Animals, DNA-Binding Proteins metabolism, Disease Models, Animal, Humans, Mice, Transcription Factors metabolism, Ubiquitin Thiolesterase metabolism, DNA-Binding Proteins genetics, Gene Deletion, Lung Neoplasms genetics, Neoplasms, Squamous Cell genetics, Transcription Factors genetics, Ubiquitin Thiolesterase genetics
Abstract: Lung squamous cell carcinoma (LSCC) is a considerable global health burden, with an incidence of over 600,000 cases per year. Treatment options are limited, and patient's 5-year survival rate is less than 5%. The ubiquitin-specific protease 28 (USP28) has been implicated in tumourigenesis through its stabilization of the oncoproteins c-MYC, c-JUN, and Δp63. Here, we show that genetic inactivation of Usp28 -induced regression of established murine LSCC lung tumours. We developed a small molecule that inhibits USP28 activity in the low nanomole range. While displaying cross-reactivity against the closest homologue USP25, this inhibitor showed a high degree of selectivity over other deubiquitinases. USP28 inhibitor treatment resulted in a dramatic decrease in c-MYC, c-JUN, and Δp63 proteins levels and consequently induced substantial regression of autochthonous murine LSCC tumours and human LSCC xenografts, thereby phenocopying the effect observed by genetic deletion. Thus, USP28 may represent a promising therapeutic target for the treatment of squamous cell lung carcinoma., Competing Interests: ER, AP, LL, TC, HS, AD, GV, ER, CD, NM, IR, EN, MG No competing interests declared, AT Andrew P Turnbull is affiliated with the CRUK Therapeutic Discovery Laboratories at the Crick Institute, for which no financial interests have been declared. APT declares competing financial interests due to financial support for the project described in this manuscript by Forma Therapeutics, Watertown, MA, USA. WK Wojciech W Krajewski is affiliated with the CRUK Therapeutic Discovery Laboratories at the Crick Institute, for which no financial interests have been declared. WWK declares competing financial interests due to financial support for the project described in this manuscript by Forma Therapeutics, Watertown, MA, USA. DG Dave Guerin is affiliated with Constellation Pharmaceuticals (Boston, USA), for which no financial interests have been declared. DG declares competing financial interests due to financial support for the project described in this manuscript by Forma Therapeutics, Watertown, MA, USA. JK Jeffrey Kearns is affiliated with the Novartis Institutes for BioMedical Research (Boston, USA), for which no financial interests have been declared. JK declares competing financial interests due to financial support for the project described in this manuscript by Forma Therapeutics, Watertown, MA, USA. SI Stephanos Ioannidis is affiliated with H3 Biomedicine (Cambridge, MA, USA), for which no financial interests have been declared. SI declares competing financial interests due to financial support for the project described in this manuscript by Forma Therapeutics, Watertown, MA, USA. MK Marie Katz is affiliated with Valo Health (Boston, USA), for which no financial interests have been declared. MK declares competing financial interests due to financial support for the project described in this manuscript by Forma Therapeutics, Watertown, MA, USA. CM Crystal McKinnon is affiliated with Valo Health (Boston, USA), for which no financial interests have been declared. CM declares competing financial interests due to financial support for the project described in this manuscript by Forma Therapeutics, Watertown, MA, USA. JO Johnathan O'Connell is affiliated with Valo Health (Boston, USA), for which no financial interests have been declared. JOC declares competing financial interests due to financial support for the project described in this manuscript by Forma Therapeutics, Watertown, MA, USA. NJ Neil Jones is affiliated with the CRUK Therapeutic Discovery Laboratories at the Crick Institute, for which no financial interests have been declared. NJ declares competing financial interests due to financial support for the project described in this manuscript by Forma Therapeutics, Watertown, MA, USA. CH Claire Heride is affiliated with the CRUK Therapeutic Discovery Laboratories at the Crick Institute, for which no financial interests have been declared. CH declares competing financial interests due to financial support for the project described in this manuscript by Forma Therapeutics, Watertown, MA, USA. MW Min Wu is affiliated with Disc Medicine (Cambridge, MA, USA), for which no financial interests have been declared. MW declares competing financial interests due to financial support for the project described in this manuscript by Forma Therapeutics, Watertown, MA, USA. CD Christopher J Dinsmore is affiliated with Disc Medicine (Cambridge, MA, USA), for which no financial interests have been declared. CJD declares competing financial interests due to financial support for the project described in this manuscript by