46 results on '"Buzza M."'
Search Results
2. Predicting Biopsy Outcomes During Active Surveillance for Prostate Cancer: External Validation of the Canary Prostate Active Surveillance Study Risk Calculators in Five Large Active Surveillance Cohorts
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Drost, FJH, Nieboer, D, Morgan, TM, Carroll, PR, Roobol, MJ, Trock, B, Ehdaie, B, Carroll, P, Filson, C, Kim, J, Logothetis, C, Morgan, T, Klotz, L, Pickles, T, Hyndman, E, Moore, CM, Gnanapragasam, V, Van Hemelrijck, M, Dasgupta, P, Bangma, C, Roobol, M, Villers, A, Rannikko, A, Valdagni, R, Perry, A, Hugosson, J, Rubio-Briones, J, Bjartell, A, Hefermehl, L, Shiong, LL, Frydenberg, M, Kakehi, Y, Chung, BH, van der Kwast, T, van der Linden, W, Hulsen, T, de Jonge, C, Kattan, M, Xinge, J, Muir, K, Lophatananon, A, Fahey, M, Steyerberg, E, Zhang, L, Beckmann, K, Denton, B, Hayen, A, Boutros, P, Guo, W, Benfante, N, Cowan, J, Patil, D, Tolosa, E, Kim, TK, Mamedov, A, Lapointe, V, Crump, T, Kimberly-Duffell, J, Santaolalla, A, Olivier, J, Rancati, T, Ahlgren, H, Mascarós, J, Löfgren, A, Lin, CH, Hirama, H, Lee, KS, Jenster, G, Auvinen, A, Haider, M, van Bochove, K, Carter, B, Gledhill, S, Buzza, M, Bruinsma, S, and Helleman, J
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Urology & Nephrology - Abstract
© 2019 European Association of Urology Two active surveillance risk calculators to predict disease reclassification on prostate biopsy are externally validated by the Movember Foundation's Global Action Plan (GAP3) consortium. They proved to be clinically useful and could reduce unnecessary biopsies, but need recalibration to local settings.
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- 2019
3. The Movember Prostate Cancer Landscape Analysis: an assessment of unmet research needs
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Kouspou, M.M. (Michelle M.), Fong, J.E. (Jenna E.), Brew, N. (Nadine), Hsiao, S.T.F. (Sarah T. F.), Davidson, S.L. (Seanna L.), Choyke, P.L. (Peter L.), Crispino, T. (Tony), Jain, S. (Suneil), Jenster, G.W. (Guido), Knudsen, B.S. (Beatrice S.), Millar, J.L. (Jeremy L.), Mittmann, N. (Nicole), Ryan, C.J. (Charles J.), Tombal, B. (Bertrand), Buzza, M. (Mark), Kouspou, M.M. (Michelle M.), Fong, J.E. (Jenna E.), Brew, N. (Nadine), Hsiao, S.T.F. (Sarah T. F.), Davidson, S.L. (Seanna L.), Choyke, P.L. (Peter L.), Crispino, T. (Tony), Jain, S. (Suneil), Jenster, G.W. (Guido), Knudsen, B.S. (Beatrice S.), Millar, J.L. (Jeremy L.), Mittmann, N. (Nicole), Ryan, C.J. (Charles J.), Tombal, B. (Bertrand), and Buzza, M. (Mark)
- Abstract
Prostate cancer is a heterogeneous cancer with widely varying levels of morbidity and mortality. Approaches to prostate cancer screening, diagnosis, surveillance, treatment and management differ around the world. To identify the highest priority research needs across the prostate cancer biomedical research domain, Movember conducted a landscape analysis with the aim of maximizing the effect of future research investment through global collaborative efforts and partnerships. A global Landscape Analysis Committee (LAC) was established to act as an independent group of experts across urology, medical oncology, radiation oncology, radiology, pathology, translational research, health economics and patient advocacy. Men with prostate cancer and thought leaders from a variety of disciplines provided a range of key insights through a range of interviews. Insights were prioritized against predetermined criteria to understand the areas of greatest unmet need. From these efforts, 17 research needs in prostate cancer were agreed on and prioritized, and 3 received the maximum prioritization score by the LAC: first, to establish more sensitive and specif
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- 2020
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4. The Movember Prostate Cancer Landscape Analysis: an assessment of unmet research needs
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Kouspou, MM, Fong, JE, Brew, N, Hsiao, ST, Davidson, SL, Choyke, PL, Crispino, T, Jain, S, Jenster, Guido, Knudsen, BS, Millar, JL, Mittmann, N, Ryan, CJ, Tombal, B, Buzza, M, Kouspou, MM, Fong, JE, Brew, N, Hsiao, ST, Davidson, SL, Choyke, PL, Crispino, T, Jain, S, Jenster, Guido, Knudsen, BS, Millar, JL, Mittmann, N, Ryan, CJ, Tombal, B, and Buzza, M
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- 2020
5. Consistent Biopsy Quality and Gleason Grading Within the Global Active Surveillance Global Action Plan 3 Initiative: A Prerequisite for Future Studies.
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Rannikko A., Moore C.M., Gnanapragasam V., Van Hemelrijck M., Dasgupta P., Bangma C., Villers A., Valdagni R., Perry A., Hugosson J., Rubio-Briones J., Bjartell A., Hefermehl L., Shiong L.L., Frydenberg M., Kakehi Y., Chung B.H., Obbink H., van der Linden W., Hulsen T., de Jonge C., Kattan M., Xinge J., Muir K., Lophatananon A., Fahey M., Steyerberg E., Zhang L., Guo W., Benfante N., Cowan J., Patil D., Tolosa E., Kim T.-K., Mamedov A., Lapointe V., Crump T., Kimberly-Duffell J., Santaolalla A., Olivier J., Rancati T., Ahlgren H., Mascaros J., Lofgren A., Lehmann K., Lin C.H., Hirama H., Lee K.S., Jenster G., Auvinen A., Haider M., van Bochove K., Carter B., Gledhill S., Buzza M., van der Kwast T.H., Helleman J., Nieboer D., Bruinsma S.M., Roobol M.J., Trock B., Ehdaie B., Carroll P., Filson C., Kim J., Logothetis C., Morgan T., Klotz L., Pickles T., Hyndman E., Rannikko A., Moore C.M., Gnanapragasam V., Van Hemelrijck M., Dasgupta P., Bangma C., Villers A., Valdagni R., Perry A., Hugosson J., Rubio-Briones J., Bjartell A., Hefermehl L., Shiong L.L., Frydenberg M., Kakehi Y., Chung B.H., Obbink H., van der Linden W., Hulsen T., de Jonge C., Kattan M., Xinge J., Muir K., Lophatananon A., Fahey M., Steyerberg E., Zhang L., Guo W., Benfante N., Cowan J., Patil D., Tolosa E., Kim T.-K., Mamedov A., Lapointe V., Crump T., Kimberly-Duffell J., Santaolalla A., Olivier J., Rancati T., Ahlgren H., Mascaros J., Lofgren A., Lehmann K., Lin C.H., Hirama H., Lee K.S., Jenster G., Auvinen A., Haider M., van Bochove K., Carter B., Gledhill S., Buzza M., van der Kwast T.H., Helleman J., Nieboer D., Bruinsma S.M., Roobol M.J., Trock B., Ehdaie B., Carroll P., Filson C., Kim J., Logothetis C., Morgan T., Klotz L., Pickles T., and Hyndman E.
- Abstract
Within the Movember Foundation's Global Action Plan Prostate Cancer Active Surveillance (GAP3) initiative, 25 centers across the globe collaborate to standardize active surveillance (AS) protocols for men with low-risk prostate cancer (PCa). A centralized PCa AS database, comprising data of more than 15 000 patients worldwide, was created. Comparability of the histopathology between the different cohorts was assessed by a centralized pathology review of 445 biopsies from 15 GAP3 centers. Grade group 1 (Gleason score 6) in 85% and grade group >=2 (Gleason score >=7) in 15% showed 89% concordance at review with moderate agreement (kappa = 0.56). Average biopsy core length was similar among the analyzed cohorts. Recently established highly adverse pathologies, including cribriform and/or intraductal carcinoma, were observed in 3.6% of the reviewed biopsies. In conclusion, the centralized pathology review of 445 biopsies revealed comparable histopathology among the 15 GAP3 centers with a low frequency of high-risk features. This enables further data analyses-without correction-toward uniform global AS guidelines for men with low-risk PCa. Patient Summary: Movember Foundation's Global Action Plan Prostate Cancer Active Surveillance (GAP3) initiative combines data from 15 000 men with low-risk prostate cancer (PCa) across the globe to standardize active surveillance protocols. Histopathology review confirmed that the histopathology was consistent with low-risk PCa in most men and comparable between different centers. A centralized pathological review showed consistent biopsy quality and Gleason grading within the global active surveillance Global Action Plan 3 initiative, a prerequisite for future studies toward uniform global guidelines for active surveillance of men with low-risk prostate cancer.Copyright © 2018
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- 2019
6. Reasons for Discontinuing Active Surveillance: Assessment of 21 Centres in 12 Countries in the Movember GAP3 Consortium.
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Perry A., Gledhill S., Morgan T., Klotz L., Pickles T., Hyndman E., Moore C.M., Dasgupta P., Villers A., Valdagni R., Carter B., Hugosson J., Rubio-Briones J., Bjartell A., Hefermehl L., Lui Shiong L., Kakehi Y., Ha Chung B., van der Kwast T., Obbink H., Hulsen T., de Jonge C., Xinge J., Muir K., Lophatananon A., Steyerberg E., Zhang L., Santa Olalla A., Beckmann K., Denton B., Hayen A., Boutros P., Guo W., Benfante N., Cowan J., Patil D., Tolosa E., Kim T.-K., Mamedov A., La Pointe V., Crump T., Kimberly-Duffell J., Santaolalla A., Olivier J., Rancati T., Ahlgren H., Mascaros J., Lofgren A., Lehmann K., Han Lin C., Hirama H., Suk Lee K., Jenster G., Auvinen A., Haider M., van Bochove K., Buzza M., Bangma C., Bruinsma S., Fahey M., Van Hemelrijck M., Ji X., Kattan M.W., Helleman J., Roobol M.J., Nieboer D., Bangma C.H., van der Linden W., Frydenberg M., Rannikko A., Lee L.S., Gnanapragasam V.J., Trock B., Ehdaie B., Carroll P., Filson C., Kim J., Logothetis C., Perry A., Gledhill S., Morgan T., Klotz L., Pickles T., Hyndman E., Moore C.M., Dasgupta P., Villers A., Valdagni R., Carter B., Hugosson J., Rubio-Briones J., Bjartell A., Hefermehl L., Lui Shiong L., Kakehi Y., Ha Chung B., van der Kwast T., Obbink H., Hulsen T., de Jonge C., Xinge J., Muir K., Lophatananon A., Steyerberg E., Zhang L., Santa Olalla A., Beckmann K., Denton B., Hayen A., Boutros P., Guo W., Benfante N., Cowan J., Patil D., Tolosa E., Kim T.-K., Mamedov A., La Pointe V., Crump T., Kimberly-Duffell J., Santaolalla A., Olivier J., Rancati T., Ahlgren H., Mascaros J., Lofgren A., Lehmann K., Han Lin C., Hirama H., Suk Lee K., Jenster G., Auvinen A., Haider M., van Bochove K., Buzza M., Bangma C., Bruinsma S., Fahey M., Van Hemelrijck M., Ji X., Kattan M.W., Helleman J., Roobol M.J., Nieboer D., Bangma C.H., van der Linden W., Frydenberg M., Rannikko A., Lee L.S., Gnanapragasam V.J., Trock B., Ehdaie B., Carroll P., Filson C., Kim J., and Logothetis C.
