放射生物LQ线性二次模型的数理基础及临床意义

目的：本文拟从对LQ模型提出的数学、物理、数理统计、放射生物学模型的研究分析LQ模型的数理基础和理论背景，系统阐述LQ模型的理论基础，为更好理解并应用放射生物LO模型提供理论基础，为临床放疗方案改变作参考。方法：从LQ模型的数学公式研究入手，充分发掘LQ模型计算公式得出的数理依据和放射生物学实验结果，分别从LQ模型的N无穷次贝努力实验的泊松概率模型、低LET射线和高LET射线对DNA双链造成击打原理和模型、笛卡尔坐标系和半对数坐标系的应用、细胞存活曲线的计算和表达等几个方面系统阐述LQ模型的理论基础。并研究了α损伤和卢的不同数学背景，从射线和细胞作用过程分析人手重新阐述了α、β值的放射生物学意义，同时研究了早晚反正组织中损伤等效剂量计算公式的应用范围。结果：通过对L0模型分析得到α损伤其实代表了高LET射线与细胞中靶DNA的作用模式，作用概率和辐射场粒子存在一次正相关关系，口是低LET射线与细胞中靶DNA作用的结果，和辐射场中粒子通量存在二次方正相关关系；早晚反应组织等效剂量除了需要满足f〉√βl/βN。外还需要满足本文（18）式提出的条件。结论：放射生物学LO模型不单是一个放射生物学模型，其模型得意提出和应用和辐射剂量学、分析数学、数理统计学、生物物理学等学科息息相关，只有深刻理解以上学科在该模型中意义才能正确理解和应用LO模型。     

滋养细胞肿瘤DNA图像定量分析

目的:探讨图像分析技术对滋养细胞肿瘤DNA定量分析的应用价值.方法:应用图像分析技术对33例滋养细胞肿瘤细胞核DNA含量进行了定量测定和比较.结果:从正常绒毛→良性葡萄胎→恶性葡萄胎→绒毛膜癌:DNA含量和非整倍体细胞呈增高趋势.恶性葡萄胎和绒毛膜癌明显高于良性葡萄胎和正常绒毛,有显著性差异(P<0.01).良性葡萄胎高于正常绒毛,但两者相比无显著性差异(P>0.05).绒毛膜癌高于恶性葡萄胎,但两者相比亦无显著性差异(P>0.05).结论:图像分析仪对滋养细胞肿瘤DNA定量分析,可对该肿瘤的诊断、化疗、预后提供重要信息.     

病毒与人类肿瘤

人类肿瘤的病因和发病机理迄今尚不清楚。肿瘤病毒是一种生物性致癌因子，具有生物的基本特性，含有DNA或RNA，能进行复制和遗传，产生子代病毒。肿瘤病毒对人有感染性，有些病毒对某些细胞具有特异亲嗜作用，引发疾病，并诱发肿瘤。肿瘤病毒的核酸能够整合到宿主细胞DNA链上，使人体细胞发生转化。有些肿瘤病毒基因组中含有病毒癌基因(viral oncogene，v-onc)，可编码转化蛋白-癌蛋白(oncoprotein)，使细胞发生恶性变化。RNA肿瘤病毒的v-onc，实际上起源于细胞癌基因(cellular oncogene，c-onc)，两者序列同源。c-onc存在于正常细胞中，而它的异常激活产生过量的编码蛋白，而又可诱发癌变。     

妊高征胎盘、脐血管中TNF-α表达及组织病理变化的研究

目的研究妊高征患者胎盘和脐血管组织中肿瘤坏死因子(TNF-α)的表达及组织的病理变化情况.方法采用SABC法对轻、中、重度妊高征共27例和正常妊娠组10例的胎盘和脐血管组织进行TNF-α的免疫组化染色,观察各组TNF-α的定位、分布和表达量的差异.同时常规HE染色观察胎盘等形态学变化.结果各组均可见TNF的表达,其定位和分布无差异,主要见于合体滋养细胞、蜕膜细胞、血管内皮细胞和平滑肌细胞等.但中、重度妊高征组TNF的表达量较正常组显著升高(P<0.05,P<0.01).此外,中、重度妊高征组可见细胞滋养细胞增生,合体细胞结节、纤维素样坏死显著增多等病理变化,与正常组相比有显著性差异.结论妊高征时,胎盘、脐血管亦可能是TNF-α的重要产生释放部位.且TNF-α可能通过某些直接或间接的途径,参与了妊高征损伤和代偿并存的复杂变化,在妊高征的发生发展中起着重要作用.     

