线性二次模型的演变和发展

细胞中的DNA是辐射敏感的靶，击中DNA双链是导致细胞死亡的主要原因。但不同组织的细胞对射线的敏感性存在差异。为了更好的解析这种差异，线性二次模型（LQ模型）被提了出来，它用α／β来反映正常组织修复损伤的能力，较好的解释了肿瘤组织与正常组织反应的差别，为我们预测放射治疗中生物效应和预后提供了依据。但一直以来由于LQ模型涉及的知识范围较广，彻底掌握并熟练应用的难度较大，为此本文从LQ模型的提出，引入时间因子、修复因子等方面简述LQ模型发展和演变的基本过程，探讨LQ模型的局限和应用条件，以期对大家掌握应用该模型能有所帮助。     

211 At标记单克隆抗体肿瘤放射免疫治疗的研究进展(文献综述)

将放射性核素标记到单抗(Monoclonal antibody, McAb)上,利用单抗的肿瘤导向作用和放射性核素的细胞毒作用进行肿瘤的放射免疫治疗,是当今肿瘤核医学的主要研究方向之一.建立有效的放射免疫治疗方法首先考虑的是放射性核素的选择以及核素的辐射特性要与肿瘤的靶特征相适应.目前治疗常用核素多是β射线辐射体如90Y等,β射线是低LET,对细胞的杀伤力较弱,β射线在生物组织中射程为1～10mm,对于微小病灶和非实体瘤,因β射线的射程远大于病灶或细胞的直径,所以β粒子的主要能量不能释放在病灶或肿瘤细胞内,不能有效地杀死病变细胞.同时β粒子的大量能量被释放在周围正常组织,造成的毒性作用非常明显,严重限制其应用.而选择发射短射程、高LET射线的核素用于导向治疗则可提高治疗效率,降低毒副作用[1,2].因此,选用发射α射线的核素标记抗肿瘤单抗,用于肿瘤的放射免疫治疗很有潜力.本文就211At标记单抗及其片段在肿瘤导向治疗中的应用研究进展作一简要综述.     

海带多糖调节小鼠小胶质细胞活化保护放射损伤后的海马记忆功能

目的:观察海带多糖(laminaria japonica polysaccharides,LJP)对小胶质细胞活性和放射诱导脑损伤后海马记忆功能的影响。方法:将120只2月龄雌性昆明小鼠随机分为对照组、LJP组、放射组、放射+LJP组,每组30只。用60Co射线制作小鼠的放射诱导脑损伤模型,LJP腹腔注射于放射前1 d进行,放射后4 d结束。采用Morris水迷宫观察LJP对放射后1 d、7 d、14 d小鼠空间记忆功能的影响;采用免疫组织化学法观察小胶质细胞标记物Iba-1的表达;ELISA检测海马中IL-1β、TNF-α含量。结果:放射后,小鼠在水迷宫中第1次找到平台的时间延长、穿越平台的次数减少(P0.05);经LJP防治后的小鼠在各时间点找到平台的时间比放射组缩短、穿越平台的次数也增加(P0.05);放射后1 d、7 d、14 d,放射组小鼠海马小胶质细胞胞体面积明显增大(P0.01),细胞突起变粗、数量明显增多(P0.01),IL-1β、TNF-α含量明显增多(P0.05);经LJP处理后,与放射组相比,小胶质细胞突起逐渐变小,细胞面积和突起数量也减少,IL-1β、TNF-α含量减少(P0.05)。LJP组和对照组未见差异。结论:LJP处理可以通过调节小胶质细胞活性、降低IL-1β、TNF-α含量保护放射损伤后的海马记忆功能。     

