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Abstract Understanding Mercury’s magnetosphere is crucial for advancing our comprehension of how the solar wind interacts with the planetary magnetospheres. Despite previous missions, several gaps remain in our knowledge of Mercury’s plasma environment. Here, we present findings from BepiColombo’s third flyby, offering a synoptic view of the large scale structure and composition of Mercury’s magnetosphere. The Mass Spectrum Analyzer (MSA), Mass Ion Analyzer (MIA), and Mass Electron Analyzer (MEA) on the magnetospheric orbiter reveal insights, including the identification of trapped energetic hydrogen (H+) with energies around 20 keV e−1 evidencing a ring current, and a cold ion plasma with energies below 50 eV e−1. Additionally, we observe a Low-Latitude Boundary Layer (LLBL), which is a region of turbulent plasma at the edge of the magnetosphere, characterized by bursty ion enhancements, indicating an ongoing injection process in the duskside magnetosphere flank. These observations during cruise phase provide a tantalizing glimpse of future discoveries expected from the Mercury Plasma Particle Experiment (MPPE) instruments after orbit insertion, promising broader impacts on our understanding of planetary magnetospheres.

Abstract Mercury’s magnetosphere is known to involve fundamental processes releasing particles and energy like at Earth due to the solar wind interaction. The resulting cycle is however much faster and involves acceleration, transport, loss, and recycling of plasma. Direct experimental evidence for the roles of electrons during this cycle is however missing. Here we show that in-situ plasma observations obtained during BepiColombo’s first Mercury flyby reveal a compressed magnetosphere hosts of quasi-periodic fluctuations, including the original observation of dynamic phenomena in the post-midnight, southern magnetosphere. The energy-time dispersed electron enhancements support the occurrence of substorm-related, multiple, impulsive injections of electrons that ultimately precipitate onto its surface and induce X-ray fluorescence. These observations reveal that electron injections and subsequent energy-dependent drift now observed throughout Solar System is a universal mechanism that generates aurorae despite the differences in structure and dynamics of the planetary magnetospheres.

The Parker Solar Probe's discovery that magnetic switchbacks and velocity spikes in the young solar wind are abundant has prompted intensive research into their origin(s) and formation mechanism(s) in the solar atmosphere. Recent studies, based on in situ measurements and numerical simulations, argue that velocity spikes are produced through interchange magnetic reconnection. Our work studies the relationship between interplanetary velocity spikes and coronal brightenings induced by changes in the photospheric magnetic field. Our analysis focuses on the characteristic periodicities of velocity spikes detected by the Proton Alpha Sensor on the Solar Orbiter during its fifth perihelion pass. Throughout the time period analyzed here, we estimate their origin along the boundary of a coronal hole. Around the boundary region, we identify periodic variations in coronal brightening activity observed by the Atmospheric Imaging Assembly onboard the Solar Dynamics Observatory. The spectral characteristics of the time series of in situ velocity spikes, remote coronal brightenings, and remote photospheric magnetic flux exhibit correspondence in their periodicities. Therefore, we suggest that the localized small-scale magnetic flux within coronal holes fuels a magnetic reconnection process that can be observed as slight brightness augmentations and outward fluctuations or jets. These dynamic elements may act as mediators, bonding magnetic reconnection with the genesis of velocity spikes and magnetic switchbacks.

Summary: Background: Pharmacological synergisms are an attractive anticancer strategy. However, with more than 5000 approved-drugs and compounds in clinical development, identifying synergistic treatments represents a major challenge. Methods: High-throughput screening was combined with target deconvolution and functional genomics to reveal targetable vulnerabilities in glioblastoma. The role of the top gene hit was investigated by RNA interference, transcriptomics and immunohistochemistry in glioblastoma patient samples. Drug combination screen using a custom-made library of 88 compounds in association with six inhibitors of the identified glioblastoma vulnerabilities was performed to unveil pharmacological synergisms. Glioblastoma 3D spheroid, organotypic ex vivo and syngeneic orthotopic mouse models were used to validate synergistic treatments. Findings: Nine targetable vulnerabilities were identified in glioblastoma and the top gene hit RRM1 was validated as an independent prognostic factor. The associations of CHK1/MEK and AURKA/BET inhibitors were identified as the most potent amongst 528 tested pairwise drug combinations and their efficacy was validated in 3D spheroid models. The high synergism of AURKA/BET dual inhibition was confirmed in ex vivo and in vivo glioblastoma models, without detectable toxicity. Interpretation: Our work provides strong pre-clinical evidence of the efficacy of AURKA/BET inhibitor combination in glioblastoma and opens new therapeutic avenues for this unmet medical need. Besides, we established the proof-of-concept of a stepwise approach aiming at exploiting drug poly-pharmacology to unveil druggable cancer vulnerabilities and to fast-track the identification of synergistic combinations against refractory cancers. Funding: This study was funded by institutional grants and charities.

