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31 results on '"Knowles, M.A."'

1. Tumor heterogeneity of fibroblast growth factor receptor 3 (FGFR3) mutations in invasive bladder cancer: implications for perioperative anti-FGFR3 treatment

Author

Pouessel, D., Neuzillet, Y., Mertens, L.S., van der Heijden, M.S., de Jong, J., Sanders, J., Peters, D., Leroy, K., Manceau, A., Maille, P., Soyeux, P., Moktefi, A., Semprez, F., Vordos, D., de la Taille, A., Hurst, C.D., Tomlinson, D.C., Harnden, P., Bostrom, P.J., Mirtti, T., Horenblas, S., Loriot, Y., Houédé, N., Chevreau, C., Beuzeboc, P., Shariat, S.F., Sagalowsky, A.I., Ashfaq, R., Burger, M., Jewett, M.A.S., Zlotta, A.R., Broeks, A., Bapat, B., Knowles, M.A., Lotan, Y., van der Kwast, T.H., Culine, S., Allory, Y., and van Rhijn, B.W.G.

Published
2016
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4. Native FGFR1 with an inhibitor

Author

Bunney, T.D., primary, Wan, S., additional, Thiyagarajan, N., additional, Sutto, L., additional, Williams, S.V., additional, Ashford, P., additional, Koss, H., additional, Knowles, M.A., additional, Gervasio, F.L., additional, Coveney, P.V., additional, and Katan, M., additional

Published
2015
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5. FGFR1 mutant with an inhibitor

Author

Bunney, T.D., primary, Wan, S., additional, Thiyagarajan, N., additional, Sutto, L., additional, Williams, S.V., additional, Ashford, P., additional, Koss, H., additional, Knowles, M.A., additional, Gervasio, F.L., additional, Coveney, P.V., additional, and Katan, M., additional

Published
2015
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6. Genome-wide association study yields variants at 20p12.2 that associate with urinary bladder cancer

Author

Rafnar, T., Sulem, P., Thorleifsson, G., Vermeulen, S., Helgason, H., Saemundsdottir, J., Gudjonsson, S.A., Sigurdsson, A., Stacey, S.N., Gudmundsson, J., Johannsdottir, H., Alexiusdottir, K., Petursdottir, V., Nikulasson, S., Geirsson, G., Jonsson, T., Aben, K.K.H., Grotenhuis, A.J., Verhaegh, G.W.C.T., Dudek, A.M.D., Witjes, J.A., Heijden, A.G. van der, Vrieling, A., Galesloot, T.E., Juan, A. de, Panadero, A., Rivera, F., Hurst, C., Bishop, D.T., Sak, S.C., Choudhury, A., Teo, M.T., Arici, C., Carta, A., Toninelli, E., Verdier, P. de, Rudnai, P., Gurzau, E, Koppova, K., Keur, K.A. van der, Lurkin, I., Goossens, M., Kellen, E., Guarrera, S., Russo, A., Critelli, R., Sacerdote, C., Vineis, P., Krucker, C., Zeegers, M.P., Gerullis, H., Ovsiannikov, D., Volkert, F., Hengstler, J.G., Selinski, S., Magnusson, O.T., Masson, G., Kong, A., Gudbjartsson, D., Lindblom, A., Zwarthoff, E., Porru, S., Golka, K., Buntinx, F., Matullo, G., Kumar, R., Mayordomo, J.I., Steineck, D.G., Kiltie, A.E., Jonsson, E., Radvanyi, F., Knowles, M.A., Thorsteinsdottir, U., Kiemeney, B., Stefansson, K., Rafnar, T., Sulem, P., Thorleifsson, G., Vermeulen, S., Helgason, H., Saemundsdottir, J., Gudjonsson, S.A., Sigurdsson, A., Stacey, S.N., Gudmundsson, J., Johannsdottir, H., Alexiusdottir, K., Petursdottir, V., Nikulasson, S., Geirsson, G., Jonsson, T., Aben, K.K.H., Grotenhuis, A.J., Verhaegh, G.W.C.T., Dudek, A.M.D., Witjes, J.A., Heijden, A.G. van der, Vrieling, A., Galesloot, T.E., Juan, A. de, Panadero, A., Rivera, F., Hurst, C., Bishop, D.T., Sak, S.C., Choudhury, A., Teo, M.T., Arici, C., Carta, A., Toninelli, E., Verdier, P. de, Rudnai, P., Gurzau, E, Koppova, K., Keur, K.A. van der, Lurkin, I., Goossens, M., Kellen, E., Guarrera, S., Russo, A., Critelli, R., Sacerdote, C., Vineis, P., Krucker, C., Zeegers, M.P., Gerullis, H., Ovsiannikov, D., Volkert, F., Hengstler, J.G., Selinski, S., Magnusson, O.T., Masson, G., Kong, A., Gudbjartsson, D., Lindblom, A., Zwarthoff, E., Porru, S., Golka, K., Buntinx, F., Matullo, G., Kumar, R., Mayordomo, J.I., Steineck, D.G., Kiltie, A.E., Jonsson, E., Radvanyi, F., Knowles, M.A., Thorsteinsdottir, U., Kiemeney, B., and Stefansson, K.

