We report on Doppler observations of three transiting planet candidates that were detected during Campaign 1 of the K2 mission. The Doppler observations were conducted with FIES, HARPS-N and HARPS. ...We measure the mass of K2-27b (EPIC 201546283b), and provide constraints and upper limits for EPIC 201295312b and EPIC 201577035b. K2-27b is a warm Neptune orbiting its host star in 6.77 days and has a radius of \(4.45^{+0.33}_{-0.33}~\mathrm{R_\oplus}\) and a mass of \(29.1^{+7.5}_{-7.4}~\mathrm{M_\oplus}\), which leads to a mean density of \(1.80^{+0.70}_{-0.55}~\mathrm{g~cm^{-3}}\). EPIC 201295312b is smaller than Neptune with an orbital period of 5.66 days, radius \(2.75^{+0.24}_{-0.22}~\mathrm{R_\oplus}\) and we constrain the mass to be below \(12~\mathrm{M_\oplus}\) at 95% confidence. We also find a long-term trend indicative of another body in the system. EPIC 201577035b, previously confirmed as the planet K2-10b, is smaller than Neptune orbiting its host star in 19.3 days, with radius \(3.84^{+0.35}_{-0.34}~\mathrm{R_\oplus}\). We determine its mass to be \(27^{+17}_{-16}~\mathrm{M_\oplus}\), with a 95% confidence uppler limit at \(57~\mathrm{M_\oplus}\), and mean density \(2.6^{+2.1}_{-1.6}~{\rm g~cm}^{-3}\). These measurements join the relatively small collection of planets smaller than Neptune with measurements or constraints of the mean density. Our code for performing K2 photometry and detecting planetary transits is now publicly available.
We report on the discovery and characterization of the transiting planet K2-39b (EPIC 206247743b). With an orbital period of 4.6 days, it is the shortest-period planet orbiting a subgiant star known ...to date. Such planets are rare, with only a handful of known cases. The reason for this is poorly understood, but may reflect differences in planet occurrence around the relatively high-mass stars that have been surveyed, or may be the result of tidal destruction of such planets. K2-39 is an evolved star with a spectroscopically derived stellar radius and mass of \(3.88^{+0.48}_{-0.42}~\mathrm{R_\odot}\) and \(1.53^{+0.13}_{-0.12}~\mathrm{M_\odot}\), respectively, and a very close-in transiting planet, with \(a/R_\star = 3.4\). Radial velocity (RV) follow-up using the HARPS, FIES and PFS instruments leads to a planetary mass of \(50.3^{+9.7}_{-9.4}~\mathrm{M_\oplus}\). In combination with a radius measurement of \(8.3 \pm 1.1~\mathrm{R_\oplus}\), this results in a mean planetary density of \(0.50^{+0.29}_{-0.17}\) g~cm\(^{-3}\). We furthermore discover a long-term RV trend, which may be caused by a long-period planet or stellar companion. Because K2-39b has a short orbital period, its existence makes it seem unlikely that tidal destruction is wholly responsible for the differences in planet populations around subgiant and main-sequence stars. Future monitoring of the transits of this system may enable the detection of period decay and constrain the tidal dissipation rates of subgiant stars.
INTRODUCTION: Luxeptinib (CG-806; LUX) is an orally active noncovalent kinase inhibitor of Bruton's tyrosine kinase (BTK), wild type and mutant forms of Fms-like tyrosine kinase 3 (FLT3) (including ...the internal tandem duplicates (ITD), tyrosine kinase domain (TKD), and F691L mutant forms), and growth receptors like KIT, CSF1R, PDGFRα, and TRKs. In prior studies, LUX has been shown to suppress aberrant proliferative signaling in B cell malignancies and acute myeloid leukemia (AML) via regulation of BTK, LYN, SYK, AKT, ERK, and MAPK. LUX is cytotoxic to primary AML cells insensitive to other FLT3 inhibitors and to malignant B-cells insensitive to ibrutinib, at pM and nM concentrations, respectively.
AIMS: The primary objectives of these studies are to assess the safety, tolerability, and pharmacokinetics (PK) of LUX and determine recommended phase 2 doses for relapsed or refractory (R/R) AML and B cell malignancy patients.
