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Kentaro Inamura,1,2 Gulanbar Amori,1,2 Takeshi Yuasa,3 Shinya Yamamoto,3 Junji Yonese,3 Yuichi Ishikawa1,21Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan; 2Department of Pathology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan; 3Department of Urology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, JapanBackground: B7-H3 (CD276), an immune checkpoint molecule, regulates the tumor-immune microenvironment and controls the aggressiveness of various tumors. Although B7-H3 expression has been associated with the number of tumor-infiltrating FOXP3+ regulatory T cells, little information is available about this association in clear cell renal cell carcinoma (ccRCC).Methods: Using 252 consecutive cases of ccRCC, we examined the association of B7-H3 expression in both the tumor cells and tumor vasculature with the number of tumor-infiltrating FOXP3+ cells and assessed whether the effects of B7-H3 expression on survival differ according to FOXP3+ cell number.Results: High B7-H3 expression was observed in the tumor cells and tumor vasculature in 15% and 54% of ccRCC cases, respectively. High FOXP3+ cell number was positively associated with B7-H3 expression in both the tumor cells (odds ratio [OR] =2.93; P=0.0041) and tumor vasculature (OR=2.45; P=0.0007). Tumor cell B7-H3 expression was associated with increased disease-specific mortality in high FOXP3+ cell number group (hazard ratio [HR] =2.98; P=0.017), but not in low FOXP3+ group (P=0.71). Tumor vasculature B7-H3 expression was also associated with increased disease-specific mortality in high FOXP3+ cell number group (HR=4.86; P=0.0025), but not in low FOXP3+ group (P=0.48).Conclusion: We demonstrate that B7-H3 expression in both tumor cells and the tumor vasculature is positively associated with FOXP3+ cell number. Such expression is also associated with increased mortality in high FOXP3+ cell number group, but not in low FOXP3+ cell number group. These findings suggest that B7-H3-expressing ccRCCs may exert tumor-promoting immunity by interacting with FOXP3+ regulatory T cells in the tumor microenvironment.Keywords: immune checkpoint inhibitor, immunotherapy, prognosis, renal cancer, TIL

Winter thunderstorms in Japan have been recognized as an ideal target to observe high‐energy atmospheric phenomena thanks to low‐charge‐center cloud structures. During four winter seasons in Japan (from 2016 October to 2020 March), seven downward terrestrial gamma‐ray flashes (TGFs) were detected by gamma‐ray and broadband low‐frequency (LF: 0.8–500 kHz) monitors. All the detected TGFs took place at the initial stage of lightning flashes. Based on the LF observation, the seven downward TGFs in the present study can be classified into two types: energetic‐bipolar and small‐bipolar types. Three of them are energetic‐bipolar events, coincident with a high peak‐current LF pulse that originates from a negative return stroke with a peak current larger than 100 kA. The others are small‐bipolar events, followed by a negative bipolar LF pulse with a moderate peak current. Three of the four small‐bipolar events are multi‐pulse TGFs, while all of the energetic‐bipolar events in this study are single‐pulse TGFs. Plain Language Summary: Terrestrial gamma‐ray flashes (TGFs) are a transient high‐energy emission from lightning discharges. While a lot of upward TGFs have been detected by satellites, a few downward TGF have been detected by ground‐based experiments. Our detection network in Japan has detected seven downward TGFs in winter thunderstorms for 4 years. Lightning discharges associated with the downward TGFs were also monitored in the low‐frequency radio band. The low‐frequency pulses associated with the downward TGFs can be classified into two types. Correlation analysis of downward TGFs with gamma‐ray and low‐frequency observations is a powerful approach to reveal the production mechanism of TGFs. Key Points: Downward terrestrial gamma‐ray flashes (TGFs) in winter thunderstorms of Japan can be classified into two types based on low‐frequency (LF) observationsThree events were single‐pulse TGFs coincident with high peak‐current LF pulses of return strokesFour events were followed by moderate peak‐current LF pulses, and three of them are multi‐pulse TGFs [ABSTRACT FROM AUTHOR]

Research describing photorefractive multiple quantum well structures is presented. With reference to Franz-Keldysh geometry properties including saturation intensity, spatial resolution, high order diffractions and electric field dependence are investigated.

