Novel functions for Rab GTPases in multiple aspects of tumour progression

Rab GTPases are master regulators of intracellular trafficking and, in recent years, their role in the control of different aspects of tumour progression has emerged. In the present review, we show that Rab GTPases are disregulated in many cancers and have central roles in tumour cell migration, invasion, proliferation, communication with stromal cells and the development of drug resistance. As a consequence, Rab proteins may be novel potential candidates for the development of anticancer drugs and, in this context, the preliminary results obtained with an inhibitor of Rab function are also discussed

The [alpha/Fe] Ratios in Dwarf Galaxies: Evidence for a Non-universal Stellar Initial Mass Function?

It is well established that the [alpha/Fe] ratios in elliptical galaxies increase with galaxy mass. This relation holds also for early-type dwarf galaxies, although it seems to steepen at low masses. The [alpha/Fe] vs. mass relation can be explained assuming that smaller galaxies form over longer timescales (downsizing), allowing a larger amount of Fe (mostly produced by long-living Type Ia Supernovae) to be released and incorporated into newly forming stars. Another way to obtain the same result is by using a flatter initial mass function (IMF) in large galaxies, increasing in this way the number of Type II Supernovae and therefore the production rate of alpha-elements. The integrated galactic initial mass function (IGIMF) theory predicts that the higher the star formation rate, the flatter the IMF. We have checked, by means of semi-analytical calculations, that the IGIMF theory, combined with the downsizing effect (i.e. the shorter duration of the star formation in larger galaxies), well reproduces the observed [alpha/Fe] vs. mass relation. In particular, we show a steepening of this relation in dwarf galaxies, in accordance with the available observations.Comment: 4 pages, 2 figures; to appear in the proceedings of the JENAM 2010 Symposium on Dwarf Galaxies (Lisbon, September 9-10, 2010

Is the interstellar gas of starburst galaxies well mixed?

The extent to which the ISM in galaxies is well mixed is not yet settled. Measured metal abundances in the diffuse neutral gas of star--forming gas--rich dwarf galaxies are deficient with respect to that of the ionized gas. The reasons, if real, are not clear and need to be based on firm grounds. Far-UV spectroscopy of giant HII regions such as NGC604 in the spiral galaxy M33 using FUSE allows us to investigate possible systematic errors in the metallicity derivation. We still find underabundances of nitrogen, oxygen, argon, and iron in the neutral phase by a factor of~6. This could either be explained by the presence of less chemically evolved gas pockets in the sightlines or by dense clouds out of which HIIregions form. Those could be more metallic than the diffuse medium.Comment: 4 pages, 2 figures;contribution to Starbursts: from 30 Dor to Lyman Break Galaxies, 6 -10 September 2004, Institute of Astronomy, University of Cambridge, U

Inactivating mutations and X-ray crystal structure of the tumor suppressor OPCML reveal cancer-associated functions

OPCML, a tumor suppressor gene, is frequently silenced epigenetically in ovarian and other cancers. Here we report, by analysis of databases of tumor sequences, the observation of OPCML somatic missense mutations from various tumor types and the impact of these mutations on OPCML function, by solving the X-ray crystal structure of this glycoprotein to 2.65 A resolution. OPCML consists of an extended arrangement of three immunoglobulin-like domains and homodimerizes via a network of contacts between membrane-distal domains. We report the generation of a panel of OPCML variants with representative clinical mutations and demonstrate clear phenotypic effects in vitro and in vivo including changes to anchorage-independent growth, interaction with activated cognate receptor tyrosine kinases, cellular migration, invasion in vitro and tumor growth in vivo. Our results suggest that clinically occurring somatic missense mutations in OPCML have the potential to contribute to tumorigenesis in a variety of cancers

Everyday cosmopolitanism in representations of Europe among young Romanians in Britain

The paper presents an analysis of everyday cosmopolitanism in constructions of Europe among young Romanian nationals living in Britain. Adopting a social representations approach, cosmopolitanism is understood as a cultural symbolic resource that is part of everyday knowledge. Through a discursively-oriented analysis of focus group data, we explore the ways in which notions of cosmopolitanism intersect with images of Europeanness in the accounts of participants. We show that, for our participants, representations of Europe are anchored in an Orientalist schema of West-vs.-East, whereby the West is seen as epitomising European values of modernity and progress, while the East is seen as backward and traditional. Our findings further show that representations of cosmopolitanism reinforce this East/West dichotomy, within a discourse of ‘Occidental cosmopolitanism’. The paper concludes with a critical discussion of the diverse and complex ideological foundations of these constructions of European cosmopolitanism and their implications

The tumor suppressor protein OPCML potentiates anti-EGFR and anti-HER2 targeted therapy in HER2-positive ovarian and breast cancer.

