In vitro antitumour activity of the novel imidazoisoquinoline SDZ 62-434.

The novel imidazoisoquinoline SDZ 62-434, originally identified as a platelet-activating factor (PAF) antagonist, has antiproliferative activity in a range of cell lines from human solid and haematological malignancies. Using an MTT cytotoxicity assay, IC50 values of 5 microM - 111 microM were observed following a 24 h exposure. Similar results were obtained using a clonogenic assay. The HT29 colon adenocarcinoma was particularly sensitive while the MCF-7 breast carcinoma was the most resistant in our panel. Only a 2-3 fold cross-resistance was seen in the doxorubicin and cisplatin resistant variants of the A2780 ovarian carcinoma; the drug did not modulate sensitivity to doxorubicin in either parent or resistant lines. No cross-resistance to SDZ 62-434 was seen in a doxorubicin-resistant MCF-7 variant. Cytotoxicity was not due to non-specific membrane lysis. The potent PAF antagonist WEB 2086 did not modulate SDZ 62-434 cytotoxicity, indicating no role for PAF receptors. Precursor incorporation studies in A2780 cells showed that DNA synthesis was inhibited more effectively than protein synthesis while RNA synthesis was unaffected. SDZ 62-434 inhibited both bombesin and platelet-derived growth factor-induced DNA synthesis in quiescent Swiss 3T3 cells. This suggests a possible role for SDZ 62-434 as an inhibitor of signal transduction in cancer cells

In vivo pharmacology and anti-tumour evaluation of the tyrphostin tyrosine kinase inhibitor RG13022.

Amplification and increased expression of many growth factor receptors, including the epidermal growth factor receptor (EGFR), has been observed in human tumours. One therapeutic strategy for overcoming EGF autocrine control of tumour growth is inhibition of EGFR protein tyrosine kinase (PTK). A series of low molecular weight molecules have been identified which inhibit the EGFR PTK in vitro and demonstrate antiproliferative activity against human cancer cell lines with high expression of EGFR. A significant growth delay in squamous cancer xenografts has been reported for one of these compounds, the tyrphostin RG13022. Based on these encouraging results, we sought to confirm the activity of RG13022 in vivo and relate the effects to the in vivo plasma disposition. RG13022 and three additional peaks were detected by HPLC following intraperitoneal administration of 20 mg kg-1 RG13022 in MF1 nu/nu mice. RG13022 demonstrated rapid biexponential elimination from plasma with a terminal half-life of 50.4 min. RG13022 plasma concentrations were less than 1 microM by 20 min post injection. A primary product was identified as the geometrical isomer (E)-RG13022. Both RG13022 and its geometrical isomer inhibited DNA synthesis in HN5 cells after a 24 h in vitro incubation (IC50 = 11 microM and 38 microM respectively). Neither RG13022 nor its geometrical isomer displayed significant cytotoxicity. RG13022 had no influence on the growth of HN5 tumours when administered chronically, starting either on the day of tumour inoculation or after establishment of tumour xenografts. The rapid in vivo elimination of RG13022 has potential significance to the development of this and other related tyrphostin tyrosine kinase inhibitors, as plasma concentrations fell below that required for in vitro activity by 20 min post injection. The lack of in vivo tumour growth delay suggests that a more optimal administration schedule for RG13022 would include more frequent injections or continuous administration. An improved formulation for RG13022 is therefore required before further development of this or other similar protein tyrosine kinase inhibitors can be made. Alternative strategies should also be sought which display longer lasting in vivo exposures

Depression, anxiety, pain and quality of life in people living with chronic hepatitis C: A systematic review and meta-analysis

Objectives: Individuals infected with hepatitis C virus (HCV) can develop extrahepatic conditions which may have a significant impact on life expectancy and quality of life. We conducted a systematic review to assess the causal relationship between HCV and extrahepatic conditions and the impact of HCV upon health-related quality of life of people in the UK. / Methods: HCV advocacy groups identified conditions that they thought most important to research, and the perspectives of various stakeholders informed the scope of the review. A comprehensive literature search of a range of electronic databases and websites was undertaken. Screening, quality assessment and data extraction were conducted using specialist software. The key criterion for inclusion in a synthesis was a study’s testing of the association between HCV and either quality of life or conditions specified as important by advocacy groups: depression, anxiety or painful conditions. Other criteria relating to study populations, measures and matching of study groups were also applied. Two reviewers assessed included studies, with disagreements resolved by a third reviewer where necessary. Studies were assessed for methodological quality using standardised appraisal tools. Metaanalyses were performed. Based on the consistency and sufficiency of research evidence, the findings were graded as strong, promising, tentative or inconclusive. / Results: 71 studies were included in the review’s syntheses. All studies were judged to be at a moderate or high risk of bias. Only two UK studies met our inclusion criteria. / Quality of life: Evidence from 22 studies indicates that people with HCV have worse quality of life than ‘general’ or ‘healthy’ populations; meta-analysis of nine studies indicated\ud that the physical (PCS) and mental health (MCS) domains of quality of life on the Health-Related Quality of Life Scale were both statistically and clinically worse among HCV-infected people (PCS: MD 5.54, 95% CI 3.73-7.35, MCS: MD 3.81, 95% CI 1.97-5.64). Evidence from seven included studies suggests that people co-infected with HCV and HIV have worse quality of life than individuals with HIV only; metaanalysis of five studies indicated that both the physical and mental health domains of quality of life were significantly worse among people who were co-infected (PCS: MD 2.57, 95% CI 1.08-4.06, MCS: MD 1.88, 95% CI 0.06-3.69). / Depression and anxiety: Evidence from 22 studies indicates that depression and anxiety are more severe, and depression is more common among people with HCV compared to those without it. Meta-analysis of 12 studies identified the severity of depression in people with HCV to be significantly greater than in those without HCV (Mean difference 0.98, 95% CI 0.43-1.53). Meta-analysis of nine studies identified the severity of clinical anxiety to be significantly greater among people with HCV (Mean difference 0.47, 95% CI 0.09-0.86). Meta-analysis of seven studies identified participants with HCV to be approximately three times more likely to be depressed compared to those without HCV (OR 2.77, 95% CI 1.62-4.74). No statistically significant evidence that anxiety is more common among people with HCV was found. / Pain: Evidence was appraised from 26 studies on painful conditions. A meta-analysis of four studies indicates that people with HCV are 17% more likely to suffer from arthralgia than those without HCV (RR 1.17, 95% CI 1.04-1.31). A meta-analysis of five studies suggested that people with HCV are significantly more likely to suffer from fibromyalgia; key differences across the studies in terms of the health status (co-morbidities) of HCV patients and comparison groups mean it is not possible to quantify the increased risk attributable to HCV. Other studies, including those on arthritis, were not amenable to meta-analysis. / Conclusions: Evidence suggests an association between HCV infection and depression, anxiety, fibromyalgia, arthralgia and health-related quality of life. However, the evidence was graded as ‘promising’ or ‘tentative’ rather than ‘strong’. More high-quality research on the association between HCV and these conditions is needed