- Abstract
Background: Careful assessment of the reasons for discontinuation of active surveillance (AS) is required for men with prostate cancer (PCa). Objective(s): Using Movember's Global Action Plan Prostate Cancer Active Surveillance initiative (GAP3) database, we report on reasons for AS discontinuation. Design, setting, and participants: We compared data from 10 296 men on AS from 21 centres across 12 countries. Outcome measurements and statistical analysis: Cumulative incidence methods were used to estimate the cumulative incidence rates of AS discontinuation. Results and limitations: During 5-yr follow-up, 27.5% (95% confidence interval [CI]: 26.4-28.6%) men showed signs of disease progression, 12.8% (95% CI: 12.0-13.6%) converted to active treatment without evidence of progression, 1.7% (95% CI: 1.5-2.0%) continued to watchful waiting, and 1.7% (95% CI: 1.4-2.1%) died from other causes. Of the 7049 men who remained on AS, 2339 had follow-up for >5 yr, 4561 had follow-up for <5 yr, and 149 were lost to follow-up. Cumulative incidence of progression was 27.5% (95% CI: 26.4-28.6%) at 5 yr and 38.2% (95% CI: 36.7-39.9%) at 10 yr. A limitation is that not all centres were included due to limited information on the reason for discontinuation and limited follow-up. Conclusion(s): Our descriptive analyses of current AS practices worldwide showed that 43.6% of men drop out of AS during 5-yr follow-up, mainly due to signs of disease progression. Improvements in selection tools for AS are thus needed to correctly allocate men with PCa to AS, which will also reduce discontinuation due to conversion to active treatment without evidence of disease progression. Patient Summary: Our assessment of a worldwide database of men with prostate cancer (PCa) on active surveillance (AS) shows that 43.6% drop out of AS within 5 yr, mainly due to signs of disease progression. Better tools are needed to select and monitor men with PCa as part of AS. After about 5 yr, about 56% of men were still
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- 2019
7. Predicting Biopsy Outcomes During Active Surveillance for Prostate Cancer: External Validation of the Canary Prostate Active Surveillance Study Risk Calculators in Five Large Active Surveillance Cohorts.
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Santaolalla A., Gnanapragasam V., Van Hemelrijck M., Dasgupta P., Auvinen A., Haider M., van Bochove K., Carter B., Gledhill S., Buzza M., Bruinsma S., Helleman J., Drost F.-J.H., Nieboer D., Morgan T.M., Carroll P.R., Roobol M.J., Trock B., Ehdaie B., Carroll P., Filson C., Kim J., Logothetis C., Morgan T., Klotz L., Pickles T., Hyndman E., Bangma C., Roobol M., Villers A., Rannikko A., Valdagni R., Perry A., Hugosson J., Rubio-Briones J., Bjartell A., Hefermehl L., Shiong L.L., Frydenberg M., Kakehi Y., Chung B.H., van der Kwast T., van der Linden W., Hulsen T., de Jonge C., Kattan M., Xinge J., Muir K., Lophatananon A., Fahey M., Steyerberg E., Zhang L., Beckmann K., Denton B., Hayen A., Boutros P., Guo W., Benfante N., Cowan J., Patil D., Tolosa E., Kim T.-K., Mamedov A., Lapointe V., Crump T., Kimberly-Duffell J., Olivier J., Rancati T., Ahlgren H., Mascaros J., Lofgren A., Lin C.H., Hirama H., Lee K.S., Moore C.M., Jenster G., Santaolalla A., Gnanapragasam V., Van Hemelrijck M., Dasgupta P., Auvinen A., Haider M., van Bochove K., Carter B., Gledhill S., Buzza M., Bruinsma S., Helleman J., Drost F.-J.H., Nieboer D., Morgan T.M., Carroll P.R., Roobol M.J., Trock B., Ehdaie B., Carroll P., Filson C., Kim J., Logothetis C., Morgan T., Klotz L., Pickles T., Hyndman E., Bangma C., Roobol M., Villers A., Rannikko A., Valdagni R., Perry A., Hugosson J., Rubio-Briones J., Bjartell A., Hefermehl L., Shiong L.L., Frydenberg M., Kakehi Y., Chung B.H., van der Kwast T., van der Linden W., Hulsen T., de Jonge C., Kattan M., Xinge J., Muir K., Lophatananon A., Fahey M., Steyerberg E., Zhang L., Beckmann K., Denton B., Hayen A., Boutros P., Guo W., Benfante N., Cowan J., Patil D., Tolosa E., Kim T.-K., Mamedov A., Lapointe V., Crump T., Kimberly-Duffell J., Olivier J., Rancati T., Ahlgren H., Mascaros J., Lofgren A., Lin C.H., Hirama H., Lee K.S., Moore C.M., and Jenster G.
- Abstract
Two active surveillance risk calculators to predict disease reclassification on prostate biopsy are externally validated by the Movember Foundation's Global Action Plan (GAP3) consortium. They proved to be clinically useful and could reduce unnecessary biopsies, but need recalibration to local settings. Background: Men with prostate cancer (PCa) on active surveillance (AS) are followed through regular prostate biopsies, a burdensome and often unnecessary intervention, not without risks. Identifying men with at a low risk of disease reclassification may help reduce the number of biopsies. Objective(s): To assess the external validity of two Canary Prostate Active Surveillance Study Risk Calculators (PASS-RCs), which estimate the probability of reclassification (Gleason grade >=7 with or without >34% of biopsy cores positive for PCa) on a surveillance biopsy, using a mix of months since last biopsy, age, body mass index, prostate-specific antigen, prostate volume, number of prior negative biopsies, and percentage (or ratio) of positive cores on last biopsy. Design, setting, and participants: We used data up to November 2017 from the Movember Foundation's Global Action Plan (GAP3) consortium, a global collaboration between AS studies. Outcome measurements and statistical analysis: External validity of the PASS-RCs for estimating reclassification on biopsy was assessed by calibration, discrimination, and decision curve analyses. Results and limitations: Five validation cohorts (Prostate Cancer Research International: Active Surveillance, Johns Hopkins, Toronto, Memorial Sloan Kettering Cancer Center, and University of California San Francisco), comprising 5105 men on AS, were eligible for analysis. The individual cohorts comprised 429-2416 men, with a median follow-up between 36 and 84 mo, in both community and academic practices mainly from western countries. Abilities of the PASS-RCs to discriminate between men with and without reclassification on biopsy were reasonab
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- 2019
8. The Movember Foundation's GAP3 cohort
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Bruinsma, S.M. (Sophie), Zhang, L. (Liying), Roobol-Bouts, M.J. (Monique), Bangma, C.H. (Chris), Steyerberg, E.W. (Ewout), Nieboer, D. (Daan), Van Hemelrijck, M. (Mieke), Trock, B.J. (Bruce), Ehdaie, B. (Behfar), Carroll, P.R. (Peter), Filson, C. (Christopher), Kim, J. (Jeri), Morgan, T. (Todd), Klotz, L. (Laurence), Pickles, T. (Tom), Hyndman, E. (Eric), Moore, C.M. (Caroline), Gnanapragasam, V. (Vincent), Dasgupta, P. (Prokar), Villers, A. (Arnoud), Rannikko, A.S. (Antti), Valdagni, R. (Riccardo), Perry, A. (Antoinette), Hugosson, J. (Jonas), Rubio-Briones, J. (Jose), Bjartell, A. (Anders), Hefermehl, L. (Lukas), Lui Shiong, L. (Lee), Frydenberg, M. (Mark), Kakehi, Y. (Yoshiyuki), Ha Chung, B. (Byung), Kwast, Th.H. (Theo) van der, Obbink, H. (Henk), van der Linden, W. (Wim), Hulsen, T. (Tim), de Jonge, C. (Cees), Kattan, M.W. (Michael), Xinge, J. (Ji), Muir, K. (Kenneth), Lophatananon, A. (Artitaya), Fahey, M. (Michael), Guo, W. (Wei), Milan, T. (Tanya), Benfante, N. (Nicole), Cowan, J. (Janet), Patil, D. (Dattatraya), Sanford, R. (Rachel), Kim, T.-K. (Tae-Kyung), Mamedov, A. (Alexandre), LaPointe, V. (Vincent), Crump, T. (Trafford), Hamoudi, R. (Rifat), Kimberly-Duffell, J. (Jenna), Santaolalla, A. (Aida), Olivier, J. (Jonathan), Janetti, E.B. (Emanuele Bianchi), Rancati, T. (Tiziana), Ahlgren, H. (Helén), Mascarós, J. (Juanma), Löfgren, A. (Annica), Lehmann, K. (Kurt), Han Lin, C. (Catherine), Hirama, H. (Hiromi), Jenster, G.W. (Guido), Auvinen, A. (Anssi), Haider, M. (Masoom), van Bochove, K. (Kees), Carter, B. (Ballentine), Kirk-Burnnand, R. (Rachelle), Gledhill, S. (Sam), Buzza, M. (Mark), Bruinsma, S.M. (Sophie), Zhang, L. (Liying), Roobol-Bouts, M.J. (Monique), Bangma, C.H. (Chris), Steyerberg, E.W. (Ewout), Nieboer, D. (Daan), Van Hemelrijck, M. (Mieke), Trock, B.J. (Bruce), Ehdaie, B. (Behfar), Carroll, P.R. (Peter), Filson, C. (Christopher), Kim, J. (Jeri), Morgan, T. (Todd), Klotz, L. (Laurence), Pickles, T. (Tom), Hyndman, E. (Eric), Moore, C.M. (Caroline), Gnanapragasam, V. (Vincent), Dasgupta, P. (Prokar), Villers, A. (Arnoud), Rannikko, A.S. (Antti), Valdagni, R. (Riccardo), Perry, A. (Antoinette), Hugosson, J. (Jonas), Rubio-Briones, J. (Jose), Bjartell, A. (Anders), Hefermehl, L. (Lukas), Lui Shiong, L. (Lee), Frydenberg, M. (Mark), Kakehi, Y. (Yoshiyuki), Ha Chung, B. (Byung), Kwast, Th.H. (Theo) van der, Obbink, H. (Henk), van der Linden, W. (Wim), Hulsen, T. (Tim), de Jonge, C. (Cees), Kattan, M.W. (Michael), Xinge, J. (Ji), Muir, K. (Kenneth), Lophatananon, A. (Artitaya), Fahey, M. (Michael), Guo, W. (Wei), Milan, T. (Tanya), Benfante, N. (Nicole), Cowan, J. (Janet), Patil, D. (Dattatraya), Sanford, R. (Rachel), Kim, T.-K. (Tae-Kyung), Mamedov, A. (Alexandre), LaPointe, V. (Vincent), Crump, T. (Trafford), Hamoudi, R. (Rifat), Kimberly-Duffell, J. (Jenna), Santaolalla, A. (Aida), Olivier, J. (Jonathan), Janetti, E.B. (Emanuele Bianchi), Rancati, T. (Tiziana), Ahlgren, H. (Helén), Mascarós, J. (Juanma), Löfgren, A. (Annica), Lehmann, K. (Kurt), Han Lin, C. (Catherine), Hirama, H. (Hiromi), Jenster, G.W. (Guido), Auvinen, A. (Anssi), Haider, M. (Masoom), van Bochove, K. (Kees), Carter, B. (Ballentine), Kirk-Burnnand, R. (Rachelle), Gledhill, S. (Sam), and Buzza, M. (Mark)
- Abstract
Objectives: The Movember Foundation launched the Global Action Plan Prostate Cancer Active Surveillance (GAP3) initiative to create a global consensus on the selection and monitoring of men with low-risk prostate cancer (PCa) on active surveillance (AS). The aim of this study is to present data on inclusion and follow-up for AS in this unique global AS database. Patients and Methods: Between 2014 and 2016, the database was created by combining patient data from 25 established AS cohorts worldwide (USA, Canada, Australasia, UK and Europe). Data on a total of 15 101 patients were included. Descriptive statistics were used to report patients' clinical and demographic characteristics at the time of PCa diagnosis, clinical follow-up, discontinuation of AS and subsequent treatment. Cumulative incidence curves were used to report discontinuation rates over time. Results: At diagnosis, the median (interquartile range [IQR]) patient age was 65 (60–70) years and the median prostate-specific antigen level was 5.4 (4.0–7.3) ng/mL. Most patients had clinical stage T1 disease (71.8%), a biopsy Gleason score of 6 (88.8%) and one tumour-positive biopsy core (60.3%). Patients on AS had a median follow-up time of 2.2 (1.0–5.0) years. After 5, 10 and 15 years of follow-up, respectively, 58%, 39% and 23% of patients were still on AS. The current version of GAP3 has limited data on magnetic resonance imaging (MRI), quality of life and genomic testing. Conclusions: GAP3 is the largest worldwide collaboration integrating patient data from men with PCa on AS. The results will allow individual patients and clinicians to have greater confidence in the personalized decision to either delay or proceed with active treatment. Longer follow-up and the evaluation of MRI, new genomic markers and patient-related outcomes will result in even more valuable data and eventually in better patient outcomes.
