Evaluation of poly (ADP-ribose) polymerase inhibitor ABT-888 combined with radiotherapy and temozolomide in glioblastoma.

BACKGROUND: The cytotoxicity of radiotherapy and chemotherapy can be enhanced by modulating DNA repair. PARP is a family of enzymes required for an efficient base-excision repair of DNA single-strand breaks and inhibition of PARP can prevent the repair of these lesions. The current study investigates the trimodal combination of ABT-888, a potent inhibitor of PARP1-2, ionizing radiation and temozolomide(TMZ)-based chemotherapy in glioblastoma (GBM) cells. METHODS: Four human GBM cell lines were treated for 5 h with 5 μM ABT-888 before being exposed to X-rays concurrently with TMZ at doses of 5 or 10 μM for 2 h. ABT-888's PARP inhibition was measured using immunodetection of poly(ADP-ribose) (pADPr). Cell survival and the different cell death pathways were examined via clonogenic assay and morphological characterization of the cell and cell nucleus. RESULTS: Combining ABT-888 with radiation yielded enhanced cell killing in all four cell lines, as demonstrated by a sensitizer enhancement ratio at 50% survival (SER50) ranging between 1.12 and 1.37. Radio- and chemo-sensitization was further enhanced when ABT-888 was combined with both X-rays and TMZ in the O6-methylguanine-DNA-methyltransferase (MGMT)-methylated cell lines with a SER50 up to 1.44. This effect was also measured in one of the MGMT-unmethylated cell lines with a SER50 value of 1.30. Apoptosis induction by ABT-888, TMZ and X-rays was also considered and the effect of ABT-888 on the number of apoptotic cells was noticeable at later time points. In addition, this work showed that ABT-888 mediated sensitization is replication dependent, thus demonstrating that this effect might be more pronounced in tumour cells in which endogenous replication lesions are present in a larger proportion than in normal cells. CONCLUSIONS: This study suggests that ABT-888 has the clinical potential to enhance the current standard treatment for GBM, in combination with conventional chemo-radiotherapy. Interestingly, our results suggest that the use of PARP inhibitors might be clinically significant in those patients whose tumour is MGMT-unmethylated and currently derive less benefit from TMZ.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Pharmacological assessment of ibuprofen arginate on platelet aggregation and colon cancer cell killing

This work was funded in part by grants from the Wellcome Trust (0852551Z108/Z, to J.A.M.) and British Heart Foundation (FS/16/1/31699, to NSK). SM is a recipient of a PhD award from the King of Saud University, AT is a recipient of a MRC PhD studentship

Using e-mail recruitment and an online questionnaire to establish effect size: A worked example

Background\ud Sample size calculations require effect size estimations. Sometimes, effect size estimations and standard deviation may not be readily available, particularly if efficacy is unknown because the intervention is new or developing, or the trial targets a new population. In such cases, one way to estimate the effect size is to gather expert opinion. This paper reports the use of a simple strategy to gather expert opinion to estimate a suitable effect size to use in a sample size calculation.\ud \ud Methods\ud Researchers involved in the design and analysis of clinical trials were identified at the University of Birmingham and via the MRC Hubs for Trials Methodology Research. An email invited them to participate.\ud \ud An online questionnaire was developed using the free online tool 'Survey Monkey©'. The questionnaire described an intervention, an electronic participant information sheet (e-PIS), which may increase recruitment rates to a trial. Respondents were asked how much they would need to see recruitment rates increased by, based on 90%. 70%, 50% and 30% baseline rates, (in a hypothetical study) before they would consider using an e-PIS in their research.\ud \ud Analyses comprised simple descriptive statistics.\ud \ud Results\ud The invitation to participate was sent to 122 people; 7 responded to say they were not involved in trial design and could not complete the questionnaire, 64 attempted it, 26 failed to complete it. Thirty-eight people completed the questionnaire and were included in the analysis (response rate 33%; 38/115). Of those who completed the questionnaire 44.7% (17/38) were at the academic grade of research fellow 26.3% (10/38) senior research fellow, and 28.9% (11/38) professor. Dependent upon the baseline recruitment rates presented in the questionnaire, participants wanted recruitment rate to increase from 6.9% to 28.9% before they would consider using the intervention.\ud \ud Conclusions\ud This paper has shown that in situations where effect size estimations cannot be collected from previous research, opinions from researchers and trialists can be quickly and easily collected by conducting a simple study using email recruitment and an online questionnaire. The results collected from the survey were successfully used in sample size calculations for a PhD research study protocol.\ud \u

