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

Tailoring CD19xCD3-DART exposure enhances T-cells to eradication of B-cell neoplasms.

Many patients with B-cell malignancies can be successfully treated, although tumor eradication is rarely achieved. T-cell-directed killing of tumor cells using engineered T-cells or bispecific antibodies is a promising approach for the treatment of hematologic malignancies. We investigated the efficacy of CD19xCD3 DART bispecific antibody in a broad panel of human primary B-cell malignancies. The CD19xCD3 DART identified 2 distinct subsets of patients, in which the neoplastic lymphocytes were eliminated with rapid or slow kinetics. Delayed responses were always overcome by a prolonged or repeated DART exposure. Both CD4 and CD8 effector cytotoxic cells were generated, and DART-mediated killing of CD4+ cells into cytotoxic effectors required the presence of CD8+ cells. Serial exposures to DART led to the exponential expansion of CD4 + and CD8 + cells and to the sequential ablation of neoplastic cells in absence of a PD-L1-mediated exhaustion. Lastly, patient-derived neoplastic B-cells (B-Acute Lymphoblast Leukemia and Diffuse Large B Cell Lymphoma) could be proficiently eradicated in a xenograft mouse model by DART-armed cytokine induced killer (CIK) cells. Collectively, patient tailored DART exposures can result in the effective elimination of CD19 positive leukemia and B-cell lymphoma and the association of bispecific antibodies with unmatched CIK cells represents an effective modality for the treatment of CD19 positive leukemia/lymphoma

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

The ultra-dense, interacting environment of a dual AGN at z ∼\sim 3.3 revealed by JWST/NIRSpec IFS

LBQS 0302-0019 is a blue quasar (QSO) at z ~ 3.3, hosting powerful outflows, and residing in a complex environment consisting of an obscured AGN candidate, and multiple companions, all within 30 kpc in projection. We use JWST NIRSpec IFS observations to characterise the ionized gas in this complex system. We develop a procedure to correct for the spurious oscillations (or 'wiggles') in NIRSpec single-spaxel spectra, due to the spatial under-sampling of the point spread function. We perform a quasar-host decomposition with the QDeblend3D tools, and use multi-component kinematic decomposition of the optical emission line profiles to infer the physical properties of the emitting gas. The quasar-host decomposition allows us to identify i) a low-velocity component possibly tracing a warm rotating disk, with a dynamical mass Mdyn $\sim 10^{11}$ Msun and a rotation-to-random motion ratio $v_{rot}$/$\sigma_0 \sim 2$; ii) a spatially unresolved ionised outflow, with a velocity of $\sim$ 1000 km/s and an outflow mass rate of $\sim 10^4$ Msun/yr. We also detect eight interacting companion objects close to LBQS 0302-0019. Optical line ratios confirm the presence of a second, obscured AGN at $\sim 20$ kpc of the primary QSO; the dual AGN dominates the ionization state of the gas in the entire NIRSpec field-of-view. This work has unveiled with unprecedented detail the complex environment of this dual AGN, which includes nine interacting companions (five of which were previously unknown), all within 30 kpc of the QSO. Our results support a scenario where mergers can trigger dual AGN, and can be important drivers for rapid early SMBH growth.Comment: 23 pages, 23 figures; accepted for publication by A&

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

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