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1. A new method of reconstructing images of gamma-ray telescopes applied to the LST-1 of CTAO

Author

Project, CTA-LST, Abe, K., Abe, S., Abhishek, A., Acero, F., Aguasca-Cabot, A., Agudo, I., Alispach, C., Crespo, N. Alvarez, Ambrosino, D., Antonelli, L. A., Aramo, C., Arbet-Engels, A., Arcaro, C., Asano, K., Aubert, P., Baktash, A., Balbo, M., Bamba, A., Larriva, A. Baquero, de Almeida, U. Barres, Barrio, J. A., Jiménez, L. Barrios, Batkovic, I., Baxter, J., González, J. Becerra, Bernardini, E., Medrano, J. Bernete, Berti, A., Bezshyiko, I., Bhattacharjee, P., Bigongiari, C., Bissaldi, E., Blanch, O., Bonnoli, G., Bordas, P., Borkowski, G., Brunelli, G., Bulgarelli, A., Burelli, I., Burmistrov, L., Buscemi, M., Cardillo, M., Caroff, S., Carosi, A., Carrasco, M. S., Cassol, F., Castrejón, N., Cauz, D., Cerasole, D., Ceribella, G., Chai, Y., Cheng, K., Chiavassa, A., Chikawa, M., Chon, G., Chytka, L., Cicciari, G. M., Cifuentes, A., Contreras, J. L., Cortina, J., Costantini, H., Da Vela, P., Dalchenko, M., Dazzi, F., De Angelis, A., de Lavergne, M. de Bony, De Lotto, B., de Menezes, R., Del Burgo, R., Del Peral, L., Delgado, C., Mengual, J. Delgado, della Volpe, D., Dellaiera, M., Di Piano, A., Di Pierro, F., Di Tria, R., Di Venere, L., Díaz, C., Dominik, R. M., Prester, D. Dominis, Donini, A., Dorner, D., Doro, M., Eisenberger, L., Elsässer, D., Emery, G., Escudero, J., Ramazani, V. Fallah, Ferrarotto, F., Fiasson, A., Foffano, L., Coromina, L. Freixas, Fröse, S., Fukazawa, Y., López, R. Garcia, Gasbarra, C., Gasparrini, D., Geyer, D., Paiva, J. Giesbrecht, Giglietto, N., Giordano, F., Gliwny, P., Godinovic, N., Grau, R., Green, D., Green, J., Gunji, S., Günther, P., Hackfeld, J., Hadasch, D., Hahn, A., Hassan, T., Hayashi, K., Heckmann, L., Heller, M., Llorente, J. Herrera, Hirotani, K., Hoffmann, D., Horns, D., Houles, J., Hrabovsky, M., Hrupec, D., Hui, D., Iarlori, M., Imazawa, R., Inada, T., Inome, Y., Inoue, S., Ioka, K., Iori, M., Iuliano, A., Martinez, I. Jimenez, Quiles, J. Jimenez, Jurysek, J., Kagaya, M., Kalashev, O., Karas, V., Katagiri, H., Kataoka, J., Kerszberg, D., Kobayashi, Y., Kohri, K., Kong, A., Kubo, H., Kushida, J., Lainez, M., Lamanna, G., Lamastra, A., Lemoigne, L., Linhoff, M., Longo, F., López-Coto, R., López-Oramas, A., Loporchio, S., Lorini, A., Bahilo, J. Lozano, Luciani, H., Luque-Escamilla, P. L., Majumdar, P., Makariev, M., Mallamaci, M., Mandat, D., Manganaro, M., Manicò, G., Mannheim, K., Marchesi, S., Mariotti, M., Marquez, P., Marsella, G., Martí, J., Martinez, O., Martínez, G., Martínez, M., Mas-Aguilar, A., Maurin, G., Mazin, D., Méndez-Gallego, J., Guillen, E. Mestre, Micanovic, S., Miceli, D., Miener, T., Miranda, J. M., Mirzoyan, R., Mizuno, T., Gonzalez, M. Molero, Molina, E., Montaruli, T., Moralejo, A., Morcuende, D., Morselli, A., Moya, V., Muraishi, H., Nagataki, S., Nakamori, T., Neronov, A., Nickel, L., Rosillo, M. Nievas, Nikolic, L., Nishijima, K., Noda, K., Nosek, D., Novotny, V., Nozaki, S., Ohishi, M., Ohtani, Y., Oka, T., Okumura, A., Orito, R., Otero-Santos, J., Ottanelli, P., Owen, E., Palatiello, M., Paneque, D., Pantaleo, F. R., Paoletti, R., Paredes, J. M., Pech, M., Pecimotika, M., Peresano, M., Pfeifle, F., Pietropaolo, E., Pihet, M., Pirola, G., Plard, C., Podobnik, F., Pons, E., Prandini, E., Priyadarshi, C., Prouza, M., Rainò, S., Rando, R., Rhode, W., Ribó, M., Righi, C., Rizi, V., Fernandez, G. Rodriguez, Frías, M. D. Rodríguez, Ruina, A., Ruiz-Velasco, E., Saito, T., Sakurai, S., Sanchez, D. A., Sano, H., Šarić, T., Sato, Y., Saturni, F. G., Savchenko, V., Schiavone, F., Schleicher, B., Schmuckermaier, F., Schubert, J. L., Schussler, F., Schweizer, T., Arroyo, M. Seglar, Siegert, T., Sitarek, J., Sliusar, V., Strišković, J., Strzys, M., Suda, Y., Tajima, H., Takahashi, H., Takahashi, M., Takata, J., Takeishi, R., Tam, P. H. T., Tanaka, S. J., Tateishi, D., Tavernier, T., Temnikov, P., Terada, Y., Terauchi, K., Terzic, T., Teshima, M., Tluczykont, M., Tokanai, F., Torres, D. F., Travnicek, P., Tutone, A., Vacula, M., Vallania, P., van Scherpenberg, J., Acosta, M. Vázquez, Ventura, S., Verna, G., Viale, I., Vigliano, A., Vigorito, C. F., Visentin, E., Vitale, V., Voitsekhovskyi, V., Voutsinas, G., Vovk, I., Vuillaume, T., Walter, R., Wan, L., Will, M., Wójtowicz, J., Yamamoto, T., Yamazaki, R., Yeung, P. K. H., Yoshida, T., Yoshikoshi, T., Zhang, W., and Zywucka, N.

