Patritumab deruxtecan (HER3-DXd) is a human epidermal growth factor receptor 3 (HER3)-directed antibody–drug conjugate composed of a fully human anti-HER3 monoclonal antibody (patritumab) covalently ...linked to a topoisomerase I inhibitor payload via a stable, tumor-selective, tetrapeptide-based cleavable linker. TOT-HER3 is a window-of-opportunity study designed to assess the biological activity, measured by CelTIL score = −0.8 × tumor cellularity (in %) + 1.3 × tumor-infiltrating lymphocytes (TILs) (in %), and clinical activity of HER3-DXd during short-term (21 days) pre-operative treatment in patients with primary operable HER2-negative early breast cancer.
Patients with previously untreated hormone receptor-positive/HER2-negative tumors were allocated to one of four cohorts according to baseline ERBB3 messenger RNA expression. All patients received one dose of HER3-DXd 6.4 mg/kg. The primary objective was to evaluate change from baseline in CelTIL score.
Seventy-seven patients were evaluated for efficacy. A significant change in CelTIL score was observed, with a median increase from baseline of 3.5 (interquartile range, −3.8 to 12.7; P = 0.003). Among patients assessable for clinical response (n = 62), an overall response rate of 45% was observed (tumor measurement by caliper), with a trend toward an increase in CelTIL score among responders compared with non-responders (mean difference, +11.9 versus +1.9). Change in CelTIL score was independent of baseline ERBB3 messenger RNA and HER3 protein levels. Genomic changes occurred, including switching toward a less proliferative tumor phenotype based on PAM50 subtypes, suppression of cell proliferation genes, and induction of genes associated with immunity. Treatment-emergent adverse events were observed in 96% of patients (14% grade ≥3); most common were nausea, fatigue, alopecia, diarrhea, vomiting, abdominal pain, and neutrophil count decrease.
A single dose of HER3-DXd was associated with clinical response, increased immune infiltration, suppression of proliferation in hormone receptor-positive/HER2-negative early breast cancer, and a tolerable safety profile consistent with previously reported results. These findings support further study of HER3-DXd in early breast cancer.
•TOT-HER3 trial showed antitumor activity of pre-operative HER3-DXd in HR+/HER2-negative early breast cancer.•HER3-DXd increased immune infiltration, suppressed proliferation, and switched tumors to a less proliferative phenotype.•HER3-DXd showed clinical and biological activity independently of baseline ERBB3 mRNA and HER3 protein levels.•These results encouraged investigation of HER3-DXd as potential neoadjuvant treatment in the ongoing SOLTI-VALENTINE trial.
Autism spectrum disorders (ASDs) represent a formidable challenge for psychiatry and neuroscience because of their high prevalence, lifelong nature, complexity and substantial heterogeneity. Facing ...these obstacles requires large-scale multidisciplinary efforts. Although the field of genetics has pioneered data sharing for these reasons, neuroimaging had not kept pace. In response, we introduce the Autism Brain Imaging Data Exchange (ABIDE)-a grassroots consortium aggregating and openly sharing 1112 existing resting-state functional magnetic resonance imaging (R-fMRI) data sets with corresponding structural MRI and phenotypic information from 539 individuals with ASDs and 573 age-matched typical controls (TCs; 7-64 years) (http://fcon_1000.projects.nitrc.org/indi/abide/). Here, we present this resource and demonstrate its suitability for advancing knowledge of ASD neurobiology based on analyses of 360 male subjects with ASDs and 403 male age-matched TCs. We focused on whole-brain intrinsic functional connectivity and also survey a range of voxel-wise measures of intrinsic functional brain architecture. Whole-brain analyses reconciled seemingly disparate themes of both hypo- and hyperconnectivity in the ASD literature; both were detected, although hypoconnectivity dominated, particularly for corticocortical and interhemispheric functional connectivity. Exploratory analyses using an array of regional metrics of intrinsic brain function converged on common loci of dysfunction in ASDs (mid- and posterior insula and posterior cingulate cortex), and highlighted less commonly explored regions such as the thalamus. The survey of the ABIDE R-fMRI data sets provides unprecedented demonstrations of both replication and novel discovery. By pooling multiple international data sets, ABIDE is expected to accelerate the pace of discovery setting the stage for the next generation of ASD studies.
