In this first-in-human phase 1 study (NCT02964013; MK-7684-001), we investigated the safety and efficacy of the anti-TIGIT (T cell immunoglobulin and ITIM domain) antibody vibostolimab as monotherapy ...or in combination with pembrolizumab.
Part A enrolled patients with advanced solid tumors, and part B enrolled patients with non-small-cell lung cancer (NSCLC). Patients received vibostolimab 2.1-700 mg alone or with pembrolizumab 200 mg in part A and vibostolimab 200 mg alone or with pembrolizumab 200 mg in part B. Primary endpoints were safety and tolerability. Secondary endpoints included pharmacokinetics and objective response rate (ORR) per RECIST v1.1.
Part A enrolled 76 patients (monotherapy, 34; combination therapy, 42). No dose-limiting toxicities were reported. Across doses, 56% of patients receiving monotherapy and 62% receiving combination therapy had treatment-related adverse events (TRAEs); grade 3-4 TRAEs occurred in 9% and 17% of patients, respectively. The most common TRAEs were fatigue (15%) and pruritus (15%) with monotherapy and pruritus (17%) and rash (14%) with combination therapy. Confirmed ORR was 0% with monotherapy and 7% with combination therapy. In part B, 39 patients had anti-PD-1 (programmed cell death protein 1)/PD-L1 (programmed death-ligand 1)-naive NSCLC (all received combination therapy), and 67 had anti-PD-1/PD-L1-refractory NSCLC (monotherapy, 34; combination therapy, 33). In patients with anti-PD-1/PD-L1-naive NSCLC: 85% had TRAEs–the most common were pruritus (38%) and hypoalbuminemia (31%); confirmed ORR was 26%, with responses occurring in both PD-L1-positive and PD-L1-negative tumors. In patients with anti-PD-1/PD-L1-refractory NSCLC: 56% receiving monotherapy and 70% receiving combination therapy had TRAEs–the most common were rash and fatigue (21% each) with monotherapy and pruritus (36%) and fatigue (24%) with combination therapy; confirmed ORR was 3% with monotherapy and 3% with combination therapy.
Vibostolimab plus pembrolizumab was well tolerated and demonstrated antitumor activity in patients with advanced solid tumors, including patients with advanced NSCLC.
•First-in-human phase 1 study in patients with advanced solid tumors who received vibostolimab alone or with pembrolizumab.•Vibostolimab plus pembrolizumab was well tolerated in advanced solid tumors.•Vibostolimab plus pembrolizumab demonstrated antitumor activity in patients with advanced solid tumors.
Among patients with advanced cutaneous squamous-cell carcinoma, the PD-1 inhibitor cemiplimab induced a response in approximately half the patients and was associated with the expected spectrum of ...adverse events.
ABSTRACT
We report the phase-connected timing ephemeris, polarization pulse profiles, Faraday rotation measurements, and Rotating-Vector-Model (RVM) fitting results of 12 millisecond pulsars (MSPs) ...discovered with the Five-hundred-meter Aperture Spherical radio Telescope (FAST) in the Commensal Radio Astronomy FAST survey (CRAFTS). The timing campaigns were carried out with FAST and Arecibo over 3 yr. 11 of the 12 pulsars are in neutron star–white dwarf binary systems, with orbital periods between 2.4 and 100 d. 10 of them have spin periods, companion masses, and orbital eccentricities that are consistent with the theoretical expectations for MSP–Helium white dwarf (He WD) systems. The last binary pulsar (PSR J1912−0952) has a significantly smaller spin frequency and a smaller companion mass, the latter could be caused by a low orbital inclination for the system. Its orbital period of 29 d is well within the range of orbital periods where some MSP–He WD systems have shown anomalous eccentricities, however, the eccentricity of PSR J1912−0952 is typical of what one finds for the remaining MSP–He WD systems.
The Community Land Model version 3 (CLM3.0) simulates land‐atmosphere exchanges in response to climatic forcings. CLM3.0 has known biases in the surface energy partitioning as a result of ...deficiencies in its hydrological and biophysical parameterizations. Such models, however, need to be robust for multidecadal global climate simulations. FLUXNET now provides an extensive data source of carbon, water and energy exchanges for investigating land processes, and it encompasses a global range of ecosystem‐climate interactions. Data from 15 FLUXNET sites are used to identify and improve model deficiencies. Including a prognostic aquifer, a bare soil evaporation resistance formulation and numerous other changes in the model result in a significantly improved soil hydrology and energy partitioning. Terrestrial water storage increased by up to 300 mm in warm climates and decreased in cold climates. Nitrogen control of photosynthesis is revealed as another missing process in the model. These improvements increase the correlation coefficient of hourly and monthly latent heat fluxes from a range of 0.5–0.6 to the range of 0.7–0.9. RMSE of the simulated sensible heat fluxes decrease by 20–50%. Primary production is overestimated during the wet season in mediterranean and tropical ecosystems. This might be related to missing carbon‐nitrogen dynamics as well as to site‐specific parameters. The new model (CLM3.5) with an improved terrestrial water cycle should lead to more realistic land‐atmosphere exchanges in coupled simulations. FLUXNET is found to be a valuable tool to develop and validate land surface models prior to their application in computationally expensive global simulations.