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- 2018
- Full Text
- View/download PDF
9. Movember GAP1 PDX project: An international collection of serially transplantable prostate cancer patient-derived xenograft (PDX) models
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Navone, NM, van Weerden, WM, Vessella, RL, Williams, ED, Wang, Y, Isaacs, JT, Nguyen, HM, Culig, Z, van der Pluijm, G, Rentsch, CA, Marques, RB, de Ridder, CMA, Bubendorf, L, Thalmann, GN, Brennen, WN, Santer, FR, Moser, PL, Shepherd, P, Efstathiou, E, Xue, H, Lin, D, Buijs, J, Bosse, T, Collins, A, Maitland, N, Buzza, M, Kouspou, M, Achtman, A, Taylor, RA, Risbridger, G, Corey, E, Navone, NM, van Weerden, WM, Vessella, RL, Williams, ED, Wang, Y, Isaacs, JT, Nguyen, HM, Culig, Z, van der Pluijm, G, Rentsch, CA, Marques, RB, de Ridder, CMA, Bubendorf, L, Thalmann, GN, Brennen, WN, Santer, FR, Moser, PL, Shepherd, P, Efstathiou, E, Xue, H, Lin, D, Buijs, J, Bosse, T, Collins, A, Maitland, N, Buzza, M, Kouspou, M, Achtman, A, Taylor, RA, Risbridger, G, and Corey, E
- Abstract
BACKGROUND: While it has been challenging to establish prostate cancer patient-derived xenografts (PDXs), with a take rate of 10-40% and long latency time, multiple groups throughout the world have developed methods for the successful establishment of serially transplantable human prostate cancer PDXs using a variety of immune deficient mice. In 2014, the Movember Foundation launched a Global Action Plan 1 (GAP1) project to support an international collaborative prostate cancer PDX program involving eleven groups. Between these Movember consortium members, a total of 98 authenticated human prostate cancer PDXs were available for characterization. Eighty three of these were derived directly from patient material, and 15 were derived as variants of patient-derived material via serial passage in androgen deprived hosts. A major goal of the Movember GAP1 PDX project was to provide the prostate cancer research community with a summary of both the basic characteristics of the 98 available authenticated serially transplantable human prostate cancer PDX models and the appropriate contact information for collaborations. Herein, we report a summary of these PDX models. METHODS: PDX models were established in immunocompromised mice via subcutaneous or subrenal-capsule implantation. Dual-label species (ie, human vs mouse) specific centromere and telomere Fluorescence In Situ Hybridization (FISH) and immuno-histochemical (IHC) staining of tissue microarrays (TMAs) containing replicates of the PDX models were used for characterization of expression of a number of phenotypic markers important for prostate cancer including AR (assessed by IHC and FISH), Ki67, vimentin, RB1, P-Akt, chromogranin A (CgA), p53, ERG, PTEN, PSMA, and epithelial cytokeratins. RESULTS: Within this series of PDX models, the full spectrum of clinical disease stages is represented, including androgen-sensitive and castration-resistant primary and metastatic prostate adenocarcinomas as well as prostate carcino
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- 2018
10. Expert consensus document: Semantics in active surveillance for men with localized prostate cancer-results of a modified Delphi consensus procedure.
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van der Linden W., Bruinsma S.M., Roobol M.J., Carroll P.R., Klotz L., Pickles T., Moore C.M., Gnanapragasam V.J., Villers A., Rannikko A., Valdagni R., Frydenberg M., Kakehi Y., Filson C.P., Bangma C.H., Trock B., Ehdaie B., Kim J., Morgan T., Hyndman E., Van Hemelrijck M., Dasgupta P., Perry A., Hugosson J., Rubio-Briones J., Bjartell A., Hefermehl L., Lui Shiong L., Ha Chung B., Suk Lee K., van der Kwast T., Obbink H., Hulsen T., de Jonge C., Kattan M., Xinge J., Muir K., Lophatananon A., Fahey M., Steyerberg E., Nieboer D., Zhang L., Guo W., Milan T., Benfante N., Cowan J., Patil D., Sanford R., Kim T.K., Mamedov A., LaPointe V., Crump T., Hamoudi R., Kimberly-Duffell J., Santaolalla A., Olivier J., Janetti E.B., Rancati T., Ahlgren H., Mascaros J., Lofgren A., Lehmann K., Han Lin C., Hirama H., Jenster G., Auvinen A., Haider M., van Bochove K., Carter B., Kirk-Burnnand R., Gledhill S., Buzza M., van der Linden W., Bruinsma S.M., Roobol M.J., Carroll P.R., Klotz L., Pickles T., Moore C.M., Gnanapragasam V.J., Villers A., Rannikko A., Valdagni R., Frydenberg M., Kakehi Y., Filson C.P., Bangma C.H., Trock B., Ehdaie B., Kim J., Morgan T., Hyndman E., Van Hemelrijck M., Dasgupta P., Perry A., Hugosson J., Rubio-Briones J., Bjartell A., Hefermehl L., Lui Shiong L., Ha Chung B., Suk Lee K., van der Kwast T., Obbink H., Hulsen T., de Jonge C., Kattan M., Xinge J., Muir K., Lophatananon A., Fahey M., Steyerberg E., Nieboer D., Zhang L., Guo W., Milan T., Benfante N., Cowan J., Patil D., Sanford R., Kim T.K., Mamedov A., LaPointe V., Crump T., Hamoudi R., Kimberly-Duffell J., Santaolalla A., Olivier J., Janetti E.B., Rancati T., Ahlgren H., Mascaros J., Lofgren A., Lehmann K., Han Lin C., Hirama H., Jenster G., Auvinen A., Haider M., van Bochove K., Carter B., Kirk-Burnnand R., Gledhill S., and Buzza M.
- Abstract
Active surveillance (AS) is broadly described as a management option for men with low-risk prostate cancer, but semantic heterogeneity exists in both the literature and in guidelines. To address this issue, a panel of leading prostate cancer specialists in the field of AS participated in a consensus-forming project using a modified Delphi method to reach international consensus on definitions of terms related to this management option. An iterative three-round sequence of online questionnaires designed to address 61 individual items was completed by each panel member. Consensus was considered to be reached if >=70% of the experts agreed on a definition. To facilitate a common understanding among all experts involved and resolve potential ambiguities, a face-to-face consensus meeting was held between Delphi survey rounds two and three. Convenience sampling was used to construct the panel of experts. In total, 12 experts from Australia, France, Finland, Italy, the Netherlands, Japan, the UK, Canada and the USA participated. By the end of the Delphi process, formal consensus was achieved for 100% (n = 61) of the terms and a glossary was then developed. Agreement between international experts has been reached on relevant terms and subsequent definitions regarding AS for patients with localized prostate cancer. This standard terminology could support multidisciplinary communication, reduce the extent of variations in clinical practice and optimize clinical decision making.Copyright © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
- Published
- 2017
11. Perceived deterrents to being a plasmapheresis donor in a voluntary, nonremunerated environment
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Bagot, KL, Bove, LL, Masser, BM, Bednall, TC, Buzza, M, Bagot, KL, Bove, LL, Masser, BM, Bednall, TC, and Buzza, M
- Abstract
BACKGROUND: As demand for plasma-derived products increases internationally, maintaining a committed plasmapheresis panel membership is critical for blood collection agencies. This study addresses the current lack of knowledge regarding deterrents to the recruitment and retention of plasmapheresis donors in a voluntary nonremunerated environment. STUDY DESIGN AND METHODS: Nine focus groups (n = 84) and six individual interviews were conducted using semistructured schedules. Three focus groups were conducted with each category of eligible whole blood (WB) donors: those who had 1) declined to convert to plasmapheresis (DTC), 2) converted but lapsed to WB (LWB), and 3) converted and lapsed from the panel completely (LFP). Transcript analysis revealed distinct deterrent categories. RESULTS: The time required for plasmapheresis was a universally identified deterrent, with concerns of donation frequency expectations shared between DTC and LWB. LWB and LFP both reported excessive questioning and paperwork, and eligibility requirements as deterrents. Unique deterrents for DTC were a lack of accurate knowledge about safety and process. LWB reported concerns about plasmapheresis donation outcomes; however, they were more committed to continuing donation than LFP, who reported donation not being salient, being too busy, and poorer donation experiences. CONCLUSION: Providing information to address safety and health concerns should be the focus for successful conversion to plasmapheresis. Setting donation frequency expectations at levels to which donors are accustomed may improve evaluations of the cost/benefit ratio of conversion and retention. Involvement levels (i.e., importance, personal meaning of donation) may be the key differentiator between those donors who return to WB and those that lapse altogether.
- Published
- 2013
12. Antihemostatic activity of human granzyme B mediated by cleavage of von Willebrand factor
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Buzza, M., Dyson, J., Choi, H., Gardiner, E., Andrews, R., Kaiserman, D., Mitchell, C., Berndt, Michael, Dong, J., Bird, P., Buzza, M., Dyson, J., Choi, H., Gardiner, E., Andrews, R., Kaiserman, D., Mitchell, C., Berndt, Michael, Dong, J., and Bird, P.
- Published
- 2008
13. Apolipoprotein AI and CIII gene polymorphisms and their association with lipid levels in Italian, Greek and Anglo-Irish populations of Australia
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Buzza, M., primary, Fripp, Y., additional, and Mitchell, R. J., additional
- Published
- 2001
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14. GENETICS OF FAMILIAL FOCAL SEGMENTAL GLOMERULOSCLEROSIS (FSGS)
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Rana, K, primary, Isbel, N, additional, Johnson, D, additional, Buzza, M, additional, Dagher, H, additional, and Savige, J, additional
- Published
- 2000
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15. Linear rheological behaviour of polyisoprene–polystyrene hetero-star and linear diblock copolymer melts
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Johnson, J. M., primary, Allgaier, J. B., additional, Wright, S. J., additional, Young, R. N., additional, Buzza, M., additional, and McLeish, T. C. B., additional
- Published
- 1995
- Full Text
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16. Development of a virtual multidisciplinary meeting framework for less common cancers.