Abstract

Contains fulltext : 138103.pdf (Publisher’s version ) (Closed access), Genome-wide association studies (GWAS) of urinary bladder cancer (UBC) have yielded common variants at 12 loci that associate with risk of the disease. We report here the results of a GWAS of UBC including 1670 UBC cases and 90 180 controls, followed by replication analysis in additional 5266 UBC cases and 10 456 controls. We tested a dataset containing 34.2 million variants, generated by imputation based on whole-genome sequencing of 2230 Icelanders. Several correlated variants at 20p12, represented by rs62185668, show genome-wide significant association with UBC after combining discovery and replication results (OR = 1.19, P = 1.5 x 10(-11) for rs62185668-A, minor allele frequency = 23.6%). The variants are located in a non-coding region approximately 300 kb upstream from the JAG1 gene, an important component of the Notch signaling pathways that may be oncogenic or tumor suppressive in several forms of cancer. Our results add to the growing number of UBC risk variants discovered through GWAS.

Published
2014

10. European genome-wide association study identifies SLC14A1 as a new urinary bladder cancer susceptibility gene

Author

Rafnar, T., Vermeulen, H.H.M., Sulem, P., Thorleifsson, G., Aben, K.K.H., Witjes, J.A., Grotenhuis, A.J., Verhaegh, G.W.C.T., Hulsbergen-van de Kaa, C.A., Besenbacher, S., Gudbjartsson, D., Stacey, S.N., Gudmundsson, J., Johannsdottir, H., Bjarnason, H., Zanon, C., Helgadottir, H., Jonasson, J.G., Tryggvadottir, L., Jonsson, E., Geirsson, G., Nikulasson, S., Petursdottir, V., Bishop, D.T., Chung-Sak, S., Choudhury, A., Elliott, F., Barrett, J.H., Knowles, M.A., Verdier, P. de, Ryk, C., Lindblom, A., Rudnai, P., Gurzau, E, Koppova, K., Vineis, P., Polidoro, S., Guarrera, S., Sacerdote, C., Panadero, A., Sanz-Velez, J.I., Sanchez, M., Valdivia, G., Garcia-Prats, M.D., Hengstler, J.G., Selinski, S., Gerullis, H., Ovsiannikov, D., Khezri, A., Aminsharifi, A., Malekzadeh, M., Berg, L.H. van den, Ophoff, R.A., Veldink, J.H., Zeegers, M.P., Kellen, E., Fostinelli, J., Andreoli, D., Arici, C., Porru, S., Buntinx, F., Ghaderi, A., Golka, K., Mayordomo, J.I., Matullo, G., Kumar, R., Steineck, G., Kiltie, A.E., Kong, A., Thorsteinsdottir, U., Stefansson, K., Kiemeney, L.A.L.M., Rafnar, T., Vermeulen, H.H.M., Sulem, P., Thorleifsson, G., Aben, K.K.H., Witjes, J.A., Grotenhuis, A.J., Verhaegh, G.W.C.T., Hulsbergen-van de Kaa, C.A., Besenbacher, S., Gudbjartsson, D., Stacey, S.N., Gudmundsson, J., Johannsdottir, H., Bjarnason, H., Zanon, C., Helgadottir, H., Jonasson, J.G., Tryggvadottir, L., Jonsson, E., Geirsson, G., Nikulasson, S., Petursdottir, V., Bishop, D.T., Chung-Sak, S., Choudhury, A., Elliott, F., Barrett, J.H., Knowles, M.A., Verdier, P. de, Ryk, C., Lindblom, A., Rudnai, P., Gurzau, E, Koppova, K., Vineis, P., Polidoro, S., Guarrera, S., Sacerdote, C., Panadero, A., Sanz-Velez, J.I., Sanchez, M., Valdivia, G., Garcia-Prats, M.D., Hengstler, J.G., Selinski, S., Gerullis, H., Ovsiannikov, D., Khezri, A., Aminsharifi, A., Malekzadeh, M., Berg, L.H. van den, Ophoff, R.A., Veldink, J.H., Zeegers, M.P., Kellen, E., Fostinelli, J., Andreoli, D., Arici, C., Porru, S., Buntinx, F., Ghaderi, A., Golka, K., Mayordomo, J.I., Matullo, G., Kumar, R., Steineck, G., Kiltie, A.E., Kong, A., Thorsteinsdottir, U., Stefansson, K., and Kiemeney, L.A.L.M.