整合素β1介导鼻咽癌放射抗拒

目的探讨整合素β1在鼻咽癌放射治疗的作用和机制。方法通过分析两个鼻咽癌表达芯片,比较整合素β1在鼻咽癌组织和非鼻咽癌组织中的表达水平差异;通过Real-time PCR,比较整合素β1在31例鼻咽癌组织和10例非鼻咽癌组织中的表达水平差异;通过分析基因表达芯片,比较鼻咽癌放射敏感细胞株CNE2和放射抗拒细胞株CNE2R中,整合素β1的表达水平;应用逆转录病毒感染鼻咽癌放射治疗抗拒细胞株CNE2R,构建两株整合素β1干扰表达细胞株;应用流式细胞分析技术,检测干扰后整合素β1表达水平;应用不同放射剂量X射线照射细胞株,通过克隆形成实验、γ-H2AX染色以及细胞周期实验,检测整合素β1干扰前后,放射抗拒细胞株CNE2R放射敏感性的变化。结果与非鼻咽癌组织相比较,鼻咽癌组织中整合素β1高表达;与鼻咽癌放射敏感细胞株相比较,鼻咽癌放射抗拒细胞中整合素β1高表达;在鼻咽癌放射抗拒细胞株中,干扰整合素β1表达后,可以有效降低放射治疗存活分数,减弱细胞DNA损伤修复。结论整合素β1介导鼻咽癌放射抗拒。     

电离辐射氧化应激致轻度认知功能障碍及其综合干预的研究

电离辐射氧化应激致机体细胞内水分子水解产生活性氧和自由基或直接损伤DNA等靶分子,脑组织细胞凋亡致海马体积缩小,并在脑膜、大脑皮层和海马的血管壁内可见β淀粉样蛋白沉积,神经组织的病理损伤,引起脑部认知功能障碍.神经功能发生改变轻度认知功能障碍成为当今研究的热点,本文系统阐述了电离辐射氧化应激致机体轻度认知功能障碍(MCI)的发生机制、临床表现与临床诊断,讨论了生物学标志物检测、影像学检查、综合干预对MCI的诊断和预防价值.     

DNA靶结构的辐射原始损伤突变的亚分子机理

放射生物学中,人们已应用靶学说在细胞和亚细胞水平上,讨论了细胞存活曲线,辐射对核酸和酶的作用;在分子水平上,讨论了DNA分子的损伤。但由于生物体的可变性、随机性,用靶学说描述上述过程都遇到了一定的困难。尽管生物体细胞的组成与功能差异很大,但在亚分子水平上,都有相同的DNA构     

单细胞凝胶电泳技术及其应用

由Ostliny于1984年首创的单细胞凝胶电脉（SCGE）用于检测CNA单或双链缺口．具有简单、灵敏、迅速且不需放射性核素标记等优点。其基本原理是将单个细胞包埋于琼脂糖凝胶中进行裂解、电泳、荧光染色和显微镜检测,细胞DNA损伤产生的链缺口在电泳中迁移形成典型的"彗星"图像（故又称CometAssay）。根据迁移长度和荧光强度即可定量分析DNA损伤,故该方法在放射生物学、遗传毒理学、群体生物学监测、肿瘤发病机制、肿瘤治疗学以及细胞凋亡等领域具有广泛的应用前景。     

人参粗提物对肠道辐射损伤的保护作用

目的 探讨人参粗提物对辐射导致急性肠道损伤的保护作用。方法 利用小动物X射线辐照仪诱导小鼠急性肠道损伤，检测小鼠辐射损伤后的生存时间。小肠组织切片行HE染色，光镜下观察肠上皮组织病理学改变。BrdU掺入实验检测肠隐窝细胞增殖与再生；应用免疫荧光染色、qRT-PCR和Western blot法检测肠细胞凋亡和DNA损伤；运用qRT-PCR检测肠细胞中细胞因子表达水平。结果 在X射线诱导小鼠急性肠道损伤模型中，人参粗提物(200 mg/kg)明显延长小鼠辐射损伤后的生存期(由6天延长至7天),并改善肠上皮组织病理状况。人参粗提物明显提高肠隐窝细胞损伤后增殖修复水平(再生隐窝数由17.1个增加到25.3个),抑制p53-PUMA介导的细胞凋亡(凋亡细胞数由1.2个下降到0.7个),减少DNA损伤累积，促进修复相关细胞因子、抑制损伤相关细胞因子的mRNA表达。结论 人参粗提物对X射线诱导的小鼠急性肠道损伤具有保护作用，其与抑制细胞凋亡、减少DNA损伤累积和调节相关细胞因子表达有关。     

