Discovery of TeV γ-ray emission from the neighbourhood of the supernova remnant G24.7+0.6 by MAGIC

SNR G24.7+0.6 is a 9.5 kyrs radio and gamma-ray supernova remnant evolving in a dense medium. In the GeV regime, SNR G24.7+0.6 (3FHL J1834.1– 0706e/FGES J1834.1–0706) shows a hard spectral index (Γ∼2) up to 200 GeV, which makes it a good candidate to be observed with Cherenkov telescopes such as MAGIC. We observed the field of view of SNR G24.7+0.6 with the MAGIC telescopes for a total of 31 hours. We detect very high energy γ-ray emission from an extended source located 0.34 degree away from the center of the radio SNR. The new source, named MAGIC J1835–069 is detected up to 5 TeV, and its spectrum is well-represented by a power-law function with spectral index of 2.74 ± 0.08. The complexity of the region makes the identification of the origin of the very-high energy emission difficult, however the spectral agreement with the LAT source and overlapping position at less than 1.5 sigma point to a common origin. We analysed 8 years of Fermi-LAT data to extend the spectrum of the source down to 60 MeV. Fermi-LAT and MAGIC spectra overlap within errors and the global broad band spectrum is described by a power-law with exponential cutoff at 1.9 ± 0.5 TeV. The detected γ-ray emission can be interpreted as the results of proton-proton interaction between the supernova and the CO-rich surrounding

A cut-off in the TeV gamma-ray spectrum of the SNR Cassiopeia A

It is widely believed that the bulk of the Galactic cosmic rays is accelerated in supernova remnants (SNRs). However, no observational evidence of the presence of particles of PeV energies in SNRs has yet been found. The young historical SNR Cassiopeia A (Cas A) appears as one of the best candidates to study acceleration processes. Between 2014 December and 2016 October, we observed Cas A with the MAGIC telescopes, accumulating 158 h of good quality data. We derived the spectrum of the source from 100 GeV to 10 TeV. We also analysed 3c8 yr of Fermi-LAT to obtain the spectral shape between 60 MeV and 500 GeV. The spectra measured by the LAT and MAGIC telescopes are compatible within the errors and show a clear turn-off (4.6\u3c3) at the highest energies, which can be described with an exponential cut-off at E_c = 3.5(^{+1.6}_{-1.0})_{stat} (^{+0.8}_{-0.9})_{sys} TeV. The gamma-ray emission from 60 MeV to 10 TeV can be attributed to a population of high-energy protons with a spectral index of 3c2.2 and an energy cut-off at 3c10 TeV. This result indicates that Cas A is not contributing to the high energy ( 3cPeV) cosmic ray sea in a significant manner at the present moment. A one-zone leptonic model fails to reproduce by itself the multiwavelength spectral energy distribution. Besides, if a non-negligible fraction of the flux seen by MAGIC is produced by leptons, the radiation should be emitted in a region with a low magnetic field (B\u2a85180 \u3bcG) like in the reverse shock

Specific activation of the CD271 intracellular domain in combination with chemotherapy or targeted therapy inhibits melanoma progression

CD271 (NGFR) is a neurotrophin receptor that belongs to the tumor necrosis receptor (TNFR) family. Upon ligand binding, CD271 can mediate either survival or cell death. While the role of CD271 as a marker of tumor-initiating cells is still a matter of debate, its role in melanoma progression has been well documented. Moreover, CD271 has been shown to be upregulated after exposure to both chemotherapy and targeted therapy. In this study, we demonstrate that activation of CD271 by a short \u3b2-amyloid-derived peptide (A\u3b2(25-35)) in combination with either chemotherapy or MAPK inhibitors induces apoptosis in 2D and 3D cultures of 8 melanoma cell lines. This combinatorial treatment significantly reduced metastasis in a zebrafish xenograft model and led to significantly decreased tumor volume in mice. Administration of A\u3b2(25-35) in ex vivo tumors from immunotherapy- and targeted therapy-resistant patients significantly reduced proliferation of melanoma cells, showing that activation of CD271 can overcome drug resistance. A\u3b2(25-35) was specific to CD271-expressing cells and induced CD271 cleavage and phosphorylation of JNK (pJNK). The direct protein-protein interaction of pJNK with CD271 led to PARP1 cleavage, p53 and caspase activation, and pJNK-dependent cell death. A\u3b2(25-35) also mediated mitochondrial reactive oxygen species (mROS) accumulation, which induced CD271 overexpression. Finally, CD271 upregulation inhibited mROS production, revealing the presence of a negative feedback loop in mROS regulation. These results indicate that targeting CD271 can activate cell death pathways to inhibit melanoma progression and potentially overcome resistance to targeted therapy