METHODS: In two studies (NCT04477291; NCT03893682), LUX (original formulation, G1) was administered continuously as oral capsules BID in 28-day cycles of ascending cohorts (relapsed or refractory de novo, secondary, or therapy-related AML or higher risk myelodysplastic syndrome (MDS), and relapsed and refractory for B cell lymphoma and chronic lymphocytic/small lymphocytic leukemia). A novel generation 3 (G3) formulation of LUX designed to increase bioavailability was tested at a single-dose (sub-study) for relative bioavailability (RBA), followed by continuous dosing in subsequent R/R AML patients.
RESULTS: In the B-cell study (as of 15 th May 2023), LUX has been administered to 36 patients at dose levels from 150 mg to 900 mg BID in patients with a median of 3 lines of prior treatment, with 47.2% having received a BTK-inhibitor. Only one (2.8%) patient had a DLT of hypertension and 14 (38.9%) experienced at least one drug related ≥Grade3 treatment emergent adverse event (TEAE). Two patients (900 mg) are currently on study with no DLT and no ≥Grade 3 related TEAEs. A Follicular lymphoma patient is at cycle 28, and achieved a best response as partial response (PR) with a decrease in lesion size of 76.2%; an SLL patient is at cycle 13, and achieved stable disease (SD) showing a decrease in lesion size of 43.1% (Figure A). The overall best response achieved among the 17 patients who have been on treatment for more than 12 weeks are stable disease (SD) (n=11), partial response (PR) (n=3), minor response (n=2) and complete response (CR) (n=1).
As of 5 th June 2023, in the AML trial, a total of 40 patients (16 (40%) FLT3-ITD, 21 (52.5%) FLT3-WT, 2 (5.0%) FLT3-TKD, and 1 (2.5%) unknown mutations) with a median of 3 prior treatments (range, 1 - 10) have been treated with LUX G1 formulation at dose levels from 450 mg - 900 mg BID (n=34) or with 50 mg BID of G3 formulation (n=6). Four (10%) experienced drug related SAE and 7 (17.5%) had a drug related grade ≥3 TEAEs. The most common related TEAEs were lymphocyte count decrease, platelet count decrease, and anemia (n=2; 5% patients each). One (2.5%) patient at 450 mg dose, reported complete remission without minimum residual disease (CRmrd) and remained on study for 56 weeks.
In the RBA sub-study, G3 (50 mg) produced comparable exposures to G1 (450-900 mg range) (Figure B) and was, therefore, selected as the starting dose for use in the R/R AML study. Six patients were treated with a continuous dosing of 50 mg BID G3; with plasma levels of 274 ng/mL and 195 ng/mL LUX observed by the end of C1D15 and C1D22 respectively. No drug related Grade ≥3 TEAEs or DLTs were observed in 50 mg BID G3 LUX treated patients; with no new safety signals observed for the G3 formulation. Based on these findings and expected exposures for higher dose levels, the cohort safety review committee has approved escalation of G3 dosing to 200 mg BID at which dosing is ongoing.
CONCLUSIONS: LUX has a favorable safety profile in patients at all tested dose levels, for multiple cycles, for both studies. Antitumor activity was observed in a heavily pretreated relapsed AML patient and in multiple B-NHL subtypes and CLL/SLL patients including several with prior ibrutinib exposure. Continuous dosing of patients with R/R AML and Higher-Risk MDS with the G3 formulation is ongoing; with updated clinical data (200 mg dose level) to be presented at the meeting.
We report the discovery and characterization of TOI-1759~b, a temperate (400 K) sub-Neptune-sized exoplanet orbiting the M~dwarf TOI-1759 (TIC 408636441). TOI-1759 b was observed by TESS to transit ...on sectors 16, 17 and 24, with only one transit observed per sector, creating an ambiguity on the orbital period of the planet candidate. Ground-based photometric observations, combined with radial-velocity measurements obtained with the CARMENES spectrograph, confirm an actual period of \(18.85019 \pm 0.00014\) d. A joint analysis of all available photometry and radial velocities reveal a radius of \(3.17 \pm 0.10\,R_\oplus\) and a mass of \(10.8 \pm 1.5\,M_\oplus\). Combining this with the stellar properties derived for TOI-1759 (\(R_\star = 0.597 \pm 0.015\,R_\odot\); \(M_\star = 0.606 \pm 0.020\,M_\odot\); \(T_{\textrm{eff}} = 4065 \pm 51\) K), we compute a transmission spectroscopic metric (TSM) value of over 80 for the planet, making it a good target for transmission spectroscopy studies. TOI-1759 b is among the top five temperate, small exoplanets (\(T_\textrm{eq} < 500\) K, \(R_p < 4 \,R_\oplus\)) with the highest TSM discovered to date. Two additional signals with periods of 80 d and \(>\) 200 d seem to be present in our radial velocities. While our data suggest both could arise from stellar activity, the later signal's source and periodicity are hard to pinpoint given the \(\sim 200\) d baseline of our radial-velocity campaign with CARMENES. Longer baseline radial-velocity campaigns should be performed in order to unveil the true nature of this long period signal.