NIV毒素和硒对软骨细胞IL-1β、TNF-α分泌的影响

目的:通过测定NIV毒素和硒作用下软骨细胞IL-1β、TNF-α含量的变化,从细胞因子角度探讨大骨节病发病机制。方法:在体外单层和立体培养的人胚软骨细胞中加入NIV毒素和硒,构建软骨损伤模型,收集软骨组织、细胞和细胞培养液,用光学显微镜观察体外构建组织的形态;用分光光度法测定软骨细胞DNA含量;用酶联免疫吸附方法(ELISA)检测细胞培养液中IL-1β、TNF-α的水平。结果:形态学观察发现NIV毒素能抑制软骨细胞生长,局部出现点片状坏死;毒素加硒后,上述损伤变化减弱。NIV毒素作用下软骨细胞DNA的合成受到抑制,但培养液中IL-1β、TNF-α含量显著升高,毒素加硒与毒素组变化趋势一致,但数值略下降。结论:NIV毒素能诱导软骨细胞IL-1β与TNF-α的分泌,这可能是造成软骨细胞损伤的原因之一。     

NF-kB介导脂氧素A4拮抗TNF-α所致的系膜细胞白介素的合成

为研究脂氧素A4(LXA4)拈抗肿瘤坏步E因子α(TNF-α)对肾小球系膜细胞的白介素(IL）-β(IL-1β)、IL-6合成的作用。对体外培养大鼠肾小球系膜细胞，用不同浓度的LXA4预刺激，再加入TNF-α共同孵育；或单用TNF-α刺激肾小球系膜细胞。在孵育后用ELISA法检测培养上清中的IL-1β,IL-6蛋白表达量；用RT-PCR法检测IL-1β、IL-6的mRNA表达量。应用凝胶电泳迁移率试验（EMSA)测定核因子-kB(NF-KB)的DNA结合活性。结果发现，LXA4呈剂量依赖性地抑制TNF-α诱导的肾小球系膜细胞IL-1β和IL-6蛋白的合成与mRNA表达，抑制NF-kB的DNA结合活性。说明LXA4通过下调NF-kB的DNA结合活性，拮抗TNF-α对肾小球系膜细胞的IL-1β、IL-6合成的促进作用。     

Equivalence of the linear-quadratic and two-lesion kinetic models

Double strand breaks (DSBs) are widely accepted as the main type of DNA damage responsible for cell killing in the range of doses and dose rates relevant to radiation therapy. Although the standard linear-quadratic (LQ) model with one first-order repair term often suffices to explain the results of some radiobiological experiments, converging lines of evidence suggest that DSBs are rejoined at two or more distinct rates. A two-lesion kinetic (TLK) model has been proposed to provide a direct link between biochemical processing of the DSBs and cell killing. A defining feature of the TLK model is that the family of all possible DSBs is subdivided into simple and complex DSBs, and each kind may have its own unique repair characteristics. Break-ends associated with both kinds of DSB are allowed to interact in pairwise fashion to form irreversible lethal and non-lethal chromosome aberrations. This paper examines the theoretical and practical linkages between the TLK and LQ models. The TLK formalism is used to derive an LQ formula with two first-order repair terms (dose protraction factors) and to relate the intrinsic radiosensitivity parameters used in one model to the parameters used in the other. Two extensive radiobiological datasets, one for CHO 10B2 cells and one for C3H 10T1/2 cells, are analysed using the TLK and LQ models. The LQ with two repair terms and the TLK are equally capable of explaining the CHO 10B2 and C3H 10T1/2 cell survival data. For the doses and dose rates most relevant to radiation therapy, tests of model equivalence indicate that an LQ formula with two first-order repair terms is an excellent approximation to the TLK model. We find the LQ and TLK models useful complementary tools for the analysis and prediction of radiobiological effects.     

