Safety and efficacy of parsaclisib in combination with obinutuzumab and bendamustine in patients with relapsed or refractory follicular lymphoma (CITADEL-102): A phase 1 study

Parsaclisib is a potent and highly selective PI3Kδ inhibitor that has shown clinical benefit with monotherapy in a phase 2 study in relapsed or refractory (R/R) follicular lymphoma (FL). CITADEL-102 (NCT03039114), a phase 1, multicenter study, assessed the efficacy of parsaclisib in combination with obinutuzumab and bendamustine in patients with R/R FL. Patients were ≥18 years of age with histologically confirmed and documented CD20-positive FL, and R/R to previous rituximab-containing treatment regimens. Part one (safety run-in) determined the maximum tolerated dose of parsaclisib in combination with standard dosage regimens of obinutuzumab and bendamustine. Part two (dose expansion) was an open-label, single-group design evaluating safety, tolerability (primary endpoint), and efficacy (secondary endpoint) of parsaclisib combination therapy. Twenty-six patients were enrolled in CITADEL-102 and all patients received parsaclisib 20 mg once daily for 8 weeks, followed by 20 mg once weekly thereafter, in combination with obinutuzumab and bendamustine. One patient in safety run-in experienced a dose-limiting toxicity of grade 4 QT interval prolongation that was considered related to parsaclisib. Eight patients (30.8%) discontinued treatment due to treatment-emergent adverse events (TEAEs) of colitis (2 [7.7%]), alanine aminotransferase and aspartate aminotransferase increase (both in one patient [3.8%]), neutropenia, thrombocytopenia, QT prolongation, tonsil cancer, and maculopapular rash (each 1 [3.8%]). The most common reported TEAEs were pyrexia (53.8%), neutropenia (50.0%), and diarrhea (46.2%). Twenty-three patients (88.5%) experienced grade 3 or 4 TEAEs; the most common were neutropenia (34.6%), febrile neutropenia (23.1%), and thrombocytopenia (19.2%). Seventeen patients (65.4%) had a complete response and 3 patients (11.5%) had a partial response, for an objective response rate of 76.9%. Overall, results from CITADEL-102 suggest that the combination of parsaclisib with obinutuzumab and bendamustine did not result in unexpected safety events, with little evidence of synergistic toxicity, and demonstrated preliminary efficacy in patients with R/R FL who progressed following prior rituximab-containing regimens

The WISSH quasars project: VIII. Outflows and metals in the circum-galactic medium around the hyper-luminous z 3c 3.6 quasar J1538+08

Context. In recent years, Ly\u3b1 nebulae have been routinely detected around high redshift, radio-quiet quasars thanks to the advent of the highly sensitive integral field spectrographs. Constraining the physical properties of the Ly\u3b1 nebulae is crucial for a full understanding of the circum-galactic medium (CGM). The CGM acts both as a repository for intergalactic and galactic baryons as well as a venue of feeding and feedback processes. The most luminous quasars are privileged test-beds to study these processes, given their large ionising fluxes and dense CGM environments in which they are expected to be embedded. Aims. We aim to characterise the rest-frame ultraviolet (UV) emission lines in the CGM around a hyper-luminous, broad emission line, radio-quiet quasar at z 3c 3.6, which exhibits powerful outflows at both nuclear and host galaxy scales. Methods. We analyse VLT/MUSE observations of the quasar J1538+08 (Lbol = 6 7 1047 erg s-1), and we performed a search for extended UV emission lines to characterise its morphology, emissivity, kinematics, and metal content. Results. We report the discovery of a very luminous ( 3c2 7 1044 erg s-1), giant Ly\u3b1 nebula and a likely associated extended (75 kpc) CIV nebula. The Ly\u3b1 nebula emission exhibits moderate blueshift ( 3c440 km s-1) compared to the quasar systemic redshift and a large average velocity dispersion (\u3c3\u304v 3c700 km s-1) across the nebula, while the CIV nebula shows average velocity dispersion of \u3c3\u304v 3c350 km s-1. The Ly\u3b1 line profile exhibits a significant asymmetry towards negative velocity values at 20-30 kpc south of the quasar and is well parametrised by the following two Gaussian components: a narrow (\u3c3 3c 470 km s-1) systemic one plus a broad (\u3c3 3c 1200 km s-1), blueshifted ( 3c1500 km s-1) one. Conclusions. Our analysis of the MUSE observation of J1538+08 reveals metal-enriched CGM around this hyper-luminous quasar. Furthermore, our detection of blueshifted emission in the emission profile of the Ly\u3b1 nebula suggests that powerful nuclear outflows can propagate through the CGM over tens of kiloparsecs

