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Role of Endoplasmic Reticulum Stress Response in Hyperthermia and Thermotolerance 内质网应激反应在高温和耐热性中的作用
Pub Date : 2020-07-15 DOI: 10.3191/thermalmed.36.46
Y. Tabuchi, Yukihiro Furusawa
Hyperthermia (HT) combined with chemotherapy, radiotherapy or both has been considered a promising approach in cancer therapy. However, one of the problems with the use of HT is the acquisition of thermotolerance (TT), which makes HT less effective. The endoplasmic reticulum (ER) is the central intracellular organelle responsible for the quality control of newly synthesized proteins. ER stress―defined as the accumulation of unfolded proteins in the ER―induces a cytoprotective program, the ER stress response, also known as the unfolded protein response (UPR). ER stress can be triggered by various pathophysiological conditions, such as heat shock, glucose starvation, hypoxia, and calcium deprivation. This response is mediated through three distinct sensor molecules, IRE1 (inositol requiring enzyme-1), PERK (protein kinase R-like ER kinase), and ATF6 (activating transcription factor 6), which locate at the ER membrane. Under nonstress conditions, BiP (HSPA5: heat shock protein family A (Hsp70) member 5) interacts with these sensor molecules. In contrast, under ER stress conditions, BiP dissociates from the protein conjugate, leading to the activation of three sensor molecules. Interestingly, IRE1, PERK and/or ATF6 signaling pathways are found to be activated in the cells treated with heat stress. In this review, the physiological roles of ER stress response in HT and TT are summarized.
热疗(HT)联合化疗、放疗或两者结合已被认为是一种很有前途的癌症治疗方法。然而,高温疗法的一个问题是获得耐热性(TT),这使得高温疗法效果不佳。内质网(ER)是细胞内的中心细胞器,负责新合成蛋白质的质量控制。内质网应激是指内质网中未折叠蛋白的积累引起细胞保护程序,即内质网应激反应,也称为未折叠蛋白反应(UPR)。内质网应激可由各种病理生理条件触发,如热休克、葡萄糖饥饿、缺氧和钙剥夺。这种反应是通过三个不同的传感器分子介导的,IRE1(肌醇需要酶-1),PERK(蛋白激酶r样内质网激酶)和ATF6(激活转录因子6),它们位于内质网膜上。在非应激条件下,BiP (HSPA5:热休克蛋白家族A (Hsp70)成员5)与这些传感器分子相互作用。相反,在内质网应激条件下,BiP与蛋白偶联物分离,导致三个传感器分子的激活。有趣的是,IRE1, PERK和/或ATF6信号通路被发现在热应激处理的细胞中被激活。本文就内质网应激反应在高温应激和高温应激中的生理作用作一综述。
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引用次数: 2
Heat Dose Index in vivo for Cancer Therapy Using Heat-generating Nanoparticles Named Magnetite Cationic Liposomes and Alternating Magnetic Field Irradiator 用磁铁矿阳离子脂质体和交变磁场辐照剂热剂量指数在体内治疗癌症
Pub Date : 2020-07-15 DOI: 10.3191/thermalmed.36.47
T. Morino, Shota Tanoue, Shuichi Miyata, K. Hirayama, A. Ito, T. Etani, T. Naiki, N. Kawai, T. Yasui
Cancer clinical research using heat-generating nanoparticles named magnetite cationic liposomes (MCL) and alternating magnetic field (AMF) irradiator has been conducted. Heat generation from intratumorally injected MCL particles was triggered by AMF irradiation to kill cancer cells nearby located. Tumor temperature was monitored as index to control treatment condition but efficacy was variable from complete regression to ineffective. In order to improve efficacy, we have proposed novel index of heat dose in vivo (J/cm3 tumor volume). Purpose of this study was to reveal actual heat dose in vivo and discuss its utility as index. In order to enable to estimate heat dose, heat generation activity of MCL particles (J/g-MCL・min) was measured under various AMF irradiation conditions by changing output power (kW) and distance from irradiation surface (mm). Treatment condition for complete regression of animal tumors with 7 mm diameter was reproduced and heat dose in vivo (J/cm3) was calculated by multiplying heat generation activity (J/gMCL・min) with MCL dosage (g-MCL/cm3) and irradiation time (min). Heat dose for tumor regression was revealed around 700-850 J/cm3 in every thrice AMF irradiations of a course. Since temperature-based treatments of large tumors were reported to fall into insufficiency, revealed heat dose was applied to design treatment condition of large tumor with 13-16 mm diameter, and complete regression was achieved by a course