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2. Feebly-interacting particles: FIPs 2022 Workshop Report

Author

C. Antel, M. Battaglieri, J. Beacham, C. Boehm, O. Buchmüller, F. Calore, P. Carenza, B. Chauhan, P. Cladè, P. Coloma, P. Crivelli, V. Dandoy, L. Darmé, B. Dey, F. F. Deppisch, A. De Roeck, M. Drewes, B. Echenard, V. V. Flambaum, P. Foldenauer, C. Gatti, M. Giannotti, A. Golutvin, M. C. Gonzalez-Garcia, S. Gori, E. Goudzovski, A. Granelli, H. Grote, S. Guellati-Khelifa, J. Hajer, P. Harris, C. Hearty, D. Heuchel, M. Hostert, S. Junius, F. Kahlhoefer, J. Klaric, F. Kling, P. Klose, J. Knolle, J. Kopp, O. Kwon, O. Lantwin, G. Lanfranchi, L. Li, A. Lindner, J. Lopez-Pavon, J. Marocco, J. W. Martin, S. Middleton, S. Milstead, I. Oceano, C. A. J. O’Hare, A. Paoloni, S. Pascoli, S. T. Petcov, M. Pospelov, R. Pöttgen, M. Raggi, G. Ripellino, I. B. Samsonov, S. Sandner, S. Söldner-Rembold, J. Shelton, N. Song, C. Sun, Y. V. Stadnik, J.-L. Tastet, N. Toro, N. Tran, N. Trevisani, S. Ulmer, S. Urrea, B. Velghe, B. Wallisch, Y. Y. Y. Wong, C. Zorbilmez, and K. Zurek

Subjects
Astrophysics, QB460-466, Nuclear and particle physics. Atomic energy. Radioactivity, QC770-798
Abstract

Abstract Particle physics today faces the challenge of explaining the mystery of dark matter, the origin of matter over anti-matter in the Universe, the origin of the neutrino masses, the apparent fine-tuning of the electro-weak scale, and many other aspects of fundamental physics. Perhaps the most striking frontier to emerge in the search for answers involves new physics at mass scales comparable to familiar matter, below the GeV-scale, or even radically below, down to sub-eV scales, and with very feeble interaction strength. New theoretical ideas to address dark matter and other fundamental questions predict such feebly interacting particles (FIPs) at these scales, and indeed, existing data provide numerous hints for such possibility. A vibrant experimental program to discover such physics is under way, guided by a systematic theoretical approach firmly grounded on the underlying principles of the Standard Model. This document represents the report of the FIPs 2022 workshop, held at CERN between the 17 and 21 October 2022 and aims to give an overview of these efforts, their motivations, and the decadal goals that animate the community involved in the search for FIPs.

Published
2023
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3. Updated and novel limits on double beta decay and dark matter-induced processes in platinum

Author

B. Broerman, M. Laubenstein, S. S. Nagorny, S. Nisi, N. Song, and A. C. Vincent

Subjects
Astrophysics, QB460-466, Nuclear and particle physics. Atomic energy. Radioactivity, QC770-798
Abstract

Abstract A 510 day long-term measurement of a 45.3 g platinum foil acting as the sample and high voltage contact in an ultra-low-background high purity germanium detector was performed at Laboratori Nazionali del Gran Sasso (Italy). The data was used for a detailed study of double beta decay modes in natural platinum isotopes. Limits are set in the range $${\mathcal {O}}(10^{14}{-} 10^{19})$$ O ( 10 14 - 10 19 ) years (90% C.L.) for several double beta decay transitions to excited states confirming, and partially extending existing limits. The highest sensitivity of the measurement, greater than $$10^{19}$$ 10 19 years, was achieved for the two neutrino and neutrinoless double beta decay modes of the isotope $$^{198}$$ 198 Pt. Additionally, novel limits for inelastic dark matter scattering on $$^{195}$$ 195 Pt are placed up to mass splittings of approximately 500 keV. We analyze several techniques to extend the sensitivity and propose a few approaches for future medium-scale experiments with platinum-group elements.

Published
2023
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4. Enhanced sequestration of molybdenum(VI) using composite constructed wetlands and responses of microbial communities

Author

B. Chen, F. J. Zhou, F. Yang, J. J. Lian, T. R. Ye, H. Y. Wu, L. M. Wang, N. Song, Y. Y. Liu, and A. Y. Hui

Subjects
adsorption mechanism, constructed wetlands, drinking water treatment residuals, molybdenum removal, response relation, Environmental technology. Sanitary engineering, TD1-1066
Abstract

The molybdenum (Mo) non-point source pollution in the mining area has an irreversible impact on the surrounding water and soil ecosystems. Herein, three integrated vertical subsurface flow constructed wetlands (CWs) were constructed to assess the effects of combination substrates and plant on the removal of Mo(VI). Results showed that CW1 with combination substrates and cattail exhibited a favorable removal performance for Mo(VI) at 80.90%. Moreover, most Mo(VI) retained in the CWs was retained in the substrate (58.13–88.04%), and the largest fraction of Mo(VI) retained was the water-soluble fraction on the surface of the combination substrates. Mo(VI) removal was also influenced by the microbial community composition in substrate, especially their co-occurrence networks. The species that showed significant positive correlation with Mo(VI) removal were Planctomycetes, Latescibacteria, Armatimonadetes, and Gemmatimonadetes. Moreover, CWs added plants showed that more co-occurrences interaction between taxa occurs, which means that the wetlands efficiently select recruitment of potential microbial consortia and change the co-occurrences to remove pollution in the substrate. These results could be useful in providing an ecology-based solution for the treatment of Mo(VI) in wastewater, especially in adjusting the microbial communities for Mo(VI) removal at the genetic level. HIGHLIGHTS Complex substrates coupled cattail enhanced Mo(VI) removal in constructed wetlands.; Adsorption was the main Mo(VI) removal mechanism by DWTRs and MCPP.; Mo(VI) removal was also influenced by microbial community composition.; Cattails changed the co-occurrences of microbes to remove pollution in substrates.;

Published
2022
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5. The influence of orbital moments in anomalous Hall effect in Co/Ni multilayers with perpendicular magnetic anisotropy

Author

N. Song, Y. X. Huang, K. Ren, J. X. Ding, T. Li, J. K. Zhang, J. L. Xie, Y. H. Xu, Z. H. Ding, J. S. Zhu, Z. Z. Wang, W. Liao, G. Li, and L. Wang

Subjects
Physics, QC1-999
Abstract

We focus on the anomalous Hall effects (AHEs) of Co/Ni multilayers with perpendicular magnetic anisotropy (PMA) by using Ta, Nb, and Cu as the buffer and top layer. An un-conventional AHE behavior was found in which the AH resistance exhibits two anti-symmetric peaks in the presence of a magnetic field. Moreover, Co/Ni multilayers with a Ta neighboring layer show reverse AH resistance compared to the Nb and Cu neighboring layers, except Ta bottom and Cu capping layers. The former can be explained by considering the influence of the external magnetic field on the interfacial spin orbit interaction due to spontaneous symmetry breaking at the ferromagnetic (FM)/FM layer interface. Furthermore, the reverse Co/Ni AHE with a Ta adjacent layer can be interpreted as the leakage spin current of proximity effects from Ta due to its larger spin–orbit coupling, and finally, taking the shunting action of the Cu layer into account, the Co/Ni AHE with Ta and Cu adjacent layers can also be explained. Our results provide a clear physics picture of the AHE in a two-dimensional nano-scaling FM/FM interface with PMA; in particular, this work shows that the non-magnetic adjacent layer with large spin–orbit coupling will play an important role in the understanding of AHE in two-dimensional FM multilayers.

Published
2022
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6. Ageing, hypertension and aortic valve stenosis – Understanding the series circuit using cardiac magnetic resonance and applanation tonometry

Author

S.L. Hungerford, A.I. Adji, N.K. Bart, L. Lin, N. Song, A. Jabbour, M.F. O'Rourke, C.S. Hayward, and D.W.M. Muller

Subjects
Ageing, Aortic valve stenosis, Applanation tonometry, Cardiac magnetic resonance, Hypertension, Valvulo-arterial impedance, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Background: Aortic stenosis (AS) is no longer considered to be a disease of fixed left ventricular (LV) afterload, but rather, functions as a series circuit, with important contributions from both the valve and vasculature. Patients with AS are typically elderly, with hypertension and a markedly remodelled aorta. The arterial component is sizeable, and yet, quantifying this to-date has been difficult to determine. We compared measurement of aortic pressure, flow and global LV load using a cardiac magnetic resonance (CMR)/applanation tonometry (AT) technique to uncouple ventriculo-arterial (VA) interactions. Methods: 20 healthy elderly patients and 20 with AS underwent a CMR/AT protocol. CMR provided LV volume and aortic flow simultaneously with AT pressure acquisition. Aortic pressure was derived by transformation of the AT waveform. Systemic vascular resistance (SVR) and global LV load were determined as the relationship of pressure to flow in the frequency domain. Values from both cohorts were compared. Results: AS patients were older (p ​

Published
2021
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7. Rankl expression predicts poor prognosis in gastric cancer patients: results from a retrospective and single-center analysis

Author

X. Zhang, Y. Song, N. Song, L. Zhang, Y. Wang, D. Li, Z. Wang, X. Qu, and Y. Liu

Subjects
RANKL, RANK, Gastric cancer, IHC, overall survival, Medicine (General), R5-920, Biology (General), QH301-705.5
Abstract

The receptor activator of nuclear factor κB ligand (RANKL)/RANK pathway plays an important role in the prognosis of several solid tumor types, but its role in gastric cancer prognosis has been poorly characterized. A total of 116 gastric cancer patients who underwent surgical resection were enrolled in this study. Expressions of RANKL and RANK in gastric cancer tissues were detected using immunohistochemical staining. Thirty-eight patients (33%) showed a high level of RANKL expression and 61 patients (53%) showed a high level of RANK expression. There was a positive correlation between expressions of RANKL and RANK (P=0.014, r=0.221). A high level of RANKL expression indicated shorter overall survival (OS) (P=0.008), and was associated with a higher pathological tumor/lymph node/metastasis (pTNM) stage (P=0.035), while no significant correlation was detected between RANK expression and clinicopathological parameters. RANKL also predicted poor prognosis in patients with high RANK expression (P=0.008) and Bormann's type III/IV (P=0.002). Furthermore, RANKL expression correlated with pTNM stage according to high RANK expression (P=0.009), while no significance was found in patients with low RANK expression (P=1.000). Together, our results revealed that high expression of RANKL could predict worse outcomes in gastric cancer especially combined with RANK detection, and thereby this pathway could be a useful prognostic indicator of gastric cancer.