Broadband distortion modeling in Lyman-α\alpha forest BAO fitting

In recent years, the Lyman-$\alpha$ absorption observed in the spectra of high-redshift quasars has been used as a tracer of large-scale structure by means of the three-dimensional Lyman-$\alpha$ forest auto-correlation function at redshift $z\simeq 2.3$, but the need to fit the quasar continuum in every absorption spectrum introduces a broadband distortion that is difficult to correct and causes a systematic error for measuring any broadband properties. We describe a $k$-space model for this broadband distortion based on a multiplicative correction to the power spectrum of the transmitted flux fraction that suppresses power on scales corresponding to the typical length of a Lyman-$\alpha$ forest spectrum. Implementing the distortion model in fits for the baryon acoustic oscillation (BAO) peak position in the Lyman-$\alpha$ forest auto-correlation, we find that the fitting method recovers the input values of the linear bias parameter $b_{F}$ and the redshift-space distortion parameter $\beta_{F}$ for mock data sets with a systematic error of less than 0.5\%. Applied to the auto-correlation measured for BOSS Data Release 11, our method improves on the previous treatment of broadband distortions in BAO fitting by providing a better fit to the data using fewer parameters and reducing the statistical errors on $\beta_{F}$ and the combination $b_{F}(1+\beta_{F})$ by more than a factor of seven. The measured values at redshift $z=2.3$ are $\beta_{F}=1.39^{+0.11\ +0.24\ +0.38}_{-0.10\ -0.19\ -0.28}$and$b_{F}(1+\beta_{F})=-0.374^{+0.007\ +0.013\ +0.020}_{-0.007\ -0.014\ -0.022}$(1$\sigma$, 2$\sigma$and 3$\sigma$ statistical errors). Our fitting software and the input files needed to reproduce our main results are publicly available.Comment: 28 pages, 15 figures, matches the published versio

Interpreting short and medium exposure etched-track radon measurements to determine whether an action level could be exceeded

Radon gas is naturally occurring, and can concentrate in the built environment. It is radioactive and high concentration levels within buildings, including homes, have been shown to increase the risk of lung cancer in the occupants. As a result, several methods have been developed to measure radon. The long-term average radon level determines the risk to occupants, but there is always pressure to complete measurements more quickly, particularly when buying and selling the home. For many years, the three-month exposure using etched-track detectors has been the de facto standard, but a decade ago, Phillips et al. (2003), in a DEFRA funded project, evaluated the use of 1-week and 1-month measurements. They found that the measurement methods were accurate, but the challenge lay in the wide variation in radon levels - with diurnal, seasonal, and other patterns due to climatic factors and room use. In the report on this work, and in subsequent papers, the group proposed methodologies for 1-week, 1-month and 3-month measurements and their interpretation. Other work, however, has suggested that 2-week exposures were preferable to 1-week ones. In practice, the radon remediation industry uses a range of exposure times, and further guidance is required to help interpret these results. This paper reviews the data from this study and a subsequent 4-year study of 4 houses, re-analysing the results and extending them to other exposures, particularly for 2-week and 2-month exposures, and provides comprehensive guidance for the use of etched-track detectors, the value and use of Seasonal Correction Factors (SCFs), the uncertainties in short and medium term exposures and the interpretation of results

Measurement of the Fermi Constant by FAST

An initial measurement of the lifetime of the positive muon to a precision of 16 parts per million (ppm) has been performed with the FAST detector at the Paul Scherrer Institute. The result is tau_mu = 2.197083 (32) (15) microsec, where the first error is statistical and the second is systematic. The muon lifetime determines the Fermi constant, G_F = 1.166353 (9) x 10^-5 GeV^-2 (8 ppm).Comment: 15 pages, 6 figure

Dynamic wavefront shaping with an acousto-optic lens for laser scanning microscopy

Acousto-optic deflectors (AODs) arranged in series and driven with linearly chirped frequencies can rapidly focus and tilt optical wavefronts, enabling high-speed 3D random access microscopy. Non-linearly chirped acoustic drive frequencies can also be used to shape the optical wavefront allowing a range of higher-order aberrations to be generated. However, to date, wavefront shaping with AODs has been achieved by using single laser pulses for strobed illumination to 'freeze' the moving acoustic wavefront, limiting voxel acquisition rates. Here we show that dynamic wavefront shaping can be achieved by applying non-linear drive frequencies to a pair of AODs with counter-propagating acoustic waves, which comprise a cylindrical acousto-optic lens (AOL). Using a cylindrical AOL we demonstrate high-speed continuous axial line scanning and the first experimental AOL-based correction of a cylindrical lens aberration at 30 kHz, accurate to 1/35th of a wave at 800 nm. Furthermore, we develop a model to show how spherical aberration, which is the major aberration in AOL-based remote-focusing systems, can be partially or fully corrected with AOLs consisting of four or six AODs, respectively

Hadronic Transitions among Quarkonium States in a Soft-Exchange-Approximation. Chiral Breaking and Spin Symmetry Breaking Processes

Although no asymptotic heavy quark spin symmetry, and even more no flavor symmetry, are expected for systems such as quarkonium, a numerical discussion shows that for some processes and in a preasymptotic region which may roughly include charmonium and bottomonium, the use of the spin-symmetry may be useful in conjunction with chiral symmetry for light hadrons (soft-exchange- approximation regime, SEA). We continue our discussion of hadronic transitions in the SEA-regime by studying in particular chiral breaking transitions such as $~^3P' \to ~^3P\pi^0$, $~^3P\eta$, level splittings and transitions which break both chiral and spin symmetry, such as $\psi ' \to J/\psi \pi^0$, $J/\psi \eta$, and $~^1P_1 \to J/\psi \pi^0$.Comment: LaTeX (style article) 19 pages, UGVA-DPT 12-80

Impact of D0-D0bar mixing on the experimental determination of gamma

Several methods have been devised to measure the weak phase gamma using decays of the type B+- --> D K+-, where it is assumed that there is no mixing in the D0-D0bar system. However, when using these methods to uncover new physics, one must entertain the real possibility that the measurements are affected by new physics effects in the D0-D0bar system. We show that even values of x_D and/or y_D around 10^{-2} can have a significant impact in the measurement of sin^2{gamma}. We discuss the errors incurred in neglecting this effect, how the effect can be checked, and how to include it in the analysis.Comment: 18 pages, Latex with epsfig, 8 figure