Neuronal and astrocytic tetraploidy is increased in drug-resistant epilepsy

Aims: Epilepsy is one of the most prevalent neurological diseases. A third of patients with epilepsy remain drug-resistant. The exact aetiology of drug-resistant epilepsy (DRE) is still unknown. Neuronal tetraploidy has been associated with neuropathology. The aim of this study was to assess the presence of tetraploid neurons and astrocytes in DRE. Methods. For that purpose, cortex, hippocampus and amygdala samples were obtained from patients subjected to surgical resection of the epileptogenic zone. Post-mortem brain tissue of subjects without previous records of neurological, neurodegenerative or psychiatric diseases was used as control. Results: The percentage of tetraploid cells was measured by immunostaining of neurons (NeuN) or astrocytes (S100β) followed by flow cytometry analysis. The results were confirmed by image cytometry (ImageStream X Amnis System Cytometer) and with an alternative astrocyte biomarker (NDRG2). Statistical comparison was performed using univariate tests. A total of 22 patients and 10 controls were included. Tetraploid neurons and astrocytes were found both in healthy individuals and DRE patients in the three brain areas analysed: cortex, hippocampus and amygdala. DRE patients presented a higher number of tetraploid neurons (p = 0.020) and astrocytes (p = 0.002) in the hippocampus than controls. These results were validated by image cytometry. Conclusions: We demonstrated the presence of both tetraploid neurons and astrocytes in healthy subjects as well as increased levels of both cell populations in DRE patients. Herein, we describe for the first time the presence of tetraploid astrocytes in healthy subjects. Furthermore, these results provide new insights into epilepsy, opening new avenues for future treatment

Sonidegib as a Locally Advanced Basal Cell Carcinoma Therapy in Real-life Clinical Setting: A National Multicentre Study

Background: Basal cell carcinoma (BCC) is the most prevalent cancer. A minority of BCCs have an aggressive behaviour (laBCC) and may require hedgehog pathway inhibitors such as sonidegib as its treatment. Objective: To describe the use of sonidegib in a large number of patients and provide more data on its real-life efficacy and safety profile.Methods: We conducted a retrospective and multicentric study that included patients treated with sonidegib. Epidemiological, effectiveness and safety data were collected.Results: A total of 82 patients with a mean age of 73.9 years were included. Ten patients had Gorlin syndrome. Median treatment duration was 6 months. Median follow-up duration was 34.2 months. Globally, 81.7% of the patients showed clinical improvement (52.4% partial response and 29.3% complete response), 12.2% clinical stability and 6.1% disease progression. There was no statistically significant difference in clinical improvement between the 24 h and 48 h sonidegib posology. After 6 months of treatment, 48.8% of the patients discontinued sonidegib. Prior vismodegib treatment and recurrent primary BCC were associated with a poorer response to sonidegib. At 6 months of treatment, 68.3% of the patients experienced at least one adverse effect. Conclusion: Sonidegib shows good effectiveness and acceptable safety profile in usual clinical practice.& COPY; 2023 AEDV. Published by Elsevier Espan & SIM;a, S.L.U.This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Regulation of cell death receptor S-nitrosylation and apoptotic signaling by Sorafenib in hepatoblastoma cells

Nitric oxide (NO) plays a relevant role during cell death regulation in tumor cells. The overexpression of nitric oxide synthase type III (NOS-3) induces oxidative and nitrosative stress, p53 and cell death receptor expression and apoptosis in hepatoblastoma cells. S-nitrosylation of cell death receptor modulates apoptosis. Sorafenib is the unique recommended molecular-targeted drug for the treatment of patients with advanced hepatocellular carcinoma. The present study was addressed to elucidate the potential role of NO during Sorafenib-induced cell death in HepG2 cells. We determined the intra- and extracellular NO concentration, cell death receptor expression and their S-nitrosylation modifications, and apoptotic signaling in Sorafenib-treated HepG2 cells. The effect of NO donors on above parameters has also been determined. Sorafenib induced apoptosis in HepG2 cells. However, low concentration of the drug (10nM) increased cell death receptor expression, as well as caspase-8 and -9 activation, but without activation of downstream apoptotic markers. In contrast, Sorafenib (10 µM) reduced upstream apoptotic parameters but increased caspase-3 activation and DNA fragmentation in HepG2 cells. The shift of cell death signaling pathway was associated with a reduction of S-nitrosylation of cell death receptors in Sorafenib-treated cells. The administration of NO donors increased S-nitrosylation of cell death receptors and overall induction of cell death markers in control and Sorafenib-treated cells. In conclusion, Sorafenib induced alteration of cell death receptor S-nitrosylation status which may have a relevant repercussion on cell death signaling in hepatoblastoma cells.Instituto de Salud Carlos III PI13/00021Ministerio de Economía y Competitividad BFU2012-32056Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía BIO-0216Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía CTS-6264Consejería de Salud, Junta de Andalucía PI13/ 0002