Published
2018
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8. Exosomes promote cetuximab resistance via the PTEN/Akt pathway in colon cancer cells

Author

S. Zhang, Y. Zhang, J. Qu, X. Che, Y. Fan, K. Hou, T. Guo, G. Deng, N. Song, C. Li, X. Wan, X. Qu, and Y. Liu

Subjects
Cetuximab, Exosome, PTEN, Akt, Colon cancer, Medicine (General), R5-920, Biology (General), QH301-705.5
Abstract

Cetuximab is widely used in patients with metastatic colon cancer expressing wildtype KRAS. However, acquired drug resistance limits its clinical efficacy. Exosomes are nanosized vesicles secreted by various cell types. Tumor cell-derived exosomes participate in many biological processes, including tumor invasion, metastasis, and drug resistance. In this study, exosomes derived from cetuximab-resistant RKO colon cancer cells induced cetuximab resistance in cetuximab-sensitive Caco-2 cells. Meanwhile, exosomes from RKO and Caco-2 cells showed different levels of phosphatase and tensin homolog (PTEN) and phosphor-Akt. Furthermore, reduced PTEN and increased phosphorylated Akt levels were found in Caco-2 cells after exposure to RKO cell-derived exosomes. Moreover, an Akt inhibitor prevented RKO cell-derived exosome-induced drug resistance in Caco-2 cells. These findings provide novel evidence that exosomes derived from cetuximab-resistant cells could induce cetuximab resistance in cetuximab-sensitive cells, by downregulating PTEN and increasing phosphorylated Akt levels.

Published
2017
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9. Rogue Wave Solutions and Generalized Darboux Transformation for an Inhomogeneous Fifth-Order Nonlinear Schrödinger Equation

Author

N. Song, W. Zhang, P. Wang, and Y. K. Xue

Subjects
Mathematics, QA1-939
Abstract

The rogue wave solutions are discussed for an inhomogeneous fifth-order nonlinear Schrödinger equation, which describes the dynamics of a site-dependent Heisenberg ferromagnetic spin chain. Using the Darboux matrix, the generalized Darboux transformation is constructed and a recursive formula is derived. Based on the transformation, the first-order to the third-order rogue wave solutions are obtained. Then, the nonlinear dynamics of the first-order to the third-order rogue waves are studied on the basis of some free parameters. Several new structures of the rogue waves are found using numerical simulation. The conclusions will be a supportive tool to study the rogue waves better.

Published
2017
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10. Search for new physics in high-mass diphoton events from proton-proton collisions at s $$ \sqrt{\textrm{s}} $$ = 13 TeV

