The relationship between tissue levels of flavone acetic acid (NSC 347512) and site dependent anti-tumour activity in murine colon tumours.

Flavone acetic acid (FAA) is extremely active against subcutaneous transplantable tumours in mice, but disappointingly there has been no demonstrable clinical activity. Previous studies have shown that lung tumour deposits are less responsive than the same cells implanted subcutaneously. The aim of this study is to examine the tissue disposition of FAA in an attempt to explain this site-dependent activity. The data show clearly that FAA clearance curves are influenced by the presence of MAC 15A tumours growing either subcutaneously or systemically. The decreased clearance of FAA from MAC 15A tumour bearing animals does not however explain the resistance of lung deposits. Neither can this be explained by differences in metabolism in these different sites. Cytotoxic metabolites have not been detected either in vitro or in vivo and their role in the mechanism of action of FAA is questionable

A downward revision to the distance of the 1806-20 cluster and associated magnetar from Gemini near-Infrared spectroscopy

We present H- and K-band spectroscopy of OB and Wolf-Rayet (WR) members of the Milky Way cluster 1806-20 (G10.0-0.3), to obtain a revised cluster distance of relevance to the 2004 giant flare from the SGR 1806-20 magnetar. From GNIRS spectroscopy obtained with Gemini South, four candidate OB stars are confirmed as late O/early B supergiants, while we support previous mid WN and late WC classifications for two WR stars. Based upon an absolute Ks-band magnitude calibration for B supergiants and WR stars, and near-IR photometry from NIRI at Gemini North plus archival VLT/ISAAC datasets, we obtain a cluster distance modulus of 14.7+/-0.35 mag. The known stellar content of the 1806-20 cluster suggests an age of 3-5 Myr, from which theoretical isochrone fits infer a distance modulus of 14.7+/-0.7 mag. Together, our results favour a distance modulus of 14.7+/-0.4 mag (8.7^+1.8_-1.5 kpc) to the 1806-20 cluster, which is significantly lower than the nominal 15 kpc distance to the magnetar. For our preferred distance, the peak luminosity of the December 2004 giant flare is reduced by a factor of three to 7 X 10^46 erg/s, such that the contamination of BATSE short gamma ray bursts (GRB's) from giant flares of extragalactic magnetars is reduced to a few percent. We infer a magnetar progenitor mass of ~48^+20_-8 Msun, in close agreement with that obtained recently for the magnetar in Westerlund 1.Comment: 6 pages, 4 figures, accepted for MNRAS Letter

Pre-clinical evaluation of a novel chloroethylating agent, Clomesone.

The in vitro activity of the novel chloroethylating agent, Clomesone, was investigated in a panel of established murine and human tumour cell lines. In vivo anti-tumour activity was examined against three transplantable adenocarcinomas of the mouse colon and in vivo bone marrow toxicity was assessed using a spleen colony forming unit assay. The pharmacokinetic behaviour of the drug in vivo and drug stability in vitro was analysed by gas chromatography with electron capture detection. Clomesone exhibited no activity in vitro against the majority of cell lines derived from solid human colorectal carcinomas. Anti-tumour activity against the murine tumours in vivo was not impressive and was accompanied by myelosuppression. Pharmacokinetic data suggested that the lack of in vivo activity was due to the failure to achieve effective anti-neoplastic drug concentrations at the tumour site. It was concluded that this study found no evidence to suggest that Clomesone was toxicologically more selective than the chloroethylnitrosoureas

Factors involved in the anti-cancer activity of the investigational agents LM985 (flavone acetic acid ester) and LM975 (flavone acetic acid).

LM985 has been shown previously to hydrolyse to flavone acetic acid (LM975) in mouse plasma and to produce significant anti-tumour effects in transplantable mouse colon tumours (MAC). It has undergone Phase I clinical trials and dose limiting toxicity was acute reversible hypotension. Substantially higher doses of LM975 can be given clinically without dose limiting toxicity. We have investigated the activity of LM975 against a panel of MAC tumours and also the in vitro cytotoxicity of both LM985 and LM975 in two cell lines derived from MAC tumours. LM985 is considerably more cytotoxic than LM975 in vitro but increased length of exposure to LM975 results in improved activity. Single in vivo injection of LM975 showed no activity against the ascitic tumour MAC 15A, moderate activity against the s.c. poorly differentiated tumour MAC 13 and produced a significant growth delay in the well differentiated MAC 26. These latter responses were considerably enhanced by repeated injection 7 days later. Pharmacokinetic studies in mice following i.p. injection of LM985 demonstrated rapid degradation of LM985 to LM975 in the peritoneum. Length of exposure as well as drug concentration appear important factors in determining anti-tumour responses

In vitro activity of the novel indoloquinone EO-9 and the influence of pH on cytotoxicity.

