253 research outputs found
Pharmacokinetic (Pk) Activity of Cabazitaxel (Cbz) in Patients (Pts) with Renal Impairment (Ri)
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Herschel Observations of the W43 "mini-starburst"
Aims: To explore the infrared and radio properties of one of the closest
Galactic starburst regions. Methods: Images obtained with the Herschel Space
Observatory at wavelengths of 70, 160, 250, 350, and 500 microns using the PACS
and SPIRE arrays are analyzed and compared with radio continuum VLA data and 8
micron images from the Spitzer Space Telescope. The morphology of the
far-infrared emission is combined with radial velocity measurements of
millimeter and centimeter wavelength transitions to identify features likely to
be associated with the W43 complex. Results: The W43 star-forming complex is
resolved into a dense cluster of protostars, infrared dark clouds, and ridges
of warm dust heated by massive stars. The 4 brightest compact sources with L >
1.5 x 10^4 Lsun embedded within the Z-shaped ridge of bright dust emission in
W43 remain single at 4" (0.1 pc) resolution. These objects, likely to be
massive protostars or compact clusters in early stages of evolution are
embedded in clumps with masses of 10^3 to 10^4 Msun, but contribute only 2% to
the 3.6 x 10^6 Lsun far-IR luminosity of W43 measured in a 16 by 16 pc box. The
total mass of gas derived from the far-IR dust emission inside this region is
~10^6 Msun. Cometary dust clouds, compact 6 cm radio sources, and warm dust
mark the locations of older populations of massive stars. Energy release has
created a cavity blowing-out below the Galactic plane. Compression of molecular
gas in the plane by the older HII region near G30.684-0.260 and the bipolar
structure of the resulting younger W43 HII region may have triggered the
current mini-star burst.Comment: 5 pages, 3 figures, accepted for A&A Special Issu
Previous SARS-CoV-2 Infection Increases B.1.1.7 Cross-Neutralization by Vaccinated Individuals
With the spread of new variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), there is a need to assess the protection conferred by both previous infections and current vaccination. Here we tested the neutralizing activity of infected and/or vaccinated individuals against pseudoviruses expressing the spike of the original SARS-CoV-2 isolate Wuhan-Hu-1 (WH1), the D614G mutant and the B.1.1.7 variant. Our data show that parameters of natural infection (time from infection and nature of the infecting variant) determined cross-neutralization. Uninfected vaccinees showed a small reduction in neutralization against the B.1.1.7 variant compared to both the WH1 strain and the D614G mutant. Interestingly, upon vaccination, previously infected individuals developed more robust neutralizing responses against B.1.1.7, suggesting that vaccines can boost the neutralization breadth conferred by natural infection
ALMA Observations of Asteroid 3 Juno at 60 Kilometer Resolution
We present Atacama Large Millimeter/submillimeter Array (ALMA) 1.3 mm
continuum images of the asteroid 3 Juno obtained with an angular resolution of
0.042 arcseconds (60 km at 1.97 AU). The data were obtained over a single 4.4
hr interval, which covers 60% of the 7.2 hr rotation period, approximately
centered on local transit. A sequence of ten consecutive images reveals
continuous changes in the asteroid's profile and apparent shape, in good
agreement with the sky projection of the three-dimensional model of the
Database of Asteroid Models from Inversion Techniques. We measure a geometric
mean diameter of 259pm4 km, in good agreement with past estimates from a
variety of techniques and wavelengths. Due to the viewing angle and inclination
of the rotational pole, the southern hemisphere dominates all of the images.
The median peak brightness temperature is 215pm13 K, while the median over the
whole surface is 197pm15 K. With the unprecedented resolution of ALMA, we find
that the brightness temperature varies across the surface with higher values
correlated to the subsolar point and afternoon areas, and lower values beyond
the evening terminator. The dominance of the subsolar point is accentuated in
the final four images, suggesting a reduction in the thermal inertia of the
regolith at the corresponding longitudes, which are possibly correlated to the
location of the putative large impact crater. These results demonstrate ALMA's
potential to resolve thermal emission from the surface of main belt asteroids,
and to measure accurately their position, geometric shape, rotational period,
and soil characteristics.Comment: 8 pages, 3 figures, 2 tables, accepted for publication in the
Astrophysical Journal Letter
First Results from High Angular Resolution ALMA Observations Toward the HL Tau Region
We present Atacama Large Millimeter/submillimeter Array (ALMA) observations
from the 2014 Long Baseline Campaign in dust continuum and spectral line
emission from the HL Tau region. The continuum images at wavelengths of 2.9,
1.3, and 0.87 mm have unprecedented angular resolutions of 0.075 arcseconds (10
AU) to 0.025 arcseconds (3.5 AU), revealing an astonishing level of detail in
the circumstellar disk surrounding the young solar analogue HL Tau, with a
pattern of bright and dark rings observed at all wavelengths. By fitting
ellipses to the most distinct rings, we measure precise values for the disk
inclination (46.72pm0.05 degrees) and position angle (+138.02pm0.07 degrees).
