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2. 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

4. Functional and molecular profiling of hematopoietic stem cells during regeneration

Author

Rydström, A, Grahn, THM, Niroula, A, Mansell, E, van der Garde, M, Pertesi, M, Subramaniam, A, Soneji, S, Zubarev, R, Enver, T, Nilsson, B, Miharada, K, Larsson, J, Karlssona, S, Rydström, A, Grahn, THM, Niroula, A, Mansell, E, van der Garde, M, Pertesi, M, Subramaniam, A, Soneji, S, Zubarev, R, Enver, T, Nilsson, B, Miharada, K, Larsson, J, and Karlssona, S

Abstract

Hematopoietic stem cells (HSCs) enable hematopoietic stem cell transplantation (HCT) through their ability to replenish the entire blood system. Proliferation of HSCs is linked to decreased reconstitution potential, and a precise regulation of actively dividing HSCs is thus essential to ensure long-term functionality. This regulation becomes important in the transplantation setting where HSCs undergo proliferation followed by a gradual transition to quiescence and homeostasis. Although mouse HSCs have been well studied under homeostatic conditions, the mechanisms regulating HSC activation under stress remain unclear. Here, we analyzed the different phases of regeneration after transplantation. We isolated bone marrow from mice at 8 time points after transplantation and examined the reconstitution dynamics and transcriptional profiles of stem and progenitor populations. We found that regenerating HSCs initially produced rapidly expanding progenitors and displayed distinct changes in fatty acid metabolism and glycolysis. Moreover, we observed molecular changes in cell cycle, MYC and mTOR signaling in both HSCs, and progenitor subsets. We used a decay rate model to fit the temporal transcription profiles of regenerating HSCs and identified genes with progressively decreased or increased expression after transplantation. These genes overlapped to a large extent with published gene sets associated with key aspects of HSC function, demonstrating the potential of this data set as a resource for identification of novel HSC regulators. Taken together, our study provides a detailed functional and molecular characterization of HSCs at different phases of regeneration and identifies a gene set associated with the transition from proliferation to quiescence.

Published
2023

6. Chemotherapy induces canalization of cell state in childhood B-cell precursor acute lymphoblastic leukemia

Author

Turati, V, Guerra-Assuncao, J, Potter, N, Gupta, R, Ecker, S, Daneviciute, A, Tarabichi, M, Webster, A, Ding, C, May, G, James, C, Brown, J, Conde, L, Russell, L, Ancliff, P, Inglott, S, Cazzaniga, G, Biondi, A, Hall, G, Lynch, M, Hubank, M, Macaulay, I, Beck, S, Van Loo, P, Jacobsen, S, Greaves, M, Herrero, J, Enver, T, Turati V. A., Guerra-Assuncao J. A., Potter N. E., Gupta R., Ecker S., Daneviciute A., Tarabichi M., Webster A. P., Ding C., May G., James C., Brown J., Conde L., Russell L. J., Ancliff P., Inglott S., Cazzaniga G., Biondi A., Hall G. W., Lynch M., Hubank M., Macaulay I., Beck S., Van Loo P., Jacobsen S. E., Greaves M., Herrero J., Enver T., Turati, V, Guerra-Assuncao, J, Potter, N, Gupta, R, Ecker, S, Daneviciute, A, Tarabichi, M, Webster, A, Ding, C, May, G, James, C, Brown, J, Conde, L, Russell, L, Ancliff, P, Inglott, S, Cazzaniga, G, Biondi, A, Hall, G, Lynch, M, Hubank, M, Macaulay, I, Beck, S, Van Loo, P, Jacobsen, S, Greaves, M, Herrero, J, Enver, T, Turati V. A., Guerra-Assuncao J. A., Potter N. E., Gupta R., Ecker S., Daneviciute A., Tarabichi M., Webster A. P., Ding C., May G., James C., Brown J., Conde L., Russell L. J., Ancliff P., Inglott S., Cazzaniga G., Biondi A., Hall G. W., Lynch M., Hubank M., Macaulay I., Beck S., Van Loo P., Jacobsen S. E., Greaves M., Herrero J., and Enver T.

