An optical transient within the error box of the gamma ray burst GRB 970508 was imaged 4 hours after the event. It displayed a strong ultraviolet excess, and reached maximum brightness 2 days later. ...The optical spectra did not show any emission lines, and no variations on time scales of minutes were observed for 1 hour during the decline phase. According to the fireball and afterglow models, the intensity should rise monotonically before the observed optical maximum, but the data indicate that another physical mechanism may be responsible for the constant phase seen during the first hours after the burst.
BVRI photometry of 107 TNOs and Centaurs establishes the range of spectral gradients to be between –5 to 55%/100 nm (with one exception). A cluster of very red Cubewanos is firmly identified in ...orbits of low inclination and eccentricity beyond 40 AU from the Sun. Further correlations between surface colours and dynamical parameters (inclination and perihelion distance) are suggested for Cubewanos and scattered disk objects, but lack complete confidence for their reality. Plutinos and Centaurs do not show any clear correlation between surface colours and orbital parameters. We present in this paper 12 spectra obtained in the visible region and nine of them for which we obtained also near infrared spectra up to 2.4 microns. A few other objects have been observed, but the data are still under reduction and analysis. The principal reported results obtained are: (i) a wide range of visible slopes; (ii) evidence for surface variations on 2001 PT13; and (iii) possible detection of few percent of water ice (1999 TC36}, 2000 EB173, 1999 DE9, 2001 PT13, 2000 QC243, 1998 SG35).
We present the properties of the supernova SN 1995ah discovered in a Blue
Compact Dwarf galaxy (BCD) around 10 days after the maximum. This is the first
supernova event observed in a BCD. The ...photometric and spectroscopic data
suggest that SN 1995ah is a Type II supernova and could belong to the rare
Bright SNII Linear subclass, for which <M(R)>~<M(B)>=-18.9+-0.6 at maximum
light.
We present the properties of the supernova SN 1995ah discovered in a Blue Compact Dwarf galaxy (BCD) around 10 days after the maximum. This is the first supernova event observed in a BCD. The ...photometric and spectroscopic data suggest that SN 1995ah is a Type II supernova and could belong to the rare Bright SNII Linear subclass, for which <M(R)>~<M(B)>=-18.9+-0.6 at maximum light.
Many receptor tyrosine kinases (RTKs) represent bona fide drug targets in oncology. Effective compounds are available, but treatment invariably leads to resistance, often due to RTK mutations. The ...discovery of second-generation inhibitors requires cellular models of resistant RTKs. An approach using artificial transmembrane domains (TMDs) to activate RTKs was explored for the rapid generation of simple, ligand-independent cellular RTK assays, including resistance mutants. The RTKs epidermal growth factor receptor (EGFR), MET, and KIT were chosen in a proof-of-concept study. Their intracellular domains were inserted into a series of expression vectors encoding artificial TMDs, and they were tested for autophosphorylation activity in transient transfection assays. Active constructs could be identified for MET and EGFR, but not for KIT. Rat1 cell pools were generated expressing the MET or EGFR constructs, and their sensitivity to reference tool compounds was compared to that of MKN-45 or A431 cells. A good correlation between natural and recombinant cells led us to build a panel of clinically relevant MET mutant cell pools, based on the wild-type construct, which were then profiled via MET autophosphorylation and soft agar assays. In summary, a platform was established that allows for the rapid generation of cellular models for RTKs and their resistance mutants.
Abstract
Kinases are important targets in oncology. However, the frequent emergence of resistance (gatekeeper) mutants in target kinases seriously limits the patient's response time to a given drug. ...Secondary drugs need to be developed that specifically target mutant enzymes. The discovery of such kinase inhibitors requires relevant assay systems. In order to efficiently analyze whether novel inhibitors target gatekeeper mutants of a given kinase in a cellular context we set out to establish a suitable cellular test system for the receptor tyrosine kinase MET. Our aim was to minimize variations such as cellular background and ligand dependent activation while putting the focus on the mutation of interest. In an approach to uncouple kinase activity from ligand activation, we screened a set of artificial transmembrane domains (TMD) to identify a TMD that induces constitutive MET autophosphorylation in transient transfections. Subsequently, Rat1 cells were transduced to express the tag-labelled intracellular wild-type (wt) MET domain harbouring the activating TMD while lacking the extracellular domain. Characterization of TMD-MET-wt in Rat1 cells showed constitutive MET expression and phosphorylation. ELISA studies to analyze the inhibition of MET phosphorylation by cognate MET inhibitors revealed comparable IC50 values to those obtained with wild-type MET naturally over expressed in MKN45 gastric carcinoma cells. Moreover, expression of TMD-MET-wt in Rat1 cells led to cell transformation as assessed by growth in soft agar as well as in vivo as a subcutaneous xenograft. Interestingly, the same artificial TMD induced constitutive activity of various gatekeeper mutants of MET when transduced into Rat1 cells. This observation allowed for the comparative analysis of various small molecule MET inhibitors on multiple MET mutants in an identical cellular background and without the need of ligand-induced kinase activation. Using a straight forward ELISA-based approach, we generated profiles of various MET inhibitors on cellular MET mutant phosphorylation and compared these with inhibition profiles obtained in biochemical MET activity assays.
Citation Format: {Authors}. {Abstract title} abstract. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A141.