We obtain a high-fidelity image of the 1.0 mm spectral index (), which
ranges from in the optically-thick central peak and two
brightest rings, increasing to 2.3-3.0 in the dark rings. The dark rings are
not devoid of emission, we estimate a grain emissivity index of 0.8 for the
innermost dark ring and lower for subsequent dark rings, consistent with some
degree of grain growth and evolution. Additional clues that the rings arise
from planet formation include an increase in their central offsets with radius
and the presence of numerous orbital resonances. At a resolution of 35 AU, we
resolve the molecular component of the disk in HCO+ (1-0) which exhibits a
pattern over LSR velocities from 2-12 km/s consistent with Keplerian motion
around a ~1.3 solar mass star, although complicated by absorption at low
blue-shifted velocities. We also serendipitously detect and resolve the nearby
protostars XZ Tau (A/B) and LkHa358 at 2.9 mm.Comment: 11 pages, 5 figures, 2 tables, accepted for publication in the
Astrophysical Journal Letter
First-in human, phase 1, dose-escalation pharmacokinetic and pharmacodynamic study of the oral dual PI3K and mTORC1/2 inhibitor PQR309 in patients with advanced solid tumors (SAKK 67/13)
BACKGROUND: PQR309 is an orally bioavailable, balanced pan-phosphatidylinositol-3-kinase (PI3K), mammalian target of rapamycin (mTOR) C1 and mTORC2 inhibitor. PATIENTS AND METHODS: This is an accelerated titration, 3 + 3 dose-escalation, open-label phase I trial of continuous once-daily (OD) PQR309 administration to evaluate the safety, pharmacokinetics (PK) and pharmacodynamics in patients with advanced solid tumours. Primary objectives were to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). RESULTS: Twenty-eight patients were included in six dosing cohorts and treated at a daily PQR309 dose ranging from 10 to 150 mg. Common adverse events (AEs; ≥30% patients) included fatigue, hyperglycaemia, nausea, diarrhoea, constipation, rash, anorexia and vomiting. Grade (G) 3 or 4 drug-related AEs were seen in 13 (46%) and three (11%) patients, respectively. Dose-limiting toxicity (DLT) was observed in two patients at 100 mg OD (>14-d interruption in PQR309 due to G3 rash, G2 hyperbilirubinaemia, G4 suicide attempt; dose reduction due to G3 fatigue, G2 diarrhoea, G4 transaminitis) and one patient at 80 mg (G3 hyperglycaemia >7 d). PK shows fast absorption (Tmax 1-2 h) and dose proportionality for Cmax and area under the curve. A partial response in a patient with metastatic thymus cancer, 24% disease volume reduction in a patient with sinonasal cancer and stable disease for more than 16 weeks in a patient with clear cell Bartholin's gland cancer were observed. CONCLUSION: The MTD and RP2D of PQR309 is 80 mg of orally OD. PK is dose-proportional. PD shows PI3K pathway phosphoprotein downregulation in paired tumour biopsies. Clinical activity was observed in patients with and without PI3K pathway dysregulation. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov # NCT01940133
Targeted Morphoproteomic Profiling of Ewing's Sarcoma Treated with Insulin-Like Growth Factor 1 Receptor (IGF1R) Inhibitors: Response/Resistance Signatures
Insulin-like growth factor 1 receptor (IGF1R) targeted therapies have resulted in responses in a small number of patients with advanced metastatic Ewing's sarcoma. We performed morphoproteomic profiling to better understand response/resistance mechanisms of Ewing's sarcoma to IGF1R inhibitor-based therapy.This pilot study assessed two patients with advanced Ewing's sarcoma treated with IGF1R antibody alone followed by combined IGF1R inhibitor plus mammalian target of rapamycin (mTOR) inhibitor treatment once resistance to single-agent IGF1R inhibitor developed. Immunohistochemical probes were applied to detect p-mTOR (Ser2448), p-Akt (Ser473), p-ERK1/2 (Thr202/Tyr204), nestin, and p-STAT3 (Tyr 705) in the original and recurrent tumor. The initial remarkable radiographic responses to IGF1R-antibody therapy was followed by resistance and then response to combined IGF1R plus mTOR inhibitor therapy in both patients, and then resistance to the combination regimen in one patient. In patient 1, upregulation of p-Akt and p-mTOR in the tumor that relapsed after initial response to IGF1R antibody might explain the resistance that developed, and the subsequent response to combined IGF1R plus mTOR inhibitor therapy. In patient 2, upregulation of mTOR was seen in the primary tumor, perhaps explaining the initial response to the IGF1R and mTOR inhibitor combination, while the resistant tumor that emerged showed activation of the ERK pathway as well.Morphoproteomic analysis revealed that the mTOR pathway was activated in these two patients with advanced Ewing's sarcoma who showed response to combined IGF1R and mTOR inhibition, and the ERK pathway in the patient in whom resistance to this combination emerged. Our pilot results suggests that morphoproteomic assessment of signaling pathway activation in Ewing's sarcoma merits further investigation as a guide to understanding response and resistance signatures