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Collins IM, Freeman J, Ludowyk J, McDonough J, Ridgwell J, Buzza M, Corcoran N, Campbell D, and Thomas B
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- Humans, Male, Young Adult, Adult, Middle Aged, Aged, Aged, 80 and over, Incidence, Victoria epidemiology, Stakeholder Participation, Referral and Consultation, Group Processes, Interdisciplinary Communication, Patient Care Team, Testicular Neoplasms diagnosis, Testicular Neoplasms epidemiology, Testicular Neoplasms therapy, Penile Neoplasms diagnosis, Penile Neoplasms epidemiology, Penile Neoplasms therapy, Digital Health
- Abstract
Less common cancers are underserved with expertise compared to other cancers. This is accentuated in regional areas where patients may need to travel for expert opinion. Development of a virtual multidisciplinary meeting (MDM) can help overcome this disadvantage but can be a challenge to establish. We describe the development of a framework for future less common cancer MDMs., (© 2025 The Author(s). Internal Medicine Journal published by John Wiley & Sons Australia, Ltd on behalf of Royal Australasian College of Physicians.)
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- 2025
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17. Equitable Access to Genomic Molecular Testing for Australian Cancer Patients: Insights from the Victorian Precision Oncology Summit.
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Dall G, Harris K, Chan N, Luen SJ, Frentzas S, Day D, Barrett M, Kilgour A, and Buzza M
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- Humans, Australia, Health Services Accessibility, Medical Oncology methods, Genetic Testing methods, Precision Medicine methods, Neoplasms genetics, Genomics methods
- Abstract
The Victorian Precision Oncology Summit, convened in 2023, was a joint initiative between the Victorian Comprehensive Cancer Centre Alliance (VCCC Alliance) and the Monash Partners Comprehensive Cancer Consortium (MPCCC) and was proposed to guide a coordinated state-wide conversation about how the oncology sector can overcome some of the current obstacles in achieving equity of access to clinical cancer genomics for Victorian patients. Themes that emerged from discussion groups at the Summit include standardisation, centralisation, funding, education and communication and insights across those themes are outlined in this manuscript. The event served as a large consultation piece for the development of a broader precision oncology roadmap, which explores equitable access to molecular testing for Victorian patients, currently in development by the VCCC Alliance and MPCCC in collaboration with other key Victorian and national stakeholders. While this symposium was a Victorian initiative, it is felt that the insights garnered from this consultation piece will be of interest to consumer groups, clinicians, researchers, educators, policy makers and other key stakeholders in other states of Australia as well as in other countries implementing comprehensive genomic profiling within complex health systems.
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- 2024
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18. Decentralized Clinical Trials as a New Paradigm of Trial Delivery to Improve Equity of Access.
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Underhill C, Freeman J, Dixon J, Buzza M, Long D, Burbury K, Sabesan S, McBurnie J, and Woollett A
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- Humans, Health Services Accessibility, Australia, Pandemics, COVID-19
- Abstract
Importance: The need to maintain clinical trial recruitment during the COVID-19 pandemic has precipitated the rapid uptake of digital health for the conduct of clinical trials. Different terms are used in different jurisdictions and clinical contexts, including digital trials, networked trials, teletrials (TT), and decentralized clinical trials (DCT) with a need to agree to terms., Observations: This clinical care review summarized publications and gray literature, including government policies for the safe conduct of clinical trials using digital health. It compares 2 frequently used methodologies, DCT and TT, first developed before the COVID-19 pandemic by trialists and stakeholders in Australia to improve access to cancer clinical trials for geographically dispersed populations. TT uses a networked approach to implement clinical trials to share care between facilities and uses an agreement between sites or a supervision plan to improve governance and safety. Government regulators have adapted existing regulations and invested in the rollout of the TT model. The term DCT emerged in the northern hemisphere and has been the subject of guidance from regulatory agencies. DCT uses digital health to deliver care in nontraditional sites, such as participants' homes, but does not mandate a networked approach between health facilities or require a supervision plan to be in place., Conclusions and Relevance: TT can be considered as a specific type of DCT with several potential advantages, including upskilling across a network. DCT is a new paradigm for the use of digital health in the safe conduct of clinical trials and is a transformative issue in cancer care, addressing disparities in access to clinical trials and improving clinical outcomes.
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- 2024
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19. Aligning organisational priorities and implementation science for cancer research.
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Best S, Thursky K, Buzza M, Klaic M, Peters S, Guccione L, Trainer A, and Francis J
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- Humans, Patient Participation, Hospitals, Research Personnel, Research, Implementation Science, Neoplasms therapy
- Abstract
Background: The challenge of implementing evidence into routine clinical practice is well recognised and implementation science offers theories, models and frameworks to promote investigation into delivery of evidence-based care. Embedding implementation researchers into health systems is a novel approach to ensuring research is situated in day-to-day practice dilemmas. To optimise the value of embedded implementation researchers and resources, the aim of this study was to investigate stakeholders' views on opportunities for implementation science research in a cancer setting that holds potential to impact on care. The research objectives were to: 1) Establish stakeholder and theory informed organisation-level implementation science priorities and 2) Identify and prioritise a test case pilot implementation research project., Methods: We undertook a qualitative study using semi-structured interviews. Participants held either a formal leadership role, were research active or a consumer advocate and affiliated with either a specialist cancer hospital or a cancer alliance of ten hospitals. Interview data were summarised and shared with participants prior to undertaking both thematic analysis, to identify priority areas for implementation research, and content analysis, to identify potential pilot implementation research projects. The selected pilot Implementation research project was prioritised using a synthesis of an organisational and implementation prioritisation framework - the organisational priority setting framework and APEASE framework., Results: Thirty-one people participated between August 2022 and February 2023. Four themes were identified: 1) Integration of services to address organisational priorities e.g., tackling fragmented services; 2) Application of digital health interventions e.g., identifying the potential benefits of digital health interventions; 3) Identification of potential for implementation research, including deimplementation i.e., discontinuing ineffective or low value care and; 4) Focusing on direct patient engagement e.g., wider consumer awareness of the challenges in delivering cancer care. Six potential pilot implementation research projects were identified and the EMBED project, to support clinicians to refer appropriate patients with cancer for genetic testing, was selected using the synthesised prioritisation framework., Conclusions: Using a theory informed and structured approach the alignment between strategic organisational priorities and implementation research priorities can be identified. As a result, the implementation research focus can be placed on activities with the highest potential impact., (© 2024. The Author(s).)
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- 2024
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20. Implementing national models utilizing telehealth for the conduct of clinical trials: A collaborative effort by the cancer sector in Victoria.
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Woollett A, Burbury K, Harris S, Dixon J, Freeman J, McBurnie J, Buzza M, Jane S, and Underhill C
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- Humans, Telemedicine, Neoplasms therapy
- Published
- 2023
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21. The Movember Global Action Plan 1 (GAP1): Unique Prostate Cancer Tissue Microarray Resource.
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Ouellet V, Erickson A, Wiley K, Morrissey C, Berge V, Moreno CS, Tasken KA, Trudel D, True LD, Lewis MS, Svindland A, Ertunc O, Vidal ID, Osunkoya AO, Jones T, Bova GS, Lamminen T, Achtman AH, Buzza M, Kouspou MM, Bigler SA, Zhou X, Freedland SJ, Mes-Masson AM, Garraway IP, Trock BJ, Taimen P, Saad F, Mirtti T, Knudsen BS, and De Marzo AM
- Subjects
- Humans, Male, Prostatectomy, Prostate pathology, Prostatic Neoplasms, Castration-Resistant
- Abstract
Background: The need to better understand the molecular underpinnings of the heterogeneous outcomes of patients with prostate cancer is a pressing global problem and a key research priority for Movember. To address this, the Movember Global Action Plan 1 Unique tissue microarray (GAP1-UTMA) project constructed a set of unique and richly annotated tissue microarrays (TMA) from prostate cancer samples obtained from multiple institutions across several global locations., Methods: Three separate TMA sets were built that differ by purpose and disease state., Results: The intended use of TMA1 (Primary Matched LN) is to validate biomarkers that help determine which clinically localized prostate cancers with associated lymph node metastasis have a high risk of progression to lethal castration-resistant metastatic disease, and to compare molecular properties of high-risk index lesions within the prostate to regional lymph node metastases resected at the time of prostatectomy. TMA2 (Pre vs. Post ADT) was designed to address questions regarding risk of castration-resistant prostate cancer (CRPC) and response to suppression of the androgen receptor/androgen axis, and characterization of the castration-resistant phenotype. TMA3 (CRPC Met Heterogeneity)'s intended use is to assess the heterogeneity of molecular markers across different anatomic sites in lethal prostate cancer metastases., Conclusions: The GAP1-UTMA project has succeeded in combining a large set of tissue specimens from 501 patients with prostate cancer with rich clinical annotation., Impact: This resource is now available to the prostate cancer community as a tool for biomarker validation to address important unanswered clinical questions around disease progression and response to treatment., (©2022 The Authors; Published by the American Association for Cancer Research.)
- Published
- 2022
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22. The Movember Prostate Cancer Landscape Analysis: an assessment of unmet research needs.
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Kouspou MM, Fong JE, Brew N, Hsiao STF, Davidson SL, Choyke PL, Crispino T, Jain S, Jenster GW, Knudsen BS, Millar JL, Mittmann N, Ryan CJ, Tombal B, and Buzza M
- Subjects
- Humans, Male, Biomedical Research, Needs Assessment, Prostatic Neoplasms diagnosis, Prostatic Neoplasms therapy
- Abstract
Prostate cancer is a heterogeneous cancer with widely varying levels of morbidity and mortality. Approaches to prostate cancer screening, diagnosis, surveillance, treatment and management differ around the world. To identify the highest priority research needs across the prostate cancer biomedical research domain, Movember conducted a landscape analysis with the aim of maximizing the effect of future research investment through global collaborative efforts and partnerships. A global Landscape Analysis Committee (LAC) was established to act as an independent group of experts across urology, medical oncology, radiation oncology, radiology, pathology, translational research, health economics and patient advocacy. Men with prostate cancer and thought leaders from a variety of disciplines provided a range of key insights through a range of interviews. Insights were prioritized against predetermined criteria to understand the areas of greatest unmet need. From these efforts, 17 research needs in prostate cancer were agreed on and prioritized, and 3 received the maximum prioritization score by the LAC: first, to establish more sensitive and specific tests to improve disease screening and diagnosis; second, to develop indicators to better stratify low-risk prostate cancer for determining which men should go on active surveillance; and third, to integrate companion diagnostics into randomized clinical trials to enable prediction of treatment response. On the basis of the findings from the landscape analysis, Movember will now have an increased focus on addressing the specific research needs that have been identified, with particular investment in research efforts that reduce disease progression and lead to improved therapies for advanced prostate cancer.
- Published
- 2020
- Full Text
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23. Consistent Biopsy Quality and Gleason Grading Within the Global Active Surveillance Global Action Plan 3 Initiative: A Prerequisite for Future Studies.
