大分割碳离子放射治疗中相对生物学效应与剂量依赖关系的研究

应用碳离子束进行大分割放射治疗从而缩短治疗周期是碳离子束治疗的优势之一。为研究大分割放疗增加单次照射剂量后,碳离子束相对生物学效应（RBE）的变化,应用细胞存活线性平方（LQ）模型推导出RBE与剂量的依赖关系。基于此关系研究了具有不同辐射敏感性的肿瘤细胞和正常组织细胞RBE随剂量的变化。结果表明,在0~20 Gy范围内,不论肿瘤细胞与正常组织细胞具有怎样的辐射敏感性,肿瘤细胞的RBE值始终大于正常组织细胞。此外,基于理论推导和对相关实验数据的分析,证实了RBE随剂量增加而递增现象的存在。这些结果对应用碳离子束进行大分割放射治疗具有重要的指导作用。Short treatment course due to the suitability of hypofractionated regimen for carbon ion beam is one of the advantages of carbon ion radiotherapy. To study the dependence of relative biological effectiveness (RBE) on dose, the relationship between RBE and dose was deduced through the linear-quadratic (LQ) model. Based on the relationship, the change of RBE of tumor cells and normal tissue cells with different radiosensitivities with dose was studied. The results showed that the RBE value of tumor cells was always greater than that of normal tissue cells in the dose range of 0~20 Gy, regardless of the radiosensitivity of tumor and normal tissue cells. In addition, based on theoretical deduction and analysis of the relevant experimental data, the existence of RBE increase with increasing dose was verified. These results are of great significance for conducting hypofractionated radiotherapy with carbon ion beam.     

基于细胞红外光谱预测乙酰化细胞的辐射敏感性

组蛋白乙酰化是表观遗传修饰的一种重要方式。肿瘤细胞的组蛋白大部分呈现低乙酰化状态,而组蛋白去乙酰化酶抑制剂（histone deacetylase inhibitor,HDACi）可以增加肿瘤细胞的乙酰化水平,诱导细胞周期阻滞及凋亡。曲古菌素A （trichostatin A,TSA）是组蛋白去乙酰化酶抑制剂的代表药物之一,能够提高肿瘤细胞组蛋白和非组蛋白的乙酰化水平。傅里叶变换红外（Fourier Transform Infrared,FTIR）光谱可以对无染色、无标记的生物样品进行无损检测,具有特征性明显、快速、分辨率高、重复性好等优点,已被广泛用于细胞的微观生物过程的研究。本文利用红外光谱技术结合免疫荧光技术的手段,研究TSA处理细胞后的乙酰化作用效果,发现红外光谱中甲基与亚甲基的伸缩振动强度之比能够表征细胞内的乙酰化水平变化,然后基于红外光谱的分析结果预测了乙酰化状态不同的细胞辐射敏感性的变化。结果表明,乙酰化细胞的辐射损伤效应可以通过甲基与亚甲基的伸缩振动强度之比进行评价,且该比值与细胞的辐射敏感性呈正相关,表明红外光谱技术可以辅助预测细胞的辐射敏感性,并进行细胞表观遗传学特征与辐射效应关系的研究。Histone acetylation is one of important epigenetic modifications, and histone in most of tumor cells shows low acetylation state. However, histone deacetylase inhibitor (HDACi) can correct abnormal acetylation status, induce cell cycle arrest and apoptosis. Trichostatin A (TSA) is one of the representatives of histone deacetylase inhibitors, which can inhibit histone deacetylase, increase the acetylation level of histone and nonhistone in cell. Fourier transform infrared (FTIR) spectroscopy is a powerful analytical tool which can detect nondestructively, quatitatively and quantitatively biological samples without bio-tagging and bio-labeling. FTIR spectroscopy technology has multiple advantages, including finger-print characteristics, rapid analysis, high resolution and good repeatability. Therefore, it has been widely used in the research of biological processes. This work applied FTIR spectroscopy to study the changes in cells treated with TSA, compared the acetylation level according to FTIR intensity ratio of methyl to methylene stretching vibration, and based on the FTIR analysis predicted the radiosensitivity of the cells with different acetylation levels. As a result, we have verified that the damage caused by radiation in acetylated cells can be evaluated by the ratio of methyl and methylene intensity which is positively correlated with cellular radiosensitivity. Therefore, this work demonstrates that FTIR spectroscopy can be useful for the prediction of radiosensitivity and may also open a door for the study of relationship between epigenetics and radiation bio-effects.     