Subjects
Astrophysics - High Energy Astrophysical Phenomena, Astrophysics - Instrumentation and Methods for Astrophysics
Abstract

Imaging atmospheric Cherenkov telescopes (IACTs) are used to observe very high-energy photons from the ground. Gamma rays are indirectly detected through the Cherenkov light emitted by the air showers they induce. The new generation of experiments, in particular the Cherenkov Telescope Array Observatory (CTAO), sets ambitious goals for discoveries of new gamma-ray sources and precise measurements of the already discovered ones. To achieve these goals, both hardware and data analysis must employ cutting-edge techniques. This also applies to the LST-1, the first IACT built for the CTAO, which is currently taking data on the Canary island of La Palma. This paper introduces a new event reconstruction technique for IACT data, aiming to improve the image reconstruction quality and the discrimination between the signal and the background from misidentified hadrons and electrons. The technique models the development of the extensive air shower signal, recorded as a waveform per pixel, seen by CTAO telescopes' cameras. Model parameters are subsequently passed to random forest regressors and classifiers to extract information on the primary particle. The new reconstruction was applied to simulated data and to data from observations of the Crab Nebula performed by the LST-1. The event reconstruction method presented here shows promising performance improvements. The angular and energy resolution, and the sensitivity, are improved by 10 to 20% over most of the energy range. At low energy, improvements reach up to 22%, 47%, and 50%, respectively. A future extension of the method to stereoscopic analysis for telescope arrays will be the next important step., Comment: Accepted in A&A

Published
2024

2. A detailed study of the very-high-energy Crab pulsar emission with the LST-1

Author

Project, CTA-LST, Abe, K., Abe, S., Abhishek, A., Acero, F., Aguasca-Cabot, A., Agudo, I., Crespo, N. Alvarez, Antonelli, L. A., Aramo, C., Arbet-Engels, A., Arcaro, C., Artero, M., Asano, K., Aubert, P., Baktash, A., Bamba, A., Larriva, A. Baquero, Baroncelli, L., de Almeida, U. Barres, Barrio, J. A., Batkovic, I., Baxter, J., González, J. Becerra, Bernardini, E., Medrano, J. Bernete, Berti, A., Bhattacharjee, P., Bigongiari, C., Bissaldi, E., Blanch, O., Bonnoli, G., Bordas, P., Brunelli, G., Bulgarelli, A., Burelli, I., Burmistrov, L., Buscemi, M., Cardillo, M., Caroff, S., Carosi, A., Carrasco, M. S., Cassol, F., Castrejón, N., Cauz, D., Cerasole, D., Ceribella, G., Chai, Y., Cheng, K., Chiavassa, A., Chikawa, M., Chon, G., Chytka, L., Cicciari, G. M., Cifuentes, A., Contreras, J. L., Cortina, J., Costantini, H., Da Vela, P., Dalchenko, M., Dazzi, F., De Angelis, A., de Lavergne, M. de Bony, De Lotto, B., de Menezes, R., Del Peral, L., Delgado, C., Mengual, J. Delgado, della Volpe, D., Dellaiera, M., Di Piano, A., Di Pierro, F., Di Tria, R., Di Venere, L., Díaz, C., Dominik, R. M., Prester, D. Dominis, Donini, A., Dorner, D., Doro, M., Eisenberger, L., Elsässer, D., Emery, G., Escudero, J., Ramazani, V. Fallah, Ferrarotto, F., Fiasson, A., Foffano, L., Coromina, L. Freixas, Fröse, S., Fukazawa, Y., López, R. Garcia, Gasbarra, C., Gasparrini, D., Gavira, L., Geyer, D., Paiva, J. Giesbrecht, Giglietto, N., Giordano, F., Gliwny, P., Godinovic, N., Grau, R., Green, D., Green, J., Gunji, S., Günther, P., Hackfeld, J., Hadasch, D., Hahn, A., Hassan, T., Hayashi, K., Heckmann, L., Heller, M., Llorente, J. Herrera, Hirotani, K., Hoffmann, D., Horns, D., Houles, J., Hrabovsky, M., Hrupec, D., Hui, D., Iarlori, M., Imazawa, R., Inada, T., Inome, Y., Ioka, K., Iori, M., Martinez, I. Jimenez, Quiles, J. Jiménez, Jurysek, J., Kagaya, M., Karas, V., Katagiri, H., Kataoka, J., Kerszberg, D., Kobayashi, Y., Kohri, K., Kong, A., Kubo, H., Kushida, J., Lainez, M., Lamanna, G., Lamastra, A., Lemoigne, L., Linhoff, M., Longo, F., López-Coto, R., López-Moya, M., López-Oramas, A., Loporchio, S., Lorini, A., Bahilo, J. Lozano, Luque-Escamilla, P. L., Majumdar, P., Makariev, M., Mallamaci, M., Mandat, D., Manganaro, M., Manicò, G., Mannheim, K., Marchesi, S., Mariotti, M., Marquez, P., Marsella, G., Martí, J., Martinez, O., Martínez, G., Martínez, M., Mas-Aguilar, A., Maurin, G., Mazin, D., Guillen, E. Mestre, Micanovic, S., Miceli, D., Miener, T., Miranda, J. M., Mirzoyan, R., Mizuno, T., Gonzalez, M. Molero, Molina, E., Montaruli, T., Moralejo, A., Morcuende, D., Morselli, A., Moya, V., Muraishi, H., Nagataki, S., Nakamori, T., Neronov, A., Nickel, L., Rosillo, M. Nievas, Nikolic, L., Nishijima, K., Noda, K., Nosek, D., Novotny, V., Nozaki, S., Ohishi, M., Ohtani, Y., Oka, T., Okumura, A., Orito, R., Otero-Santos, J., Ottanelli, P., Owen, E., Palatiello, M., Paneque, D., Pantaleo, F. R., Paoletti, R., Paredes, J. M., Pech, M., Pecimotika, M., Peresano, M., Pfeiffle, F., Pietropaolo, E., Pihet, M., Pirola, G., Plard, C., Podobnik, F., Pons, E., Prandini, E., Priyadarshi, C., Prouza, M., Rando, R., Rhode, W., Ribó, M., Righi, C., Rizi, V., Fernandez, G. Rodriguez, Frías, M. D. Rodríguez, Saito, T., Sakurai, S., Sanchez, D. A., Sano, H., Šarić, T., Sato, Y., Saturni, F. G., Savchenko, V., Schiavone, F., Schleicher, B., Schmuckermaier, F., Schubert, J. L., Schussler, F., Schweizer, T., Arroyo, M. Seglar, Siegert, T., Silvia, R., Sitarek, J., Sliusar, V., Strišković, J., Strzys, M., Suda, Y., Tajima, H., Takahashi, H., Takahashi, M., Takata, J., Takeishi, R., Tam, P. H. T., Tanaka, S. J., Tateishi, D., Tavernier, T., Temnikov, P., Terada, Y., Terauchi, K., Terzic, T., Teshima, M., Tluczykont, M., Tokanai, F., Torres, D. F., Travnicek, P., Truzzi, S., Tutone, A., Vacula, M., Vallania, P., van Scherpenberg, J., Acosta, M. Vázquez, Verna, G., Viale, I., Vigliano, A., Vigorito, C. F., Visentin, E., Vitale, V., Voitsekhovskyi, V., Voutsinas, G., Vovk, I., Vuillaume, T., Walter, R., Wan, L., Will, M., Yamamoto, T., Yamazaki, R., Yeung, P. K. H., Yoshida, T., Yoshikoshi, T., Zhang, W., and Zywucka, N.