Abstract

Comparison of intratumor genetic heterogeneity in cancer at diagnosis and relapse suggests that chemotherapy induces bottleneck selection of subclonal genotypes. However, evolutionary events subsequent to chemotherapy could also explain changes in clonal dominance seen at relapse. We therefore investigated the mechanisms of selection in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) during induction chemotherapy where maximal cytoreduction occurs. To distinguish stochastic versus deterministic events, individual leukemias were transplanted into multiple xenografts and chemotherapy administered. Analyses of the immediate post-treatment leukemic residuum at single-cell resolution revealed that chemotherapy has little impact on genetic heterogeneity. Rather, it acts on extensive, previously unappreciated, transcriptional and epigenetic heterogeneity in BCP-ALL, dramatically reducing the spectrum of cell states represented, leaving a genetically polyclonal but phenotypically uniform population, with hallmark signatures relating to developmental stage, cell cycle and metabolism. Hence, canalization of the cell state accounts for a significant component of bottleneck selection during induction chemotherapy.

Published
2021

11. Regulome analysis in B-acute lymphoblastic leukemia exposes Core Binding Factor addiction as a therapeutic vulnerability

Author

Wray, Jason P., Deltcheva, Elitza M., Boiers, Charlotta, Chhetri, Jyoti Bikram, Brown, John, Gagrica, Sladjana, Martens, Joost H.A., Stunnenberg, Hendrik G., Enver, T., Richardson, S., Wray, Jason P., Deltcheva, Elitza M., Boiers, Charlotta, Chhetri, Jyoti Bikram, Brown, John, Gagrica, Sladjana, Martens, Joost H.A., Stunnenberg, Hendrik G., Enver, T., and Richardson, S.

Abstract

Contains fulltext : 285571.pdf (Publisher’s version ) (Open Access)

Published
2022

14. The onset of circulation triggers a metabolic switch required for endothelial to hematopoietic transition

Author

Azzoni, E, Frontera, V, Anselmi, G, Rode, C, James, C, Deltcheva, E, Demian, A, Brown, J, Barone, C, Patelli, A, Harman, J, Nicholls, M, Conway, S, Morrissey, E, Jacobsen, S, Sparrow, D, Harris, A, Enver, T, de Bruijn, M, Azzoni, Emanuele, Frontera, Vincent, Anselmi, Giorgio, Rode, Christina, James, Chela, Deltcheva, Elitza M, Demian, Atanasiu S, Brown, John, Barone, Cristiana, Patelli, Arianna, Harman, Joe R, Nicholls, Matthew, Conway, Simon J, Morrissey, Edward, Jacobsen, Sten Eirik W, Sparrow, Duncan B, Harris, Adrian L, Enver, Tariq, de Bruijn, Marella F T R, Azzoni, E, Frontera, V, Anselmi, G, Rode, C, James, C, Deltcheva, E, Demian, A, Brown, J, Barone, C, Patelli, A, Harman, J, Nicholls, M, Conway, S, Morrissey, E, Jacobsen, S, Sparrow, D, Harris, A, Enver, T, de Bruijn, M, Azzoni, Emanuele, Frontera, Vincent, Anselmi, Giorgio, Rode, Christina, James, Chela, Deltcheva, Elitza M, Demian, Atanasiu S, Brown, John, Barone, Cristiana, Patelli, Arianna, Harman, Joe R, Nicholls, Matthew, Conway, Simon J, Morrissey, Edward, Jacobsen, Sten Eirik W, Sparrow, Duncan B, Harris, Adrian L, Enver, Tariq, and de Bruijn, Marella F T R

Abstract

Hematopoietic stem cells (HSCs) emerge during development from the vascular wall of the main embryonic arteries. The onset of circulation triggers several processes that provide critical external factors for HSC generation. Nevertheless, it is not fully understood how and when the onset of circulation affects HSC emergence. Here we show that in Ncx1−/− mouse embryos devoid of circulation the HSC lineage develops until the phenotypic pro-HSC stage. However, these cells reside in an abnormal microenvironment, fail to activate the hematopoietic program downstream of Runx1, and are functionally impaired. Single-cell transcriptomics shows that during the endothelial-to-hematopoietic transition, Ncx1−/− cells fail to undergo a glycolysis to oxidative phosphorylation metabolic switch present in wild-type cells. Interestingly, experimental activation of glycolysis results in decreased intraembryonic hematopoiesis. Our results suggest that the onset of circulation triggers metabolic changes that allow HSC generation to proceed.

