Incomplete oncologic resections and damage to vital structures during colorectal cancer surgery increases morbidity and mortality. Moreover, neoadjuvant chemoradiotherapy has become the standard ...treatment modality for locally advanced rectal cancer, where subsequent downstaging can make identification of the primary tumor more challenging during surgery. Near-infrared (NIR) fluorescence imaging can aid surgeons by providing real-time visualization of tumors and vital structures during surgery.
We present the first-in-human clinical experience of a novel NIR fluorescent peptide, cRGD-ZW800-1, for the detection of colon cancer. cRGD-ZW800-1 was engineered to have an overall zwitterionic chemical structure and neutral charge to lower nonspecific uptake and thus background fluorescent signal. We performed a phase I study in 11 healthy volunteer as well as a phase II feasibility study in 12 patients undergoing an elective colon resection, assessing 0.005, 0.015, and 0.05 mg/kg cRGD-ZW800-1 for the intraoperative visualization of colon cancer.
cRGD-ZW800-1 appears safe, and exhibited rapid elimination into urine after a single low intravenous dose. Minimal invasive intraoperative visualization of colon cancer through full-thickness bowel wall was possible after an intravenous bolus injection of 0.05 mg/kg at least 2 hours prior to surgery. Longer intervals between injection and imaging improved the tumor-to-background ratio.
cRGD-ZW800-1 enabled fluorescence imaging of colon cancer in both open and minimal invasive surgeries. Further development of cRGD-ZW800-1 for widespread use in cancer surgery may be warranted given the ubiquitous overexpression of various integrins on different types of tumors and their vasculature.
Euclid preparation Bodendorf, C.; Grupp, F.; Hormuth, F. ...
Astronomy and astrophysics (Berlin),
06/2022, Letnik:
662
Journal Article
Recenzirano
Odprti dostop
Euclid
will be the first space mission to survey most of the extragalactic sky in the 0.95–2.02 µm range, to a 5
σ
point-source median depth of 24.4 AB mag. This unique photometric dataset will find ...wide use beyond
Euclid’s
core science. In this paper, we present accurate computations of the Euclid
Y
E
,
J
E
, and
H
E
passbands used by the Near-Infrared Spectrometer and Photometer (NISP), and the associated photometric system. We pay particular attention to passband variations in the field of view, accounting for, among other factors, spatially variable filter transmission and variations in the angle of incidence on the filter substrate using optical ray tracing. The response curves’ cut-on and cut-off wavelengths – and their variation in the field of view – are determined with ~0.8 nm accuracy, essential for the photometric redshift accuracy required by
Euclid.
After computing the photometric zero points in the AB mag system, we present linear transformations from and to common ground-based near-infrared photometric systems, for normal stars, red and brown dwarfs, and galaxies separately. A
Python
tool to compute accurate magnitudes for arbitrary passbands and spectral energy distributions is provided. We discuss various factors, from space weathering to material outgassing, that may slowly alter
Euclid
’s spectral response. At the absolute flux scale, the
Euclid
in-flight calibration program connects the NISP photometric system to
Hubble
Space Telescope spectrophotometric white dwarf standards; at the relative flux scale, the chromatic evolution of the response is tracked at the milli-mag level. In this way, we establish an accurate photometric system that is fully controlled throughout
Euclid’s
lifetime.
Neuroblastoma and other pediatric tumors show a paucity of gene mutations, which has sparked an interest in their epigenetic regulation. Several tumor types include phenotypically divergent cells, ...resembling cells from different lineage development stages. It has been proposed that super-enhancer-associated transcription factor (TF) networks underlie lineage identity, but the role of these enhancers in intratumoral heterogeneity is unknown. Here we show that most neuroblastomas include two types of tumor cells with divergent gene expression profiles. Undifferentiated mesenchymal cells and committed adrenergic cells can interconvert and resemble cells from different lineage differentiation stages. ChIP-seq analysis of isogenic pairs of mesenchymal and adrenergic cells identified a distinct super-enhancer landscape and super-enhancer-associated TF network for each cell type. Expression of the mesenchymal TF PRRX1 could reprogram the super-enhancer and mRNA landscapes of adrenergic cells toward a mesenchymal state. Mesenchymal cells were more chemoresistant in vitro and were enriched in post-therapy and relapse tumors. Two super-enhancer-associated TF networks, which probably mediate lineage control in normal development, thus dominate epigenetic control of neuroblastoma and shape intratumoral heterogeneity.
