Activin and TGFβ use diverging mitogenic signaling in advanced colon cancer.

BackgroundUnderstanding cell signaling pathways that contribute to metastatic colon cancer is critical to risk stratification in the era of personalized therapeutics. Here, we dissect the unique involvement of mitogenic pathways in a TGFβ or activin-induced metastatic phenotype of colon cancer.MethodMitogenic signaling/growth factor receptor status and p21 localization were correlated in primary colon cancers and intestinal tumors from either AOM/DSS treated ACVR2A (activin receptor 2) -/- or wild type mice. Colon cancer cell lines (+/- SMAD4) were interrogated for ligand-induced PI3K and MEK/ERK pathway activation and downstream protein/phospho-isoform expression/association after knockdown and pharmacologic inhibition of pathway members. EMT was assessed using epithelial/mesenchymal markers and migration assays.ResultsIn primary colon cancers, loss of nuclear p21 correlated with upstream activation of activin/PI3K while nuclear p21 expression was associated with TGFβ/MEK/ERK pathway activation. Activin, but not TGFβ, led to PI3K activation via interaction of ACVR1B and p85 independent of SMAD4, resulting in p21 downregulation. In contrast, TGFβ increased p21 via MEK/ERK pathway through a SMAD4-dependent mechanism. While activin induced EMT via PI3K, TGFβ induced EMT via MEK/ERK activation. In vivo, loss of ACVR2A resulted in loss of pAkt, consistent with activin-dependent PI3K signaling.ConclusionAlthough activin and TGFβ share growth suppressive SMAD signaling in colon cancer, they diverge in their SMAD4-independent pro-migratory signaling utilizing distinct mitogenic signaling pathways that affect EMT. p21 localization in colon cancer may determine a dominant activin versus TGFβ ligand signaling phenotype warranting further validation as a therapeutic biomarker prior to targeting TGFβ family receptors

A pulsational distance to Omega Centauri based on Near-Infrared Period-Luminosity relations of RR Lyrae stars

We present new Near-Infrared (J,K) magnitudes for 114 RR Lyrae stars in the globular cluster Omega Cen (NGC 5139) which we combine with data from the literature to construct a sample of 180 RR Lyrae stars with J and K mean magnitudes on a common photometric system. This is presently the largest such sample in any stellar system. We also present updated predictions for J,K-band Period-Luminosity relations for both fundamental and first-overtone RR Lyrae stars, based on synthetic horizontal branch models with metal abundance ranging from Z=0.0001 to Z=0.004. By adopting for the Omega Cen variables with measured metal abundances an alpha-element enhancement of a factor of 3 (about 0.5 dex) with respect to iron we find a true distance modulus of 13.70 (with a random error of 0.06 and a systematic error of 0.06), corresponding to a distance d=5.5 Kpc (with both random and systematic errors equal to 0.03 Kpc). Our estimate is in excellent agreement with the distance inferred for the eclipsing binary OGLEGC-17, but differ significantly from the recent distance estimates based on cluster dynamics and on high amplitude Delta Scuti stars.Comment: 24 pages, 7 figures, accepted for publication on The Astrophysical Journa

the combination of a smoking cessation programme with rehabilitation increases stop smoking rate

Objective and study design: A parallel group study to investigate the effectiveness of a smoking cessation programme performed during routine rehabilitation practice for outpatients. Patients and methods: The study participants comprised an intervention group of 102 consecutive smokers who underwent a smoking cessation programme in a rehabilitation centre and a control group of 101 consecutive smokers who were referred to a smoking cessation centre in a pulmonary hospital. All participants underwent physical examination, pulmonary function tests and received identical behavioural and/or pharmacological treatment. In addition, the intervention group underwent rehabilitation practice 3 times a week for 3 months. Results: The continuous abstinence rate at 12 months, which was validated by an expired air carbon monoxide concentration of 10 parts per million or less and a household interview, was 68% in the intervention group and 32% in the control group. Multivariable analysis showed that rehabilitation was significantly associated with smoking cessation after ad justing for years of smoking, number of cigarettes smoked, gender and treatment (odds ratio = 4.34, p < 0.001). Conclusion: This study suggests that smoking cessation programmes during routine rehabilitation may be highly effective in helping smoking withdrawal and should be a strongly recommended component of rehabilitation practice