Abstract

Contains fulltext : 97884.pdf (publisher's version ) (Closed access), Three genome-wide association studies in Europe and the USA have reported eight urinary bladder cancer (UBC) susceptibility loci. Using extended case and control series and 1000 Genomes imputations of 5 340 737 single-nucleotide polymorphisms (SNPs), we searched for additional loci in the European GWAS. The discovery sample set consisted of 1631 cases and 3822 controls from the Netherlands and 603 cases and 37 781 controls from Iceland. For follow-up, we used 3790 cases and 7507 controls from 13 sample sets of European and Iranian ancestry. Based on the discovery analysis, we followed up signals in the urea transporter (UT) gene SLC14A. The strongest signal at this locus was represented by a SNP in intron 3, rs17674580, that reached genome-wide significance in the overall analysis of the discovery and follow-up groups: odds ratio = 1.17, P = 7.6 x 10(-11). SLC14A1 codes for UTs that define the Kidd blood group and are crucial for the maintenance of a constant urea concentration gradient in the renal medulla and, through this, the kidney's ability to concentrate urine. It is speculated that rs17674580, or other sequence variants in LD with it, indirectly modifies UBC risk by affecting urine production. If confirmed, this would support the 'urogenous contact hypothesis' that urine production and voiding frequency modify the risk of UBC.