ABSTRACT
How are accretion discs affected by their outflows? To address this question for white dwarfs accreting from cool giants, we performed optical, radio, X-ray, and ultraviolet observations of ...the outflow-driving symbiotic star MWC 560 (≡V694 Mon) during its 2016 optical high state. We tracked multi-wavelength changes that signalled an abrupt increase in outflow power at the initiation of a months-long outflow fast state, just as the optical flux peaked: (1) an abrupt doubling of Balmer absorption velocities; (2) the onset of a 20 μJy per month increase in radio flux; and (3) an order-of-magnitude increase in soft X-ray flux. Juxtaposing to prior X-ray observations and their coeval optical spectra, we infer that both high-velocity and low-velocity optical outflow components must be simultaneously present to yield a large soft X-ray flux, which may originate in shocks where these fast and slow absorbers collide. Our optical and ultraviolet spectra indicate that the broad absorption-line gas was fast, stable, and dense (≳106.5 cm−3) throughout the 2016 outflow fast state, steadily feeding a lower density (≲105.5 cm−3) region of radio-emitting gas. Persistent optical and ultraviolet flickering indicate that the accretion disc remained intact. The stability of these properties in 2016 contrasts to their instability during MWC 560’s 1990 outburst, even though the disc reached a similar accretion rate. We propose that the self-regulatory effect of a steady fast outflow from the disc in 2016 prevented a catastrophic ejection of the inner disc. This behaviour in a symbiotic binary resembles disc/outflow relationships governing accretion state changes in X-ray binaries.
Recent data from LHC13 by the TOTEM Collaboration indicate an unexpected decrease in the value of the ρ parameter and a σtot value in agreement with the trend of previous measurements at 7 and 8 TeV. ...These data at 13 TeV are not simultaneously described by the predictions from Pomeron models selected by the COMPETE Collaboration but show agreement with the maximal Odderon dominance, as recently demonstrated by Martynov and Nicolescu. Here, we present a detailed analysis on the applicability of Pomeron dominance by means of a general class of forward scattering amplitude, consisting of even-under-crossing leading contributions associated with single, double, and triple poles in the complex angular momentum plane and subleading even and odd Regge contributions. The analytic connection between σtot and ρ is obtained by means of singly subtracted dispersion relations, and we carry out fits to pp and p¯p data in the interval 5 GeV–13 TeV. The data set comprises all the accelerator data below 7 TeV, and we consider two independent ensembles by adding either only the TOTEM data or the TOTEM and ATLAS data at the LHC energy region. In the data reductions to each ensemble, the uncertainty regions are evaluated with both one and two standard deviations (∼68% and ∼95% CL, respectively). Besides the general analytic model, we investigate four particular cases of interest, three of them typical of outstanding models in the literature. We conclude that, within the experimental and theoretical uncertainties and both ensembles, the general model and three particular cases are not able to describe the σtot and ρ data at 13 TeV simultaneously. However, if the discrepancies between the TOTEM and ATLAS data are not resolved, one Pomeron model, associated with double and triple poles and with only 7 free parameters, seems not to be excluded by the complete set of experimental information presently available.
I analyze the K2 and TESS data taken in 2016, 2019, and 2021 of the symbiotic X-ray binaries GX 1+4 and IGR J16194−2810. GX 1+4 consists of a pulsar accreting from a red giant companion in a 1160-day ...orbit. Since 1984, the pulsar has shown a continuous spin-down rate of
Ṗ
= −0.1177(3) mHZ yr
−1
. I report the detection of the spin period at an average value of 180.426(1) seconds as observed with the K2 mission and confirm that the spin period continues to increase at a rate of ∼1.61×10
−7
s s
−1
. The K2 and hard X-rays, as observed with
Swift
/BAT, varied in tandem, in agreement with proposals from other authors that the optical light arises from reprocessed X-ray emission. In the case of IGR J16194−2810, the X-ray and optical spectroscopy have been interpreted as arising from a neutron star accreting from an M2 III red giant companion. Its orbital period is unknown, though I report here the detection of a modulation with a period of 242.837 min and interpret it as the neutron star spin period. IGR J16194−2810 is thus the second symbiotic X-ray binary whose spin period has been detected in optical wavelengths. This period, however, was only detected during the TESS observations of Sector 12 in 2019. The non-detection of this modulation during the observations of Sector 39 in 2021 is perhaps related to a low inclination of the orbit.
The recurrent nova (RN) V3890 Sgr was observed during the seventh day after the onset of its most recent outburst, with the Chandra ACIS-S camera and High Energy Transmission Gratings. A rich ...emission line spectrum was detected, due to transitions of Fe-L and K-shell ions ranging from neon to iron. The measured absorbed flux is 10−10 erg cm−2 s−1 in the 1.4-15 range (0.77-8.86 keV). The line profiles are asymmetric, blueshifted, and skewed toward the blue side, as if the ejecta moving toward us are less absorbed than the receding ejecta. The full width at half-maximum of most emission lines is 1000-1200 km s−1, with some extended blue wings. The spectrum is thermal and consistent with a plasma in collisional ionization equilibrium with column density 1.3 × 1022 cm−2 and at least two components at temperatures of about 1 and 4 keV, possibly a forward and a reverse shock, or regions with differently mixed ejecta and a red giant wind. The spectrum is remarkably similar to the symbiotic RNe V745 Sco and RS Oph, but we cannot distinguish whether the shocks occurred at a distance of a few au from the red giant, or near the giant's photosphere, in a high-density medium containing only a low mass. The ratios of the flux in lines of aluminum, magnesium, and neon relative to the flux in lines of silicon and iron probably indicate a carbon-oxygen white dwarf.