Published
2021

19. The T cell differentiation landscape is shaped by tumour mutations in lung cancer

Author

Ghorani, E, Reading, JL, Henry, JY, de Massy, MR, Rosenthal, R, Turati, V, Joshi, K, Furness, AJS, Aissa, AB, Saini, SK, Ramskov, S, Georgiou, A, Sunderland, MW, Wong, YNS, De Mucha, MV, Day, W, Galvez-Cancino, F, Becker, PD, Uddin, I, Ismail, M, Ronel, T, Woolston, A, Jamal-Hanjani, M, Veeriah, S, Birkbak, NJ, Wilson, GA, Litchfield, K, Conde, L, Guerra-Assuncao, JA, Blighe, K, Biswas, D, Salgado, R, Lund, T, Al Bakir, M, Moore, DA, Hiley, CT, Loi, S, Sun, Y, Yuan, Y, AbdulJabbar, K, Turajilic, S, Herrero, J, Enver, T, Hadrup, SR, Hackshaw, A, Peggs, KS, McGranahan, N, Chain, B, Swanton, C, Quezada, SA, Ghorani, E, Reading, JL, Henry, JY, de Massy, MR, Rosenthal, R, Turati, V, Joshi, K, Furness, AJS, Aissa, AB, Saini, SK, Ramskov, S, Georgiou, A, Sunderland, MW, Wong, YNS, De Mucha, MV, Day, W, Galvez-Cancino, F, Becker, PD, Uddin, I, Ismail, M, Ronel, T, Woolston, A, Jamal-Hanjani, M, Veeriah, S, Birkbak, NJ, Wilson, GA, Litchfield, K, Conde, L, Guerra-Assuncao, JA, Blighe, K, Biswas, D, Salgado, R, Lund, T, Al Bakir, M, Moore, DA, Hiley, CT, Loi, S, Sun, Y, Yuan, Y, AbdulJabbar, K, Turajilic, S, Herrero, J, Enver, T, Hadrup, SR, Hackshaw, A, Peggs, KS, McGranahan, N, Chain, B, Swanton, C, and Quezada, SA

Abstract

Tumour mutational burden (TMB) predicts immunotherapy outcome in non-small cell lung cancer (NSCLC), consistent with immune recognition of tumour neoantigens. However, persistent antigen exposure is detrimental for T cell function. How TMB affects CD4 and CD8 T cell differentiation in untreated tumours, and whether this affects patient outcomes is unknown. Here we paired high-dimensional flow cytometry, exome, single-cell and bulk RNA sequencing from patients with resected, untreated NSCLC to examine these relationships. TMB was associated with compartment-wide T cell differentiation skewing, characterized by loss of TCF7-expressing progenitor-like CD4 T cells, and an increased abundance of dysfunctional CD8 and CD4 T cell subsets, with significant phenotypic and transcriptional similarity to neoantigen-reactive CD8 T cells. A gene signature of redistribution from progenitor-like to dysfunctional states associated with poor survival in lung and other cancer cohorts. Single-cell characterization of these populations informs potential strategies for therapeutic manipulation in NSCLC.