Published
2011

12. A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci.

Author

Garcia-Closas, M., Chatterjee, N., Malats, N., Wu, X., Figueroa, J.D., Real, F.X., Berg, D.P.G. van den, Matullo, G., Baris, D., Thun, M., Kiemeney, L.A.L.M., Vilneis, P., De Vivo, I., Albanes, D., Purdue, M., Rafnar, T., Hildebrandt, M.A.T., Kiltie, A.E., Cussenot, O., Golka, K., Kumar, R., Taylor, J.A., Mayordomo, J.I., Jacobs, K.B., Kogevinas, M., Hutchinson, A., Wang, Z., Fu, Y., Prokunina-Olsson, L., Burdett, L., Yeager, M., Wheeler, W., Tardon, A., Serra, C., Carrato, A., Garcia-Closas, R., Lloreta, J., Johnson, A., Schwenn, M., Karagas, M.R., Schned, A., Andriole, G.L., Grubb, R., Black, A., Jacobs, E.J., Diver, W.R., Gapstur, S.M., Weinstein, S.J., Virtamo, J., Cortessis, V.K., Gago-Dominguez, M., Pike, M.C., Stern, M.C., Yuan, J.M., Hunter, D.J., McGrath, M., Dinney, C.P., Czerniak, B., Chen, M., Yang, H., Vermeulen, S., Aben, K.K.H., Witjes, J.A., Makkinje, R.R., Sulem, P., Besenbacher, S., Riboli, E., Brennan, P., Panico, S., Navarro, C, Allen, N.E., Bueno-De-Mesquita, H.B., Trichopoulos, D., Caporaso, N., Landi, M.T., Canzian, F., Ljungberg, B, Tjonneland, A., Clavel-Chapelon, F., Bishop, D.T., Teo, M.T., Knowles, M.A., Guarrera, S., Polidoro, S., Ricceri, F., Sacerdote, C., Allione, A., Cancel-Tassin, G., Selinski, S., Hengstler, J.G., Dietrich, H., Fletcher, T., Rudnai, P., Gurzau, E, Koppova, K., Bolick, S.C., Godfrey, A., Xu, Z., Garcia-Closas, M., Chatterjee, N., Malats, N., Wu, X., Figueroa, J.D., Real, F.X., Berg, D.P.G. van den, Matullo, G., Baris, D., Thun, M., Kiemeney, L.A.L.M., Vilneis, P., De Vivo, I., Albanes, D., Purdue, M., Rafnar, T., Hildebrandt, M.A.T., Kiltie, A.E., Cussenot, O., Golka, K., Kumar, R., Taylor, J.A., Mayordomo, J.I., Jacobs, K.B., Kogevinas, M., Hutchinson, A., Wang, Z., Fu, Y., Prokunina-Olsson, L., Burdett, L., Yeager, M., Wheeler, W., Tardon, A., Serra, C., Carrato, A., Garcia-Closas, R., Lloreta, J., Johnson, A., Schwenn, M., Karagas, M.R., Schned, A., Andriole, G.L., Grubb, R., Black, A., Jacobs, E.J., Diver, W.R., Gapstur, S.M., Weinstein, S.J., Virtamo, J., Cortessis, V.K., Gago-Dominguez, M., Pike, M.C., Stern, M.C., Yuan, J.M., Hunter, D.J., McGrath, M., Dinney, C.P., Czerniak, B., Chen, M., Yang, H., Vermeulen, S., Aben, K.K.H., Witjes, J.A., Makkinje, R.R., Sulem, P., Besenbacher, S., Riboli, E., Brennan, P., Panico, S., Navarro, C, Allen, N.E., Bueno-De-Mesquita, H.B., Trichopoulos, D., Caporaso, N., Landi, M.T., Canzian, F., Ljungberg, B, Tjonneland, A., Clavel-Chapelon, F., Bishop, D.T., Teo, M.T., Knowles, M.A., Guarrera, S., Polidoro, S., Ricceri, F., Sacerdote, C., Allione, A., Cancel-Tassin, G., Selinski, S., Hengstler, J.G., Dietrich, H., Fletcher, T., Rudnai, P., Gurzau, E, Koppova, K., Bolick, S.C., Godfrey, A., and Xu, Z.

Abstract

Contains fulltext : 88946.pdf (publisher's version ) (Closed access)

