Patients with advanced sarcomas have a poor prognosis and few treatment options that improve overall survival. Chemotherapy and targeted therapies offer short-lived disease control. We assessed ...pembrolizumab, an anti-PD-1 antibody, for safety and activity in patients with advanced soft-tissue sarcoma or bone sarcoma.
In this two-cohort, single-arm, open-label, phase 2 study, we enrolled patients with soft-tissue sarcoma or bone sarcoma from 12 academic centres in the USA that were members of the Sarcoma Alliance for Research through Collaboration (SARC). Patients with soft-tissue sarcoma had to be aged 18 years or older to enrol; patients with bone sarcoma could enrol if they were aged 12 years or older. Patients had histological evidence of metastatic or surgically unresectable locally advanced sarcoma, had received up to three previous lines of systemic anticancer therapy, had at least one measurable lesion according to the Response Evaluation Criteria In Solid Tumors version 1.1, and had at least one lesion accessible for biopsy. All patients were treated with 200 mg intravenous pembrolizumab every 3 weeks. The primary endpoint was investigator-assessed objective response. Patients who received at least one dose of pembrolizumab were included in the safety analysis and patients who progressed or reached at least one scan assessment were included in the activity analysis. Accrual is ongoing in some disease cohorts. This trial is registered with ClinicalTrials.gov, number NCT02301039.
Between March 13, 2015, and Feb 18, 2016, we enrolled 86 patients, 84 of whom received pembrolizumab (42 in each disease cohort) and 80 of whom were evaluable for response (40 in each disease cohort). Median follow-up was 17·8 months (IQR 12·3–19·3). Seven (18%) of 40 patients with soft-tissue sarcoma had an objective response, including four (40%) of ten patients with undifferentiated pleomorphic sarcoma, two (20%) of ten patients with liposarcoma, and one (10%) of ten patients with synovial sarcoma. No patients with leiomyosarcoma (n=10) had an objective response. Two (5%) of 40 patients with bone sarcoma had an objective response, including one (5%) of 22 patients with osteosarcoma and one (20%) of five patients with chondrosarcoma. None of the 13 patients with Ewing's sarcoma had an objective response. The most frequent grade 3 or worse adverse events were anaemia (six 14%), decreased lymphocyte count (five 12%), prolonged activated partial thromboplastin time (four 10%), and decreased platelet count (three 7%) in the bone sarcoma group, and anaemia, decreased lymphocyte count, and prolonged activated partial thromboplastin time in the soft-tissue sarcoma group (three 7% each). Nine (11%) patients (five 12% in the bone sarcoma group and four 10% in the soft-tissue sarcoma group) had treatment-emergent serious adverse events (SAEs), five of whom had immune-related SAEs, including two with adrenal insufficiency, two with pneumonitis, and one with nephritis.
The primary endpoint of overall response was not met for either cohort. However, pembrolizumab showed encouraging activity in patients with undifferentiated pleomorphic sarcoma or dedifferentiated liposarcoma. Enrolment to expanded cohorts of those subtypes is ongoing to confirm and characterise the activity of pembrolizumab.
Merck, SARC, Sarcoma Foundation of America, QuadW Foundation, Pittsburgh Cure Sarcoma, and Ewan McGregor.
Metallothionein 3 (MT-3) is a small, cysteine-rich protein that binds to essential metals required for homeostasis, as well as to heavy metals that have the potential to exert toxic effects on cells. ...MT-3 is expressed by epithelial cells of the human kidney, including the cells of the proximal tubule. Our laboratory has previously shown that mortal cultures of human proximal tubular (HPT) cells express MT-3 and form domes in the cell monolayer, a morphological feature indicative of vectorial active transport, an essential function of the proximal tubule. However, an immortalized proximal tubular cell line HK-2 lacks the expression of MT-3 and fails to form domes in the monolayer. Transfection of HK-2 cells with the MT-3 gene restores dome formation in these cells suggesting that MT-3 is required for vectorial active transport. In order to determine how MT-3 imparts this essential feature to the proximal tubule, we sought to identify proteins that interact either directly or indirectly with MT-3. Using a combination of pulldowns, co-immunoprecipitations, and mass spectrometry analysis, putative protein interactants were identified and subsequently confirmed by Western analysis and confocal microscopy, following which proteins with direct physical interactions were investigated through molecular docking. Our data shows that MT-3 interacts with myosin-9, aldolase A, enolase 1, β-actin, and tropomyosin 3 and that these interactions are maximized at the periphery of the apical membrane of doming proximal tubule cells. Together these observations reveal that MT-3 interacts with proteins involved in cytoskeletal organization and energy metabolism, and these interactions at the apical membrane support vectorial active transport and cell differentiation in proximal tubule cultures.