Published
2020

21. P03.30 Tumur mutations drive dysfunctional T cell differentiation in lung cancer

Author

Ghorani, E, primary, Reading, J, additional, Henry, J, additional, Robert de Massy, M, additional, Rosenthal, R, additional, Turati, V, additional, Furness, A, additional, Ben Aissa, A, additional, Kumar Saini, S, additional, Ramskov, S, additional, Georgiou, A, additional, Vila De Mucha, M, additional, Uddin, I, additional, Ronel, T, additional, Salgado, R, additional, Lund, T, additional, Herrero, J, additional, Enver, T, additional, Hadrup, S, additional, Hackshaw, A, additional, Peggs, K, additional, McGranahan, N, additional, Chain, B, additional, Swanton, C, additional, and Quezada, S, additional

Published
2020
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25. LUBAC is essential for embryogenesis by preventing cell death and enabling haematopoiesis

Author

Peltzer, N, Darding, M, Montinaro, A, Draber, P, Draberova, H, Kupka, S, Rieser, E, Fisher, A, Hutchinson, C, Taraborrelli, L, Hartwig, T, Lafont, E, Haas, TL, Shimizu, Y, Boiers, C, Sarr, A, Rickard, J, Alvarez-Diaz, S, Ashworth, MT, Beal, A, Enver, T, Bertin, J, Kaiser, W, Strasser, A, Silke, J, Bouillet, P, Walczak, H, Peltzer, N, Darding, M, Montinaro, A, Draber, P, Draberova, H, Kupka, S, Rieser, E, Fisher, A, Hutchinson, C, Taraborrelli, L, Hartwig, T, Lafont, E, Haas, TL, Shimizu, Y, Boiers, C, Sarr, A, Rickard, J, Alvarez-Diaz, S, Ashworth, MT, Beal, A, Enver, T, Bertin, J, Kaiser, W, Strasser, A, Silke, J, Bouillet, P, and Walczak, H

Abstract

The linear ubiquitin chain assembly complex (LUBAC) is required for optimal gene activation and prevention of cell death upon activation of immune receptors, including TNFR1 1 . Deficiency in the LUBAC components SHARPIN or HOIP in mice results in severe inflammation in adulthood or embryonic lethality, respectively, owing to deregulation of TNFR1-mediated cell death2-8. In humans, deficiency in the third LUBAC component HOIL-1 causes autoimmunity and inflammatory disease, similar to HOIP deficiency, whereas HOIL-1 deficiency in mice was reported to cause no overt phenotype9-11. Here we show, by creating HOIL-1-deficient mice, that HOIL-1 is as essential for LUBAC function as HOIP, albeit for different reasons: whereas HOIP is the catalytically active component of LUBAC, HOIL-1 is required for LUBAC assembly, stability and optimal retention in the TNFR1 signalling complex, thereby preventing aberrant cell death. Both HOIL-1 and HOIP prevent embryonic lethality at mid-gestation by interfering with aberrant TNFR1-mediated endothelial cell death, which only partially depends on RIPK1 kinase activity. Co-deletion of caspase-8 with RIPK3 or MLKL prevents cell death in Hoil-1-/- (also known as Rbck1-/-) embryos, yet only the combined loss of caspase-8 with MLKL results in viable HOIL-1-deficient mice. Notably, triple-knockout Ripk3-/-Casp8-/-Hoil-1-/- embryos die at late gestation owing to haematopoietic defects that are rescued by co-deletion of RIPK1 but not MLKL. Collectively, these results demonstrate that both HOIP and HOIL-1 are essential LUBAC components and are required for embryogenesis by preventing aberrant cell death. Furthermore, they reveal that when LUBAC and caspase-8 are absent, RIPK3 prevents RIPK1 from inducing embryonic lethality by causing defects in fetal haematopoiesis.

Published
2018

26. 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. Developmental biology: Instructions writ in blood

Author

Enver, T and Jacobsen, SE

Abstract

It seems that growth factors may instruct blood-cell progenitors to develop into specific mature cell types, actively determining lineage choice. But is this reductionist view of cell fate overly simplistic? © 2009 Macmillan Publishers Limited. All rights reserved.

