Pharmacological targeting of the receptor ALK inhibits tumorigenicity and overcomes chemoresistance in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive disease characterized by its metastatic potential and chemoresistance. These traits are partially attributable to the highly tumorigenic pancreatic cancer stem cells (PaCSCs). Interestingly, these cells show unique features in order to sustain their identity and functionality, some of them amenable for therapeutic intervention. Screening of phospho-receptor tyrosine kinases revealed that PaCSCs harbored increased activation of anaplastic lymphoma kinase (ALK). We subsequently demonstrated that oncogenic ALK signaling contributes to tumorigenicity in PDAC patient-derived xenografts (PDXs) by promoting stemness through ligand-dependent activation. Indeed, the ALK ligands midkine (MDK) or pleiotrophin (PTN) increased self-renewal, clonogenicity and CSC frequency in several in vitro local and metastatic PDX models. Conversely, treatment with the clinically-approved ALK inhibitors Crizotinib and Ensartinib decreased PaCSC content and functionality in vitro and in vivo, by inducing cell death. Strikingly, ALK inhibitors sensitized chemoresistant PaCSCs to Gemcitabine, as the most used chemotherapeutic agent for PDAC treatment. Consequently, ALK inhibition delayed tumor relapse after chemotherapy in vivo by effectively decreasing the content of PaCSCs. In summary, our results demonstrate that targeting the MDK/PTN-ALK axis with clinically-approved inhibitors impairs in vivo tumorigenicity and chemoresistance in PDAC suggesting a new treatment approach to improve the long-term survival of PDAC patients

VAV2 signaling promotes regenerative proliferation in both cutaneous and head and neck squamous cell carcinoma

Regenerative proliferation capacity and poor differentiation are histological features usually linked to poor prognosis in head and neck squamous cell carcinoma (hnSCC). However, the pathways that regulate them remain ill-characterized. Here, we show that those traits can be triggered by the RHO GTPase activator VAV2 in keratinocytes present in the skin and oral mucosa. VAV2 is also required to maintain those traits in hnSCC patient-derived cells. This function, which is both catalysis- and RHO GTPase-dependent, is mediated by c-Myc- and YAP/TAZ-dependent transcriptomal programs associated with regenerative proliferation and cell undifferentiation, respectively. High levels of VAV2 transcripts and VAV2-regulated gene signatures are both associated with poor hnSCC patient prognosis. These results unveil a druggable pathway linked to the malignancy of specific SCC subtypes. The Rho signalling pathway is frequently activated in squamous carcinomas. Here, the authors find that the Rho GEF VAV2 is over expressed in both cutaneous and head and neck squamous cell carcinomas and that at the molecular level VAV2 promotes a pro-tumorigenic stem cell-like signalling programme

Stereoscopic disambiguation of vector magnetograms: first applications to SO/PHI-HRT data

Spectropolarimetric reconstructions of the photospheric vector magnetic field are intrinsically limited by the 180$^\circ$-ambiguity in the orientation of the transverse component. So far, the removal of such an ambiguity has required assumptions about the properties of the photospheric field, which makes disambiguation methods model-dependent. The basic idea is that the unambiguous line-of-sight component of the field measured from one vantage point will generally have a non-zero projection on the ambiguous transverse component measured by the second telescope, thereby determining the ``true'' orientation of the transverse field. Such an idea was developed and implemented in the Stereoscopic Disambiguation Method (SDM), which was recently tested using numerical simulations. In this work we present a first application of the SDM to data obtained by the High Resolution Telescope (HRT) onboard Solar Orbiter during the March 2022 campaign, when the angle with Earth was 27 degrees. The method is successfully applied to remove the ambiguity in the transverse component of the vector magnetogram solely using observations (from HRT and from the Helioseismic and Magnetic Imager), for the first time. The SDM is proven to provide observation-only disambiguated vector magnetograms that are spatially homogeneous and consistent. A discussion about the sources of error that may limit the accuracy of the method, and of the strategies to remove them in future applications, is also presented.Comment: 32 pages, 12 figures, accepted in A&A on 09/07/202