Subjects
Astrophysics - High Energy Astrophysical Phenomena
Abstract

Context: There are currently three pulsars firmly detected by imaging atmospheric Cherenkov telescopes (IACTs), two of them reaching TeV energies, challenging models of very-high-energy (VHE) emission in pulsars. More precise observations are needed to better characterize pulsar emission at these energies. The LST-1 is the prototype of the Large-Sized Telescope, that will be part of the Cherenkov Telescope Array Observatory (CTAO). Its improved performance over previous IACTs makes it well suited for studying pulsars. Aims: To study the Crab pulsar emission with the LST-1, improving and complementing the results from other telescopes. These observations can also be used to characterize the potential of the LST-1 to study other pulsars and detect new ones. Methods: We analyzed a total of $\sim$103 hours of gamma-ray observations of the Crab pulsar conducted with the LST-1 in the period from September 2020 to January 2023. The observations were carried out at zenith angles less than 50 degrees. A new analysis of the Fermi-LAT data was also performed, including $\sim$14 years of observations. Results: The Crab pulsar phaseogram, long-term light-curve, and phase-resolved spectra are reconstructed with the LST-1 from 20 GeV to 450 GeV for P1 and up to 700 GeV for P2. The pulsed emission is detected with a significance of 15.2$\sigma$. The two characteristic emission peaks of the Crab pulsar are clearly detected (>10$\sigma$), as well as the so-called bridge emission (5.7$\sigma$). We find that both peaks are well described by power laws, with spectral indices of $\sim$3.44 and $\sim$3.03 respectively. The joint analysis of Fermi-LAT and LST-1 data shows a good agreement between both instruments in the overlapping energy range. The detailed results obtained in the first observations of the Crab pulsar with LST-1 show the potential that CTAO will have to study this type of sources., Comment: Accepted by A&A