放射生物学数学模型的研究进展

目的：放射生物学数学模型随着放射治疗的发展不断被提出,最早提出了L-Q模型和靶模型,由于靶模型形式较为复杂、参数较多,L-Q模型得到了广泛的应用。但是随着SRS、SBRT大剂量放疗的出现,越来越多的证据表明,L-Q模型在大剂量范围计算精度不高,尤其是从常规低剂量到大剂量。研究者提出了新的放射生物学数学模型。方法：本文按照模型被提出的时间顺序对L-Q模型、SH-MT模型、ML-Q模型、USC模型、gL-Q模型进行阐述。结果：ML-Q模型、USC模型、gL-Q模型与实验数据符合较好。结论 ：相比较而言,对于目前SRS、SBRT大剂量照射,USC模型和gL-Q模型可能更为适用,但USC模型和gL-Q模型的适用性和模型中的参数仍需进一步的确认。     

Radiobiological assessment of non-standard and novel radiotherapy treatments using the linear-quadratic model

The linear-quadratic (LQ) model is useful in the radiobiological assessment of a wide variety of radiotherapy treatment techniques, not being confined to analysis of fractionated treatments alone. The model uses parameters that must be separately specified for tumours and dose-limiting normal tissues, and may therefore be used to help identify treatments that are most likely to maximise tumour cell kill while minimising the risk of severe normal-tissue damage. Additionally, the model is capable of making tentative allowance for the tumour repopulation that can occur during extended treatments. Intercomparisons between different types of treatment are made through the concept of the Extrapolated Response Dose (ERD). The ERD is calculated for each critical tissue and takes account of both the radiobiological parameters and the dose/time pattern of radiation delivery. Known tolerance doses for specified organs may be expressed as an ERD_tolerance value, and, if a proposed ‘new’ treatment is to be successful, its associated ERD value must not exceed ERD_tolerance. Examples of this procedure are given in this paper. It is particularly important that medical physicists fully appreciate the scope and limitations of LQ equations, as the analysis of radiobiology problems using the model often requires a degree of mathematical understanding that clinicians may not possess.     

链脲佐菌素小鼠糖尿病胰岛结构改变的定量病理学测试及分析

目的:定量揭示链脲佐菌素（Streptozotocin, STZ）诱发的小鼠糖尿病胰岛结构改变的特点,为分析胰岛功能改变补充定量病理学基础。方法:腹腔注射STZ,诱发Balb/c小鼠糖尿病;过量CO2处死小鼠并取胰腺,常规病理制样、胰岛素免疫组化染色、图像测试及定量分析。结果:造模第8周,糖尿病组（DM组）小鼠血糖显著高于正常对照组（NC组）小鼠,DM组小鼠血糖均值为19.3 mmol/L;相比NC组小鼠,DM组小鼠胰岛数目、β细胞数目及面积显著减少（P<0.05）,计算得出β细胞数量丧失约62.7％,胰岛β细胞面积丧失约27.0%,胰岛素阳性单位（PU值）表达减少约53.8％。DM组小鼠胰岛β细胞面积密度（AAβ,PI）、面数密度（NAβ,PI）、数量百分比（βPer）均显著降低（P<0.05）,其中PU值、AAβ,PI、βPer与血糖升高呈负相关,皮尔森相关系数（R值）分别为-0.653、-0.736和-0.899（显著性均<0.05）;建立造模时间（t）与胰岛β细胞数量百分比改变的函数:[βPer(%)=79.68-9.74t+0.38t2+0.06t3-4.66×10-3t4+2.86×10-5t5+1.68×10-5t6]。结论:通过定量病理学技术测量糖尿病小鼠模型胰岛和β细胞形态学改变的相关指标,能够帮助准确评估胰岛的损伤情况,并建立血糖变化和所测量数值的相关数学模型,用以预测血糖升高导致胰岛损伤的具体情况。 【关键词】糖尿病;胰岛;定量病理学;阳性单位;链脲佐菌素     

Is the increased relative biological effectiveness of high LET particles due to spatial or temporal effects? Characterization and OER in V79-4 cells

