Messing Up the Cancer Stem Cell Chemoresistance Mechanisms Supported by Tumor Microenvironment

Despite the recent advances in cancer patient management and in the development of targeted therapies, systemic chemotherapy is currently used as a first-line treatment for many cancer types. After an initial partial response, patients become refractory to standard therapy fostering rapid tumor progression. Compelling evidence highlights that the resistance to chemotherapeutic regimens is a peculiarity of a subpopulation of cancer cells within tumor mass, known as cancer stem cells (CSCs). This cellular compartment is endowed with tumor-initiating and metastasis formation capabilities. CSC chemoresistance is sustained by a plethora of grow factors and cytokines released by neighboring tumor microenvironment (TME), which is mainly composed by adipocytes, cancer-associated fibroblasts (CAFs), immune and endothelial cells. TME strengthens CSC refractoriness to standard and targeted therapies by enhancing survival signaling pathways, DNA repair machinery, expression of drug efflux transporters and antiapoptotic proteins. In the last years many efforts have been made to understand CSCTME crosstalk and develop therapeutic strategy halting this interplay. Here, we report the combinatorial approaches, which perturb the interaction network between CSCs and the different component of TME

Effective targeting of breast cancer stem cells by combined inhibition of Sam68 and Rad51

: Breast cancer (BC) is the second cause of cancer-related deceases in the worldwide female population. Despite the successful treatment advances, 25% of BC develops resistance to current therapeutic regimens, thereby remaining a major hurdle for patient management. Current therapies, targeting the molecular events underpinning the adaptive resistance, still require effort to improve BC treatment. Using BC sphere cells (BCSphCs) as a model, here we showed that BC stem-like cells express high levels of Myc, which requires the presence of the multifunctional DNA/RNA binding protein Sam68 for the DNA-damage repair. Analysis of a cohort of BC patients displayed that Sam68 is an independent negative factor correlated with the progression of the disease. Genetic inhibition of Sam68 caused a defect in PARP-induced PAR chain synthesis upon DNA-damaging insults, resulting in cell death of TNBC cells. In contrast, BC stem-like cells were able to survive due to an upregulation of Rad51. Importantly, the inhibition of Rad51 showed synthetic lethal effect with the silencing of Sam68, hampering the cell viability of patient-derived BCSphCs and stabilizing the growth of tumor xenografts, including those TNBC carrying BRCA mutation. Moreover, the analysis of Myc, Sam68 and Rad51 expression demarcated a signature of a poor outcome in a large cohort of BC patients. Thus, our findings suggest the importance of targeting Sam68-PARP1 axis and Rad51 as potential therapeutic candidates to counteract the expansion of BC cells with an aggressive phenotype

Probing black hole accretion tracks, scaling relations, and radiative efficiencies from stacked X-ray active galactic nuclei

The masses of supermassive black holes at the centres of local galaxies appear to be tightly correlated with the mass and velocity dispersions of their galactic hosts. However, the local Mbh–Mstar relation inferred from dynamically measured inactive black holes is up to an order-of-magnitude higher than some estimates from active black holes, and recent work suggests that this discrepancy arises from selection bias on the sample of dynamical black hole mass measurements. In this work, we combine X-ray measurements of the mean black hole accretion luminosity as a function of stellar mass and redshift with empirical models of galaxy stellar mass growth, integrating over time to predict the evolving Mbh–Mstar relation. The implied relation is nearly independent of redshift, indicating that stellar and black hole masses grow, on average, at similar rates. Matching the de-biased local Mbh–Mstar relation requires a mean radiative efficiency ε ≳ 0.15, in line with theoretical expectations for accretion on to spinning black holes. However, matching the ‘raw’ observed relation for inactive black holes requires ε ∼ 0.02, far below theoretical expectations. This result provides independent evidence for selection bias in dynamically estimated black hole masses, a conclusion that is robust to uncertainties in bolometric corrections, obscured active black hole fractions, and kinetic accretion efficiency. For our fiducial assumptions, they favour moderate-to-rapid spins of typical supermassive black holes, to achieve ε ∼ 0.12–0.20. Our approach has similarities to the classic Soltan analysis, but by using galaxy-based data instead of integrated quantities we are able to focus on regimes where observational uncertainties are minimized

A quasar-galaxy mixing diagram: quasar spectral energy distribution shapes in the optical to near-infrared

We define a quasar-galaxy mixing diagram using the slopes of their spectral energy distributions (SEDs) from 1 \u3bcm to 3000 \uc5 and from 1 to 3 \u3bcm in the rest frame. The mixing diagram can easily distinguish among quasar-dominated, galaxy-dominated and reddening-dominated SED shapes. By studying the position of the 413 XMM-selected type 1 AGN in the wide-field `Cosmic Evolution Survey' in the mixing diagram, we find that a combination of the Elvis et al. mean quasar SED with various contributions from galaxy emission and some dust reddening is remarkably effective in describing the SED shape from 0.3 to 3 \u3bcm for large ranges of redshift, luminosity, black hole mass and Eddington ratio of type 1 AGN. In particular, the location in the mixing diagram of the highest luminosity AGN is very close (within 1\u3c3) to that of the Elvis et al. SED template. The mixing diagram can also be used to estimate the host galaxy fraction and reddening in quasar. We also show examples of some outliers which might be AGN in different evolutionary stages compared to the majority of AGN in the quasar-host galaxy co-evolution cycle