Author

The CMS collaboration, A. Hayrapetyan, A. Tumasyan, W. Adam, J. W. Andrejkovic, T. Bergauer, S. Chatterjee, K. Damanakis, M. Dragicevic, P. S. Hussain, M. Jeitler, N. Krammer, A. Li, D. Liko, I. Mikulec, J. Schieck, R. Schöfbeck, D. Schwarz, M. Sonawane, S. Templ, W. Waltenberger, C.-E. Wulz, M. R. Darwish, T. Janssen, T. Van Laer, P. Van Mechelen, N. Breugelmans, J. D’Hondt, S. Dansana, A. De Moor, M. Delcourt, F. Heyen, S. Lowette, I. Makarenko, D. Müller, S. Tavernier, M. Tytgat, G. P. Van Onsem, S. Van Putte, D. Vannerom, B. Bilin, B. Clerbaux, A. K. Das, G. De Lentdecker, H. Evard, L. Favart, P. Gianneios, J. Jaramillo, A. Khalilzadeh, F. A. Khan, K. Lee, M. Mahdavikhorrami, A. Malara, S. Paredes, M. A. Shahzad, L. Thomas, M. Vanden Bemden, C. Vander Velde, P. Vanlaer, M. De Coen, D. Dobur, G. Gokbulut, Y. Hong, J. Knolle, L. Lambrecht, D. Marckx, K. Mota Amarilo, A. Samalan, K. Skovpen, N. Van Den Bossche, J. van der Linden, L. Wezenbeek, A. Benecke, A. Bethani, G. Bruno, C. Caputo, J. De Favereau De Jeneret, C. Delaere, I. S. Donertas, A. Giammanco, A. O. Guzel, Sa. Jain, V. Lemaitre, J. Lidrych, P. Mastrapasqua, T. T. Tran, S. Wertz, G. A. Alves, M. Alves Gallo Pereira, E. Coelho, G. Correia Silva, C. Hensel, T. Menezes De Oliveira, A. Moraes, P. Rebello Teles, M. Soeiro, A. Vilela Pereira, W. L. Aldá Júnior, M. Barroso Ferreira Filho, H. Brandao Malbouisson, W. Carvalho, J. Chinellato, E. M. Da Costa, G. G. Da Silveira, D. De Jesus Damiao, S. Fonseca De Souza, R. Gomes De Souza, M. Macedo, J. Martins, C. Mora Herrera, L. Mundim, H. Nogima, J. P. Pinheiro, A. Santoro, A. Sznajder, M. Thiel, C. A. Bernardes, L. Calligaris, T. R. Fernandez Perez Tomei, E. M. Gregores, I. Maietto Silverio, P. G. Mercadante, S. F. Novaes, B. Orzari, Sandra S. Padula, A. Aleksandrov, G. Antchev, R. Hadjiiska, P. Iaydjiev, M. Misheva, M. Shopova, G. Sultanov, A. Dimitrov, L. Litov, B. Pavlov, P. Petkov, A. Petrov, E. Shumka, S. Keshri, S. Thakur, T. Cheng, T. Javaid, L. Yuan, Z. Hu, Z. Liang, J. Liu, K. Yi, G. M. Chen, H. S. Chen, M. Chen, F. Iemmi, C. H. Jiang, A. Kapoor, H. Liao, Z.-A. Liu, R. Sharma, J. N. Song, J. Tao, C. Wang, J. Wang, Z. Wang, H. Zhang, J. Zhao, A. Agapitos, Y. Ban, S. Deng, B. Guo, C. Jiang, A. Levin, C. Li, Q. Li, Y. Mao, S. Qian, S. J. Qian, X. Qin, X. Sun, D. Wang, H. Yang, L. Zhang, Y. Zhao, C. Zhou, S. Yang, Z. You, K. Jaffel, N. Lu, G. Bauer, B. Li, J. Zhang, X. Gao, Z. Lin, C. Lu, M. Xiao, C. Avila, D. A. Barbosa Trujillo, A. Cabrera, C. Florez, J. Fraga, J. A. Reyes Vega, F. Ramirez, C. Rendón, M. Rodriguez, A. A. Ruales Barbosa, J. D. Ruiz Alvarez, D. Giljanovic, N. Godinovic, D. Lelas, A. Sculac, M. Kovac, A. Petkovic, T. Sculac, P. Bargassa, V. Brigljevic, B. K. Chitroda, D. Ferencek, K. Jakovcic, S. Mishra, A. Starodumov, T. Susa, A. Attikis, K. Christoforou, A. Hadjiagapiou, C. Leonidou, J. Mousa, C. Nicolaou, L. Paizanos, F. Ptochos, P. A. Razis, H. Rykaczewski, H. Saka, A. Stepennov, M. Finger, A. Kveton, E. Carrera Jarrin, Y. Assran, B. El-mahdy, S. Elgammal, M. A. Mahmoud, Y. Mohammed, K. Ehataht, M. Kadastik, T. Lange, S. Nandan, C. Nielsen, J. Pata, M. Raidal, L. Tani, C. Veelken, H. Kirschenmann, K. Osterberg, M. Voutilainen, S. Bharthuar, N. Bin Norjoharuddeen, E. Brücken, F. Garcia, P. Inkaew, K. T. S. Kallonen, T. Lampén, K. Lassila-Perini, S. Lehti, T. Lindén, L. Martikainen, M. Myllymäki, M. m. Rantanen, H. Siikonen, J. Tuominiemi, P. Luukka, H. Petrow, M. Besancon, F. Couderc, M. Dejardin, D. Denegri, J. L. Faure, F. Ferri, S. Ganjour, P. Gras, G. Hamel de Monchenault, M. Kumar, V. Lohezic, J. Malcles, F. Orlandi, L. Portales, A. Rosowsky, M. Ö. Sahin, A. Savoy-Navarro, P. Simkina, M. Titov, M. Tornago, F. Beaudette, G. Boldrini, P. Busson, A. Cappati, C. Charlot, M. Chiusi, F. Damas, O. Davignon, A. De Wit, I. T. Ehle, B. A. Fontana Santos Alves, S. Ghosh, A. Gilbert, R. Granier de Cassagnac, A. Hakimi, B. Harikrishnan, L. Kalipoliti, G. Liu, M. Nguyen, C. Ochando, R. Salerno, J. B. Sauvan, Y. Sirois, L. Urda Gómez, E. Vernazza, A. Zabi, A. Zghiche, J.-L. Agram, J. Andrea, D. Apparu, D. Bloch, J.-M. Brom, E. C. Chabert, C. Collard, S. Falke, U. Goerlach, R. Haeberle, A.-C. Le Bihan, M. Meena, O. Poncet, G. Saha, M. A. Sessini, P. Van Hove, P. Vaucelle, A. Di Florio, D. Amram, S. Beauceron, B. Blancon, G. Boudoul, N. Chanon, D. Contardo, P. Depasse, C. Dozen, H. El Mamouni, J. Fay, S. Gascon, M. Gouzevitch, C. Greenberg, G. Grenier, B. Ille, E. Jourd‘huy, I. B. Laktineh, M. Lethuillier, L. Mirabito, S. Perries, A. Purohit, M. Vander Donckt, P. Verdier, J. Xiao, I. Lomidze, T. Toriashvili, Z. Tsamalaidze, V. Botta, S. Consuegra Rodríguez, L. Feld, K. Klein, M. Lipinski, D. Meuser, A. Pauls, D. Pérez Adán, N. Röwert, M. Teroerde, S. Diekmann, A. Dodonova, N. Eich, D. Eliseev, F. Engelke, J. Erdmann, M. Erdmann, P. Fackeldey, B. Fischer, T. Hebbeker, K. Hoepfner, F. Ivone, A. Jung, M. y. Lee, F. Mausolf, M. Merschmeyer, A. Meyer, S. Mukherjee, D. Noll, F. Nowotny, A. Pozdnyakov, Y. Rath, W. Redjeb, F. Rehm, H. Reithler, V. Sarkisovi, A. Schmidt, A. Sharma, J. L. Spah, A. Stein, F. Torres Da Silva De Araujo, S. Wiedenbeck, S. Zaleski, C. Dziwok, G. Flügge, T. Kress, A. Nowack, O. Pooth, A. Stahl, T. Ziemons, A. Zotz, H. Aarup Petersen, M. Aldaya Martin, J. Alimena, S. Amoroso, Y. An, J. Bach, S. Baxter, M. Bayatmakou, H. Becerril Gonzalez, O. Behnke, A. Belvedere, S. Bhattacharya, F. Blekman, K. Borras, A. Campbell, A. Cardini, C. Cheng, F. Colombina, M. De Silva, G. Eckerlin, D. Eckstein, L. I. Estevez Banos, O. Filatov, E. Gallo, A. Geiser, V. Guglielmi, M. Guthoff, A. Hinzmann, L. Jeppe, B. Kaech, M. Kasemann, C. Kleinwort, R. Kogler, M. Komm, D. Krücker, W. Lange, D. Leyva Pernia, K. Lipka, W. Lohmann, F. Lorkowski, R. Mankel, I.-A. Melzer-Pellmann, M. Mendizabal Morentin, A. B. Meyer, G. Milella, K. Moral Figueroa, A. Mussgiller, L. P. Nair, J. Niedziela, A. Nürnberg, Y. Otarid, J. Park, E. Ranken, A. Raspereza, D. Rastorguev, J. Rübenach, L. Rygaard, A. Saggio, M. Scham, S. Schnake, P. Schütze, C. Schwanenberger, D. Selivanova, K. Sharko, M. Shchedrolosiev, D. Stafford, F. Vazzoler, A. Ventura Barroso, R. Walsh, Q. Wang, Y. Wen, K. Wichmann, L. Wiens, C. Wissing, Y. Yang, A. Zimermmane Castro Santos, A. Albrecht, S. Albrecht, M. Antonello, S. Bein, L. Benato, S. Bollweg, M. Bonanomi, P. Connor, K. El Morabit, Y. Fischer, E. Garutti, A. Grohsjean, J. Haller, H. R. Jabusch, G. Kasieczka, P. Keicher, R. Klanner, W. Korcari, T. Kramer, C. c. Kuo, V. Kutzner, F. Labe, J. Lange, A. Lobanov, C. Matthies, L. Moureaux, M. Mrowietz, A. Nigamova, Y. Nissan, A. Paasch, K. J. Pena Rodriguez, T. Quadfasel, B. Raciti, M. Rieger, D. Savoiu, J. Schindler, P. Schleper, M. Schröder, J. Schwandt, M. Sommerhalder, H. Stadie, G. Steinbrück, A. Tews, M. Wolf, S. Brommer, M. Burkart, E. Butz, T. Chwalek, A. Dierlamm, A. Droll, N. Faltermann, M. Giffels, A. Gottmann, F. Hartmann, R. Hofsaess, M. Horzela, U. Husemann, J. Kieseler, M. Klute, R. Koppenhöfer, J. M. Lawhorn, M. Link, A. Lintuluoto, B. Maier, S. Maier, S. Mitra, M. Mormile, Th. Müller, M. Neukum, M. Oh, E. Pfeffer, M. Presilla, G. Quast, K. Rabbertz, B. Regnery, N. Shadskiy, I. Shvetsov, H. J. Simonis, L. Sowa, L. Stockmeier, K. Tauqeer, M. Toms, N. Trevisani, R. F. Von Cube, M. Wassmer, S. Wieland, F. Wittig, R. Wolf, X. Zuo, G. Anagnostou, G. Daskalakis, A. Kyriakis, A. Papadopoulos, A. Stakia, P. Kontaxakis, G. Melachroinos, Z. Painesis, I. Papavergou, I. Paraskevas, N. Saoulidou, K. Theofilatos, E. Tziaferi, K. Vellidis, I. Zisopoulos, G. Bakas, T. Chatzistavrou, G. Karapostoli, K. Kousouris, I. Papakrivopoulos, E. Siamarkou, G. Tsipolitis, A. Zacharopoulou, K. Adamidis, I. Bestintzanos, I. Evangelou, C. Foudas, C. Kamtsikis, P. Katsoulis, P. Kokkas, P. G. Kosmoglou Kioseoglou, N. Manthos, I. Papadopoulos, J. Strologas, C. Hajdu, D. Horvath, K. Márton, A. J. Rádl, F. Sikler, V. Veszpremi, M. Csanád, K. Farkas, A. Fehérkuti, M. M. A. Gadallah, Á. Kadlecsik, P. Major, G. Pásztor, G. I. Veres, B. Ujvari, G. Zilizi, G. Bencze, S. Czellar, J. Molnar, Z. Szillasi, T. Novak, J. Babbar, S. Bansal, S. B. Beri, V. Bhatnagar, G. Chaudhary, S. Chauhan, N. Dhingra, A. Kaur, H. Kaur, M. Kaur, S. Kumar, K. Sandeep, T. Sheokand, J. B. Singh, A. Singla, A. Ahmed, A. Bhardwaj, A. Chhetri, B. C. Choudhary, A. Kumar, M. Naimuddin, K. Ranjan, M. K. Saini, S. Saumya, S. Baradia, S. Barman, S. Das Gupta, S. Dutta, S. Sarkar, M. M. Ameen, P. K. Behera, S. C. Behera, G. Dash, P. Jana, P. Kalbhor, S. Kamble, J. R. Komaragiri, D. Kumar, P. R. Pujahari, N. R. Saha, A. K. Sikdar, R. K. Singh, P. Verma, S. Verma, A. Vijay, S. Dugad, G. B. Mohanty, B. Parida, M. Shelake, P. Suryadevara, A. Bala, S. Banerjee, R. M. Chatterjee, M. Guchait, Sh. Jain, A. Jaiswal, G. Majumder, K. Mazumdar, S. Parolia, A. Thachayath, S. Bahinipati, C. Kar, D. Maity, P. Mal, T. Mishra, V. K. Muraleedharan Nair Bindhu, K. Naskar, A. Nayak, S. 