Abstract AMS-02 on board the International Space Station provides precise measurements of cosmic rays (CR) near Earth, while Voyager measures CRs in the local interstellar medium, beyond the effects ...of solar modulation. Based on these data, we test and revise various CR propagation scenarios under standard assumptions: pure diffusion, diffusion with convection, diffusion with reacceleration, and diffusion with reacceleration and convection. We report on the scenarios’ performance against CR measurements, aiming to limit the number of model parameters as much as possible. For each scenario, we find parameters that are able to reproduce Voyager and AMS-02 data for the entire energy band for all the CR species tested. Above several GV, we observe a similar injection spectral index for He and C, with He harder than H. Some scenarios previously disfavored are now reconsidered. For example, contrary to usual assumptions, we find that the pure diffusion scenario does not need an upturn in the diffusion coefficient at low energy, while it needs the same number of low-energy breaks in the injection spectrum as diffusive-reacceleration scenarios. We show that scenarios differ in modeled spectra of one order of magnitude for positrons at ∼1 GeV and of a factor of 2 for antiprotons at several GV. The force-field approximation describes well the AMS-02 and Voyager spectra analyzed, except antiprotons. We confirm the ∼10 GeV excess in the antiproton spectrum for all scenarios. Also, for all scenarios, the resulting modulation should be stronger for positrons than for nuclei, with reacceleration models requiring much larger modulation.
Abstract The Sun is one of the most luminous γ -ray sources in the sky and continues to challenge our understanding of its high-energy emission mechanisms. This study provides an in-depth ...investigation of the solar disk γ -ray emission, using data from the Fermi Large Area Telescope spanning 2008 August to 2022 January. We focus on γ -ray events with energies exceeding 5 GeV, originating from 0.°5 angular aperture centered on the Sun, and implement stringent time cuts to minimize potential sample contaminants. We use a helioprojection method to resolve the γ -ray events relative to the solar rotation axes and combine statistical tests to investigate the distribution of events over the solar disk. We found that integrating observations over large time windows may overlook relevant asymmetrical features, which we reveal in this work through a refined time-dependent morphological analysis. We describe significant anisotropic trends and confirm compelling evidence of energy-dependent asymmetry in the solar disk γ -ray emission. Intriguingly, the asymmetric signature coincides with the Sun’s polar field flip during the cycle 24 solar maximum, around 2014 June. Our findings suggest that the Sun’s magnetic configuration plays a significant role in shaping the resulting γ -ray signature, highlighting a potential link between the observed anisotropies, solar cycle, and the solar magnetic fields. These insights pose substantial challenges to established emission models, prompting fresh perspectives on high-energy solar astrophysics.
We identified genetic mutations in CD19 and loss of heterozygosity at the time of CD19
relapse to chimeric antigen receptor (CAR) therapy. The mutations are present in the vast majority of resistant ...tumor cells and are predicted to lead to a truncated protein with a nonfunctional or absent transmembrane domain and consequently to a loss of surface antigen. This irreversible loss of CD19 advocates for an alternative targeting or combination CAR approach.
Abstract
Gamma rays are produced by cosmic-ray (CR) protons interacting with the particles at the solar photosphere and by CR electrons and positrons (CRes) via inverse Compton scattering of solar ...photons. The former comes from the solar disk while the latter extends beyond the disk. Evaluation of these emissions requires the flux and spectrum of CRs in the vicinity of the Sun, while most observations provide flux and spectra near the Earth, at around 1 au from the Sun. Past estimates of the quiet Sun gamma-ray emission use phenomenological modulation procedures to estimate spectra near the Sun. We show that CRe transport in the inner heliosphere requires a kinetic approach and use a novel approximation to determine the variation of CRe flux and spectrum from 1 au to the Sun including the effects of (1) the structure of the large-scale magnetic field, (2) small scale turbulence in the solar wind from several in situ measurements, in particular, those by Parker Solar Probe that extend this information to 0.1 au, and (3) most importantly, energy losses due to synchrotron and inverse Compton processes. We present results on the flux and spectrum variation of CRes from 1 au to the Sun for several transport models. In forthcoming papers we will use these results for a more accurate estimate of quiet Sun inverse Compton gamma-ray spectra, and, for the first time, the spectra of extreme ultraviolet to hard X-ray photons produced by synchrotron emission. These can be compared with the quiet Sun gamma-ray observation by the Fermi and X-ray upper limits set by RHESSI.
