New Cepheid variables in the young open clusters Berkeley 51 and Berkeley 55

As part of a wider investigation of evolved massive stars in Galactic open clusters, we have spectroscopically identified three candidate classical Cepheids in the little-studied clusters Berkeley 51, Berkeley 55 and NGC 6603. Using new multi-epoch photometry, we confirm that Be 51 #162 and Be 55 #107 are bona fide Cepheids, with pulsation periods of 9.83±0.01 d and 5.850±0.005 d respectively, while NGC 6603 star W2249 does not show significant photometric variability. Using the period-luminosity relationship for Cepheid variables, we determine a distance to Be 51 of 5.3 +1.0 −0.8 kpc and an age of 44 +9 −8 Myr, placing it in a sparsely-attested region of the Perseus arm. For Be 55, we find a distance of 2.2±0.3 kpc and age of 63 +12 −11 Myr, locating the cluster in the Local arm. Taken together with our recent discovery of a long-period Cepheid in the starburst cluster VdBH222, these represent an important increase in the number of young, massive Cepheids known in Galactic open clusters. We also consider new Gaia (data release 2) parallaxes and proper motions for members of Be 51 and Be 55; the uncertainties on the parallaxes do not allow us to refine our distance estimates to these clusters, but the well-constrained proper motion measurements furnish further confirmation of cluster membership. However, future final Gaia parallaxes for such objects should provide valuable independent distance measurements, improving the calibration of the period-luminosity relationship, with implications for the distance ladder out to cosmological scales

NGC 3105: a young open cluster with low metallicity

NGC 3105 is a young open cluster hosting blue, yellow and red supergiants. This rare combination makes it an excellent laboratory to constrain evolutionary models of high-mass stars. It is poorly studied and fundamental parameters such as its age or distance are not well defined. We intend to characterize in an accurate way the cluster as well as its evolved stars, for which we derive for the first time atmospheric parameters and chemical abundances. We identify 126 B-type likely members within a radius of 2.7$\pm$0.6 arcmin, which implies an initial mass, $M_{cl}\approx$4100 M$_{\odot}$. We find a distance of 7.2$\pm$0.7 kpc for NGC 3105, placing it at $R_{GC}$=10.0$\pm$1.2 kpc. Isochrone fitting supports an age of 28$\pm$6 Ma, implying masses around 9.5 M$_{\odot}$ for the supergiants. A high fraction of Be stars ($\approx$25 %) is found at the top of the main sequence down to spectral type b3. From the spectral analysis we estimate for the cluster a $v_{rad}$=+46.9$\pm$0.9 km s$^{-1}$ and a low metallicity, [Fe/H]=-0.29$\pm$0.22. We also have determined, for the first time, chemical abundances for Li, O, Na, Mg, Si, Ca, Ti, Ni, Rb, Y, and Ba for the evolved stars. The chemical composition of the cluster is consistent with that of the Galactic thin disc. An overabundance of Ba is found, supporting the enhanced $s$-process. NGC 3105 has a low metallicity for its Galactocentric distance, comparable to typical LMC stars. It is a valuable spiral tracer in a very distant region of the Carina-Sagittarius spiral arm, a poorly known part of the Galaxy. As one of the few Galactic clusters containing blue, yellow and red supergiants, it is massive enough to serve as a testbed for theoretical evolutionary models close to the boundary between intermediate and high-mass stars.Comment: 18 pages, 13 figures. Accepted for publication in A&

Testing the chemical tagging technique with open clusters

Context. Stars are born together from giant molecular clouds and, if we assume that the priors were chemically homogeneous and well-mixed, we expect them to share the same chemical composition. Most of the stellar aggregates are disrupted while orbiting the Galaxy and most of the dynamic information is lost, thus the only possibility of reconstructing the stellar formation history is to analyze the chemical abundances that we observe today. Aims. The chemical tagging technique aims to recover disrupted stellar clusters based merely on their chemical composition. We evaluate the viability of this technique to recover co-natal stars that are no longer gravitationally bound. Methods. Open clusters are co-natal aggregates that have managed to survive together. We compiled stellar spectra from 31 old and intermediate-age open clusters, homogeneously derived atmospheric parameters, and 17 abundance species, and applied machine learning algorithms to group the stars based on their chemical composition. This approach allows us to evaluate the viability and efficiency of the chemical tagging technique. Results. We found that stars at different evolutionary stages have distinct chemical patterns that may be due to NLTE effects, atomic diffusion, mixing, and biases. When separating stars into dwarfs and giants, we observed that a few open clusters show distinct chemical signatures while the majority show a high degree of overlap. This limits the recovery of co-natal aggregates by applying the chemical tagging technique. Nevertheless, there is room for improvement if more elements are included and models are improved.Comment: accepted for publication in Astronomy and Astrophysics. Corrected typo

ESPRESSO Mass determination of TOI-263b: An extreme inhabitant of the brown dwarf desert

The TESS mission has reported a wealth of new planetary systems around bright and nearby stars amenable for detailed characterization of the planet properties and their atmospheres. However, not all interesting TESS planets orbit around bright host stars. TOI-263b is a validated ultra-short period substellar object in a 0.56-day orbit around a faint (V=18.97) M3.5 dwarf star. The substellar nature of TOI-263b was explored using multi-color photometry, which determined a true radius of 0.87+-0.21 Rj, establishing TOI-263b's nature ranging from an inflated Neptune to a brown dwarf. The orbital period-radius parameter space occupied by TOI-263b is quite unique, which prompted a further characterization of its true nature. Here, we report radial velocity measurements of TOI-263 obtained with 3 VLT units and the ESPRESSO spectrograph to retrieve the mass of TOI-263b. We find that TOI-263b is a brown dwarf with a mass of 61.6+-4.0 Mj. Additionally, the orbital period of the brown dwarf is found to be synchronized with the rotation period of the host star, and the system is found to be relatively active, possibly revealing a star--brown dwarf interaction. All these findings suggest that the system's formation history might be explained via disc fragmentation and later migration to close-in orbits. If the system is found to be unstable, TOI-263 is an excellent target to test the migration mechanisms before the brown dwarf becomes engulfed by its parent star.Comment: Accepted for Publication in Astronomy and Astrophysic

