Margetuximab is an anti-HER2 antibody that binds with elevated affinity to both the lower and higher affinity forms of CD16A, an Fc-receptor important for antibody dependent cell-mediated ...cytotoxicity (ADCC) against tumor cells. A Phase 1 study was initiated to evaluate the toxicity profile, maximum tolerated dose (MTD), pharmacokinetics, and antitumor activity of margetuximab in patients with HER2-overexpressing carcinomas.
Patients with HER2-positive breast or gastric cancer, or other carcinomas that overexpress HER2, for whom no standard therapy was available, were treated with margetuximab by intravenous infusion at doses of 0.1–6.0 mg/kg for 3 of every 4 weeks (Regimen A) or once every 3 weeks (10–18 mg/kg) (Regimen B).
Sixty-six patients received margetuximab (34 patients for Regimen A and 32 patients for Regimen B). The MTD was not reached for either regimen. Treatment was well-tolerated, with mostly Grade 1 and 2 toxicities consisting of constitutional symptoms such as pyrexia, nausea, anemia, diarrhea, and fatigue. Among 60 response-evaluable patients, confirmed partial responses and stable disease were observed in 7 (12%) and 30 (50%) patients, respectively; 26 (70%) of these patients had received prior HER2-targeted therapy. Tumor reductions were observed in over half (18/23, 78%) of response-evaluable patients with breast cancer including durable (>30 weeks) responders.Ex vivo analyses of patient peripheral blood mononuclear cell samples confirmed the ability of margetuximab to support enhanced ADCC compared with trastuzumab.
Margetuximab was well-tolerated and has promising single-agent activity. Further development efforts of margetuximab as single agent and in combination with other therapeutic agents are ongoing.
NCT01148849.
DNA ligases catalyze the repair of phosphate backbone breaks in DNA, acting with highest activity on breaks in one strand of duplex DNA. Some DNA ligases have also been observed to ligate two DNA ...fragments with short complementary overhangs or blunt-ended termini. In this study, several wild-type DNA ligases (phage T3, T4, and T7 DNA ligases, Paramecium bursaria chlorella virus 1 (PBCV1) DNA ligase, human DNA ligase 3, and Escherichia coli DNA ligase) were tested for their ability to ligate DNA fragments with several difficult to ligate end structures (blunt-ended termini, 3'- and 5'- single base overhangs, and 5'-two base overhangs). This analysis revealed that T4 DNA ligase, the most common enzyme utilized for in vitro ligation, had its greatest activity on blunt- and 2-base overhangs, and poorest on 5'-single base overhangs. Other ligases had different substrate specificity: T3 DNA ligase ligated only blunt ends well; PBCV1 DNA ligase joined 3'-single base overhangs and 2-base overhangs effectively with little blunt or 5'- single base overhang activity; and human ligase 3 had highest activity on blunt ends and 5'-single base overhangs. There is no correlation of activity among ligases on blunt DNA ends with their activity on single base overhangs. In addition, DNA binding domains (Sso7d, hLig3 zinc finger, and T4 DNA ligase N-terminal domain) were fused to PBCV1 DNA ligase to explore whether modified binding to DNA would lead to greater activity on these difficult to ligate substrates. These engineered ligases showed both an increased binding affinity for DNA and increased activity, but did not alter the relative substrate preferences of PBCV1 DNA ligase, indicating active site structure plays a role in determining substrate preference.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
We analyze the dust properties of 57 870
μ
m-selected dusty star-forming galaxies in GOODS-S using new deep Atacama Large Millimeter/Submillimeter Array 1.2, 2, and 3 mm continuum imaging ...together with other far-infrared through millimeter data. We fit the spectral energy distributions (SEDs) with optically thin modified blackbodies to constrain the emissivity indices and effective dust temperatures, finding a median emissivity index of
β
=
1.78
−
0.25
+
0.43
and a median temperature of
T
d
=
33.6
−
5.4
+
12.1
K. We observe a negative correlation between
β
and
T
d
. By testing several SED models, we determine that the derived emissivity indices can be influenced by opacity assumptions. Our temperature measurements are consistent with no evolution in dust temperature with redshift.