treatment. MCL dosage of temperature-based condition was found far lower than that of heat dose. Low MCL dosages (g-MCL/cm3) would cause shortage of heat dose (J/cm3) and insufficient anticancer activity, although tumor temperature could be raised by heat transfer to monitoring sites. These results showed utility of heat dose in vivo as index to ensure clinical efficacy and concomitantly to make useless invasive probe for temperature monitoring. Procedure to design treatment condition and required performance of AMF irradiator Heat dose in vivo of nanoparticles ・ T. Morino et al. 47 ― ― Received: 15 April, 2020, Accepted: 17 June, 2020: *Correspondence author; Tel, +81-52-853-8266; Fax, +81-52-852-3179; e-mail; t-morino@med.nagoya-cu.ac.jp doi: 10.3191/thermalmed.36.47 ©2020 Japanese Society for Thermal Medicine
利用磁铁矿阳离子脂质体(MCL)和交变磁场(AMF)照射体进行了肿瘤临床研究。AMF辐射触发肿瘤内注射MCL颗粒产生的热量杀死附近的癌细胞。监测肿瘤温度作为控制治疗情况的指标,但疗效从完全回归到无效不等。为了提高疗效,我们提出了新的体内热剂量指标(J/cm3肿瘤体积)。本研究的目的是揭示体内实际热剂量,并探讨其作为指标的实用性。为了估算热剂量,通过改变输出功率(kW)和距离辐照面距离(mm),测量了不同AMF辐照条件下MCL颗粒的产热活性(J/g-MCL·min)。再现直径为7 mm的动物肿瘤完全消退的治疗条件,通过生热活性(J/gMCL·min)与MCL剂量(g-MCL/cm3)和照射时间(min)的乘法计算体内热剂量(J/cm3)。在一个疗程中,每三次AMF照射,肿瘤消退的热剂量约为700-850 J/cm3。由于有报道称以温度为基础的大肿瘤治疗不足,因此采用显示热剂量设计13- 16mm直径大肿瘤的治疗条件,通过一个疗程的治疗达到完全回归。温度条件下的MCL用量远低于热剂量。低MCL剂量(g-MCL/cm3)会导致热剂量(J/cm3)不足和抗癌活性不足,尽管通过向监测点的热传递可以提高肿瘤温度。这些结果表明,体内热剂量是保证临床疗效的指标,同时也使侵入性探针在体温监测中变得无用。纳米颗粒在体内的热剂量研究·T. Morino et al. 47 - -收稿日期:2020年4月15日,接受日期:2020年6月17日:*通讯作者;电话:+ 81-52-853-8266;传真+ 81-52-852-3179;电子邮件;t-morino@med.nagoya-cu.ac.jp doi: 10.3191/thermalmed.36.47©2020日本热医学学会
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引用次数: 1
Heating Characteristics of RF Capacitive-type Heating Device 射频电容式加热装置的加热特性
Pub Date : 2020-07-15 DOI: 10.3191/thermalmed.36.59
H. Kato, Tsuneo Takasugi, Ryujiro Tanaka, Yasuji Yamamoto
RF Capacitive-type heating device (8 MHz) manufactured by Yamamoto Vinita Co., Ltd., improved the generator from EX edition with self-excited oscillator using tube to GR edition with solid-state amplifier using crystal oscillation, which led to downsizing. To prove heating characteristics of the new device, we compared the heating performance of both devices on basic heating characteristics and assumed clinical use using agar phantoms. 1) Waveforms of RF generated by both devices were similar, and those were not distorted. 2) In the experiment using a phantom for measuring the heating electricity, both devices were able to uniformly heat the phantom, and those heating efficiencies were 63 and 64%, respectively. 3) A phantom was sandwiched between a pair of electrodes, the diameter of lower electrode was fixed at 30 cm, and that of upper electrode was changed from 30 to 7 cm. The range of the heating area became shallower as the electrode became smaller. Those phenomena were same on both devices. 4) In case of a protrusion on upper side of the phantom, the temperature rise of the protrusion was higher than its surroundings. Those tendencies were same on both devices. 5) When there was an air cavity in the phantom, the temperature rises in the phantom near the air cavity facing the electrode was small, and that not facing the electrode was large. Those phenomena were the same on both devices. 6) When there was a bone in the phantom, the temperature rises in the phantom near the bone facing the electrode was small, and that not facing it was large. The temperature of the bone itself rose a little. Those phenomena were same on both devices. 7) Regardless of electrodes set in parallel or not parallel, the temperature distributions of the depth direction were same. But the temperature rises in one side of the phantom at the closer distance between two electrodes rose larger than the opposite side. Those phenomena were same on both devices. From the above, the heating device GR edition using the solid-state amplifier is upward compatible with respect to the heating device EX edition using the oscillating tube.