Materials with low stacking fault energies have been long sought for their many desirable mechanical attributes. Although there have been many successful reports of low stacking fault alloys (for ...example Cu-based and Mg-based), many have lacked sufficient strength to be relevant for structural applications. The recent discovery and development of multicomponent equiatomic alloys (or high-entropy alloys) that form as simple solid solutions on ideal lattices has opened the door to investigate changes in stacking fault energy in materials that naturally exhibit high mechanical strength. We report in this article our efforts to determine the stacking fault energies of two- to five-component alloys. A range of methods that include ball milling, arc melting, and casting, is used to synthesize the alloys. The resulting structure of the alloys is determined from x-ray diffraction measurements. First-principles electronic structure calculations are employed to determine elastic constants, lattice parameters, and Poisson’s ratios for the same alloys. These values are then used in conjunction with x-ray diffraction measurements to quantify stacking fault energies as a function of the number of components in the equiatomic alloys. We show that the stacking fault energies decrease with the number of components. Nonequiatomic alloys are also explored as a means to further reduce stacking fault energy. We show that this strategy leads to a means to further reduce the stacking fault energy in this class of alloys.
Transport measurements are presented up to fields of 29 T in the recently discovered heavy-fermion superconductor UTe2 with magnetic field H applied along the easy magnetization a axis of the ...body-centered orthorhombic structure. The thermoelectric power varies linearly with temperature above the superconducting transition, TSC=1.5 K, indicating that superconductivity develops in a Fermi liquid regime. As a function of field the thermoelectric power shows successive anomalies which appear at critical values of the magnetic polarization. Remarkably, the lowest magnetic field instability for H∥a occurs for the same critical value of the magnetization (0.4 μB) than the first order metamagnetic transition at 35 T for field applied along the b axis. It can be clearly identified as a Lifshitz transition. The estimated number of charge carriers at low temperature reveals a metallic ground state distinct from LDA calculations indicating that strong electronic correlations are a major issue.
The neutral heating efficiency is commonly defined as the fraction of the solar extreme ultraviolet and X-ray energy absorbed by a planetary atmosphere that ends up as local heat. It is a crucial ...parameter that determines the upper atmospheric temperature and, consequently, the thermal escape rate on both solar system bodies and exoplanets. Combining the Mars Atmosphere and Volatile Evolution measurements of a variety of atmospheric parameters, we calculate the neutral heating efficiency in the dayside Martian upper atmosphere based on a complicated network of microscopic processes, including photon and photoelectron impact processes, as well as exothermic chemical reactions. Our calculations indicate that neutral heating is mainly contributed by photon impact at low altitudes, of which the bulk occurs via CO2 photodissociation, and exothermic chemistry at high altitudes, of which the bulk occurs via and dissociative recombination. Collisional quenching of metastable neutrals and ions, which is of great interest in the literature, contributes to local heating by no more than 10% at all altitudes. In the dayside median sense, the neutral heating efficiency remains roughly constant at 20% from 150 to 200 km and increases steadily to 32% near 250 km. The heating efficiency at 150-200 km shows a weak correlation with solar zenith angle, increases modestly with increasing solar activity, and is clearly enhanced over strong crustal magnetic anomalies. Throughout the study, strict local heating is assumed, but nonlocal heating does not affect our results near or below 200 km.
Quavonlimab (MK-1308), a novel anti-CTLA-4 antibody, in combination with pembrolizumab was investigated in a phase I study.
Dose-escalation (DE) phase: patients with advanced/metastatic solid tumors ...received an initial flat dose of quavonlimab as monotherapy 25 mg (cohort 1), 75 mg (cohort 2), or 200 mg (cohort 3) followed by four treatments of the same quavonlimab dose plus pembrolizumab every 3 weeks (Q3W). Dose-confirmation phase (DC): patients with stage IIIB/IV non-small-cell lung cancer (NSCLC) received first-line quavonlimab 25 mg Q3W (arm A), 25 mg Q6W (arm B), 75 mg Q6W (arm C), or 75 mg Q3W (arm E) plus pembrolizumab. Primary objectives were safety and tolerability and establishment of the recommended phase II dose (RP2D) of quavonlimab when used with pembrolizumab. Objective response rate (ORR) was a secondary endpoint. Efficacy based on PD-L1 expression, tumor mutational burden (TMB), and changes in circulating CD4+/CD8+ cells were exploratory endpoints.
