The epidermal growth factor receptor (EGFR) is highly expressed in a significant number of human malignancies, and its expression is associated with tumor aggressiveness and overall treatment ...resistance. The monoclonal antibody cetuximab is increasingly used in clinical settings as a treatment modality in combination with more conventional therapies, such as radio- and chemotherapy. Currently, little is known about tumor-specific uptake and overall pharmacokinetics. Noninvasive quantification of cetuximab uptake could provide important diagnostic information for patient selection and therapy evaluation. To this end, we have developed and validated a novel probe using cetuximab labeled with the long-lived positron emitter 89Zr for PET imaging.
Tumor cell lines with varying EGFR expression levels were used for in vivo tumor imaging experiments. PET with 89Zr-labeled cetuximab (3.75+/-0.14 MBq) was performed on tumor-bearing NMRI-nu mice at multiple time points after injection (ranging from 1 to 120 h) and quantified by drawing regions of interest on selected tissues. Uptake was compared by biodistribution gamma-counting, and ex vivo EGFR expression levels were quantified using Western blot analysis.
Uptake of 89Zr-labeled cetuximab was demonstrated in the EGFR-positive tumors. However, the EGFR levels measured in vivo did not correlate with the relative signal obtained by PET. Tumor-to-blood ratios were significantly higher in the cell lines with intermediate (compared with the high) EGFR expression starting from 24 h after injection. Normal tissue uptake was unaffected by the different tumor types. Ex vivo gamma-counting experiments confirmed the observed in vivo PET results. A similar disparity was found between 89Zr-labeled cetuximab tumor uptake and in vivo EGFR expression levels as demonstrated by Western blotting.
The 89Zr-labeled cetuximab imaging probe is a promising tool for noninvasive evaluation of cetuximab uptake. Our results demonstrate a disparity between in vivo EGFR expression levels and cetuximab uptake. In a general sense, the results indicate a disparity between antibody uptake and expression levels of a biologic target in a tumor, suggesting that additional pharmacokinetic or pharmacodynamic mechanisms influence tumor delivery of this therapy. These additional mechanisms may explain why receptor expression levels alone are not sufficient to predict patient response.
Carbonic anhydrase (CA) IX is a transmembrane protein overexpressed in many frequently occurring tumors associated with tumor hypoxia. Sulfonamides and their bioisosteres are known to inhibit CA IX ...activity. In this study, 4-(2-aminoethyl)benzenesulfonamide was conjugated to a tridentate ligand,
N-2-picolyl-
N-acetic acid and labeled with a
99mTc(
I)-tricarbonyl moiety resulting in
99mTc(CO)
3 (L) (L=
N-(pyridin-2-yl-methyl)-
N2-(4-sulfamoylphenyl)-ethylaminoethyl acetate) complex,
99mTc-
5. Similarly the corresponding rhenium congener (Re-
4) was synthesized. The in vitro CA IX affinity and inhibitory activity of Re-
4 were determined and
99mTc-
5 was evaluated as a tracer for in vivo visualisation of CA IX expression.
Evaluation of the in vitro affinity (inhibition constant,
K
i) of Re-
4 for CA isozymes I, II, IX and XII was carried out by assaying the CA catalyzed CO
2 hydration activity and efficacy studies were performed in HT 29 cell lines expressing CA IX under normoxia or hypoxia. Biodistribution studies of
99mTc-
5 were performed in xenograft mice bearing CA IX expressing tumors.
The in vitro affinity of Re-
4 for CA IX was 58 nM and CA IX induced acidification of extracellular medium was efficiently reduced (
P<.05) in the presence of 1 mM Re-
4. Biodistribution studies indicated a maximal tumor uptake of
99mTc-
5 of 0.1% ID/g at 30 min post injection.
99mTc-
5 and its rhenium congener were synthesized and characterized. In vitro studies showed that the rhenium compound has a high affinity for CA IX and effectively inhibits CA IX activity. In vivo studies revealed a limited tracer accumulation in a CA IX expressing tumor but with increasing tumor-to-blood activity ratios as a function of time.