Yamamoto Vinita株式会社生产的射频电容式加热装置(8 MHz),将发生器从使用电子管的EX型自激振荡器改进为使用晶体振荡的固态放大器的GR型,从而实现了小型化。为了证明新设备的加热特性,我们使用琼脂模型比较了两种设备在基本加热特性和假定临床使用方面的加热性能。1)两种器件产生的射频波形相似,没有失真。2)在用模体测量加热电的实验中,两种装置都能均匀地加热模体,加热效率分别为63%和64%。3)在一对电极之间夹一个模体,将下电极的直径固定为30 cm,将上电极的直径从30 cm改为7 cm。电极越小,受热范围越浅。这些现象在两个设备上都是一样的。4)当幻肢上部有突出物时,突出物的温升高于其周围环境。这两种设备上的趋势都是一样的。5)当模体内有气腔时,靠近电极的气腔的模体温升较小,而不面向电极的气腔的模体温升较大。这些现象在两种设备上都是一样的。(6)当体模中有骨时,体模中靠近电极的骨温升小,而非靠近电极的骨温升大。骨头本身的温度上升了一点。这些现象在两个设备上都是一样的。7)无论电极平行或不平行设置,深度方向的温度分布是相同的。但是,在两个电极之间距离较近的地方,幻影一侧的温度上升幅度大于另一侧。这些现象在两个设备上都是一样的。由上可知,使用固态放大器的加热装置GR版本相对于使用振荡管的加热装置EX版本向上兼容。
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引用次数: 1
Alternative Role of Ubiquitination for Recovery from Heat Shock 泛素化在热休克恢复中的替代作用
Pub Date : 2020-03-15 DOI: 10.3191/thermalmed.38.27
Y. Nakagawa, T. Kirita, Eiichiro Mori
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引用次数: 0
Medium Temperature Independent Cytotoxicity of Cell-adhesive Heat-generating Nanoparticles Named Magnetite Cationic Liposomes and its Therapeutic Use 磁铁矿阳离子脂质体细胞黏附热纳米颗粒的中温非依赖性细胞毒性及其治疗应用
Pub Date : 2020-03-15 DOI: 10.3191/thermalmed.36.25
T. Morino, H. Takase, T. Etani, T. Naiki, N. Kawai, A. Ito, T. Yasui
Cancer clinical research using heat-generating nanoparticles named magnetite cationic liposomes (MCL) has been conducted. Heat generation from intratumorally injected MCL particles was induced by alternating magnetic field (AMF) irradiation to kill cancer cells nearby located. Its feasibility and safety have been shown but efficacy was variable among tumors whose temperature rises were similarly achieved. To ensure efficacy heat dose divided by tumor volume (J/cm3) has been proposed as candidate index to control clinical treatment. Purpose of this study is to investigate cytotoxicity of MCL particles upon AMF irradiation and discuss validity of the proposed index. MCL particles were shown to adsorb human prostate cancer cells in vitro at 2 ng-MCL/cell, depending on positive zeta potential derived from a cationic lipid component. Optical and electron microscopic observations showed majority of MCL particles located on cell membrane and scarcely in cytosol. Heat generation activities of MCL particles were represented by specific absorption rate (SAR) with unit of J/g-MCL・min and were shown variable due to irradiation conditions. Cytotoxicity of MCL particles upon AMF irradiation was found under a condition supplying heat dose of 1.2×10-4 J/cell with concomitant cellular morphological changes and membrane burst. Notably, temperature rise of culture medium was not observed under this condition. Cytotoxicity of MCL particles was considered to be caused by heat generated locally on cell membrane (J/cell) independently of medium temperature. These results would support the proposed heat dose index (J/cm3 tumor volume) to control clinical treatment instead of tumor temperature.
