Cytokines in clinical cancer immunotherapy

Cytokines are soluble proteins that mediate cell-to-cell communication. Based on the discovery of the potent anti-tumour activities of several pro-inflammatory cytokines in animal models, clinical research led to the approval of recombinant interferon-alpha and interleukin-2 for the treatment of several malignancies, even if efficacy was only modest. These early milestones in immunotherapy have been followed by the recent addition to clinical practice of antibodies that inhibit immune checkpoints, as well as chimeric antigen receptor T cells. A renewed interest in the anti-tumour properties of cytokines has led to an exponential increase in the number of clinical trials that explore the safety and efficacy of cytokine-based drugs, not only as single agents, but also in combination with other immunomodulatory drugs. These second-generation drugs under clinical development include known molecules with novel mechanisms of action, new targets, and fusion proteins that increase half-life and target cytokine activity to the tumour microenvironment or to the desired effector immune cells. In addition, the detrimental activity of immunosuppressive cytokines can be blocked by antagonistic antibodies, small molecules, cytokine traps or siRNAs. In this review, we provide an overview of the novel trends in the cytokine immunotherapy field that are yielding therapeutic agents for clinical trials

Picoflare jets power the solar wind emerging from a coronal hole on the Sun.

Coronal holes are areas on the Sun with open magnetic field lines. They are a source region of the solar wind, but how the wind emerges from coronal holes is not known. We observed a coronal hole using the Extreme Ultraviolet Imager on the Solar Orbiter spacecraft. We identified jets on scales of a few hundred kilometers, which last 20 to 100 seconds and reach speeds of ~100 kilometers per second. The jets are powered by magnetic reconnection and have kinetic energy in the picoflare range. They are intermittent but widespread within the observed coronal hole. We suggest that such picoflare jets could produce enough high-temperature plasma to sustain the solar wind and that the wind emerges from coronal holes as a highly intermittent outflow at small scales

Small-scale EUV features as the drivers of coronal upflows in the quiet Sun

Context. Coronal upflows in the quiet Sun are seen in a wide range of features, including jets and filament eruptions. The in situ measurements from Parker Solar Probe within ≈0.2 au have demonstrated that the solar wind is highly structured, showing abrupt and near-ubiquitous magnetic field reversals (i.e., switchbacks) on different timescales. The source of these structures has been associated with supergranular structures on the solar disc. This raises the question of whether there are additional small coronal features that contribute energy to the corona and produce plasma that potentially feeds into the solar wind. / Aims. During the Solar Orbiter first science perihelion, high-resolution images of the solar corona were recorded using the Extreme Ultraviolet High Resolution Imager (HRIEUV) from the Extreme Ultraviolet Imager (EUI). The Hinode spacecraft was also observing at the same location providing coronal spectroscopic measurements. Combining the two datasets allows us to determine the cause of the weak upflows observed in the quiet Sun and the associated activity. / Methods. We used a multi-spacecraft approach to characterise regions of upflows. The upflows were identified in the Fe XII emission line by the Hinode EUV Imaging Spectrometer (EIS). We then used imaging data from the Atmospheric Imaging Assembly on board the Solar Dynamics Observatory (SDO/AIA) and the High Resolution Imagers (HRI) from EUI on board the Solar Orbiter to identify coronal features and magnetic field data from the SDO Helioseismic and Magnetic Imager (HMI). Interface Region Imaging Spectrograph (IRIS) observations were also used to understand the photospheric and chromospheric driving mechanisms. / Results. We have identified two regions of coronal upflows in the quiet Sun, with respective sizes and lifetimes of (20 Mm2, 20 min) and (180 Mm2, several hours), which are contrasting dynamic events. Both examples show weak flux cancellation, indicating that the source of the upflows and enhancements is related to the magnetic field changes. The first event, a larger upflow region, shows velocities of up to −8.6 km s−1 at the footpoint of a complex loop structure. We observe several distinct extreme ultraviolet (EUV) features including frequent loop brightenings and plasma blobs travelling along closed coronal loops. The second upflow region has velocities of up to −7.2 km s−1. Within it, a complex EUV feature that lasts for about 20 min can be seen. This main feature has several substructures. During its appearance, a clear mini-filament eruption takes place at its location, before the EUV feature disappears. / Conclusions. Two features, with contrasting properties, show upflows with comparable magnitudes. The first event, a complex loop structure, shares several similarities with active region upflows. The second one, a complex small-scale feature that could not have been well resolved with previous instruments, triggered a cascade of events, including a mini-filament that lead to a measurable upflow. This is remarkable for an EUV feature that many instruments can barely resolve. The complexity of the two events, including small loop brightenings and travelling plasma blobs for the first and EUV small-scale loops and mini-filament for the second one would not have been identifiable as the sources of upflow without an instrument with the spatial resolution of HRIEUV at this distance to the Sun. These results reinforce the importance of the smallest-scale features in the Sun and their potential relevance for and impact on the solar corona and the solar wind