- Author
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van der Kwast TH, Helleman J, Nieboer D, Bruinsma SM, Roobol MJ, Trock B, Ehdaie B, Carroll P, Filson C, Kim J, Logothetis C, Morgan T, Klotz L, Pickles T, Hyndman E, Moore CM, Gnanapragasam V, Van Hemelrijck M, Dasgupta P, Bangma C, Roobol M, Villers A, Rannikko A, Valdagni R, Perry A, Hugosson J, Rubio-Briones J, Bjartell A, Hefermehl L, Shiong LL, Frydenberg M, Kakehi Y, Chung BH, van der Kwast T, Obbink H, van der Linden W, Hulsen T, de Jonge C, Kattan M, Xinge J, Muir K, Lophatananon A, Fahey M, Steyerberg E, Nieboer D, Zhang L, Guo W, Benfante N, Cowan J, Patil D, Tolosa E, Kim TK, Mamedov A, LaPointe V, Crump T, Kimberly-Duffell J, Santaolalla A, Nieboer D, Olivier JT, Rancati T, Ahlgren H, Mascarós J, Löfgren A, Lehmann K, Lin CH, Hirama H, Lee KS, Jenster G, Auvinen A, Bjartell A, Haider M, van Bochove K, Carter B, Gledhill S, Buzza M, Bangma C, Roobol M, Bruinsma S, and Helleman J
- Subjects
- Biopsy standards, Biopsy statistics & numerical data, Humans, Male, Neoplasm Grading, Quality of Health Care, Watchful Waiting organization & administration, Watchful Waiting statistics & numerical data, Prostatic Neoplasms pathology, Watchful Waiting standards
- Abstract
Within the Movember Foundation's Global Action Plan Prostate Cancer Active Surveillance (GAP3) initiative, 25 centers across the globe collaborate to standardize active surveillance (AS) protocols for men with low-risk prostate cancer (PCa). A centralized PCa AS database, comprising data of more than 15000 patients worldwide, was created. Comparability of the histopathology between the different cohorts was assessed by a centralized pathology review of 445 biopsies from 15 GAP3 centers. Grade group 1 (Gleason score 6) in 85% and grade group ≥2 (Gleason score ≥7) in 15% showed 89% concordance at review with moderate agreement (κ=0.56). Average biopsy core length was similar among the analyzed cohorts. Recently established highly adverse pathologies, including cribriform and/or intraductal carcinoma, were observed in 3.6% of the reviewed biopsies. In conclusion, the centralized pathology review of 445 biopsies revealed comparable histopathology among the 15 GAP3 centers with a low frequency of high-risk features. This enables further data analyses-without correction-toward uniform global AS guidelines for men with low-risk PCa. PATIENT SUMMARY: Movember Foundation's Global Action Plan Prostate Cancer Active Surveillance (GAP3) initiative combines data from 15000 men with low-risk prostate cancer (PCa) across the globe to standardize active surveillance protocols. Histopathology review confirmed that the histopathology was consistent with low-risk PCa in most men and comparable between different centers., (Crown Copyright © 2018. Published by Elsevier B.V. All rights reserved.)
- Published
- 2019
- Full Text
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24. Movember GAP1 PDX project: An international collection of serially transplantable prostate cancer patient-derived xenograft (PDX) models.
- Author
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Navone NM, van Weerden WM, Vessella RL, Williams ED, Wang Y, Isaacs JT, Nguyen HM, Culig Z, van der Pluijm G, Rentsch CA, Marques RB, de Ridder CMA, Bubendorf L, Thalmann GN, Brennen WN, Santer FR, Moser PL, Shepherd P, Efstathiou E, Xue H, Lin D, Buijs J, Bosse T, Collins A, Maitland N, Buzza M, Kouspou M, Achtman A, Taylor RA, Risbridger G, and Corey E
- Subjects
- Animals, Biomarkers, Tumor metabolism, Disease Models, Animal, Humans, Male, Mice, Prostatic Neoplasms metabolism, Heterografts, Neoplasm Transplantation methods, Prostatic Neoplasms pathology, Xenograft Model Antitumor Assays
- Abstract
Background: While it has been challenging to establish prostate cancer patient-derived xenografts (PDXs), with a take rate of 10-40% and long latency time, multiple groups throughout the world have developed methods for the successful establishment of serially transplantable human prostate cancer PDXs using a variety of immune deficient mice. In 2014, the Movember Foundation launched a Global Action Plan 1 (GAP1) project to support an international collaborative prostate cancer PDX program involving eleven groups. Between these Movember consortium members, a total of 98 authenticated human prostate cancer PDXs were available for characterization. Eighty three of these were derived directly from patient material, and 15 were derived as variants of patient-derived material via serial passage in androgen deprived hosts. A major goal of the Movember GAP1 PDX project was to provide the prostate cancer research community with a summary of both the basic characteristics of the 98 available authenticated serially transplantable human prostate cancer PDX models and the appropriate contact information for collaborations. Herein, we report a summary of these PDX models., Methods: PDX models were established in immunocompromised mice via subcutaneous or subrenal-capsule implantation. Dual-label species (ie, human vs mouse) specific centromere and telomere Fluorescence In Situ Hybridization (FISH) and immuno-histochemical (IHC) staining of tissue microarrays (TMAs) containing replicates of the PDX models were used for characterization of expression of a number of phenotypic markers important for prostate cancer including AR (assessed by IHC and FISH), Ki67, vimentin, RB1, P-Akt, chromogranin A (CgA), p53, ERG, PTEN, PSMA, and epithelial cytokeratins., Results: Within this series of PDX models, the full spectrum of clinical disease stages is represented, including androgen-sensitive and castration-resistant primary and metastatic prostate adenocarcinomas as well as prostate carcinomas with neuroendocrine differentiation. The annotated clinical characteristics of these PDXs were correlated with their marker expression profile., Conclusion: Our results demonstrate the clinical relevance of this series of PDXs as a platform for both basic science studies and therapeutic discovery/drug development. The present report provides the prostate cancer community with a summary of the basic characteristics and a contact information for collaborations using these models., (© 2018 Wiley Periodicals, Inc.)
- Published
- 2018
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25. Intense Exercise for Survival among Men with Metastatic Castrate-Resistant Prostate Cancer (INTERVAL-GAP4): a multicentre, randomised, controlled phase III study protocol.
- Author
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Newton RU, Kenfield SA, Hart NH, Chan JM, Courneya KS, Catto J, Finn SP, Greenwood R, Hughes DC, Mucci L, Plymate SR, Praet SFE, Guinan EM, Van Blarigan EL, Casey O, Buzza M, Gledhill S, Zhang L, Galvão DA, Ryan CJ, and Saad F
- Subjects
- Androstenes therapeutic use, Benzamides, Clinical Trials, Phase III as Topic, Disease Progression, Humans, Male, Multicenter Studies as Topic, Nitriles, Phenylthiohydantoin analogs & derivatives, Phenylthiohydantoin therapeutic use, Randomized Controlled Trials as Topic, Receptors, Androgen drug effects, United States epidemiology, Androgen Antagonists therapeutic use, Exercise Therapy methods, Prostatic Neoplasms, Castration-Resistant mortality, Prostatic Neoplasms, Castration-Resistant therapy, Quality of Life
- Abstract
Introduction: Preliminary evidence supports the beneficial role of physical activity on prostate cancer outcomes. This phase III randomised controlled trial (RCT) is designed to determine if supervised high-intensity aerobic and resistance exercise increases overall survival (OS) in patients with metastatic castrate-resistant prostate cancer (mCRPC)., Methods and Analysis: Participants (n=866) must have histologically documented metastatic prostate cancer with evidence of progressive disease on androgen deprivation therapy (defined as mCRPC). Patients can be treatment-naïve for mCRPC or on first-line androgen receptor-targeted therapy for mCRPC (ie, abiraterone or enzalutamide) without evidence of progression at enrolment, and with no prior chemotherapy for mCRPC. Patients will receive psychosocial support and will be randomly assigned (1:1) to either supervised exercise (high-intensity aerobic and resistance training) or self-directed exercise (provision of guidelines), stratified by treatment status and site. Exercise prescriptions will be tailored to each participant's fitness and morbidities. The primary endpoint is OS. Secondary endpoints include time to disease progression, occurrence of a skeletal-related event or progression of pain, and degree of pain, opiate use, physical and emotional quality of life, and changes in metabolic biomarkers. An assessment of whether immune function, inflammation, dysregulation of insulin and energy metabolism, and androgen biomarkers are associated with OS will be performed, and whether they mediate the primary association between exercise and OS will also be investigated. This study will also establish a biobank for future biomarker discovery or validation., Ethics and Dissemination: Validation of exercise as medicine and its mechanisms of action will create evidence to change clinical practice. Accordingly, outcomes of this RCT will be published in international, peer-reviewed journals, and presented at national and international conferences. Ethics approval was first obtained at Edith Cowan University (ID: 13236 NEWTON), with a further 10 investigator sites since receiving ethics approval, prior to activation., Trial Registration Number: NCT02730338., Competing Interests: Competing interests: MB and SG are employees of Movember Foundation, which is the funder of this research., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)
- Published
- 2018
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26. Janus and patchy nanoparticles: general discussion.
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Striolo A, Kim J, Liz-Marzán L, Tadiello L, Pauly M, Murphy C, Roig A, Gracias D, Xia Y, Reguera J, Mueller A, Critchley K, Brust M, Scarabelli L, Mayer M, Thiele M, Buzza M, Deák A, Bago Rodriguez AM, Kuttner C, Wolf H, Kay E, Stocco A, Portehault D, Mattoussi H, Heatley K, Kumacheva E, González G, Hanske C, Tong W, Tahir MN, Abécassis B, Granick S, Duguet E, Synytska A, and Velikov K
- Published
- 2016
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27. Anisotropic nanoparticles: general discussion.
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Castelli A, Striolo A, Roig A, Murphy C, Reguera J, Liz-Marzán L, Mueller A, Critchley K, Zhou Y, Brust M, Thill A, Scarabelli L, Tadiello L, König TA, Reiser B, López-Quintela MA, Buzza M, Deák A, Kuttner C, Gonzalez Solveyra E, Pasquato L, Portehault D, Mattoussi H, Kotov NA, Kumacheva E, Heatley K, Bergueiro J, González G, Tong W, Tahir MN, Abécassis B, Rojas-Carrillo O, Xia Y, Mayer M, and Peddis D
- Published
- 2016
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- View/download PDF
28. Particles at interfaces: general discussion.
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Striolo A, Kim J, Murphy C, Liz-Marzán L, Lahann J, Reguera J, Zhou Y, Brust M, Thill A, Scarabelli L, König TA, Buzza M, Kuttner C, Gonzalez Solveyra E, Wolf H, Vermant J, Pauly M, Harvie A, Pasquato L, Stocco A, Mattoussi H, Kumacheva E, Heatley K, Hanske C, Faller R, French D, Honciuc A, Binks B, and Sicard F
- Published
- 2016
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29. Perceived deterrents to being a plasmapheresis donor in a voluntary, nonremunerated environment.
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Bagot KL, Bove LL, Masser BM, Bednall TC, and Buzza M
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- Adult, Attitude to Health, Australia, Blood Banks, Female, Focus Groups, Humans, Interviews as Topic, Male, Middle Aged, Patient Selection, Safety, Time Factors, Tissue and Organ Procurement, Blood Donors psychology, Plasmapheresis psychology, Volunteers psychology
- Abstract
Background: As demand for plasma-derived products increases internationally, maintaining a committed plasmapheresis panel membership is critical for blood collection agencies. This study addresses the current lack of knowledge regarding deterrents to the recruitment and retention of plasmapheresis donors in a voluntary nonremunerated environment., Study Design and Methods: Nine focus groups (n = 84) and six individual interviews were conducted using semistructured schedules. Three focus groups were conducted with each category of eligible whole blood (WB) donors: those who had 1) declined to convert to plasmapheresis (DTC), 2) converted but lapsed to WB (LWB), and 3) converted and lapsed from the panel completely (LFP). Transcript analysis revealed distinct deterrent categories., Results: The time required for plasmapheresis was a universally identified deterrent, with concerns of donation frequency expectations shared between DTC and LWB. LWB and LFP both reported excessive questioning and paperwork, and eligibility requirements as deterrents. Unique deterrents for DTC were a lack of accurate knowledge about safety and process. LWB reported concerns about plasmapheresis donation outcomes; however, they were more committed to continuing donation than LFP, who reported donation not being salient, being too busy, and poorer donation experiences., Conclusion: Providing information to address safety and health concerns should be the focus for successful conversion to plasmapheresis. Setting donation frequency expectations at levels to which donors are accustomed may improve evaluations of the cost/benefit ratio of conversion and retention. Involvement levels (i.e., importance, personal meaning of donation) may be the key differentiator between those donors who return to WB and those that lapse altogether., (© 2012 American Association of Blood Banks.)