YBCO thick films were grown using liquid phase epitaxy with the aim of achieving high current wire application of high temperature superconductors.

Metalorganic deposition was used to fabricate YBa2Cu3O7-x films on buffered metal tapes.

Around 17:00 on January 12, 2020 (UTC), radiation detectors installed at two locations with a 1.35 km separation in Kanazawa City, Japan, captured a total of four gamma‐ray enhancements. The first pair was simultaneously observed at the two locations at 17:03 and were abruptly terminated by a lightning discharge. The remaining two enhancements were also nearly simultaneously observed ∼3 min later, and one of them was also terminated by another lightning discharge. At the last termination, a downward terrestrial gamma‐ray flash and a negative energetic in‐cloud pulse were observed. Both pairs were associated with thundercloud cells. In the first pair, simultaneous detection in two locations 1.35 km apart suggests either a gamma‐ray glow emerged in‐between and time variability of its intensity were directly observed or there were two (or more) gamma‐ray glows in the cell which reached the two detectors coincidentally. In the latter pair, the peak time in the downwind detector was ∼40 s later than that of the upwind detector. If the irradiation region moved with the cell, it would have taken ∼110 s. The discrepancy suggests either the glow moved 2.5 times faster than the cell or there were two (or more) glows in the cell. Also, the fact that the thunderstorm cell hosting the latter glows experienced the lightning discharge ∼3 min before suggests that the strong electric field in the cell can develop within a few minutes. Plain Language Summary: Thunderclouds sometime emit gamma rays with a duration of minutes, which are called "gamma‐ray glow". It is bremsstrahlung emission from high‐energy electrons accelerated in the cloud. At around 17:00 (UTC) January 12, 2020, two radiation detectors installed 1.35 km apart in Kanazawa City, Japan, captured a total of four count rate enhancements. The first two disappeared with a lightning discharge, and the last one with another lightning, in this case accompanied by an intense gamma ray flash called a "downward terrestrial gamma‐ray flash" (TGF). The overall behavior is similar to another gamma‐ray glow observed in the same location on January 2018 (e.g. Wada et al. 2019, https://doi.org/10.1038/s42005-019-0168-y). This is also the third report of gamma‐ray glow termination associated with both lightning discharges and TGFs. However, while the 2018 event can be explained well by assuming that the electron acceleration region moves with the thundercloud cell (monitored by rainfall map) and then terminated by a lightning discharge, the time profiles of the four current events cannot. To explain the behavior of the 2020 data, new models such as electron acceleration region(s) rapidly emerging in a thundercloud cell, and/or multiple electron acceleration regions co‐existing in a single cell, are discussed. Key Points: Four gamma‐ray enhancements were observed at two locations 1.35 km apart along the wind direction, and their time profiles were analyzedThe termination of three of them was also recorded. The last one was associated with a downward terrestrial gamma‐ray flash and a negative energetic in‐cloud pulseThe acceleration region of gamma‐ray glows in a thundercloud can develop within a few minutes after experiencing a discharge [ABSTRACT FROM AUTHOR]

During three winter seasons from November 2016 to March 2019, 11 gamma‐ray glows were detected at a single observation site of our ground‐based gamma‐ray monitoring network in Kanazawa, Japan. These events are analyzed with observations of an X‐band radar network, a ceilometer, a disdrometer, and a weather monitor. All the detected glows were connected to convective high‐reflectivity regions of more than 35 dBZ, developed up to an altitude of >2 km. They were also accompanied by heavy precipitation of graupels. Therefore, graupels in the lower layer of thunderclouds that correspond to high‐reflectivity regions can form strong electric fields producing gamma‐ray glows. Also, these events are compared with a limited sample of nondetection cases, but no significant differences in meteorological conditions were found between detection and nondetection cases in the present study. Plain Language Summary: Strong electric fields inside thunderclouds can accelerate electrons to relativistic energies, and gamma‐ray photons from the accelerated electrons can be observed as minute‐lasting "gamma‐ray glows." During winter thunderstorms in Japan, we detected eleven gamma‐ray glows at sea level. The observations were combined with meteorological measurements such as atmospheric temperature, cloud bases, types of precipitation particles, and radar‐echo measurements. All the detected gamma‐ray glows were taking place during a passage of tall and well‐developed radar‐echo regions, and accompanied by heavy precipitation of graupel/hail pellets. The graupel/hail particles in the lower layer of thunderclouds could have contributed to gamma‐ray glows production. Key Points: Eleven gamma‐ray glows were observed during three winter seasons at a single observation site in JapanAll the detected gamma‐ray glows were associated with tall and well‐developed radar‐echo structures of thunderstormsGraupel pallets in the lower layer of thunderclouds could be related to downward electron acceleration for the gamma‐ray glows [ABSTRACT FROM AUTHOR]

