Dark matter elastic scattering off nuclei can result in the excitation and ionization of the recoiling atom through the so-called Migdal effect. The energy deposition from the ionization electron ...adds to the energy deposited by the recoiling nuclear system and allows for the detection of interactions of sub-GeV/c^{2} mass dark matter. We present new constraints for sub-GeV/c^{2} dark matter using the dual-phase liquid argon time projection chamber of the DarkSide-50 experiment with an exposure of (12 306±184) kg d. The analysis is based on the ionization signal alone and significantly enhances the sensitivity of DarkSide-50, enabling sensitivity to dark matter with masses down to 40 MeV/c^{2}. Furthermore, it sets the most stringent upper limit on the spin independent dark matter nucleon cross section for masses below 3.6 GeV/c^{2}.
We present a search for dark matter particles with sub-GeV/c^{2} masses whose interactions have final state electrons using the DarkSide-50 experiment's (12 306±184) kg d low-radioactivity liquid ...argon exposure. By analyzing the ionization signals, we exclude new parameter space for the dark matter-electron cross section σover ¯_{e}, the axioelectric coupling constant g_{Ae}, and the dark photon kinetic mixing parameter κ. We also set the first dark matter direct-detection constraints on the mixing angle |U_{e4}|^{2} for keV/c^{2} sterile neutrinos.
Histone deacetylase (HDAC) overexpression has been documented in various cancers and may be associated with worse outcomes. Data from early-phase studies of advanced non-small cell lung cancer ...(NSCLC) suggest encouraging antitumor activity with the combination of an HDAC inhibitor and either platinum-based chemotherapy or an EGFR inhibitor; however, toxicity is a limiting factor in the use of pan-HDAC inhibitors. Selective inhibition of HDAC6 may represent a potential therapeutic target and preclinical studies revealed immunomodulatory effects with HDAC6 inhibition, suggesting the potential for combination with immune checkpoint inhibitors. This phase Ib, multicenter, single-arm, open-label, dose-escalation study investigated the HDAC6 inhibitor ACY-241 (citarinostat) plus nivolumab in patients with previously treated advanced NSCLC who had not received a prior HDAC or immune checkpoint inhibitor.
The orally administered ACY-241 dose was escalated (180, 360, or 480 mg once daily). Nivolumab was administered at 240 mg (day 15 of cycle 1, then every 2 weeks thereafter). The primary endpoint was to determine the maximum tolerated dose (MTD) of ACY-241 plus nivolumab. Secondary endpoints included safety, tolerability, and preliminary antitumor activity. Pharmacodynamics was an exploratory endpoint.
A total of 18 patients were enrolled, with 17 patients treated. No dose-limiting toxicities (DLTs) occurred with ACY-241 at 180 or 360 mg; 2 DLTs occurred at 480 mg. The MTD of ACY-241 was 360 mg. The most common grade ≥ 3 treatment-emergent adverse events were dyspnea (n = 3; 18%) and pneumonia (n = 3; 18%). At the 180-mg dose, 1 complete response and 2 partial responses (PRs) were observed. At the 360-mg dose, 3 PRs were observed; 1 patient achieved stable disease (SD) and 1 experienced progressive disease (PD). At the 480-mg dose, no responses were observed; 1 patient achieved SD and 3 experienced PD. Acetylation analyses revealed transient increases in histone and tubulin acetylation levels following treatment. An increase in infiltrating total CD3
T cells was observed following treatment.
The study identified an MTD for ACY-241 plus nivolumab and the data suggest that the combination may be feasible in patients with advanced NSCLC. Responses were observed in patients with advanced NSCLC.
https://clinicaltrials.gov/ct2/show/NCT02635061 (identifier, NCT02635061).
SPC2996 is a novel locked nucleic acid phosphorothioate antisense molecule targeting the mRNA of the Bcl-2 oncoprotein. We investigated the mechanism of action of SPC2996 and the basis for its ...clinically observed immunostimulatory effects in chronic lymphocytic leukemia (CLL). Patients with relapsed CLL were treated with a maximum of six doses of SPC2996 (0.2-6 mg/kg) in a multicenter phase I trial. Microarray-based transcriptional profiling of circulating CLL cells was carried out before and after the first infusion of SPC2996 in 18 patients. Statistically significant transcriptomic changes were observed at doses 4 mg/kg and occurred as early as 24 h after the first infusion of the oligonucleotide. SPC2996 induced the upregulation of 466 genes including a large number of immune response and apoptotic regulator molecules, which were enriched for Toll-like receptor response genes. Serum measurements confirmed the release of pro-inflammatory cytokines including chemokine (C-C motif) ligand 3 (macrophage inflammatory protein 1α) and tumor necrosis factor-α, thereby validating the in vivo transcriptomic data at the protein level. SPC2996 caused a 50% reduction of circulating lymphocytes in five of 18 (28%) patients, which was found to be independent of its immunostimulatory and anti-Bcl-2 effects.
We present a novel approach for the search of dark matter in the DarkSide-50 experiment, relying on Bayesian Networks. This method incorporates the detector response model into the likelihood ...function, explicitly maintaining the connection with the quantity of interest. No assumptions about the linearity of the problem or the shape of the probability distribution functions are required, and there is no need to morph signal and background spectra as a function of nuisance parameters. By expressing the problem in terms of Bayesian Networks, we have developed an inference algorithm based on a Markov Chain Monte Carlo to calculate the posterior probability. A clever description of the detector response model in terms of parametric matrices allows us to study the impact of systematic variations of any parameter on the final results. Our approach not only provides the desired information on the parameter of interest, but also potential constraints on the response model. Our results are consistent with recent published analyses and further refine the parameters of the detector response model.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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