Design, synthesis and biological evaluation of retinoid and non-retinoid mimetics of fenretinide as chemotherapeutic agents

Fenretinide is a potent chemotherapeutic and chemopreventive against a range of cancer tumour cell lines, namely Ewing’s Sarcoma Family of Tumours (ESFT) which is an aggressive malignant tumour primarily affecting children and young adults. The mechanism of action of the drug is not known. The major disadvantage to fenretinide as a treatment for cancer is its poor in vivo efficacy due to poor oral bioavailability, requiring the patient to take many tablets per day regularly in order to achieve an adequate plasma concentration. By use of computational drug design and medicinal chemistry-led design, we have identified both novel retinoid and non-retinoid mimetics of fenretinide, which demonstrate comparable in vitro activity to fenretinide against ESFT cell types. This research has investigated the molecular features of fenretinide which contribute to its inhibition of cell growth in order to establish structure-activity relationships (SAR). We have also investigated the mechanism of cell death for a number of compounds and have identified molecules which appear to induce cell death via a similar mechanism to fenretinide as well as those which function via an alternative mechanism. Additional studies aimed at understanding the mechanism of action of fenretinide through affinity chromatography studies, have implicated several proteins as potential binding partners for further investigation. The outcomes of the current project may aid the design of future retinoid or non-retinoid analogues of fenretinide with improved efficacy, whilst retaining the minimal toxicity profile of fenretinide as well as to better understand the mechanism of the chemotherapeutic induction of the cell death process in ESFT cells

A New Clamp for End-To-End Intestinal Anastomosis

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Statistical Uncertainties in Temperature Diagnostics for Hot Coronal Plasma Using the ASCA SIS

Statistical uncertainties in determining the temperatures of hot (0.5 keV to 10 keV) coronal plasmas are investigated. The statistical precision of various spectral temperature diagnostics is established by analyzing synthetic ASCA Solid-state Imaging Spectrometer (SIS) CCD spectra. The diagnostics considered are the ratio of hydrogen-like to helium-like line complexes of $Z\ge14$ elements, line-free portions of the continuum, and the entire spectrum. While fits to the entire spectrum yield the highest statistical precision, it is argued that fits to the line-free continuum are less susceptible to atomic data uncertainties but lead to a modest increase in statistical uncertainty over full spectral fits. Temperatures deduced from line ratios can have similar accuracy but only over a narrow range of temperatures. Convenient estimates of statistical accuracies for the various temperature diagnostics are provided which may be used in planning ASCA SIS observations.Comment: postscript file of 8 pages+3 figures; 4 files tarred, compressed and uuencoded. To appear in the Astrophysical Journal Letters; contents copyright 1994 American Astronomical Societ

A Novel Longitudinal Mode in the Coupled Quantum Chain Compound KCuF3

Inelastic neutron scattering measurements are reported that show a new longitudinal mode in the antiferromagnetically ordered phase of the spin-1/2 quasi-one-dimensional antiferromagnet KCuF3. This mode signals the cross-over from one-dimensional to three-dimensional behavior and indicates a reduction in the ordered spin moment of a spin-1/2 antiferromagnet. The measurements are compared with recent quantum field theory results and are found to be in excellent agreement. A feature of the data not predicted by theory is a damping of the mode by decay processes to the transverse spin-wave branches.Comment: 9 pages of text plus 4 postscript figures (1 color

Scattering and Iron Fluorescence Revealed During Absorption Dips in Circinus X-1

We show that dramatic spectral evolution associated with dips occurring near phase zero in RXTE observations of Cir X-1 is well-fit by variable and at times heavy absorption (N_H > 10^24 cm^-2) of a bright component, plus an underlying faint component which is not attenuated by the variable column and whose flux is ~10% of that of the unabsorbed bright component. A prominent Fe emission line at ~6.5 keV is evident during the dips. The absolute line flux outside the dips is similar to that during the dips, indicating that the line is associated with the faint component. These results are consistent with a model in which the bright component is radiation received directly from a compact source while the faint component may be attributed to scattered radiation. Our results are also generally consistent with those of Brandt et al., who found that a partial- covering model could explain ASCA spectra of a low-to-high transition in Cir X-1. The relative brightness of the two components in our model requires a column density of ~2*10^23 cm^-2 if the faint component is due to Thomson scattering in material that mostly surrounds the source. We find that illumination of such a scattering cloud by the observed direct component would produce an Fe K-alpha fluorescence flux that is in rough agreement with the flux of the observed emission line. We also conclude that if the scattering medium is not highly ionized, our line of sight to the compact source does not pass through it. Finally, we discuss simple pictures of the absorbers responsible for the dips themselves.Comment: Accepted for publication in The Astrophysical Journal (23 pages, including 11 figures