Intensity contrast of solar network and faculae close to the solar limb, observed from two vantage points

The brightness of faculae and network depends on the angle at which they are observed and the magnetic flux density. Close to the limb, assessment of this relationship has until now been hindered by the increasingly lower signal in magnetograms. This preliminary study aims at highlighting the potential of using simultaneous observations from different vantage points to better determine the properties of faculae close to the limb. We use data from the Solar Orbiter/Polarimetric and Helioseismic Imager (SO/PHI), and the Solar Dynamics Observatory/Helioseismic and Magnetic Imager (SDO/HMI), recorded at $\sim60^\circ$ angular separation of their lines of sight at the Sun. We use continuum intensity observed close to the limb by SO/PHI and complement it with the co-observed $B_{\rm LOS}$ from SDO/HMI, originating closer to disc centre (as seen by SDO/HMI), thus avoiding the degradation of the magnetic field signal near the limb. We derived the dependence of facular brightness in the continuum on disc position and magnetic flux density from the combined observations of SO/PHI and SDO/HMI. Compared with a single point of view, we were able to obtain contrast values reaching closer to the limb and to lower field strengths. We find the general dependence of the limb distance at which the contrast is maximum on the flux density to be at large in line with single viewpoint observations, in that the higher the flux density is, the closer the turning point lies to the limb. There is a tendency, however, for the maximum to be reached closer to the limb when determined from two vantage points. We note that due to the preliminary nature of this study, these results must be taken with caution. Our analysis shows that studies involving two viewpoints can significantly improve the detection of faculae near the solar limb and the determination of their brightness contrast relative to the quiet Sun

The ratio of horizontal to vertical displacement in solar oscillations estimated from combined SO/PHI and SDO/HMI observations

In order to make accurate inferences about the solar interior using helioseismology, it is essential to understand all the relevant physical effects on the observations. One effect to understand is the (complex-valued) ratio of the horizontal to vertical displacement of the p- and f-modes at the height at which they are observed. Unfortunately, it is impossible to measure this ratio directly from a single vantage point, and it has been difficult to disentangle observationally from other effects. In this paper we attempt to measure the ratio directly using 7.5 hours of simultaneous observations from the Polarimetric and Helioseismic Imager on board Solar Orbiter and the Helioseismic and Magnetic Imager on board the Solar Dynamics Observatory. While image geometry problems make it difficult to determine the exact ratio, it appears to agree well with that expected from adiabatic oscillations in a standard solar model. On the other hand it does not agree with a commonly used approximation, indicating that this approximation should not be used in helioseismic analyses. In addition, the ratio appears to be real-valued.Comment: Accepted for publication in Astronomy & Astrophysics. 8 pages, 8 figure

Coronal voids and their magnetic nature

Context: Extreme ultraviolet (EUV) observations of the quiet solar atmosphere reveal extended regions of weak emission compared to the ambient quiescent corona. The magnetic nature of these coronal features is not well understood. // Aims: We study the magnetic properties of the weakly emitting extended regions, which we name coronal voids. In particular, we aim to understand whether these voids result from a reduced heat input into the corona or if they are associated with mainly unipolar and possibly open magnetic fields, similar to coronal holes. // Methods: We defined the coronal voids via an intensity threshold of 75% of the mean quiet-Sun (QS) EUV intensity observed by the high-resolution EUV channel (HRIEUV) of the Extreme Ultraviolet Imager on Solar Orbiter. The line-of-sight magnetograms of the same solar region recorded by the High Resolution Telescope of the Polarimetric and Helioseismic Imager allowed us to compare the photospheric magnetic field beneath the coronal voids with that in other parts of the QS. // Results: The coronal voids studied here range in size from a few granules to a few supergranules and on average exhibit a reduced intensity of 67% of the mean value of the entire field of view. The magnetic flux density in the photosphere below the voids is 76% (or more) lower than in the surrounding QS. Specifically, the coronal voids show much weaker or no network structures. The detected flux imbalances fall in the range of imbalances found in QS areas of the same size. // Conclusions: We conclude that coronal voids form because of locally reduced heating of the corona due to reduced magnetic flux density in the photosphere. This makes them a distinct class of (dark) structure, different from coronal holes

