Analysis of the miRNA expression from the adipose tissue surrounding the adrenal neoplasia

BackgroundPrimary aldosteronism (PA) is characterized by several metabolic changes such as insulin resistance, metabolic syndrome, and adipose tissue (AT) inflammation. Mi(cro)RNAs (miRNAs) are a class of non-coding small RNA molecules known to be critical regulators in several cellular processes associated with AT dysfunction. The aim of this study was to evaluate the expression of some miRNAs in visceral and subcutaneous AT in patients undergoing adrenalectomy for aldosterone-secreting adrenal adenoma (APA) compared to the samples of AT obtained in patients undergoing adrenalectomy for non-functioning adrenal mass (NFA). MethodsThe quantitative expression of selected miRNA using real-time PCR was analyzed in surrounding adrenal neoplasia, peri-renal, and subcutaneous AT samples of 16 patients with adrenalectomy (11 patients with APA and 5 patients with NFA). ResultsReal-time PCR cycles for miRNA-132, miRNA-143, and miRNA-221 in fat surrounding adrenal neoplasia and in peri-adrenal AT were significantly higher in APA than in patients with NFA. Unlike patients with NFA, miRNA-132, miRNA-143, miRNA-221, and miRNA-26b were less expressed in surrounding adrenal neoplasia AT compared to subcutaneous AT in patients with APA. ConclusionThis study, conducted on tissue expression of miRNAs, highlights the possible pathophysiological role of some miRNAs in determining the metabolic alterations in patients with PA

The synergism between DHODH inhibitors and dipyridamole leads to metabolic lethality in acute myeloid leukemia

Dihydroorotate Dehydrogenase (DHODH) is a key enzyme of the de novo pyrimidine biosynthesis, whose inhibition can induce differentiation and apoptosis in acute myeloid leukemia (AML). DHODH inhibitors had shown promising in vitro and in vivo activity on solid tumors, but their effectiveness was not confirmed in clinical trials, probably because cancer cells exploited the pyrimidine salvage pathway to survive. Here, we investigated the antileukemic activity of MEDS433, the DHODH inhibitor developed by our group, against AML. Learning from previous failures, we mimicked human conditions (performing experiments in the presence of physiological uridine plasma levels) and looked for synergic combinations to boost apoptosis, including classical antileukemic drugs and dipyridamole, a blocker of the pyrimidine salvage pathway. MEDS433 induced apoptosis in multiple AML cell lines, not only as a consequence of differentiation, but also directly. Its combination with antileukemic agents further increased the apoptotic rate, but when experiments were performed in the presence of physiological uridine concentrations, results were less impressive. Conversely, the combination of MEDS433 with dipyridamole induced metabolic lethality and differentiation in all AML cell lines; this extraordinary synergism was confirmed on AML primary cells with different genetic backgrounds and was unaffected by physiological uridine concentrations, predicting in human activity

SUPER VI. A giant molecular halo around a z∼2 quasar

We present the discovery of copious molecular gas in the halo of cid_346, a z = 2.2 quasar studied as part of the SINFONI survey for Unveiling the Physics and Effect of Radiative feedback (SUPER). New Atacama Compact Array (ACA) CO(3−2) observations detect a much higher flux (by a factor of 14 ± 5) than measured on kiloparsec scales (r ≲ 8 kpc) using previous snapshot Atacama Large Millimeter/submillimeter Array data. Such additional CO(3−2) emission traces a structure that extends out to r ∼ 200 kpc in projected size, as inferred through direct imaging and confirmed by an analysis of the uv visibilities. This is the most extended molecular circumgalactic medium (CGM) reservoir that has ever been mapped. It shows complex kinematics, with an overall broad line profile (FWHM = 1000 km s−1) that is skewed towards redshifted velocities up to at least v ∼ 1000 km s−1. Using the optically thin assumption, we estimate a strict lower limit for the total molecular CGM mass observed by ACA of MmolCGM > 1010 M⊙. There is however room for up to MmolCGM ∼ 1.7 × 1012 M⊙, once optically thick CO emission with αCO = 3.6 M⊙ (K km s−1 pc2)−1 and L′CO(3−2)/L′CO(1−0) = 0.5 are assumed. Since cid_346 hosts quasar-driven ionised outflows and since there is no evidence of merging companions or an overdensity, we suggest that outflows may have played a crucial rule in seeding metal-enriched, dense gas on halo scales. However, the origin of such an extended molecular CGM remains unclear