LWIR HgCdTe: Innovative detectors in an incumbent technology

HgCdTe is the current material of choice for high performance imagers operating at relatively high temperatures. Its lack of technological maturity compared with silicon and wide-band gap III-V compounds is more than offset by its outstanding IR sensitivity and by the relatively benign effect of its materials defects. This latter property has allowed non-equilibrium growth techniques, metal oxide chemical vapor deposition (MOCVD) and molecular beam epitaxy (MBE), to produce device quality long wavelength infrared (LWIR) HgCdTe even on common substrates like GaAs and GaAs/Si. Detector performance in these exotic materials structures is comparable in many ways with devices in equilibrium-grown material. Lifetimes are similar. RoA values at 77K as high as several hundred have been seen in HgCdTe/GaAs/Si with 9.5 micron cut-off wavelength. HgCdTe/GaAs layers with approx. 15 micron cut-off wavelengths have given average 77K RoAs of greater than 2. Hybrid focal plane arrays have been evaluated with excellent operability

Internal construct validity of the Warwick-Edinburgh Mental Well-being Scale (WEMWBS): a Rasch analysis using data from the Scottish Health Education Population Survey

Background: The Warwick-Edinburgh Mental Well-Being Scale (WEMWBS) was developed to meet demand for instruments to measure mental well-being. It comprises 14 positively phrased Likert-style items and fulfils classic criteria for scale development. We report here the internal construct validity of WEMWBS from the perspective of the Rasch measurement model. Methods: The model was applied to data collected from 779 respondents in Wave 12 (Autumn 2006) of the Scottish Health Education Population Survey. Respondents were aged 16–74 (average 41.9) yrs. Results: Initial fit to model expectations was poor. The items 'I've been feeling good about myself', 'I've been interested in new things' and 'I've been feeling cheerful' all showed significant misfit to model expectations, and were deleted. This led to a marginal improvement in fit to the model. After further analysis, more items were deleted and a strict unidimensional seven item scale (the Short Warwick Edinburgh Mental Well-Being Scale (SWEMWBS)) was resolved. Many items deleted because of misfit with model expectations showed considerable bias for gender. Two retained items also demonstrated bias for gender but, at the scale level, cancelled out. One further retained item 'I've been feeling optimistic about the future' showed bias for age. The correlation between the 14 item and 7 item versions was 0.954. Given fit to the Rasch model, and strict unidimensionality, SWEMWBS provides an interval scale estimate of mental well-being. Conclusion: A short 7 item version of WEMWBS was found to satisfy the strict unidimensionality expectations of the Rasch model, and be largely free of bias. This scale, SWEMWBS, provides a raw score-interval scale transformation for use in parametric procedures. In terms of face validity, SWEMWBS presents a more restricted view of mental well-being than the 14 item WEMWBS, with most items representing aspects of psychological and eudemonic well-being, and few covering hedonic well-being or affect. However, robust measurement properties combined with brevity make SWEMWBS preferable to WEMWBS at present for monitoring mental well-being in populations. Where face validity is an issue there remain arguments for continuing to collect data on the full 14 item WEMWBS

Rapid X-ray variability in the Seyfert galaxy NGC 6814

The HEAO-1 A-2 high time resolution X-ray observations of the X-ray emitting Seyfert I Galaxy NGC 6814 are reported. In sharp distinction with a sample of over 30 active galactic nuclei this object showed strong X-ray variability on timescales less than 3 hours. The mean flux on a timescale of 90 minutes varied by a factor of approximately 2.5 corresponding to Delta L sub x being approximately 1 x 10 to the 43rd power ergs/sec. An autocorrelation analysis shows a characteristic time for variability of 100 (+60 or -25) seconds. There is no indication of spectral variability with an upper limit on a change in the power law spectral index of the absolute value of Delta gamma .37, for a factor two change in intensity. The constraints of such rapid variability on a wide variety of X-ray source mechanisms are considered