R1507, an Anti-Insulin-Like Growth Factor-1 Receptor (IGF-1R) Antibody, and EWS/FLI-1 siRNA in Ewing's Sarcoma: Convergence at the IGF/IGFR/Akt Axis
A subset of patients with Ewing's sarcoma responds to anti-insulin-like growth factor-1 receptor (IGF-1R) antibodies. Mechanisms of sensitivity and resistance are unknown. We investigated whether an anti-IGF-1R antibody acts via a pathway that could also be suppressed by small interfering (si) RNA against the EWS/FLI-1 fusion protein, the hallmark of Ewing's sarcoma. The growth of two Ewing's sarcoma cell lines (TC-32 and TC-71) was inhibited by the fully human anti-IGF-1R antibody, R1507 (clonogenic and MTT assays). TC-32 and TC-71 cells express high levels of IGF-2, while RD-ES and A4573 Ewing's cell lines, which were less responsive to R1507 in our assays, express low or undetectable IGF-2, respectively. TC-71 cells also expressed high levels of IGF-1R, and R1507 decreased steady-state levels of this receptor by internalization/degradation, an effect which was associated with a decrease in p-IGF-1R, p-IRS-1, and p-Akt. EWS/FLI-1 siRNA also decreased p-Akt, due to its ability to increase IGF-BP3 levels and subsequently decrease IGF-1 and IGF-2 levels, thus inhibiting signaling through p-IGF-1R. This inhibition correlated with growth suppression and apoptosis. The attenuation of Akt activation was confirmed in TC-71 and HEK-293 (human embryonic kidney) cells by transfecting them with IGF-1R siRNA. We conclude that antibodies and siRNA to IGF-1R, as well as siRNA to EWS/FLI-1, act via intersecting IGF/IGF-1R signals that suppress a common point in this pathway, namely the phosphorylation of Akt
The Effects of Previous Misestimation of Task Duration on Estimating Future Task Duration
It is a common time management problem that people underestimate the duration of tasks, which has been termed the "planning fallacy." To overcome this, it has been suggested that people should be informed about how long they previously worked on the same task. This study, however, tests whether previous misestimation also affects the duration estimation of a novel task, even if the feedback is only self-generated. To test this, two groups of participants performed two unrelated, laboratory-based tasks in succession. Learning was manipulated by permitting only the experimental group to retrospectively estimate the duration of the first task before predicting the duration of the second task. Results showed that the experimental group underestimated the duration of the second task less than the control group, which indicates a general kind of learning from previous misestimation. The findings imply that people could be trained to carefully observe how much they misestimate task duration in order to stimulate learning. The findings are discussed in relation to the anchoring account of task duration misestimation and the memory-bias account of the planning fallacy. © 2014 Springer Science+Business Media New York
Preclinical and randomized phase I studies of plitidepsin in adults hospitalized with COVID-19
Plitidepsin, a marine-derived cyclic-peptide, inhibits SARS-CoV-2 replication at nanomolar concentrations by targeting the host protein eukaryotic translation elongation factor 1A. Here, we show that plitidepsin distributes preferentially to lung over plasma, with similar potency against across several SARS-CoV-2 variants in preclinical studies. Simultaneously, in this randomized, parallel, open-label, proof-of-concept study (NCT04382066) conducted in 10 Spanish hospitals between May and November 2020, 46 adult hospitalized patients with confirmed SARS-CoV-2 infection received either 1.5 mg (n = 15), 2.0 mg (n = 16), or 2.5 mg (n = 15) plitidepsin once daily for 3 d. The primary objective was safety; viral load kinetics, mortality, need for increased respiratory support, and dose selection were secondary end points. One patient withdrew consent before starting procedures; 45 initiated treatment; one withdrew because of hypersensitivity. Two Grade 3 treatment-related adverse events were observed (hypersensitivity and diarrhea). Treatment-related adverse events affecting more than 5% of patients were nausea (42.2%), vomiting (15.6%), and diarrhea (6.7%). Mean viral load reductions from baseline were 1.35, 2.35, 3.25, and 3.85 log10 at days 4, 7, 15, and 31. Nonmechanical invasive ventilation was required in 8 of 44 evaluable patients (16.0%); six patients required intensive care support (13.6%), and three patients (6.7%) died (COVID-19-related). Plitidepsin has a favorable safety profile in patients with COVID-19
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