Tusamitamab 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.
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.
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.
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.
•Tusamitamab ravtansine (SAR408701) is a humanized monoclonal antibody covalently linked to a cytotoxic maytansinoid.•This potential first-in-class antibody–drug conjugate selectively targets tumor cells expressing CEACAM5.•100 mg/m2 i.v. every 2 weeks is the maximum tolerated dose of tusamitamab ravtansine, with reversible keratopathy as the DLT.•Tusamitamab ravtansine has a favorable safety profile with infrequent hematological toxicities vs that reported for docetaxel.•Signals of antitumor activity were observed during tusamitamab ravtansine dose escalation.
ABSTRACT
With the purpose of assessing classic spectroscopic methods on high-resolution and high signal-to-noise ratio spectra in the near-infrared wavelength region, we selected a sample of 65 F-, ...G-, and K-type stars observed with CARMENES, the new, ultra-stable, double-channel spectrograph at the 3.5 m Calar Alto telescope. We computed their stellar atmospheric parameters (Teff, log g, ξ, and Fe/H) by means of the stepar code, a python implementation of the equivalent width method that employs the 2017 version of the moog code and a grid of MARCS model atmospheres. We compiled four Fe i and Fe ii line lists suited to metal-rich dwarfs, metal-poor dwarfs, metal-rich giants, and metal-poor giants that cover the wavelength range from 5300 to 17 100 Å, thus substantially increasing the number of identified Fe i and Fe ii lines up to 653 and 23, respectively. We examined the impact of the near-infrared Fe i and Fe ii lines upon our parameter determinations after an exhaustive literature search, placing special emphasis on the 14 Gaia benchmark stars contained in our sample. Even though our parameter determinations remain in good agreement with the literature values, the increase in the number of Fe i and Fe ii lines when the near-infrared region is taken into account reveals a deeper Teff scale that might stem from a higher sensitivity of the near-infrared lines to Teff.
Context.
Despite swift progress in the characterisation of exoplanet atmospheres in composition and structure, the study of atmospheric dynamics has not progressed at the same speed. While ...theoretical models have been developed to describe the lower layers of the atmosphere, and independently, the exosphere, little is known about the intermediate layers up to the thermosphere.
Aims.
We aim to provide a clearer picture of atmospheric dynamics for the class of ultra-hot Jupiters, which are highly irradiated gas giants, based on the example of WASP-76 b.
Methods.
We jointly analysed two datasets that were obtained with the HARPS and ESPRESSO spectrographs to interpret the resolved planetary sodium doublet. We then applied the MERC code, which retrieves wind patterns, speeds, and temperature profiles on the line shape of the sodium doublet. An updated version of MERC, with added planetary rotation, also provides the possibility of modelling the latitude dependence of the wind patterns.
Results.
We retrieve the highest Bayesian evidence for an isothermal atmosphere, interpreted as a mean temperature of 3389 ± 227 K, a uniform day- to nightside wind of 5.5
−2.0
+1.4
km s
−1
in the lower atmosphere with a vertical wind in the upper atmosphere of 22.7
−4.1
+4.9
km s
−1
, switching atmospheric wind patterns at 10
−3
bar above the reference surface pressure (10 bar).
Conclusions.
Our results for WASP-76 b are compatible with previous studies of the lower atmospheric dynamics of WASP-76 b and other ultra-hot Jupiters. They highlight the need for vertical winds in the intermediate atmosphere above the layers probed by global circulation model studies to explain the line broadening of the sodium doublet in this planet. This work demonstrates the capability of exploiting the resolved spectral line shapes to observationally constrain possible wind patterns in exoplanet atmospheres. This is an invaluable input to more sophisticated 3D atmospheric models in the future.
Burnout in health care professionals could have serious negative consequences on quality of patient care, professional satisfaction and personal life. Our aim was to investigate the burnout ...prevalence, work and lifestyle factors potentially affecting burnout amongst European oncologists≤40 (YOs).
A survey was conducted using the validated Maslach Burnout Inventory (MBI) and additional questions exploring work/lifestyle factors. Statistical analyses were carried out to identify factors associated with burnout.