Pleiades low-mass brown dwarfs: the cluster L dwarf sequence

We present a search for low-mass brown dwarfs in the Pleiades open cluster. The identification of Pleiades members fainter and cooler than those currently known allows us to constrain evolutionary models for L dwarfs and to extend the study of the cluster mass function to lower masses. We conducted a 1.8 deg^2 near-infrared J-band survey at the 3.5m Calar Alto Telescope, with completeness J~19.0. The detected sources were correlated with those of previously available optical I-band images (completeness I~22). Using a J versus I-J colour-magnitude diagram, we identified 18 faint red L-type candidates, with magnitudes 17.43.2. If Pleiades members, their masses would span ~0.040-0.020 M_Sol. We performed follow-up HKs-band imaging to further confirm their cluster membership by photometry and proper motion. Out of 11 IJ candidates with proper motion measurements, we find six cluster members, two non-members and three whose membership is uncertain and depends on the intrinsic velocity dispersion of Pleiades brown dwarfs. This dispersion (>4 mas yr^-1) is at least four times that of cluster stars with masses >1 M_Sol. Five of the seven other IJ candidates are discarded because their J-Ks colours are bluer than those of confirmed members. The J versus I-J sequence of the L-type candidates at J>18 is not as red as theoretical models predict; it rather follows the field L-dwarf sequence translated to the cluster distance. This sequence overlapping, also observed in the J versus J-H and J-K diagrams, suggests that Pleiades and field L dwarfs may have similar spectral energy distributions and luminosities, and thus possibly similar radii. Also, we find alpha=0.5+-0.2 for a power-law approximation dN/dM propor. M^-alpha of the survey mass spectrum in the mass range 0.5-0.026 M_Sol.Comment: 14 pages, 7 figures, accepted for publication in Astronomy and Astrophysic

The extreme HBL behaviour of Markarian 501 during 2012

A multiwavelength campaign was organized to take place between March and July of 2012. Excellent temporal coverage was obtained with more than 25 instruments, including the MAGIC, FACT and VERITAS Cherenkov telescopes, the instruments on board the Swift and Fermi spacecraft, and the telescopes operated by the GASP-WEBT collaboration. Mrk 501 showed a very high energy (VHE) gamma-ray flux above 0.2 TeV of $\sim$0.5 times the Crab Nebula flux (CU) for most of the campaign. The highest activity occurred on 2012 June 9, when the VHE flux was $\sim$3 CU, and the peak of the high-energy spectral component was found to be at $\sim$2 TeV. This study reports very hard X-ray spectra, and the hardest VHE spectra measured to date for Mrk 501. The fractional variability was found to increase with energy, with the highest variability occurring at VHE, and a significant correlation between the X-ray and VHE bands. The unprecedentedly hard X-ray and VHE spectra measured imply that their low- and high-energy components peaked above 5 keV and 0.5 TeV, respectively, during a large fraction of the observing campaign, and hence that Mrk 501 behaved like an extreme high-frequency- peaked blazar (EHBL) throughout the 2012 observing season. This suggests that being an EHBL may not be a permanent characteristic of a blazar, but rather a state which may change over time. The one-zone synchrotron self-Compton (SSC) scenario can successfully describe the segments of the SED where most energy is emitted, with a significant correlation between the electron energy density and the VHE gamma-ray activity, suggesting that most of the variability may be explained by the injection of high-energy electrons. The one-zone SSC scenario used reproduces the behaviour seen between the measured X-ray and VHE gamma-ray fluxes, and predicts that the correlation becomes stronger with increasing energy of the X-rays

Detection of the blazar S4 0954+65 at very-high-energy with the MAGIC telescopes during an exceptionally high optical state