Plant trait information is essential for understanding plant evolution, vegetation dynamics, and vegetation responses to disturbance and management. Furthermore, in Mediterranean ecosystems, changes ...in fire regime may be more relevant than direct changes in climatic conditions, making the knowledge of fire-related traits especially important. Thus the purpose of this data set was to compile the most updated and comprehensive information on fire-related traits for vascular plant species of the Mediterranean Basin, that is, traits related to plant persistence and regeneration after fire. Data were collected from an extensive literature review and from field and experimental observations. The data source is documented for each value. Since life history traits may vary spatially or with environmental conditions, we did not aggregate them by species; i.e., traits and species are repeated in different records if they were observed by different researchers and/or in different locations. Life history traits included in the data set are: life form, resprouting ability (after fire, after clipping, or after other disturbances that remove all the aboveground biomass), resprouting bud source, heat-stimulated germination, other germination cues, seed bank location and longevity, post-fire seedling emergence and survival, maturity age of resprouts and saplings, and seed mass. Several traits are unknown for many species; consequently, the data set reflects the state of the knowledge on the topic. However, since the ability to resprout is a trait of paramount relevance in fire-prone environments, it was considered a core trait in the data set, and thus species whose resprouting capacity was unknown were not included. Life form is also provided for all taxa. The structure of the database allows different levels of information (and accuracy) for each entry, and thus some traits may include different types of data (quantitative, semi-quantitative, or categorical) from different sources. The data set is structured in 8263 records and 11 columns, obtained from 301 published and unpublished sources of information. It includes 952 taxa determined at specific or infraspecific level, which comprise 859 species, 384 genera, and 79 families. Although this is the most comprehensive data set of fire-relevant plant traits for Mediterranean species, there is still a considerable need for observations and experiments, especially in little-studied Mediterranean areas, such as northern Africa.
Prokaryotic restriction enzymes, recombinases and Cas proteins are powerful DNA engineering and genome editing tools. However, in many primary cell types, the efficiency of genome editing remains ...low, impeding the development of gene- and cell-based therapeutic applications. A safe strategy for robust and efficient enrichment of precisely genetically engineered cells is urgently required. Here, we screen for mutations in the receptor for Diphtheria Toxin (DT) which protect human cells from DT. Selection for cells with an edited DT receptor variant enriches for simultaneously introduced, precisely targeted gene modifications at a second independent locus, such as nucleotide substitutions and DNA insertions. Our method enables the rapid generation of a homogenous cell population with bi-allelic integration of a DNA cassette at the selection locus, without clonal isolation. Toxin-based selection works in both cancer-transformed and non-transformed cells, including human induced pluripotent stem cells and human primary T-lymphocytes, as well as it is applicable also in vivo, in mice with humanized liver. This work represents a flexible, precise, and efficient selection strategy to engineer cells using CRISPR-Cas and base editing systems.
Abstract
We report on the detection and analysis of extended X-ray emission by the Chandra X-ray Observatory stemming from the 2006 eruption of the recurrent nova RS Oph. The extended emission was ...detected 1254 and 1927 days after the start of the 2006 eruption and is consistent with a bipolar flow oriented in the East–West direction of the sky with opening angles of approximately 70°. The length of both lobes appeared to expand from 1.″3 in 2009 to 2.″0 in 2011, suggesting a projected expansion rate of 1.1 ± 0.1 mas day
−1
and an expansion velocity of 4600 km s
−1
(
D
/2.4 kpc) in the plane of the sky. This expansion rate is consistent with previous estimates from optical and radio observations of material in a similar orientation. The X-ray emission does not show any evidence of cooling between 2009 and 2011, consistent with free expansion of the material. This discovery suggests that some mechanism collimates ejecta away from the equatorial plane, and that after that material passes through the red giant wind, it expands freely into the cavity left by the 1985 eruption. We expect similar structures to arise from the latest eruption and to expand into the cavity shaped by the 2006 eruption.
The role of low-
x
parton dynamics in dictating the high-energy behavior of forward scattering observables at LHC energies is investigated using a QCD-based model with even-under-crossing amplitude ...dominance at high-energies. We explore the effects of different sets of pre- and post-LHC fine-tuned parton distributions on the forward quantities
σ
tot
and
ρ
, from
pp
and
p
¯
p
scattering in the interval 10 GeV–13 TeV. We also investigate the role of the leading soft contribution, the low-energy cuttoff, and the energy dependence of the semihard form factor on these observables. We show that in all cases investigated the highly restrictive data on
ρ
parameter at
s
=
13
TeV indicate that a crossing-odd component may play a crucial role in forward elastic scattering at the highest energies, namely the Odderon contribution.
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