Published
2010

13. A sequence variant at 4p16.3 confers susceptibility to urinary bladder cancer.

Author

Kiemeney, L.A.L.M., Sulem, P., Besenbacher, S., Vermeulen, S., Sigurdsson, A., Thorleifsson, G., Gudbjartsson, D.F., Stacey, S.N., Gudmundsson, J., Zanon, C., Kostic, J., Masson, G., Bjarnason, H., Palsson, S., Skarphedinsson, O.B., Gudjonsson, S.A., Witjes, J.A., Grotenhuis, A.J., Verhaegh, G.W.C.T., Bishop, D.T., Sak, S.C., Choudhury, A., Elliott, F., Barrett, J.H., Hurst, C.D., Verdier, P. de, Ryk, C., Rudnai, P., Gurzau, E, Koppova, K., Vineis, P., Polidoro, S., Guarrera, S., Sacerdote, C., Campagna, M., Placidi, D., Arici, C., Zeegers, M.P., Kellen, E., Gutierrez, B.S., Sanz-Velez, J.I., Sanchez-Zalabardo, M., Valdivia, G., Garcia-Prats, M.D., Hengstler, J.G., Blaszkewicz, M., Dietrich, H., Ophoff, R.A., Berg, L.H. van den, Alexiusdottir, K., Kristjansson, K., Geirsson, G., Nikulasson, S., Petursdottir, V., Kong, A., Thorgeirsson, T.E., Mungan, N.A., Lindblom, A., Es, M.A. van, Porru, S., Buntinx, F., Golka, K., Mayordomo, J.I., Kumar, R., Matullo, G., Steineck, G., Kiltie, A.E., Aben, K.K.H., Jonsson, E., Thorsteinsdottir, U., Knowles, M.A., Rafnar, T., Stefansson, K., Kiemeney, L.A.L.M., Sulem, P., Besenbacher, S., Vermeulen, S., Sigurdsson, A., Thorleifsson, G., Gudbjartsson, D.F., Stacey, S.N., Gudmundsson, J., Zanon, C., Kostic, J., Masson, G., Bjarnason, H., Palsson, S., Skarphedinsson, O.B., Gudjonsson, S.A., Witjes, J.A., Grotenhuis, A.J., Verhaegh, G.W.C.T., Bishop, D.T., Sak, S.C., Choudhury, A., Elliott, F., Barrett, J.H., Hurst, C.D., Verdier, P. de, Ryk, C., Rudnai, P., Gurzau, E, Koppova, K., Vineis, P., Polidoro, S., Guarrera, S., Sacerdote, C., Campagna, M., Placidi, D., Arici, C., Zeegers, M.P., Kellen, E., Gutierrez, B.S., Sanz-Velez, J.I., Sanchez-Zalabardo, M., Valdivia, G., Garcia-Prats, M.D., Hengstler, J.G., Blaszkewicz, M., Dietrich, H., Ophoff, R.A., Berg, L.H. van den, Alexiusdottir, K., Kristjansson, K., Geirsson, G., Nikulasson, S., Petursdottir, V., Kong, A., Thorgeirsson, T.E., Mungan, N.A., Lindblom, A., Es, M.A. van, Porru, S., Buntinx, F., Golka, K., Mayordomo, J.I., Kumar, R., Matullo, G., Steineck, G., Kiltie, A.E., Aben, K.K.H., Jonsson, E., Thorsteinsdottir, U., Knowles, M.A., Rafnar, T., and Stefansson, K.

Abstract

Contains fulltext : 87396.pdf (publisher's version ) (Closed access)

Published
2010

14. Sequence variant on 8q24 confers susceptibility to urinary bladder cancer.

Author

Kiemeney, L.A.L.M., Thorlacius, S., Sulem, P., Geller, F., Aben, K.K.H., Stacey, S.N., Gudmundsson, J., Jakobsdottir, M., Bergthorsson, J.T., Sigurdsson, A., Blondal, T., Witjes, J.A., Vermeulen, H.H.M., Hulsbergen-van de Kaa, C.A., Swinkels, D.W., Ploeg, M., Cornel, E.B., Vergunst, H., Thorgeirsson, T.E., Gudbjartsson, D.F., Gudjonsson, S.A., Thorleifsson, G., Kristinsson, K.T., Mouy, M., Snorradottir, S., Placidi, D., Campagna, M., Arici, C., Koppova, K., Gurzau, E, Rudnai, P., Kellen, E., Polidoro, S., Guarrera, S., Sacerdote, C., Sanchez, M., Saez, B., Valdivia, G., Ryk, C., Verdier, P. de, Lindblom, A., Golka, K., Bishop, D.T., Knowles, M.A., Nikulasson, S., Petursdottir, V., Jonsson, E., Geirsson, G., Kristjansson, B., Mayordomo, J.I., Steineck, G., Porru, S., Buntinx, F., Zeegers, M., Fletcher, T., Kumar, R., Matullo, G., Vineis, P., Kiltie, A.E., Gulcher, J.R., Thorsteinsdottir, U., Kong, A., Rafnar, T., Stefansson, K., Kiemeney, L.A.L.M., Thorlacius, S., Sulem, P., Geller, F., Aben, K.K.H., Stacey, S.N., Gudmundsson, J., Jakobsdottir, M., Bergthorsson, J.T., Sigurdsson, A., Blondal, T., Witjes, J.A., Vermeulen, H.H.M., Hulsbergen-van de Kaa, C.A., Swinkels, D.W., Ploeg, M., Cornel, E.B., Vergunst, H., Thorgeirsson, T.E., Gudbjartsson, D.F., Gudjonsson, S.A., Thorleifsson, G., Kristinsson, K.T., Mouy, M., Snorradottir, S., Placidi, D., Campagna, M., Arici, C., Koppova, K., Gurzau, E, Rudnai, P., Kellen, E., Polidoro, S., Guarrera, S., Sacerdote, C., Sanchez, M., Saez, B., Valdivia, G., Ryk, C., Verdier, P. de, Lindblom, A., Golka, K., Bishop, D.T., Knowles, M.A., Nikulasson, S., Petursdottir, V., Jonsson, E., Geirsson, G., Kristjansson, B., Mayordomo, J.I., Steineck, G., Porru, S., Buntinx, F., Zeegers, M., Fletcher, T., Kumar, R., Matullo, G., Vineis, P., Kiltie, A.E., Gulcher, J.R., Thorsteinsdottir, U., Kong, A., Rafnar, T., and Stefansson, K.