The WISSH quasars project IV. Broad line region versus kiloparsec-scale winds

Winds accelerated by active galactic nuclei (AGNs) are invoked in the most successful models of galaxy evolution to explain the observed physical and evolutionary properties of massive galaxies. Winds are expected to deposit energy and momentum into the interstellar medium (ISM), thus regulating both star formation and supermassive black hole (SMBH) growth. We undertook a multiband observing program aimed at obtaining a complete census of winds in a sample of WISE/SDSS selected hyper-luminous (WISSH) quasars (QSOs) at z ≈ 2–4. We analyzed the rest-frame optical (i.e. LBT/LUCI and VLT/SINFONI) and UV (i.e. SDSS) spectra of 18 randomly selected WISSH QSOs to measure the SMBH mass and study the properties of winds both in the narrow line region (NLR) and broad line region (BLR) traced by blueshifted or skewed [OIII] and CIV emission lines, respectively. These WISSH QSOs are powered by SMBH with masses ≳109 M⊙ accreting at 0.4 < λEdd < 3.1. We found the existence of two subpopulations of hyper-luminous QSOs characterized by the presence of outflows at different distances from the SMBH. One population (i.e. [OIII] sources) exhibits powerful [OIII] outflows, a rest-frame equivalent width (REW) of the CIV emission REWCIV ≈ 20–40 Å, and modest CIV velocity shift (vCIVpeak) with respect to the systemic redshift (vCIVpeak <~ 2000 km s−1). The second population (i.e. Weak [OIII] sources), representing ~70% of the analyzed WISSH QSOs, shows weak or absent [OIII] emission and an extremely large blueshifted CIV emission (vCIVpeak up to ~8000 km s−1 and REWCIV <~ 20 Å). We propose two explanations for the observed behavior of the strength of the [OIII] emission in terms of the orientation effects of the line of sight and ionization cone. The dichotomy in the presence of BLR and NLR winds could be likely due to inclination effects considering a polar geometry scenario for the BLR winds. In a few cases these winds are remarkably as powerful as those revealed in the NLR in the [OIII] QSOs (Ėkin ~ 1044−45 erg s−1). We also investigated the dependence of these CIV winds on fundamental AGN parameters such as bolometric luminosity (LBol), Eddington ratio (λEdd), and UV-to-X-ray continuum slope (αOX). We found a strong correlation with LBol and an anti-correlation with αOX whereby the higher the luminosity, the steeper the ionizing continuum described by means of αOX and the larger the blueshift of the CIV emission line. Finally, the observed dependence vCIVpeak ∝ LBol0.28 ± 0.04 is consistent with a radiatively-driven-winds scenario, where a strong UV continuum is necessary to launch the wind and a weakness of the X-rayemission is fundamental to prevent overionization of the wind itself