Published
2024

3. Dark Matter Line Searches with the Cherenkov Telescope Array

Author

Abe, S., Abhir, J., Abhishek, A., Acero, F., Acharyya, A., Adam, R., Aguasca-Cabot, A., Agudo, I., Aguirre-Santaella, A., Alfaro, J., Alfaro, R., Alvarez-Crespo, N., Batista, R. Alves, Amans, J. -P., Amato, E., Ambrosi, G., Angel, L., Aramo, C., Arcaro, C., Arnesen, T. T. H., Arrabito, L., Asano, K., Ascasibar, Y., Aschersleben, J., Ashkar, H., Backes, M., Baktash, A., Balazs, C., Balbo, M., Larriva, A. Baquero, Martins, V. Barbosa, de Almeida, U. Barres, Barrio, J. A., Batković, I., Batzofin, R., Baxter, J., González, J. Becerra, Beck, G., Benbow, W., Berge, D., Bernardini, E., Bernete, J., Bernlöhr, K., Berti, A., Bertucci, B., Bhattacharjee, P., Bhattacharyya, S., Bigongiari, C., Biland, A., Bissaldi, E., Biteau, J., Blanch, O., Blazek, J., Bocchino, F., Boisson, C., Bolmont, J., Bonnoli, G., Bonollo, A., Bordas, P., Bosnjak, Z., Bottacini, E., Böttcher, M., Bringmann, T., Bronzini, E., Brose, R., Brown, A. M., Brunelli, G., Bulgarelli, A., Bulik, T., Burelli, I., Burmistrov, L., Burton, M., Buscemi, M., Bylund, T., Cailleux, J., Campoy-Ordaz, A., Cantlay, B. K., Capasso, G., Caproni, A., Capuzzo-Dolcetta, R., Caraveo, P., Caroff, S., Carosi, A., Carosi, R., Carquin, E., Carrasco, M. -S., Cassol, F., Castaldini, L., Castrejon, N., Castro-Tirado, A. J., Cerasole, D., Cerruti, M., Chadwick, P. M., Chaty, S., Chen, A. W., Chernyakova, M., Chiavassa, A., Chudoba, J., Chytka, L., Cicciari, G. M., Cifuentes, A., Araujo, C. H. Coimbra, Colapietro, M., Conforti, V., Conte, F., Contreras, J. L., Costa, A., Costantini, H., Cotter, G., Cristofari, P., Cuevas, O., Curtis-Ginsberg, Z., D'Amico, G., D'Ammando, F., Dai, S., Dalchenko, M., Dazzi, F., De Angelis, A., de Lavergne, M. de Bony, De Caprio, V., Pino, E. M. de Gouveia Dal, De Lotto, B., De Lucia, M., de Menezes, R., de Naurois, M., de Souza, V., del Peral, L., del Valle, M. V., Giler, A. G. Delgado, Mengual, J. Delgado, Delgado, C., Dell'aiera, M., della Volpe, D., Depaoli, D., Di Girolamo, T., Di Piano, A., Di Pierro, F., Di Tria, R., Di Venere, L., Díaz, C., Diebold, S., Dinesh, A., Djuvsland, J., Dominik, R. M., Prester, D. Dominis, Donini, A., Dorner, D., Dörner, J., Doro, M., Dournaux, J. -L., Duangchan, C., Dubos, C., Ducci, L., Dwarkadas, V. V., Ebr, J., Eckner, C., Egberts, K., Einecke, S., Elsässer, D., Emery, G., Errando, M., Escanuela, C., Escarate, P., Godoy, M. Escobar, Escudero, J., Esposito, P., Ettori, S., Falceta-Goncalves, D., Fedorova, E., Fegan, S., Feng, Q., Ferrand, G., Ferrarotto, F., Fiandrini, E., Fiasson, A., Filipovic, M., Fioretti, V., Fiori, M., Foffano, L., Guiteras, L. Font, Fontaine, G., Fröse, S., Fukazawa, Y., Fukui, Y., Furniss, A., Galanti, G., Galaz, G., Galelli, C., Gallozzi, S., Gammaldi, V., Garczarczyk, M., Gasbarra, C., Gasparrini, D., Ghalumyan, A., Gianotti, F., Giarrusso, M., Paiva, J. G. Giesbrecht Formiga, Giglietto, N., Giordano, F., Giuffrida, R., Glicenstein, J. -F., Glombitza, J., Goldoni, P., González, J. M., González, M. M., Coelho, J. Goulart, Gradetzke, T., Granot, J., Grasso, D., Grau, R., Gréaux, L., Green, D., Green, J. G., Grolleron, G., Guedes, L. M. V., Gueta, O., Hackfeld, J., Hadasch, D., Hamal, P., Hanlon, W., Hara, S., Harvey, V. M., Hassan, T., Hayashi, K., Heß, B., Heckmann, L., Heller, M., Cadena, S. Hernández, Hervet, O., Hinton, J., Hiroshima, N., Hnatyk, B., Hnatyk, R., Hofmann, W., Holder, J., Horan, D., Horvath, P., Hovatta, T., Hrabovsky, M., Hrupec, D., Iarlori, M., Inada, T., Incardona, F., Inoue, S., Inoue, Y., Iocco, F., Iori, M., Ishio, K., Jamrozy, M., Janecek, P., Jankowsky, F., Jean, P., Quiles, J. Jimenez, Jin, W., Juramy-Gilles, C., Jurysek, J., Kagaya, M., Kalekin, O., Karas, V., Katagiri, H., Kataoka, J., Kaufmann, S., Kazanas, D., Kerszberg, D., Kieda, D. B., Kleiner, T., Kluge, G., Kobayashi, Y., Kohri, K., Komin, N., Kornecki, P., Kosack, K., Kowal, G., Kubo, H., Kushida, J., La Barbera, A., La Palombara, N., Láinez, M., Lamastra, A., Lapington, J., Laporte, P., Lazarević, S., Lazendic-Galloway, J., Lemoine-Goumard, M., Lenain, J. -P., Leone, F., Leonora, E., Leto, G., Lindfors, E., Linhoff, M., Liodakis, I., Lipniacka, A., Lombardi, S., Longo, F., López-Coto, R., López-Moya, M., López-Oramas, A., Loporchio, S., Bahilo, J. Lozano, Luque-Escamilla, P. L., Macias, O., Majumdar, P., Mallamaci, M., Malyshev, D., Mandat, D., Manicò, G., Mariotti, M., Márquez, I., Marquez, P., Marsella, G., Martí, J., Martínez, G. A., Martínez, M., Martinez, O., Marty, C., Mas-Aguilar, A., Mastropietro, M., Mazin, D., Menchiari, S., Mestre, E., Meunier, J. -L., Meyer, D. M. -A., Meyer, M., Miceli, D., Miceli, M., Michailidis, M., Michałowski, J., Miener, T., Miranda, J. M., Mitchell, A., Mizote, M., Mizuno, T., Moderski, R., Molero, M., Molfese, C., Molina, E., Montaruli, T., Moralejo, A., Morcuende, D., Morselli, A., Moulin, E., Zamanillo, V. Moya, Munari, K., Murach, T., Muraczewski, A., Muraishi, H., Nakamori, T., Nayak, A., Nemmen, R., Neto, J. P., Nickel, L., Niemiec, J., Nieto, D., Rosillo, M. Nievas, Nikołajuk, M., Nikolić, L., Nishijima, K., Noda, K., Nosek, D., Novotny, V., Nozaki, S., Ohishi, M., Ohtani, Y., Okumura, A., Olive, J. -F., Ong, R. A., Orienti, M., Orito, R., Orlandini, M., Orlando, E., Orlando, S., Ostrowski, M., Otero-Santos, J., Oya, I., Pagano, I., Pagliaro, A., Palatiello, M., Panebianco, G., Paneque, D., Pantaleo, F. R., Paredes, J. M., Parmiggiani, N., Patricelli, B., Pe'er, A., Pech, M., Pecimotika, M., Pensec, U., Peresano, M., Pérez-Romero, J., Persic, M., Peters, K. P., Petruk, O., Piano, G., Pierre, E., Pietropaolo, E., Pihet, M., Pinchbeck, L., Pirola, G., Pittori, C., Plard, C., Podobnik, F., Pohl, M., Pollet, V., Ponti, G., Prandini, E., Principe, G., Priyadarshi, C., Produit, N., Prouza, M., Pueschel, E., Pühlhofer, G., Pumo, M. L., Queiroz, F., Quirrenbach, A., Rainò, S., Rando, R., Razzaque, S., Regeard, M., Reimer, A., Reimer, O., Reisenegger, A., Rhode, W., Ribeiro, D., Ribó, M., Ricci, C., Richtler, T., Rico, J., Rieger, F., Riitano, L., Rizi, V., Roache, E., Fernandez, G. Rodriguez, Frías, M. D. Rodríguez, Rodríguez-Vázquez, J. J., Romano, P., Romeo, G., Rosado, J., de Leon, A. Rosales, Rowell, G., Rudak, B., Ruiter, A. J., Rulten, C. B., Sadeh, I., Saha, L., Saito, T., Salzmann, H., Sánchez-Conde, M., Sandaker, H., Sangiorgi, P., Sano, H., Santander, M., Santos-Lima, R., Sapienza, V., Šarić, T., Sarkar, A., Sarkar, S., Saturni, F. G., Savarese, S., Scherer, A., Schiavone, F., Schipani, P., Schleicher, B., Schovanek, P., Schubert, J. L., Schwanke, U., Arroyo, M. Seglar, Seitenzahl, I. R., Sergijenko, O., Servillat, M., Siegert, T., Siejkowski, H., Siqueira, C., Sliusar, V., Slowikowska, A., Sol, H., Spencer, S. T., Spiga, D., Stamerra, A., Stanič, S., Starecki, T., Starling, R., Stawarz, Ł., Steppa, C., Hatlen, E. Sæther, Stolarczyk, T., Strišković, J., Suda, Y., Świerk, P., Tajima, H., Tak, D., Takahashi, M., Takeishi, R., Tavernier, T., Tejedor, L. A., Terauchi, K., Teshima, M., Testa, V., Tian, W. W., Tibaldo, L., Tibolla, O., Peixoto, C. J. Todero, Torradeflot, F., Torres, D. F., Tosti, G., Tothill, N., Toussenel, F., Tramacere, A., Travnicek, P., Tripodo, G., Trois, A., Truzzi, S., Tutone, A., Vaclavek, L., Vacula, M., Vallania, P., Vallés, R., van Eldik, C., van Scherpenberg, J., Vandenbroucke, J., Vassiliev, V., Acosta, M. Vázquez, Vecchi, M., Ventura, S., Vercellone, S., Verna, G., Viana, A., Viaux, N., Vigliano, A., Vignatti, J., Vigorito, C. F., Villanueva, J., Visentin, E., Vitale, V., Vodeb, V., Voisin, V., Voitsekhovskyi, V., Vorobiov, S., Voutsinas, G., Vovk, I., Vuillaume, T., Wagner, S. J., Walter, R., White, M., White, R., Wierzcholska, A., Will, M., Williams, D. A., Wohlleben, F., Wolter, A., Yamamoto, T., Yang, L., Yoshida, T., Yoshikoshi, T., Zaharijas, G., Zampieri, L., Sanchez, R. Zanmar, Zavrtanik, D., Zavrtanik, M., Zdziarski, A. A., Zech, A., Zhang, W., Zhdanov, V. I., Ziętara, K., Živec, M., and Zuriaga-Puig, J.