白血病抑制因子在子宫肌瘤组织中表达的研究

目的了解白血病抑制因子(LIF)在子宫肌瘤组织和正常子宫肌组织中的表达是否存在差异,探讨LIF与子宫肌瘤发病的相关性。方法运用免疫组织化学技术检测30例子宫肌瘤病人子宫肌瘤组织(实验组)和正常子宫肌组织(对照组)中LIF的表达。结果 LIF在所有标本中均有低表达,但在实验组和对照组无明显差异(P0.05)。结论 LIF与子宫肌瘤的发病可能无明显关系,但可能对维持子宫肌组织的正常分化、使子宫肌瘤组织不发生恶变具有一定的作用。     

同一创面不同病程糖尿病足创面组织细胞凋亡率、Bcl-2、Bax及肿瘤坏死因子α的相关性

文题释义：“4C”法：通过颜色(Colour)、毛细血管出血(Capillary bleeding)、收缩力(Contractility)和紧张度(Consistency)判断是否坏死的方法。一般认为组织呈现暗紫/黄/白色、质地软、切割不出血和刺激无收缩状态，为坏死指征，在临床清创时应被清除。 细胞凋亡：是指机体为维持内环境稳定，由基因控制的细胞自主、有序性的死亡形式。主要分为生理和病理两大类，生理性凋亡是指机体内某些细胞生来就注定在一段时间后死去，在尽完自己的职责之后正常死亡；而病理性凋亡则是指细胞在没有完成自己的使命时受到不可抗外力刺激而不正常死亡，从而引发各种疾病。 背景：研究发现，难愈性溃疡创面不易愈合与细胞凋亡失衡和炎症失调有关，以往的研究均在不同个体的某一类型组织取样研究，研究结果数据间可能存在个体差异的影响，且无同一糖尿病足创面不同病程组织的细胞凋亡率、Bcl-2、Bax、肿瘤坏死因子α表达水平之间相关性研究报道。 目的：分析糖尿病足不同病程创面组织细胞凋亡率、Bcl-2、Bax和肿瘤坏死因子α表达水平间的关系及作用机制。 方法：重庆医科大学附属第二医院急诊科收治的15例Wagner 2，3级糖尿病足患者，选择典型的糖尿病足创面，采用“4C”法将局部感染控制后的创面组织区分为坏死、过渡和正常组织后分别采集标本，测定细胞凋亡率、Bcl-2、Bax、Bax/Bcl-2和肿瘤坏死因子α，并对结果进行统计分析。研究经重庆医科大学附属第二医院伦理委员会批准，编号：(2019)329号，所有患者均签署了知情同意书。 结果与结论：①糖尿病足创面正常、过渡、坏死组织的细胞凋亡率分别为(16.67±2.48)%、(43.68±2.22)%和(72.12±4.53)%，差异有显著性意义(P < 0.01)；②坏死、过渡和正常组织间Bcl-2、Bax、肿瘤坏死因子α表达水平和Bax/Bcl-2差异有显著性意义(P < 0.01)，Bcl-2表达：坏死组织<过渡组织<正常组织，Bax、肿瘤坏死因子α表达及Bax/Bcl-2：坏死组织>过渡组织>正常组织；③Bcl-2、Bax、Bax/Bcl-2、肿瘤坏死因子α和细胞凋亡率间呈曲线关系，曲线回归分析结果显示，糖尿病足创面内肿瘤坏死因子α与Bax、Bax/Bcl-2、细胞凋亡率呈高度正相关，与Bcl-2呈高度负相关；④从结果可得出，细胞凋亡机制与炎症反应参与了糖尿病足创面病理过程，其作用机制可能与下调Bcl-2表达，上调Bax和肿瘤坏死因子α表达，提高Bax/Bcl-2水平，引起组织细胞凋亡率增大有关。 ORCID: 0000-0002-9760-8666(郑敏) 中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程     

人组织因子途径抑制因子重组蛋白表达菌株的建立

组织因子途径抑制因子是机体凝血过程的主要抑制因子，在血栓形成性疾病的防治中具有广阔的应用前景。本研究采用pGEX—2T为表达载体、大肠杆菌细胞为表达宿主进行了人组织因子途径抑制因子重组蛋白的制备。制备的重组蛋白产量较高，纯化过程简单，且具有良好的抑制组织因子的功能。     