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- 2013
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30. A prospective trial assessing the safety and efficacy of collecting up to 840 mL of plasma in conjunction with saline infusion during plasmapheresis.
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Buzza M, Marks DC, Capper H, Cassin E, Badcock CA, Reid S, Kwok M, Yang H, Lee J, Corrigan C, Hartkopf-Theis T, and Keller A
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- Adult, Aged, Blood Donors, Blood Proteins metabolism, Blood Volume, Cross-Over Studies, Female, Humans, Immunoglobulin G blood, Male, Middle Aged, Plasmapheresis adverse effects, Prospective Studies, Surveys and Questionnaires, Blood Banking methods, Infusions, Intravenous methods, Plasmapheresis methods, Plasmapheresis standards, Sodium Chloride administration & dosage
- Abstract
Background: The demand for plasma for manufacturing intravenous immunoglobulin and other plasma derivatives is increasing. A prospective study was conducted to determine whether up to 840 mL of plasma could be safely and effectively collected in conjunction with saline infusion during plasmapheresis., Study Design and Methods: Ninety-one plasma donors were enrolled in a modified 3 × 3 crossover study to assess the equivalence of three plasma collection methods: 750 mL of plasma with no saline (control, Method 1), 840 mL of plasma with a 250-mL saline infusion during and at the end of the donation (Method 2), and 800 mL of plasma with a 500-mL saline infusion at the end of the donation (Method 3). The primary efficacy endpoint was the total protein concentration of the collected plasma. Secondary efficacy endpoints were immunoglobulin (Ig)G and Factor (F)VIII plasma concentration and donors' acceptance of the new procedures. Safety was determined from the adverse event (AE) rate., Results: The total protein, IgG, and FVIII concentrations in plasma collected under Methods 2 and 3 were significantly lower than those in plasma collected under Method 1 (p < 0.0001). These variables were also significantly lower in plasma collected under Method 2 compared to Method 3. During the study, 75 AEs were recorded, 73 of which were mild to moderate. Significantly more donors (31%) preferred Method 2 compared to Method 3 (p = 0.006)., Conclusions: Saline infusion during plasmapheresis led to hemodilution of plasma proteins. However, the benefits to donor safety and satisfaction are compelling reasons to implement saline infusion during plasmapheresis., (© 2012 American Association of Blood Banks.)
- Published
- 2012
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31. Understanding the plasmapheresis donor in a voluntary, nonremunerated environment.
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Bove LL, Bednall T, Masser B, and Buzza M
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- Adult, Aged, Attitude, Female, Humans, Male, Middle Aged, Reward, Blood Donors, Plasmapheresis
- Abstract
Background: Increasing demand for plasma-derived products presents a major recruitment and retention challenge for blood collection agencies; however, little is known about what motivates individuals to become committed plasmapheresis donors. This study explored triggers for individuals' first plasma donation and factors associated with continuing donations., Study Design and Methods: A total of 103 plasma donors were recruited into 11 focus groups. Reasons for donating were discussed using a semistructured questioning approach. Transcripts were analyzed using a grounded theory approach. Categories of perceptions, beliefs, and attitudes were developed from the data, cross-validated, and when relevant, assigned to higher-order themes., Results: Awareness of plasmapheresis was most often gained when donors were unable to donate whole blood. Accordingly, the main trigger for conversion to plasma donation was a personal request by collection staff. A key benefit of plasma donation was its increased frequency, which facilitated the establishment of a routine and relationship development with staff and donors, whereas the key reported sacrifice was the greater donation time. Disappointment was the main response to an inability to donate. Functional tokens and refreshments were valued by donors, although it was felt that money spent on tokens would be better invested in making operations more efficient., Conclusion: Suitable whole blood donors should be made aware of plasmapheresis and its associated benefits through collection staff. Sustained donation can be encouraged by the establishment of a regular schedule and positive interactions with collection staff and other donors to enhance the donors' subjective well-being., (© 2011 American Association of Blood Banks.)
- Published
- 2011
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32. The granzyme B inhibitor, PI-9, is differentially expressed during placental development and up-regulated in hydatidiform moles.
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Buzza MS, Hosking P, and Bird PI
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- Carcinoma metabolism, Cell Line, Female, Gene Expression Regulation, Developmental, Granzymes, Humans, Hydatidiform Mole embryology, Hydatidiform Mole pathology, Immunohistochemistry, Mothers, Placenta metabolism, Placenta pathology, Pregnancy, Gene Expression Regulation, Neoplastic, Hydatidiform Mole metabolism, Neoplasm Proteins metabolism, Placentation, Serine Endopeptidases metabolism, Serine Proteinase Inhibitors metabolism, Serpins metabolism, Up-Regulation
- Abstract
The intracellular serpin Proteinase Inhibitor-9 (PI-9) is a potent inhibitor of the cytotoxic lymphocyte (CL) proteinase granzyme B, a major effector molecule used by CLs to induce target cell apoptosis. PI-9 is produced by CLs to protect against mis-directed granzyme B. However, PI-9 expression has also been reported in immune privileged tissues. In the present study, cell-specific expression of PI-9 in placental tissue of various gestational ages was examined by immunohistochemistry. PI-9 is highly expressed by the extravillous trophoblasts that have invaded the decidua, and this high expression is maintained throughout pregnancy. Similar levels were also observed in proliferative villous cytotrophoblasts. Syncytial trophoblasts generally do not produce PI-9 to a significant level until the last few weeks of pregnancy. The villous stroma contains mixed populations of PI-9 positive and negative cells throughout pregnancy, with highest expression during the second trimester. Compared to first trimester placentas, syncytial trophoblasts of partial and complete hydatidiform moles showed marked up-regulation of PI-9. Examination of choriocarcinoma cell lines also demonstrated a very high level of PI-9 is produced by these cells, which may provide protection from granzyme B-mediated apoptosis. The cell-specific expression of PI-9 in the placenta is consistent with a function in the maintenance of immune privilege, and it is proposed that up-regulated expression of PI-9 in gestational trophoblastic diseases contributes to disease pathogenesis via immune evasion.
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- 2006
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33. Persistent familial hematuria in children and the locus for thin basement membrane nephropathy.
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Rana K, Wang YY, Powell H, Jones C, McCredie D, Buzza M, Udawela M, and Savige J
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- Adolescent, Biopsy, Child, Child, Preschool, Chromosomes, Human, X, Erythrocyte Count, Erythrocyte Indices, Female, Genetic Linkage, Haplotypes, Hematuria blood, Hematuria urine, Humans, Kidney pathology, Kidney surgery, Kidney Glomerulus pathology, Male, Pedigree, Autoantigens genetics, Basement Membrane pathology, Collagen Type IV genetics, Hematuria genetics, Nephritis, Hereditary genetics, Nephritis, Hereditary pathology
- Abstract
This study examined how often children with persistent familial hematuria were from families where hematuria segregated with the known genetic locus for the condition known as benign familial hematuria or thin basement membrane nephropathy (TBMN) at COL4A3/COL4A4. Twenty-one unrelated children with persistent familial hematuria as well as their families were studied for segregation of hematuria with haplotypes at the COL4A3/COL4A4 locus for benign familial hematuria and at the COL4A5 locus for X-linked Alport syndrome. Eight families (38%) had hematuria that segregated with COL4A3/COL4A4, and four (19%) had hematuria that segregated with COL4A5. At most, eight of the other nine families could be explained by disease at the COL4A3/COL4A4 locus if de novo mutations, non-penetrant hematuria or coincidental hematuria in unaffected family members was present individually or in combination. This study confirms that persistent familial hematuria is not always linked to COL4A3/COL4A4 (or COL4A5) and suggests the possibility of a further genetic locus for benign familial hematuria. This study also highlights the risk of excluding X-linked Alport syndrome on the basis of the absence of a family history or of kidney failure.
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- 2005
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34. The high resolution crystal structure of the human tumor suppressor maspin reveals a novel conformational switch in the G-helix.
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Law RH, Irving JA, Buckle AM, Ruzyla K, Buzza M, Bashtannyk-Puhalovich TA, Beddoe TC, Nguyen K, Worrall DM, Bottomley SP, Bird PI, Rossjohn J, and Whisstock JC
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- Animals, Binding Sites, Cathepsin L, Cathepsins chemistry, Chickens, Circular Dichroism, Cysteine Endopeptidases chemistry, Extracellular Matrix, Genes, Tumor Suppressor, Homozygote, Humans, Mice, Models, Molecular, Plasmids metabolism, Protein Binding, Protein Conformation, Protein Structure, Secondary, Rats, Recombinant Proteins chemistry, Spectrophotometry, Static Electricity, Temperature, Xenopus, Crystallography, X-Ray methods, Serpins chemistry
- Abstract
Maspin is a serpin that acts as a tumor suppressor in a range of human cancers, including tumors of the breast and lung. Maspin is crucial for development, because homozygous loss of the gene is lethal; however, the precise physiological role of the molecule is unclear. To gain insight into the function of human maspin, we have determined its crystal structure in two similar, but non-isomorphous crystal forms, to 2.1- and 2.8-A resolution, respectively. The structure reveals that maspin adopts the native serpin fold in which the reactive center loop is expelled fully from the A beta-sheet, makes minimal contacts with the core of the molecule, and exhibits a high degree of flexibility. A buried salt bridge unique to maspin orthologues causes an unusual bulge in the region around the D and E alpha-helices, an area of the molecule demonstrated in other serpins to be important for cofactor recognition. Strikingly, the structural data reveal that maspin is able to undergo conformational change in and around the G alpha-helix, switching between an open and a closed form. This change dictates the electrostatic character of a putative cofactor binding surface and highlights this region as a likely determinant of maspin function. The high resolution crystal structure of maspin provides a detailed molecular framework to elucidate the mechanism of function of this important tumor suppressor.
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- 2005
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35. The genetics of thin basement membrane nephropathy.
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Rana K, Wang YY, Buzza M, Tonna S, Zhang KW, Lin T, Sin L, Padavarat S, and Savige J
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- Diagnosis, Differential, Gene Frequency, Genetic Techniques, Glomerulonephritis, Membranous diagnosis, Glomerulonephritis, Membranous metabolism, Humans, Mutation, Polymorphism, Genetic, Autoantigens genetics, Collagen Type IV genetics, Glomerulonephritis, Membranous genetics
- Abstract
The diagnosis of thin basement membrane nephropathy (TBMN) usually is made on the basis of the clinical features or the glomerular membrane ultrastructural appearance. Only now are we beginning to understand the genetics of TBMN and the role of diagnostic genetic testing. The similarity of clinical and glomerular membrane features first suggested TBMN might represent the carrier state for autosomal-recessive Alport syndrome. This was confirmed subsequently by the demonstration that 40% of families with TBMN have hematuria that segregates with the corresponding locus ( COL4A3/COL4A4 ), and identical mutations occur in both conditions. To date, about 20 COL4A3 and COL4A4 mutations have been shown in TBMN, and these mainly are single nucleotide substitutions that are different in each family. The families in whom hematuria does not appear to segregate with the COL4A3/COL4A4 locus cannot all be explained by de novo mutations, and nonpenetrant or coincidental hematuria. This suggests a further TBMN locus. In patients with persistent hematuria, testing for COL4A3 and COL4A4 mutations to diagnose TBMN is problematic because of the huge size of these genes, their frequent polymorphisms, and the likelihood of a further gene locus. It is far more practicable to perform genetic testing to exclude or confirm X-linked Alport syndrome because this condition is the major differential diagnosis of TBMN and has a very different prognosis.
