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    Contents lists available at ScienceDirect
    Nuclear Inst. and Methods in Physics Research B
    journal homepage:
    Application of a vertical charged-particle irradiation platform in glioblastoma multiforme cancer stem cell research 
    a Department of Electronic Engineering, National Kaohsiung University of Science and Technology, Kaohsiung, Taiwan b Nuclear Science and Technology Development Center, National Tsing Hua University, Hsinchu, Taiwan c Department of Radiation Oncology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan d Department of Medical Imaging and Radiological Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan e Institute for Radiological Research, Chang Gung University and Chang Gung Memorial Hospital, Taoyuan, Taiwan
    Charged-particle accelerator
    Cell irradiation platform
    Cancer stem cell
    Double-strand break repair 
    Cancer stem cells (CSCs) are characterized by two critical properties similar to those of normal stem cells, namely, self-renewal and differentiation. Therefore, they play a crucial role in tumor development and tumor treatment responses. Glioblastoma multiforme (GBM) is the most aggressive form of Phosphatase Inhibitor Cocktail II tumor in humans, with extremely poor survival rates. GBM CSCs are believed to contribute to cancer initiation, invasion, metas-tasis, and recurrence, and they can also lead to poor conventional radiation therapy and chemotherapy out-comes. Efficiently eliminating CSCs is thus crucial to developing GBM treatment strategies. This study aimed to demonstrate the application of a vertical charged-particle irradiation platform in CSC research. The cell irra-diation results indicated that GBM CSCs were more radio-resistant and had a higher survival rate than ordinary GBM tumor cells. Expression of DNA double-strand break (DSB) repair modulation protein in GBM CSCs was also higher than in ordinary GBM tumor cells, suggesting that the radioresistance of GBM CSCs might be relative to efficient DNA DSB repair. Targeting the DNA DSB repair mechanism could thus be a potential strategy for enhancing GBM tumor control. All of the results demonstrated that the vertical charged-particle irradiation platform provides a suitable environment for CSC charged-particle irradiation research.
    1. Introduction
    Glioblastoma multiforme (GBM) is the most common and lethal primary brain tumor in adults. Mean survival of GBM patients is ap-proximately 12–15 months after diagnosis [1], with the 5-year survival rate at less than 5% [2]. Poor chemotherapy and radiation therapy outcomes of GBMs represent a challenge for neuro-oncologists. It has been demonstrated that poor prognosis of GBM is strongly correlated with GBM cancer stem cells (CSCs) [3].
    CSCs, or cancer initiation cells, are a rare and quiescent sub-population of cancer cells that are considered responsible for cancer initiation, invasive growth, metastasis, and recurrence [4]. CSCs were first identified in solids tumors by Al-Hajj et al. in 2003 [5]. Since then, an increasing number of CSCs have been discovered in various tumor types, including leukemia, lung, breast, colon, and brain tumors. Tirino et al. reported that CSCs exhibit the characteristics of normal stem cells, such as self-renewal and differentiation [6]. Other studies have found
    Corresponding author.
    1 I-Chun Cho and Fang-Hsin Chen contributed equally to this work. 
    that these characteristics prove CSCs's connection with indefinite tumor growth and tumor population heterogeneity [7,8]. Although CSCs have been extensively studied for over a decade, a thorough knowledge of them is still lacking. Indeed, the origin of CSCs remains a mystery for oncology scientists. CSCs may have originated from normal stem cell tumorigenesis or multiple mutagenesis of differentiated cells [9]. One thing that has been confirmed by research is their high resistance to traditional cancer treatment methods, such as radiation therapy and chemotherapy [10]. Therefore, effectively eliminating CSCs in tumors is critical to developing cancer treatment strategies.
    It is believed that high linear energy transfer (LET) particles, such as α-particles or carbon ions, can induce complex and irreparable DNA damage in cells along their trajectory. Therefore, high-LET particle therapy—such as boron neutron capture or carbon therapy—has been widely employed by oncologists to improve the prognosis of patients with GBM cancer. In this study, we demonstrated the application of a vertical charged-particle irradiation platform in examining
    radiobiological response in general GBM cells and GBM CSCs following 2.0-MeV α-particle irradiation. Recruitment and dissipation of the DNA double-strand break (DSB) repair protein γ-H2AX were examined to evaluate the DNA damage repair capacity of test cells after α-particle and X-ray irradiation. We also compared the cell survival rate of general GBM cells and GBM CSCs after radiation exposure to assess their radioresistance.