Coronal voids and their magnetic nature

Context. Extreme ultraviolet (EUV) observations of the quiet solar atmosphere reveal extended regions of weak emission compared to the ambient quiescent corona. The magnetic nature of these coronal features is not well understood.Aims. We study the magnetic properties of the weakly emitting extended regions, which we name coronal voids. In particular, we aim to understand whether these voids result from a reduced heat input into the corona or if they are associated with mainly unipolar and possibly open magnetic fields, similar to coronal holes. Methods. We defined the coronal voids via an intensity threshold of 75% of the mean quiet-Sun (QS) EUV intensity observed by the high- resolution EUV channel (HRIEUV) of the Extreme Ultraviolet Imager on Solar Orbiter. The line-of-sight magnetograms of the same solar region recorded by the High Resolution Telescope of the Polarimetric and Helioseismic Imager allowed us to compare the photospheric magnetic field beneath the coronal voids with that in other parts of the QS.Results. The coronal voids studied here range in size from a few granules to a few supergranules and on average exhibit a reduced intensity of 67% of the mean value of the entire field of view. The magnetic flux density in the photosphere below the voids is 76% (or more) lower than in the surrounding QS. Specifically, the coronal voids show much weaker or no network structures. The detected flux imbalances fall in the range of imbalances found in QS areas of the same size. Conclusions. We conclude that coronal voids form because of locally reduced heating of the corona due to reduced magnetic flux density in the photosphere. This makes them a distinct class of (dark) structure, different from coronal holes

Bat pluripotent stem cells reveal unique entanglement between host and viruses

Bats have evolved features unique amongst mammals, including flight, laryngeal echolocation, and certain species have been shown to have a unique immune response that may enable them to tolerate viruses such as SARS-CoVs, MERS-CoVs, Nipah, and Marburg viruses. Robust cellular models have yet to be developed for bats, hindering our ability to further understand their special biology and handling of viral pathogens. To establish bats as new model study species, we generated induced pluripotent stem cells (iPSCs) from a wild greater horseshoe bat (Rhinolophus ferrumequinum) using a modified Yamanaka protocol. Rhinolophids are amongst the longest living bat species and are asymptomatic carriers of coronaviruses, including one of the viruses most closely related to SARS-CoV-2. Bat induced pluripotent stem (BiPS) cells were stable in culture, readily differentiated into all three germ layers, and formed complex embryoid bodies, including organoids. The BiPS cells were found to have a core pluripotency gene expression program similar to that of other species, but it also resembled that of cells attacked by viruses. The BiPS cells produced a rich set of diverse endogenized viral sequences and in particular retroviruses. We further validated our protocol by developing iPS cells from an evolutionary distant bat species Myotis myotis (greater mouse-eared bat) non-lethally sampled in the wild, which exhibited similar attributes to the greater horseshoe bat iPS cells, suggesting that this unique pluripotent state evolved in the ancestral bat lineage. Although previous studies have suggested that bats have developed powerful strategies to tame their inflammatory response, our results argue that they have also evolved mechanisms to accommodate a substantial load of endogenous viral sequences and suggest that the natural history of bats and viruses is more profoundly intertwined than previously thought. Further study of bat iPS cells and their differentiated progeny should advance our understanding of the role bats play as virus hosts, provide a novel method of disease surveillance, and enable the functional studies required to ascertain the molecular basis of bats’ unique traits.N

7th Drug hypersensitivity meeting: part two

No abstract availabl