BackgroundThe survival rates for pediatric patients with relapsed and refractory tumors are poor. Successful treatment strategies are currently lacking and there remains an unmet need for novel therapies for these patients. We report here the results of a phase 1 study of talimogene laherparepvec (T-VEC) and explore the safety of this oncolytic immunotherapy for the treatment of pediatric patients with advanced non–central nervous system tumors.MethodsT-VEC was delivered by intralesional injection at 106 plaque-forming units (PFU)/ml on the first day, followed by 108 PFU/ml on the first day of week 4 and every 2 weeks thereafter. The primary objective was to evaluate the safety and tolerability as assessed by the incidence of dose-limiting toxicities (DLTs). Secondary objectives included efficacy indicated by response and survival per modified immune-related response criteria simulating the Response Evaluation Criteria in Solid Tumors (irRC-RECIST).ResultsFifteen patients were enrolled into two cohorts based on age: cohort A1 (n = 13) 12 to ≤21 years old (soft-tissue sarcoma, n = 7; bone sarcoma, n = 3; neuroblastoma, n = 1; nasopharyngeal carcinoma, n = 1; and melanoma, n = 1) and cohort B1 (n = 2) 2 to

Background: Cancer therapies targeting actionable molecular alterations (AMA) have developed, but the clinical routine impact of high-throughput molecular profiling remains unclear. We present a monocentric experience of molecular profiling based on liquid biopsy in patients with cancer. Methods: Patients included had solid cancer and underwent cfDNA genomic profiling with FoudationOne Liquid CDx (F1LCDx) test, analyzing 324 genes. Primary endpoint was to describe patients with an AMA for whom clinical decisions were impacted by F1LCDx test results. Results: 191 patients were included, mostly with lung cancer (46%). An AMA was found in 52%. The most common molecular alterations were: TP53 (52%), KRAS (14%) and DNMT3 (11%). The most common AMA were: CHEK2 (10%), PIK3CA (9%), ATM (7%). There was no difference in progression-free survival (2.66 months vs. 3.81 months, p = 0.17), overall survival (5.3 months vs. 7.1 months, p = 0.64), or PFS2/PFS1 ratio ≥ 1.3 (20% vs. 24%, p = 0.72) between patients receiving a molecularly matched therapy (MMT) or a non-MMT, respectively. Patients with a MMT had an overall response rate of 19% and a disease control of 32%. Conclusions: Routine cfDNA molecular profiling is feasible and can lead to the access of targeted therapies. However, no notable benefit in patient’s outcomes was shown in this unselected pan-cancer study.

Ho-Bouldoires, Sollier, Zamfirov and Broders-Bondon et al. show that high frequency pulsatile mechanical stresses maintain the physiological level of mice colon stem cells through the mechanosensitive Ret kinase and that Ret activation is elevated in human colon cancer tissue. They go on to show that the maintenance of such stimulation in the form of tumour growth pressure results in mechanically-induced hyperproliferation and tumorigenic transformation of stem cells, which can be prevented by Ret kinase inhibition.

The discovery of a myriad of exoplanets in the past decades has revolutionized the understanding of our place in the Universe. How different are exoplants and do some of them harbor life, just like Earth? To do so, their parent stars must drive a stellar wind and carve what we call astrospheres into the surrounding interstellar medium. Astrospheres are ubiquitous in our immediate neighborhood and show similar structure to our heliosphere. Voyager 1 and 2, Ulysses, Cassini, and IBEX have shown that the interaction between interstellar medium and solar wind is much more complex and involved than previously believed. This stellar-interstellar interaction is key to understand astrospheres and the shielding they provide to the planetary systems they harbor. This article summarizes a whitepaper that was submitted to NASA’s 2023/2024 decadal survey which is being conducted by the US National Academies. It is based in parts on a proposal submitted to the European Space Agency (ESA) in response to its 2021 call for medium-class mission proposals. The whitepaper and this article propose to study the interaction described above in situ at the heliospheric boundaries and to explore the very local interstellar medium beyond. Furthermore, they highlight possible European contributions to a NASA-led Interstellar Probe (ISP).

