International Open Laboratory
Dr. Held Lab (MGH)
Our Lab is an International Open Laboratory led by Dr. Kathryn D. Held, an Associate Professor and Associate Radiation Biologist of Radiation Oncology, Harvard Medical School, Massachusetts General Hospital and President of National Council on Radiation Protection and Measurements (NCRP). Our laboratory location is at Gunma University Initiative for Advanced Research (GIAR) in Maebashi, Gunma prefecture, Japan.We conduct multidisciplinary research programs investigating the essential characteristics of radiation effects on cell to cell communications, such as from normal cells to normal cells; cancer cells to cancer cells; cancer cells to normal cells or vice versa, and exploring the relationships between irradiated cells and un-irradiated cells including neurons and glial cells.
Future perspective of the lab
Our bystander-related research involves two general sub-areas.
1. In one topic, we are continuing our ongoing studies on the role of DNA repair processes in responses of bystander cells, the chemical nature of the signaling molecules and the long-term importance of the bystander effect, primarily using fibroblasts and tumor cells.Prior studies by some of our team members had been consistent with the idea, also suggested by others, that the ATR-related DNA damage response is important for bystander responsive cells. We continue to investigate this pathway.In planned studies, we will also investigate the potential roles of immune system-related mediators in signaling.
2. Our second bystander-related topic is cell-cell communications in the brain. Previously we showed that there is an acute, transient, radiation-induced effect on synaptic function and higher brain function within 24 h following irradiation; the responses also could be caused by indirect signaling from irradiated glial cells to neurons. In response to radiation, increases of ROS, NO, and other inflammatory signals may change expression of receptors in neurons. The irradiated glial cells might produce or release a gliotransmitter, that may affect the synaptic function of neurons. Gliotransmitters such as glutamate could trigger excitotoxicity and cause neurotoxicity underlying many acute incidents such as brain ischemia and trauma. Here, we are investigating the possibility of the radiation-induced bystander effect in neurons and also in glial cells by focusing on radiation effects on cell communications between neurons and glial cells.
We are also greatly interested in the use of charged particles in cancer therapy, including several clinically relevant topics: hypofractionation, hypoxia, cancer stem cells, role of DNA damage response mechanisms and interactions of radiation with immunotherapy. For these questions, we interact with other GIAR and Gunma University investigators.
Held KD, Kawamura H, Kaminuma T, Paz AE, Yoshida Y, Liu Q, Willers H, Takahashi A. Effects of charged particles on human tumor cells. Front Oncol 2016 Feb 12; 6:23.
Niimi A, Yamauchi M, Limsirichaikul S, Sekine R, Oike T, Sato H, Suzuki K, Held KD, Nakano T, Shibata A. Identification of DNA double strand breaks at chromosome boundaries along the track of particle irradiation. Genes Chromosomes Cancer 2016 Aug;55(8):650-60.
Ikeda H, Souda H, Puspitasari A, Held KD, Hidema J, Nikawa T, Yoshida Y, Kanai T, Takahashi A. A new system for three-dimensional clinostat synchronized X-irradiation with a high-speed shutter for space radiation research. Biol Sci Space 2016; 30:8-16.
Ikeda H, Souda H, Puspitasari A, Held KD, Hidema J, Nikawa T, Yoshida Y, Kanai T, Takahashi A. Development and performance evaluation of a three-dimensional clinostat synchronized heavy-ion irradiation system. Life Sci Space Res (Amst). 2017 Feb; 12:51-60.
Performance evaluation of new devices to synchronize heavy-ion or X-ray irradiation and simulated microgravity for space radiation research ~ Improvement of a control stage ~; Akihisa Takahashi, Hiroko Ikeda, Hikaru Souda, Anggraeini Puspitasari, Kathryn D. Held, Jun Hidema, Takeshi Nikawa, Yukari Yoshida, and Tatsuaki Kanai; International Symposium on Space Technology and Science, Proceeding, Theses ID; 2017-p-09.