SUPER VII. morphology and kinematics of H alpha emission in AGN host galaxies at cosmic noon using SINFONI

We present spatially resolved H α properties of 21 type 1 AGN host galaxies at z ∼ 2 derived from the SUPER survey. These targets were observed with the adaptive optics capabilities of the SINFONI spectrograph, a near-infrared integral field spectrograph, that provided a median spatial resolution of 0.3 arcsec (∼2 kpc). We model the H α emission line profile in each pixel to investigate whether it traces gas in the narrow line region or if it is associated with star formation. To do this, we first investigate the presence of resolved H α emission after subtracting the AGN PSF. We find extended H α emission in 16 out of the 21 type 1 AGN host galaxies (76 per cent). Based on the BPT diagnostics, optical line flux ratios and line widths (FWHM), we show that the H α emission in five galaxies is ionized by the AGN (30 per cent), in four galaxies by star formation (25 per cent) and for the rest (45 per cent), the ionization source is unconstrained. Two galaxies show extended H α FWHM >600 km s−1, which is interpreted as a part of an AGN-driven outflow. Morphological and kinematic maps of H α emission in targets with sufficient signal-to-noise ratio suggest the presence of rotationally supported discs in six galaxies and possible presence of companions in four galaxies. In two galaxies, we find an anticorrelation between the locations of extended H α emission and [O iii]-based ionized outflows, indicating possible negative feedback at play. However, in the majority of galaxies, we do not find evidence of outflows impacting H α-based star formation

SUPER VII. morphology and kinematics of H α emission in AGN host galaxies at cosmic noon using SINFONI

We present spatially resolved H α properties of 21 type 1 AGN host galaxies at z ∼ 2 derived from the SUPER survey. These targets were observed with the adaptive optics capabilities of the SINFONI spectrograph, a near-infrared integral field spectrograph, that provided a median spatial resolution of 0.3 arcsec (∼2 kpc). We model the H α emission line profile in each pixel to investigate whether it traces gas in the narrow line region or if it is associated with star formation. To do this, we first investigate the presence of resolved H α emission after subtracting the AGN PSF. We find extended H α emission in 16 out of the 21 type 1 AGN host galaxies (76 per cent). Based on the BPT diagnostics, optical line flux ratios and line widths (FWHM), we show that the H α emission in five galaxies is ionized by the AGN (30 per cent), in four galaxies by star formation (25 per cent) and for the rest (45 per cent), the ionization source is unconstrained. Two galaxies show extended H α FWHM >600 km s−1, which is interpreted as a part of an AGN-driven outflow. Morphological and kinematic maps of H α emission in targets with sufficient signal-to-noise ratio suggest the presence of rotationally supported discs in six galaxies and possible presence of companions in four galaxies. In two galaxies, we find an anticorrelation between the locations of extended H α emission and [O III]-based ionized outflows, indicating possible negative feedback at play. However, in the majority of galaxies, we do not find evidence of outflows impacting H α-based star formation

The main sequence at z ∼ 1.3 contains a sizable fraction of galaxies with compact star formation sizes: a new population of early post-starbursts?