Abstract

Contains fulltext : 71044.pdf (publisher's version ) (Closed access), We conducted a genome-wide SNP association study on 1,803 urinary bladder cancer (UBC) cases and 34,336 controls from Iceland and The Netherlands and follow up studies in seven additional case-control groups (2,165 cases and 3,800 controls). The strongest association was observed with allele T of rs9642880 on chromosome 8q24, 30 kb upstream of MYC (allele-specific odds ratio (OR) = 1.22; P = 9.34 x 10(-12)). Approximately 20% of individuals of European ancestry are homozygous for rs9642880[T], and their estimated risk of developing UBC is 1.49 times that of noncarriers. No association was observed between UBC and the four 8q24 variants previously associated with prostate, colorectal and breast cancers, nor did rs9642880 associate with any of these three cancers. A weaker signal, but nonetheless of genome-wide significance, was captured by rs710521[A] located near TP63 on chromosome 3q28 (allele-specific OR = 1.19; P = 1. 15 x 10(-7)).

Published
2008

16. Disruption of the FA/BRCA pathway in bladder cancer

Author

Neveling, K., primary, Kalb, R., additional, Florl, A.R., additional, Herterich, S., additional, Friedl, R., additional, Hoehn, H., additional, Hader, C., additional, Hartmann, F.H., additional, Nanda, I., additional, Steinlein, C., additional, Schmid, M., additional, Tönnies, H., additional, Hurst, C.D., additional, Knowles, M.A., additional, Hanenberg, H., additional, Schulz, W.A., additional, and Schindler, D., additional

Published
2007
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23. Mechanisms of FGFR3 actions in endocrine resistant breast cancer.

Author

Tomlinson, D.C., Knowles, M.A., and Speirs, V.

Abstract

Although endocrine therapy has dramatically improved the treatment of breast cancer therapeutic resistance and tumour recurrence occurs, even in estrogen receptor (ER) positive cases. Identifying and understanding the molecular mechanisms which underpin endocrine resistance is therefore important if future therapeutic strategies are to be developed. Members of the fibroblast growth factor (FGF) and fibroblast growth factor receptor (FGFR) families have been implicated in breast cancer development and progression. Our results demonstrate that culture of michigan cancer foundation - 1 (MCF)7 cells with FGF1 results in reduced sensitivity to tamoxifen in vitro. Furthermore, our tissue microarray expression data demonstrates that FGFR3 expression is increased in tamoxifen resistant breast tumours. To confirm that activation of FGFR3 reduced sensitivity to tamoxifen we used an inducible activation system and a constitutively active mutant of FGFR3 expressed in MCF7 cells. Activation of FGFR3 reduced sensitivity to tamoxifen and Fulvestrant but did not lead to phosphorylation of ER demonstrating that FGFR3 does not feedback to modulate ER activity. FGFR3 activation in MCF7 cells stimulated activation of the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signalling pathways, both of which have been implicated in tamoxifen resistance in breast cancer. Furthermore, our data indicates that activation of phospholipase C gamma is a key-signalling event regulating MAPK and PI3K activation and that its activation reduces sensitivity to tamoxifen. Therefore, we hypothesise that FGFRs could play an integral part, not only in breast cancer development but also in resistance to endocrine-therapy. [ABSTRACT FROM AUTHOR]

Published
2012
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25. Symposium 23B: Molecular diagnosis of bladder cancer.