Hada M, Ikeda H, Rhone JR, Beitman AJ, Plante I, Souda H, Yoshida Y, Held KD, Fujiwara K, Saganti PB, Takahashi A. Increased chromosome aberrations in cells exposed simultaneously to simulated microgravity and radiation. Int. J. Mol. Sci., 20(1): 43, 2018.
Sato H, Niimi A, Yasuhara T, Permata TBM, Hagiwara Y, Isono M, Nuryadi E, Sekine R, Oike T, Kakoti S, Yoshimoto Y, Held KD, Susuki Y, Kono K, Miyagawa K, Nakano T, Shibata A. DNA double-strand break repair pathway regulates PD-L1 expression in cancer cells. Nat Commun. 2017 Nov 24;8(1):1751.
Hagiwara Y, Niimi A, Isono M, Yamauchi M, Yasuhara T, Limsirichaikul S, Oike T, Sato H, Held KD, Nakano T, Shibata A.3D-structured illumination microscopy reveals clustered DNA double-strand break formation in widespread gH2AX foci after high LET heavy-ion particle radiation. Oncotarget 2017 Nov 25; 8(65):109370-109381.
Hagiwara Y, Oike T, Niimi A, Sato H, Limsirichaikul S, Held KD, Nakano T, Shibata A. Clustered DNA double-strand break formation and the repair pathway following heavy-ion irradiation. J Rad Res. 2019 Jan 1;60(1):69-79.
Permata TBM, Hagiwara Y, Sato H, Yasuhara T, Oike T, Gondhowiardjo S, Held KD, Nakano T, Shibata A. Base excision repair regulates PD-L1 expression in cancer cells. Oncogene. 2019. In press.
Participation in Conferences
Held, KD. Integrating physics, chemistry, molecular and cellular biology, and human studies in radiation research, The 4th International Symposium of Gunma University Initiative for Advanced Research (GIAR), November 7th 2017.
Held, KD, Special lecture at The 5th International Symposium of Gunma University Program for Leading Graduate Schools, Maebashi, Gunma, Japan. November 2nd – 3rd, 2017.
Anggraeini Puspitasari, Noriko Koganezawa, Hidemasa Kawamura, Hiroyuki Yamazaki, Akihisa Takahashi, Tomoaki Shirao, Takashi Nakano, Kathryn D Held. “The effect of X-irradiation on neuronal function”. The 23rd Annual Meeting of International Association for the sensitization of Cancer Treatment, in KARUIZAWA, July 2017. Symposium.
Takahashi A, Ikeda H, Souda H, Puspitasari A, Held KD, Hidema J, Nikawa T, Yoshida Y, Kanai T, “Performance evaluation of new devices to synchronize X-ray or heavy-ion irradiation and simulated microgravity for space radiation research”, 31st International Symposium on Space Technology and Science, Matsuyama, Japan, June 2017.
Takahashi A, Ikeda H, Souda H, Puspitasari A, Held KD, Hidema J, Nikawa T, Yoshida Y, Kanai T, “New devices to synchronize irradiation and simulated µG for space radiation research”, The 5th International Symposium on Space Radiation and Particle Radiotherapy, including the 8th International Workshop on Space Research Radiation (IWSRR) and the 17th Ion Beams in Biology and Medicine (IBIBAM), Suzhou, China, May 2017.
Anggraeini Puspitasari, Noriko Koganezawa, Tomoaki Shirao, Kathryn D Held. “Effect of Radiation on Higher Brain Function: Neuroscience’s Investigation”. International Workshop of Gunma University Program for Leading Graduate Schools at Tojo-hall Gunma University on Feb 8, 2017 (invited); Educational.
Ikeda H, Muratani M, Puspitasari A, Held KD, Hidema J, Yoshida Y, Takahashi A. Gene expression profile changes of human fibroblasts using device to synchronize carbon-ion irradiation and simulated microgravity. Talk presented by Dr. Ikeda at the 5th International Symposium on Space Radiation and Particle Radiotherapy, Suzhou, China, May 2017.