Evidence of external reconnection between an erupting mini-filament and ambient loops observed by Solar Orbiter/EUI

Mini-filament eruptions are one of the most common small-scale transients in the solar atmosphere. However, their eruption mechanisms are still not understood thoroughly. Here, with a combination of 174 A images of high spatio-temporal resolution taken by the Extreme Ultraviolet Imager on board Solar Orbiter and images of the Atmospheric Imaging Assembly on board Solar Dynamics Observatory, we investigate in detail an erupting mini-filament over a weak magnetic field region on 2022 March 4. Two bright ribbons clearly appeared underneath the erupting mini-filament as it quickly ascended, and subsequently, some dark materials blew out when the erupting mini-filament interacted with the outer ambient loops, thus forming a blowout jet characterized by a widening spire. At the same time, multiple small bright blobs of 1-2 Mm appeared at the interaction region and propagated along the post-eruption loops toward the footpoints of the erupting fluxes at a speed of ~ 100 km/s. They also caused a semi-circular brightening structure. Based on these features, we suggest that the mini-filament eruption first experiences internal and then external reconnection, the latter of which mainly transfers mass and magnetic flux of the erupting mini-filament to the ambient corona.Comment: 8 pages, 6 figures, accepted for publication in Astronomy & Astrophysic

Telomerase and pluripotency factors jointly regulate stemness in pancreatic cancer stem cells

© 2021 by the authors.To assess the role of telomerase activity and telomere length in pancreatic CSCs we used different CSC enrichment methods (CD133, ALDH, sphere formation) in primary patient-derived pancreatic cancer cells. We show that CSCs have higher telomerase activity and longer telomeres than bulk tumor cells. Inhibition of telomerase activity, using genetic knockdown or pharmacological inhibitor (BIBR1532), resulted in CSC marker depletion, abrogation of sphere formation in vitro and reduced tumorigenicity in vivo. Furthermore, we identify a positive feedback loop between stemness factors (NANOG, OCT3/4, SOX2, KLF4) and telomerase, which is essential for the self-renewal of CSCs. Disruption of the balance between telomerase activity and stemness factors eliminates CSCs via induction of DNA damage and apoptosis in primary patient-derived pancreatic cancer samples, opening future perspectives to avoid CSC-driven tumor relapse. In the present study, we demonstrate that telomerase regulation is critical for the “stemness” maintenance in pancreatic CSCs and examine the effects of telomerase inhibition as a potential treatment option of pancreatic cancer. This may significantly promote our understanding of PDAC tumor biology and may result in improved treatment for pancreatic cancer patients.This research was funded by a Max Eder Fellowship of the German Cancer Aid (111746), a German Cancer Aid Priority Program ‘Translational Oncology’ 70112505, by a Collaborative Research Centre grant (316249678—SFB 1279) of the German Research Foundation, and by a Hector Foundation Cancer Research grant (M65.1) to P.C.H., B.S.J. is supported by a Rámon y Cajal Merit Award (RYC2012-12104) from the Ministerio de Economía y Competitividad, Spain and a Coordinated grant (GC16173694BARB) from the Fundación Asociación Española Contra el Cáncer (AECC). K.W. is supported by a Baustein 3.2 by Ulm University