Thirty-nine patients were enrolled in DE n = 14 (cohort 1); n = 17 (cohort 2); n = 8 (cohort 3) and 134 in DC n = 40 (arm A); n = 40 (arm B); n = 40 (arm C); n = 14 (arm E). Maximum-tolerated dose was not reached. Grade 3-5 treatment-related adverse events (AEs; graded according to NCI CTCAE v4.03) occurred in 0%, 23.5%, and 75.0% of patients in DE cohorts 1, 2, and 3, respectively, and 35.0%, 30.0%, 35.0%, and 57.1% of patients in DC arms A, B, C, and E, respectively. Efficacy was observed at all dose levels/schedules in patients with NSCLC. ORRs were 40.0% 95% confidence interval (CI), 24.9-56.7; arm A, 37.5% (95% CI, 22.7-54.2; arm B), 27.5% (95% CI, 14.6-43.9; arm C), and 35.7% (95% CI, 12.8-64.9; arm E). PD-L1 expression and total number of circulating CD4+ cells correlated with ORR.
Quavonlimab 25 mg Q6W plus pembrolizumab demonstrated similar efficacy and a better safety profile among all quavonlimab doses/schedules evaluated; this regimen was the chosen RP2D.
•Quavonlimab, a novel anti-CTLA-4 antibody, in combination with pembrolizumab was investigated in a first-in-human study.•The combination therapy was safe and tolerable and showed antitumor activity in patients with advanced NSCLC.•Data from this study led to a recommended phase II dose of 25 mg Q6W for quavonlimab when used with pembrolizumab.
Abstract
PSR J2150+3427 is a 0.654 s pulsar discovered by the Commensal Radio Astronomy FAST Survey. From the follow-up observations, we find that the pulsar is in a highly eccentric orbit (
e
= ...0.601) with an orbital period of 10.592 days and a projected semimajor axis of 25.488 lt-s. Using 2.7 yr of timing data, we also measured the rate of periastron advance
ω
̇
= 0.0115(4) deg yr
−1
. An estimate for the total mass of the system using the
ω
̇
gives
M
tot
= 2.59(13)
M
⊙
, which is consistent with most of the known double neutron star (DNS) systems and one neutron star (NS)–white dwarf (WD) system named B2303+46. Combining
ω
̇
with the mass function of the system gives the masses of
M
p
< 1.67 and
M
c
> 0.98
M
⊙
for the pulsar and the companion star, respectively. This constraint, along with the spin period and orbital parameters, suggests that it is possibly a DNS system, and we cannot entirely rule out the possibility of an NS–WD system. Future timing observations will vastly improve the uncertainty in
ω
̇
, and are likely to allow the detection of additional relativistic effects, which can be used to modify the values of
M
p
and
M
c
. With a spin-down luminosity of
E
̇
= 5.07(6) × 10
29
erg s
−1
, PSR J2150+3427 is a very low-luminosity pulsar, with only the binary pulsar J2208+4610 having a smaller
E
̇
.
The Neutral Gas and Ion Mass Spectrometer of the Mars Atmosphere and Volatile Evolution provides a large data set to explore the ion composition and structure of the Martian ionosphere. Here, the ...dayside measurements are used to investigate the minor ion density profiles with distinctive peaks above 150 km, revealing a systematic trend of decreasing peak altitude with increasing ion mass. We specifically focus on a subset of species including O+, N
2+/CO+, C+, N+, He+, and O++, all of which are mainly produced via direct photoionization of parent neutrals. Our analysis reveals weak or no variation with solar zenith angle (SZA) in both peak density and altitude, which is an expected result because these ion peaks are located within the optically thin regions subject to the same level of solar irradiance independent of SZA. In contrast, the solar cycle variations of peak density and altitude increase considerably with increasing solar activity, as a result of enhanced photoionization frequency and atmospheric expansion at high solar activities. He+ serves as an exception in that its peak density increases toward large SZA and meanwhile shows no systematic variation with solar activity. The thermospheric He distribution on Mars should play an important role in determining these observed variations. Finally, the peak altitudes for all species are elevated by at least several km within the weakly magnetized regions, possibly attributable to the suppression of vertical diffusion by preferentially horizontal magnetic fields in these regions.
Key Points
The peak density and altitude for most minor ion species produced via direct photoionization show weak or no SZA variation
The minor ion peak density and altitude tend to increase significantly with increasing solar activity
The minor ion peak density and altitude show clear and consistent difference between the strongly and weakly magnetized regions
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