Published
2016
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30. Culture Adaptation Alters Transcriptional Hierarchies among Single Human Embryonic Stem Cells Reflecting Altered Patterns of Differentiation

Author

Gokhale, P.J., Au-Young, J.K., Dadi, S., Keys, D.N., Harrison, N.J., Jones, M., Soneji, S., Enver, T., Sherlock, J.K., Andrews, P.W., and Wang, K

Abstract

We have used single cell transcriptome analysis to re-examine the substates of early passage, karyotypically Normal, and late passage, karyotypically Abnormal (‘Culture Adapted’) human embryonic stem cells characterized by differential expression of the cell surface marker antigen, SSEA3. The results confirmed that culture adaptation is associated with alterations to the dynamics of the SSEA3(+) and SSEA3(-) substates of these cells, with SSEA3(-) Adapted cells remaining within the stem cell compartment whereas the SSEA3(-) Normal cells appear to have differentiated. However, the single cell data reveal that these substates are characterized by further heterogeneity that changes on culture adaptation. Notably the Adapted population includes cells with a transcriptome substate suggestive of a shift to a more naïve-like phenotype in contrast to the cells of the Normal population. Further, a subset of the Normal SSEA3(+) cells expresses genes typical of endoderm differentiation, despite also expressing the undifferentiated stem cell genes, POU5F1 (OCT4) and NANOG, whereas such apparently lineage-primed cells are absent from the Adapted population. These results suggest that the selective growth advantage gained by genetically variant, culture adapted human embryonic stem cells may derive in part from a changed substate structure that influences their propensity for differentiation.

Published
2015

31. Outcomes of Older Adults with Burn Injury: University Clinical Center of Kosovo

Author

Shkelzen, B Duci, Hysni, M Arifi, Hasan, R Ahmeti, Violeta, K Zatriqi, Zejn, A Buja, Enver, T Hoxha, and Agon, Y Mekaj

Subjects
Short Communication, Kosovo, Adults, Old, Burns
Abstract

BACKGROUND Advances in burn care over the past 50 years have brought about remarkable improvement in mortality rates such that survival has become an expected outcome even in patients with extensive injuries. Although these improvements have occurred in all age groups, survival in older adults still lags far behind that in younger cohorts. This study determines the outcomes of older adults with burn injury in University Clinical Center of Kosovo. METHODS This is a retrospective study that includes 56 burn patients, older than 60 years who were admitted at the Department of Plastic Surgery, between 1 January 2004 and 31 December 2013. Data processing was done with the statistical package of Stat 3. From the statistical parameters the structural index, arithmetic median, and standard deviation were calculated. RESULTS Fifty six burned patient older than 60 years were included during a 10-year period. Of the 56 elderly patients 29 were women and 27 were men with a mean age of 66.7 years (range, 60-85 years). The differences were not statistically significant for both genders regarding the causes of burn injury. CONCLUSION Considering the gradual increase of the elderly population in our country based on the data of the Ministry of Public Services, an increase is expected to the incidence of burn injuries in the population of this category of our country.

Published
2015

32. Expression of the fetal hematopoiesis regulator FEV indicates leukemias of prenatal origin

Author

Liu, T-H, primary, Tang, Y-J, additional, Huang, Y, additional, Wang, L, additional, Guo, X-L, additional, Mi, J-Q, additional, Liu, L-G, additional, Zhu, H, additional, Zhang, Y, additional, Chen, L, additional, Liu, X, additional, Zhang, L-H, additional, Ye, Q-J, additional, Li, B-S, additional, Tang, J-Y, additional, Ford, A, additional, Enver, T, additional, Liu, F, additional, Chen, G-Q, additional, and Hong, D-L, additional

Published
2016
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34. Early dynamic fate changes in haemogenic endothelium characterized at the single-cell level

Author

Swiers, G, Baumann, C, O'Rourke, J, Giannoulatou, E, Taylor, S, Joshi, A, Moignard, V, Pina, C, Bee, T, Kokkaliaris, K, Yoshimoto, M, Yoder, M, Frampton, J, Schroeder, T, Enver, T, Göttgens, B, and De Bruijn, M

