ハーバード大／MGH Dr. Held ラボ
The International Open Laboratory anticipates conducting studies in several inter-related areas to address some of the numerous challenges and opportunities for radiation biology research relevant to heavy ion therapy. First, our MGH team has long had an interest in elucidating molecular mechanisms underlying the radiation-induced bystander effect. The bystander effect is the observation that unirradiated cells near to (e.g., in cell cultures) or more distant from (e.g., in organs and organisms) irradiated cells show biological changes as a result of receiving signals transmitted from the irradiated cells. There are important questions about whether the cells that receive the radiation-stimulated intercellular signals respond in ways that are detrimental, e.g., leading to cancer or tissue damage, or beneficial, e.g., removing damaged cells. Equally important are questions about the nature of the signals, which have been suggested to be reactive oxygen or nitrogen species, cytokines, cAMP, etc. We will continue 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. Second, with regards to the use of charged particles in cancer therapy, we are interested in several clinically relevant topics: hypofractionation, hypoxia and cancer stem cells. Frequently, heavy ion therapy is given in a smaller number of larger dose fractions compared to conventional photon therapy, and there are data to suggest this hypofractionation is more effective biologically. This may be due to effects on vasculature, immune stimulation or other mechanisms, but studies are needed on the mechanisms and magnitude of the effectiveness. Also, it has long been realized that hypoxic cells, which are present in many tumors and are resistant to conventional radiation therapy, are less resistant to heavy ion therapy, although the magnitude of this effect in various tumor types and fractionation patterns is not clear. Lastly, a number of studies have indicated that cancer stem cells are more resistant to conventional photon irradiation than non-stem cancer cells, but more recent data suggest that cancer stem cells may be less resistant to carbon ion therapy. It is important to clearly elucidate the generality of these findings in several cancer types and evaluate the underlying molecular processes.
MGH（マサチューセッツ総合病院）は、HMS（ハーバードメディカルスクール＝ハーバード大学 医学系大学院）にとって最古で最大規模の教育研究病院であり、200年近い協力関係にある。また、MGH所属の多くの医師・研究者が、HMSにおいても教員の地位を持っている。 MGHは、全米で３番目に古い総合病院で、全米病院ランキングのトップ５に継続的に入っている。（US News & World Report)
・Wakatsuki M, Magpayo N, Kawamura H, Held KD. The lack of a bystander response induced by X-rays, protons and heavy ions in chondrosarcoma cells. Int J Radiat Oncol Biol Phys 2012; 84(1):e103-8.
・Butterworth KT, McGarry CK, Clasie B, Carabe-Fernandez A, Schuemann J, Depauw N, Tang S, McMahon SJ, Schettino G, O’Sullivan JM, Lu H-M, Kooy H, Paganetti H, Hounsell AR, Held KD, Prise KM. Relative biological effectiveness (RBE) and out-of-field cell survival responses to passive scattering and pencil beam scanning proton beam deliveries. Phys Med Biol. 2012; 57:6671-6680.
・Liu Q, Xu C, Kirubakaran S, Zhang X, Hur W, Liu Y, Kwaitkowski NP, Wang J, Westover KD, Gao P, Ercan D, Niepel M, Thoreen CC, Kang SA, Patricelli MP, Wang Y, Tupper T, Altabef A, Kawamura H, Held KD, Chou DM, Elledge SJ, Janne PA, Wong K, Sabatini DM, Gray NS. Biochemical, cellular and in vivo characterization of Torin2, an ATP-competitive mTOR, ATM and ATR inhibitor. Cancer Res. 2013; 73(8):2574-2586.
・Durante M, Reppingen N, Held KD. Immunologically augmented cancer treatment using modern radiotherapy. Trends Mol Med. 2013; 19(9):565-582.
・Kesler CT*, Kuo A*, Wong H-K, Masuck DJ, Shah JL, Kozak KR, Held KD, Padera TP. Vascular endothelial growth factor-C enhances radiosensitivity of lymphatic endothelial cells. Angiogenesis 2014; 17(2):419-427.
・Liu Q, Ghosh P, Magpayo N, Tang S, Testa M, Biggs P, Paganetti H, Efstathiou JA, Lu HM, Held KD, Willers H. Lung cancer cell line screen links Fanconi anemia/BRCA pathway defects to increased relative biological effectiveness of proton radiation. Int J Radiat Oncol Biol Phys. 2015; 91(5):1081-1089.
・Liu Q, Wang M, Kern AM, Khaled S, Han J, Yeap BY, Hong HS, Settleman J, Benes CH, Held KD, Efstathiou JA, Willers H. Adapting a drug screening platform to discover associations of molecular targeted radiosensitizers with genomic biomarkers. Molec Cancer Res. In press.
・Held KD. Charged particles for cancer treatment: The benefits of ions over photons. Symposium on Targeting Tumors: Ion Beam Accelerators Take Aim at Cancer at the AAAS Annual Meeting, Chicago, IL, February, 2014
・Held KD. High-LET-induced DNA damage and bystander signaling. 13th International Workshop on Radiation Damage to DNA, MIT, Cambridge, MA, June 2014.