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&

AGN wind scaling relations and the co-evolution of black holes and galaxies

Feedback from accreting SMBHs is often identified as the main mechanism responsible for regulating star-formation in AGN host galaxies. However, the relationships between AGN activity, radiation, winds, and star-formation are complex and still far from being understood. We study scaling relations between AGN properties, host galaxy properties and AGN winds. We then evaluate the wind mean impact on the global star-formation history, taking into account the short AGN duty cycle with respect to that of star-formation. We first collect AGN wind observations for 94 AGN with detected massive winds at sub-pc to kpc spatial scales. We then fold AGN wind scaling relations with AGN luminosity functions, to evaluate the average AGN wind mass-loading factor as a function of cosmic time. We find strong correlations between the AGN molecular and ionised wind mass outflow rates and the AGN bolometric luminosity. The power law scaling is steeper for ionised winds (slope 1.29+/-0.38) than for molecular winds (0.76+/-0.06), meaning that the two rates converge at high bolometric luminosities. The molecular gas depletion timescale and the molecular gas fraction of galaxies hosting powerful AGN winds are 3-10 times shorter and smaller than those of main-sequence galaxies with similar SFR, stellar mass and redshift. These findings suggest that, at high AGN bolometric luminosity, the reduced molecular gas fraction may be due to the destruction of molecules by the wind, leading to a larger fraction of gas in the atomic ionised phase. The AGN wind mass-loading factor $\eta=\dot M_{OF}/SFR$ is systematically higher than that of starburst driven winds. Our analysis shows that AGN winds are, on average, powerful enough to clean galaxies from their molecular gas only in massive systems at z<=2, i.e. a strong form of co-evolution between SMBHs and galaxies appears to break down for the least massive galaxies.This work was supported by ASI/INAF contract I/009/10/0 and INAF PRIN 2011, 2012 and 2014. MB acknowledges support from the FP7 Career Integration Grant “eEASy” (CIG 321913). LZ acknowledges support from ASI/INAF grant I/037/12/0. CF acknowledges funding from the European Union Horizon 2020 research and innovation programme under the Marie SklodowskaCurie grant agreement No 664931. CC acknowledges funding from the European Union Horizon 2020 research and innovation programme under the Marie SklodowskaCurie grant agreement No 664931 and support from Swiss National Science Foundation Grants PP00P2 138979 and PP00P2 166159. RM acknowledges the ERC Advanced Grant 695671 QUENCH and support from the Science and Technology Facilities Council (STFC)

A study of CP violation in the decays B±→[K+K-π+π-]Dh± (h= K, π) and B±→[π+π-π+π-]Dh±

The first study of CP violation in the decay mode B±→[K+K-π+π-]Dh± , with h= K, π , is presented, exploiting a data sample of proton–proton collisions collected by the LHCb experiment that corresponds to an integrated luminosity of 9 \,fb - 1 . The analysis is performed in bins of phase space, which are optimised for sensitivity to local CP asymmetries. CP -violating observables that are sensitive to the angle γ of the Unitarity Triangle are determined. The analysis requires external information on charm-decay parameters, which are currently taken from an amplitude analysis of LHCb data, but can be updated in the future when direct measurements become available. Measurements are also performed of phase-space integrated observables for B±→[K+K-π+π-]Dh± and B±→[π+π-π+π-]Dh± decays

Study of charmonium decays to KS0KπK^0_S K \pi in the B→(KS0Kπ)KB \to (K^0_S K \pi) K channels

A study of the $B^+\to K^0_SK^+K^-\pi^+$ and $B^+\to K^0_SK^+K^+\pi^-$ decays is performed using proton-proton collisions at center-of-mass energies of 7, 8 and 13 TeV at the LHCb experiment. The $K^0_SK \pi$ invariant mass spectra from both decay modes reveal a rich content of charmonium resonances. New precise measurements of the $\eta_c$ and $\eta_c(2S)$ resonance parameters are performed and branching fraction measurements are obtained for $B^+$ decays to $\eta_c$, $J/\psi$, $\eta_c(2S)$ and $\chi_{c1}$ resonances. In particular, the first observation and branching fraction measurement of $B^+ \to \chi_{c0} K^0 \pi^+$ is reported as well as first measurements of the $B^+\to K^0K^+K^-\pi^+$ and $B^+\to K^0K^+K^+\pi^-$ branching fractions. Dalitz plot analyses of $\eta_c \to K^0_SK\pi$ and $\eta_c(2S) \to K^0_SK\pi$ decays are performed. A new measurement of the amplitude and phase of the $K \pi$ $S$-wave as functions of the $K \pi$ mass is performed, together with measurements of the $K^*_0(1430)$, $K^*_0(1950)$ and $a_0(1700)$ parameters. Finally, the branching fractions of $\chi_{c1}$ decays to $K^*$ resonances are also measured.Comment: All figures and tables, along with any supplementary material and additional information, are available at https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-051.html (LHCb public pages