Subjects
Genetically modified mouse, Male, Endothelium, Hemangioblasts, Transgene, Green Fluorescent Proteins, General Physics and Astronomy, Mice, Transgenic, Biology, General Biochemistry, Genetics and Molecular Biology, Article, chemistry.chemical_compound, Mice, Pregnancy, medicine, Animals, Hemogenic endothelium, Regulation of gene expression, Multidisciplinary, Gene Expression Regulation, Developmental, General Chemistry, Embryo, Mammalian, Cell biology, Haematopoiesis, medicine.anatomical_structure, Enhancer Elements, Genetic, RUNX1, chemistry, Immunology, Core Binding Factor Alpha 2 Subunit, Female, Stem cell, Single-Cell Analysis
Abstract

Haematopoietic stem cells (HSCs) are the founding cells of the adult haematopoietic system, born during ontogeny from a specialized subset of endothelium, the haemogenic endothelium (HE) via an endothelial-to-haematopoietic transition (EHT). Although recently imaged in real time, the underlying mechanism of EHT is still poorly understood. We have generated a Runx1 +23 enhancer-reporter transgenic mouse (23GFP) for the prospective isolation of HE throughout embryonic development. Here we perform functional analysis of over 1,800 and transcriptional analysis of 268 single 23GFP(+) HE cells to explore the onset of EHT at the single-cell level. We show that initiation of the haematopoietic programme occurs in cells still embedded in the endothelial layer, and is accompanied by a previously unrecognized early loss of endothelial potential before HSCs emerge. Our data therefore provide important insights on the timeline of early haematopoietic commitment.

Published
2013

35. Surgical Treatment of 55 Patients with Pressure Ulcers at the Department of Plastic and Reconstructive Surgery Kosovo during the Period 2000-2010: A Retrospective Study

Author

Musli Gashi, Vildane H. Ismajli, Shkelzen B Duci, Agon Y Mekaj, Mimoza E. Selmani, Enver T. Hoxha, Zejn A Buja, Hysni M Arifi, and Adem N. Kllokoqi

Subjects
medicine.medical_specialty, Reconstructive surgery, Article Subject, business.industry, Incidence (epidemiology), lcsh:Surgery, Retrospective cohort study, Topical treatment, lcsh:RD1-811, bacterial infections and mycoses, Surgery, fluids and secretions, Medicine, In patient, business, Surgical treatment, Surgical interventions, Research Article
Abstract

Objective. The objective of this study is to determine the incidence of PUs, the distribution of PUs, common injuries contributing to the occurrence of PUs in patients admitted to the Department of Plastic and Reconstructive Surgery Kosovo for surgical interventions of PUs, localization of PUs in body, the topical treatment of pressure ulcers before surgical intervention, the methods of surgical interventions, number of surgical interventions, duration of treatment, complications, and mortality. Materials and Methods. This study includes 55 patients with PUs treated surgically in 2000–2010 period in the Department of Plastic and Reconstructive Surgery Kosovo. The data were collected and analyzed from the archives and protocols of the University Clinical Center of Kosovo. Data processing was done with the statistical package In Stat 3. From statistical parameters arithmetic median and standard deviation were calculated. Data testing is done with χ2-test and the difference is significant if P<0.05. Conclusion. Despite preventive measures against PUs, the incidence of Pus remains high.

Published
2012

37. Dysregulated mitophagy and mitochondrial transport in sensori-motor neuropathy due to “Dominant Optic Atrophy” plus with OPA1 (Optic Atrophy 1) mutations

Author

Liao, C., primary, Diot, A., additional, Ashley, N., additional, Morten, K., additional, Fratter, C., additional, Moroni, I., additional, Bianchi, S., additional, Lamperti, C., additional, Dombi, E., additional, Downes, S., additional, Sitarz, K., additional, Yu-Wai-Man, P., additional, Simon, A., additional, Reilly, M., additional, Enver, T., additional, Iborra, F., additional, Votruba, M., additional, Mortiboys, H., additional, Zeviani, M., additional, and Poulton, J., additional

Published
2015
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40. Stem cell programs are retained in human leukemic lymphoblasts