Euclid
is poised to survey galaxies across a cosmological volume of unprecedented size, providing observations of more than a billion objects distributed over a third of the full sky. Approximately ...20 million of these galaxies will have their spectroscopy available, allowing us to map the three-dimensional large-scale structure of the Universe in great detail. This paper investigates prospects for the detection of cosmic voids therein and the unique benefit they provide for cosmological studies. In particular, we study the imprints of dynamic (redshift-space) and geometric (Alcock–Paczynski) distortions of average void shapes and their constraining power on the growth of structure and cosmological distance ratios. To this end, we made use of the Flagship mock catalog, a state-of-the-art simulation of the data expected to be observed with
Euclid
. We arranged the data into four adjacent redshift bins, each of which contains about 11 000 voids and we estimated the stacked void-galaxy cross-correlation function in every bin. Fitting a linear-theory model to the data, we obtained constraints on
f
/
b
and
D
M
H
, where
f
is the linear growth rate of density fluctuations,
b
the galaxy bias,
D
M
the comoving angular diameter distance, and
H
the Hubble rate. In addition, we marginalized over two nuisance parameters included in our model to account for unknown systematic effects in the analysis. With this approach,
Euclid
will be able to reach a relative precision of about 4% on measurements of
f
/
b
and 0.5% on
D
M
H
in each redshift bin. Better modeling or calibration of the nuisance parameters may further increase this precision to 1% and 0.4%, respectively. Our results show that the exploitation of cosmic voids in
Euclid
will provide competitive constraints on cosmology even as a stand-alone probe. For example, the equation-of-state parameter,
w
, for dark energy will be measured with a precision of about 10%, consistent with previous more approximate forecasts.
Modelling the water transport along the soil–plant–atmosphere continuum is fundamental to estimating and predicting transpiration fluxes. A Finite-difference Ecosystem-scale Tree Crown Hydrodynamics ...model (FETCH3) for the water fluxes across the soil–plant–atmosphere continuum is presented here. The model combines the water transport pathways into one vertical dimension, and assumes that the water flow through the soil, roots, and above-ground xylem can be approximated as flow in porous media. This results in a system of three partial differential equations, resembling the Richardson–Richards equation, describing the transport of water through the plant system and with additional terms representing sinks and sources for the transfer of water from the soil to the roots and from the leaves to the atmosphere. The numerical scheme, developed in Python 3, was tested against exact analytical solutions for steady state and transient conditions using simplified but realistic model parameterizations. The model was also used to simulate a previously published case study, where observed transpiration rates were available, to evaluate model performance. With the same model setup as the published case study, FETCH3 results were in agreement with observations. Through a rigorous coupling of soil, root xylem, and stem xylem, FETCH3 can account for variable water capacitance, while conserving mass and the continuity of the water potential between these three layers. FETCH3 provides a ready-to-use open access numerical model for the simulation of water fluxes across the soil–plant–atmosphere continuum.
Synthetic vaccines, based on antigenic peptides that comprise MHC−I and MHC‐II T‐cell epitopes expressed by tumors, show great promise for the immunotherapy of cancer. For optimal immunogenicity, the ...synthetic peptides (SPs) should be adjuvanted with suitable immunostimulatory additives. Previously, we have shown that improved immunogenicity in vivo is obtained with vaccine modalities in which an SP is covalently connected to an adjuvanting moiety, typically a ligand to Toll‐like receptor 2 (TLR2). SPs were covalently attached to UPam, which is a derivative of the classic TLR2 ligand Pam3CysSK4. A disadvantage of the triply palmitoylated UPam is its high lipophilicity, which precludes universal adoption of this adjuvant for covalent modification of various antigenic peptides as it renders the synthetic vaccine insoluble in several cases. Here, we report a novel conjugatable TLR2 ligand, mini‐UPam, which contains only one palmitoyl chain, rather than three, and therefore has less impact on the solubility and other physicochemical properties of a synthetic peptide. In this study, we used SPs that contain the clinically relevant neoepitopes identified in a melanoma patient who completely recovered after T‐cell therapy. Homogeneous mini‐UPam‐SP conjugates have been prepared in good yields by stepwise solid‐phase synthesis that employed a mini‐UPam building block pre‐prepared in solution and the standard set of Fmoc‐amino acids. The immunogenicity of the novel mini‐UPam‐SP conjugates was demonstrated by using the cancer patient's T‐cells.
Less lipophilic ligands: A novel TLR2 ligand has been designed and synthesized to be subsequently conjugated with synthetic peptides containing clinically relevant neoepitopes. By treating HEK‐TLR2 cells, human moDCs and antigen specific human T‐cells with these new constructs, the immunogenic potential of the new TLR2 ligand and the conjugation of TLR ligands with neoepitopes was assessed.
Euclid preparation Aghanim, N.; Bermejo-Climent, J. R.; Paoletti, D. ...
Astronomy and astrophysics (Berlin),
01/2022, Letnik:
657
Journal Article
Recenzirano
Odprti dostop
The combination and cross-correlation of the upcoming
Euclid
data with cosmic microwave background (CMB) measurements is a source of great expectation since it will provide the largest lever arm of ...epochs, ranging from recombination to structure formation across the entire past light cone. In this work, we present forecasts for the joint analysis of
Euclid
and CMB data on the cosmological parameters of the standard cosmological model and some of its extensions. This work expands and complements the recently published forecasts based on
Euclid
-specific probes, namely galaxy clustering, weak lensing, and their cross-correlation. With some assumptions on the specifications of current and future CMB experiments, the predicted constraints are obtained from both a standard Fisher formalism and a posterior-fitting approach based on actual CMB data. Compared to a
Euclid
-only analysis, the addition of CMB data leads to a substantial impact on constraints for all cosmological parameters of the standard Λ-cold-dark-matter model, with improvements reaching up to a factor of ten. For the parameters of extended models, which include a redshift-dependent dark energy equation of state, non-zero curvature, and a phenomenological modification of gravity, improvements can be of the order of two to three, reaching higher than ten in some cases. The results highlight the crucial importance for cosmological constraints of the combination and cross-correlation of
Euclid
probes with CMB data.