Puspitasari A, Koganezawa N, Shirao T, Kojima N, Held KD, Takahashi A, Nakano T. Acute effects of low-LET and high-LET radiation on fear memory formation and its underlying mechanisms. Talk presented by Dr. Puspitasari at the 5th International Symposium on Space Radiation and Particle Radiotherapy, Suzhou, China, May 2017.
Puspitasari A, Kawamura H, Takahashi A, Yoshida Y, Shirao T, Nakano T, Held KD. Acute and chronic effects of low dose of X-irradiation on immature hippocampal neurons in vitro. Poster presented by Dr. Puspitasari at the 7th International Society of Radiation
Neurobiology Conference, Yuzawa, Japan, February 2017.
Puspitasari A, Kawamura H, Held KD, Shirao T, Nakano T. The radiation-induced bystander effects on synaptic function of mature neurons. Poster presented by Dr. Puspitasari at the 62nd Annual Meeting of the Radiation Research Society, Hawaii, October 2016.
Held KD. Radiation effects on normal brain: Concerns for radiation therapy and space missions. Invited talk presented at the 6th International Society of Radiation Neurobiology (ISRN) Conference, Nagasaki, Japan, February 2016.
Held KD. International research collaborations in radiation research for cancer therapy and space exploration. Invited talk presented at the 28th Annual meeting of the Japanese Society for Radiation Oncology (JASTRO), Gunma, Japan, November 2015.
Held KD. Recent findings of radiation biology research. Invited educational seminar presented at 12th International Stereotactic Radiosurgery Society Congress, Yokohama, Japan, June 2015.
Held, KD. Charged particle radiobiology research at MGH and thoughts on research at GIAR. Invited talk presented at the 1st International Symposium of Gunma University Initiative for Advanced Research, February, 2015.
Roppongi RT, Dhume SH, Padmanabhan N, et al. LRRTMs Organize Synapses through Differential Engagement of Neurexin and PTPσ [published online ahead of print, 2020 Jan 23]. Neuron. 2020;S0896-6273(20)30003-9. doi:10.1016/j.neuron.2020.01.003
Roppongi RT, Champagne-Jorgensen KP, Siddiqui TJ. (2017). Low Density Primary Hippocampal Neuron Culture. Journal of Visualized Experiments. J Vis Exp. (122). First Listed Author
Roppongi RT, Karimi B, Siddiqui TJ. (2016). Role of LRRTMs in synapse development and plasticity. Neuroscience Research. Neuroscience Research. 116: 18-28. First Listed Author
Ohara Y, Koganezawa N, Yamazaki H, Roppongi RT, Sato K, Sekino Y, Shirao T. (2015). Early-stage development of human-induced pluripotent stem cell (hiPSC)-derived neurons. Journal of Neuroscience Research. 93(12): 1804-1813. Co-Author Published
Yamazaki H, Kojima N, Kato K, Hirose E, Iwasaki T, Mizui T, Takahashi H, Hanamura K, Roppongi RT, Koibuchi N, Sekino Y, Mori N, Shirao T. “Spikar, a novel drebrin-binding protein, regulates the formation and stabilization of dendritic spines.” J Neurochem 128(4): 507-22 (2013)
Roppongi, Kojima N, Hanamura K, Yamazaki H, Shirao T. “Selective reduction of drebrin and actin in dendritic spines of hippocampal neurons by activation of 5-HT(2A) receptors.” Neuroscience Letters 547: 76-81 (2013)
Hanamura, K, Mizui T, Kakizaki T, Roppongi RT, Yamazaki H, Yanagawa Y, Shirao T. “Low accumulation of drebrin at glutamatergic postsynaptic sites on GABAergic neurons” Neuroscience 169: 1489-1500 (2010)