利用磁铁矿阳离子脂质体(MCL)作为发热纳米颗粒进行癌症临床研究。采用交变磁场(AMF)照射诱导MCL颗粒在瘤内产生热量,杀死肿瘤附近的癌细胞。其可行性和安全性已得到证实,但在温度升高相似的肿瘤中,其疗效是不同的。为保证疗效,提出热剂量除以肿瘤体积(J/cm3)作为控制临床治疗的候选指标。本研究的目的是研究AMF照射下MCL颗粒的细胞毒性,并讨论所提出的指标的有效性。MCL颗粒在体外以2 ng-MCL/细胞的速度吸附人前列腺癌细胞,这取决于来自阳离子脂质成分的正zeta电位。光学和电镜观察显示,MCL颗粒大部分位于细胞膜上,很少位于细胞质中。MCL颗粒的产热活性以比吸收率(SAR)表示,单位为J/g-MCL·min,并随辐照条件的变化而变化。在提供1.2×10-4 J/细胞热剂量的条件下,发现MCL颗粒在AMF照射下具有细胞毒性,并伴有细胞形态改变和膜破裂。值得注意的是,在这种条件下,培养基没有出现升温现象。MCL颗粒的细胞毒性被认为是由细胞膜(J/cell)局部产生的热量引起的,与介质温度无关。这些结果将支持热剂量指数(J/cm3肿瘤体积)代替肿瘤温度来控制临床治疗。
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引用次数: 3
Expression and Post-translational Modification of Heat Shock Protein 27 (HSP27) in Cancer 热休克蛋白27 (HSP27)在肿瘤中的表达及翻译后修饰
Pub Date : 2020-03-15 DOI: 10.3191/thermalmed.36.1
T. Oya-Ito, T. Takagi, Keisuke Shima, Y. Naito
Heat shock protein 27 (HSP27) is induced by heat shock, environmental, and pathophysiological stressors. HSP27 functions as a molecular chaperone and an anti-apoptotic protein in cells. Dynamic changes such as phosphorylation and oligomerization of HSP27 allow cells to adapt to changes in physiological functions and mount a protective response to damage. HSP27 is highly expressed in aggressive cancers, where it is involved in numerous pro-tumorigenic signaling pathways and is associated with poor prognosis and treatment resistant. This review focuses on the recent findings of the role of HSP27, particularly posttranslational modification of HSP27 in cancer, and the strategies for therapeutic purposes by using HSP27 inhibitors.
热休克蛋白27 (HSP27)是由热休克、环境和病理生理应激源诱导的。HSP27在细胞中具有分子伴侣和抗凋亡蛋白的功能。HSP27的磷酸化和寡聚化等动态变化使细胞能够适应生理功能的变化,并对损伤产生保护反应。HSP27在侵袭性癌症中高表达,参与多种致瘤性信号通路,与预后不良和治疗耐药相关。本文综述了近年来关于HSP27在肿瘤中的作用的研究进展,特别是HSP27在肿瘤中的翻译后修饰,以及使用HSP27抑制剂的治疗策略。
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引用次数: 0
Development of a Microwave Resonator and Effects of Electric and Magnetic Fields on Cultured Cancer Cells 微波谐振器的研制及电磁场对培养癌细胞的影响
Pub Date : 2020-02-01 DOI: 10.3191/THERMALMED.37.15
Mamiko Asano
: Microwaves can both electrically and magnetically permeate a target substance ; however, the permeation can also be affected by the components and composition of the target substance. These factors complicate our understanding of how microwave irradiation affects living cells, thus limiting the therapeutic application of microwave irradiation, such as in cancer treatment. We previously investigated how microwave irradiation promotes cell death in cancer cells and now aim to evaluate the potential mechanisms underlying microwave-induced cell death. In this study, we investigated the mechanism underlying cell death in response to microwave heating. First, a microwave resonator that could precisely control microwave energy and separately generate an electric field and a magnetic field in a dish was developed. This system was employed to confirm whether it is the electric or the magnetic field in the microwave that affects the death of the human pancreatic carcinoma cell line, Panc-1. Cells were killed at the position where the electric field strength was at a maximum, suggesting that dielectric loss might affect cell death. Meanwhile, cell death was not induced at the position where the magnetic field strength was at a maximum, suggesting that the magnetic field might not affect cell death.