A series of glycolipids have been prepared which contain a cluster galactoside moiety with high affinity for the hepatic asialoglycoprotein receptor and a bile acid ester moiety which mediates stable ...incorporation into liposomes. Loading of liposomes with these glycolipids at a ratio of 5% (w/w) resulted in efficient recognition and uptake of the liposomes by the liver. Preinjection with asialofetuin almost completely inhibited the uptake, establishing that the liposomes were selectively recognized and processed by the asialoglycoprotein receptor on liver parenchymal cells. In contrast, a glycolipid content of 50% (w/w) led to a liver uptake that could not be inhibited by preinjection with asialofetuin, indicating that the liposomes were now processed by the Gal/Fuc-recognizing receptor on liver macrophages. The results presented in this study are important for future targeting of water-soluble and amphiphilic drugs, enveloped in these glycolipid-laden liposomes, to parenchymal liver cells.
Aims. To understand the stellar population content of early-type dwarf galaxies (dEs) and their environmental dependence, we compare the slopes and intrinsic scatter of color–magnitude relations ...(CMRs) for three nearby clusters, Fornax, Virgo, and Coma. Additionally, we present and compare internal color profiles of these galaxies to identify central blue regions with younger stars. Methods. We use the imaging of the HST/ACS Fornax cluster in the magnitude range of −18.7 ≤ Mg′ ≤ −16.0 to derive magnitudes, colors, and color profiles, which we compare with literature measurements from the HST/ACS Virgo and Coma Cluster Survey. We take advantage of HST accuracy to investigate and parameterize the (g′−z′) color profiles of these dEs. Results. Based on analysis of the color profiles, we report on a large number of dEs with young stellar populations at their center in all three clusters. While for Virgo and Coma the number of blue-cored dEs is found to be 85%±2% and 53%±3%, respectively, for Fornax, we find that all galaxies have a blue core. We show that bluer cores reside in fainter dEs, similar to the trend seen in nucleated dEs. We find no correlation between the luminosity of the galaxy and the size of its blue core. Moreover, a comparison of the CMRs of the three clusters shows that the scatter in the CMR of Virgo is considerably larger than in the Fornax and Coma clusters. Presenting adaptive smoothing we show that the galaxies on the blue side of the CMR often show evidence for dust extinction, which strengthens the interpretation that the bluer colors are due to young stellar populations. We also find that outliers on the red side of the CMR are more compact than what is expected for their luminosity. We find several of these red outliers in Virgo, often close to more massive galaxies. No red outlying compact early-types are found in Fornax and Coma in this magnitude range while we find three in the Virgo cluster. We show that the CMR of the Fornax and Virgo clusters are slightly bluer than that of Coma. We suggest that the large number of outliers and larger scatter found for Virgo CMR are a result of the alternative assembly history of this cluster.
Euclid preparation Gómez-Alvarez, P.; Altieri, B.; Laureijs, R. ...
Astronomy and astrophysics (Berlin),
01/2022, Letnik:
657
Journal Article
Recenzirano
Odprti dostop
Context.
While
Euclid
is an ESA mission specifically designed to investigate the nature of dark energy and dark matter, the planned unprecedented combination of survey area (∼15 000 deg
2
), spatial ...resolution, low sky-background, and depth also make
Euclid
an excellent space observatory for the study of the low surface brightness Universe. Scientific exploitation of the extended low surface brightness structures requires dedicated calibration procedures that are yet to be tested.
Aims.
We investigate the capabilities of
Euclid
to detect extended low surface brightness structure by identifying and quantifying sky-background sources and stray-light contamination. We test the feasibility of generating sky flat-fields to reduce large-scale residual gradients in order to reveal the extended emission of galaxies observed in the
Euclid
survey.
Methods.
We simulated a realistic set of
Euclid
/VIS observations, taking into account both instrumental and astronomical sources of contamination, including cosmic rays, stray-light, zodiacal light, interstellar medium, and the cosmic infrared background, while simulating the effects of background sources in the field of view.
Results.
We demonstrate that a combination of calibration lamps, sky flats, and self-calibration would enable recovery of emission at a limiting surface brightness magnitude of
μ
lim
= 29.5
−0.27
+0.08
mag arcsec
−2
(3
σ
, 10 × 10 arcsec
2
) in the Wide Survey, and it would reach regions deeper by 2 mag in the Deep Surveys.
Conclusions.Euclid
/VIS has the potential to be an excellent low surface brightness observatory. Covering the gap between pixel-to-pixel calibration lamp flats and self-calibration observations for large scales, the application of sky flat-fielding will enhance the sensitivity of the VIS detector at scales larger than 1″, up to the size of the field of view, enabling
Euclid
to detect extended surface brightness structures below
μ
lim
= 31 mag arcsec
−2
and beyond.
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