17,952 research outputs found

    Targeting colorectal cancer via its microenvironment by inhibiting IGF-1 receptor-insulin receptor substrate and STAT3 signaling.

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    The tumor microenvironment (TME) exerts critical pro-tumorigenic effects through cytokines and growth factors that support cancer cell proliferation, survival, motility and invasion. Insulin-like growth factor-1 (IGF-1) and signal transducer and activator of transcription 3 (STAT3) stimulate colorectal cancer development and progression via cell autonomous and microenvironmental effects. Using a unique inhibitor, NT157, which targets both IGF-1 receptor (IGF-1R) and STAT3, we show that these pathways regulate many TME functions associated with sporadic colonic tumorigenesis in CPC-APC mice, in which cancer development is driven by loss of the Apc tumor suppressor gene. NT157 causes a substantial reduction in tumor burden by affecting cancer cells, cancer-associated fibroblasts (CAF) and myeloid cells. Decreased cancer cell proliferation and increased apoptosis were accompanied by inhibition of CAF activation and decreased inflammation. Furthermore, NT157 inhibited expression of pro-tumorigenic cytokines, chemokines and growth factors, including IL-6, IL-11 and IL-23 as well as CCL2, CCL5, CXCL7, CXCL5, ICAM1 and TGFβ; decreased cancer cell migratory activity and reduced their proliferation in the liver. NT157 represents a new class of anti-cancer drugs that affect both the malignant cell and its supportive microenvironment

    Evolution and excitation conditions of outflows in high-mass star-forming regions

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    Theoretical models suggest that massive stars form via disk-mediated accretion, with bipolar outflows playing a fundamental role. A recent study toward massive molecular outflows has revealed a decrease of the SiO line intensity as the object evolves. The present study aims at characterizing the variation of the molecular outflow properties with time, and at studying the SiO excitation conditions in outflows associated with massive YSOs. We used the IRAM30m telescope to map 14 massive star-forming regions in the SiO(2-1), SiO(5-4) and HCO+(1-0) outflow lines, and in several dense gas and hot core tracers. Hi-GAL data was used to improve the spectral energy distributions and the L/M ratio, which is believed to be a good indicator of the evolutionary stage of the YSO. We detect SiO and HCO+ outflow emission in all the sources, and bipolar structures in six of them. The outflow parameters are similar to those found toward other massive YSOs. We find an increase of the HCO+ outflow energetics as the object evolve, and a decrease of the SiO abundance with time, from 10^(-8) to 10^(-9). The SiO(5-4) to (2-1) line ratio is found to be low at the ambient gas velocity, and increases as we move to high velocities, indicating that the excitation conditions of the SiO change with the velocity of the gas (with larger densities and/or temperatures for the high-velocity gas component). The properties of the SiO and HCO+ outflow emission suggest a scenario in which SiO is largely enhanced in the first evolutionary stages, probably due to strong shocks produced by the protostellar jet. As the object evolves, the power of the jet would decrease and so does the SiO abundance. During this process, however, the material surrounding the protostar would have been been swept up by the jet, and the outflow activity, traced by entrained molecular material (HCO+), would increase with time.Comment: 31 pages, 10 figures and 5 tables (plus 2 figures and 3 tables in the appendix). Accepted for publication in A&A. [Abstract modified to fit the arXiv requirements.

    Activation of G proteins by GIV-GEF is a pivot point for insulin resistance and sensitivity.