Abridged: We measured photometric and spectroscopic \(P_{\rm rot}\) for a large sample of nearby bright M dwarfs with spectral types from M0 to M9, as part of our continual effort to fully ...characterize the Guaranteed Time Observation programme stars of the CARMENES survey. We determine \(P_{\rm rot}\) for 129 stars. Combined with the literature, we tabulate \(P_{\rm rot}\) for 261 stars, or 75% of our sample. We evaluate the plausibility of all periods available for this sample by comparing them with activity signatures and checking for consistency between multiple measurements. We find that 166 of these stars have independent evidence that confirmed their \(P_{\rm rot}\). There are inconsistencies in 27 periods, which we classify as debated. A further 68 periods are identified as provisional detections that could benefit from independent verification. We provide an empirical relation for the \(P_{\rm rot}\) uncertainty as a function of the \(P_{\rm rot}\) value, based on the dispersion of the measurements. We show that published formal errors seem to be often underestimated for periods \(\gtrsim 10\) d. We highlight the importance of independent verification on \(P_{\rm rot}\) measurements, especially for inactive M dwarfs. We examine rotation-activity relations with emission in X-rays, H\(\alpha\), Ca II H & K, and surface magnetic field strengths. We find overall agreement with previous works, as well as tentative differences in the partially versus fully convective subsamples. We show \(P_{\rm rot}\) as a function of stellar mass, age, and galactic kinematics. With the notable exception of three transiting planet systems and TZ Ari, all known planet hosts in this sample have \(P_{\rm rot} \gtrsim 15\) d. This indicates that important limitations need to be overcome before the radial velocity technique can be routinely used to detect and study planets around young and active stars.
Lightcurves of many classical novae deviate from the canonical "fast rise - smooth decline" pattern and display complex variability behavior. We present the first TESS-space-photometry-based ...investigation of this phenomenon. We use TESS Sector 41 full-frame images to extract a lightcurve of the slow Galactic nova V606 Vul that erupted nine days prior to the start of the TESS observations. The lightcurve covers the first of two major peaks of V606 Vul that was reached 19 days after the start of the eruption. The nova reached its brightest visual magnitude V=9.9 in its second peak 64 days after the eruption onset, following the completion of Sector 41 observations. To increase the confidence level of the extracted lightcurve, we performed the analysis using four different codes implementing the aperture photometry (Lightkurve, VaST) and image subtraction (TESSreduce, tequila_shots) and find good agreement between them. We performed ground-based photometric and spectroscopic monitoring to complement the TESS data. The TESS lightcurve reveals two features: periodic variations (0.12771d, 0.01mag average peak-to-peak amplitude) that disappeared when the source was within 1mag of peak optical brightness and a series of isolated mini-flares (with peak-to-peak amplitudes of up to 0.5mag) appearing at seemingly random times. We interpret the periodic variations as the result of azimuthal asymmetry of the photosphere engulfing the nova-hosting binary that was distorted by and rotating with the binary. Whereas we use spectra to associate the two major peaks in the nova lightcurve with distinct episodes of mass ejection, the origin of mini-flares remains elusive.
Tumor hypoxia contributes resistance to chemo- and radiotherapy, while oxygenated tumors are sensitive to these treatments. The indirect detection of hypoxic tumors is possible by targeting carbonic ...anhydrase IX (CA IX), an enzyme overexpressed in hypoxic tumors, with sulfonamide-based imaging agents. In this study, we present the design and synthesis of novel gallium-radiolabeled small-molecule sulfonamides targeting CA IX. The compounds display favorable in vivo pharmacokinetics and stability. We demonstrate that our lead compound, 68Ga-2, discriminates CA IX-expressing tumors in vivo in a mouse xenograft model using positron emission tomography (PET). This compound shows specific tumor accumulation and low uptake in blood and clears intact to the urine. These findings were reproduced in a second study using PET/computed tomography. Small molecules investigated to date utilizing 68Ga for preclinical CA IX imaging are scarce, and this is one of the first effective 68Ga compounds reported for PET imaging of CA IX.