VizieR Online Data Catalog: Spectrum of QSO XMMC 2028 (Brusa+, 2015)

Observations of the CO(3-2) transition of XID2028, redshifted to 2mm, obtained with the PdBI Interferometer. Dates of observations: 31-May, 1, 6, June 2014. XID2028 was observed with receivers tuned to a frequency of 133.37GHz, corresponding to the expected frequency of the CO(3-2) emission line, with the PdBI array in the (D) configuration. The continuum is not detected with a 3σ upper limit on its flux of 0.3mJy

Spectral energy distributions of type 1 AGN in XMM-COSMOS – II. Shape evolution

The mid-infrared-to-ultraviolet (0.1–10 μm) spectral energy distribution (SED) shapes of 407 X-ray-selected radio-quiet type 1 active galactic nuclei (AGN) in the wide-field ‘Cosmic Evolution Survey’ (COSMOS) have been studied for signs of evolution. For a sub-sample of 200 radio-quiet quasars with black hole mass estimates and host galaxy corrections, we studied their mean SEDs as a function of a broad range of redshift, bolometric luminosity, black hole mass and Eddington ratio, and compared them with the Elvis et al. (E94) type 1 AGN mean SED. We found that the mean SEDs in each bin are closely similar to each other, showing no statistical significant evidence of dependence on any of the analysed parameters. We also measured the SED dispersion as a function of these four parameters, and found no significant dependences. The dispersion of the XMM-COSMOS SEDs is generally larger than E94 SED dispersion in the ultraviolet, which might be due to the broader ‘window function’ for COSMOS quasars, and their X-ray-based selection

The Imaging X-ray Polarimetry Explorer (IXPE): Technical Overview

The Imaging X-ray Polarimetry Explorer (IXPE) will expand the information space for study of cosmic sources, by adding linear polarization to the properties (time, energy, and position) observed in x-ray astronomy. Selected in 2017 January as a NASA Astrophysics Small Explorer (SMEX) mission, IXPE will be launched into an equatorial orbit in 2021. The IXPE mission will provide scientifically meaningful measurements of the x-ray polarization of a few dozen sources in the 2-8 keV band, including polarization maps of several x-ray-bright extended sources and phase-resolved polarimetry of many bright pulsating x-ray sources

Observations of 4U 1626-67 with the Imaging X-ray Polarimetry Explorer

We present measurements of the polarization of X-rays in the 2-8 keV band from the pulsar in the ultracompact low mass X-ray binary 4U1626-67 using data from the Imaging X-ray Polarimetry Explorer (IXPE). The 7.66 s pulsations were clearly detected throughout the IXPE observations as well as in the NICER soft X-ray observations, which we use as the basis for our timing analysis and to constrain the spectral shape over 0.4-10 keV energy band. Chandra HETGS high-resolution X-ray spectra were also obtained near the times of the IXPE observations for firm spectral modeling. We find an upper limit on the pulse-averaged linear polarization of <4% (at 95% confidence). Similarly, there was no significant detection of polarized flux in pulse phase intervals when subdividing the bandpass by energy. However, spectropolarimetric modeling over the full bandpass in pulse phase intervals provide a marginal detection of polarization of the power-law spectral component at the 4.8 +/- 2.3% level (90% confidence). We discuss the implications concerning the accretion geometry onto the pulsar, favoring two-component models of the pulsed emission.Comment: 19 pages, 7 figures, 7 tables; accepted for publication in the Astrophysical Journa

X-ray polarimetry reveals the magnetic field topology on sub-parsec scales in Tycho's supernova remnant

Supernova remnants are commonly considered to produce most of the Galactic cosmic rays via diffusive shock acceleration. However, many questions about the physical conditions at shock fronts, such as the magnetic-field morphology close to the particle acceleration sites, remain open. Here we report the detection of a localized polarization signal from some synchrotron X-ray emitting regions of Tycho's supernova remnant made by the Imaging X-ray Polarimetry Explorer. The derived polarization degree of the X-ray synchrotron emission is 9+/-2% averaged over the whole remnant, and 12+/-2% at the rim, higher than the 7-8% polarization value observed in the radio band. In the west region the polarization degree is 23+/-4%. The X-ray polarization degree in Tycho is higher than for Cassiopeia A, suggesting a more ordered magnetic-field or a larger maximum turbulence scale. The measured tangential polarization direction corresponds to a radial magnetic field, and is consistent with that observed in the radio band. These results are compatible with the expectation of turbulence produced by an anisotropic cascade of a radial magnetic-field near the shock, where we derive a magnetic-field amplification factor of 3.4+/-0.3. The fact that this value is significantly smaller than those expected from acceleration models is indicative of highly anisotropic magnetic-field turbulence, or that the emitting electrons either favor regions of lower turbulence, or accumulate close to where the magnetic-field orientation is preferentially radially oriented due to hydrodynamical instabilities.Comment: 31 pages, 7 figures, 3 tables. Accepted for publication in ApJ. Revised versio