We report the development of a 4-color simultaneous camera for the 1.52~m Telescopio Carlos Sánchez (TCS) in the Teide Observatory, Canaries, Spain. The new instrument, named MuSCAT2, has a ...capability of 4-color simultaneous imaging in \(g\) (400--550 nm), \(r\) (550--700 nm), \(i\) (700--820 nm), and \(z_s\) (820--920 nm) bands. MuSCAT2 equips four 1024\(\times\)1024 pixel CCDs, having a field of view of 7.4\(\times\)7.4 arcmin\(^2\) with a pixel scale of 0.44 arcsec per pixel. The principal purpose of MuSCAT2 is to perform high-precision multi-color exoplanet transit photometry. We have demonstrated photometric precisions of 0.057%, 0.050%, 0.060%, and 0.076% as root-mean-square residuals of 60~s binning in \(g\), \(r\), \(i\) and \(z_s\) bands, respectively, for a G0 V star WASP-12 (\(V=11.57\pm0.16\)). MuSCAT2 has started science operations since January 2018, with over 250 telescope nights per year. MuSCAT2 is expected to become a reference tool for exoplanet transit observations, and will substantially contribute to the follow-up of the TESS and PLATO space missions.
Broad-band (ultraviolet to near-infrared) observations of the intense gamma ray burst GRB 990123 started ∼8.5 hours after the event and continued until 18 February 1999. When combined with other ...data, in particular from the Robotic Telescope and Transient Source Experiment (ROTSE) and the Hubble Space Telescope (HST), evidence emerges for a smoothly declining light curve, suggesting some color dependence that could be related to a cooling break passing the ultraviolet-optical band at about 1 day after the high-energy event. The steeper decline rate seen after 1.5 to 2 days may be evidence for a collimated jet pointing toward the observer.
Cytogenetic abnormalities are found in around half of MDS patients (pts) and have both clinical impact and may be subtype-defining, e.g. in 5q-syndrome. Interstitial deletion of the long arm of chr.5 ...del(5q) is the most common aberration (almost 20% of cases with abnormal cytogenetics). Del(5q) is heterogeneous, occurring as a sole abnormality or in combination, with the deleted region often truncated within or extended and/or beyond the CDR boundaries. Isolated del(5q) is frequently shorter and confers a more favorable prognosis with regard to survival and lenalidomide (LEN) responsiveness, while del(5q) in the context of a complex karyotype (CK) imparts a poor prognosis. In addition to chromosomal lesions, somatic mutations can contribute to the pathogenesis of MDS, including del(5q). We theorized that recognition of molecular defects in MDS with del(5q) may clarify the pathogenic mechanisms behind this lesion and help explain the clinical heterogeneity.
We analyzed 225 pts with myeloid neoplasia and del(5q) using WES (n= 107 samples) and targeted multiplexed PCR (top 60 most frequently mutated genes) (n =133 samples); serial analysis was performed in 15 pts studied at ≥2 time points, 11 during LEN therapy and 4 upon relapse/progression. A total of 116 samples had a CK with other lesions such as -7/del(7q) found in 31% cases, and 18% had -17/del(17p).
WES (average depth >60x) was followed by a bioanalytic pipeline, detecting ≥1 mutated gene in 71% of cases. Candidate somatic alterations were found in 357 genes and selected for further analysis. When focused on hemizygous mutations within the retained 5q allele, CSNK1A1 mutations were the most common, found in 4 pts, while other genes were only sporadically affected. Among heterozygous mutations on the non-deleted portion of del(5q) and other chromosomes (Chr), we found several novel mutations, in addition to TP53 (n=26), DNMT3A (n=8), PRPF8 (n =8), RUNX1 (n=5), TET2 (n=5), and ASXL1 (n=4), among others. Furthermore, LOH/haploinsuffciency of genes on 7q (e.g., LUC7L2, CUX1, EZH2 and MLL3) appears to be a common defect seen in pts with non-isolated del(5q), suggesting synergistic functional defects. When functionally grouping gene mutations, DNA methylation family (8 cases) and transcription factor mutations (29 cases) were associated with advanced disease (AD) and a CK. Heterozygous mutations in TP53 (34%) or deletions involving the TP53 locus (23%) resulted in total of 42% of cases carrying either TP53 LOH or mutation. TP53 lesions were more common in pts with AD vs. low risk. (21 vs. 5 p =.0008). In contrast, TP53 mutations are found in 8-10% of cases of MDS.