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- 2005
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36. Thin basement membrane nephropathy.
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Savige J, Rana K, Tonna S, Buzza M, Dagher H, and Wang YY
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- Biopsy, Chromosomes, Human, X, Diagnosis, Differential, Genetic Linkage, Genetic Predisposition to Disease, Global Health, Humans, Kidney pathology, Kidney Diseases diagnosis, Kidney Diseases epidemiology, Kidney Diseases physiopathology, Nephritis, Hereditary diagnosis, Nephritis, Hereditary genetics, Pedigree, Prevalence, Risk Factors, Basement Membrane pathology, Kidney Diseases pathology
- Abstract
Thin basement membrane nephropathy. Thin basement membrane nephropathy (TBMN) is the most common cause of persistent glomerular bleeding in children and adults, and occurs in at least 1% of the population. Most affected individuals have, in addition to the hematuria, minimal proteinuria, normal renal function, a uniformly thinned glomerular basement membrane (GBM) and a family history of hematuria. Their clinical course is usually benign. However, some adults with TBMN have proteinuria >500 mg/day or renal impairment. This is more likely in hospital-based series of biopsied patients than in the uninvestigated, but affected, family members. The cause of renal impairment in TBMN is usually not known, but may be due to secondary focal segmental glomerulosclerosis (FSGS) or immunoglobulin A (IgA) glomerulonephritis, to misdiagnosed IgA disease or X-linked Alport syndrome, or because of coincidental disease. About 40% families with TBMN have hematuria that segregates with the COL4A3/COL4A4 locus, and many COL4A3 and COL4A4 mutations have now been described. These genes are also affected in autosomal-recessive Alport syndrome, and at least some cases of TBMN represent the carrier state for this condition. Families with TBMN in whom hematuria does not segregate with the COL4A3/COL4A4 locus can be explained by de novo mutations, incomplete penetrance of hematuria, coincidental hematuria in family members without COL4A3 or COL4A4 mutations, and by a novel gene locus for TBMN. A renal biopsy is warranted in TBMN only if there are atypical features, or if IgA disease or X-linked Alport syndrome cannot be excluded clinically. In IgA disease, there is usually no family history of hematuria. X-linked Alport syndrome is much less common than TBMN and can often be identified in family members by its typical clinical features (including retinopathy), a lamellated GBM without the collagen alpha3(IV), alpha4(IV), and alpha5(IV) chains, and by gene linkage studies or the demonstration of a COL4A5 mutation. Technical difficulties in the demonstration and interpretation of COL4A3 and COL4A4 mutations mean that mutation detection is not used routinely in the diagnosis of TBMN.
- Published
- 2003
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37. Clinical, histopathologic, and genetic studies in nine families with focal segmental glomerulosclerosis.
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Rana K, Isbel N, Buzza M, Dagher H, Henning P, Kainer G, and Savige J
- Subjects
- Adolescent, Adult, Age of Onset, Aged, Biopsy, Child, Chromosomes, Human, Pair 1 genetics, Chromosomes, Human, Pair 11 genetics, Female, Genes, Dominant, Genes, Recessive, Genetic Heterogeneity, Glomerulosclerosis, Focal Segmental epidemiology, Glomerulosclerosis, Focal Segmental pathology, Hematuria etiology, Humans, Hypertension, Renal etiology, Kidney pathology, Lod Score, Male, Middle Aged, Pedigree, Pre-Eclampsia etiology, Pregnancy, Proteinuria etiology, Glomerulosclerosis, Focal Segmental genetics
- Abstract
Background: Familial forms of focal segmental glomerulosclerosis (FSGS) are caused by mutations in genes at 1q25-31 (gene for steroid-resistant nephrotic syndrome 2 [NPHS2]), 11q21-22, 19q13 (gene for alpha-actinin 4 and NPHS1), and at additional unidentified chromosomal loci., Methods: We describe clinical and histopathologic features and results of linkage analysis in nine consecutive index cases with familial FSGS who, together with their families, were referred for genetic studies., Results: Two of the index cases presented in childhood (22%) and seven cases presented in adolescence or adulthood (78%). Six of their families (67%), including the two cases with childhood-onset disease, showed probable autosomal recessive inheritance. FSGS segregated at the 1q25-31 locus in two of these families and at the 11q21-22 locus in four families. None had disease caused by mutations in genes at the 19q13 locus, and no locus was identified in the three remaining families. Clinical features of proteinuria, minimal hematuria, hypertension, preeclampsia, and progressive renal impairment were usually present with autosomal recessive or dominant inheritance and with disease that segregated at the different loci. Eighteen renal biopsies from affected members of eight families showed a strong correlation between tubulointerstitial damage and percentage of obsolescent glomeruli (rho = +0.76; P < 0.01). None of the 13 patients from eight families who underwent transplantation developed recurrent FSGS in their grafts. In general, carriers of autosomal recessive disease had no distinctive clinical features apart from the development of preeclampsia in successive pregnancies., Conclusion: Familial forms of FSGS are not uncommon, and presentation frequently is in adolescence or adulthood, even when inheritance is autosomal recessive. Furthermore, carriers of autosomal recessive FSGS often have no distinctive phenotype.
- Published
- 2003
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38. Mutations in the COL4A4 gene in thin basement membrane disease.
- Author
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Buzza M, Dagher H, Wang YY, Wilson D, Babon JJ, Cotton RG, and Savige J
- Subjects
- Adolescent, Adult, Aged, Amino Acid Substitution, Child, Codon, Nonsense, Codon, Terminator, Female, Frameshift Mutation, Glycine, Humans, Male, Middle Aged, Basement Membrane pathology, Collagen Type IV genetics, Hematuria genetics, Hematuria pathology, Mutation
- Abstract
Background: Patients with thin basement membrane disease (TBMD) are often from families where hematuria segregates with the COL4A3 and COL4A4 genes. These genes also are affected in autosomal recessive Alport syndrome. The aim of this study was to demonstrate COL4A4 mutations in TBMD., Methods: Forty-eight unrelated individuals with TBMD who had no family members with autosomal recessive Alport syndrome were examined for COL4A4 mutations. The diagnosis of TBMD had been confirmed by renal biopsy (43/48, 90%) or by a family history of hematuria but without a renal biopsy (5/48, 10%). The 47 coding exons of COL4A4 were screened for mutations with the methods of enzyme mismatch cleavage or single stranded conformational polymorphism (SSCP) analysis, and exons that demonstrated electrophoretic abnormalities were sequenced., Results: Nine variants that altered the coding sequences were identified. These were nonsense and frameshift mutations that resulted in stop codons (N = 3), and glycine (N = 3) and non-glycine missense variants (N = 3). Four intronic variants and three neutral polymorphisms were also detected. In total, four variants were considered 'pathogenic' principally because they resulted in stop codons or were not present in non-hematuric normal subjects. Three variants were considered 'possibly pathogenic' but two of these were each present in one of 46 non-hematuric normal subjects., Conclusions: Pathogenic COL4A4 mutations were demonstrated in three of the nine (33%) families in whom hematuria segregated with the COL4A3/COL4A4 locus. Two stop codons (R1377X and 2788/91delG) and a glycine substitution (G960R) resulted in hematuria in all 16 members who were tested from these three families. The S969X mutation described here in TBMD for the first time, as well as the R1377X mutation, also occur in autosomal recessive Alport syndrome.
- Published
- 2003
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39. Perforin-independent expression of granzyme B and proteinase inhibitor 9 in human testis and placenta suggests a role for granzyme B-mediated proteolysis in reproduction.
- Author
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Hirst CE, Buzza MS, Sutton VR, Trapani JA, Loveland KL, and Bird PI
- Subjects
- Animals, Female, Granzymes, Humans, Immunohistochemistry, In Situ Hybridization, Male, Membrane Glycoproteins genetics, Mice, Mice, Inbred BALB C, Perforin, Placenta cytology, Placenta metabolism, Pore Forming Cytotoxic Proteins, Reverse Transcriptase Polymerase Chain Reaction, Serine Endopeptidases genetics, Serpins genetics, Serpins immunology, Sertoli Cells immunology, Testis cytology, Testis metabolism, Testis pathology, Tissue Distribution, Trophoblasts immunology, Membrane Glycoproteins metabolism, Reproduction physiology, Serine Endopeptidases metabolism, Serpins metabolism, Sertoli Cells metabolism, Trophoblasts metabolism
- Abstract
Granzyme B (graB) plays a pivotal role in cytotoxic lymphocyte granule-mediated apoptosis through cleavage of intracellular proteins in target cells. Proteinase inhibitor-9 (PI-9) is a potent inhibitor of graB and is highly expressed in cytotoxic lymphocytes. Here, we show by immunohistochemistry that PI-9 is also abundantly expressed in human testicular Sertoli cells and placental syncytial trophoblasts. Postulating that PI-9 protects these tissues from graB-producing auto- or allo-reactive cytotoxic lymphocytes, we also stained sections for graB. Unexpectedly, graB was observed in non-cytotoxic cells in both tissues. In the adult human testis, graB was present in spermatogenic cells within the seminiferous tubule, and this was verified by in-situ hybridization and reverse transcription-polymerase chain reaction (RT-PCR). Immunohistochemical analysis of term placentae demonstrated graB in syncytial trophoblasts, and this was confirmed by RT-PCR on primary trophoblasts from term placenta. Perforin, which is co-produced with graB by activated cytotoxic lymphocytes and is required for graB release into the target cell, was not detected in either testis or placenta. We postulate that, in these organs, graB has a perforin-independent role, involving hydrolysis of extracellular matrix components. In the testis, graB may facilitate migration of developing germ cells, while in the placenta, it may contribute to extracellular matrix remodelling during parturition.
- Published
- 2001
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40. A comparison of the clinical, histopathologic, and ultrastructural phenotypes in carriers of X-linked and autosomal recessive Alport's syndrome.
- Author
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Dagher H, Buzza M, Colville D, Jones C, Powell H, Fassett R, Wilson D, Agar J, and Savige J
- Subjects
- Adolescent, Adult, Age Distribution, Aged, Aged, 80 and over, Biopsy, Child, Comorbidity, Eye Abnormalities epidemiology, Female, Genetic Linkage, Hearing Loss epidemiology, Humans, Kidney pathology, Kidney Glomerulus ultrastructure, Kidney Tubules ultrastructure, Male, Middle Aged, Nephritis, Hereditary epidemiology, Phenotype, Sex Distribution, Genetic Carrier Screening, Nephritis, Hereditary diagnosis, Nephritis, Hereditary genetics
- Abstract
Previous series that described phenotypes in carriers of Alport's syndrome did not distinguish genetically between carriers of X-linked and autosomal recessive disease. In this study, modes of inheritance in unselected families with Alport's syndrome associated with two city and two provincial hospitals were determined using microsatellite markers, and carriers of disease haplotypes were identified within these families. All 47 carriers (100%) from 18 families with X-linked Alport's syndrome had dysmorphic hematuria on phase-contrast microscopy, but few developed renal failure (3 of 40 carriers; 8%), clinical hearing loss (2 of 45 carriers; 4%), retinopathy (1 of 30 carriers; 3%), or lenticonus (0 of 30 carriers; 0%). Eleven of the 14 carriers (79%) from 2 families with autosomal recessive disease had dysmorphic hematuria, but none had renal failure, clinical hearing loss, retinopathy, or lenticonus. Urinary red blood cell counts in carriers of X-linked Alport's syndrome were greater than those in carriers of autosomal recessive disease (P < 0.0001), but the frequency of proteinuria and hypertension and levels of proteinuria were not different. There was more tubulointerstitial damage in carriers of X-linked disease (P = 0.012); however, carriers of autosomal recessive disease had more widespread and more uniform thinning of the glomerular basement membrane (P < 0.0001) and less lamellation (P < 0.04).