Author

Fan, D, primary, Zhou, X, additional, Li, Z, additional, Li, Z-Q, additional, Duan, C, additional, Liu, T, additional, Zhang, F, additional, Huang, Y, additional, Zhang, Y, additional, Gao, F, additional, Guo, Y, additional, Gupta, R, additional, Chen, G, additional, Enver, T, additional, Tang, J, additional, and Hong, D, additional

Published
2014
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42. The Tetraspanin CD9 Affords High-Purity Capture of All Murine Hematopoietic Stem Cells

Author

Karlsson, G., Rorby, E., Pina, C., Soneji, S., Reckzeh, K., Miharada, K., Karlsson, C., Guo, Y., Fugazza, C., Gupta, R., Martens, J.H., Stunnenberg, H.G., Karlsson, S., Enver, T., Karlsson, G., Rorby, E., Pina, C., Soneji, S., Reckzeh, K., Miharada, K., Karlsson, C., Guo, Y., Fugazza, C., Gupta, R., Martens, J.H., Stunnenberg, H.G., Karlsson, S., and Enver, T.

Abstract

Contains fulltext : 117279.pdf (publisher's version ) (Open Access)

Published
2013

43. A retrospective study of 69 patients admitted at the intensive care unit University Clinical Center of Kosovo during the period 2008-2012

Author

Hysni M Arifi, Zejn A Buja, Shkelzen B Duci, Agon Y Mekaj, Enver T. Hoxha, Astrit R. Hamza, and Mimoza E. Selmani

Subjects
High rate, medicine.medical_specialty, education.field_of_study, business.industry, Mortality rate, Population, Developing country, Retrospective cohort study, Intensive care unit, law.invention, Age groups, law, Emergency medicine, medicine, Intensive care medicine, education, business, Male to female
Abstract

Background: Burns are the third most common cause of mortality in children and adolescents. It is also a major cause of morbidity and mortality in individuals of all age groups, particularly in individuals living in the developing countries. Objective: The objective of this study is to determine the causes of extensive burn injuries in our population, sex, age, distribution of extensive burn injuries by years, duration of treatment, the methods of treatment and mortality. Materials and Methods: In this retrospective study, we retrospectively analyzed data of 69 patients during the 4-year period between January 2008 and January 2012, with extensive burn injuries admitted to the ICU-University Clinical Center of Kosovo. Among them, 53 patients were males and 16 were females with a male to female ratio of 3.3:1. Conclusion: The high rate of transferring patients for treatment abroad to other countries of 28.9% and high mortality rate of extensive burns in our country with 11 cases (15.9%) is a reflection of lack of burn care in our department.

Published
2014
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44. BLUEPRINT to decode the epigenetic signature written in blood

Author

Adams, D., Altucci, L., Antonarakis, S.E., Ballesteros, J., Beck, S., Bird, A., Bock, C., Boehm, B., Campo, E., Caricasole, A., Dahl, F., Dermitzakis, E.T., Estivill, X., Enver, T., Esteller, M., Ferguson-Smith, A., Fitzgibbon, J., Flicek, P., Giehl, C., Graf, T., Grosveld, F., Guigo, R., Gut, I., Helin, K., Jarvius, J., Küppers, R., Lehrach, H., Lengauer, T., Lernmark, A., Leslie, D., Loeffler, M., Macintyre, E., Mai, A., Martens, J.H.A., Minucci, S., Ouwehand, W.H., Pelicci, P.G., Pendeville, H., Porse, B., Rakyan, V., Reik, W., Schrappe, M., Schübeler, D., Seifert, M., Siebert, R., Simmons, D., Soranza, N., Spicuglia, S., Stratton, M., Stunnenberg, H.G., Tanay, A., Torrents, D., Vellenga, E., Vingron, M., Valencia, A., Walter, J., Willcocks, S., Adams, D., Altucci, L., Antonarakis, S.E., Ballesteros, J., Beck, S., Bird, A., Bock, C., Boehm, B., Campo, E., Caricasole, A., Dahl, F., Dermitzakis, E.T., Estivill, X., Enver, T., Esteller, M., Ferguson-Smith, A., Fitzgibbon, J., Flicek, P., Giehl, C., Graf, T., Grosveld, F., Guigo, R., Gut, I., Helin, K., Jarvius, J., Küppers, R., Lehrach, H., Lengauer, T., Lernmark, A., Leslie, D., Loeffler, M., Macintyre, E., Mai, A., Martens, J.H.A., Minucci, S., Ouwehand, W.H., Pelicci, P.G., Pendeville, H., Porse, B., Rakyan, V., Reik, W., Schrappe, M., Schübeler, D., Seifert, M., Siebert, R., Simmons, D., Soranza, N., Spicuglia, S., Stratton, M., Stunnenberg, H.G., Tanay, A., Torrents, D., Vellenga, E., Vingron, M., Valencia, A., Walter, J., and Willcocks, S.

