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991.
Tao Chen Fiona K. Middleton Susanna Falcon Philip M. Reaper John R. Pollard Nicola J. Curtin 《Molecular oncology》2015,9(2):463-472
Background
ATR, which signals DNA damage to S/G2 cell cycle checkpoints and for repair, is an attractive target in cancer therapy. ATR inhibitors are being developed and a pharmacodynamic assay is needed to support clinical studies.Methods
Phosphorylation of ATR targets, Chk1 and H2AX, was evaluated in MCF7 and K562 cells, human volunteer PBMCs and whole blood by Western blot, immunofluorescence microscopy and flow cytometry after DNA damage. The effect of cell cycle phase, ATR knockdown and inhibition on these phosphorylation events was determined.Results
Hydroxyurea, UV and 4NQO induced Chk1 and H2AX phosphorylation in MCF7 and K562 cells. UV/4NQO activation of ATR was detectable in non‐cycling cells. Chk1 phosphorylation was reduced by ATR knockdown and reflects ATR activity for 3 h, H2AX phosphorylation after UV/4NQO is ATR‐dependent for 1 h but increasingly ATM and DNA‐PK‐dependent at later time points. In isolated PBMCs both phospho‐targets were detectable after UV/4NQO but in PBMCs from whole blood treated with 4NQO only H2AX was detectable.Conclusion
PhosphoChk1 and H2AX are useful biomarkers for ATR inhibition using a variety of immuno‐detection methods, but timing may be critical. Importantly, ATR activity is detectable in non‐cycling PBMCs allowing them to be used as a surrogate tissue for biomarker measurement. In PBMCs from whole blood treated with 4NQO phosphoH2AX was the most useful biomarker of ATR activity and a clinically viable pharmacodynamic assay for ATR inhibitors has been developed. 相似文献992.
Duncan S. Buchan Fiona McSeveney Gillian McLellan 《Clinical physiology and functional imaging》2019,39(1):51-56
The purpose of this study was to evaluate the agreement between several activity measures using raw acceleration data from accelerometers worn concurrently on the dominant and non‐dominant wrist. Fifty‐five adults (31·9 ± 9·7 years, 26 males) wore two ActiGraph GT3X+ monitors continuously for 1 day, one on their non‐dominant wrist and the other on their dominant wrist. Paired t‐tests were undertaken with sequential Holm‐Bonferroni corrections to compare wear time, moderate‐vigorous physical activity (MVPA), time spent in 10‐min bouts of MVPA (MVPA10 min) and the average magnitude of dynamic wrist acceleration (ENMO). Level of agreement between outcome variables from the wrists was examined using intraclass correlation coefficients (ICC, single measures, absolute agreement) with 95% confidence intervals and limits of agreement (LoA). Time spent across acceleration levels in 40 mg resolution were also examined. There were no significant differences between the non‐dominant and dominant wrist for ENMO, wear time, MVPA or MVPA10 min. Agreement between wrists was strong for most outcomes (ICC ≥0·92) including wear time, ENMO, MVPA, MVPA10 min and the distribution of time across acceleration levels. Agreement was strong in the low acceleration bands (ICC = 0·970 and 0·922) with a mean bias of 3·08 min (LoA ?55·18 to 61·34) and ?5·43 (LoA ?43·47 to 32·62). In summary, ENMO, MVPA, MVPA10 min, wear time and the distribution of time across acceleration levels compared well at the group level. The LOA from the two lowest acceleration levels suggest further work over a longer monitoring period is needed to determine whether outputs from each wrist are comparable. 相似文献
993.
Dominik F. Draxler Maria Daglas Anushka Fernando Gryselda Hanafi Fiona McCutcheon Heidi Ho Adam Galle Julia Gregory Pia Larsson Charithani Keragala David K. Wright Elnaz Tavancheh Amanda E. Au Be'eri Niego Kirsty Wilson Magdalena Plebanski Maithili Sashindranath Robert L. Medcalf 《Journal of thrombosis and haemostasis》2019,17(12):2174-2187
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995.
Gbolahan Somoye Vanessa Harry Scott Semple George Plataniotis Neil Scott Fiona J. Gilbert David Parkin 《European radiology》2012,22(11):2319-2327
Objectives
To assess the predictive value of diffusion weighted imaging (DWI) for survival in women treated for advanced cancer of the cervix with concurrent chemo-radiotherapy.Methods
Twenty women treated for advanced cancer of the cervix were recruited and followed up for a median of 26 (range <1 to 43) months. They each had DWI performed before treatment, 2?weeks after beginning therapy (midtreatment) and at the end of treatment. Apparent diffusion coefficient (ADC) values were calculated from regions of interest (ROI). All participants were reviewed for follow-up data. ADC values were compared with mortality status (Mann–Whitney test). Time to progression and overall survival were assessed (Kaplan–Meier survival graphs).Results
There were 14 survivors. The median midtreatment ADC was statistically significantly higher in those alive compared to the non-survivors, 1.55 and 1.36 (×10?3/mm2/s), respectively, P?=?0.02. The median change in ADC 14?days after treatment commencement was significantly higher in the alive group compared to non-survivors, 0.28 and 0.14 (×10?3/mm2/s), respectively, P?=?0.02. There was no evidence of a difference between survivors and non-survivors for pretreatment baseline or post-therapy ADC values.Conclusion
Functional DWI early in the treatment of advanced cancer of the cervix may provide useful information in predicting survival.Key Points
? Diffusion weighted magnetic resonance imaging (DWI) is increasingly used in cervical cancer. ? Functional DWI early in treatment of cervical cancer may help predict survival. ? DWI may help clinicians to tailor or individualise treatment appropriately. ? This may limit toxicity from ineffective treatment and allow early alternative therapy. 相似文献996.
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