- Participation in Conferences
Roppongi RT, Miao S, Shirao T “Activation of 5-HT2A receptor in Vitro reduces drebrin cluster from dendritic spines via NMDA receptor activation.” (2014) The 5th Annual Meeting ISRN, Gunma, JapanKoganezawa N, Ohara Y, Yamazaki H, Roppongi RT, Sato K, Sekino Y, Shirao T (2014) “Early stage development of human iPSCs-derived neurons.” Society for Neuroscience 44nd Annual Meeting, Washington DC, USA
Sekino Y, Ootsu M, Ohara Y, Yamazaki H, Sato K, Roppongi RT, Koganezawa N, Shirao T (2014) “Effects of valproic acid and astemizole on the neurite growth of human iPSCs-derived neurons.” Safety Phamacology Society, The 14th Annual Meeting, Washington DC, USA
Roppongi RT “Early development of iPSC-drived neurons.” The 6th ISN special conference satellite symposium 2014, Tokyo, Japan (Invited Presentations)
T. Roppongi, K.Hanamura, Y. Ishizuka, T. Shirao “5-HT2A receptor activation reduces the accumulation of drebrin in dendritic spines.” The 24th ISN Biennial Meeting 2013, Cancun, Mexico
Roppongi RT, Shirao T. (2012) “5-HT2A receptor activation is reduces the accumulation of drebrin in dendritic spines.” Society for Neuroscience 42nd Annual Meeting, New Orleans, USA
2016 Best Presentation, Manitoba Neuroscience Meeting, Winnipeg, Canada
2013 ISN-ESN Travel Award, 24th Biennial Meeting of ISN-ESN, Cancun, Mexico
2012 SFN-JNS Travel Award, Society for Neuroscience, New Orleans, America
2011 DEAN’S AWARD for Excellent Research Activity, Gunma University, Japan
2010 DEAN’S AWARD for Excellent Research Activity, Gunma University, Japan
2009 Best Presentation Award, 59th The Kitakanto Medical Jorunal, Japan
N. C. Luong*, Y. Abiko*, T. Shibata, K. Uchida, E. Warabi, M. Suzuki, T. Noguchi, A. Matsuzawa, Y. Kumagai, Redox cycling of 9,10-phenanthrenequinone activates epidermal growth factor receptor signaling through S-oxidation of protein tyrosine phosphatase 1B, J. Toxicol. Sci., 45 (6): 349-363, 2020. (*, equal contribution).
E. Dóka*, T. Ida*, M. Dagnell*, Y. Abiko*, N. C. Luong*, N. Balog, T. Takata, B. Espinosa, A. Nishimura, Q. Cheng, Y. Funato, H. Miki, J. M. Fukuto, J. R. Prigge, E. E. Schmidt, E. S. J. Arnér, Y. Kumagai, T. Akaike, P. Nagy, Control of protein function through oxidation and reduction of persulfidated states, Sci. Adv., 6 (1): eaax8358, 2020. (*, equal contribution).
Y. Abiko, Y. Nakai, N. C. Luong, C. L. Bianco, J. M. Fukuto, Y. Kumagai, Interaction of quinone-related electron acceptors with hydropersulfide Na2S2: Evidence for one electron reduction reaction, Chem. Res. Toxicol., 32 (4): 551-556, 2019.
Y. Abiko, L. Sha, Y. Shinkai, T. Unoki, N. C. Luong, Y. Tsuchiya, Y. Watanabe, R. Hirose, T. Akaike, Y. Kumagai, 1,4-Naphthoquinone activates the HSP90/HSF1 pathway through the S-arylation of HSP90 in A431 cells: Negative regulation of the redox signal transduction pathway by persulfides/polysulfides, Free Radic. Biol. Med., 104: 118-128, 2017.
Y. Kumagai, Y. Abiko, N. C. Luong, Chemical toxicology of reactive species in the atmosphere: two decades of progress in an electron acceptor and an electrophile, J. Toxicol. Sci., 41 (Special): SP37-SP47, 2016.