The very high energy (VHE ¿ 100 GeV) -ray MAGIC observations of the blazar S4 0954+65, were triggered by an exceptionally high flux state of emission in the optical. This blazar has a disputed redshift of z = 0.368 or z ¿ 0.45 and an uncertain classification among blazar subclasses. The exceptional source state described here makes for an excellent opportunity to understand physical processes in the jet of S4 0954+65 and thus contribute to its classification. Methods. We investigated the multiwavelength (MWL) light curve and spectral energy distribution (SED) of the S4 0954+65 blazar during an enhanced state in February 2015 and have put it in context with possible emission scenarios. We collected photometric data in radio, optical, X-ray, and ¿-ray. We studied both the optical polarization and the inner parsec-scale jet behavior with 43 GHz data. Results. Observations with the MAGIC telescopes led to the first detection of S4 0954+65 at VHE. Simultaneous data with Fermi-LAT at high energy ¿-ray(HE, 100 MeV < E < 100 GeV) also show a period of increased activity. Imaging at 43 GHz reveals the emergence of a new feature in the radio jet in coincidence with the VHE flare. Simultaneous monitoring of the optical polarization angle reveals a rotation of approximately 100. Conclusions. The high emission state during the flare allows us to compile the simultaneous broadband SED and to characterize it in the scope of blazar jet emission models. The broadband spectrum can be modeled with an emission mechanism commonly invoked for flat spectrum radio quasars (FSRQs), that is, inverse Compton scattering on an external soft photon field from the dust torus, also known as external Compton. The light curve and SED phenomenology is consistent with an interpretation of a blob propagating through a helical structured magnetic field and eventually crossing a standing shock in the jet, a scenario typically applied to FSRQs and low-frequency peaked BL Lac objects (LBL). © ESO 2018.The financial support of the German BMBF and MPG, the Italian INFN and INAF, the Swiss National Fund SNF, the ERDF under the Spanish MINECO (FPA2015-69818-P, FPA2012-36668, FPA2015-68378-P, FPA2015-69210-C6-2-R, FPA2015-69210-C6-4-R, FPA2015-69210-C6-6-R, AYA2015-71042-P, AYA2016-76012-C3-1-P, ESP2015-71662-C2-2-P, CSD2009-00064), and the Japanese JSPS and MEXT is gratefully acknowledged. This work was also supported by the Spanish Centro de Excelencia “Severo Ochoa” SEV-2012-0234 and SEV-2015-0548, and Unidad de Excelencia “María de Maeztu” MDM-2014-0369, by the Croatian Science Foundation (HrZZ) Project IP-2016-06-9782 and the University of Rijeka Project 13.12.1.3.02, by the DFG Collaborative Research Centers SFB823/C4 and SFB876/C3, the Polish National Research Centre grant UMO-2016/22/M/ST9/00382 and by the Brazilian MCTIC, CNPq, and FAPERJ. IA acknowledges support by a Ramón y Cajal grant of the Ministerio de Economía, Industria y Competitividad (MINECO) of Spain. The research at the IAA–CSIC was supported in part by the MINECO through grants AYA2016–80889–P, AYA2013–40825–P, and AYA2010–14844, and by the regional government of Andalucía through grant P09–FQM–4784.Peer Reviewe

MAGIC gamma-ray and multi-frequency observations of flat spectrum radio quasar PKS 1510-089 in early 2012

Aims. Amongst more than fifty blazars detected in very high energy (VHE, E> 100 GeV) γ rays, only three belong to the subclass of flat spectrum radio quasars (FSRQs). The detection of FSRQs in the VHE range is challenging, mainly because of their soft spectra in the GeV-TeV regime. MAGIC observed PKS 1510−089 (z = 0.36) starting 2012 February 3 until April 3 during a high activity state in the high energy (HE, E> 100 MeV) γ-ray band observed by AGILE and Fermi. MAGIC observations result in the detection of a source with significance of 6.0 standard deviations (σ). We study the multi-frequency behaviour of the source at the epoch of MAGIC observation, collecting quasi-simultaneous data at radio and optical (GASP-WEBT and F-Gamma collaborations, REM, Steward, Perkins, Liverpool, OVRO, and VLBA telescopes), X-ray (Swift satellite), and HE γ-ray frequencies. Methods. We study the VHE γ-ray emission, together with the multi-frequency light curves, 43 GHz radio maps, and spectral energy distribution (SED) of the source. The quasi-simultaneous multi-frequency SED from the millimetre radio band to VHE γ rays is modelled with a one-zone inverse Compton model. We study two different origins of the seed photons for the inverse Compton scattering, namely the infrared torus and a slow sheath surrounding the jet around the Very Long Baseline Array (VLBA) core. Results. We find that the VHE γ-ray emission detected from PKS 1510−089 in 2012 February-April agrees with the previous VHE observations of the source from 2009 March-April. We find no statistically significant variability during the MAGIC observations on daily, weekly, or monthly time scales, while the other two known VHE FSRQs (3C 279 and PKS 1222+216) have shown daily scale to sub-hour variability. The γ-ray SED combining AGILE, Fermi and MAGIC data joins smoothly and shows no hint of a break. The multi-frequency light curves suggest a common origin for the millimetre radio and HE γ-ray emission, and the HE γ-ray flaring starts when the new component is ejected from the 43 GHz VLBA core and the studied SED models fit the data well. However, the fast HE γ-ray variability requires that within the modelled large emitting region, more compact regions must exist. We suggest that these observed signatures would be most naturally explained by a turbulent plasma flowing at a relativistic speed down the jet and crossing a standing conical shock