Subjects
High Energy Physics - Phenomenology, Astrophysics - High Energy Astrophysical Phenomena, High Energy Physics - Experiment
Abstract

Monochromatic gamma-ray signals constitute a potential smoking gun signature for annihilating or decaying dark matter particles that could relatively easily be distinguished from astrophysical or instrumental backgrounds. We provide an updated assessment of the sensitivity of the Cherenkov Telescope Array (CTA) to such signals, based on observations of the Galactic centre region as well as of selected dwarf spheroidal galaxies. We find that current limits and detection prospects for dark matter masses above 300 GeV will be significantly improved, by up to an order of magnitude in the multi-TeV range. This demonstrates that CTA will set a new standard for gamma-ray astronomy also in this respect, as the world's largest and most sensitive high-energy gamma-ray observatory, in particular due to its exquisite energy resolution at TeV energies and the adopted observational strategy focussing on regions with large dark matter densities. Throughout our analysis, we use up-to-date instrument response functions, and we thoroughly model the effect of instrumental systematic uncertainties in our statistical treatment. We further present results for other potential signatures with sharp spectral features, e.g.~box-shaped spectra, that would likewise very clearly point to a particle dark matter origin., Comment: 44 pages JCAP style (excluding author list and references), 19 figures; minor changes to match published version

Published
2024
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5. The Density of Renal Lymphatics Correlates With Clinical Outcomes in IgA Nephropathy

Author

Rodas L, Barnadas E, Pereira A, Castrejon N, Saurina A, Calls J, Calzada Y, Alvaro Madrid Aris, Blasco M, Poch E, García-Herrera A, and Quintana LF

Subjects
IgAN, end-stage kidney disease, lymphatics, proteinuria
Abstract

INTRODUCTION: IgA nephropathy (IgAN) is the most common primary glomerulonephritis (GN) worldwide. The disease course fluctuates, and the most important challenge is the considerable variation in the time lag between diagnosis and the development of a hard clinical end point, such as end-stage kidney disease (ESKD). The reaction of renal tissue to damage resembles the common wound-healing response. One part of this repair in IgAN is the expansion of lymphatic vessels known as lymphangiogenesis. The aim of this work was to establish the prognostic value of the density of lymphatic vessels in the renal biopsy at the time of diagnosis, for predicting the risk of ESKD in a Spanish cohort of patients with IgAN. METHODS: We performed a retrospective multicenter study of 76 patients with IgAN. The end point of the study was progression to ESKD. The morphometric analysis of lymphatic vessels was performed on tissue sections stained with antipodoplanin antibody. RESULTS: Density of lymphatic vessels was significantly higher in patients with IgAN with mesangial hypercellularity >50%, segmental sclerosis, higher degrees of interstitial fibrosis, and tubular atrophy. Patients with more lymphatic vessels had significantly higher values of proteinuria and lower estimated glomerular filtration rate (eGFR). A density of lymphatic vessels =8 per mm(2) was associated with a significantly higher rate of progression to ESKD at 3 years from biopsy. After adjustment for the International IgAN prediction score, at the multivariate logistic regression, high density of lymphatic vessels (=8 per mm(2)) remained significantly associated with a higher rate of early progression to ESKD. CONCLUSION: This study contributes to the understanding of the natural history of the progression to ESKD in patients with IgAN revealing the density of lymphatics vessels may optimize the prognostic value of the International IgA predicting tool to calculate the risk of ESKD, favoring the evaluation of new targeted therapies.

Published
2022

6. A New Overgrowth Syndrome is due to Mutations inRNF125

Author

Tenorio J, Mansilla A, Valencia M, Martínez-Glez V, Romanelli V, Arias P, Castrejon N, Poletta F, Guillén-Navarro E, Gordo G, Mansilla E, García-Santiago F, González-Casado I, Vallespín E, Palomares M, Mori MA, Santos-Simarro F, García-Miñaur S, Fernández L, Mena R, Benito-Sanz S, del Pozo Á, Silla JC, Ibañez K, López-Granados E, Martín-Trujillo A, Montaner D, SOGRI Consortium, Heath KE, Campos-Barros Á, Dopazo J, Nevado J, Monk D, Ruiz-Pérez VL, and Lapunzina P

Subjects
Male, CIENCIAS MÉDICAS Y DE LA SALUD, RNF125, Ubiquitin-Protein Ligases, Inmunología, Hypoglycemia, Biology, macrocephaly, medicine.disease_cause, Downregulation and upregulation, Intellectual disability, Genetics, medicine, Humans, Missense mutation, Registries, overgrowth, Growth Disorders, Genetics (clinical), Mutation, Macrocephaly, Syndrome, medicine.disease, Pedigree, Ubiquitin ligase, Medicina Básica, intellectual disability, Spain, Overgrowth syndrome, biology.protein, Cancer research, Female, medicine.symptom, autoimmune disorder
Abstract

