Loss of TRAIL-receptors is a recurrent feature in pancreatic cancer and determines the prognosis of patients with no nodal metastasis after surgery.

Agonistic antibodies targeting TRAIL-receptors 1 and 2 (TRAIL-R1 and TRAIL-R2) are being developed as a novel therapeutic approach in cancer therapy including pancreatic cancer. However, the cellular distribution of these receptors in primary pancreatic cancer samples has not been sufficiently investigated and no study has yet addressed the issue of their prognostic significance in this tumor entity. Applying tissue microarray (TMA) analysis, we performed an immunohistochemical assessment of TRAIL-receptors in surgical samples from 84 consecutive patients affected by pancreatic adenocarcinoma and in 26 additional selected specimens from patients with no lymph nodes metastasis at the time of surgery. The prognostic significance of membrane staining and staining intensity for TRAIL-receptors was evaluated. The fraction of pancreatic cancer samples with positive membrane staining for TRAIL-R1 and TRAIL-R2 was lower than that of cells from surrounding non-tumor tissues (TRAIL-R1: p<0.001, TRAIL-R2: p = 0.006). In addition, subgroup analyses showed that loss of membrane staining for TRAIL-R2 was associated with poorer prognosis in patients without nodal metastases (multivariate Cox regression analysis, Hazard Ratio: 0.44 [95% confidence interval: 0.22-0.87]; p = 0.019). In contrast, analysis of decoy receptors TRAIL-R3 and -R4 in tumor samples showed an exclusively cytoplasmatic staining pattern and no prognostic relevance. This is a first report on the prognostic significance of TRAIL-receptors expression in pancreatic cancer showing that TRAIL-R2 might represent a prognostic marker for patients with early stage disease. In addition, our data suggest that loss of membrane-bound TRAIL-receptors could represent a molecular mechanism for therapeutic failure upon administration of TRAIL-receptors-targeting antibodies in pancreatic cancer. This hypothesis should be evaluated in future clinical trials

Constraining the Distribution of L- & T-Dwarfs in the Galaxy

We estimate the thin disk scale height of the Galactic population of L- & T-dwarfs based on star counts from 15 deep parallel fields from the Hubble Space Telescope. From these observations, we have identified 28 candidate L- & T- dwarfs based on their (i'-z') color and morphology. By comparing these star counts to a simple Galactic model, we estimate the scale height to be 350+-50 pc that is consistent with the increase in vertical scale with decreasing stellar mass and is independent of reddening, color-magnitude limits, and other Galactic parameters. With this refined measure, we predict that less than 10^9 M_{sol} of the Milky Way can be in the form L- & T- dwarfs, and confirm that high-latitude, z~6 galaxy surveys which use the i'-band dropout technique are 97-100% free of L- & T- dwarf interlopers.Comment: 4 pages, 4 figures, accepted to ApJ

Retinal degeneration modulates intracellular localization of CDC42 in photoreceptors

Purpose: Rho GTPases such as RAS-related C3 botulinum substrate 1 (RAC1) and cell division cycle 42 homolog (S. cerevisiae; CDC42) have been linked to cellular processes including movement, development, and apoptosis. Recently, RAC1 has been shown to be a pro-apoptotic factor in the retina during light-induced photoreceptor degeneration. Here, we analyzed the role of CDC42 in the degenerating retina. Methods: Photoreceptor degeneration was studied in a mouse model for autosomal dominant retinitis pigmentosa (VPP) with or without a rod-specific knockdown of Cdc42, as well as in wild-type and Cdc42 knockdown mice after light exposure. Gene and protein expression were analyzed by real-time PCR, western blotting, and immunofluorescence. Retinal morphology and function were assessed by light microscopy and electroretinography, respectively. Results: CDC42 accumulated in the perinuclear region of terminal deoxynucleotidyl transferase dUTP nick end labeling–negative photoreceptors during retinal degeneration induced by excessive light exposure and in the rd1, rd10, and VPP mouse models of retinitis pigmentosa. The knockdown of Cdc42 did not affect retinal morphology or function in the adult mice and did not influence photoreceptor apoptosis or molecular signaling during induced and inherited retinal degeneration. Conclusions: Retinal degeneration induces the accumulation of CDC42 in the perinuclear region of photoreceptors. In contrast to RAC1, however, lack of CDC42 does not affect the progression of degeneration. CDC42 is also dispensable for normal morphology and function of adult rod photoreceptor cells