微波既能电又能磁地渗透目标物质;然而,渗透也会受到目标物质的成分和组成的影响。这些因素使我们对微波辐射如何影响活细胞的理解复杂化,从而限制了微波辐射的治疗应用,例如在癌症治疗中。我们之前研究了微波辐射如何促进癌细胞的死亡,现在的目标是评估微波诱导细胞死亡的潜在机制。在这项研究中,我们研究了微波加热下细胞死亡的机制。首先,研制了一种能够精确控制微波能量并在碟形天线中分别产生电场和磁场的微波谐振器。该系统用于确定是电场还是磁场在微波中影响人胰腺癌细胞系Panc-1的死亡。细胞在电场强度最大的位置死亡,说明介电损耗可能影响细胞死亡。同时,在磁场强度最大的位置没有诱导细胞死亡,说明磁场可能不影响细胞死亡。
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引用次数: 1
Stress-induced Cellular Senescence Contributes to Chronic Inflammation and Cancer Progression 应激诱导的细胞衰老有助于慢性炎症和癌症进展
Pub Date : 2019-12-15 DOI: 10.3191/thermalmed.35.41
Shinko Kobashigawa, Yoshihiko M. Sakaguchi, S. Masunaga, Eiichiro Mori
Cellular senescence has long been considered to act as a tumor suppressor or tumor suppression mechanism and described as a phenomenon of irreversible cell cycle arrest. Cellular senescence, however, is now considered to have physiological functions other than tumor suppression; it has been found to be involved in embryogenesis, tissue/organ aging, and wound healing. Surprisingly, cellular senescence is also demonstrated to have a tumor progressive role in certain situations. Senescent cells exhibit secretory phenotypes called senescence-associated secretory phenotype (SASP), which secrete a variety of SASP factors including inflammatory cytokines, chemokines, and growth factors, as well as matrix remodeling factors that promote the alteration of neighboring tissue microenvironments. Such SASP factors have been known to drive the mechanisms underlying the pleiotropic features of cellular senescence. In this review, we examine current knowledge of cellular senescence at molecular and cellular levels, with a focus on chronic inflammation and tumor progression.
细胞衰老一直被认为是一种肿瘤抑制或肿瘤抑制机制,并被描述为一种不可逆的细胞周期阻滞现象。然而,细胞衰老现在被认为具有除肿瘤抑制之外的生理功能;它已被发现参与胚胎发生、组织/器官老化和伤口愈合。令人惊讶的是,在某些情况下,细胞衰老也被证明具有肿瘤进展作用。衰老细胞表现出分泌表型,称为衰老相关分泌表型(senescence-associated secretory phenotype, SASP),分泌多种SASP因子,包括炎症因子、趋化因子和生长因子,以及促进邻近组织微环境改变的基质重塑因子。已知这些SASP因子驱动细胞衰老多效性特征的机制。在这篇综述中,我们在分子和细胞水平上研究细胞衰老的现有知识,重点关注慢性炎症和肿瘤进展。
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引用次数: 6
A Review of Current Microwave Cancer Therapy and Mechanism of Cell Death by Microwave Irradiation 微波肿瘤治疗及细胞死亡机制研究进展
Pub Date : 2019-09-30 DOI: 10.3191/thermalmed.35.33
Mamiko Asano, Jun-Ichi Sugiyama, K. Tabuse
Microwaves (frequency: 0.3‒300 GHz) have the ability to heat materials according to their dielectric properties and are used in microwave ovens for heating food and to yield improvements in the synthesis of medicine and decomposition of environmental pollutants, among other applications. In the medical field, microwaves have been used in cancer treatments such as hyperthermia and microwave coagulation therapy, and favorable treatment results have been obtained. Cancer treatments also have advantages for various types of cancers and have few serious side effects. In contrast, in cancer cell death by microwave heating, the cells are reportedly killed via different pathways compared with that by normal heating. In the future, the treatment efficiency needs to be improved, and the associated side effects can be reduced by analyzing the cell death mechanism in detail. In this review, we outline the latest methods of microwave cancer therapy and introduce the mechanism of cancer cell death by microwave irradiation with a focus on authorsʼ reports.