The novel indoloquinone compound EO-9 is shortly to undergo phase I clinical evaluation as a potential bioreductive drug. Preclinical studies have shown that EO-9 has greater activity against cells derived from human solid tumours than leukaemias in vitro. The results of this study extend the preclinical data available on EO-9 by demonstrating that EO-9 induces a broad spectrum of activity (IC50 values range from 8 to 590 ng ml-1) against a panel of human and murine tumour cell lines. Some evidence exists of selectivity towards leukaemia and human colon cell lines as opposed to murine colon cells. The response of cells to Mitomycin C were not comparable to EO-9 suggesting that the mechanism of action of these compounds is different. The cytotoxic properties of EO-9 under aerobic conditions are significantly influenced by extracellular pH. Reduction of pH from 7.4 to 5.8 increases cell kill from 40% to 95% in DLD-1 cells. In addition, EO-9 is unstable at acidic pH (T1/2 = 37 min at pH 5.5) compared to neutral pH T1/2 = 6.3 h). The major breakdown product in vitro was identified as EO-5A which proved relatively inactive compared to EO-9 (IC50 = 50 and 0.6 ug ml-1 respectively). These studies suggest that if EO-9 can be delivered to regions of low pH within solid tumours, a therapeutic advantage may be obtained

'I would rather die': reasons given by 16-year-olds for not continuing their study of mathematics

Improving participation rates in specialist mathematics after the subject ceases to be compulsory at age 16 is part of government policy in England. This article provides independent and recent support for earlier findings concerning reasons for non- participation, based on free response and closed items in a questionnaire with a sample of over 1500 students in 17 schools, close to the moment of choice. The analysis supports findings that perceived difficulty and lack of confidence are important reasons for students not continuing with mathematics, and that perceived dislike and boredom, and lack of relevance, are also factors. There is a close relationship between reasons for non-participation and predicted grade, and a weaker relation to gender. An analysis of the effects of schools, demonstrates that enjoyment is the main factor differentiating schools with high and low participation indices. Building on discussion of these findings, ways of improving participation are briefly suggested

Multi-color Molecular Visualization of Signaling Proteins Reveals How C-Terminal Src Kinase Nanoclusters Regulate T Cell Receptor Activation

Elucidating the mechanisms that controlled T cell activation requires visualization of the spatial organization of multiple proteins on the submicron scale. Here, we use stoichiometrically accurate, multiplexed, singlemolecule super-resolution microscopy (DNA-PAINT) to image the nanoscale spatial architecture of the primary inhibitor of the T cell signaling pathway, Csk, and two binding partners implicated in its membrane association, PAG and TRAF3. Combined with a newly developed co-clustering analysis framework, we find that Csk forms nanoscale clusters proximal to the plasma membrane that are lost post-stimulation and are re-recruited at later time points. Unexpectedly, these clusters do not co-localize with PAG at the membrane but instead provide a ready pool of monomers to downregulate signaling. By generating CRISPR-Cas9 knockout T cells, our data also identify that a major risk factor for autoimmune diseases, the protein tyrosine phosphatase non-receptor type 22 (PTPN22) locus, is essential for Csk nanocluster re-recruitment and for maintenance of the synaptic PAG population

HST/NICMOS observations of the GLIMPSE9 stellar cluster

We present HST/NICMOS photometry, and low-resolution K-band spectra of the GLIMPSE9 stellar cluster. The newly obtained color-magnitude diagram shows a cluster sequence with H-Ks =1 mag, indicating an interstellar extinction Aks=1.6\pm0.2 mag. The spectra of the three brightest stars show deep CO band-heads, which indicate red supergiants with spectral type M1-M2. Two 09-B2 supergiants are also identified, which yield a spectrophotometric distance of 4.2\pm0.4 kpc. Presuming that the population is coeval, we derive an age between 15 and 27 Myr, and a total cluster mass of 1600\pm400 Msun, integrated down to 1 Msun. In the vicinity of GLIMPSE9 are several HII regions and SNRs, all of which (including GLIMPSE 9) are probably associated with a giant molecular cloud (GMC) in the inner galaxy. GLIMPSE9 probably represents one episode of massive star formation in this GMC. We have identified several other candidate stellar clusters of the same complex.Comment: 13 pages, 14 figures. accepted for publication in ApJ. A version with high-resolution figures can be found at the following location ftp://ftp.rssd.esa.int/pub/mmessine/ms.pdf New version with updated reference

Effect of magnetic state on the γ−α\gamma -\alpha transition in iron: First-principle calculations of the Bain transformation path

Energetics of the fcc ($\gamma$) - bcc ($\alpha$) lattice transformation by the Bain tetragonal deformation is calculated for both magnetically ordered and paramagnetic (disordered local moment) states of iron. The first-principle computational results manifest a relevance of the magnetic order in a scenario of the $\gamma$ - $\alpha$ transition and reveal a special role of the Curie temperature of $\alpha$-Fe, $T_C$, where a character of the transformation is changed. At a cooling down to the temperatures $T < T_C$ one can expect that the transformation is developed as a lattice instability whereas for $T > T_C$ it follows a standard mechanism of creation and growth of an embryo of the new phase. It explains a closeness of $T_C$ to the temperature of start of the martensitic transformation, $M_s$.Comment: 4 pages, 3 figures, submitted in Phys. Rev. Letter

Contacting the spirits of the dead: paranormal belief and the teenage worldview

A number of previous studies have examined both the overall level of belief expressed by young people in the paranormal and the major demographic predictors of such belief. Building on this research tradition, the present study examines how one specific paranormal belief concerning contact with the spirits of the dead integrates with the wider teenage worldview. Data provided by 33,982 pupils age 13 to 15 years throughout England and Wales demonstrated that almost one in three young people (31%) believed that it is possible to contact the spirits of the dead. Compared with young people who did not share this belief, the young people who believed in the possibility of contacting the spirits of the dead displayed lower psychological wellbeing, higher anxiety, greater isolation, greater alienation, less positive social attitudes, and less socially conforming lifestyles. Overall, paranormal beliefs seem to be associated with a less healthy worldview, in both personal and social terms