・Held KD. Education and training needs in the radiation sciences. 60th Annual Meeting of the Radiation Research Society, Las Vegas, NV, September, 2014.
・Held KD. Charged particle radiobiology research at MGH and thoughts on research at GIAR. The 1st International Symposium of Gunma University Initiative for Advanced Research (GIAR), Gunma, Japan, February 2015.
The radiation-induced bystander effect occurs when un‐irradiated cells exhibit effects like those in irradiated cells as a result of signals received from nearby irradiated cells such as Reactive Oxygen Species (ROS), Nitric Oxide (NO) and other inflammatory signals (cytokines, TNF‐alpha, etc.). The bystander effect is being observed in various situation, this effect on neurons and glial cells are poorly understood.
Although mature well-developed neurons are known to be radioresistant (Shirai et al., 2006; Shirai et al., 2013), which is not causing immediate neuronal cell death, indeed there is an effect of irradiation on neuronal function (Puspitasari et al., 2016).
The previous study showed that there is an acute transient radiation-induced effect on the synaptic dysfunction of higher brain function within 24 h following irradiation; this effect also could be caused by the indirect effect from irradiated glial cells to the neurons. In response to irradiation increase of ROS, NO, and other inflammatory signals may change expressions of receptors in neurons. The irradiated glial cells might produce or release a gliotransmitter; that may affect the synaptic function of neurons. Gliotransmitter such as glutamate could trigger excitotoxicity and cause neurotoxic underlying many acute incidents such as brain ischemia and trauma. Homeostatic maintenance of glutamate by both neurons and astrocytes also is thought to play a major role in the radiation response (Sanchez et al., 2010). Here, we would like to reveal the possibility of the radiation-induced bystander effect in neurons and also in glial cells. We are now focusing on radiation effects on cells communications of neurons and glial cells.
・X Irradiation Induces Acute Cognitive Decline via Transient Synaptic Dysfunction, Anggraeini Puspitasari, Noriko Koganezawa, Yuta Ishizuka, Nobuhiko Kojima, Natsume Tanaka, Takashi Nakano and Tomoaki Shirao, Radiation Research Apr 2016, Vol. 185, No. 4 (April 2016) pp. 423-430 (presence of peer review)
・A New System for Three-dimensional Clinostat Synchronized X-irradiation with a High-speed Shutter for Space Radiation Research, Hiroko Ikeda, Hikaru Souda, Anggraeini Puspitasari, Kathryn D. Held, Jun Hidema, Takeshi Nikawa, Yukari Yoshida, Tatsuaki Kanai, Akihisa Takahashi, Biological Sciences in Space, 2016.12.19.
・Development and performance evaluation of a three-dimensional clinostat synchronized heavy-ion irradiation system, Hiroko Ikeda, Hikaru Souda, Anggraeini Puspitasari, Kathryn D. Held, Jun Hidema, Takeshi Nikawa, Yukari Yoshida, Tatsuaki Kanai, Akihisa Takahashi, Life Sciences in Space Research, 2017.1.21.
・The 2nd International Symposium of Gunma University Program for Leading Graduate School. Anggraeini Puspitasari; Title “Early effects of X irradiation on learning and synaptic proteins”. (invited),2014
・Society for Neuroscience 2014, Washington DC, US. Anggraeini Puspitasari, Noriko Koganezawa, Nobuhiko Kojima, Mayu Isono, Yukari Yoshida, Tomoaki Shirao. [Acute effect of X irradiation and carbon ion-irradiation on fear memory formation and its underlying mechanism],2014
・The 37th Annual Meeting of the Japan Neuroscience Society. Neuroscience 2014, Yokohama, japan. Anggraeini Puspitasari, Noriko Koganezawa, Nobuhiko Kojima, Mayu Isono, Yukari Yoshida, Tomoaki Shirao. [Acute effect of carbon ion irradiation on hippocampal neuronal cell death and fear memory formation],2014
・The 25th Meeting of the International Society for Neurochemistry, Cairns, Australia, ISN 2015 Biennial Meeting. Anggraeini Puspitasari, Noriko Koganezawa, Yuki kajita, Tomoaki Shirao [Transient effect of X-irradiation and Carbon ion irradiation on synaptic function],2015
・The 6th International Society of Radiation Neurobiology Conference (ISRN-2016-Nagasaki, Japan). Anggraeini Puspitasari with the title [Irradiation effects on higher brain function with low and high LET radiation]. (invited),2015
・The 58th Annual Meeting of the Japanese Society for Neurochemistry, Omiya, Saitama, Japan. Anggraeini Puspitasari, [The acute immediate effect of X-irradiation and Carbon ion irradiation on synaptic function and fear memory formation.],2015
・The 3rd International Symposium of Gunma University Initiative for Advanced Research (GIAR); Gunma, Japan. What is the radiation-induced bystander effect? From the point of view of Neurons and Glia,2016
・The 62nd annual International Meeting Radiation Research Society, Waikoloa Village-Big Island, Hawaii. Anggraeini Puspitasari, Hidemasa Kawamura, Kathryn D. Held, Tomoaki Shirao, Takashi Nakano. [The radiation-induced bystander effects on synaptic function of mature neurons.],2016
・International Workshop of Gunma University Program for Leading Graduate Schools on Feb 8, 2017 (invited); Effect of Radiation on Higher Brain Function : Neuroscience’s Investigation.