Effects of Nitric Oxide on Growth and Sensitivity of Human Glioma A172 Cells to ^60Co and X-ray Radiation

Nitric oxide (NO)has been implicated both in regression and progression of tumors due to its production by both tumor cells and infiltrating lymphocytes. Ionizing radiation causes the regression of tumors, and can augment the production of NO by macrophages in vitro. The authors examined the effect of nitric oxide (NO) generating agent sodium nitroprusside (SNP) on the growth and radiosensitivity of cultured glioma A172 cells to ^60Co or X-ray radiation.     

Stochastic responses of tumor-immune system with periodic treatment

We investigate the stochastic responses of a tumor–immune system competition model with environmental noise and periodic treatment. Firstly, a mathematical model describing the interaction between tumor cells and immune system under external fluctuations and periodic treatment is established based on the stochastic differential equation. Then, sufficient conditions for extinction and persistence of the tumor cells are derived by constructing Lyapunov functions and Ito's formula. Finally, numerical simulations are introduced to illustrate and verify the results. The results of this work provide the theoretical basis for designing more effective and precise therapeutic strategies to eliminate cancer cells, especially for combining the immunotherapy and the traditional tools.     

A Method to Design Synthetic Cell-Cycle Networks

The interactions among proteins, DNA and RNA in an organism form elaborate cell-cycle networks which govern cell growth and proliferation. Understanding the common structure of cell-cycle networks will be of great benefit to science research. Here, inspired by the importance of the cell-cycle regulatory network of yeast which has been studied intensively, we focus on small networks with 11 nodes, equivalent to that of the cell-cycle regulatory network used by Li et al. [Proc. Natl. Acad. Sci. USA 101（2004）4781] Using a Boolean model, we study the correlation between structure and function, and a possible common structure. It is found that cascade-like networks with a great number of interactions between nodes are stable. Based on these findings, we are able to construct synthetic networks that have the same functions as the cell-cycle regulatory network.     

Research on spatial-variant property of bistatic ISAR imaging plane of space target

The imaging plane of inverse synthetic aperture radar(ISAR) is the projection plane of the target. When taking an image using the range-Doppler theory, the imaging plane may have a spatial-variant property, which causes the change of scatter’s projection position and results in migration through resolution cells. In this study, we focus on the spatial-variant property of the imaging plane of a three-axis-stabilized space target. The innovative contributions are as follows. 1) The target motion model in orbit is provided based on a two-body model. 2) The instantaneous imaging plane is determined by the method of vector analysis. 3) Three Euler angles are introduced to describe the spatial-variant property of the imaging plane, and the image quality is analyzed. The simulation results confirm the analysis of the spatial-variant property. The research in this study is significant for the selection of the imaging segment, and provides the evidence for the following data processing and compensation algorithm.     

乏氧细胞线粒体与肿瘤辐射抗性

综述了乏氧环境对细胞整体和对线粒体的影响,正常细胞线粒体呼吸链在乏氧环境下的损伤及其与肿瘤的关系,并对肿瘤细胞适应乏氧环境的机制进行了阐述。总结了线粒体作为供能细胞器,对肿瘤细胞在乏氧条件下生长、侵袭和转移及获取能量过程中的作用,并介绍了中国科学科院近代物理研究所利用重离子辐照所做的相关研究成果,包括不同剂量重离子对线粒体DNA超螺旋构象及线粒体功能的影响,同一剂量不同时间重离子辐照后对线粒体DNA 4 977 大片段损伤累积的影响。The hypoxia environment on the cells and mitochondria, and the damage of normal cells mitochondrial respiratory chain in hypoxia and its relationship with tumors are reviewed. In addition, the tumor radiation resistance mechanism in hypoxia are summarized. It also expounds that mitochondria, as energy supply organelles for cells, are related to tumor cells growth, invasion and metastasis in hypoxia environment, besides, it gives a brief introduction to the mitochondria study of the Institute of Modern Physics, Chinese Academy of Sciences with heavy ion irradiation, including effects of different dose of heavy ion on mitochondrial DNA superhelix conformation and function of mitochondria,and the influence on mitochondrial DNA 4 977 damage cumulation in different time after the same dose of heavy ion irradiation.     