Aerosols have important impacts on air quality and climate, but the processes affecting their removal from the atmosphere are not fully understood and are poorly constrained by observations. This ...makes modelled aerosol lifetimes uncertain. In this study, we make use of an observational constraint on aerosol lifetimes provided by radionuclide measurements and investigate the causes of differences within a set of global models. During the Fukushima Dai-Ichi nuclear power plant accident of March 2011, the radioactive isotopes cesium-137 (137Cs) and xenon-133 (133Xe) were released in large quantities. Cesium attached to particles in the ambient air, approximately according to their available aerosol surface area. 137Cs size distribution measurements taken close to the power plant suggested that accumulation-mode (AM) sulfate aerosols were the main carriers of cesium. Hence, 137Cs can be used as a proxy tracer for the AM sulfate aerosol's fate in the atmosphere. In contrast, the noble gas 133Xe behaves almost like a passive transport tracer. Global surface measurements of the two radioactive isotopes taken over several months after the release allow the derivation of a lifetime of the carrier aerosol. We compare this to the lifetimes simulated by 19 different atmospheric transport models initialized with identical emissions of 137Cs that were assigned to an aerosol tracer with each model's default properties of AM sulfate, and 133Xe emissions that were assigned to a passive tracer. We investigate to what extent the modelled sulfate tracer can reproduce the measurements, especially with respect to the observed loss of aerosol mass with time. Modelled 137Cs and 133Xe concentrations sampled at the same location and times as station measurements allow a direct comparison between measured and modelled aerosol lifetime. The e-folding lifetime τe, calculated from station measurement data taken between 2 and 9 weeks after the start of the emissions, is 14.3 days (95 % confidence interval 13.1–15.7 days). The equivalent modelled τe lifetimes have a large spread, varying between 4.8 and 26.7 days with a model median of 9.4 ± 2.3 days, indicating too fast a removal in most models. Because sufficient measurement data were only available from about 2 weeks after the release, the estimated lifetimes apply to aerosols that have undergone long-range transport, i.e. not for freshly emitted aerosol. However, modelled instantaneous lifetimes show that the initial removal in the first 2 weeks was quicker (lifetimes between 1 and 5 days) due to the emissions occurring at low altitudes and co-location of the fresh plume with strong precipitation. Deviations between measured and modelled aerosol lifetimes are largest for the northernmost stations and at later time periods, suggesting that models do not transport enough of the aerosol towards the Arctic. The models underestimate passive tracer (133Xe) concentrations in the Arctic as well but to a smaller extent than for the aerosol (137Cs) tracer. This indicates that in addition to too fast an aerosol removal in the models, errors in simulated atmospheric transport towards the Arctic in most models also contribute to the underestimation of the Arctic aerosol concentrations.
We investigate the nature of a sample of 92 Spitzer MIPS 24 km-selected galaxies in the CDF-S, showing power-law-like emission in the Spitzer IRAC 3.6-8 km bands. The main goal is to determine ...whether the galaxies not detected in X-rays (47% of the sample) are part of the hypothetical population of obscured AGNs not detected even in deep X-ray surveys. The majority of the IR power-law galaxies are ULIRGs at z > 1, and those with LIRG-like IR luminosities are usually detected in X-rays. The optical-to-IR SEDs of the X-ray-detected galaxies are almost equally divided between a BLAGN SED class (similar to an optically selected QSO) and an NLAGN SED (similar to the BLAGN SED but with an obscured UV/optical continuum). A small fraction of SEDs resemble warm ULIRGs (e.g., Mrk 231). Most galaxies not detected in X-rays have SEDs in the NLAGN+ULIRG class as they tend to be optically fainter and possibly more obscured. Moreover, the IR power-law galaxies have SEDs significantly different from those of high-z (z sub(sp) > 1) IR (24 km) selected and optically bright (VVDS I sub(AB) , 24) star-forming galaxies whose SEDs show a very prominent stellar bump at 1.6 km. The galaxies detected in X-rays have 2-8 keV rest-frame luminosities typical of AGNs. The galaxies not detected in X-rays have global X-ray-to-mid-IR SED properties that make them good candidates to contain IR-bright X-ray-absorbed AGNs. If all these sources are actually obscured AGNs, we would observe a ratio of obscured to unobscured 24 km-detected AGNs of 2:1, whereas models predict a ratio of up to 3:1. Additional studies using Spitzer to detect X-ray-quiet AGNs are likely to find more such obscured sources.
Summary Objective The purpose of this work was to review the current literature on cartilage and meniscal T2 relaxation time. Methods Electronic searches in PubMed were performed to identify relevant ...studies about T2 relaxation time measurements as non-invasive biomarker for knee osteoarthritis (OA) and cartilage repair procedures. Results Initial osteoarthritic changes include proteoglycan loss, deterioration of the collagen network, and increased water content within the articular cartilage and menisci. T2 relaxation time measurements are affected by these pathophysiological processes. It was demonstrated that cartilage and meniscal T2 relaxation time values were significantly increased in subjects with compared to those without radiographic OA and focal knee lesions, respectively. Subjects with OA risk factors such as overweight/obesity showed significantly greater cartilage T2 values than normal controls. Elevated cartilage and meniscal T2 relaxation times were found in subjects with vs without knee pain. Increased cartilage T2 at baseline predicted morphologic degeneration in the cartilage, meniscus, and bone marrow over 3 years. Furthermore, cartilage repair tissue could be non-invasively assessed by using T2 mapping. Reproducibility errors for T2 measurements were reported to be smaller than the T2 differences in healthy and diseased cartilage indicating that T2 relaxation time may be a reliable discriminatory biomarker. Conclusions Cartilage and meniscal T2 mapping may be suitable as non-invasive biomarker to diagnose early stages of knee OA and to monitor therapy of OA.