MAGIC observations of the microquasar V404 Cygni during the 2015 outburst

146siThe microquasar V404 Cygni underwent a series of outbursts in 2015, June 15–31, during which its flux in hard X-rays (20–40 keV) reached about 40 times the Crab nebula flux. Because of the exceptional interest of the flaring activity from this source, observations at several wavelengths were conducted. The MAGIC telescopes, triggered by the INTEGRAL alerts, followed-up the flaring source for several nights during the period June 18–27, for more than 10 h. One hour of observation was simultaneously conducted on a giant 22 GHz radio flare and a hint of signal at GeV energies seen by Fermi-LAT. The MAGIC observations did not show significant emission in any of the analysed time intervals. The derived flux upper limit, in the energy range 200–1250 GeV, is 4.8 × 10−12 photons cm−2 s−1. We estimate the gamma-ray opacity during the flaring period, which along with our non-detection points to an inefficient acceleration in the V404 Cyg jets if a very high energy emitter is located further than 1 × 1010 cm from the compact object.openopenAhnen, M. L.; Ansoldi, S.; Antonelli, L. A.; Arcaro, C.; Babić, A.; Banerjee, B.; Bangale, P.; Barres de Almeida, U.; Barrio, J. A.; Becerra González, J.; Bednarek, W.; Bernardini, E.; Berti, A.; Biasuzzi, B.; Biland, A.; Blanch, O.; Bonnefoy, S.; Bonnoli, G.; Carosi, R.; Carosi, A.; Chatterjee, A.; Colin, P.; Colombo, E.; Contreras, J. L.; Cortina, J.; Covino, S.; Cumani, P.; Da Vela, P.; Dazzi, F.; De Angelis, A.; De Lotto, B.; de Oña Wilhelmi, E.; Di Pierro, F.; Doert, M.; Domínguez, A.; Dominis Prester, D.; Dorner, D.; Doro, M.; Einecke, S.; Eisenacher Glawion, D.; Elsaesser, D.; Engelkemeier, M.; Fallah Ramazani, V.; Fernández-Barral, A.; Fidalgo, D.; Fonseca, M. V.; Font, L.; Fruck, C.; Galindo, D.; García López, R. J.; Garczarczyk, M.; Gaug, M.; Giammaria, P.; Godinović, N.; Gora, D.; Griffiths, S.; Guberman, D.; Hadasch, D.; Hahn, A.; Hassan, T.; Hayashida, M.; Herrera, J.; Hose, J.; Hrupec, D.; Hughes, G.; Ishio, K.; Konno, Y.; Kubo, H.; Kushida, J.; Kuveždić, D.; Lelas, D.; Lindfors, E.; Lombardi, S.; Longo, F.; López, M.; Maggio, C.; Majumdar, P.; Makariev, M.; Maneva, G.; Manganaro, M.; Mannheim, K.; Maraschi, L.; Mariotti, M.; Martínez, M.; Mazin, D.; Menzel, U.; Minev, M.; Mirzoyan, R.; Moralejo, A.; Moreno, V.; Moretti, E.; Neustroev, V.; Niedzwiecki, A.; Nievas Rosillo, M.; Nilsson, K.; Ninci, D.; Nishijima, K.; Noda, K.; Nogués, L.; Paiano, S.; Palacio, J.; Paneque, D.; Paoletti, R.; Paredes, J. M.; Paredes-Fortuny, X.; Pedaletti, G.; Peresano, M.; Perri, L.; Persic, M.; Prada