- Published
- 2001
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41. COL4A4 mutation in thin basement membrane disease previously described in Alport syndrome.
- Author
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Buzza M, Wang YY, Dagher H, Babon JJ, Cotton RG, Powell H, Dowling J, and Savige J
- Subjects
- Basement Membrane pathology, DNA Mutational Analysis, Family Health, Female, Genes, Recessive, Hematuria genetics, Hematuria pathology, Humans, Male, Middle Aged, Pedigree, Collagen genetics, Kidney pathology, Nephritis, Hereditary genetics, Nephritis, Hereditary pathology, Point Mutation
- Abstract
Background: Carriers of autosomal-recessive and X-linked Alport syndrome often have a thinned glomerular basement membrane (GBM) and have mutations in the COL4A3/COL4A4 and COL4A5 genes respectively. Recently, we have shown that many individuals with thin basement membrane disease (TBMD) are also from families where hematuria segregates with the COL4A3/COL4A4 locus. This study describes the first COL4A4 mutation in an individual with biopsy-proven TBMD who did not have a family member with autosomal-recessive or X-linked Alport syndrome, inherited renal failure, or deafness., Methods: The index case and all available family members were examined for dysmorphic hematuria> 50,000/mL using phase contrast microscopy and for segregation of hematuria with the COL4A3/COL4A4 and COL4A5 loci using DNA satellite markers. COL4A4 exons from the index case were then studied using the enzyme mismatch cleavage method, and exons that demonstrated abnormal cleavage products were sequenced., Results: Hematuria in this family segregated with a haplotype at the COL4A3/COL4A4 locus (P = 0.031) but not with haplotypes at the COL4A5 locus. A mutation in COL4A4 that changed C to T resulting in an arginine residue being replaced by a stop codon (R1377X) was demonstrated in exon 44, which encodes part of the alpha 4(IV) collagen sequence close to the junction with the noncollagenous domain. This mutation was present in all five family members with hematuria, but not in the four unaffected family members, 33 unrelated individuals with TBMD, or 22 nonhematuric normals., Conclusions: R1377X has been described previously in a compound heterozygous form of autosomal-recessive Alport syndrome. Our observation is evidence that TBMD can represent a carrier state for autosomal-recessive Alport syndrome in at least some individuals.
- Published
- 2001
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42. Nucleocytoplasmic distribution of the ovalbumin serpin PI-9 requires a nonconventional nuclear import pathway and the export factor Crm1.
- Author
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Bird CH, Blink EJ, Hirst CE, Buzza MS, Steele PM, Sun J, Jans DA, and Bird PI
- Subjects
- Amino Acid Sequence, Biological Transport, Cell Nucleus metabolism, Cells, Cultured, Humans, Molecular Sequence Data, Nuclear Proteins metabolism, Plasmids, Exportin 1 Protein, Carrier Proteins metabolism, Karyopherins, Receptors, Cytoplasmic and Nuclear, Serpins metabolism, T-Lymphocytes, Cytotoxic metabolism
- Abstract
Proteinase inhibitor 9 (PI-9) is a human serpin present in the cytoplasm of cytotoxic lymphocytes and epithelial cells. It inhibits the cytotoxic lymphocyte granule proteinase granzyme B (graB) and is thought to protect cytotoxic lymphocytes and bystander cells from graB-mediated apoptosis. Following uptake into cells, graB promotes DNA degradation, rapidly translocating to the nucleus, where it binds a nuclear component. PI-9 should therefore be found in cytotoxic lymphocyte and bystander cell nuclei to ensure complete protection against graB. Here we demonstrate by microscopy and subcellular fractionation experiments that PI-9 is present in the nuclei of human cytotoxic cells, endothelial cells, and epithelial cells. We also show that the related serpins, PI-6, monocyte neutrophil elastase inhibitor (MNEI), PI-8, plasminogen activator inhibitor 2 (PAI-2), and the viral serpin CrmA exhibit similar nucleocytoplasmic distributions. Because these serpins lack classical nuclear localization signals and are small enough to diffuse through nuclear pores, we investigated whether import occurs actively or passively. Large (approximately 70 kDa) chimeric proteins comprising PI-9, PI-6, PI-8, MNEI, or PAI-2 fused to green fluorescent protein (GFP) show similar nucleocytoplasmic distributions to the parent proteins, indicating that nuclear import is active. By contrast, CrmA-GFP is excluded from nuclei, indicating that CrmA is not actively imported. In vitro nuclear transport assays show that PI-9 accumulates at a rate above that of passive diffusion, that it requires cytosolic factors but not ATP, and that it does not bind an intranuclear component. Furthermore, PI-9 is exported from nuclei via a leptomycin B-sensitive pathway, implying involvement of the export factor Crm1p. We conclude that the nucleocytoplasmic distribution of PI-9 and related serpins involves a nonconventional nuclear import pathway and Crm1p.
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- 2001
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43. The granzyme B inhibitor, PI-9, is present in endothelial and mesothelial cells, suggesting that it protects bystander cells during immune responses.
- Author
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Buzza MS, Hirst CE, Bird CH, Hosking P, McKendrick J, and Bird PI
- Subjects
- Ascitic Fluid metabolism, Cell Line, Cell Line, Transformed, Cells, Cultured, Endothelium cytology, Endothelium drug effects, Epithelial Cells cytology, Epithelial Cells drug effects, Granzymes, Humans, Immunohistochemistry, Inflammation metabolism, RNA, Messenger biosynthesis, Serine Proteinase Inhibitors genetics, Serine Proteinase Inhibitors immunology, Serpins genetics, Serpins immunology, Tetradecanoylphorbol Acetate pharmacology, Up-Regulation, Endothelium immunology, Epithelium immunology, Serine Endopeptidases metabolism, Serine Proteinase Inhibitors biosynthesis, Serpins biosynthesis
- Abstract
Proteinase inhibitor 9 (PI-9) is a 42-kDa human intracellular serpin present in cytotoxic lymphocytes (CLs). PI-9 is an extremely efficient inhibitor of the pro-apoptotic CL granule proteinase granzyme B and is thought to function in the cytosol of CLs to protect against apoptosis induced by endogenously expressed or released granzyme B, particularly during target cell killing. Here we show by immunohistochemistry that PI-9 is also present in endothelial cells, in every tissue examined. Cultured endothelial cells express functional PI-9 (as assessed by binding to recombinant granzyme B) localized to the cytoplasm and nucleus. Immunohistochemistry also showed PI-9 in mesothelial cells, and this was confirmed by analysis of primary cells cultured from pleural and serous effusions. Granzyme B expression was not detected in either endothelial or mesothelial cells. In both cell types, PI-9 is up-regulated at the mRNA and protein level by exposure to the phorbol ester PMA, consistent with a response to inflammatory stimuli. We postulate that PI-9 is present in these lining cell types to protect against misdirected, free granzyme B released during a local immune response., (Copyright 2001 Academic Press.)
- Published
- 2001
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44. Segregation of hematuria in thin basement membrane disease with haplotypes at the loci for Alport syndrome.
- Author
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Buzza M, Wilson D, and Savige J
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Child, Collagen genetics, Female, Genes, Recessive, Genetic Linkage, Haplotypes, Hematuria pathology, Humans, Male, Middle Aged, Pedigree, X Chromosome, Basement Membrane pathology, Hematuria genetics, Nephritis, Hereditary genetics
- Abstract
Background: Inherited hematuria is common and is usually attributed to thin basement membrane disease (TBMD). The aim of this study was to determine how often hematuria in families with TBMD segregated with haplotypes at the chromosomal loci for autosomal recessive and X-linked Alport syndrome (COL4A3/COL4A4 and COL4A5, respectively)., Methods: The families of 22 individuals with TBMD on renal biopsy and with urinary glomerular red blood cell (RBC) counts of more than 50,000/mL were studied using phase-contrast microscopy of the urine and DNA microsatellite markers. Eighteen families had at least two members with hematuria., Results: Hematuria segregated with or was consistent with segregation at the COL4A3/COL4A4 locus in eight (36%) families (P < 0.05 in 5 of these) and at the COL4A5 locus in four (18%) families (P < 0.05 in 2). The lack of segregation in the other 10 (45%) families may have occurred because of incomplete penetrance of the hematuria, de novo mutations, coincidental hematuria in other family members, or the presence of a novel gene locus. In four different families, three of which had hematuria that segregated with the COL4A3/COL4A4 locus, four family members with the hematuria haplotype had spouses with coincidental hematuria (4 of 29, 14%). However, none of their four offspring who had also inherited the hematuria haplotype had the clinical features of autosomal recessive Alport syndrome., Conclusions: Hematuria in families with TBMD commonly segregates with the COL4A3/COL4A4 locus and thus results from mutations in the same genes as autosomal recessive Alport syndrome. Sometimes TBMD may be confused with the carrier state for X-linked Alport syndrome. However, nearly half of the families in this study had hematuria that did not segregate with the loci for either autosomal recessive or X-linked Alport syndrome.
- Published
- 2001
- Full Text
- View/download PDF
45. Haematuria in asymptomatic individuals.
- Author
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Savige J, Buzza M, and Dagher H
- Subjects
- Basement Membrane abnormalities, Glomerulonephritis genetics, Hematuria genetics, Humans, Glomerulonephritis complications, Hematuria etiology, Kidney Glomerulus abnormalities
- Published
- 2001
- Full Text
- View/download PDF
46. Expression and purification of recombinant human granzyme B from Pichia pastoris.
- Author
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Sun J, Bird CH, Buzza MS, McKee KE, Whisstock JC, and Bird PI
- Subjects
- Amino Acid Sequence, Apoptosis drug effects, Base Sequence, Cell Line, Chromatography, Affinity, Cloning, Molecular, DNA Primers genetics, Gene Expression, Granzymes, Humans, Kinetics, Molecular Sequence Data, Recombinant Proteins genetics, Recombinant Proteins isolation & purification, Recombinant Proteins metabolism, Serine Endopeptidases metabolism, Pichia genetics, Serine Endopeptidases genetics, Serine Endopeptidases isolation & purification
- Abstract
Granzyme B is a cytotoxic lymphocyte granule serine proteinase that is pivotal in the induction of target cell apoptosis. Here we describe the expression of recombinant human granzyme B in Pichia pastoris as a chimeric zymogen comprising the alpha-factor signal sequence, a prodomain including an enterokinase cleavage site, and the mature granzyme B sequence followed by a hexahistidine tag. Inactive zymogen is purified from the medium by immobilized cobalt chelate affinity chromatography and then activated by enterokinase (final yield is approximately 1 mg per liter). The recombinant enzyme resembles native granzyme B in size and glycosylation, hydrolyzes the substrate Boc-Ala-Ala-Asp-thiobenzyl ester with equivalent efficiency (K(m) 82 microM; k(cat) 12 s(-1)), processes procaspase-3 to subunit form, and is inhibited by the cognate serpin PI-9. It efficiently induces DNA degradation and apoptosis of human cells. The availability of recombinant human granzyme B will facilitate further investigation of its structure and role in immune effector cells., (Copyright 1999 Academic Press.)
- Published
- 1999
- Full Text
- View/download PDF
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