Context. The CARMENES survey is a high-precision radial velocity (RV) programme that aims to detect Earth-like planets orbiting low-mass stars. Aims. We develop least-squares fitting algorithms to ...derive the RVs and additional spectral diagnostics implemented in the SpEctrum Radial Velocity AnaLyser (SERVAL), a publicly available python code. Methods. We measured the RVs using high signal-to-noise templates created by coadding all available spectra of each star. We define the chromatic index as the RV gradient as a function of wavelength with the RVs measured in the echelle orders. Additionally, we computed the differential line width by correlating the fit residuals with the second derivative of the template to track variations in the stellar line width. Results. Using HARPS data, our SERVAL code achieves a RV precision at the level of 1 m/s. Applying the chromatic index to CARMENES data of the active star YZ CMi, we identify apparent RV variations induced by stellar activity. The differential line width is found to be an alternative indicator to the commonly used full width half maximum. Conclusions. We find that at the red optical wavelengths (700–900 nm) obtained by the visual channel of CARMENES, the chromatic index is an excellent tool to investigate stellar active regions and to identify and perhaps even correct for activity-induced RV variations.
Context. M dwarfs are known to generate the strongest magnetic fields among main-sequence stars with convective envelopes, but we are still lacking a consistent picture of the link between the ...magnetic fields and underlying dynamo mechanisms, rotation, and activity. Aims. In this work we aim to measure magnetic fields from the high-resolution near-infrared spectra taken with the CARMENES radial-velocity planet survey in a sample of 29 active M dwarfs and compare our results against stellar parameters. Methods. We used the state-of-the-art radiative transfer code to measure total magnetic flux densities from the Zeeman broadening of spectral lines and filling factors. Results. We detect strong kG magnetic fields in all our targets. In 16 stars the magnetic fields were measured for the first time. Our measurements are consistent with the magnetic field saturation in stars with rotation periods P < 4 d. The analysis of the magnetic filling factors reveal two different patterns of either very smooth distribution or a more patchy one, which can be connected to the dynamo state of the stars and/or stellar mass. Conclusions. Our measurements extend the list of M dwarfs with strong surface magnetic fields. They also allow us to better constrain the interplay between the magnetic energy, stellar rotation, and underlying dynamo action. The high spectral resolution and observations at near-infrared wavelengths are the beneficial capabilities of the CARMENES instrument that allow us to address important questions about the stellar magnetism.
Aims. We aim at detecting water vapor in the atmosphere of the hot Jupiter HD 209458 b and perform a multi-band study in the near infrared with CARMENES. Methods. The water vapor absorption lines ...from the atmosphere of the planet are Doppler-shifted due to the large change in its radial velocity during transit. This shift is of the order of tens of km s−1, whilst the Earth’s telluric and the stellar lines can be considered quasi-static. We took advantage of this shift to remove the telluric and stellar lines using SYSREM, which performs a principal component analysis including proper error propagation. The residual spectra contain the signal from thousands of planetary molecular lines well below the noise level. We retrieve the information from those lines by cross-correlating the residual spectra with models of the atmospheric absorption of the planet. Results. We find a cross-correlation signal with a signal-to-noise ratio (S/N) of 6.4, revealing H2O in HD 209458 b. We obtain a net blueshift of the signal of –5.2 −1.3+2.6 $^{+2.6}_{-1.3}$ −1.3+2.6 km s−1 that, despite the large error bars, is a firm indication of day- to night-side winds at the terminator of this hot Jupiter. Additionally, we performed a multi-band study for the detection of H2O individually from the three near infrared bands covered by CARMENES. We detect H2O from its 0.96–1.06 μm band with a S/N of 5.8, and also find hints of a detection from the 1.06–1.26 μm band, with a low S/N of 2.8. No clear planetary signal is found from the 1.26–1.62 μm band. Conclusions. Our significant H2O signal at 0.96–1.06 μm in HD 209458 b represents the first detection of H2O from this band individually, the bluest one to date. The unfavorable observational conditions might be the reason for the inconclusive detection from the stronger 1.15 and 1.4 μm bands. H2O is detected from the 0.96–1.06 μm band in HD 209458 b, but hardly in HD 189733 b, which supports a stronger aerosol extinction in the latter, in line with previous studies. Future data gathered at more stable conditions and with larger S/N at both optical and near-infrared wavelengths could help to characterize the presence of aerosols in HD 209458 b and other planets.
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