Moroni, P. G.; Prandini, E.; Puljak, I.; Garcia, J. R.; Reichardt, I.; Rhode, W.; Ribó, M.; Rico, J.; Saito, T.; Satalecka, K.; Schroeder, S.; Schweizer, T.; Sillanpää, A.; Sitarek, J.; Šnidarić, I.; Sobczynska, D.; Stamerra, A.; Strzys, M.; Surić, T.; Takalo, L.; Tavecchio, F.; Temnikov, P.; Terzić, T.; Tescaro, D.; Teshima, M.; Torres, D. F.; Torres-Albà, N.; Treves, A.; Vanzo, G.; Vazquez Acosta, M.; Vovk, I.; Ward, J. E.; Will, M.; Zarić, D.; Collaboration), (The MAGIC; Loh, A.; Rodriguez, J.Ahnen, M. L.; Ansoldi, S.; Antonelli, L. A.; Arcaro, C.; Babić, A.; Banerjee, B.; Bangale, P.; Barres de Almeida, U.; Barrio, J. A.; Becerra González, J.; Bednarek, W.; Bernardini, E.; Berti, Alessio; Biasuzzi, B.; Biland, A.; Blanch, O.; Bonnefoy, S.; Bonnoli, G.; Carosi, R.; Carosi, A.; Chatterjee, A.; Colin, P.; Colombo, E.; Contreras, J. L.; Cortina, J.; Covino, S.; Cumani, P.; Da Vela, P.; Dazzi, F.; De Angelis, A.; De Lotto, B.; de Oña Wilhelmi, E.; Di Pierro, F.; Doert, M.; Domínguez, A.; Dominis Prester, D.; Dorner, D.; Doro, M.; Einecke, S.; Eisenacher Glawion, D.; Elsaesser, D.; Engelkemeier, M.; Fallah Ramazani, V.; Fernández Barral, A.; Fidalgo, D.; Fonseca, M. V.; Font, L.; Fruck, C.; Galindo, D.; García López, R. J.; Garczarczyk, M.; Gaug, M.; Giammaria, P.; Godinović, N.; Gora, D.; Griffiths, S.; Guberman, D.; Hadasch, D.; Hahn, A.; Hassan, T.; Hayashida, M.; Herrera, J.; Hose, J.; Hrupec, D.; Hughes, G.; Ishio, K.; Konno, Y.; Kubo, H.; Kushida, J.; Kuveždić, D.; Lelas, D.; Lindfors, E.; Lombardi, S.; Longo, Francesco; López, M.; Maggio, C.; Majumdar, P.; Makariev, M.; Maneva, G.; Manganaro, M.; Mannheim, K.; Maraschi, L.; Mariotti, M.; Martínez, M.; Mazin, D.; Menzel, U.; Minev, M.; Mirzoyan, R.; Moralejo, A.; Moreno, V.; Moretti, E.; Neustroev, V.; Niedzwiecki, A.; Nievas Rosillo, M.; Nilsson, K.; Ninci, D.; Nishijima, K.; Noda, K.; Nogués, L.; Paiano, S.; Palacio, J.; Paneque, D.; Paoletti, R.; Paredes, J. M.; Paredes Fortuny, X.; Pedaletti, G.; Peresano, M.; Perri, L.; Persic, M.; Prada Moroni, P. G.; Prandini, E.; Puljak, I.; Garcia, J. R.; Reichardt, I.; Rhode, W.; Ribó, M.; Rico, J.; Saito, T.; Satalecka, K.; Schroeder, S.; Schweizer, T.; Sillanpää, A.; Sitarek, J.; Šnidarić, I.; Sobczynska, D.; Stamerra, A.; Strzys, M.; Surić, T.; Takalo, L.; Tavecchio, F.; Temnikov, P.; Terzić, T.; Tescaro, D.; Teshima, M.; Torres, D. F.; Torres Albà, N.; Treves, A.; Vanzo, G.; Vazquez Acosta, M.; Vovk, I.; Ward, J. E.; Will, M.; Zarić, D.; Collaboration), (The MAGIC; Loh, A.; Rodriguez, J

Electrophysiology in chronic inflammatory demyelinating polyneuropathy with IGIV.