WASP-14 b: Transit Timing analysis of 19 light curves

Although WASP-14 b is one of the most massive and densest exoplanets on a tight and eccentric orbit, it has never been a target of photometric follow-up monitoring or dedicated observing campaigns. We report on new photometric transit observations of WASP-14 b obtained within the framework of "Transit Timing Variations @ Young Exoplanet Transit Initiative" (TTV@YETI). We collected 19 light-curves of 13 individual transit events using six telescopes located in five observatories distributed in Europe and Asia. From light curve modelling, we determined the planetary, stellar, and geometrical properties of the system and found them in agreement with the values from the discovery paper. A test of the robustness of the transit times revealed that in case of a non-reproducible transit shape the uncertainties may be underestimated even with a wavelet-based error estimation methods. For the timing analysis we included two publicly available transit times from 2007 and 2009. The long observation period of seven years (2007-2013) allowed us to refine the transit ephemeris. We derived an orbital period 1.2 s longer and 10 times more precise than the one given in the discovery paper. We found no significant periodic signal in the timing-residuals and, hence, no evidence for TTV in the system.Comment: 12 pages, 10 figures, 7 table

On the kinematic deconvolution of the local neighbourhood luminosity function

A method for inverting the statistical star counts equation, including proper motions, is presented; in order to break the degeneracy in that equation it uses the supplementary constraints required by dynamical consistency. The inversion gives access to both the kinematics and the luminosity function of each population in three r\'egimes: the singular ellipsoid, the constant ratio Schwarzschild ellipsoid plane parallel models and the epicyclic model. This more realistic model is taylored to account for local neighbourhood density and velocity distribution. The first model is fully investigated both analytically and via means of a non-parametric inversion technique, while the second model is shown to be formally its equivalent. The effect of noise and incompleteness in apparent magnitude is investigated. The third model is investigated via a 5D+2D non-parametric inversion technique where positivity of the underlying luminosity function is explicitely accounted for. It is argued that its future application to data such as the Tycho catalogue (and in the upcoming satellite GAIA) could lead -- provided the vertical potential, and/or the asymmetric drift or w_0 are known -- to a non-parametric determination of the local neighbourhood luminosity function without any reference to stellar evolution tracks. It should also yield the proportion of stars for each kinematic component and a kinematic diagnostic to split the thin disk from the thick disk or the halo.Comment: 18 pages, LateX (or Latex, etc), mnras, accepted for publicatio

A lucky imaging multiplicity study of exoplanet host stars

To understand the influence of additional wide stellar companions on planet formation, it is necessary to determine the fraction of multiple stellar systems amongst the known extrasolar planet population. We target recently discovered radial velocity exoplanetary systems observable from the northern hemisphere and with sufficiently high proper motion to detect stellar companions via direct imaging. We utilize the Calar Alto 2.2m telescope in combination with its lucky imaging camera AstraLux. 71 planet host stars have been observed so far, yielding one new low-mass (0.239 \pm 0.022M\odot) stellar companion, 4.5 arcsec (227AU of projected separation) northeast of the planet host star HD185269, detected via astrometry with AstraLux. We also present follow-up astrometry on three previously discovered stellar companions, showing for the first time common proper motion of the 0.5 arcsec companion to HD126614. Additionally, we determined the achieved detection limits for all targets, which allows us to characterize the detection space of possible further companions of these stars

Rapid degradation of dominant-negative Rab27 proteins in vivo precludes their use in transgenic mouse models

BACKGROUND: Transgenic mice have proven to be a powerful system to study normal and pathological gene functions. Here we describe an attempt to generate a transgenic mouse model for choroideremia (CHM), a slow-onset X-linked retinal degeneration caused by mutations in the Rab Escort Protein-1 (REP1) gene. REP1 is part of the Rab geranylgeranylation machinery, a modification that is essential for Rab function in membrane traffic. The loss of REP1 in CHM patients may trigger retinal degeneration through its effects on Rab proteins. We have previously reported that Rab27a is the Rab most affected in CHM lymphoblasts and hypothesised that the selective dysfunction of Rab27a (and possibly a few other Rab GTPases) plays an essential role in the retinal degenerative process. RESULTS: To investigate this hypothesis, we generated several lines of dominant-negative, constitutively-active and wild-type Rab27a (and Rab27b) transgenic mice whose expression was driven either by the pigment cell-specific tyrosinase promoter or the ubiquitous β-actin promoter. High levels of mRNA and protein were observed in transgenic lines expressing wild-type or constitutively active Rab27a and Rab27b. However, only modest levels of transgenic protein were expressed. Pulse-chase experiments suggest that the dominant-negative proteins, but not the constitutively-active or wild type proteins, are rapidly degraded. Consistently, no significant phenotype was observed in our transgenic lines. Coat-colour was normal, indicating normal Rab27a activity. Retinal function as determined by fundoscopy, angiography, electroretinography and histology was also normal. CONCLUSIONS: We suggest that the instability of the dominant-negative mutant Rab27 proteins in vivo precludes the use of this approach to generate mouse models of disease caused by Rab27 GTPases