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Latorre, J. Mao, H. B. Newman, G. Reales Gutiérrez, M. Spiropulu, J. R. Vlimant, S. Xie, R. Y. Zhu, J. Alison, S. An, P. Bryant, M. Cremonesi, V. Dutta, T. Ferguson, T. A. Gómez Espinosa, A. Harilal, A. Kallil Tharayil, C. Liu, T. Mudholkar, S. Murthy, P. Palit, K. Park, M. Paulini, A. Roberts, A. Sanchez, W. Terrill, J. P. Cumalat, W. T. Ford, A. Hart, A. Hassani, G. Karathanasis, N. Manganelli, A. Perloff, C. Savard, N. Schonbeck, K. Stenson, K. A. Ulmer, S. R. Wagner, N. Zipper, D. Zuolo, J. Alexander, S. Bright-Thonney, X. Chen, D. J. Cranshaw, J. Fan, X. Fan, S. Hogan, P. Kotamnives, J. Monroy, M. Oshiro, J. R. Patterson, M. Reid, A. Ryd, J. Thom, P. Wittich, R. Zou, M. Albrow, M. Alyari, O. Amram, G. Apollinari, A. Apresyan, L. A. T. Bauerdick, D. Berry, J. Berryhill, P. C. Bhat, K. Burkett, J. N. Butler, A. Canepa, G. B. Cerati, H. W. K. Cheung, F. Chlebana, G. Cummings, J. Dickinson, I. Dutta, V. D. Elvira, Y. Feng, J. Freeman, A. Gandrakota, Z. Gecse, L. Gray, D. Green, A. Grummer, S. Grünendahl, D. Guerrero, O. Gutsche, R. M. Harris, R. Heller, T. C. Herwig, J. Hirschauer, B. Jayatilaka, S. Jindariani, M. Johnson, U. Joshi, T. Klijnsma, B. Klima, K. H. M. Kwok, S. Lammel, D. Lincoln, R. Lipton, T. Liu, C. Madrid, K. Maeshima, C. Mantilla, D. Mason, P. McBride, P. Merkel, S. Mrenna, S. Nahn, J. Ngadiuba, D. Noonan, S. Norberg, V. Papadimitriou, N. Pastika, K. Pedro, C. Pena, F. Ravera, A. Reinsvold Hall, L. Ristori, M. Safdari, E. Sexton-Kennedy, N. Smith, A. Soha, L. Spiegel, S. Stoynev, J. Strait, L. Taylor, S. Tkaczyk, N. V. Tran, L. Uplegger, E. W. Vaandering, I. Zoi, C. Aruta, P. Avery, D. Bourilkov, P. Chang, V. Cherepanov, R. D. Field, E. Koenig, M. Kolosova, J. Konigsberg, A. Korytov, K. Matchev, N. Menendez, G. Mitselmakher, K. Mohrman, A. Muthirakalayil Madhu, N. Rawal, S. Rosenzweig, Y. Takahashi, T. Adams, A. Al Kadhim, A. Askew, S. Bower, R. Habibullah, V. Hagopian, R. Hashmi, R. S. Kim, T. Kolberg, G. Martinez, H. Prosper, P. R. Prova, M. Wulansatiti, R. Yohay, B. Alsufyani, M. M. Baarmand, S. Butalla, S. Das, T. Elkafrawy, M. Hohlmann, M. Rahmani, E. Yanes, M. R. Adams, A. Baty, C. Bennett, R. Cavanaugh, R. Escobar Franco, O. Evdokimov, C. E. Gerber, M. Hawksworth, A. Hingrajiya, D. J. Hofman, J. h. Lee, D. S. Lemos, A. H. Merrit, C. Mills, S. Nanda, G. Oh, B. Ozek, D. Pilipovic, R. Pradhan, E. Prifti, T. Roy, S. Rudrabhatla, M. B. Tonjes, N. Varelas, M. A. Wadud, Z. Ye, M. Alhusseini, D. Blend, K. Dilsiz, L. Emediato, G. Karaman, O. K. Köseyan, J.-P. Merlo, A. Mestvirishvili, O. Neogi, H. Ogul, Y. Onel, A. Penzo, C. Snyder, E. Tiras, B. Blumenfeld, L. Corcodilos, J. Davis, A. V. Gritsan, L. Kang, S. Kyriacou, P. Maksimovic, M. Roguljic, J. Roskes, S. Sekhar, M. Swartz, A. Abreu, L. F. Alcerro Alcerro, J. Anguiano, S. Arteaga Escatel, P. Baringer, A. Bean, Z. Flowers, D. Grove, J. King, G. Krintiras, M. Lazarovits, C. Le Mahieu, J. Marquez, M. Murray, M. Nickel, M. Pitt, S. Popescu, C. Rogan, C. Royon, R. Salvatico, S. Sanders, C. Smith, G. Wilson, B. Allmond, R. Gujju Gurunadha, A. Ivanov, K. Kaadze, Y. Maravin, J. Natoli, D. Roy, G. Sorrentino, A. Baden, A. Belloni, J. Bistany-riebman, Y. M. Chen, S. C. Eno, N. J. Hadley, S. Jabeen, R. G. Kellogg, T. Koeth, B. Kronheim, Y. Lai, S. Lascio, A. C. Mignerey, S. Nabili, C. Palmer, C. Papageorgakis, M. M. Paranjpe, L. Wang, J. Bendavid, I. A. Cali, P. c. Chou, M. D’Alfonso, J. Eysermans, C. Freer, G. Gomez-Ceballos, M. Goncharov, G. Grosso, P. Harris, D. Hoang, D. Kovalskyi, J. Krupa, L. Lavezzo, Y.-J. Lee, K. Long, C. Mcginn, A. Novak, C. Paus, C. Roland, G. Roland, S. Rothman, G. S. F. Stephans, B. Wyslouch, T. J. Yang, B. Crossman, B. M. Joshi, C. Kapsiak, M. Krohn, D. Mahon, J. Mans, B. Marzocchi, M. Revering, R. Rusack, R. Saradhy, N. Strobbe, K. Bloom, D. R. Claes, G. Haza, J. Hossain, C. Joo, I. Kravchenko, J. E. Siado, W. Tabb, A. Vagnerini, A. Wightman, F. Yan, D. Yu, H. Bandyopadhyay, L. Hay, H. w. Hsia, I. Iashvili, A. Kalogeropoulos, A. Kharchilava, M. Morris, D. Nguyen, S. Rappoccio, H. Rejeb Sfar, A. Williams, P. Young, G. Alverson, E. Barberis, J. Bonilla, J. Dervan, Y. Haddad, Y. Han, A. Krishna, J. Li, M. Lu, G. Madigan, R. Mccarthy, D. M. Morse, V. Nguyen, T. Orimoto, A. Parker, L. Skinnari, D. Wood, J. Bueghly, S. Dittmer, K. A. Hahn, Y. Liu, Y. Miao, D. G. Monk, M. H. Schmitt, A. Taliercio, M. Velasco, G. Agarwal, R. Band, R. Bucci, S. Castells, A. Das, R. Goldouzian, M. Hildreth, K. W. Ho, K. Hurtado Anampa, T. Ivanov, C. Jessop, K. Lannon, J. Lawrence, N. Loukas, L. Lutton, J. Mariano, N. Marinelli, I. Mcalister, T. McCauley, C. Mcgrady, C. Moore, Y. Musienko, H. Nelson, M. Osherson, A. Piccinelli, R. Ruchti, A. Townsend, Y. Wan, M. Wayne, H. Yockey, M. Zarucki, L. Zygala, A. Basnet, B. Bylsma, M. Carrigan, L. S. Durkin, C. Hill, M. Joyce, M. Nunez Ornelas, K. Wei, B. L. Winer, B. R. Yates, H. Bouchamaoui, P. Das, G. Dezoort, P. Elmer, A. Frankenthal, B. Greenberg, N. Haubrich, K. Kennedy, G. Kopp, S. Kwan, D. Lange, A. Loeliger, D. Marlow, I. Ojalvo, J. Olsen, A. Shevelev, D. Stickland, C. Tully, S. Malik, A. S. Bakshi, S. Chandra, R. Chawla, A. Gu, L. Gutay, M. Jones, A. W. Jung, A. M. Koshy, M. Liu, G. Negro, N. Neumeister, G. Paspalaki, S. Piperov, V. Scheurer, J. F. Schulte, M. Stojanovic, J. Thieman, A. K. Virdi, F. Wang, W. Xie, J. Dolen, N. Parashar, A. Pathak, D. Acosta, T. Carnahan, K. M. Ecklund, P. J. Fernández Manteca, S. Freed, P. Gardner, F. J. M. Geurts, W. Li, J. Lin, O. Miguel Colin, B. P. Padley, R. Redjimi, J. Rotter, E. Yigitbasi, Y. Zhang, A. Bodek, P. de Barbaro, R. Demina, J. L. Dulemba, A. Garcia-Bellido, O. Hindrichs, A. Khukhunaishvili, N. Parmar, P. Parygin, E. Popova, R. Taus, B. Chiarito, J. P. Chou, S. V. Clark, D. Gadkari, Y. Gershtein, E. Halkiadakis, M. Heindl, C. Houghton, D. Jaroslawski, S. Konstantinou, I. Laflotte, A. Lath, R. Montalvo, K. Nash, J. Reichert, H. Routray, P. Saha, S. Salur, S. Schnetzer, S. Somalwar, R. Stone, S. A. Thayil, S. Thomas, J. Vora, H. Wang, D. Ally, A. G. Delannoy, S. Fiorendi, S. Higginbotham, T. Holmes, A. R. Kanuganti, N. Karunarathna, L. Lee, E. Nibigira, S. Spanier, D. Aebi, M. Ahmad, T. Akhter, O. Bouhali, R. Eusebi, J. Gilmore, T. Huang, T. Kamon, S. Luo, R. Mueller, D. Overton, D. Rathjens, A. Safonov, N. Akchurin, J. Damgov, N. Gogate, V. Hegde, A. Hussain, Y. Kazhykarim, K. Lamichhane, A. Mankel, T. Peltola, I. Volobouev, E. Appelt, Y. Chen, S. Greene, A. Gurrola, W. Johns, R. Kunnawalkam Elayavalli, A. Melo, F. Romeo, P. Sheldon, S. Tuo, J. Velkovska, J. Viinikainen, B. Cardwell, B. Cox, J. Hakala, R. Hirosky, A. Ledovskoy, C. Neu, P. E. Karchin, A. Aravind, K. Black, T. Bose, S. Dasu, I. De Bruyn, P. Everaerts, C. Galloni, H. He, M. Herndon, A. Herve, C. K. Koraka, A. Lanaro, R. Loveless, J. Madhusudanan Sreekala, A. Mallampalli, A. Mohammadi, G. Parida, L. Pétré, D. Pinna, A. Savin, V. Shang, W. H. Smith, D. Teague, H. F. Tsoi, W. Vetens, A. Warden, S. Afanasiev, V. Alexakhin, V. Andreev, Yu. Andreev, T. Aushev, M. Azarkin, A. Babaev, V. Blinov, E. Boos, V. Borshch, D. Budkouski, V. Bunichev, V. Chekhovsky, R. Chistov, M. Danilov, A. Dermenev, T. Dimova, D. Druzhkin, M. Dubinin, L. Dudko, A. Ershov, G. Gavrilov, V. Gavrilov, S. Gninenko, V. Golovtcov, N. Golubev, I. Golutvin, I. Gorbunov, A. Gribushin, Y. Ivanov, V. Kachanov, V. Karjavine, A. Karneyeu, V. Kim, M. Kirakosyan, D. Kirpichnikov, M. Kirsanov, V. Klyukhin, O. Kodolova, D. Konstantinov, V. Korenkov, A. Kozyrev, N. Krasnikov, A. Lanev, P. Levchenko, N. Lychkovskaya, V. Makarenko, A. Malakhov, V. Matveev, V. Murzin, A. Nikitenko, S. Obraztsov, V. Oreshkin, V. Palichik, V. Perelygin, M. Perfilov, S. Polikarpov, V. Popov, O. Radchenko, M. Savina, V. Savrin, V. Shalaev, S. Shmatov, S. Shulha, Y. Skovpen, S. Slabospitskii, V. Smirnov, D. Sosnov, V. Sulimov, A. Terkulov, O. Teryaev, I. Tlisova, A. Toropin, L. Uvarov, A. Uzunian, A. Vorobyev, G. Vorotnikov, N. Voytishin, B. S. Yuldashev, A. Zarubin, I. Zhizhin, and A. Zhokin