During a winter thunderstorm on 6 February 2017 in Japan, photonuclear reactions such as 14N(γ, n)13N were triggered by a downward terrestrial gamma‐ray flash (TGF), as reported by Enoto et al. (2017, https://doi.org/10.1038/nature24630). In the present paper, we compare the observation with a simulation model of downward TGFs and subsequent photonuclear reactions constructed by the first paper of the series and Wada, Enoto, Nakazawa, et al. (2019, https://doi.org/10.1103/physrevlett.123.061103). The observation and model consist of three components: annihilation gamma rays from positrons produced by β+‐decay nuclei, deexcitation gamma rays originating from neutron captures, and radiation doses by TGF photons. Each component of the observation is reproduced by the simulation model, and we constrain a relation between the number of avalanche electrons and their production altitude of the downward TGF. The constraints by three components match within an order of magnitude. The downward TGF is estimated to comprise (0.5–2.5) × 1019 avalanche electrons above 1 MeV produced at an altitude of 1.4–2.7 km. Despite differences in altitude, direction, and season, downward TGFs in winter thunderstorms are thought to have the same mechanism of electron acceleration and multiplication in lightning as TGFs observed by in‐orbit satellites. Plain Language Summary: Lightning flashes are sometimes accompanied by strong high‐energy emission called "terrestrial gamma‐ray flashes" (TGFs). The energy of gamma rays in TGFs is high enough to trigger nuclear reactions with atmospheric nuclei such as nitrogen and oxygen. The nuclear reactions produce neutrons and unstable isotopes that emit positrons. In the companion paper of this series, we calculated the nuclear reactions and propagation processes of their products such as positrons and neutrons and modeled their characteristics at ground level by simulations. In the present paper, the simulation model is compared with the actual observation of a TGF and nuclear reactions during winter thunderstorms in Japan. The model successfully reproduces the observation and estimate the production altitude the number of energetic electrons involved in the TGF. Key Points: A simulation model of photonuclear reactions in lightning is compared with an observation during a winter thunderstorm reported by Enoto et al. (2017, https://doi.org/10.1038/nature24630)Three detected signatures originating from positrons, neutrons, and TGF photons are reproduced by the simulation modelA downward TGF triggering photonuclear reactions comprised 1018 to 1019 avalanche electrons produced at 1.4–2.7 km above sea level [ABSTRACT FROM AUTHOR]