Total of 737 surveys (all ages) were collected from 41 European countries. Countries were divided into six regions. Results from 595 (81%) YOs were included (81% medical oncologists; 52% trainees, 62% women). Seventy-one percent of YOs showed evidence of burnout (burnout subdomains: depersonalization 50%; emotional exhaustion 45; low accomplishment 35%). Twenty-two percent requested support for burnout during training and 74% reported no hospital access to support services. Burnout rates were significantly different across Europe (P<0.0001). Burnout was highest in central European (84%) and lowest in Northern Europe (52%). Depersonalization scores were higher in men compared with women (60% versus 45% P=0.0001) and low accomplishment was highest in the 26–30 age group (P<0.01). In multivariable linear regression analyses, European region, work/life balance, access to support services, living alone and inadequate vacation time remained independent burnout factors (P<0.05).
This is the largest burnout survey in European Young Oncologists. Burnout is common amongst YOs and rates vary across Europe. Achieving a good work/life balance, access to support services and adequate vacation time may reduce burnout levels. Raising awareness, support and interventional research are needed.
In recent years, the advent of a new generation of radial velocity instruments has allowed us to detect planets with increasingly lower mass and to break the one Earth-mass barrier. Here we report a ...new milestone in this context by announcing the detection of the lowest-mass planet measured so far using radial velocities: L 98-59 b, a rocky planet with half the mass of Venus. It is part of a system composed of three known transiting terrestrial planets (planets b–d). We announce the discovery of a fourth nontransiting planet with a minimum mass of 3.06
−0.37
+0.33
M
⊕
and an orbital period of 12.796
−0.019
+0.020
days and report indications for the presence of a fifth nontransiting terrestrial planet. With a minimum mass of 2.46
−0.82
+0.66
M
⊕
and an orbital period 23.15
−0.17
+0.60
days, this planet, if confirmed, would sit in the middle of the habitable zone of the L 98-59 system. L 98-59 is a bright M dwarf located 10.6ṗc away. Positioned at the border of the continuous viewing zone of the
James Webb
Space Telescope, this system is destined to become a corner stone for comparative exoplanetology of terrestrial planets. The three transiting planets have transmission spectrum metrics ranging from 49 to 255, which undoubtedly makes them prime targets for an atmospheric characterization with the
James Webb
Space Telescope, the
Hubble
Space Telescope, Ariel, or ground-based facilities such as NIRPS or ESPRESSO. With an equilibrium temperature ranging from 416 to 627 K, they offer a unique opportunity to study the diversity of warm terrestrial planets without the unknowns associated with different host stars. L 98-59 b and c have densities of 3.6
−1.5
+1.4
and 4.57
−0.85
+0.77
g cm
−3
, respectively, and have very similar bulk compositions with a small iron core that represents only 12 to 14% of the total mass, and a small amount of water. However, with a density of 2.95
−0.51
+0.79
g cm
−3
and despite a similar core mass fraction, up to 30% of the mass of L 98-59 d might be water.
Classical Cepheids in open clusters play an important role in benchmarking stellar evolution models, in addition to anchoring the cosmic distance scale and invariably securing the Hubble constant. ...Three pertinent clusters hosting classical Cepheids and red (super)giants are: NGC 6649, NGC 6664, and Berkeley 55. These clusters form the basis of analysis to assess newly acquired spectra (≈50), archival photometry, and
Gaia
DR2 data. Importantly, for the first time chemical abundances were determined for the evolved members of NGC 6649 and NGC 6664. We find that they are slightly metal-poor relative to the mean Galactic gradient. Also, an overabundance of Ba is observed. These two clusters likely belong to the thin disc and the latter finding supports the “
s
-enhanced” scenario of D’Orazi et al. (2009). NGC 6664 and Berkeley 55 exhibit radial velocities consistent with Galactic rotation, while NGC 6649 displays a peculiar velocity. The resulting age estimates for the clusters (≈70 Ma) imply masses of ≈6
M
⊙
for the (super)giant demographic. Lastly, the observed yellow-to-red (super)giant ratio is lower than expected and the overall differences that are relative to the models reflect the outstanding theoretical uncertainties.