Atacama Large Millimeter/submillimeter Array (ALMA) measurements for 93 Herschel-selected galaxies at 1.1 ≤ z ≤ 1.7 in COSMOS reveal a sizable (>29%) population with compact star formation (SF) sizes, lying on average >×3.6 below the optical stellar mass (M ⋆)─size relation of disks. This sample widely spans the star-forming main sequence (MS), having 108 ≤ M ⋆ ≤ 1011.5 M ☉ and 20 ≤ star formation rate (SFR) ≤ 680 M ☉ yr−1. The 32 size measurements and 61 upper limits are measured on ALMA images that combine observations of CO(5─4), CO(4─3), CO(2─1), and λ obs ∼ 1.1─1.3 mm continuum, all tracing the star-forming molecular gas. These compact galaxies have instead normally extended K band sizes, suggesting strong specific SFR gradients. Compact galaxies comprise the 50 ± 18% of MS galaxies at M ⋆ > 1011 M ☉. This is not expected in standard bimodal scenarios, where MS galaxies are mostly steadily growing extended disks. We suggest that compact MS objects are early post-starburst galaxies in which the merger-driven boost of SF has subsided. They retain their compact SF size until either further gas accretion restores premerger galaxy-wide SF, or until becoming quenched. The fraction of merger-affected SF inside the MS seems thus larger than anticipated and might reach ∼50% at the highest M ⋆. The presence of large galaxies above the MS demonstrates an overall poor correlation between galaxy SF size and specific SFR

Dihydroorotate dehydrogenase inhibition reveals metabolic vulnerability in chronic myeloid leukemia

The development of different generations of BCR-ABL1 tyrosine kinase inhibitors (TKIs) has led to the high overall survival of chronic myeloid leukemia (CML) patients. However, there are CML patients who show resistance to TKI therapy and are prone to progress to more advanced phases of the disease. So, implementing an alternative approach for targeting TKIs insensitive cells would be of the essence. Dihydroorotate dehydrogenase (DHODH) is an enzyme in the de novo pyrimidine biosynthesis pathway that is located in the inner membrane of mitochondria. Here, we found that CML cells are vulnerable to DHODH inhibition mediated by Meds433, a new and potent DHODH inhibitor recently developed by our group. Meds433 significantly activates the apoptotic pathway and leads to the reduction of amino acids and induction of huge metabolic stress in CML CD34+ cells. Altogether, our study shows that DHODH inhibition is a promising approach for targeting CML stem/progenitor cells and may help more patients discontinue the therapy

The WISSH QSOs project IX. Cold gas content and environment of luminous QSOs at z~2.4-4.7

Sources at the brightest end of QSO luminosity function during the peak epoch of star formation and black hole accretion (z~2-4, i.e. Cosmic noon) are privileged sites to study the feeding & feedback cycle of massive galaxies. We perform the first systematic study of cold gas properties in the most luminous QSOs, by characterising their host-galaxies and environment. We analyse ALMA, NOEMA and JVLA observations of FIR continuum, CO and [CII] emission lines in eight QSOs ($L_{\rm Bol}>3\times10^{47}$ erg/s) from the WISSH sample at z~2.4-4.7. We report a 100% emission line detection rate and a 80% detection rate in continuum emission, and we find CO emission to be consistent with the steepest CO ladders observed so far. Sub-mm data reveal presence of (one or more) bright companion galaxies around 80% of WISSH QSOs, at projected distances of 6-130 kpc. We observe a variety of sizes for the molecular gas reservoirs (1.7-10 kpc), associated with rotating disks with disturbed kinematics. WISSH QSOs typically show lower CO luminosity and higher star formation efficiency than FIR matched, z~0-3 main-sequence galaxies, implying that, given the observed SFR ~170-1100 $M_\odot$/yr, molecular gas is converted into stars on <50 Myr. Most targets show extreme dynamical to black-hole mass ratios $M_{\rm dyn}/M_{\rm BH}\sim3-10$, two orders of magnitude smaller than local relations. The molecular gas fraction in WISSH hosts is lower by a factor of ~10-100 than in star forming galaxies with similar $M_*$. WISSH QSOs undergo an intense growth phase of both the central SMBH and host-galaxy. They pinpoint high-density sites where giant galaxies assemble and mergers play a major role in the build-up of the final host-galaxy mass. The observed low molecular gas fraction and short depletion timescale are likely due to AGN feedback, as traced by fast AGN-driven ionised outflows in all our targets.Comment: Accepted for publication in A&