Overgrowth syndromes (OGS) are a group of disorders in which all parameters of growth and physical development are above the mean for age and sex. We evaluated a series of 270 families from the Spanish Overgrowth Syndrome Registry with no known OGS. We identified one de novo deletion and three missense mutations in RNF125 in six patients from four families with overgrowth, macrocephaly, intellectual disability, mild hydrocephaly, hypoglycemia, and inflammatory diseases resembling Sjögren syndrome. RNF125 encodes an E3 ubiquitin ligase and is a novel gene of OGS. Our studies of the RNF125 pathway point to upregulation of RIG-I-IPS1-MDA5 and/or disruption of the PI3K-AKT and interferon signaling pathways as the putative final effectors. Fil: Tenorio, Jair. Centro de Investigación Biomédica en Red de Enfermedades Raras. Madrid; España. Universidad Autónoma de Madrid; España Fil: Mansilla, Alicia. Instituto Cajal. Madrid; España Fil: Valencia, María. Centro de Investigación Biomédica en Red de Enfermedades Raras. Madrid; España. Universidad Autónoma de Madrid; España Fil: Martínez Glez, Víctor. Centro de Investigación Biomédica en Red de Enfermedades Raras. Madrid; España. Universidad Autónoma de Madrid; España Fil: Romanelli, Valeria. Centro de Investigación Biomédica en Red de Enfermedades Raras. Madrid; España Fil: Arias, Pedro. Centro de Investigación Biomédica en Red de Enfermedades Raras. Madrid; España. Universidad Autónoma de Madrid; España Fil: Castrejón, Nerea. Hospital San Juan de Dios. Barcelona; España Fil: Poletta, Fernando Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas ; Argentina Fil: Guillén Navarro, Encarna. Centro de Investigación Biomédica en Red de Enfermedades Raras. Madrid; España. Hospital Virgen de la Arrixaca. Murcia; España Fil: Gordo, Gema. Universidad Autónoma de Madrid; España Fil: Mansilla, Elena. Centro de Investigación Biomédica en Red de Enfermedades Raras. Madrid; España. Universidad Autónoma de Madrid; España Fil: García Santiago, Fé. Centro de Investigación Biomédica en Red de Enfermedades Raras. Madrid; España. Universidad Autónoma de Madrid; España Fil: González Casado, Isabel. Hospital Universitario La Paz. Madrid; España Fil: Vallespín, Elena. Centro de Investigación Biomédica en Red de Enfermedades Raras. Madrid; España. Universidad Autónoma de Madrid; España Fil: Palomares, María. Centro de Investigación Biomédica en Red de Enfermedades Raras. Madrid; España. Universidad Autónoma de Madrid; España Fil: Mori, María A.. Centro de Investigación Biomédica en Red de Enfermedades Raras. Madrid; España. Universidad Autónoma de Madrid; España Fil: Santos Simarro, Fernando. Centro de Investigación Biomédica en Red de Enfermedades Raras. Madrid; España. Universidad Autónoma de Madrid; España Fil: García Miñaur, Sixto. Centro de Investigación Biomédica en Red de Enfermedades Raras. Madrid; España. Universidad Autónoma de Madrid; España Fil: Fernández, Luis. Centro de Investigación Biomédica en Red de Enfermedades Raras. Madrid; España. Universidad Autónoma de Madrid; España Fil: Mena, Rocío. Centro de Investigación Biomédica en Red de Enfermedades Raras. Madrid; España. Universidad Autónoma de Madrid; España Fil: Benito Sanz, Sara. Centro de Investigación Biomédica en Red de Enfermedades Raras. Madrid; España. Universidad Autónoma de Madrid; España Fil: del Pozo, Ángela. Hospital Universitario La Paz. Madrid; España Fil: Silla, Juan Carlos. Hospital Universitario La Paz. Madrid; España Fil: Ibañez, Kristina. Hospital Universitario La Paz. Madrid; España Fil: López Granados, Eduardo. Hospital Universitario La Paz. Madrid; España Fil: Martín Trujillo, Alex. Cancer Epigenetics and Biology Program. Barcelona; España Fil: Montaner, David. Centro de Investigación Biomédica en Red de Enfermedades Raras. Madrid; España. Centro de Investigación Príncipe Felipe. Valencia; España Fil: The SOGRI Consortium. Hospital Universitario La Paz. Madrid; España Fil: Heath, Karen E. Centro de Investigación Biomédica en Red de Enfermedades Raras. Madrid; España. Hospital Universitario La Paz. Madrid; España Fil: Campos Barros, Ángel. Centro de Investigación Biomédica en Red de Enfermedades Raras. Madrid; España. Hospital Universitario La Paz. Madrid; España Fil: Dopazo, Joaquín. Centro de Investigación Biomédica en Red de Enfermedades Raras. Madrid; España. Centro de Investigación Príncipe Felipe. Valencia; España Fil: Nevado, Julián. Centro de Investigación Biomédica en Red de Enfermedades Raras. Madrid; España. Hospital Universitario La Paz. Madrid; España Fil: Monk, David. Cancer Epigenetics and Biology Program. Barcelona; España Fil: Ruiz Pérez, Víctor. Centro de Investigación Biomédica en Red de Enfermedades Raras. Madrid; España. Universidad Autónoma de Madrid; España Fil: Lapunzina, Pablo. Centro de Investigación Biomédica en Red de Enfermedades Raras. Madrid; España. Universidad Autónoma de Madrid; España

Published
2014

7. Cinacalcet inhibits neuroblastoma tumor growth and upregulates cancer-testis antigens

Author

Rodriguez-Hernandez CJ, Mateo-Lozano S, Garcia-López M, Casalà C, Briansó F, Castrejon N, Rodriguez E, Suñol M, Carcaboso AM, Lavarino C, Mora J, and de Torres C

Subjects
neuroblastoma, calcium-sensing receptor, cancer-testis antigens, cinacalcet, ER stress, neoplasms
Abstract

The calcium-sensing receptor is a G protein-coupled receptor that exerts cell-type specific functions in numerous tissues and some cancers. We have previously reported that this receptor exhibits tumor suppressor properties in neuroblastoma. We have now assessed cinacalcet, an allosteric activator of the CaSR approved for clinical use, as targeted therapy for this developmental tumor using neuroblastoma cell lines and patient-derived xenografts (PDX) with different MYCN and TP53 status. In vitro, acute exposure to cinacalcet induced endoplasmic reticulum stress coupled to apoptosis via ATF4-CHOP-TRB3 in CaSR-positive, MYCN-amplified cells. Both phenotypes were partially abrogated by phospholipase C inhibitor U73122. Prolonged in vitro treatment also promoted dose- and time-dependent apoptosis in CaSR-positive, MYCN-amplified cells and, irrespective of MYCN status, differentiation in surviving cells. Cinacalcet significantly inhibited tumor growth in MYCN-amplified xenografts and reduced that of MYCN-non amplified PDX. Morphology assessment showed fibrosis in MYCN-amplified xenografts exposed to the drug. Microarrays analyses revealed up-regulation of cancer-testis antigens (CTAs) in cinacalcet-treated MYCN-amplified tumors. These were predominantly CTAs encoded by genes mapping on chromosome X, which are the most immunogenic. Other modulated genes upon prolonged exposure to cinacalcet were involved in differentiation, cell cycle exit, microenvironment remodeling and calcium signaling pathways. CTAs were up-regulated in PDX and in vitro models as well. Moreover, progressive increase of CaSR expression upon cinacalcet treatment was seen both in vitro and in vivo. In summary, cinacalcet reduces neuroblastoma tumor growth and up-regulates CTAs. This effect represents a therapeutic opportunity and provides surrogate circulating markers of neuroblastoma response to this treatment.

Published
2016

9. Feasibility and Impact of Embedding an Extended DNA and RNA Tissue-Based Sequencing Panel for the Routine Care of Patients with Advanced Melanoma in Spain.

Author

Castrejon N, Martin R, Carrasco A, Castillo P, Garcia A, Albero-González R, García M, Marginet M, Palau N, Hernández M, Montironi C, Clot G, Arance A, Alos L, and Teixido C

Subjects
Humans, Male, Female, Middle Aged, Aged, Spain, Adult, High-Throughput Nucleotide Sequencing methods, Aged, 80 and over, Feasibility Studies, Proto-Oncogene Proteins B-raf genetics, Biomarkers, Tumor genetics, Skin Neoplasms genetics, Skin Neoplasms pathology, Melanoma genetics, Melanoma pathology, Melanoma therapy, Mutation
Abstract

Targeted NGS allows a fast and efficient multi-gene analysis and the detection of key gene aberrations in melanoma. In this study, we aim to describe the genetic alterations in a series of 87 melanoma cases using the oncomine focus assay (OFA), relate these results with the clinicopathological features of the patients, and compare them with our previous study results in which we used a smaller panel, the oncomine solid tumor (OST) DNA kit. Patients diagnosed with advanced melanoma at our center from 2020 to 2022 were included and DNA and RNA were extracted for sequencing. Common mutated genes were BRAF (29%), NRAS (28%), ALK , KIT , and MAP2K1 (5% each). Co-occurring mutations were detected in 29% of the samples, including BRAF with KIT , CTNNB1 , EGFR , ALK , HRAS , or MAP2K1. Amplifications and rearrangements were detected in 5% of cases. Only BRAF mutation showed a significant statistical association with sun exposure. For patients with a given genetic profile, the melanoma survival and recurrence-free survival rates were equivalent, but not for stage and LDH values. This expanded knowledge of molecular alterations has helped to more comprehensively characterize our patients and has provided relevant information for deciding the best treatment strategy., Competing Interests: C.T. declared no competing non-financial interests but reported advisory and consulting fees from Merck Sharp and Dohme (MSD), Novartis, and AstraZeneca, lecture fees from Roche, Pfizer, Biocartis, and MSD, and research from Novartis and AstraZeneca. Other authors declare no conflicts of interest.