Abstract

Item does not contain fulltext

Published
2012

46. The TEL-AML1 leukemia fusion gene dysregulates the TGF-beta pathway in early B lineage progenitor cells

Author

Ford, A, Palmi, C, Bueno, C, Hong, D, Cardus, P, Knight, D, Cazzaniga, G, Enver, T, Greaves, M, Ford, AM, Greaves, M., PALMI, CHIARA, Ford, A, Palmi, C, Bueno, C, Hong, D, Cardus, P, Knight, D, Cazzaniga, G, Enver, T, Greaves, M, Ford, AM, Greaves, M., and PALMI, CHIARA

Abstract

Chromosome translocation to generate the TEL-AML1 (also known as ETV6-RUNX1) chimeric fusion gene is a frequent and early or initiating event in childhood acute lymphoblastic leukemia (ALL). Our starting hypothesis was that the TEL-AML1 protein generates and maintains preleukemic clones and that conversion to overt disease requires secondary genetic changes, possibly in the context of abnormal immune responses. Here, we show that a murine B cell progenitor cell line expressing inducible TEL-AML1 proliferates at a slower rate than parent cells but is more resistant to further inhibition of proliferation by TGF-beta. This facilitates the competitive expansion of TEL-AML1-expressing cells in the presence of TGF-beta. Further analysis indicated that TEL-AML1 binds to a principal TGF-beta signaling target, Smad3, and compromises its ability to activate target promoters. In mice expressing a TEL-AML1 transgene, early, pre-pro-B cells were increased in number and also showed reduced sensitivity to TGF-beta-mediated inhibition of proliferation. Moreover, expression of TEL-AML1 in human cord blood progenitor cells led to the expansion of a candidate preleukemic stem cell population that had an early B lineage phenotype (CD34+CD38-CD19+) and a marked growth advantage in the presence of TGF-beta. Collectively, these data suggest a plausible mechanism by which dysregulated immune responses to infection might promote the malignant evolution of TEL-AML1-expressing preleukemic clones.

Published
2009

47. Stem cell researchers find their niche

Author

Dzierzak, E.A. (Elaine), Enver, T. (Tariq), Dzierzak, E.A. (Elaine), and Enver, T. (Tariq)

Abstract

The EuroSTELLS Workshop 'Stem Cell Niches', organised by Anna Bigas, Ernest Arenas and Pasqualino Loi, took place in January 2008 in Barcelona, Spain. The goal of the conference was to promote scientific collaboration and synergy between stem cell researchers worldwide and those in the EuroSTELLS consortia (an initiative of the European Science Foundation EUROCORES Programme), and to stimulate discussion of the latest results in the field of stem cell niches.

Published
2008
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49. Quiescent leukaemic cells account for minimal residual disease in childhood lymphoblastic leukaemia

Author

Lutz, C, primary, Woll, P S, additional, Hall, G, additional, Castor, A, additional, Dreau, H, additional, Cazzaniga, G, additional, Zuna, J, additional, Jensen, C, additional, Clark, S A, additional, Biondi, A, additional, Mitchell, C, additional, Ferry, H, additional, Schuh, A, additional, Buckle, V, additional, Jacobsen, S-E W, additional, and Enver, T, additional

Published
2012
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