Subjects
Beyond Standard Model, Hadron-Hadron Scattering, Photon Production, Nuclear and particle physics. Atomic energy. Radioactivity, QC770-798
Abstract

Abstract Results are presented from a search for new physics in high-mass diphoton events from proton-proton collisions at s $$ \sqrt{s} $$ = 13 TeV. The data set was collected in 2016–2018 with the CMS detector at the LHC and corresponds to an integrated luminosity of 138 fb −1. Events with a diphoton invariant mass greater than 500 GeV are considered. Two different techniques are used to predict the standard model backgrounds: parametric fits to the smoothly-falling background and a first-principles calculation of the standard model diphoton spectrum at next-to-next-to-leading order in perturbative quantum chromodynamics calculations. The first technique is sensitive to resonant excesses while the second technique can identify broad differences in the invariant mass shape. The data are used to constrain the production of heavy Higgs bosons, Randall-Sundrum gravitons, the large extra dimensions model of Arkani-Hamed, Dimopoulos, and Dvali (ADD), and the continuum clockwork mechanism. No statistically significant excess is observed. The present results are the strongest limits to date on ADD extra dimensions and RS gravitons with a coupling parameter greater than 0.1.

Published
2024
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11. Construction of transgenic swine with induced expression of Cre recombinase

Author

L. Chen, L. Li, D. Pang, Z. Li, T. Wang, M. Zhang, N. Song, S. Yan, L.X. Lai, and H. Ouyang

Subjects
Cre recombinase, somatic cell nuclear transfer (SCNT), pig, Animal culture, SF1-1100
Abstract

Miniature pigs have been recognized as valuable experimental animals in medical research. However, porcine models related to gene knockout of human diseases are not widely available. The objective of this study was to establish Mx1-Cre pigs using somatic cell nuclear transfer. In this study, we created transgenic pigs using somatic cell nuclear transfer (SCNT). Transfer of 210, 230, 250 and 215 zygotes to four surrogates produced 10 piglets. The Cre recombinase expression in transgenic pigs was studied using reverse transcriptase (RT)-PCR and immunohistochemistry. Mx1-Cre swine were shown to harbor the Cre gene in their genomic DNA using the PCR. In conclusion, Mx1-Cre transgenic piglets were successfully produced by SCNT. These transgenic swine, in conjunction with inducible systems for controlling Cre expression and function, are likely to have a profound impact on the study of human diseases.

Published
2010
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14. Preclinical PET Imaging of Granzyme B Shows Promotion of Immunological Response Following Combination Paclitaxel and Immune Checkpoint Inhibition in Triple Negative Breast Cancer

Author

Tiara S. Napier, Chanelle L. Hunter, Patrick N. Song, Benjamin M. Larimer, and Anna G. Sorace

Subjects
PET, GZP-PET, tumor microenvironment, immunotherapy, anti-PD-1, anti-CTLA4, Pharmacy and materia medica, RS1-441
Abstract

Advancements in monitoring and predicting of patient-specific response of triple negative breast cancer (TNBC) to immunotherapy (IMT) with and without chemotherapy are needed. Using granzyme B-specific positron emission tomography (GZP-PET) imaging, we aimed to monitor changes in effector cell activation in response to IMT with chemotherapy in TNBC. TNBC mouse models received the paclitaxel (PTX) ± immune checkpoint inhibitors anti-programmed death 1 (anti-PD1) and anti-cytotoxic T-lymphocyte 4 (anti-CTLA4). GZP-PET imaging was performed on treatment days 0, 3, and 6. Mean standard uptake value (SUVmean), effector cell fractions, and SUV histograms were compared. Mice were sacrificed at early imaging timepoints for cytokine and histological analyses. GZP-PET imaging data revealed differences prior to tumor volume changes. By day six, responders had SUVmean ≥ 2.2-fold higher (p < 0.0037) and effector cell fractions ≥ 1.9-fold higher (p = 0.03) compared to non-responders. IMT/PTX resulted in a significantly different SUV distribution compared to control, indicating broader distribution of activated intratumoral T-cells. IMT/PTX resulted in significantly more necrotic tumor tissue and increased levels of IL-2, 4, and 12 compared to control. Results implicate immunogenic cell death through upregulation of key Th1/Th2 cytokines by IMT/PTX. Noninvasive PET imaging can provide data on the TNBC tumor microenvironment, specifically intratumoral effector cell activation, predicting response to IMT plus chemotherapy.

Published
2022
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16. Mass Measurement of Upper fp -Shell N=Z−2 and N=Z−1 Nuclei and the Importance of Three-Nucleon Force along the N=Z Line

Author

M. Wang, Y. H. Zhang, X. Zhou, X. H. Zhou, H. S. Xu, M. L. Liu, J. G. Li, Y. F. Niu, W. J. Huang, Q. Yuan, S. Zhang, F. R. Xu, Yu. A. Litvinov, K. Blaum, Z. Meisel, R. F. Casten, R. B. Cakirli, R. J. Chen, H. Y. Deng, C. Y. Fu, W. W. Ge, H. F. Li, T. Liao, S. A. Litvinov, P. Shuai, J. Y. Shi, Y. N. Song, M. Z. Sun, Q. Wang, Y. M. Xing, X. Xu, X. L. Yan, J. C. Yang, Y. J. Yuan, Q. Zeng, and M. Zhang

Subjects
General Physics and Astronomy
Published
2023
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17. Mass measurements show slowdown of rapid proton capture process at waiting-point nucleus 64Ge

Author

X. Zhou, M. Wang, Y. H. Zhang, Yu. A. Litvinov, Z. Meisel, K. Blaum, X. H. Zhou, S. Q. Hou, K. A. Li, H. S. Xu, R. J. Chen, H. Y. Deng, C. Y. Fu, W. W. Ge, J. J. He, W. J. Huang, H. Y. Jiao, H. F. Li, J. G. Li, T. Liao, S. A. Litvinov, M. L. Liu, Y. F. Niu, P. Shuai, J. Y. Shi, Y. N. Song, M. Z. Sun, Q. Wang, Y. M. Xing, X. Xu, F. R. Xu, X. L. Yan, J. C. Yang, Y. Yu, Q. Yuan, Y. J. Yuan, Q. Zeng, M. Zhang, and S. Zhang

Subjects
General Physics and Astronomy, Präzisionsexperimente - Abteilung Blaum
Abstract

X-ray bursts are among the brightest stellar objects frequently observed in the sky by space-based telescopes. A type-I X-ray burst is understood as a violent thermonuclear explosion on the surface of a neutron star, accreting matter from a companion star in a binary system. The bursts are powered by a nuclear reaction sequence known as the rapid proton capture process (rp process), which involves hundreds of exotic neutron-deficient nuclides. At so-called waiting-point nuclides, the process stalls until a slower β+ decay enables a bypass. One of the handful of rp process waiting-point nuclides is 64Ge, which plays a decisive role in matter flow and therefore the produced X-ray flux. Here we report precision measurements of the masses of 63Ge, 64,65As and 66,67Se—the relevant nuclear masses around the waiting-point 64Ge—and use them as inputs for X-ray burst model calculations. We obtain the X-ray burst light curve to constrain the neutron-star compactness, and suggest that the distance to the X-ray burster GS 1826–24 needs to be increased by about 6.5% to match astronomical observations. The nucleosynthesis results affect the thermal structure of accreting neutron stars, which will subsequently modify the calculations of associated observables.

Published
2023
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20. Data from Quantitative Longitudinal Imaging Reveals that Inhibiting Hedgehog Activity Alleviates the Hypoxic Tumor Landscape

Author

Lalita A. Shevde, Rajeev S. Samant, Anna G. Sorace, Heba A. Alsheikh, Patrick N. Song, Sarah C. Kammerud, Dominique C. Hinshaw, Shamik Das, and Tshering D. Lama-Sherpa

Abstract

Metastases account for the majority of mortalities related to breast cancer. The onset and sustained presence of hypoxia strongly correlates with increased incidence of metastasis and unfavorable prognosis in patients with breast cancer. The Hedgehog (Hh) signaling pathway is dysregulated in breast cancer, and its abnormal activity enables tumor progression and metastasis. In addition to programming tumor cell behavior, Hh activity enables tumor cells to craft a metastasis-conducive microenvironment. Hypoxia is a prominent feature of growing tumors that impacts multiple signaling circuits that converge upon malignant progression. We investigated the role of Hh activity in crafting a hypoxic environment of breast cancer. We used radioactive tracer [18F]-fluoromisonidazole (FMISO) positron emission tomography (PET) to image tumor hypoxia. We show that tumors competent for Hh activity are able to establish a hypoxic milieu; pharmacologic inhibition of Hh signaling in a syngeneic mammary tumor model mitigates tumor hypoxia. Furthermore, in hypoxia, Hh activity is robustly activated in tumor cells and institutes increased HIF signaling in a VHL-dependent manner. The findings establish a novel perspective on Hh activity in crafting a hypoxic tumor landscape and molecularly navigating the tumor cells to adapt to hypoxic conditions.Implications: Importantly, we present a translational strategy of utilizing longitudinal hypoxia imaging to measure the efficacy of vismodegib in a preclinical model of triple-negative breast cancer.

Published
2023
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21. Supplementary Figure from Quantitative Longitudinal Imaging Reveals that Inhibiting Hedgehog Activity Alleviates the Hypoxic Tumor Landscape

Author

Lalita A. Shevde, Rajeev S. Samant, Anna G. Sorace, Heba A. Alsheikh, Patrick N. Song, Sarah C. Kammerud, Dominique C. Hinshaw, Shamik Das, and Tshering D. Lama-Sherpa

Abstract

Supplementary Figure from Quantitative Longitudinal Imaging Reveals that Inhibiting Hedgehog Activity Alleviates the Hypoxic Tumor Landscape

Published
2023
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22. Supplementary Data from Quantitative Longitudinal Imaging Reveals that Inhibiting Hedgehog Activity Alleviates the Hypoxic Tumor Landscape

Author

Lalita A. Shevde, Rajeev S. Samant, Anna G. Sorace, Heba A. Alsheikh, Patrick N. Song, Sarah C. Kammerud, Dominique C. Hinshaw, Shamik Das, and Tshering D. Lama-Sherpa

Abstract

Supplementary Data from Quantitative Longitudinal Imaging Reveals that Inhibiting Hedgehog Activity Alleviates the Hypoxic Tumor Landscape

Published
2023
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23. Localized Waves for the Coupled Mixed Derivative Nonlinear Schrödinger Equation in a Birefringent Optical Fiber

Author

N. Song, Y. X. Lei, Y. F. Zhang, and W. Zhang

Subjects
Nonlinear Sciences::Exactly Solvable and Integrable Systems, Statistical and Nonlinear Physics, Mathematical Physics
Abstract

In this paper, the higher-order localized waves for the coupled mixed derivative nonlinear Schrödinger equation are investigated using generalized Darboux transformation. On the basis of seed solutions and a Lax pair, the first- and second-order localized wave solutions are derived from the Nth-order iteration formulas of generalized Darboux transformation. Then, the dynamics of the localized waves are analyzed and displayed via numerical simulation. It is found that the second-order rouge wave split into three first-order rogue waves due to the influence of the separation function. In addition, a series of novel dynamic evolution plots exhibit that rogue waves coexist with dark-bright solitons and breathers.