During 2017–2018 winter operation of the Gamma‐Ray Observation of Winter Thunderclouds experiment in Japan, two downward terrestrial gamma‐ray flashes (TGFs) that triggered atmospheric photonuclear reactions were detected. They took place during winter thunderstorms on 5 December 2017 and 9 January 2018 at Kanazawa, Ishikawa Prefecture, Japan. Each event coincided with an intracloud/intercloud discharge, which had a negative‐polarity peak current higher than 150 kA. Their radio waveforms in the low‐frequency band are categorized as a distinct lightning type called "energetic in‐cloud pulse" (EIP). Negative‐polarity EIPs have been previously suggested to be highly associated with downward TGFs, and the present observations provide evidence of the correlation between them for the first time. Furthermore, both of the downward TGFs followed "gamma‐ray glows," minute‐lasting high‐energy emissions from thunderclouds. It is suggested that the negative EIPs took place with downward propagating negative leaders or upward positive ones developed in highly electrified regions responsible for the gamma‐ray glows. Plain Language Summary: We observed, on the ground, intense and brief gamma‐ray emissions, called "downward terrestrial gamma‐ray flashes," twice during winter thunderstorms in Japan. They coincided with a kind of in‐cloud lightning discharges called "negative energetic in‐cloud pulses." They have been previously predicted to have a connection to downward terrestrial gamma‐ray flashes, and we observationally confirm the prediction for the first time. Furthermore, the two downward terrestrial gamma‐ray flashes were preceded by weak and minute‐lasting gamma‐ray emissions coming from thunderclouds, called "gamma‐ray glows." High electric fields inside thunderclouds required to produce gamma‐ray glows were thus related to the downward terrestrial gamma‐ray flashes and the negative energetic in‐cloud pulses. Key Points: Two downward terrestrial gamma‐ray flashes detected in Japan were coincident with high peak‐current lightning dischargesThe lightning discharges can be categorized as negative energetic in‐cloud pulsesBoth cases took place in highly electrified regions responsible for production of gamma‐ray glows [ABSTRACT FROM AUTHOR]

Objectives In the present study, we explored the real-world efficacy of the immuno-oncology checkpoint inhibitor nivolumab and the tyrosine kinase inhibitor cabozantinib in the second-line setting. Methods Using the International Metastatic Renal Cell Carcinoma Database Consortium (imdc) dataset, a retrospective analysis of patients with metastatic renal cell carcinoma (mrcc) treated with nivolumab or cabozantinib in the second line after prior therapy targeted to the vascular endothelial growth factor receptor (vegfr) was performed. Baseline characteristics and imdc risk factors were collected. Overall survival (os) and time to treatment failure (ttf) were calculated using Kaplan-Meier curves. Overall response rates (orrs) were determined for each therapy. Multivariable Cox regression analysis was performed to determine survival differences between cabozantinib and nivolumab treatment. Results The analysis included 225 patients treated with nivolumab and 53 treated with cabozantinib. No significant difference in median os was observed: 22.10 months [95% confidence interval (ci): 17.18 months to not reached] with nivolumab and 23.70 months (95% ci: 15.52 months to not reached) with cabozantinib (p = 0.61). The ttf was also similar at 6.90 months (95% ci: 4.60 months to 9.20 months) with nivolumab and 7.39 months (95% ci: 5.52 months to 12.85 months) with cabozantinib (p = 0.20). The adjusted hazard ratio (hr) for nivolumab compared with cabozantinib was 1.30 (95% ci: 0.73 to 2.3), p = 0.38. When adjusted by imdc criteria and age, the hr was 1.32 (95% ci: 0.74 to 2.38), p = 0.35. Conclusions Real-world imdc data indicate comparable os and ttf for nivolumab and cabozantinib. Both agents are reasonable therapeutic options for patients progressing after initial first-line vegfr-targeted therapy. [ABSTRACT FROM AUTHOR]

Abstract: An on‐ground observation program for high‐energy atmospheric phenomena in winter thunderstorms along the Japan Sea has been performed via measurements of gamma ray radiation, atmospheric electric field, and low‐frequency radio band. On 11 February 2017, the radiation detectors recorded gamma ray emission lasting for 75 s, and then abruptly terminated with a nearby lightning discharge. The gamma ray spectrum extended up to 20 MeV and was reproduced by a cutoff power law model with a photon index of 1 . 3 6 − 0 . 04 + 0 . 03, being consistent with Bremsstrahlung radiation from a thundercloud (known as a gamma‐ray glow or a thunderstorm ground enhancement). The low‐frequency radio monitors, installed ∼50 km away from the gamma ray observation site recorded leader development of an intracloud/intercloud discharge spreading over ∼60 km area with a ∼300‐ms duration. The timing of the gamma ray termination coincided with the moment when the leader development of the intracloud/intercloud discharge passed 0.7 km horizontally away from the radiation monitors. The intracloud/intercloud discharge started ∼15 km away from the gamma ray observation site. Therefore, the glow was terminated by the leader development, while it did not trigger the lightning discharge in the present case. [ABSTRACT FROM AUTHOR]