Patients with chronic inflammatory demyelinating polyneuropathy (CIDP) received immune globulin intravenous, 10% caprylate/chromatography purified (IGIV-C, Gamunex; n=59) or placebo (n=58) every 3 weeks for up to 24 weeks (first period) in a randomized, double-blind, parallel-group, response-conditional, crossover study. Motor and sensory nerves were assessed at baseline and endpoint/week 24. A nonsignificant trend toward improvement in the proximal amplitude of the most severely affected motor nerve was observed with IGIV-C (0.69+/-1.86 mV) versus placebo (0.47+/-2.29 mV), and a greater improvement of 1.08+/-2.15 mV with IGIV-C versus 0.46+/-2.03 mV with placebo (P=0.089) was observed with exclusion of data from Erb's point stimulation. Greater improvements from baseline favoring IGIV-C were observed for 127/142 electrophysiologic parameters. The averaged motor amplitudes from all motor nerves significantly improved with IGIV-C versus placebo [treatment difference, 0.62 mV; 95% confidence interval (CI), 0.05, 1.20; P=0.035], and conduction block decreased significantly (treatment difference, -5.54%; 95% CI, -10.43, -0.64; P=0.027), particularly in the lower limbs. Overall, the data suggest that IGIV-C improves electrophysiologic parameters in CIDP

Deep observations of the globular cluster M15 with the MAGIC telescopes

Abstract A population of globular clusters (GCs) has been recently established by the Fermi-LAT telescope as a new class of GeV γ-ray sources. Leptons accelerated to TeV energies, in the inner magnetospheres of MSPs or in their wind regions, should produce γ-rays through the inverse Compton scattering in the dense radiation field from the huge population of stars. We have conducted deep observations of the GC M15 with the MAGIC telescopes and used 165 h in order to search for γ-ray emission. A strong upper limit on the TeV γ-ray flux < 3.2×10−13cm−2s−1 above 300 GeV (⁠<0.26 per cent of the Crab nebula flux) has been obtained. We interpret this limit as a constraint on the efficiency of the acceleration of leptons in the magnetospheres of the MSPs. We constrain the injection rate of relativistic leptons, ηe, from the MSPs magnetospheres and their surrounding. We conclude that ηe must be lower than expected from the modelling of high-energy processes in MSP inner magnetospheres. For leptons accelerated with the power-law spectrum in the MSP wind regions, ηe is constrained to be much lower than derived for the wind regions around classical pulsars. These constraints are valid for the expected range of magnetic field strengths within the GC and for the range of likely energies of leptons injected from the inner magnetospheres, provided that the leptons are not removed from the GC very efficiently due to advection process. We discuss consequences of these constraints for the models of radiation processes around millisecond pulsars

An intermittent extreme BL Lac: MWL study of 1ES 2344+514 in an enhanced state

Extreme high-frequency BL Lacs (EHBL) feature their synchrotron peak of the broad-band spectral energy distribution (SED) at vs 65 1017 Hz. The BL Lac object 1ES 2344+514 was included in the EHBL family because of its impressive shift of the synchrotron peak in 1996. During the following years, the source appeared to be in a low state without showing any extreme behaviours. In 2016 August, 1ES 2344+514 was detected with the groundbased \u3b3 -ray telescope FACT during a high \u3b3 -ray state, triggering multiwavelength (MWL) observations. We studied the MWL light curves of 1ES 2344+514 during the 2016 flaring state, using data from radio to very-high-energy (VHE) \u3b3 -rays taken with OVRO, KAIT, KVA, NOT, some telescopes of the GASP-WEBT collaboration at the Teide, Crimean, and St. Petersburg observatories, Swift-UVOT, Swift-XRT, Fermi-LAT, FACT, and MAGIC. With simultaneous observations of the flare, we built the broad-band SED and studied it in the framework of a leptonic and a hadronic model. The VHE \u3b3 -ray observations show a flux level of 55 per cent of the Crab Nebula flux above 300 GeV, similar to the historical maximum of 1995. The combination of MAGIC and Fermi-LAT spectra provides an unprecedented characterization of the inverse-Compton peak for this object during a flaring episode. The _ index of the intrinsic spectrum in the VHE \u3b3 -ray band is 2.04 \ub1 0.12stat \ub1 0.15sys.We find the source in an extreme state with a shift of the position of the synchrotron peak to frequencies above or equal to 1018 Hz