Picoflare jets power the solar wind emerging from a coronal hole on the Sun

Coronal holes are areas on the Sun with open magnetic field lines. They are a source region of the solar wind, but how the wind emerges from coronal holes is not known. We observed a coronal hole using the Extreme Ultraviolet Imager on the Solar Orbiter spacecraft. We identified jets on scales of a few hundred kilometers, which last 20 to 100 seconds and reach speeds of ~100 kilometers per second. The jets are powered by magnetic reconnection and have kinetic energy in the picoflare range. They are intermittent but widespread within the observed coronal hole. We suggest that such picoflare jets could produce enough high-temperature plasma to sustain the solar wind and that the wind emerges from coronal holes as a highly intermittent outflow at small scales.Comment: This is the author's version of the work. The definitive version was published in Science on 24 August 202

Ultra-high-resolution Observations of Persistent Null-point Reconnection in the Solar Corona

Magnetic reconnection is a key mechanism involved in solar eruptions and is also a prime possibility to heat the low corona to millions of degrees. Here, we present ultra-high-resolution extreme ultraviolet observations of persistent null-point reconnection in the corona at a scale of about 390 km over one hour observations of the Extreme-Ultraviolet Imager on board Solar Orbiter spacecraft. The observations show formation of a null-point configuration above a minor positive polarity embedded within a region of dominant negative polarity near a sunspot. The gentle phase of the persistent null-point reconnection is evidenced by sustained point-like high-temperature plasma (about 10 MK) near the null-point and constant outflow blobs not only along the outer spine but also along the fan surface. The blobs appear at a higher frequency than previously observed with an average velocity of about 80 km/s and life-times of about 40 s. The null-point reconnection also occurs explosively but only for 4 minutes, its coupling with a mini-filament eruption generates a spiral jet. These results suggest that magnetic reconnection, at previously unresolved scales, proceeds continually in a gentle and/or explosive way to persistently transfer mass and energy to the overlying corona.Comment: 27 pages, 7 figure

Differential Role of Human Choline Kinase α and β Enzymes in Lipid Metabolism: Implications in Cancer Onset and Treatment

11 pages, 6 figures, 1 table.Background The Kennedy pathway generates phosphocoline and phosphoethanolamine through its two branches. Choline Kinase (ChoK) is the first enzyme of the Kennedy branch of synthesis of 1phosphocholine, the major component of the plasma membrane. ChoK family of proteins is composed by ChoKα and ChoKβ isoforms, the first one with two different variants of splicing. Recently ChoKα has been implicated in the carcinogenic process, since it is over-expressed in a variety of human cancers. However, no evidence for a role of ChoKβ in carcinogenesis has been reported. Methodology/Principal Findings Here we compare the in vitro and in vivo properties of ChoKα1 and ChoKβ in lipid metabolism, and their potential role in carcinogenesis. Both ChoKα1 and ChoKβ showed choline and ethanolamine kinase activities when assayed in cell extracts, though with different affinity for their substrates. However, they behave differentially when overexpressed in whole cells. Whereas ChoKβ display an ethanolamine kinase role, ChoKα1 present a dual choline/ethanolamine kinase role, suggesting the involvement of each ChoK isoform in distinct biochemical pathways under in vivo conditions. In addition, while overexpression of ChoKα1 is oncogenic when overexpressed in HEK293T or MDCK cells, ChoKβ overexpression is not sufficient to induce in vitro cell transformation nor in vivo tumor growth. Furthermore, a significant upregulation of ChoKα1 mRNA levels in a panel of breast and lung cancer cell lines was found, but no changes in ChoKβ mRNA levels were observed. Finally, MN58b, a previously described potent inhibitor of ChoK with in vivo antitumoral activity, shows more than 20-fold higher efficiency towards ChoKα1 than ChoKβ. Conclusion/Significance This study represents the first evidence of the distinct metabolic role of ChoKα and ChoKβ isoforms, suggesting different physiological roles and implications in human carcinogenesis. These findings constitute a step forward in the design of an antitumoral strategy based on ChoK inhibition.This work has been supported by grants to JCL from Comunidad de Madrid (GR-SAL-0821-2004), Ministerio de Ciencia e Innovación (SAF2008-03750, RD06/0020/0016), Fundación Mutua Madrileña, and by a grant to ARM from Fundación Mutua Madrileña.Peer reviewe