Published
2024
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10. Restrospective reappraisal of the prognostic classification of spitzoid melanocytic neoplasms after BRAF and NRAS mutation characterisation: a single institution experience.

Author

Moysset I, Castrejon N, Garcia-Herrera A, Castillo P, Marginet M, Teixido C, Podlipnik S, Albero-Gonzalez R, Montironi C, Navarro J, Rovira C, Puig S, Carrera C, and Alos L

Subjects
Humans, Biomarkers, Tumor genetics, Prognosis, Retrospective Studies, GTP Phosphohydrolases genetics, Melanoma genetics, Melanoma pathology, Melanoma classification, Melanoma diagnosis, Membrane Proteins genetics, Mutation, Nevus, Epithelioid and Spindle Cell genetics, Nevus, Epithelioid and Spindle Cell pathology, Proto-Oncogene Proteins B-raf genetics, Skin Neoplasms genetics, Skin Neoplasms pathology, Skin Neoplasms classification, Skin Neoplasms diagnosis
Abstract

Aims: The current WHO classification of melanocytic tumours excludes neoplasms showing BRAF or NRAS mutations from the Spitz category. This study aimed to review and reclassify atypical melanocytic tumours with spitzoid morphological features diagnosed between 2009 and 2021 in our hospital after expanding the molecular profile, including BRAF and NRAS mutations in all cases., Methods and Results: A total of 71 neoplasms showing spitzoid features (Spitz-like) and atypia were included. The risk of progression of tumours was first studied by integrating the morphology, immunohistochemistry (p16, Ki67, HMB45 and PRAME) and fluorescence in-situ hybridisation (FISH) results (melanoma multiprobe and 9p21). In a second step, after expanding the molecular study, including BRAF and NRAS mutational status, the neoplasms were finally classified into four subgroups: atypical Spitz tumour (AST, n = 45); BRAF-mutated naevus/low-grade melanocytoma with spitzoid morphology (BAMS, n = 2); Spitz melanoma (SM, n = 14); and BRAF or NRAS mutated melanoma with spitzoid features (MSF, n = 10). Follow-up of patients revealed uneventful results for AST and BAMS. Only one SM presented lymph node metastasis after 134 months. Conversely, patients with MSF showed an unfavourable outcome: three developed lymph node metastases after a mean time of 22 months, with one patient presenting distant metastasis and dying of the disease 64 months from diagnosis. The progression-free survival showed significant differences between the four groups of spitzoid tumours (P < 0.001) and between both melanoma subtypes (P = 0.012)., Conclusions: The classification and prognostication of atypical neoplasms with spitzoid features requires the integration of histomorphology with the molecular investigation of tumours, which should include BRAF and NRAS mutational status., (© 2024 John Wiley & Sons Ltd.)

Published
2024
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11. Combined WNT-activated deep-penetrating/plexiform melanocytoma: insights into clinicopathological and molecular characterization.

Author

Castillo P, Castrejon N, Marginet M, Massi D, Alamon F, Teixido C, Montironi C, Garcia-Herrera A, Albero-Gonzalez R, Matas J, Puig S, and Alos L

Subjects
Male, Female, Humans, Child, Preschool, Child, Adolescent, Young Adult, Adult, Middle Aged, Aged, Ki-67 Antigen metabolism, In Situ Hybridization, Fluorescence, Lymphatic Metastasis, Mutation, Antigens, Neoplasm, Melanoma diagnosis, Melanoma genetics, Melanoma metabolism, Nevus, Epithelioid and Spindle Cell, Skin Neoplasms diagnosis, Skin Neoplasms genetics, Skin Neoplasms pathology, Succinimides
Abstract

Background: A combined deep-penetrating tumour redefined as WNT-activated deep-penetrating/plexiform melanocytoma (DPM), may pose challenging clinical and histological diagnoses., Objectives: To review the clinicopathological characteristics of combined DPMs and characterize the molecular profile of atypical and malignant forms., Methods: The study included 51 patients with combined DPMs diagnosed at the Hospital Clinic of Barcelona and the University of Florence between 2012 and 2020. Clinical data, dermoscopy images (when available) and histological characteristics were reviewed. Immunohistochemistry for β-catenin, LEF1, HMB45, Ki67, p16 and PRAME (preferentially expressed antigen in melanoma) was performed. Atypical forms underwent next-generation sequencing (NGS) panel analysis, including driver genes implicated in DPMs, TERT-promoter (p) mutations and the investigation of the 9p21 locus via fluorescence in situ hybridization., Results: Among the 51 patients (32 females and 19 males, age range 4-74 years), 68% with available clinical data (15/22) were initially suspected of having melanoma. Except for one patient, complete excision resulted in no recurrences or metastases. One patient who had an incompletely excised combined DPM developed a lymph node melanoma metastasis 10 years later. In the 51 patients, 10 samples (20%) showed atypical histological features; 7 (14%) exhibited a significant loss of p16 expression; and 2 (4%) showed a high-proliferative index (Ki67 over 5%). NGS analysis in 11 patients revealed a double mutation BRAFV600E and exon 3 CTNNB1; no TERTp mutations were detected., Conclusions: Clinical suspicion of melanoma is common in combined DPMs, but malignant progression is infrequent in tumours lacking high-grade atypia or proliferation. These findings are congruent with the consideration of these lesions as intermediate-grade tumours or melanocytomas., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Published
2024
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12. Flanagan's condensed protocol for neurodegenerative diseases. Implementation in a clinical autopsy setting with partial supervision of a neuropathologist.