Background
This is the fourth updated Enhanced Recovery After Surgery (ERAS
®
) Society guideline presenting a consensus for optimal perioperative care in colorectal surgery and providing graded ...recommendations for each ERAS item within the ERAS
®
protocol.
Methods
A wide database search on English literature publications was performed. Studies on each item within the protocol were selected with particular attention paid to meta-analyses, randomised controlled trials and large prospective cohorts and examined, reviewed and graded according to Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system.
Results
All recommendations on ERAS
®
protocol items are based on best available evidence; good-quality trials; meta-analyses of good-quality trials; or large cohort studies. The level of evidence for the use of each item is presented accordingly.
Conclusions
The evidence base and recommendation for items within the multimodal perioperative care pathway are presented by the ERAS
®
Society in this comprehensive consensus review.
We use a subignition scale laser, the 30 kJ Omega, and a novel shallow-cone target to study laser-plasma interactions at the ablation-plasma density scale lengths and laser intensities anticipated ...for direct drive shock-ignition implosions at National Ignition Facility scale. Our results show that, under these conditions, the dominant instability is convective stimulated Raman scatter with experimental evidence of two plasmon decay (TPD) only when the density scale length is reduced. Particle-in-cell simulations indicate this is due to TPD being shifted to lower densities, removing the experimental back-scatter signature and reducing the hot-electron temperature. The experimental laser energy-coupling to hot electrons was found to be 1%–2.5%, with electron temperatures between 35 and 45 keV. Radiation-hydrodynamics simulations employing these hot-electron characteristics indicate that they should not preheat the fuel in MJ-scale shock ignition experiments.
We report on a measurement of the cosmic ray energy spectrum by the Telescope Array Low-Energy Extension (TALE) air fluorescence detector (FD). The TALE air FD is also sensitive to the Cherenkov ...light produced by shower particles. Low-energy cosmic rays, in the PeV energy range, are detectable by TALE as Cherenkov events. Using these events, we measure the energy spectrum from a low energy of ∼2 PeV to an energy greater than 100 PeV. Above 100 PeV, TALE can detect cosmic rays using air fluorescence. This allows for the extension of the measurement to energies greater than a few EeV. In this paper, we describe the detector, explain the technique, and present results from a measurement of the spectrum using ∼1000 hr of observation. The observed spectrum shows a clear steepening near 1017.1 eV, along with an ankle-like structure at 1016.2 eV. These features present important constraints on the origin of galactic cosmic rays and on propagation models. The feature at 1017.1 eV may also mark the end of the galactic cosmic ray flux and the start of the transition to extragalactic sources.
We present constraints on the tensor-to-scalar ratio
r
using
Planck
data. We use the latest release of
Planck
maps, processed with the
NPIPE
code, which produces calibrated frequency maps in ...temperature and polarisation for all
Planck
channels from 30 GHz to 857 GHz using the same pipeline. We computed constraints on
r
using the
BB
angular power spectrum, and we also discuss constraints coming from the
TT
spectrum. Given
Planck
’s noise level, the
TT
spectrum gives constraints on
r
that are cosmic-variance limited (with
σ
r
= 0.093), but we show that the marginalised posterior peaks towards negative values of
r
at about the 1.2
σ
level. We derived
Planck
constraints using the
BB
power spectrum at both large angular scales (the ‘reionisation bump’) and intermediate angular scales (the ‘recombination bump’) from
ℓ
= 2 to 150 and find a stronger constraint than that from
TT
, with
σ
r
= 0.069. The
Planck
BB
spectrum shows no systematic bias and is compatible with zero, given both the statistical noise and the systematic uncertainties. The likelihood analysis using
B
modes yields the constraint
r
< 0.158 at 95% confidence using more than 50% of the sky. This upper limit tightens to
r
< 0.069 when
Planck
EE
,
BB
, and
EB
power spectra are combined consistently, and it tightens further to
r
< 0.056 when the
Planck
TT
power spectrum is included in the combination. Finally, combining
Planck
with BICEP2/Keck 2015 data yields an upper limit of
r
< 0.044.