Safety, pharmacokinetics, and antitumor activity of the anti-CEACAM5-DM4 antibody–drug conjugate tusamitamab ravtansine (SAR408701) in patients with advanced solid tumors: first-in-human dose-escalation study

Antibody–drug conjugate; Dose-escalation study; Tusamitamab ravtansineConjugado anticuerpo-fármaco; Estudio de escalada de dosis; Tusamitamab ravtansinaConjugat anticossos-fàrmac; Estudi d'escalada de dosi; Tusamitamab ravtansinaTusamitamab ravtansine (SAR408701) is an antibody–drug conjugate composed of a humanized monoclonal antibody that binds carcinoembryonic antigen-related cell adhesion molecule-5 (CEACAM5) and a cytotoxic maytansinoid that selectively targets CEACAM5-expressing tumor cells. In this phase I dose-escalation study, we evaluated the safety, pharmacokinetics, and preliminary antitumor activity of tusamitamab ravtansine in patients with solid tumors. Patients and methods Eligible patients were aged ≥18 years, had locally advanced/metastatic solid tumors that expressed or were likely to express CEACAM5, and had an Eastern Cooperative Oncology Group Performance Status of 0 or 1. Patients were treated with ascending doses of tusamitamab ravtansine intravenously every 2 weeks (Q2W). The first three dose levels (5, 10, and 20 mg/m2) were evaluated using an accelerated escalation protocol, after which an adaptive Bayesian procedure was used. The primary endpoint was the incidence of dose-limiting toxicities (DLTs) during the first two cycles, graded using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03 criteria. Results Thirty-one patients received tusamitamab ravtansine (range 5-150 mg/m2). The DLT population comprised 28 patients; DLTs (reversible grade 3 microcystic keratopathy) occurred in three of eight patients treated with tusamitamab ravtansine 120 mg/m2 and in two of three patients treated with 150 mg/m2. The maximum tolerated dose was identified as 100 mg/m2. Twenty-two patients (71%) experienced ≥1 treatment-related treatment-emergent adverse event (TEAE), seven patients (22.6%) experienced ≥1 treatment-related grade ≥3 TEAE, and three patients (9.7%) discontinued treatment due to TEAEs. The most common TEAEs were asthenia, decreased appetite, keratopathy, and nausea. Three patients had confirmed partial responses. The mean plasma exposure of tusamitamab ravtansine increased in a dose-proportional manner from 10 to 150 mg/m2. Conclusions Tusamitamab ravtansine had a favorable safety profile with reversible, dose-related keratopathy as the DLT. Based on the overall safety profile, pharmacokinetic data, and Bayesian model recommendations, the maximum tolerated dose of tusamitamab ravtansine was defined as 100 mg/m2 Q2W.This work was supported by Sanofi, France (no grant number)

Two phase I studies of BI 836880, a vascular endothelial growth factor/angiopoietin-2 inhibitor, administered once every 3 weeks or once weekly in patients with advanced solid tumors

BACKGROUND: BI 836880 is a humanized bispecific nanobody® that inhibits vascular endothelial growth factor and angiopoietin-2. Here, we report results from two phase I, nonrandomized, dose-escalation studies (NCT02674152 and NCT02689505; funded by Boehringer Ingelheim) evaluating BI 836880 in patients with confirmed locally advanced or metastatic solid tumors, refractory to standard therapy, or for which standard therapy was ineffective. PATIENTS AND METHODS: Patients aged ≥18 years, with an Eastern Cooperative Oncology Group performance status of 0-2 and adequate organ function received escalating intravenous doses of BI 836880 once every 3 weeks (Q3W; Study 1336.1) or once weekly (QW; Study 1336.6). Primary objectives were maximum tolerated dose (MTD) and recommended phase II dose of BI 836880, based on dose-limiting toxicities (DLTs) during the first cycle. RESULTS: Patients received one of five dosages of 40-1000 mg Q3W (29 patients) or 40-240 mg QW (24 patients). One DLT occurred with Q3W treatment [Grade (G) 3 pulmonary embolism (1000 mg)]. Five DLTs occurred in four patients treated QW [G2 proteinuria (120 mg); G3 hypertension (180 mg); G3 proteinuria and G3 hypertension (240 mg); and G4 respiratory distress (240 mg)]. All patients experienced adverse events, most commonly hypertension with Q3W treatment (89.7%; G3 41.4%), and asthenia with QW treatment (62.5%). Two patients treated Q3W (both 1000 mg) and three patients treated QW (120 mg, 2 patients; 180 mg, 1 patient) experienced partial response. CONCLUSIONS: The MTD of BI 836880 was 720 mg Q3W and 180 mg QW. BI 836880 was generally manageable and demonstrated preliminary efficacy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.govNCT02674152; https://clinicaltrials.gov/ct2/show/NCT02674152 and NCT02689505; https://clinicaltrials.gov/ct2/show/NCT0268950

Efficacy and safety of tacrolimus compared with ciclosporin A in renal transplantation: three-year observational results

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