Author

López A, López-Muñoz S, Caballero G, Castrejon N, Rojo L, Vidal-Robau N, Muñoz A, Ortiz E, Rodrigo M, García A, Cuatrecasas M, Ribalta T, and Aldecoa I

Abstract

The Condensed Protocol (CP) was originally developed for the evaluation of Alzheimer's Disease (AD) and other neurodegenerative diseases as a workable alternative to the complex and costly established autopsy guidelines. The study objective is to examine the degree of implementation of the CP in the pathology department of a third level university hospital in a period of 5 years. Clinical autopsies performed between 2016 and 2021 on patients aged 65 years or over and did not require a specific neuropathological examination were reviewed. Histological screening and staging of neurodegenerative diseases was performed using the original immunohistochemical stains. Out of 255 autopsies, 204 met the inclusion criteria and 190 could be reviewed. The CP was applied to 99 cases; histological signs of neurodegenerative disease were observed in 92. Sampling errors were detected in 59 cases. Immunohistochemical studies were performed in 68 cases. The diseases identified were: 31 cases of AD (12 low grade; 19 intermediate), 18 amyloid angiopathy, 15 primary age-related tauopathy, 6 argyrophilic grain disease, 3 progressive supranuclear palsy, 1 Lewy body disease (of 22 cases), and 2 limbic-predominant age TDP43 encephalopathy (of 5 cases). In 30 out of 83 cases, there was more severe vascular pathology in complete sections of frontal cortex and lentiform nucleus. The CP allows reliable detection and staging of AD and related neurodegenerative diseases in clinical autopsies. However, supervision by a neuropathologist seems necessary for a fully successful implementation of the CP in a clinical hospital setting., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Published
2024
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13. Clinicopathological evaluation of the programmed cell death 1 (PD1)/programmed cell death-ligand 1 (PD-L1) axis in post-transplant lymphoproliferative disorders: association with Epstein-Barr virus, PD-L1 copy number alterations, and outcome.

Author

Veloza L, Teixido C, Castrejon N, Climent F, Carrió A, Marginet M, Soldini D, González-Farré B, Ribera-Cortada I, Lopez-Guillermo A, González-Barca E, Sierra A, Herrera M, Gómez C, Garcia A, Balagué O, Campo E, and Martinez A

Subjects
Adult, Aged, Apoptosis, Epstein-Barr Virus Infections diagnosis, Epstein-Barr Virus Infections mortality, Epstein-Barr Virus Infections virology, Female, Humans, Immunohistochemistry, In Situ Hybridization, Fluorescence, Lymphoproliferative Disorders diagnosis, Lymphoproliferative Disorders mortality, Lymphoproliferative Disorders virology, Male, Middle Aged, Prognosis, B7-H1 Antigen metabolism, DNA Copy Number Variations, Epstein-Barr Virus Infections pathology, Herpesvirus 4, Human isolation & purification, Lymphoproliferative Disorders pathology, Programmed Cell Death 1 Receptor metabolism
Abstract

Aims: The clinical implications of the programmed cell death 1 (PD1)/programmed cell death-ligand 1 (PD-L1) axis in patients with post-transplant lymphoproliferative disorders are largely unknown, and its association with Epstein-Barr virus (EBV) status and PD-L1 copy number alterations (CNAs) has not been thoroughly studied., Methods and Results: PD1/PD-L1 expression was studied in 50 adult post-transplant lymphoproliferative disorders, and the correlations with PD-L1 CNAs, EBV, clinicopathological features and outcome were evaluated. Thirty-seven (74%) cases were classified as diffuse large B-cell lymphoma (DLBCL), nine (18%) cases were classified as polymorphic, and four (8%) cases were classified as classic Hodgkin lymphoma. Thirty-four cases were EBV-positive, with 29 of 34 (85%) having latency II or III, and 15 of 34 (44%) having viral replication. PD-L1 expression in tumour cells and tumour-associated macrophages was observed in 30 (60%) and 37 (74%) cases, respectively. PD1 positivity was seen in 16 (32%) cases. PD-L1 expression was associated with EBV with latency II or III (P = 0.001) and organ rejection (P = 0.04), and, in DLBCL, with non-germinal centre type DLBCL (P < 0.001). Cases with PD-L1-positive tumour cells showed a higher number of PD-L1 CNAs than PD-L1-negative cases (P = 0.001). Patients with EBV/latency III/replication and simultaneous PD-L1 expression showed the worst overall survival (P < 0.001)., Conclusions: The PD1/PD-L1 axis is deregulated in post-transplant lymphoproliferative disorders, with frequent PD-L1 expression and PD1 negativity. PD-L1 expression is associated with EBV latency II or III and PD-L1 CNAs, and probably reflects a proinflammatory tumour microenvironment. The combined analysis of EBV status and PD-L1 expression may help to identify deeply immunosuppressed patients who can benefit from immune reconstitution approaches., (© 2019 John Wiley & Sons Ltd.)

Published
2019
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14. Postmortem Interval and Diagnostic Performance of the Autopsy Methods.

Author

Hurtado JC, Quintó L, Castillo P, Carrilho C, Fernandes F, Jordao D, Lovane L, Navarro M, Casas I, Bene R, Nhampossa T, Santos Ritchie P, Bandeira S, Sambo C, Chicamba V, Mocumbi S, Jaze Z, Mabota F, Ismail MR, Lorenzoni C, Guisseve A, Rakislova N, Marimon L, Castrejon N, Sanz A, Cossa A, Mandomando I, Munguambe K, Maixenchs M, Muñoz-Almagro C, Macete E, Alonso P, Vila J, Bassat Q, Menéndez C, Martínez MJ, and Ordi J

Subjects
Adult, Bacteria metabolism, Child, Female, Humans, Infant, Newborn, Autopsy methods, Postmortem Changes
Abstract

Postmortem studies, including the complete diagnostic autopsy (CDA) and the minimally invasive autopsy (MIA), an innovative approach to post-mortem sampling and cause of death investigation, are commonly performed within 24 hours after death because the quality of the tissues deteriorates over time. This short timeframe may hamper the feasibility of the procedure. In this study, we compared the diagnostic performance of the two postmortem procedures when carried out earlier and later than 24 hours after death, as well as the impact of increasing postmortem intervals (PMIs) on the results of the microbiological tests in a series of 282 coupled MIA/CDA procedures performed at the Maputo Central Hospital in Mozambique between 2013 and 2015. 214 procedures were conducted within 24 hours of death (early autopsies), and 68 after 24 hours of death (late autopsies). No significant differences were observed in the number of non-conclusive diagnoses (2/214 [1%] vs. 1/68 [1%] p = 0.5645 for the CDA; 27/214 [13%] vs. 5/68 [7%] p = 0.2332 for the MIA). However, increasing PMIs were associated with a raise in the number of bacteria identified (rate: 1.014 per hour [95%CI: 1.002-1.026]; p = 0.0228). This increase was mainly due to rising numbers of bacteria of the Enterobacteriaceae family and Pseudomonas genus strains. Thus, performing MIA or CDA more than 24 hours after death can still render reliable diagnostic results, not only for non-infectious conditions but also for many infectious diseases, although, the contribution of Enterobacteriaceae and Pseudomonas spp. as etiological agents of infections leading to death may be overestimated.

Published
2018
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