Abstract We present initial results of low‐energy ion observations from BepiColombo's first Mercury flyby. Unprecedentedly high time resolution measurements of low energy ions at Mercury by BepiColombo Mio reveal rapid (a few seconds) and large (1–2 orders of magnitude) fluctuations of ion flux around the magnetopause and within the magnetosphere. Around the magnetic equator in the pre‐midnight magnetotail, Mio observed plasma sheet ions consistent with previous observations. In the midnight magnetotail near the closest approach, Mio observed the co‐existence of high‐energy (∼keV/q) and low‐energy (

Summary: Background: Medulloblastoma is the most frequent brain malignancy of childhood. The current multimodal treatment comes at the expense of serious and often long-lasting side effects. Drug repurposing is a strategy to fast-track anti-cancer therapy with low toxicity. Here, we showed the ability of β-blockers to potentiate radiotherapy in medulloblastoma with bad prognosis. Methods: Medulloblastoma cell lines, patient-derived xenograft cells, 3D spheroids and an innovative cerebellar organotypic model were used to identify synergistic interactions between β-blockers and ionising radiations. Gene expression profiles of β-adrenergic receptors were analysed in medulloblastoma samples from 240 patients. Signaling pathways were explored by RT-qPCR, RNA interference, western blotting and RNA sequencing. Medulloblastoma cell bioenergetics were evaluated by measuring the oxygen consumption rate, the extracellular acidification rate and superoxide production. Findings: Low concentrations of β-blockers significantly potentiated clinically relevant radiation protocols. Although patient biopsies showed detectable expression of β-adrenergic receptors, the ability of the repurposed drugs to potentiate ionising radiations did not result from the inhibition of the canonical signaling pathway. We highlighted that the efficacy of the combinatorial treatment relied on a metabolic catastrophe that deprives medulloblastoma cells of their adaptive bioenergetics capacities. This led to an overproduction of superoxide radicals and ultimately to an increase in ionising radiations-mediated DNA damages. Interpretation: These data provide the evidence of the efficacy of β-blockers as potentiators of radiotherapy in medulloblastoma, which may help improve the treatment and quality of life of children with high-risk brain tumours. Funding: This study was funded by institutional grants and charities.

(1) Background: Children and young adults with cancer are poorly represented in COVID-19 vaccination studies, and long-term protection conferred by vaccination is not known. (2) Objectives: 1. To determine the adverse effects associated with BNT162B2 vaccination in children and young adults with cancer. 2. To assess its efficacy in stimulating immunological response and in preventing severe COVID-19 disease. (3) Methods: Retrospective single-center study evaluating patients aged 8 to 22 years, with cancer, who underwent vaccination from January 2021 to June 2022. ELISA serologies and serum neutralization were collected monthly from the first injection. Serologies below 26 were considered negative, while those above 264 BAU/mL were considered positive and indicative of protection. Antibodies titers were considered positive above 20. Data on adverse events and infections were collected. (4) Results: 38 patients were included (M/F = 1.7, median age 16 years), of whom 63% had a localized tumor and 76% were undergoing treatment at the time of the first vaccination. Two or three vaccine injections were administered in 90% of patients. Adverse events were mainly systemic and not severe, except for seven grade 3 toxicities. Four cancer-related deaths were reported. Median serology was negative the month following the first vaccination and became protective during the third month. At 3 and 12 months, median serology was 1778 and 6437 BAU/mL, respectively. Serum neutralization was positive in 97% of the patients. COVID-19 infection occurred despite vaccination in 18%; all were mild forms. (5) Conclusions: In children and young adults with cancer, vaccination was well tolerated and conferred effective serum neutralization. COVID-19 infections were mild, and vaccine seroconversion persisted after 12 months in most patients. The value of additional vaccination should be further established.

This work introduces a new measurement methodology for enhancing gas detection by tuning the magnitude and polarity of back-gate voltage of a field-effect transistor (FET)-based sensor. The aim is to simultaneously strengthen the sensor response and accelerate the sensor recovery. In addition, this methodology can consume less energy compared with conventional measurements by direct current bias. To illustrate the benefits of the proposed methodology, we fabricated and characterized a polypyrrole/graphene (PPy/G) FET sensor for ammonia (NH3) detection. Our experiment, simulation and calculation results demonstrated that the redox reaction between the NH3 molecules and the PPy/G sensitive layer could be controlled by altering the polarity and the magnitude of the back-gate voltage. This proof-of-principle measurement methodology, which solves the inherent contradiction between high response and slow recovery of the chemiresistive sensor, could be extended to detect other gases, so as to improve global gas measurement systems. It opens up a new route for FET-based gas sensors in practical applications.