Y. Abiko, N. C. Luong, Y. Kumagai, A Biotin-PEAC5-maleimide labeling assay to detect electrophiles, J. Toxicol. Sci., 40 (3): 405-411, 2015.
Participation in Conferences
Y. Kumagai, Y. Abiko, N. C. Luong, S-Sulfuration of Cys215 is required for reversibility of PTP1B activity, Poster, The 26th Annual Conference of the Society for Redox Biology and Medicine, Las Vegas, USA, November 2019.
N. C. Luong, Y. Abiko, Y. Kumagai, 9,10-Phenanthraquinone, an atmospheric quinone, activated EGFR signaling through S-oxidation of PTP1B in A431 cells, Poster, The Society of Toxicology’s 58th Annual Meeting, Baltimore, USA, 3/2019.
N. C. Luong, Y. Abiko, Y. Kumagai, Persulfide as a protection factor to block peroxidation of protein cysteine residues, Poster, Forum: Annual Meeting on Pharmaceutical Health Science-Environmental Toxicology, Nagasaki, Japan, 9/2018.
N. C. Luong, Y. Abiko, Y. Kumagai, Activation of epidermal growth factor receptor signaling through S-oxidation of protein tyrosine phosphatase 1B in A431 cells by reactive oxygen species produced from 9,10-phenanthraquinone, Poster, The 8th International Congress of ASIAN Society of Toxicology, Pattaya, Thailand, 6/2018.
N. C. Luong, Y. Abiko, Y. Kumagai, Protection of protein tyrosine phosphatase 1B by persulfides against 9,10-phenanthraquinone-produced reactive oxygen species in vitro, Poster, The 45th Annual Meeting of the Japanese Society of Toxicology, Osaka, Japan, 7/2018.
N. C. Luong, Y. Abiko, Y. Kumagai, Reactive oxygen species produced from 9,10-phenanthraquinone activate epidermal growth factor receptor signaling through oxidative modification of protein tyrosine phosphatase 1B, Poster, The 44th Annual Meeting of the Japanese Society of Toxicology, Yokohama, Japan, 7/2017.
N. C. Luong, Y. Abiko, Y. Kumagai, Paraquat-generated reactive oxygen species activate epidermal growth factor receptor signaling pathway in A431 cells, Oral, Forum: Annual Meeting on Pharmaceutical Health Science-Environmental Toxicology, Tokyo, Japan, 9/2016.
N. C. Luong, Y. Abiko, M. Hisamori, K. Taguchi, Y. Kumagai, Interaction of 9,10-phenanthraquinone-produced reactive oxygen species with thioredoxin at a redox-active Cys32 and Cys35, Oral, Tsukuba Global Science Week 2015, Tsukuba International Congress Center, Tsukuba, Japan, 9/2015.
N. C. Luong, Y. Abiko, Y. Kumagai, 9,10-Phenathraquinone-derived reactive oxygen species activate EGFR/ERK signaling pathway in A431 cells, Oral, Forum: Annual Meeting on Pharmaceutical Health Science-Environmental Toxicology, Kobe, Japan, 9/2015.
2020 Young Investigator Award, University of Tsukuba, Japan
2018 Best Poster Award, Japan-Korea Joint Symposium, Forum 2018: Pharmaceutical Health Science-Environmental Toxicology, The Pharmaceutical Society of Japan, Nagasaki, Japan
2018 Young Investigator Award, The 8th International Congress of Asian Society of Toxicology, Pattaya, Thailand
2016-2020 Japanese Government Scholarship for Doctoral degree, MEXT
2014-2016 Japanese Government Scholarship for Master degree, MEXT
2015 Young Investigator Award, Forum 2015: Pharmaceutical Health Science-Environmental Toxicology, The Pharmaceutical Society of Japan, Kobe, Japan