重离子束在微生物诱变育种及生物能源开发中的应用

作为一种新型的辐射诱变源, 重离子束在辐射诱变育种中的优越性已经显现。 在此基础上综述了重离子束用于微生物诱变育种的基本原理、 独特优点、 所取得的成果及研究进展, 并对其在新型生物能源开发中的潜力进行了展望。As a new radiation source, heavy ion beams have demonstrated the outstanding advantage in mutation breeding. Based on this background, the basic principal and unique peculiarity of heavy ion beams, the achievement and the progress in the research of microbial mutation breeding are reviewed in the paper. The potential application of heavy ion beams to new biological energy is also prospected.     

辐射基因治疗在肿瘤治疗中的研究现状

目前肿瘤基因治疗尚存在许多问题, 距临床应用还有相当的距离, 但是在传统的放疗、化疗和手术治疗的基础上, 辐射与基因治疗的有机结合在肿瘤治疗中却显示出可喜的前景。综述了近年来这一领域的研究进展, 探讨了这一疗法对肿瘤治疗的应用前景。Although tumor gene therapy has a distance to clinical use due to some problems, the combination of irradiation and gene therapy holds much promise in cancer therapy based on the traditional radiotherapy, chemotherapy and surgery. We have termed this therapeutic radiogenic therapy. This review focuses on the group of radiogenic therapy that are either: ⑴ improvement of gene transfer efficiency by irradiation; ⑵ radiotherapy combined with cytokines gene delivery or enhancement of the immunity of tumor cells by transgene; ⑶ directly stimulated by radiation to produce either directly or indirectly cytotoxic agents; ⑷ increasing of radiosensitivity in gene therapy; ⑸ radioprotective gene therapy enhances radiation tumor killing effect while protecting the normal tissue and organs with transgene using transfer vector.     

Extinction Effects of Multiplicative Non-Gaussian L′evy Noise in a Tumor Growth System with Immunization

The extinction phenomenon induced by multiplicative non-Gaussian Levy noise in a tumor growth model with immune response is discussed. Under the influence of the stochastic immune rate, the model is analyzed in terms of a stochastic differential equation with multiplicative noise. By means of the theory of the infinitesimal generator of Hunt processes, the escape probability, which is used to measure the noise-induced extinction probability of tumor cells, is explicitly expressed as a function of initial tumor cell density, stability index and noise intensity. Based on the numerical calculations, it is found that for different initial densities of tumor cells, noise parameters play opposite roles on the escape probability. The optimally selected values of the multiplicative noise intensity and the stability index are found to maximize the escape probability.     

Estimating the effectiveness of human-cell irradiation by protons of a therapeutic beam of the joint institute for nuclear research phasotron using cytogenetic methods

The effectiveness of the impact of therapeutic proton beams in human cells with respect to the criterion of formation of chromosome aberrations in human-blood lymphocytes is estimated. The physical characteristics of radiation (proton LET at the input of the object and in the region of the modified Bragg peak) and the role of the biological factor (the differences in the radiosensitivity of nondividing cells corresponding to the irradiation of normal tissues along the proton-beam path and tumor tissues) are taken into account. The relative biological effectiveness of protons is ∼1 at the beam input of the object and ∼1.2 in the Bragg peak region. Taking into account the higher radiosensitivity of dividing cells in the G ₂ phase of the cell cycle, the irradiation effectiveness increases to ∼1.4.     

Genetic variations in medical research in the past,at present and in the future

As we look so different, our genomic sequences vary enormously. The differences in our genome, genetic variations, have played very significant roles in medical research and have contributed to improvement of medical managements in the last 2–3 decades. Genetic variations include germline variations, somatic mutations, and diversities in receptor genes of rearranged immune cells, T cells and B cells. Germline variants are in some cases causative of genetic diseases, are associated with the risk of various diseases, and also affect drug efficacies or adverse events. Some somatic mutations are causative of tumor development. Recent DNA sequencing technologies allow us to perform single-cell analysis or detailed repertoire analysis of B and T cells. It is critically important to investigate temporal changes in immune environment in various anatomical regions in the next one to two decades. In this review article, we would like to introduce the roles of genetic variations in medical fields in the past, at present and in the future.     