ABSTRACT
We report on the high-resolution spectroscopic observations of two planetary transits of the hot Jupiter KELT-7b (Mp = 1.28 ± 0.17MJup, Teq = 2028 K) observed with the High Optical ...Resolution Spectrograph (HORuS) mounted on the 10.4-m Gran Telescopio Canarias (GTC). A new set of stellar parameters are obtained for the rapidly rotating parent star from the analysis of the spectra. Using the newly derived stellar mass and radius, and the planetary transit data of the Transiting Exoplanet Survey Satellite (TESS) together with the HORuS velocities and the photometric and spectroscopic data available in the literature, we update and improve the ephemeris of KELT-7b. Our results indicate that KELT-7 has an angle λ = −10.55 ± 0.27 deg between the sky projections of the star’s spin axis and the planet’s orbital axis. By combining this angle and our newly derived stellar rotation period of 1.38 ± 0.05 d, we obtained a 3D obliquity ψ = 12.4 ± 11.7 deg (or 167.6 deg), thus reinforcing that KELT-7 is a well-aligned planetary system. We search for the presence of Hα, Li i, Na i, Mg i, and Ca ii features in the transmission spectrum of KELT-7b but we are only able to determine upper limits of 0.08–1.4 per cent on their presence after accounting for the contribution of the stellar variability to the extracted planetary spectrum. We also discuss the impact of stellar variability on the planetary data. Our results reinforce the importance of monitoring the parent star when performing high-resolution transmission spectroscopy of the planetary atmosphere in the presence of stellar activity.
Abstract
NGC 6067 is a young open cluster hosting the largest population of evolved stars among known Milky Way clusters in the 50–150 Ma age range. It thus represents the best laboratory in our ...Galaxy to constrain the evolutionary tracks of 5–7 M⊙ stars. We have used high-resolution spectra of a large sample of bright cluster members (45), combined with archival photometry, to obtain accurate parameters for the cluster as well as stellar atmospheric parameters. We derive a distance of 1.78 ± 0.12 kpc, an age of 90 ± 20 Ma and a tidal radius of 14.8$^{+6.8}_{-3.2}$ arcmin. We estimate an initial mass above 5700 M⊙, for a present-day evolved population of two Cepheids, two A supergiants and 12 red giants with masses ≈6 M⊙. We also determine chemical abundances of Li, O, Na, Mg, Si, Ca, Ti, Ni, Rb, Y and Ba for the red clump stars. We find a supersolar metallicity, Fe/H = +0.19 ± 0.05, and a homogeneous chemical composition, consistent with the Galactic metallicity gradient. The presence of a Li-rich red giant, star 276 with A(Li) = 2.41, is also detected. An overabundance of Ba is found, supporting the enhanced s-process. The ratio of yellow to red giants is much smaller than 1, in agreement with models with moderate overshooting, but the properties of the cluster Cepheids do not seem consistent with current Padova models for supersolar metallicity.
Aims
. We determine the radii and masses of 293 nearby, bright M dwarfs of the CARMENES survey. This is the first time that such a large and homogeneous high-resolution (
R
> 80 000) spectroscopic ...survey has been used to derive these fundamental stellar parameters.
Methods
. We derived the radii using Stefan–Boltzmann’s law. We obtained the required effective temperatures
T
eff
from a spectral analysis and we obtained the required luminosities
L
from integrated broadband photometry together with the
Gaia
DR2 parallaxes. The mass was then determined using a mass-radius relation that we derived from eclipsing binaries known in the literature. We compared this method with three other methods: (1) We calculated the mass from the radius and the surface gravity log
g
, which was obtained from the same spectral analysis as
T
eff
. (2) We used a widely used infrared mass-magnitude relation. (3) We used a Bayesian approach to infer stellar parameters from the comparison of the absolute magnitudes and colors of our targets with evolutionary models.
Results
. Between spectral types M0 V and M7 V our radii cover the range 0.1
R
⊙
<
R
< 0.6
R
⊙
with an error of 2–3% and our masses cover 0.09 ℳ
⊙
< ℳ< 0.6ℳ
⊙
with an error of 3–5%. We find good agreement between the masses determined with these different methods for most of our targets. Only the masses of very young objects show discrepancies. This can be well explained with the assumptions that we used for our methods.
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