Loss of SMAD4 Is Associated With Poor Tumor Immunogenicity and Reduced PD-L1 Expression in Pancreatic Cancer

Transforming Growth Factor β (TGFβ) is a key mediator of immune evasion in pancreatic ductal adenocarcinoma (PDAC), and the addition of TGFβ inhibitors in select immunotherapy regimens shows early promise. Though the TGFβ target SMAD4 is deleted in approximately 55% of PDAC tumors, the effects of SMAD4 loss on tumor immunity have yet to be fully explored. Using a combination of genomic databases and PDAC specimens, we found that tumors with loss of SMAD4 have a comparatively poor T-cell infiltrate. SMAD4 loss was also associated with a reduction in several chemokines with known roles in T-cell recruitment, which was recapitulated using knockdown of SMAD4 in PDAC cell lines. Accordingly, JURKAT T-cells were poorly attracted to conditioned media from PDAC cells with knockdown of SMAD4 and lost their ability to produce IFNγ. However, while exogenous TGFβ modestly reduced PD-L1 expression in SMAD4-intact cell lines, SMAD4 and PD-L1 positively correlated in human PDAC samples. PD-L1 status was closely related to tumor-infiltrating lymphocytes, particularly IFNγ-producing T-cells, which were more abundant in SMAD4-expressing tumors. Low concentrations of IFNγ upregulated PD-L1 in tumor cells in vitro, even when administered alongside high concentrations of TGFβ. Hence, while SMAD4 may have a modest inhibitory effect on PD-L1 in tumor cells, SMAD4 indirectly promotes PD-L1 expression in the pancreatic tumor microenvironment by enhancing T-cell infiltration and IFNγ biosynthesis. These data suggest that pancreatic cancers with loss of SMAD4 represent a poorly immunogenic disease subtype, and SMAD4 status warrants further exploration as a predictive biomarker for cancer immunotherapy

Star Counts in the Globular Cluster Omega Centauri. I. Bright Stellar Components

We present an extensive photometry on HB, RGB, and MSTO stars in Omega Cen. The central regions of the cluster were covered with a mosaic of F435W, F625W, and F658N-band data collected with ACS/HST. The outer reaches were covered with a large set of U,B,V,I-band data collected with the [email protected] ESO/MPI telescope. The final catalogue includes ~1.7 million stars. We identified ~3,200 likely HB stars and ~12,500 stars brighter than the subgiant branch and fainter than the RGB bumps. The HB morphology changes with the radial distance. The relative number of extreme HB stars decreases from ~30% to ~21% when moving from the center toward the outer regions of the cluster, while the fraction of less hot HB stars increases from ~62% to ~72%. We performed a detailed comparison between observed ratios of different stellar tracers and predictions based on canonical evolutionary models with a primordial helium (Y=0.23) content and metal abundances (Z=0.0002,0.001) that bracket the observed spread in metallicity of Omega Cen stars. We found that the empirical star counts of HB stars are on average larger (30%-40%) than predicted. Moreover, the rate of HB stars is 43% larger than the MSTO rate. The discrepancy between the rate of HB compared with the rate of RG and MSTO stars supports the evidence that we are facing a true excess of HB stars. The same comparison was performed by assuming a mix of stellar populations made with 70% of canonical stars and 30% of He-enhanced stars. The discrepancy between theory and observations decreases by a factor of two when compared with rates predicted by canonical He content models, but still 15%-25% (Y=0.42) and 15%-20% (Y=0.33) higher than observed. Furthermore, the ratio between HB and MSTO star counts are ~24% (Y=0.42) and 30% (Y=0.33) larger than predicted lifetime ratios.Comment: 54 pages, 17 figures,to be published in ApJ, see link at http://stellari.wiki.zoho.co