This paper is one in a series reporting results from small telescope observations of variable young stars. Here, we study the repeating outbursts of three likely Be stars based on long-term optical, ...near-infrared, and mid-infrared photometry for all three objects, along with follow-up spectra for two of the three. The sources are characterised as rare, truly regularly outbursting Be stars. We interpret the photometric data within a framework for modelling light curve morphology, and find that the models correctly predict the burst shapes, including their larger amplitudes and later peaks towards longer wavelengths. We are thus able to infer the start and end times of mass loading into the circumstellar disks of these stars. The disk sizes are typically 3-6 times the areas of the central star. The disk temperatures are ~40%, and the disk luminosities are ~10% of those of the central Be star, respectively. The available spectroscopy is consistent with inside-out evolution of the disk. Higher excitation lines have larger velocity widths in their double-horned shaped emission profiles. Our observations and analysis support the decretion disk model for outbursting Be stars.
Studying rotational variability of young stars is enabling us to investigate a multitude of properties of young star-disk systems. We utilise high cadence, multi-wavelength optical time series data ...from the Hunting Outbursting Young Stars citizen science project to identify periodic variables in the Pelican Nebula (IC5070). A double blind study using nine different period-finding algorithms was conducted and a sample of 59 periodic variables was identified. We find that a combination of four period finding algorithms can achieve a completeness of 85% and a contamination of 30% in identifying periods in inhomogeneous data sets. The best performing methods are periodograms that rely on fitting a sine curve. Utilising GaiaEDR3 data, we have identified an unbiased sample of 40 periodic YSOs, without using any colour or magnitude selections. With a 98.9% probability we can exclude a homogeneous YSO period distribution. Instead we find a bi-modal distribution with peaks at three and eight days. The sample has a disk fraction of 50%, and its statistical properties are in agreement with other similarly aged YSOs populations. In particular, we confirm that the presence of the disk is linked to predominantly slow rotation and find a probability of 4.8\(\times\)10\(^{-3}\) that the observed relation between period and presence of a disk has occurred by chance. In our sample of periodic variables, we also find pulsating giants, an eclipsing binary, and potential YSOs in the foreground of IC5070.
RW Aur is a binary system composed of two young, low-mass stars. The primary, RW Aur A, has undergone visual dimming events (\(\Delta V =2-3\)~mag) in 2011, 2014-16, and 2017-2018. Visual and IR ...observations indicate a gray absorber that moved into the line-of-sight. This dimming is also associated with changes in the outflow. In 2017, when the optical brightness was almost 2~mag below the long-term average we triggered a Chandra observation to measure the absorbing column density \(N_\mathrm{H}\) and to constrain dust properties and the gas-to-dust ratio of the absorber. In 2017, the X-ray spectrum is more absorbed than it was in the optically bright state (\(N_\mathrm{H} = (4\pm 1) \times 10^{23}\;\mathrm{cm}^{-2}\)) and shows significantly more hot plasma than in X-ray observations taken before. Also, a new emission feature at \(6.63\pm0.02\) keV (statistic) \(\pm0.02\) keV (systematic) appeared indicating an Fe abundance an order of magnitude above Solar, in contrast with previous sub-Solar Fe abundance measurements. Comparing X-ray absorbing column density \(N_\mathrm{H}\) and optical extinction \(A_V\), we find that either the gas-to-dust ratio in the absorber is orders of magnitude higher than in the ISM or the absorber has undergone significant dust evolution. Given the high column density coupled with changes in the X-ray spectral shape, this absorber is probably located in the inner disk. We speculate that a break-up of planetesimals or a terrestrial planet could supply large grains causing gray absorption; some of these grains would be accreted and enrich the stellar corona with iron which could explain the inferred high abundance.
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