Author

Knowles, M.A., Têtu, B., Tiguert, R., Bernier, V., Couture, C., Fradet, Y., Stoehr, R., Knuechel, R., Hartmann, A., van Rhijn, B. W.G., van der Kwast, T.H., Vis, A.N., Kirkeis, W.J., Radvanyi, R., Chopin, D.K., and Zwarthoff, E.C.

Subjects
*CANCER diagnosis, *BLADDER cancer, *CONFERENCES & conventions, *TUMORS
Abstract

Reports on the topic related to molecular diagnosis of bladder cancer that was discussed during a symposium. Molecular changes in bladder carcinogenesis; Genetic alterations in flat urothelial neoplasia; Features of bladder cancer.

Published
2002
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26. N-Methyl-N-nitrosourea induces dysplasia and cell surface markers of neoplasia in long-term rat bladder organ cultures.

Author

Knowles, M.A., Jani, H., Hicks, R.M., and Berry, R.J.

Abstract

Untreated organ cultures of normal rat bladder can be maintained for long periods, up to 160 days, in a supplemented Waymouth's medium MB 752/1. During that time, the urothelium retains a similar appearance to that seen , namely a three-cell thick epithelium with specialised superficial cells whose characteristic surface features are identifiable by scanning electron microscopy. These superficial cells cover the major part of the explants, but the surface features of basal and intermediate cells can be observed on the cut edges and re-epithelialising surfaces of the explant. These are described and illustrated. When normal cultures are treated with the direct-acting carcinogen, N-methyl-N-nitrosourea (MNU), the response of the urothelium resembles to a certain extent the response to MNU instilled directly into the bladder. A histological progression is seen through mild to severe dysplasia which resembles carcinoma in situ. However, no marked changes in growth pattern, such as the development of papillary or nodular hyperplasia are seen. It is suggested that this is related to the failure of the vascular and stromal elements of the explants to respond to MNU treatment . The development of urothelial dysplasia is reflected by marked changes in cell surface differentiation, including development of pleomorphic microvilli, which closely resemble those seen following MNU treatment . These changes appeared earlier and were far more severe than . The significance of pleomorphic microvilli in bladder cultures is considered. A few were seen in control cultures but primarily on epithelial outgrowths onto the Millipore filter support, suggesting a relationship to the distance of the urothelium from viable stromal support. In the MNU-treated cultures, they were numerous and found on the surface of cells covering most of the explants. They were not solely related to the proliferative state of the urothelium in these cultures. This culture system provides a useful model with which to study the effects on the urothelium of various known and suspect carcinogens. [ABSTRACT FROM PUBLISHER]

Published
1985

27. Transforming growth factors induce markers of neoplasia in cultured addt rat bladder.

Author

Knowles, M.A., Hicks, R.M., Dave, H., Harvey, A.E., Roberts, A.B., and Sporn, M.B.