On the distance and reddening of the starburst galaxy IC10

We present deep and accurate optical photometry of the Local Group starburst galaxy IC10. The photometry is based on two sets of images collected with the Advanced Camera for Surveys and with the Wide Field Planetary Camera 2 on board the Hubble Space Telescope. We provide new estimates of the Red Giant Branch tip (TRGB) magnitude, m_{F814W}^{TRGB}=21.90+-0.03, and of the reddening, E(B-V)=0.78+-0.06, using field stars in the Small Magellanic Cloud (SMC) as a reference. Adopting the SMC and two globulars, Omega Centauri and 47 Tucanae, as references we estimate the distance modulus to IC10: independent calibrations give weighted average distances of mu=24.51+-0.08 (TRGB) and mu=24.56+-0.08 (RR Lyrae). We also provide a new theoretical calibration for the TRGB luminosity, and using these predictions we find a very similar distance to IC10 (mu~24.60+-0.15). These results suggest that IC10 is a likely member of the M31 subgroup.Comment: 4 pages, 4 figures, ApJ Letters accepte

B, V, I photometry of the complete sample of 23 Cepheids in the field of NGC 1866

We present the result of BVI photometry, obtained by using FORS@VLT, of the Cepheids present in the field of the Large Magellanic Cloud cluster NGC 1866. We found the 22 known variables plus an additional new Cepheid located about 10' from the cluster center. The accuracy of the photometry allowed us to derive B, V and I mean magnitudes with an uncertainty lower than 0.02 mag for 22 out of the 23 objects, with the exception of only one Cepheid (WS9) which presents a noisy light curve due to the probable occurrence of image blending. As a result, we provide accurate observational data for a substantial sample of variables all lying at the same distance and with a common original composition. The resulting period-luminosity relations are presented and briefly discussed.Comment: 4 pages, 6 figure, to appear in the proceedings of the Workshop "Stellar pulsation and evolution", 2005. Monte Porzio Catone, Italy. Eds.: A. R. Walker and G. Bon

Relative distances of Omega Centauri and 47 Tucanae

We present precise optical and near-infrared ground-based photometry of two Globular Clusters (GCs): Omega Cen and 47 Tuc. These photometric catalogs are unbiased in the Red Giant Branch (RGB) region close to the tip. We provide new estimates of the RGB tip (TRGB) magnitudes--m_I(TRGB)=9.84+/-0.05, Omega Cen; m_I(TRGB)=9.46+/-0.06, 47 Tuc--and use these to determine the relative distances of the two GCs. We find that distance ratios based on different calibrations of the TRGB, the RR Lyrae stars and kinematic distances agree with each other within one sigma. Absolute TRGB and RR Lyrae distance moduli agree within 0.10--0.15 mag, while absolute kinematic distance moduli are 0.2--0.3 mag smaller. Absolute distances to 47 Tuc based on the Zero-Age-Horizontal-Branch and on the white dwarf fitting agree within 0.1 mag, but they are 0.1--0.3 mag smaller than TRGB and RR Lyrae distances.Comment: 5 pages, 4 figures, accepted for publication by ApJ

Cytoplasmic PML promotes TGF-β-associated epithelial–mesenchymal transition and invasion in prostate cancer

Epithelial–mesenchymal transition (EMT) is a key event that is involved in the invasion and dissemination of cancer cells. Although typically considered as having tumour-suppressive properties, transforming growth factor (TGF)-β signalling is altered during cancer and has been associated with the invasion of cancer cells and metastasis. In this study, we report a previously unknown role for the cytoplasmic promyelocytic leukaemia (cPML) tumour suppressor in TGF-β signalling-induced regulation of prostate cancer-associated EMT and invasion. We demonstrate that cPML promotes a mesenchymal phenotype and increases the invasiveness of prostate cancer cells. This event is associated with activation of TGF-β canonical signalling pathway through the induction of Sma and Mad related family 2 and 3 (SMAD2 and SMAD3) phosphorylation. Furthermore, the cytoplasmic localization of promyelocytic leukaemia (PML) is mediated by its nuclear export in a chromosomal maintenance 1 (CRM1)-dependent manner. This was clinically tested in prostate cancer tissue and shown that cytoplasmic PML and CRM1 co-expression correlates with reduced disease-specific survival. In summary, we provide evidence of dysfunctional TGF-β signalling occurring at an early stage in prostate cancer. We show that this disease pathway is mediated by cPML and CRM1 and results in a more aggressive cancer cell phenotype. We propose that the targeting of this pathway could be therapeutically exploited for clinical benefit