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    Insulin resistance (IR) is a metabolic disorder characterized by impaired insulin signaling and cellular glucose uptake. The current paradigm for insulin signaling centers upon the insulin receptor (InsR) and its substrate IRS1; the latter is believed to be the sole conduit for postreceptor signaling. Here we challenge that paradigm and show that GIV/Girdin, a guanidine exchange factor (GEF) for the trimeric G protein Gαi, is another major hierarchical conduit for the metabolic insulin response. By virtue of its ability to directly bind InsR, IRS1, and phosphoinositide 3-kinase, GIV serves as a key hub in the immediate postreceptor level, which coordinately enhances the metabolic insulin response and glucose uptake in myotubes via its GEF function. Site-directed mutagenesis or phosphoinhibition of GIV-GEF by the fatty acid/protein kinase C-theta pathway triggers IR. Insulin sensitizers reverse phosphoinhibition of GIV and reinstate insulin sensitivity. We also provide evidence for such reversible regulation of GIV-GEF in skeletal muscles from patients with IR. Thus GIV is an essential upstream component that couples InsR to G-protein signaling to enhance the metabolic insulin response, and impairment of such coupling triggers IR. We also provide evidence that GIV-GEF serves as therapeutic target for exogenous manipulation of physiological insulin response and reversal of IR in skeletal muscles

    High spatial resolution and high contrast optical speckle imaging with FASTCAM at the ORM

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    In this paper, we present an original observational approach, which combines, for the first time, traditional speckle imaging with image post-processing to obtain in the optical domain diffraction-limited images with high contrast (1e-5) within 0.5 to 2 arcseconds around a bright star. The post-processing step is based on wavelet filtering an has analogy with edge enhancement and high-pass filtering. Our I-band on-sky results with the 2.5-m Nordic Telescope (NOT) and the lucky imaging instrument FASTCAM show that we are able to detect L-type brown dwarf companions around a solar-type star with a contrast DI~12 at 2" and with no use of any coronographic capability, which greatly simplifies the instrumental and hardware approach. This object has been detected from the ground in J and H bands so far only with AO-assisted 8-10 m class telescopes (Gemini, Keck), although more recently detected with small-class telescopes in the K band. Discussing the advantage and disadvantage of the optical regime for the detection of faint intrinsic fluxes close to bright stars, we develop some perspectives for other fields, including the study of dense cores in globular clusters. To the best of our knowledge this is the first time that high contrast considerations are included in optical speckle imaging approach.Comment: Proceedings of SPIE conference - Ground-based and Airborne Instrumentation for Astronomy III (Conference 7735), San Diego 201

    Chemical abundances of damped Lyman alpha systems in the XQ-100 survey

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    The XQ-100 survey has provided high signal-noise spectra of 100 redshift 3-4.5 quasars with the X-Shooter spectrograph. The metal abundances for 13 elements in the 41 damped Lyman alpha systems (DLAs) identified in the XQ-100 sample are presented, and an investigation into abundances of a variety of DLA classes is conducted. The XQ-100 DLA sample contains five DLAs within 5000 km/s of their host quasar (proximate DLAs; PDLAs) as well as three sightlines which contain two DLAs within 10,000 km/s of each other along the same line-of-sight (multiple DLAs; MDLAs). Combined with previous observations in the literature, we demonstrate that PDLAs with logN(HI)<21.0 show lower [S/H] and [Fe/H] (relative to intervening systems with similar redshift and N(HI)), whilst higher [S/H] and [Si/H] are seen in PDLAs with logN(HI)>21.0. These abundance discrepancies are independent of their line-of-sight velocity separation from the host quasar, and the velocity width of the metal lines (v90). Contrary to previous studies, MDLAs show no difference in [alpha/Fe] relative to single DLAs matched in metallicity and redshift. In addition, we present follow-up UVES data of J0034+1639, a sightline containing three DLAs, including a metal-poor DLA with [Fe/H]=-2.82 (the third lowest [Fe/H] in DLAs identified to date) at z=4.25. Lastly we study the dust-corrected [Zn/Fe], emphasizing that near-IR coverage of X-Shooter provides unprecedented access to MgII, CaII and TiII lines (at redshifts 3-4) to provide additional evidence for subsolar [Zn/Fe] ratio in DLAs.Comment: Accepted to MNRAS. 19 pages plus Appendix material (102 pages total
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