Evaluating the incidence of pathological complete response in current international rectal cancer practice: the barriers to widespread safe deferral of surgery

This is the peer reviewed version of the following article: , which has been published in final form at https://doi.org/10.1111/codi.14361. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions."Colorectal Disease © 2018 The Association of Coloproctology of Great Britain and Ireland Introduction: The mainstay of management for locally advanced rectal cancer is chemoradiotherapy followed by surgical resection. Following chemoradiotherapy, a complete response may be detected clinically and radiologically (cCR) prior to surgery or pathologically after surgery (pCR). We aim to report the overall complete pathological response (pCR) rate and the reliability of detecting a cCR by conventional pre-operative imaging. Methods: A pre-planned analysis of the European Society of Coloproctology (ESCP) 2017 audit was performed. Patients treated by elective rectal resection were included. A pCR was defined as a ypT0 N0 EMVI negative primary tumour; a partial response represented any regression from baseline staging following chemoradiotherapy. The primary endpoint was the pCR rate. The secondary endpoint was agreement between post-treatment MRI restaging (yMRI) and final pathological staging. Results: Of 2572 patients undergoing rectal cancer surgery in 277 participating centres across 44 countries, 673 (26.2%) underwent chemoradiotherapy and surgery. The pCR rate was 10.3% (67/649), with a partial response in 35.9% (233/649) patients. Comparison of AJCC stage determined by post-treatment yMRI with final pathology showed understaging in 13% (55/429) and overstaging in 34% (148/429). Agreement between yMRI and final pathology for T-stage, N-stage, or AJCC status were each graded as ‘fair’ only (n = 429, Kappa 0.25, 0.26 and 0.35 respectively). Conclusion: The reported pCR rate of 10% highlights the potential for non-operative management in selected cases. The limited strength of agreement between basic conventional post-chemoradiotherapy imaging assessment techniques and pathology suggest alternative markers of response should be considered, in the context of controlled clinical trials

Outcomes from elective colorectal cancer surgery during the SARS‐CoV‐2 pandemic

Aim This study aimed to describe the change in surgical practice and the impact of SARS-CoV-2 on mortality after surgical resection of colorectal cancer during the initial phases of the SARS-CoV-2 pandemic. Method This was an international cohort study of patients undergoing elective resection of colon or rectal cancer without preoperative suspicion of SARS-CoV-2. Centres entered data from their first recorded case of COVID-19 until 19 April 2020. The primary outcome was 30-day mortality. Secondary outcomes included anastomotic leak, postoperative SARS-CoV-2 and a comparison with prepandemic European Society of Coloproctology cohort data. Results From 2073 patients in 40 countries, 1.3% (27/2073) had a defunctioning stoma and 3.0% (63/2073) had an end stoma instead of an anastomosis only. Thirty-day mortality was 1.8% (38/2073), the incidence of postoperative SARS-CoV-2 was 3.8% (78/2073) and the anastomotic leak rate was 4.9% (86/1738). Mortality was lowest in patients without a leak or SARS-CoV-2 (14/1601, 0.9%) and highest in patients with both a leak and SARS-CoV-2 (5/13, 38.5%). Mortality was independently associated with anastomotic leak (adjusted odds ratio 6.01, 95% confidence interval 2.58–14.06), postoperative SARS-CoV-2 (16.90, 7.86–36.38), male sex (2.46, 1.01–5.93), age >70 years (2.87, 1.32–6.20) and advanced cancer stage (3.43, 1.16–10.21). Compared with prepandemic data, there were fewer anastomotic leaks (4.9% versus 7.7%) and an overall shorter length of stay (6 versus 7 days) but higher mortality (1.7% versus 1.1%). Conclusion Surgeons need to further mitigate against both SARS-CoV-2 and anastomotic leak when offering surgery during current and future COVID-19 waves based on patient, operative and organizational risks