A total of 34 pts were treated with LEN and subgrouped into responders (n=17) vs. refractory (n=9) with an overall response rate of 65%. When mutational profiles were compared, the presence of TP53 mutations did not preclude responsiveness to LEN. CK was present in 12% of responders vs. 67% of refractory pts. The most frequent Chr abnormalities were -7/7q (0% vs. 67% in responders vs. refractory) and 17p-(6% vs. 67% in responders vs. refractory) suggestive of their role in LEN resistance.
In addition to cross sectional analysis, our WES study using paired Germline/tumor samples followed by deep sequencing facilitated analyses of clonal architecture by examining clonal dynamics over time. Assessment of del(5q) clone size by allelic imbalance combined with clonal burden by VAF allowed us to reconstruct the clonal hierarchy: in 73% of cases, del(5q) appeared to be the initial defect followed by subsequent mutations (e.g., TP53, DNMT3A, IDH2). In contrast, in 24% of cases, TP53, RUNX1, JARID2, were the primary defect followed by a subclonal del(5q) events. Serial samples collected before and after therapy demonstrated that responses were associated with decreased clonal burden for del(5q) but persistence of certain mutations. In refractory cases, persistent subclonal lesions and the appearance of new lesions were associated with progression. For example, pts with TP53, LAMB4, EPHA6 progressed and acquired additional lesions such as CSMD2 or KCND2, and did not see the disappearance of TP53 alterations upon treatment.
In conclusion, no unifying somatic defect was found in pts with del(5q) regardless if the deletion event was primary or subclonal. Most commonly associated lesions were not present on the retained 5q alleles but rather other chr yet modified clinical behavior, including responsiveness to LEN.
Bejar:Celgene: Consultancy, Honoraria; Alexion: Other: ad hoc advisory board; Genoptix Medical Laboratory: Consultancy, Honoraria, Patents & Royalties: MDS prognostic gene signature. Sekeres:Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; TetraLogic: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees.
The sigma Orionis substellar population Navascués, David Barrado y; Béjar, Víctor J. S; Mundt, Reinhard ...
arXiv (Cornell University),
03/2003
Journal Article
Odprti dostop
VLT/FORS spectroscopy and 2MASS near-infrared photometry, together with
previously known data, have been used to establish the membership and the
properties of a sample of low-mass candidate members ...of the sigma Orionis
cluster with masses spanning from 1 Msun down to about 0.013 Msun (i.e.,
deuterium-burning mass limit). We have observed K-band infrared excess and
remarkably intense H(alpha) emission in various cluster members, which, in
addition to the previously detected forbidden emision lines and the presence of
LiI in absorption at 6708 A, have allowed us to tentatively classify sigma
Orionis members as classical or weak-line TTauri stars and substellar analogs.
Variability of the H(alpha) line has been investigated and detected in some
objects. Based on the K-band infrared excesses and the intensity of H(alpha)
emission, we estimate that the minimum disk frequency of the sigma Orionis
low-mass population is in the range 5-12%.
VLT/FORS spectroscopy and 2MASS near-infrared photometry, together with previously known data, have been used to establish the membership and the properties of a sample of low-mass candidate members ...of the sigma Orionis cluster with masses spanning from 1 Msun down to about 0.013 Msun (i.e., deuterium-burning mass limit). We have observed K-band infrared excess and remarkably intense H(alpha) emission in various cluster members, which, in addition to the previously detected forbidden emision lines and the presence of LiI in absorption at 6708 A, have allowed us to tentatively classify sigma Orionis members as classical or weak-line TTauri stars and substellar analogs. Variability of the H(alpha) line has been investigated and detected in some objects. Based on the K-band infrared excesses and the intensity of H(alpha) emission, we estimate that the minimum disk frequency of the sigma Orionis low-mass population is in the range 5-12%.
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