Published
2022
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26. Data from 18F-FMISO PET Imaging Identifies Hypoxia and Immunosuppressive Tumor Microenvironments and Guides Targeted Evofosfamide Therapy in Tumors Refractory to PD-1 and CTLA-4 Inhibition

Author

Benjamin M. Larimer, Anna G. Sorace, Eddy S. Yang, Jianbo Wang, Yufeng Li, Deborah Della Manna, Allyson Angermeier, Patrick N. Song, and Kirsten M. Reeves

Abstract

Purpose:Hypoxia is a common characteristic of many tumor microenvironments, and it has been shown to promote suppression of antitumor immunity. Despite strong biological rationale, longitudinal correlation of hypoxia and response to immunotherapy has not been investigated.Experimental Design:In this study, we probed the tumor and its surrounding microenvironment with 18F-FMISO PET imaging to noninvasively quantify tumor hypoxia in vivo prior to and during PD-1 and CTLA-4 checkpoint blockade in preclinical models of breast and colon cancer.Results:Longitudinal imaging identified hypoxia as an early predictive biomarker of therapeutic response (prior to anatomic changes in tumor volume) with a decreasing standard uptake value (SUV) ratio in tumors that effectively respond to therapy. PET signal correlated with ex vivo markers of tumor immune response including cytokines (IFNγ, GZMB, and TNF), damage-associated molecular pattern receptors (TLR2/4), and immune cell populations (macrophages, dendritic cells, and cytotoxic T cells). Responding tumors were marked by increased inflammation that were spatially distinct from hypoxic regions, providing a mechanistic understanding of the immune signaling pathways activated. To exploit image-guided combination therapy, hypoxia signal from PET imaging was used to guide the addition of a hypoxia targeted treatment to nonresponsive tumors, which ultimately provided therapeutic synergy and rescued response as determined by longitudinal changes in tumor volume.Conclusions:The results generated from this work provide an immediately translatable paradigm for measuring and targeting hypoxia to increase response to immune checkpoint therapy and using hypoxia imaging to guide combinatory therapies.

Published
2023
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27. Supplementary Data from 18F-FMISO PET Imaging Identifies Hypoxia and Immunosuppressive Tumor Microenvironments and Guides Targeted Evofosfamide Therapy in Tumors Refractory to PD-1 and CTLA-4 Inhibition

Author

Benjamin M. Larimer, Anna G. Sorace, Eddy S. Yang, Jianbo Wang, Yufeng Li, Deborah Della Manna, Allyson Angermeier, Patrick N. Song, and Kirsten M. Reeves

Abstract

Supplementary Data from 18F-FMISO PET Imaging Identifies Hypoxia and Immunosuppressive Tumor Microenvironments and Guides Targeted Evofosfamide Therapy in Tumors Refractory to PD-1 and CTLA-4 Inhibition

Published
2023
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30. A prospective study on vulvovaginal candidiasis: multicentre molecular epidemiology of pathogenic yeasts in China

Author

N. Song, S. Kan, Q. Pang, H. Mei, H. Zheng, D. Li, F. Cui, G. Lv, R. An, P. Li, Z. Xiong, S. Fan, M. Zhang, Y. Chen, Q. Qiao, X. Liang, M. Cui, Q. Liao, X. Li, and W. Liu

Subjects
China, Molecular Epidemiology, Antifungal Agents, Infectious Diseases, Candida albicans, Humans, Female, Prospective Studies, Dermatology, Candidiasis, Vulvovaginal, Phylogeny, Multilocus Sequence Typing
Abstract

Vulvovaginal candidiasis (VVC) is frequent in women of reproductive age, but very limited data are available on the epidemiology in cases of VVC in China.The current study has been conducted to reveal the prevalence, species distribution of yeast causing VVC and molecular genetics of Candida albicans in China.Vaginal swabs were collected from 543 VVC outpatients recruited in 12 hospitals in China between September 2017 and March 2018. They were preliminarily incubated on Sabouraud dextrose agar and then positive subjects of which were then transmitted to our institute for further identification. CHROMagar™ was used to isolate Candida species, and all isolates were finally identified by DNA sequencing. Multilocus sequence typing (MLST) was used to analyse phylogenetic relationships of the various C. albicans isolates.Eleven different yeast species were identified in 543 isolates, among which C. albicans (84.7%) was the most frequent, followed by C. glabrata (8.7%). We obtained 117 unique diploid sequence types from 451 clinical C. albicans isolates and 92 isolates (20.4%) belonged to a New Clade. All the strains appearing in the New Clade were from northern China and they were isolated from non-recurrent VVC.Our findings suggest that C. albicans are still the main cause of VVC in China and the majority of C. albicans isolates belongs to Clade 1 with DST 79 and DST 45 being two most common. Moreover, the New Clade revealed in our study seems to be specific to northern China.

Published
2021
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31. Mathematical Model of Triple-Negative Breast Cancer in Response to Combination Chemotherapies

Author

Angelica A. Davenport, Yun Lu, Carlos A. Gallegos, Adriana V. F. Massicano, Katherine A. Heinzman, Patrick N. Song, Anna G. Sorace, and N. G. Cogan

Subjects
Pharmacology, Computational Theory and Mathematics, General Mathematics, General Neuroscience, Immunology, General Agricultural and Biological Sciences, General Biochemistry, Genetics and Molecular Biology, General Environmental Science
Published
2022
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32. [The analysis to data from Chinese Rheumatism Data Center external quality assurance program for autoantibodies in 2021]

Author

Y N, Bai, C W, Deng, N, Song, J L, Qin, M T, Li, X F, Zeng, and C J, Hu

Abstract

To evaluate the data obtained from the external quality assurance program initiated by Chinese Rheumatism Data Center (CRDC-QAP) for autoantibodies detection in 2021, so as to assess the consensus and differences in cross-laboratory testing to autoantibodies in China. This is a retrospective study. After collecting data from the first half year (from May 15th to July 10th) and the second half year (from August 15th to November 19th) of CRDC-QAP program for autoantibody detection in 2021, it firstly analyzed the qualitative consensus of the cross-laboratory results. Secondly, it compared the positivity grade of numeric results according to the Sample to cut-off ratio (S/CO ratio) calculation. Finally, the mean and coefficient variation (通过分析2021年国家风湿病数据中心（CRDC）自身抗体室间比对活动中全国各地回报的检测数据，评价国内不同实验室间自身抗体相关检测项目的一致性。采用回顾性研究，收集自2021年自愿报名参加CRDC上半年（从5月15日至7月10日）和下半年（从8月15日至11月19日）自身抗体室间比对活动的实验室回报结果。首先，定性分析不同实验室回报结果的一致性；其次，对预期结果为“阳性”比对样本且以量值形式回报的结果，按照S/CO比值分析不同实验室回报结果的阳性等级；最后，分析三个主要厂家按量值形式回报结果的平均值和变异系数。结果显示，自愿参加CRDC自身抗体室间比对活动上半年和下半年的实验室数量分别为303和332家。除抗β2糖蛋白Ⅰ型抗体IgM（aβ2-GPI）项目之外，其余项目不同实验室的定性结果一致性均大于96%。抗环瓜氨酸化多肽抗体（anti-CCP）和抗线粒体2型抗体（AMA-M2）等按量值形式回报结果的反应强度一致性良好（90%）。使用化学发光免疫试验开展自身抗体检测的实验室占比已经超过50%。不同生产厂家按量值形式回报结果的变异系数差异较大（

Published
2022

33. $B\rho$-defined isochronous mass spectrometry: a new approach for high-precision mass measurements of short-lived nuclei

Author

M. Wang, M. Zhang, X. Zhou, Y. H. Zhang, Yu. A. Litvinov, H. S. Xu, R. J. Chen, H. Y. Deng, C. Y. Fu, W. W. Ge, H. F. Li, T. Liao, S. A. Litvinov, P. Shuai, J. Y. Shi, M. Si, R. S. Sidhu, Y. N. Song, M. Z. Sun, S. Suzuki, Q. Wang, Y. M. Xing, X. Xu, T. Yamaguchi, X. L. Yan, J. C. Yang, Y. J. Yuan, Q. Zeng, and X. H. Zhou

Subjects
Physics - Instrumentation and Detectors, nucl-ex, physics.ins-det, Nuclear Experiment
Abstract

A novel technique for broadband high-precision mass measurements of short-lived exotic nuclides is reported. It is based on the isochronous mass spectrometry (IMS) and realizes simultaneous determinations of revolution time and velocity of short-lived stored ions at the cooler storage ring CSRe in Lanzhou. The new technique, named as the $B\rho$-defined IMS or $B\rho$-IMS, boosts the efficiency, sensitivity, and accuracy of mass measurements, and is applied here to measure masses of neutron-deficient $fp$-shell nuclides. In a single accelerator setting, masses of $^{46}$Cr, $^{50}$Fe and $^{54}$Ni are determined with relative uncertainties of (5~-~6)$\times10^{-8}$, thereby improving the input data for testing the unitarity of the Cabibbo-Kobayashi-Maskawa quark mixing matrix. This is the technique of choice for future high-precision measurements of the most rarely produced shortest-lived nuclides., Comment: 8 pages, 4 figures

Published
2022
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34. Localized wave solutions to a variable-coefficient coupled Hirota equation in inhomogeneous optical fiber

Author

N. Song, H. J. Shang, Y. F. Zhang, and W. X. Ma

Subjects
Control and Systems Engineering, Applied Mathematics, Mechanical Engineering, Aerospace Engineering, Ocean Engineering, Electrical and Electronic Engineering
Abstract

Higher-order localized waves for a variable-coefficient coupled Hirota equation describes the vector optical pulses in inhomogeneous optical fiber and are investigated via generalized Darboux transformation in this work. Based on its Lax pair and seed solutions, the localized wave solutions are calculated, evolution plots are constructed, and the dynamics of the obtained localized waves are analyzed through numerical simulation. It is observed that the first- and second-order localized waves interact with dark-bright solitons or breathers, and the functions α(t), β(t), and δ(t) determine the propagation shape of the localized waves. The presented results contribute to enriching the dynamics of localized waves in inhomogeneous optical fiber. Keywords: variable-coefficient coupled Hirota equation; generalized Darboux transformation; soliton; breather

Published
2022
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35. [A case of ultrasound-guided microwave ablation for Graves disease]

Author

Y N, Song, W Y, Shi, J J, Chen, Q, Wang, X Q, Li, M, Liu, B Y, Cao, X, Ni, and C X, Gong

Subjects
Radiofrequency Ablation, Treatment Outcome, Catheter Ablation, Humans, Microwaves, Graves Disease, Ultrasonography, Interventional, Ultrasonography
Abstract

患儿 女，13岁，因“诊断毒性弥漫性甲状腺肿4年，乏力1个月”就诊，患儿9岁时因“颈粗、怕热多汗1周”就诊于北京儿童医院内分泌遗传代谢科，经过体格检查、甲状腺激素水平、甲状腺激素抗体、影像学检查等，诊断为格雷夫斯病，先后予甲巯咪唑、丙硫氧嘧啶治疗，3年内复发3次，表现为难治复发性，先后2次行超声引导下甲状腺微波消融术，第2次术后随访9个月，甲状腺功能正常，已停药。.