Abstract

Transforming growth factors α and β (TGF-α and TGF-β) isolated from normal mouse kidney induced gross morphological changes in rat urothelial cells maintained in organ culture. These morphological effects are similar to those observed after long-term treatment of rat bladder organ cultures with the carcinogen N-methyl-N-nitrosourea or the promoting agents sodium saccharin and sodium cyclamate. Cultures were treated continuously with 5-25 µg/ml of Bio-Gel P-30-purified TGF containing both TGF-α and TGF-β between days 1 and 14 in culture, or with 5 µg/ml from days 28 to 42. Controls received 1-10 ng/ml epidermal growth factor (EGF) or control medium. Untreated controls retained a normal urothelium throughout the period of study. Mature superficial-type cells covered most of the surface and less mature forms appeared on the cut sides and damaged areas where cells followed the normal pattern of urothelial differentiation. EGF at 5 and 10 ng/ml caused necrosis of the entire urothelium but at 1 and 2 ng/ml had minimal effects on histology and scanning electron microscopical appearance up to 14 days in culture. Crude P-30-purified TGFs induced a series of dose-related changes from 4 days, which were maximal at 8 days and persisted or decreased between 8 and 14 days. These included hyperplash, loss of epithelial polarity, hyperchromasia and elongation of basal cells between the overlying cell layers to reach the culture surface. Scanning electron microscopy showed the a apearance at the culture surface of immature cells with gross surface abnormalities including large numbers of blebs, stubby microvilli and long pleomorphic microvilli. Immature cells on the sides of the culture and in damaged areas developed similar features. At crude TGF doses of 10 µg/ml many superficial cells were rounded, some became cystic and epithelial necrosis was observed. Cultures treated with h. p. l. c.-purified TGF-β at 80 ng/ml in the presence of 2 ng/ml EGF showed similar effects to those treated with 5 µg/ml P-30-purified TGF. Fully differentiated cultures treated from 28 to 42 days with crude TGF, showed changes similar to those seen in early cultures. However, histological changes, particularly basal cell elongation were more widespread and there was an abnormal development of globular prouses between the membrane ridges of mature superficial cells. Neither crude TGF nor EGF stimulated growth in soft agar of isolated epithelial cells from freshly killed rats or organ cultures pretreated for 7 days with [ABSTRACT FROM PUBLISHER]

Published
1985

28. What we could do now: molecular pathology of bladder cancer

Author

Knowles, M.A.

Abstract

There is much information on the genetic alterations that contribute to the development of bladder cancer. Because it is hypothesised that the genotype of the cancer cell plays a major role in determining phenotype, this genetic information should impact on clinical practice. To date however, this has not happened. Some of the alterations identified in bladder cancer have clear associations with outcome--for example, mutational inactivation of the cell cycle regulator proteins p53 and the retinoblastoma protein (Rb). However, as single markers, these events have insufficient predictive power to be applied in the management of individual patients. The use of panels of markers is a potential solution to this problem. Examples of suitable panels include those genes/proteins with known impact on specific cell cycle checkpoints or with impact on cellular phenotypes, such as immortalisation, invasion, or metastasis. To evaluate such marker panels, large tumour series will be needed--for example, archival samples from completed clinical trials. The use of these valuable resources will require coordination of sample provision. This might involve central collection and distribution of tissue blocks, sections, or tissue arrays and the provision of patient follow up information to laboratories participating in a study. With the availability of microarray technologies, including cDNA and comparative genomic hybridisation arrays, the transcriptome and genome of transitional cell carcinomas of different phenotypes can be compared and will undoubtedly provide a wealth of information with potential diagnostic and prognostic uses. Although these studies can be initiated using small local tissue collections, high quality collection of fresh tissues from new clinical trials will be crucial for proper evaluation of associations with clinical outcome. Funding for molecular pathological studies to date has been poor. To begin to translate molecular information from the laboratory to the clinic and to make maximum use of valuable urological patient resources in the UK, adequate funding and scientific energy are required. Whereas the latter is not in doubt, present funding for this type of translational research is inadequate.

Published
2001

29. Pre-septal cellulitis and facial erysipelas due to <em>Moraxella</em> species.

Author

Cox, N.H., Knowles, M.A., and Porteus, L.D.

Subjects
*CELLULITIS, *ERYSIPELAS, *MORAXELLA, *CONNECTIVE tissue diseases, *PYODERMA, *PENICILLIN
Abstract

We describe a patient with an acute ulcerated pre-septal cellulitis with subsequent spread across the face, in whom conjunctival swabs demonstrated the presence of Moraxella species. Unusually, this organism was resistant to penicillin. Clinical improvement was only achieved when treatment with co-amoxiclav was commenced on the basis of the antibiotic sensitivities demonstrated by culture of this organism. Moraxella species are rare skin pathogens but may be underestimated as they usually respond to a wide range of antibiotics; they should be considered as a cause of facial cellulitis or erysipelas which responds poorly to conventional therapy. [ABSTRACT FROM AUTHOR]

Published
1994
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