微波(频率:0.3-300 GHz)具有根据介质特性加热材料的能力,在微波炉中用于加热食品,并在药物合成和环境污染物分解等应用中产生改进。在医学领域,微波已被用于癌症治疗,如热疗和微波凝血治疗,并取得了良好的治疗效果。癌症治疗对各种类型的癌症也有好处,而且几乎没有严重的副作用。相比之下,在微波加热的癌细胞死亡中,据报道,与正常加热相比,细胞通过不同的途径被杀死。在未来,需要通过详细分析细胞死亡机制来提高治疗效率,减少相关副作用。本文综述了微波治疗癌症的最新方法,介绍了微波照射导致癌细胞死亡的机制,重点介绍了作者的报道。
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引用次数: 0
Outcome of Cancer Clinical Researches Using Heat-Generating Nanoparticles and Novel Concept of its Therapeutic Use 产热纳米颗粒癌症临床研究成果及其治疗应用新概念
Pub Date : 2019-09-30 DOI: 10.3191/thermalmed.35.23
T. Morino, T. Etani, T. Naiki, N. Kawai, T. Kikumori, Y. Nishida, N. Yamamoto, T. Yasui
Cancer clinical researches using heat-generating nanoparticles have been conducted in four Japanese universities including authorsʼ universities. The nanoparticles were injected intratumorally and its heat generation was induced by external magnetic field irradiation to kill cancer cells. Three kinds of composite magnetites nanoparticles were applied to clinical researches in combination with either types of magnetic field irradiators generating different frequencies. In this paper we reviewed results of these researches with our unpublished data and discussed its potential and further refinement. Critical issues of clinical feasibility were not found in key process of treatment such as nanoparticles injection, magnetites imaging and magnetic field irradiation. A combinational use of magnetite cationic liposomes (MCL) and alternating magnetic field (AMF) irradiator was found to exhibit tumor regression activity without adverse events such as skin burn and histological damages of surrounding normal tissues. However, efficacies were found variable among tumors whose temperature rise was commonly achieved. In order to ensure efficacy, we discussed importance of MCL dosage divided by tumor volume (mg/cm3) and proposed total heat dose divided by tumor volume (J/cm3) as candidate index to control clinical treatments.
包括作者所在大学在内的四所日本大学进行了利用发热纳米粒子的癌症临床研究。将纳米颗粒注入肿瘤内,外加磁场照射诱导其产生热量杀死癌细胞。将三种复合磁铁矿纳米颗粒与产生不同频率的磁场照射器联合应用于临床研究。在本文中,我们结合未发表的数据对这些研究结果进行了回顾,并讨论了其潜力和进一步的完善。在纳米颗粒注射、磁铁矿成像、磁场照射等治疗关键环节未发现临床可行性的关键问题。研究发现,磁铁矿阳离子脂质体(MCL)和交变磁场(AMF)照射剂的联合使用显示出肿瘤消退活性,而没有皮肤烧伤和周围正常组织的组织学损伤等不良事件。然而,在体温普遍升高的肿瘤中,疗效是不同的。为了保证疗效,我们讨论了MCL剂量除以肿瘤体积(mg/cm3)的重要性,提出了总热剂量除以肿瘤体积(J/cm3)作为控制临床治疗的候选指标。
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引用次数: 5
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Thermal Medicine
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