Forma Therapeutics, Watertown, MA, USA. TH Tim R Hammonds is affiliated with the CRUK Therapeutic Discovery Laboratories at the Crick Institute, for which no financial interests have been declared. TRH declares competing financial interests due to financial support for the project described in this manuscript by Forma Therapeutics, Watertown, MA, USA. SK Sunkyu Kim is affiliated with Incyte (Wilmington, DE, USA), for which no financial interests have been declared. SK declares competing financial interests due to financial support for the project described in this manuscript by Forma Therapeutics, Watertown, MA, USA. DK DK declares competing financial interests due to financial support for the project described in this manuscript by Forma Therapeutics, Watertown, MA, USA. SU SU declares competing financial interests due to financial support for the project described in this manuscript by Forma Therapeutics, Watertown, MA, USA. MC MJC declares competing financial interests due to financial support for the project described in this manuscript by Forma Therapeutics, Watertown, MA, USA. BK BMK declares competing financial interests due to financial support for the project described in this manuscript by Forma Therapeutics, Watertown, MA, USA. AB AB declares competing financial interests due to financial support for the project described in this manuscript by Forma Therapeutics, Watertown, MA, USA., (© 2021, Ruiz et al.)
Published: 2021
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47. Immunogenomics of Colorectal Cancer Response to Checkpoint Blockade: Analysis of the KEYNOTE 177 Trial and Validation Cohorts.

Author: Bortolomeazzi M, Keddar MR, Montorsi L, Acha-Sagredo A, Benedetti L, Temelkovski D, Choi S, Petrov N, Todd K, Wai P, Kohl J, Denner T, Nye E, Goldstone R, Ward S, Wilson GA, Al Bakir M, Swanton C, John S, Miles J, Larijani B, Kunene V, Fontana E, Arkenau HT, Parker PJ, Rodriguez-Justo M, Shiu KK, Spencer J, and Ciccarelli FD
Subjects: Antibodies, Monoclonal, Humanized adverse effects, Biomarkers, Tumor genetics, CD8-Positive T-Lymphocytes drug effects, CD8-Positive T-Lymphocytes immunology, Clinical Trials as Topic, Colorectal Neoplasms genetics, Colorectal Neoplasms immunology, Cytotoxicity, Immunologic drug effects, Gene Expression Profiling, Humans, Immune Checkpoint Inhibitors adverse effects, Lymphocytes, Tumor-Infiltrating drug effects, Lymphocytes, Tumor-Infiltrating immunology, Mutation, Nivolumab adverse effects, Predictive Value of Tests, Programmed Cell Death 1 Receptor antagonists & inhibitors, RNA-Seq, Reproducibility of Results, Time Factors, Transcriptome, Treatment Outcome, Tumor-Associated Macrophages drug effects, Tumor-Associated Macrophages immunology, Exome Sequencing, Antibodies, Monoclonal, Humanized therapeutic use, Colorectal Neoplasms drug therapy, Immune Checkpoint Inhibitors therapeutic use, Immunogenetic Phenomena, Immunogenetics, Nivolumab therapeutic use, Tumor Microenvironment
Abstract: Background & Aims: Colorectal cancer (CRC) shows variable response to immune checkpoint blockade, which can only partially be explained by high tumor mutational burden (TMB). We conducted an integrated study of the cancer tissue and associated tumor microenvironment (TME) from patients treated with pembrolizumab (KEYNOTE 177 clinical trial) or nivolumab to dissect the cellular and molecular determinants of response to anti- programmed cell death 1 (PD1) immunotherapy., Methods: We selected multiple regions per tumor showing variable T-cell infiltration for a total of 738 regions from 29 patients, divided into discovery and validation cohorts. We performed multiregional whole-exome and RNA sequencing of the tumor cells and integrated these with T-cell receptor sequencing, high-dimensional imaging mass cytometry, detection of programmed death-ligand 1 (PDL1) interaction in situ, multiplexed immunofluorescence, and computational spatial analysis of the TME., Results: In hypermutated CRCs, response to anti-PD1 immunotherapy was not associated with TMB but with high clonality of immunogenic mutations, clonally expanded T cells, low activation of Wnt signaling, deregulation of the interferon gamma pathway, and active immune escape mechanisms. Responsive hypermutated CRCs were also rich in cytotoxic and proliferating PD1 + CD8 T cells interacting with PDL1 + antigen-presenting macrophages., Conclusions: Our study clarified the limits of TMB as a predictor of response of CRC to anti-PD1 immunotherapy. It identified a population of antigen-presenting macrophages interacting with CD8 T cells that consistently segregate with response. We therefore concluded that anti-PD1 agents release the PD1-PDL1 interaction between CD8 T cells and macrophages to promote cytotoxic antitumor activity., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
Published: 2021
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48. JunD, not c-Jun, is the AP-1 transcription factor required for Ras-induced lung cancer.