The efficiency of producing biological damage varies with radiation quality. Conventional explanations rely on spatial differences in the radiation track structure; generally however there are also very large temporal differences in delivery of the radiation at the cellular level. High-LET radiation normally deposits substantial amounts of energy by individual heavily ionizing tracks on a timescale of the order of picoseconds. By contrast each low-LET radiation track deposits a small amount of energy. Many of these tracks, distributed over the whole cell, are required to deliver an equivalent dose to a high-LET track and they are usually delivered over much longer timescales (typically seconds) during which chemical, biochemical and biological processes are occurring. In this paper the design, characterization and initial application of a high-brightness, laser-plasma ultrasoft x-ray source is described. This has been used to investigate the importance of the temporal differences by irradiating mammalian cells with an energy deposition with spatial properties of low-LET radiation and temporal properties similar to high-LET radiation. The present system delivers a typical dose, to the incident surface of the cells, of 0.12 Gy per pulse delivered in <10 ps. The capabilities of the x-ray source were tested by determining the survival of V79-4 hamster cells irradiated with picosecond pulses of ultrasoft x-rays under aerobic and anaerobic conditions, which were found to be consistent with previously published non pulsed data with x-rays of similar energy. These results support the expectation that the disappearance of an oxygen effect for high-LET radiation particles is due to their spatial properties rather than the very short timescale of each particle traversal. For other effects, particularly non-targeted phenomena such as induced genomic instability, expectations may be less clear cut.     

Development of semi-empirical model for radiochemical reactions.

A mathematical model, which represents the radio-chemical reactions in water, was developed to study the effect of the radio-chemical products on cell killing. The five differential equations were solved using dose rate equation and cell survival as a function of dose was computed. The known chemical rate constants were taken from the literature and unknown constants were determined by curve fitting to an experimental data. Sensitivity studies were performed by varying the rate constants and showed that the yield of H-radical had little effect whereas the change in concentration of OH-radical and direct interaction resulted in significant change on cell survival. The sensitivity studies showed good agreement with the observed effects. In conclusion, we developed a mathematical model that could be used as a means for the estimation of radiation damage.     

A mathematical model of malignant tissue sterilization probability

Conclusions 1. A mathematical model for determining the PS of malignant tissue as a function of its volume and DF scheme was developed. It is assumed that malignant tissue consists both of typical cells and cells with enhanced radioresistance. The number of radioresistant malignant cells is proportional to the total number of cells in the tumor. The dependence of the survival rate of typical and radioresistant cell subpopulations on the radiation dose is described by LQ functions. 2. A software complex for determining the LQ function parameters and the relative number of radioresistant cells based on clinical data was developed. 3. The developed software complex calculates the PS of malignant tissue as a function of its volume, type, and DF scheme. 4. Four examples of practical use of the software complex for determining parameters of the mathematical model and calculating the PS of malignant tissue are presented. This work was supported by the Russian Foundation for Basic Research (project No. 980100057).     

An approach to modelling radiation damage by fast ionizing particles

This paper presents a statistical approach to modelling the damaging effects of radiation by fast heavy ionizing particles in small biological structures such as enzymes, viruses, and some cells. Irreparable damage is assumed to be caused by the occurrence of ionizations within sensitive regions of a structure. For structures containing double-stranded DNA, one or more ionizations occurring within each strand of the DNA will cause inactivation; for simpler structures without double-stranded DNA a single ionization within the structure will be sufficient for inactivation. Damaging ionizations occur along tracks of primary irradiating particles or along tracks of secondary particles released at primary ionizations. An inactivation probability is derived for each damage mechanism, and is expressed in integral form in terms of the radius of the biological structure (assumed spherical), the rate of ionization along primary tracks, and the maximum energy for secondary particles. The performance of each model is assessed by comparing results from the model with results derived from data from various experimental studies extracted from the literature. For the simpler structures, where a single ionization is sufficient for inactivation, the model gives qualitatively promising results. However, for larger more complex structures containing double-stranded DNA, the model requires some further refinements.