The spike aspartic acid-614 to glycine (D614G) substitution is prevalent in global severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strains, but its effects on viral pathogenesis and ...transmissibility remain unclear. We engineered a SARS-CoV-2 variant containing this substitution. The variant exhibits more efficient infection, replication, and competitive fitness in primary human airway epithelial cells but maintains similar morphology and in vitro neutralization properties, compared with the ancestral wild-type virus. Infection of human angiotensin-converting enzyme 2 (ACE2) transgenic mice and Syrian hamsters with both viruses resulted in similar viral titers in respiratory tissues and pulmonary disease. However, the D614G variant transmits significantly faster and displayed increased competitive fitness than the wild-type virus in hamsters. These data show that the D614G substitution enhances SARS-CoV-2 infectivity, competitive fitness, and transmission in primary human cells and animal models.
We present the results from a 1.1-mm imaging survey of the SSA22 field, known for having an overdensity of z = 3.1 Lyman α emitting galaxies (LAEs), taken with the astronomical thermal emission ...camera (AzTEC) on the Atacama Submillimeter Telescope Experiment (ASTE). We imaged a 950-arcmin2 field down to a 1σ sensitivity of 0.7–1.3 mJy beam−1 to find 125 submillimetre galaxies (SMGs) with a signal-to-noise ratio ≥3.5. Counterpart identification using radio and near/mid-infrared data was performed and one or more counterpart candidates were found for 59 SMGs. Photometric redshifts based on optical to near-infrared images were evaluated for 45 of these SMGs with Spitzer/IRAC data and the median value is found to be z = 2.4. By combining these estimations with estimates from the literature, we determined that 10 SMGs might lie within the large-scale structure at z = 3.1. The two-point angular cross-correlation function between LAEs and SMGs indicates that the positions of the SMGs are correlated with the z = 3.1 protocluster. These results suggest that the SMGs were formed and evolved selectively in the high dense environment of the high-redshift Universe. This picture is consistent with the predictions of the standard model of hierarchical structure formation.
Biomass burning is the largest combustion-related source of volatile organic compounds (VOCs) to the atmosphere. We describe the development of a state-of-the-science model to simulate the ...photochemical formation of secondary organic aerosol (SOA) from biomass-burning emissions observed in dry (RH <20%) environmental chamber experiments. The modeling is supported by (i) new oxidation chamber measurements, (ii) detailed concurrent measurements of SOA precursors in biomass-burning emissions, and (iii) development of SOA parameters for heterocyclic and oxygenated aromatic compounds based on historical chamber experiments. We find that oxygenated aromatic compounds, including phenols and methoxyphenols, account for slightly less than 60% of the SOA formed and help our model explain the variability in the organic aerosol mass (R 2 = 0.68) and O/C (R 2 = 0.69) enhancement ratios observed across 11 chamber experiments. Despite abundant emissions, heterocyclic compounds that included furans contribute to ∼20% of the total SOA. The use of pyrolysis-temperature-based or averaged emission profiles to represent SOA precursors, rather than those specific to each fire, provide similar results to within 20%. Our findings demonstrate the necessity of accounting for oxygenated aromatics from biomass-burning emissions and their SOA formation in chemical mechanisms.
The properties of supersonic, compressible plasma turbulence determine the behavior of many terrestrial and astrophysical systems. In the interstellar medium and molecular clouds, compressible ...turbulence plays a vital role in star formation and the evolution of our galaxy. Observations of the density and velocity power spectra in the Orion B and Perseus molecular clouds show large deviations from those predicted for incompressible turbulence. Hydrodynamic simulations attribute this to the high Mach number in the interstellar medium (ISM), although the exact details of this dependence are not well understood. Here we investigate experimentally the statistical behavior of boundary-free supersonic turbulence created by the collision of two laser-driven high-velocity turbulent plasma jets. The Mach number dependence of the slopes of the density and velocity power spectra agree with astrophysical observations, and supports the notion that the turbulence transitions from being Kolmogorov-like at low Mach number to being more Burgers-like at higher Mach numbers.
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