・ The 7th International Society of Radiation Neurobiology Conference on Feb 9-10, 2017; Acute and Chronic Effect of Low Dose X-irradiation on Immature Hippocampal Neurons In Vitro.
•2017 – 2018 Granted research from KAKENHI; Grant-in-Aid for Young Scientists B category.
•2012 – 2016; Scholarships from “The Program for Cultivating Global Leaders in Heavy Ion Therapeutics and Engineering”, Gunma University.
•2015; Gunma University Graduate School of Medicine, DEAN’S AWARD for an excellent presentation at Seminar for Presentation and Discussion. [The irradiation effects on higher brain function with electromagnetic radiation and particulate radiation], Gunma University.
•2015; Best Poster Presentation Award, “International Society of Radiation Neurobiology 5th Conference, Takasaki, Japan.” [The irradiation effects on higher brain function with low-LET radiation and high LET radiation], Gunma University.
•2015; Granted research from “The Program for Cultivating Global Leaders in Heavy Ion Therapeutics and Engineering”, Gunma University.
•2014; Best Presentation Award “The 2nd International Seminar of the Gunma University Program for Cultivating Global Leaders in Heavy Ion Therapeutic and Engineering”, with the title [Early effects of X-irradiation on learning and synaptic protein], Gunma University.
•2014; Granted research from “The Program for Cultivating Global Leaders in Heavy Ion Therapeutics and Engineering”, Gunma University.
•2013; Granted research from “The Program for Cultivating Global Leaders in Heavy Ion Therapeutics and Engineering”, Gunma University.
・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., 12:51-60.2017.
・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, 30:8-16, 2016.
・Yokota Y, Funayama T, Mutou-Yoshihara Y, Ikeda H, Kobayashi Y. The bystander cell-killing effect mediated by nitric oxide in normal human fibroblasts varies with irradiation dose but not with radiation quality. Int. J. Radiat. Biol., 91:383-388, 2015.
・Autsavapromporn N, Suzuki M, Funayama T, Usami N, Plante I, Yokota Y, Mutou Y, Ikeda H, Kobayashi K, Kobayashi Y, Uchihori Y, Hei TK, Azzam EI, Murakami T. Gap junction communication and the propagation of bystander effects induced by microbeam irradiation in human fibroblast cultures: the impact of radiation quality. Radiat. Res., 180:367-375, 2013.
・Ikeda H, Muratani M, Puspitasari A, Held KD, Hidema J, Yoshida Y, Takahashi A. Comprehensive gene expression analysis of human fibroblasts after combined exposure to microgravity and heavy-ions for simulating space conditions. 7th International Society of Radiation Neurobiology Conference, Niigata, Japan, 2017.
・Ikeda H, Hidema J, Nikawa T, Yoshida Y, Souda H, Kanai T, Takahashi A. Development of 3D-clinostat synchronized heavy-ion irradiation system. 11th Asian Microgravity Symposium, Hokkaido, Japan, 2016.
・Ikeda H, Yokota Y, Funayama T, Kanai T, Nakano T, Kobayashi Y. Patterning irradiation for contact co-culture of different type cells using heavy-ion microbeam. 12th International Workshop on Microbeam Probes of Cellular Radiation Response, Tsuruga, Japan, 2015.
・Ikeda H, Yokota Y, Funayama T, Kanai T, Nakano T, Kobayashi Y. Analysis of medium-mediated bystander effects induced by carbon-ion irradiation between human lung normal and cancer cells. 15th International Congress of Radiation Research, Kyoto, Japan, 2015.
・Ikeda H, Funayama T, Yokota Y, Kanai T, Kobayashi Y. Establishment of experimental systems for analyzing bystander effects induced by heavy-ion irradiation between normal and cancer cells. 11th International Workshop on Microbeam Probes of Cellular Radiation Response, Bordeaux, France, 2013.
・Ikeda H. Support project of research for thesis in Fiscal Year 2014: Financial support for participating in “2015 Radiation Epidemiology and Dosimetry Course” at the National Cancer Institute, Roclville, MD, USA, 2015.
・Ikeda H. Support project of research for thesis in Fiscal Year 2014: Supporting for PhD student, 2014-2015.
・Ikeda H. Award for Emerging Technology. 11th Young Researcher’s Presentation and Discussion Meeting, Atomic Energy Society of Japan, Kanto-Koetsu Branch, 2012.