Published
2022

36. Quantitative Longitudinal Imaging Reveals that Inhibiting Hedgehog Activity Alleviates the Hypoxic Tumor Landscape

Author

Sarah C. Kammerud, Rajeev S. Samant, Anna G. Sorace, Tshering D. Lama-Sherpa, Lalita A. Shevde, Heba Allah Alsheikh, Shamik Das, Patrick N. Song, and Dominique C. Hinshaw

Subjects
Cancer Research, Mammary tumor, Tumor hypoxia, business.industry, Vismodegib, Hypoxia (medical), medicine.disease, Metastasis, Breast cancer, Oncology, Tumor progression, Cancer research, Medicine, medicine.symptom, business, Molecular Biology, FMISO, medicine.drug
Abstract

Metastases account for the majority of mortalities related to breast cancer. The onset and sustained presence of hypoxia strongly correlates with increased incidence of metastasis and unfavorable prognosis in breast cancer patients. The Hedgehog (Hh) signaling pathway is dysregulated in breast cancer, and its abnormal activity enables tumor progression and metastasis. In addition to programming tumor cell behavior, Hh activity enables tumor cells to craft a metastasis-conducive microenvironment. Hypoxia is a prominent feature of growing tumors that impacts multiple signaling circuits that converge upon malignant progression. We investigated the role of Hh activity in crafting a hypoxic environment of breast cancer. We used radioactive tracer [18F]-fluoromisonidazole (FMISO) positron emission tomography (PET) to image tumor hypoxia. We show that tumors competent for Hh activity are able to establish a hypoxic milieu; pharmacological inhibition of Hh signaling in a syngeneic mammary tumor model mitigates tumor hypoxia. Furthermore, in hypoxia, Hh activity is robustly activated in tumor cells and institutes increased HIF signaling in a VHL-dependent manner. The findings establish a novel perspective on Hh activity in crafting a hypoxic tumor landscape and molecularly navigating the tumor cells to adapt to hypoxic conditions. Importantly, we present a translational strategy of utilizing longitudinal hypoxia imaging to measure the efficacy of Vismodegib in a preclinical model of triple-negative breast cancer. Implications: Using clinically relevant FMISO-PET imaging can be effectively utilized to monitor response to Vismodegib therapy.

Published
2021
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38. Higher-order localized wave solutions to a coupled fourth-order nonlinear Schrödinger equation

Author

N. Song, H. J. Shang, Y. F. Zhang, and W. X. Ma

Subjects
Statistical and Nonlinear Physics, Condensed Matter Physics
Abstract

In this paper, higher-order localized waves for a coupled fourth-order nonlinear Schrödinger equation are investigated via a generalized Darboux transformation. The [Formula: see text]th-order localized wave solutions of this equation are derived via Lax pair and Darboux matrix. Evolution plots are made and dynamical characteristics of the obtained higher-order localized waves are analyzed through numerical simulation. It is observed that rogue waves coexist with dark–bright solitons and breathers. The presented results also show that different values of the involved parameters have diverse effects on the higher-order localized waves.

Published
2022
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39. [The clinical characteristics of nuclear dense fine speckled pattern in 95 289 patients]

Author

Y M, Luo, R, Wang, Y N, Bai, N, Song, M T, Li, X F, Zeng, and C J, Hu

Subjects
Antibodies, Antinuclear, Humans, Female, Fluorescent Antibody Technique, Indirect, Skin Diseases, Adaptor Proteins, Signal Transducing, Autoimmune Diseases, Transcription Factors
Abstract

To investigate the distribution and clinical significance of nuclear dense fine speckled (DFS) pattern in various diseases. A total of 95 289 patients who received DFS tests at Peking Union Medical College Hospital from January 2019 to December 2020 were included in this study. The results of indirect immunofluorescence assay (IIF) for detection of antinuclear antibody (ANA) were evaluated. The positive rates of ANA and DFS were 39.60% (37 733/95 289) and 1.19% (1 139/95 289) respectively. The positive rate of DFS in ANA-positive patients was 3.02% (1 139/37 733). DFS and ANA positivity were significantly different among different age groups rather than gender. The positivity rate of DFS reached the peak (55.57%, 633/1 139) in young patients between 21-40 years, while positive ANA with negative DFS was mainly observed in patients between 41-60 years (37.26%, 13 636/36 594). Additionally, single ANA-positivity were mainly detected in rheumatology department (59.23%, 18 402/31 066), whereas positive DFS was more common in obstetrics and gynecology department (3.08%, 49/1 593). There were 82.88% (944/1 139) patients with positive DFS diagnosed with non-autoimmune disease (non-AID), and 19.49%(222/1 139) with dermatosis. Positive DFS with higher titer (≥1∶320) was detected more frequently in autoimmune disease (AID) patients (5.13%, 10/195) than in non-AID patients (1.69%, 16/944) (探讨抗核抗体（ANA）致密斑点型（DFS）在不同疾病中的分布及临床意义。回顾分析2019年1月至2020年12月北京协和医院95 289例连续送检标本间接免疫荧光法（IIF）检测ANA的结果。结果显示，ANA阳性率39.60%（37 733/95 289），DFS阳性率1.19%（1 139/95 289）；在ANA阳性患者中，DFS阳性率3.02%（1 139/37 733）。DFS阳性者在21~40岁比例为55.57%（633/1 139），而ANA阳性（除外DFS阳性）者在41~60岁比例为37.26%（13 636/36 594）。ANA阳性（除外DFS阳性）者主要在风湿免疫科（59.23%，18 402/31 066），而DFS阳性者主要在妇产科（3.08%，49/1 593）。1 139例DFS阳性者中，自身免疫病（AID）者195例（17.12%，195/1 139）；非AID者944例（82.88%，944/1 139），其中以皮肤病占比最高（19.49%，222/1 139）。AID患者中出现高滴度（≥1∶320）DFS的比例（5.13%，10/195）高于非AID患者（1.69%，16/944；

Published
2022

44. [89Zr]-Atezolizumab-PET Imaging Reveals Longitudinal Alterations in PDL1 during Therapy in TNBC Preclinical Models

Author

Adriana V. F. Massicano, Patrick N. Song, Ameer Mansur, Sharon L. White, Anna G. Sorace, and Suzanne E. Lapi

Subjects
Cancer Research, Oncology, immuno-PET, 89Zr, [89Zr]-Atezolizumab, PDX, dosimetry, MDA-MB-231
Abstract

Triple-negative breast cancers (TNBCs) currently have limited treatment options; however, PD-L1 is an indicator of susceptibility to immunotherapy. Currently, assessment of PD-L1 is limited to biopsy samples. These limitations may be overcome with molecular imaging. In this work, we describe chemistry development and optimization, in vitro, in vivo, and dosimetry of [89Zr]-Atezolizumab for PD-L1 imaging. Atezolizumab was conjugated to DFO and radiolabeled with 89Zr. Tumor uptake and heterogeneity in TNBC xenograft and patient-derived xenograft (PDX) mouse models were quantified following [89Zr]-Atezolizumab-PET imaging. PD-L1 expression in TNBC PDX models undergoing therapy and immunohistochemistry (IHC) was used to validate imaging. SUV from PET imaging was quantified and used to identify heterogeneity. PET/CT imaging using [89Zr]-Atezolizumab identified a significant increase in tumor:muscle SUVmean 1 and 4 days after niraparib therapy and revealed an increased trend in PD-L1 expression following other cytotoxic therapies. A preliminary dosimetry study indicated the organs that will receive a higher dose are the spleen, adrenals, kidneys, and liver. [89Zr]-Atezolizumab PET/CT imaging reveals potential for the noninvasive detection of PD-L1-positive TNBC tumors and allows for quantitative and longitudinal assessment. This has potential significance for understanding tumor heterogeneity and monitoring early expression changes in PD-L1 induced by therapy.

Published
2023
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45. Generalized Darboux transformation and nonlinear analysis of higher-order localized wave solutions

Author

N. Shi, X. Y. Zhao, and N. Song

Subjects
Physics, 0209 industrial biotechnology, Control and Optimization, Series (mathematics), Basis (linear algebra), Breather, Mechanical Engineering, Mathematical analysis, 02 engineering and technology, Function (mathematics), 01 natural sciences, Nonlinear system, symbols.namesake, 020901 industrial engineering & automation, Transformation (function), Control and Systems Engineering, Modeling and Simulation, 0103 physical sciences, symbols, Electrical and Electronic Engineering, 010301 acoustics, Nonlinear Schrödinger equation, Civil and Structural Engineering, Free parameter
Abstract

In this paper, higher-order localized waves of three-component coupled nonlinear Schrodinger equation are investigated using generalized Darboux transformation. By constructing a novel seed solution as the function of evolution time and normalized distance, a series of new phenomena for higher-order localized waves are displayed with numerical simulations. Specially, the angles between propagation directions of dark-bright solitons(breathers) and the positive direction of x-axis are analysed on the basis of free parameters. The results obtained will contribute to reveal dynamic features of localized waves for the coupled system.