Measurement of lepton universality parameters in B+→K+ℓ+ℓ−B^+\to K^+\ell^+\ell^- and B0→K∗0ℓ+ℓ−B^0\to K^{*0}\ell^+\ell^- decays

A simultaneous analysis of the $B^+\to K^+\ell^+\ell^-$ and $B^0\to K^{*0}\ell^+\ell^-$ decays is performed to test muon-electron universality in two ranges of the square of the dilepton invariant mass, $q^2$. The measurement uses a sample of beauty meson decays produced in proton-proton collisions collected with the LHCb detector between 2011 and 2018, corresponding to an integrated luminosity of $9$ $\text{fb}^{-1}$. A sequence of multivariate selections and strict particle identification requirements produce a higher signal purity and a better statistical sensitivity per unit luminosity than previous LHCb lepton universality tests using the same decay modes. Residual backgrounds due to misidentified hadronic decays are studied using data and included in the fit model. Each of the four lepton universality measurements reported is either the first in the given $q^2$ interval or supersedes previous LHCb measurements. The results are compatible with the predictions of the Standard Model.Comment: All figures and tables, along with any supplementary material and additional information, are available at https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-045.html (LHCb public pages

Search for D∗(2007)0→μ+μ−D^{*}(2007)^0\to\mu^+\mu^- in B−→π−μ+μ−B^-\to\pi^-\mu^+\mu^- decays

The very rare $D^{*}(2007)^0\to\mu^+\mu^-$ decay is searched for by analysing $B^-\to\pi^-\mu^+\mu^-$ decays. The analysis uses a sample of beauty mesons produced in proton-proton collisions collected with the LHCb detector between 2011 and 2018, corresponding to an integrated luminosity of 9 fb$^{-1}$. The signal signature corresponds to simultaneous peaks in the $\mu^+\mu^-$ and $\pi^-\mu^+\mu^-$ invariant masses. No evidence for an excess of events over background is observed and an upper limit is set on the branching fraction of the decay at ${\cal B}(D^{*}(2007)^0\to\mu^+\mu^-) < 2.6\times 10^{-8}$ at $90\%$ confidence level. This is the first limit on the branching fraction of $D^{*}(2007)^0\to\mu^+\mu^-$ decays and the most stringent limit on $D^{*}(2007)^0$ decays to leptonic final states. The analysis is the first search for a rare charm-meson decay exploiting production via beauty decays.Comment: All figures and tables, along with machine-readable versions and any supplementary material and additional information, are available at https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2023-004.html (LHCb public pages

Measurement of the CKM angle γ\gamma in the B0→DK∗0B^0 \to DK^{*0} channel using self-conjugate D→KS0h+h−D \to K_S^0 h^+ h^- decays

A model-independent study of CP violation in $B^0 \to DK^{*0}$ decays is presented using data corresponding to an integrated luminosity of 9fb$^{-1}$ collected by the LHCb experiment at centre-of-mass energies of $\sqrt{s}=7, \, 8$ and $13$TeV. The CKM angle $\gamma$ is determined by examining the distributions of signal decays in phase-space bins of the self-conjugate $D \to K_S^0 h^+ h^-$ decays, where $h = \pi, K$. Observables related to CP violation are measured and the angle $\gamma$ is determined to be $\gamma=(49^{+ 23}_{-18})^\circ$. Measurements of the amplitude ratio and strong-phase difference between the favoured and suppressed $B^0$ decays are also presented.Comment: All figures and tables, along with machine-readable versions and any supplementary material and additional information, are available at https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2023-009.html (LHCb public pages