Author: Ruiz EJ, Lan L, Diefenbacher ME, Riising EM, Da Costa C, Chakraborty A, Hoeck JD, Spencer-Dene B, Kelly G, David JP, Nye E, Downward J, and Behrens A
Subjects: Animals, Gene Expression Regulation, Neoplastic genetics, Gene Silencing, Genes, jun genetics, MAP Kinase Kinase 7 genetics, MAP Kinase Kinase 7 metabolism, MAP Kinase Signaling System, Mice, Phosphorylation, Proto-Oncogene Proteins c-jun genetics, Transcription Factor AP-1 metabolism, Adenocarcinoma of Lung genetics, Adenocarcinoma of Lung metabolism, Carcinogenesis genetics, Carcinogenesis metabolism, Lung Neoplasms genetics, Lung Neoplasms metabolism, Proto-Oncogene Proteins c-jun metabolism, ras Proteins metabolism
Abstract: The AP-1 transcription factor c-Jun is required for Ras-driven tumorigenesis in many tissues and is considered as a classical proto-oncogene. To determine the requirement for c-Jun in a mouse model of K-RasG12D-induced lung adenocarcinoma, we inducibly deleted c-Jun in the adult lung. Surprisingly, we found that inactivation of c-Jun, or mutation of its JNK phosphorylation sites, actually increased lung tumor burden. Mechanistically, we found that protein levels of the Jun family member JunD were increased in the absence of c-Jun. In c-Jun-deficient cells, JunD phosphorylation was increased, and expression of a dominant-active JNKK2-JNK1 transgene further increased lung tumor formation. Strikingly, deletion of JunD completely abolished Ras-driven lung tumorigenesis. This work identifies JunD, not c-Jun, as the crucial substrate of JNK signaling and oncogene required for Ras-induced lung cancer.
Published: 2021
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49. Trends in the use, complications, and costs of permanent pacemakers in Australia: A nationwide study from 2008 to 2017.

Author: Westaway S, Nye E, Gallagher C, Tu SJ, Clarke N, Hanna-Rivero N, Emami M, Kadhim K, Pitman BM, Mahajan R, Lau DH, Young GD, Sanders P, and Wong CX
Subjects: Aged, Aged, 80 and over, Australia, Costs and Cost Analysis, Female, Humans, Male, Middle Aged, Postoperative Complications epidemiology, Postoperative Complications etiology, Procedures and Techniques Utilization statistics & numerical data, Procedures and Techniques Utilization trends, Retrospective Studies, Time Factors, Pacemaker, Artificial adverse effects, Pacemaker, Artificial economics, Pacemaker, Artificial statistics & numerical data, Pacemaker, Artificial trends
Abstract: Objective: To characterize contemporary pacemaker procedure trends., Methods: Nationwide analysis of pacemaker procedures and costs between 2008 and 2017 in Australia. The main outcome measures were total, age- and gender-specific implant, replacement, and complication rates, and costs., Results: Pacemaker implants increased from 12,153 to 17,862. Implantation rates rose from 55.3 to 72.6 per 100,000, a 2.8% annual increase (incidence rate ratio [IRR] 1.028; 95% CI, 1.02-1.04; p < .001). Pacemaker implants in the 80+ age group were 17.37-times higher than the < 50 group (95% CI 16.24-18.59; p < .001), and in males were 1.48-times higher than in females (95% CI 1.42-1.55; p < .001). However, there were similar increases according to age (p = .10) and gender (p = .68) over the study period. Left ventricular lead rates were stable (IRR 0.995; 95% CI 0.98-1.01; p = .53). Generator replacements decreased from 20.5 to 18.3 per 100,000 (IRR 0.975; 95% CI 0.97-0.98; p < .001). Although procedures for generator-related complications were stable (IRR 0.995; 95% CI 0.98-1.01; p = .54), those for lead-related complications decreased (IRR 0.985; 95% CI 0.98-0.99; p < .001). Rates for all pacemaker procedures were consistently greater in males (p < .001). Although annual costs of all pacemaker procedures increased from $178 million to $329 million, inflation-adjusted costs were more stable, rising from $294 million to $329 million., Conclusions: Increasing demand for pacemaker implants is driven by the ageing population and rising rates across all ages, while replacement and complication procedure rates appeared more stable. Males have consistently greater pacemaker procedure rates than females. Our findings have significant clinical and public health implications for healthcare resource planning., (© 2021 Wiley Periodicals LLC.)