Published
2021
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46. Abstract PS3-07: Molecular imaging of hypoxia and granzyme B alterations during combination treatment with immunotherapy in triple negative breast cancer

Author

Ben M. Larimer, Tiara Napier, Chanelle L. Hunter, Patrick N. Song, and Anna G. Sorace

Subjects
Cancer Research, business.industry, medicine.medical_treatment, Immunotherapy, Hypoxia (medical), Granzyme B, Combined treatment, Oncology, Cancer research, Medicine, Molecular imaging, medicine.symptom, business, Triple-negative breast cancer
Abstract

Background: Although a portion of triple negative breast cancer (TNBC) is sensitive to chemotherapeutic treatment with agents such as paclitaxel (PTX), patients have a high risk of recurrence and short overall and progression-free survival. Clinical trials for TNBC using immune checkpoint inhibitors such as anti-programmed cell death 1 (PD1) have met some success; however, only a small percentage of patients have a positive response to immunotherapy and there is risk for severe side effects. Therefore, there is a need for improvements in monitoring and predicting patient-specific response. The goal of this study is to use non-invasive visualization of the tumor microenvironment to collect longitudinal information that can be used to study tumor response to immunotherapy. By applying positron emission tomography (PET) imaging techniques to investigate changes in the tumor microenvironment (hypoxia and immune cell activation), we seek to predict early response to immunotherapy and better identify which treatments will be effective for individual tumors in TNBC. Methods: A TNBC mouse mammary carcinoma cell line, 4T1, was transduced with CMV-luciferase and 2x105 cells were injected into the third mammary fat pad of 5-6 week old female Balb/c mice (N=28). Mice in cohort 1 received: PTX (10 mg/kg), anti-PD1 (200 µg), both, or vehicle control (saline) (n=4/group). Mice in cohort 2 received: anti-PD1 (n=5), combination PTX/anti-PD1 (n=4), or vehicle control (saline; n=3). Treatments were administered intraperitoneally on days 0, 2, and 5 for cohort 1 (n=16) who underwent granzyme B-PET imaging ([68Ga]-NOTA-GZP-PET) and on days 0, 2, 5, and 8 for cohort 2 (n=12) who underwent hypoxia imaging with [18F]-fluoromisonidazole (FMISO)-PET imaging. Bioluminescence (BLI) imaging and caliper measurements were performed to track tumor size changes at multiple timepoints and tumors were collected for histological validation on day 20. Mean standard uptake value (SUVmean) was calculated as percent of day 0, and statistical analyses were performed with unpaired t-tests and Wilcoxon-rank sum tests. Results: Voxel analysis of GZP-PET images revealed an 42.9% increase in T cell activation of TNBC tumors treated with single-agent PTX compared to anti-PD1 alone on day 3 (p=0.08). FMISO-PET revealed that tumors treated with anti-PD1 alone had lower hypoxic fraction compared to control group tumors (p=0.10) and tumors treated with combination PTX/anti-PD1 (p=0.17) on day 3. BLI data showed that treatment with PTX and anti-PD1 significantly decreased viability signal between days 3 and 6 for cohort 1 (p=0.04). Non-responders to treatment had a significantly higher tumor volume compared to responders starting on day 6 (p Citation Format: Tiara S. Napier, Chanelle L. Hunter, Patrick N. Song, Ben M. Larimer, Anna G. Sorace. Molecular imaging of hypoxia and granzyme B alterations during combination treatment with immunotherapy in triple negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS3-07.

Published
2021
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47. Abstract PS10-21: Identifying efficacy of targeted HER2 antibodies in sensitization of HER2 positive breast cancer to fractionated radiation

Author

Yun Lu, Tiara Napier, Katherine Heinzman, Suzanne E. Lapi, Patrick N. Song, Anna G. Sorace, and Sharon Samuel

Subjects
Oncology, Cancer Research, medicine.medical_specialty, Combination therapy, Tumor hypoxia, business.industry, medicine.medical_treatment, Cancer, medicine.disease, Radiation therapy, Breast cancer, In vivo, Trastuzumab, Internal medicine, Cancer cell, medicine, skin and connective tissue diseases, business, medicine.drug
Abstract

Introduction: Tumor hypoxia contributes to intra-tumoral heterogeneity and decreases efficacy of cytotoxic therapy. Fractionated radiation therapy has emerged as an alternative to single dose radiation, and is a component of standard-of-care therapy for patients with unresectable human epidermal growth factor receptor 2 (HER2+) breast cancer. Because radiation therapy is dependent on tissue oxygenation, therapies that increase oxygenation could radio-sensitize tumors. The goal of this study is to investigate if molecular imaging with [18F]-fluoromisonidazole (FMISO)-PET can quantify anti-HER2 therapy-induced changes in tumor oxygenation and utilize imaging metrics to enhance the effectiveness of fractionated radiation. Improving treatment synergy in HER2+ breast cancer has potential to increase therapeutic effectiveness without increasing cytotoxic therapy. Methods: For in vitro studies, HER2+ breast cancer cells (BT474, SKBR3, MDA-MB-361 and MDA-MB-453) were treated with various sequencing of combination trastuzumab (1 µg/mL) and fractionated radiation (6/3 Gy) and assessed for cell death. HER2+ cancer cells (BT474 and MDA-MB-361) were also treated with combination trastuzumab and fractionated radiation and analyzed for DNA double strand breaks (DSB) through flow cytometry. For in vivo studies, HER2+ cell line (BT474 and MDA-MB-361) and HER2+ patient derived xenograft (BCM 3472) tumors were engrafted into mice and treated with trastuzumab (4 mg/kg) on days 0 and 3 and fractionated radiation (6/3 Gy) on days 1, 2 and 3 (or single agent control). [18F]-FMISO-PET imaging was conducted on day 0, 3 and 7. At the imaging endpoint, tumors were either extracted for biological validation or continued to measure tumor size changes for longitudinal assessment of response. Bliss test of independence and a non-parametric T-test was used to assess for treatment synergy and significance, respectively. Results: In vitro cell death assay revealed single agent trastuzumab or fractionated radiation treated groups exhibited 15.2% ± 6.5% or 53.6% ± 9% cell death respectively, while trastuzumab prior to fractionated radiation groups exhibited 72.5% ± 2.5% cell death (p = 0.01) on day 7 in MDA-MB-361 cells. Flow cytometry analysis showed MDA-MB-361 cells treated with trastuzumab prior to fractionated radiation exhibited 62.4% ± 8.7% DSB, which significantly increased from single agent trastuzumab (0.74% ± 0.39%) or fractionated radiation groups (37.3% ± 7.3%) (p = 0.01). In vivo, MDA-MB-361 tumors treated with trastuzumab and fractionated radiation had a [18F]-FMISO SUVmean of 0.20 ± 0.09, while tumors treated with fractionated radiation had a [18F]-FMISO SUVmean of 0.31 ± 0.06 on day 7 (p = 0.05). MDA-MB-361 tumors treated with trastuzumab and fractionated radiation experienced a 26.1% ± 16.8% decrease in tumor volume, while tumors treated with single agent fractionated radiation experienced a 10.4% ± 2.8% decrease in tumor volume from day 0 to day 7 (p = 0.11). 30 days after start of therapy, MDA-MB-361 tumors treated with single agent fractionated radiation had a tumor volume of 471.8 ± 120 mm3, whereas tumors treated with combination trastuzumab and fractionated radiation had a tumor volume of 116 ± 38 mm3 (p < 0.01). Bliss test of independence confirmed in vivo treatment synergy of trastuzumab and fractionated radiation starting 14 days after start of therapy. Conclusion: HER2+ breast cancer treated with trastuzumab prior to fractionated radiation synergistically increases efficacy of radiotherapy in vitro and in vivo. [18F]-FMISO-PET imaging has potential to identify in vivo response to combination therapies and better understand changes in the tumor microenvironment to guide combination therapy. Acknowledgements: We thank the American Cancer Society for RSG-18-006-01-CCE and NIH NCI R01 CA240589. Citation Format: Patrick N. Song, Yun Lu, Tiara Napier, Sharon Samuel, Katherine Heinzman, Suzanne E. Lapi, Anna G. Sorace. Identifying efficacy of targeted HER2 antibodies in sensitization of HER2 positive breast cancer to fractionated radiation [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-21.

Published
2021
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50. Imaging for Response Assessment in Cancer Clinical Trials

Author

Suzanne E. Lapi, Benjamin M. Larimer, Tiara Napier, Savannah C. Partridge, Anna G. Sorace, Samuel J. Galgano, Kirsten Reeves, C. Chad Quarles, Stefanie Woodard, Andrew D. Smith, Patrick N. Song, Asser Abou Elkassem, and Thomas E. Yankeelov

Subjects
medicine.medical_specialty, medicine.diagnostic_test, Imaging biomarker, business.industry, Magnetic resonance imaging, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Positron emission tomography, Response Evaluation Criteria in Solid Tumors, 030220 oncology & carcinogenesis, Medicine, Radiology, Nuclear Medicine and imaging, Radiology, Molecular imaging, business, Diffusion Kurtosis Imaging, FMISO, Diffusion MRI
Abstract

The use of biomarkers is integral to the routine management of cancer patients, including diagnosis of disease, clinical staging and response to therapeutic intervention. Advanced imaging metrics with computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET) are used to assess response during new drug development and in cancer research for predictive metrics of response. Key components and challenges to identifying an appropriate imaging biomarker are selection of integral vs integrated biomarkers, choosing an appropriate endpoint and modality, and standardization of the imaging biomarkers for cooperative and multicenter trials. Imaging biomarkers lean on the original proposed quantified metrics derived from imaging such as tumor size or longest dimension, with the most commonly implemented metrics in clinical trials coming from the Response Evaluation Criteria in Solid Tumors (RECIST) criteria, and then adapted versions such as immune-RECIST (iRECIST) and Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST) for immunotherapy response and PET imaging, respectively. There have been many widely adopted biomarkers in clinical trials derived from MRI including metrics that describe cellularity and vascularity from diffusion-weighted (DW)-MRI apparent diffusion coefficient (ADC) and Dynamic Susceptibility Contrast (DSC) or dynamic contrast enhanced (DCE)-MRI (Ktrans, relative cerebral blood volume (rCBV)), respectively. Furthermore, Fluorodexoyglucose (FDG), fluorothymidine (FLT), and fluoromisonidazole (FMISO)-PET imaging, which describe molecular markers of glucose metabolism, proliferation and hypoxia have been implemented into various cancer types to assess therapeutic response to a wide variety of targeted- and chemotherapies. Recently, there have been many functional and molecular novel imaging biomarkers that are being developed that are rapidly being integrated into clinical trials (with anticipation of being implemented into clinical workflow in the future), such as artificial intelligence (AI) and machine learning computational strategies, antibody and peptide specific molecular imaging, and advanced diffusion MRI. These include prostate-specific membrane antigen (PSMA) and trastuzumab-PET, vascular tumor burden extracted from contrast-enhanced CT, diffusion kurtosis imaging, and CD8 or Granzyme B PET imaging. Further excitement surrounds theranostic procedures such as the combination of 68Ga/111In- and 177Lu-DOTATATE to use integral biomarkers to direct care and personalize therapy. However, there are many challenges in the implementation of imaging biomarkers that remains, including understand the accuracy, repeatability and reproducibility of both acquisition and analysis of these imaging biomarkers. Despite the challenges associated with the biological and technical validation of novel imaging biomarkers, a distinct roadmap has been created that is being implemented into many clinical trials to advance the development and implementation to create specific and sensitive novel imaging biomarkers of therapeutic response to continue to transform medical oncology.

Published
2020
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