OPCML is a tumor suppressor gene that is frequently inactivated in ovarian cancer and many other cancers by somatic methylation. We have previously shown that OPCML exerts its suppressor function by negatively regulating a spectrum of receptor tyrosine kinases (RTKs), such as ErbB2/HER2, FGFR1 and EphA2, thus attenuating their related downstream signaling. The physical interaction of OPCML with this defined group of RTKs is a prerequisite for their downregulation. Overexpression/gene amplification of EGFR and HER2 is a frequent event in multiple cancers including ovarian and breast cancers. Molecular therapeutics against EGFR/HER2 or EGFR only, such as lapatinib and erlotinib respectively, were developed to target these receptors but resistance often occurs in relapsing cancers. Here we show that, though OPCML interacts only with HER2 and not with EGFR, the interaction of OPCML with HER2 disrupts the formation of the HER2-EGFR heterodimer and this translates into a better response to both lapatinib and erlotinib in HER2-expressing ovarian and breast cancer cell lines. Also, we show that high OPCML expression is associated with better response to lapatinib therapy in breast cancer patients and better survival in HER2-overexpressing ovarian cancer patients, suggesting that OPCML co-therapy could be a valuable sensitizing approach to RTK inhibitors

On the dust abundance gradients in late-type galaxies: I. Effects of destruction and growth of dust in the interstellar medium

We present basic theoretical constraints on the effects of destruction by supernovae (SNe) and growth of dust grains in the interstellar medium (ISM) on the radial distribution of dust in late-type galaxies. The radial gradient of the dust-to-metals ratio is shown to be essentially flat (zero) if interstellar dust is not destroyed by SN shock waves and all dust is produced in stars. If there is net dust destruction by SN shock waves, the dust-to-metals gradient is flatter than or equal to the metallicity gradient (assuming the gradients have the same sign). Similarly, if there is net dust growth in the ISM, then the dust-to-metals gradient is steeper than or equal to the metallicity gradient. The latter result implies that if dust gradients are steeper than metallicity gradients, i.e., the dust-to-metals gradients are not flat, then it is unlikely dust destruction by SN shock waves is an efficient process, while dust growth must be a significant mechanism for dust production. Moreover, we conclude that dust-to-metals gradients can be used as a diagnostic for interstellar dust growth in galaxy discs, where a negative slope indicates dust growth.Comment: 12 pages, 4 figures. Accepted for publication in MNRA

The interplay between ionized gas and massive stars in the HII galaxy IIZw70: integral field spectroscopy with PMAS

We performed an integral field spectroscopic study for the HII galaxy IIZw70 in order to investigate the interplay between its ionized interstellar medium (ISM) and the massive star formation (SF). Observations were taken in the optical spectral range (3700-6800 A) with the Potsdam Multi-Aperture Spectrophotometer (PMAS) attached to the 3.5 m telescope at CAHA. We created and analysed maps of spatially distributed emission-lines, continuum emission and properties of the ionized ISM (e.g. physical-chemical conditions, dust extinction, kinematics). We investigated the relation of these properties to the spatial distribution and evolutionary stage of the massive stars. For the first time we have detected the presence of Wolf-Rayet (WR) stars in this galaxy. The peak of the ionized gas emission coincides with the location of the WR bump. The region of the galaxy with lower dust extinction corresponds to the region that shows the lowest values of velocity dispersion and radial velocity. The overall picture suggests that the ISM of this region is being disrupted via photoionization and stellar winds, leading to a spatial decoupling between gas+stars and dust clouds. The bulk of dust appears to be located at the boundaries of the region occupied by the probable ionizing cluster. We also found that this region is associated to the nebular emission in HeII4686 and to the intensity maximum of most emission lines. This indicates that the hard ionizing radiation responsible for the HeII4686 nebular emission can be related to the youngest stars. Within $\sim$ 0.4 x 0.3 kpc^2 in the central burst, we derived O/H using direct determinations of Te[OIII]. We found abundances in the range 12+log(O/H)=7.65-8.05, yielding an error-weighted mean of 12+log(O/H)=7.86 $\pm$0.05.Comment: 10 pages, 10 figures, accepted for publication in A&A, minor changes adde

Top-heavy integrated galactic stellar initial mass functions (IGIMFs) in starbursts

Star formation rates (SFR) larger than 1000 Msun/ yr are observed in extreme star bursts. This leads to the formation of star clusters with masses > 10^6 Msun in which crowding of the pre-stellar cores may lead to a change of the stellar initial mass function (IMF). Indeed, the large mass-to-light ratios of ultra-compact dwarf galaxies and recent results on globular clusters suggest the IMF to become top-heavy with increasing star-forming density. We explore the implications of top-heavy IMFs in these very massive and compact systems for the integrated galactic initial mass function (IGIMF), which is the galaxy-wide IMF, in dependence of the star-formation rate of galaxies. The resulting IGIMFs can have slopes, alpha_3, for stars more massive than about 1 Msun between 1.5 and the Salpeter slope of 2.3 for an embedded cluster mass function (ECMF) slope (beta) of 2.0, but only if the ECMF has no low-mass clusters in galaxies with major starbursts. Alternatively, beta would have to decrease with increasing SFR >10 Msun/ yr such that galaxies with major starbursts have a top-heavy ECMF. The resulting IGIMFs are within the range of observationally deduced IMF variations with redshift.Comment: Accepted for publication in MNRAS, reference adde