Ultrasound exposure in the presence of hematoporphyrin induced loss of membrane integral proteins and inactivity of cell proliferation associated enzymes in sarcoma 180 cells in vitro

Ultrasonically induced effects of hematoporphyrin (HPD) on cell damage and membrane protein alteration of S180 isolated tumor cells in vitro were investigated, and the potential mechanisms of sonodynamic therapy (SDT) inhibiting tumor growth were discussed. Tumor cells suspended in air-saturated PBS (pH 7.2) were exposed to ultrasound at 1.8 MHz for up to 180 s in the presence and absence of HPD. The viability of cells was determined by a trypan blue exclusion test. To estimate the damage effects of SDT on plasma membrane of tumor cells primarily, membrane integral proteins (EGFR, Ras, Fas, FasL) and cell proliferation associated enzymes (adenylate cyclase and guanylate cyclase) were checked with immunochemical methods. The results indicated that the intensity threshold for ultrasonically induced cell damage at 1.8 MHz was 3 W/cm². At this condition, the expression of the integral proteins was obviously inhibited and the activity of the enzymes was decreased post ultrasound treatment in the presence of 20 μg/ml HPD. Loss of the membrane proteins and inactivity of AC and GC post SDT was time-dependent. This paper reveals SDT can cause the loss of tumor cell membrane integral proteins and inactivity of the enzymes associated with cell proliferation which might be attributed to a sonochemical activation mechanism. The mechanisms by that tumor growth is inhibited by SDT can be understood as that the growth signaling pathway is partially interdicted and the resistance of tumor cells to the specifically activated immune cells is weakened.     

内源性蛋白质分子成像的研究进展

酰氨质子转移（amide proton transfer, APT）成像是一种新的分子MRI技术,它可用来测量组织中内源性蛋白质. 理论上,APT-MRI信号强度主要取决于游离蛋白质的酰氨质子浓度以及交换速度,而酰氨质子交换速度与组织pH有关. 因此,APT-MRI技术已经被用于无创性中风pH成像（通常pH降低）和肿瘤蛋白质含量成像（通常蛋白质量提高）. 近期对大鼠的实验表明,APT-MRI技术可用来区分放射性坏死和胶质瘤. 该综述文章简要地介绍了APT成像的基本原理以及它在动物模型与临床中风和肿瘤成像中的应用.     

Multiscale models for the growth of avascular tumors

In the past 30 years we have witnessed an extraordinary progress on the research in the molecular biology of cancer, but its medical treatment, widely based on empirically established protocols, still has many limitations. One of the reasons for that is the limited quantitative understanding of the dynamics of tumor growth and drug response in the organism. In this review we shall discuss in general terms the use of mathematical modeling and computer simulations related to cancer growth and its applications to improve tumor therapy. Particular emphasis is devoted to multiscale models which permit integration of the rapidly expanding knowledge concerning the molecular basis of cancer and the complex, nonlinear interactions among tumor cells and their microenvironment that will determine the neoplastic growth at the tissue level.     

超声声动力学激活血卟啉抗肿瘤效应研究的新进展

在综合国内外有关文献的基础上,评述了超声声动力学激活血卟啉抗肿瘤效应研究的新进展,不仅阐明了超声声动力学疗法（SDT）及其离体,活体实验研究现状和杀伤肿瘤细胞的检测方法,而且提供了实验中得到的最佳声参量范围,最后指出了今后研究应注意的问题。     

Human genetic deficits in glycan formation

Glycans are associated with most proteins found in secretions and on the surface of mammalian cells. Glycans of secreted glycoproteins affect many protein properties such as solubility, stability, protease sensitivity, and polarity, while glycans on cell surface glycoproteins are involved in various cellular functions including cell-cell and cell-matrix interactions during embryogenesis, immune reactions, and tumor development. Recent advances in human genomic research together with newly developed and sensitive methods for the analysis of glycan structures have elucidated the etiology of a growing number of human genetic diseases with aberrant glycan formation. Among these diseases, defects of protein N-glycosylation and O-mannosylation are reviewed here. The former is relatively common and the latter is rather uncommon. Both types of defects lead to severe abnormalities, which indicate the importance of glycosylation. Sequencing of the human genome is essentially complete and now glycobiology becomes an important area of postgenomic research. Glycobiology is expected to produce remarkable advances in the understanding and treatment of certain genetic diseases.