Stimulated Raman scattering microscopy : an emerging tool for drug discovery

Optical microscopy techniques have emerged as a cornerstone of biomedical research, capable of probing the cellular functions of a vast range of substrates, whilst being minimally invasive to the cells or tissues of interest. Incorporating biological imaging into the early stages of the drug discovery process can provide invaluable information about drug activity within complex disease models. Spontaneous Raman spectroscopy has been widely used as a platform for the study of cells and their components based on chemical composition; but slow acquisition rates, poor resolution and a lack of sensitivity have hampered further development. A new generation of stimulated Raman techniques is emerging which allows the imaging of cells, tissues and organisms at faster acquisition speeds, and with greater resolution and sensitivity than previously possible. This review focuses on the development of stimulated Raman scattering (SRS), and covers the use of bioorthogonal tags to enhance sample detection, and recent applications of both spontaneous Raman and SRS as novel imaging platforms to facilitate the drug discovery process

Improved vision based pose estimation for industrial robots via sparse regression

In this work amonocular machine vision based pose estimation system is developed for industrial robots and the accuracy of the estimated pose is im-proved via sparse regression. The proposed sparse regressionbased methodis usedimprove the accuracy obtained from the Levenberg-Marquardt (LM) based pose estimation algorithmduring the trajectory tracking of an industrial robot’s end effector. The proposed method utilizes a set of basis functions to sparsely identify the nonlinear relationship between the estimated pose and the true pose provided by a laser tracker.Moreover,a camera target was designed and fitted with fiducial markers,andto prevent ambiguities in pose estimation, the markers are placed in such a way to guarantee the detection of at least two distinct nonparallel markers from a single camera within ± 90° in all directions of the cam-era’s view. The effectiveness of the proposed method is validated by an experi-mental study performed using a KUKA KR240 R2900 ultra robot while follow-ing sixteen distinct trajectories based on ISO 9238. The obtained results show that the proposed method provides parsimonious models which improve the pose estimation accuracy and precision of the vision based system during trajectory tracking of industrial robots' end effector

Spin Wave Theory of Double Exchange Ferromagnets

We construct the 1/S spin-wave expansion for double exchange ferromagnets at T=0. It is assumed that the value of Hund's rule coupling, J_H, is sufficiently large, resulting in a fully saturated, ferromagnetic half-metallic ground state. We evaluate corrections to the magnon dispersion law, and we also find that, in contrast to earlier statements in the literature, magnon-electron scattering does give rise to spin wave damping. We analyse the momentum dependence of these quantities and discuss the experimental implications for colossal magnetoresistance compounds.Comment: 4 pages, Latex-Revtex, 2 PostScript figures. Minor revisions, references added. See also cond-mat/990921

Closed-loop separation control over a sharp edge ramp using Genetic Programming

We experimentally perform open and closed-loop control of a separating turbulent boundary layer downstream from a sharp edge ramp. The turbulent boundary layer just above the separation point has a Reynolds number $Re_{\theta}\approx 3\,500$ based on momentum thickness. The goal of the control is to mitigate separation and early re-attachment. The forcing employs a spanwise array of active vortex generators. The flow state is monitored with skin-friction sensors downstream of the actuators. The feedback control law is obtained using model-free genetic programming control (GPC) (Gautier et al. 2015). The resulting flow is assessed using the momentum coefficient, pressure distribution and skin friction over the ramp and stereo PIV. The PIV yields vector field statistics, e.g. shear layer growth, the backflow area and vortex region. GPC is benchmarked against the best periodic forcing. While open-loop control achieves separation reduction by locking-on the shedding mode, GPC gives rise to similar benefits by accelerating the shear layer growth. Moreover, GPC uses less actuation energy.Comment: 24 pages, 24 figures, submitted to Experiments in Fluid