Ultra-high-resolution observations of persistent null-point reconnection in the solar corona

Funding: X.C., H.L., J.C., Y.L.W., M.D.D., Y.G., and W.T.F. are funded by NSFC grants 11722325, 11733003, 11790303, and 11790300, and by the National Key R&D Program of China under grant 2021YFA1600504. X.C. is also supported by the Alexander von Humboldt foundation. L.P.C. gratefully acknowledges funding from the European Union. G.A. acknowledges financial support from the French national space agency (CNES), as well as from the Programme National Soleil Terre (PNST) of the CNRS/INSU also co-funded by CNES and CEA. X.S. acknowledges financial support by National Key R&D Program of China (2021YFA1600503), NSFC grant 11790301, and the mobility program (M-0068) of the Sino-German Science Center. A.N.Z. thanks to the Belgian Federal Science Policy Office (BELSPO) for the provision of financial support in the framework of the PRODEX Programme of the European Space Agency (ESA) under contract number 4000136424. D.M.L. is grateful to the Science Technology and Facilities Council for the award of an Ernest Rutherford Fellowship (ST/R003246/1).Magnetic reconnection is a key mechanism involved in solar eruptions and is also a prime possibility to heat the low corona to millions of degrees. Here, we present ultra-high-resolution extreme ultraviolet observations of persistent null-point reconnection in the corona at a scale of about 390 km over one hour observations of the Extreme-Ultraviolet Imager on board Solar Orbiter spacecraft. The observations show formation of a null-point configuration above a minor positive polarity embedded within a region of dominant negative polarity near a sunspot. The gentle phase of the persistent null-point reconnection is evidenced by sustained point-like high-temperature plasma (about 10 MK) near the null-point and constant outflow blobs not only along the outer spine but also along the fan surface. The blobs appear at a higher frequency than previously observed with an average velocity of about 80 km s-1 and life-times of about 40 s. The null-point reconnection also occurs explosively but only for 4 minutes, its coupling with a mini-filament eruption generates a spiral jet. These results suggest that magnetic reconnection, at previously unresolved scales, proceeds continually in a gentle and/or explosive way to persistently transfer mass and energy to the overlying corona.Publisher PDFPeer reviewe

First perihelion of EUI on the Solar Orbiter mission

CONTEXT: The Extreme Ultraviolet Imager (EUI) on board Solar Orbiter consists of three telescopes: the two High Resolution Imagers, in EUV (HRIEUV) and in Lyman-α (HRILya), and the Full Sun Imager (FSI). Solar Orbiter/EUI started its Nominal Mission Phase on 2021 November 27. AIMS: Our aim is to present the EUI images from the largest scales in the extended corona off-limb down to the smallest features at the base of the corona and chromosphere. EUI is therefore a key instrument for the connection science that is at the heart of the Solar Orbiter mission science goals. METHODS: The highest resolution on the Sun is achieved when Solar Orbiter passes through the perihelion part of its orbit. On 2022 March 26, Solar Orbiter reached, for the first time, a distance to the Sun close to 0.3 au. No other coronal EUV imager has been this close to the Sun. RESULTS: We review the EUI data sets obtained during the period 2022 March–April, when Solar Orbiter quickly moved from alignment with the Earth (2022 March 6), to perihelion (2022 March 26), to quadrature with the Earth (2022 March 29). We highlight the first observational results in these unique data sets and we report on the in-flight instrument performance. CONCLUSIONS: EUI has obtained the highest resolution images ever of the solar corona in the quiet Sun and polar coronal holes. Several active regions were imaged at unprecedented cadences and sequence durations. We identify in this paper a broad range of features that require deeper studies. Both FSI and HRIEUV operated at design specifications, but HRILya suffered from performance issues near perihelion. We conclude by emphasizing the EUI open data policy and encouraging further detailed analysis of the events highlighted in this paper