Abstract
The quiet Sun, i.e., in its nonflaring state or nonflaring regions, emits thermal radiation from radio to ultraviolet. The quiet Sun also produces nonthermal radiation observed in gamma rays ...due to interactions of Galactic cosmic rays (GCRs) with the solar atmosphere and photons. We report on a new component: the synchrotron emission by GCR electrons in the solar magnetic field. To the best of our knowledge this is the first time this emission has been theoretically claimed and modeled. We find that the measured GCR electrons with energies from tens of GeV to a few TeV produce synchrotron emission in X-rays, which is a few orders of magnitude lower than current upper limits of the quiet Sun set by RHESSI and FOXSI, with no energy losses included. For a radially decreasing solar magnetic field we find the expected synchrotron intensity to be almost constant in the solar disk, to peak in the close proximity of the Sun, and to quickly drop away from the Sun. We also estimate the synchrotron emission from radio to gamma rays, and we compare it with current observations, especially with LOFAR. While it is negligible from radio to UV compared to the solar thermal radiation, this emission can potentially be observed at high energies with NuSTAR and more promising future FOXSI observations. This could potentially allow for constraining GCR densities and magnetic-field intensities at the Sun. This study provides a more complete description and a possible new way for understanding the quiet Sun and its environment.
We report a patient relapsing 9 months after CD19-targeted CAR T cell (CTL019) infusion with CD19
leukemia that aberrantly expressed the anti-CD19 CAR. The CAR gene was unintentionally introduced ...into a single leukemic B cell during T cell manufacturing, and its product bound in cis to the CD19 epitope on the surface of leukemic cells, masking it from recognition by and conferring resistance to CTL019.
Primary resistance to CD19-directed chimeric antigen receptor T-cell therapy (CART19) occurs in 10% to 20% of patients with acute lymphoblastic leukemia (ALL); however, the mechanisms of this ...resistance remain elusive. Using a genome-wide loss-of-function screen, we identified that impaired death receptor signaling in ALL led to rapidly progressive disease despite CART19 treatment. This was mediated by an inherent resistance to T-cell cytotoxicity that permitted antigen persistence and was subsequently magnified by the induction of CAR T-cell functional impairment. These findings were validated using samples from two CAR T-cell clinical trials in ALL, where we found that reduced expression of death receptor genes was associated with worse overall survival and reduced T-cell fitness. Our findings suggest that inherent dysregulation of death receptor signaling in ALL directly leads to CAR T-cell failure by impairing T-cell cytotoxicity and promoting progressive CAR T-cell dysfunction. SIGNIFICANCE: Resistance to CART19 is a significant barrier to efficacy in the treatment of B-cell malignancies. This work demonstrates that impaired death receptor signaling in tumor cells causes failed CART19 cytotoxicity and drives CART19 dysfunction, identifying a novel mechanism of antigen-independent resistance to CAR therapy.
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Well-differentiated (WDLPS) and dedifferentiated (DDLPS) liposarcoma are characterized by co-amplification of the murine double minute-2 (MDM2) and cyclin-dependent kinase-4 (CDK4) oncogenes. ...Siremadlin, a p53-MDM2 inhibitor, was combined with ribociclib, a CDK4/6 inhibitor, in patients with locally advanced/metastatic WDLPS or DDLPS who had radiologically progressed on, or despite, prior systemic therapy.
In this proof-of-concept, phase Ib, dose-escalation study, patients received siremadlin and ribociclib across different regimens until unacceptable toxicity, disease progression, and/or treatment discontinuation: Regimen A 4-week cycle: siremadlin once daily (QD) and ribociclib QD (2 weeks on, 2 weeks off), Regimen B 3-week cycle: siremadlin once every 3 weeks; ribociclib QD (2 weeks on, 1 week off), and Regimen C 4-week cycle: siremadlin once every 4 weeks; ribociclib QD (2 weeks on, 2 weeks off). The primary objective was to determine the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) of siremadlin plus ribociclib in one or more regimens.
As of October 16, 2019 (last patient last visit), 74 patients had enrolled. Median duration of exposure was 13 (range, 1-174) weeks. Dose-limiting toxicities occurred in 10 patients, most of which were Grade 3/4 hematologic events. The RDE was siremadlin 120 mg every 3 weeks plus ribociclib 200 mg QD (Regimen B). Three patients achieved a partial response, and 38 achieved stable disease. One patient (Regimen C) died as a result of treatment-related hematotoxicity.
Siremadlin plus ribociclib demonstrated manageable toxicity and early signs of antitumor activity in patients with advanced WDLPS or DDLPS.
A recent redetermination of the nonthermal component of the hard X-ray to soft -ray emission from the Galactic ridge, using the SPI instrument on the International Gamma-Ray Astrophysics Laboratory ...(INTEGRAL), is shown to be well reproduced as inverse Compton emission from the interstellar medium. Both cosmic-ray primary electrons and secondary electrons and positrons contribute to the emission. The prediction uses the GALPROP model and includes a new calculation of the interstellar radiation field. This may solve a long-standing mystery of the origin of this emission, and potentially opens a new window on Galactic cosmic rays.
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