Published: 2021
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50. The Transcription Co-Repressors MTG8 and MTG16 Regulate Exit of Intestinal Stem Cells From Their Niche and Differentiation Into Enterocyte vs Secretory Lineages.

Author: Baulies A, Angelis N, Foglizzo V, Danielsen ET, Patel H, Novellasdemunt L, Kucharska A, Carvalho J, Nye E, De Coppi P, and Li VSW
Subjects: Animals, Basic Helix-Loop-Helix Transcription Factors, Cell Culture Techniques, Cell Differentiation, Cell Lineage, Mice, Stem Cell Niche, Stem Cells metabolism, Co-Repressor Proteins physiology, DNA-Binding Proteins physiology, Enterocytes cytology, Enterocytes metabolism, Proto-Oncogene Proteins physiology, Repressor Proteins physiology, Stem Cells cytology, Transcription Factors physiology
Abstract: Background & Aims: Notch signaling maintains intestinal stem cells (ISCs). When ISCs exit the niche, Notch signaling among early progenitor cells at position +4/5 regulates their specification toward secretory vs enterocyte lineages (binary fate). The transcription factor ATOH1 is repressed by Notch in ISCs; its de-repression, when Notch is inactivated, drives progenitor cells to differentiate along the secretory lineage. However, it is not clear what promotes transition of ISCs to progenitors and how this fate decision is established., Methods: We sorted cells from Lgr5-GFP knockin intestines from mice and characterized gene expression patterns. We analyzed Notch regulation by examining expression profiles (by quantitative reverse transcription polymerase chain reaction and RNAscope) of small intestinal organoids incubated with the Notch inhibitor DAPT, intestine tissues from mice given injections of the γ-secretase inhibitor dibenzazepine, and mice with intestine-specific disruption of Rbpj. We analyzed intestine tissues from mice with disruption of the RUNX1 translocation partner 1 gene (Runx1t1, also called Mtg8) or CBFA2/RUNX1 partner transcriptional co-repressor 3 (Cbfa2t3, also called Mtg16), and derived their organoids, by histology, immunohistochemistry, and RNA sequencing (RNA-seq). We performed chromatin immunoprecipitation and sequencing analyses of intestinal crypts to identify genes regulated by MTG16., Results: The transcription co-repressors MTG8 and MTG16 were highly expressed by +4/5 early progenitors, compared with other cells along crypt-villus axis. Expression of MTG8 and MTG16 were repressed by Notch signaling via ATOH1 in organoids and intestine tissues from mice. MTG8- and MTG16-knockout intestines had increased crypt hyperproliferation and expansion of ISCs, but enterocyte differentiation was impaired, based on loss of enterocyte markers and functions. Chromatin immunoprecipitation and sequencing analyses showed that MTG16 bound to promoters of genes that are specifically expressed by stem cells (such as Lgr5 and Ascl2) and repressed their transcription. MTG16 also bound to previously reported enhancer regions of genes regulated by ATOH1, including genes that encode Delta-like canonical Notch ligand and other secretory-specific transcription factors., Conclusions: In intestine tissues of mice and human intestinal organoids, MTG8 and MTG16 repress transcription in the earliest progenitor cells to promote exit of ISCs from their niche (niche exit) and control the binary fate decision (secretory vs enterocyte lineage) by repressing genes regulated by ATOH1., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)
Published: 2020
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