TNF-α活化人瘢痕疙瘩成纤维细胞NF-κB的实验研究

目的：观察肿瘤坏死因子－α（TNF-α）对瘢痕疙瘩成纤维细胞（KFB）以及正常皮肤成纤维细胞（NSF）核因子-kappa B（NF-κB）的影响，以探讨瘢痕疙瘩的发生机制。 方法:原代培养成纤维细胞；免疫荧光技术观察NF-κB p65和IκB-α在静息状态和TNF-α刺激后的成纤维细胞中分布；应用TransAMTM NF-κB p65 kit试剂盒检测NF-κB p65 DNA结合活性；应用Western blotting检测IκB-α蛋白水平。 结果: TNF-α刺激后，NF-κB p65从细胞浆转移至细胞核；NF-κB p65 DNA结合活性水平在刺激后1 h达到高峰，4 h接近正常；细胞浆IκB-α蛋白水平在刺激后15 min降至最低值，4 h基本接近正常；KFB较NSF对TNF-α的刺激更为敏感。结论: KFB较NSF对TNF-α活化 NF-κB更为敏感, 可能是瘢痕疙瘩形成的潜在发病机制。     

壳聚糖载基因纳米粒子的研究

以壳聚糖为基质研究载基因纳米粒子的制备及其对血管平滑肌细胞的转染效率。制备载绿色荧光蛋白(Enhanced green fluorescen t prote in,EGFP)和组织因子途径抑制因子(T issue factor pathw ay inh ib itor,TFP I)质粒DNA的壳聚糖纳米粒子,透射电镜观察两种纳米粒子皆呈球形,光子相关色谱仪(PCS)测定显示纳米粒子的平均粒径为149 nm,粒径分布在80~250 nm之间;载基因纳米粒子的DNA包埋效率和DNA含量分别为96%±1.38%和37%±3.0%。载基因壳聚糖纳米粒子可以有效地保护DNA,防止核酸酶对其的降解作用。血管平滑肌细胞转染实验表明,纳米粒子对细胞基本无毒性,其转染效率与阳离子脂质体转染试剂L ipofectAM INETM相近。     

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.     

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.     

Biological optimization of heterogeneous dose distributions in systemic radiotherapy

The standard computational method developed for internal radiation dosimetry is the MIRD (medical internal radiation dose) formalism, based on the assumption that tumor control is given by uniform dose and activity distributions. In modern systemic radiotherapy, however, the need for full 3D dose calculations that take into account the heterogeneous distribution of activity in the patient is now understood. When information on nonuniform distribution of activity becomes available from functional imaging, a more patient specific 3D dosimetry can be performed. Application of radiobiological models can be useful to correlate the calculated heterogeneous dose distributions to the current knowledge on tumor control probability of a homogeneous dose distribution. Our contribution to this field is the introduction of a parameter, the F factor, already used by our group in studying external beam radiotherapy treatments. This parameter allows one to write a simplified expression for tumor control probability (TCP) based on the standard linear quadratic (LQ) model and Poisson statistics. The LQ model was extended to include different treatment regimes involving source decay, incorporating the repair "micro" of sublethal radiation damage, the relative biological effectiveness and the effective "waste" of dose delivered when repopulation occurs. The sensitivity of the F factor against radiobiological parameters (alpha, beta, micro) and the influence of the dose volume distribution was evaluated. Some test examples for 131I and 90Y labeled pharmaceuticals are described to further explain the properties of the F factor and its potential applications. To demonstrate dosimetric feasibility and advantages of the proposed F factor formalism in systemic radiotherapy, we have performed a retrospective planning study on selected patient case. F factor formalism helps to assess the total activity to be administered to the patient taking into account the heterogeneity in activity uptake and dose distribution, giving the same TCP of a homogeneous prescribed dose distribution. Animal studies and collection of standardized clinical data are needed to ascertain the effects of nonuniform dose distributions and to better assess the radiobiological input parameters of the model based on LQ model.     

生长因子在关节软骨损伤修复中的应用进展

关节是人体重要的运动器官,其组织结构特殊,成熟关节软骨组织没有血供,一旦损伤难以自愈.临床上常用的关节软骨损伤修复手段有微骨裂术、关节软骨移植、关节置换术、软骨组织工程等,但这些方法的修复效果都不理想.生长因子是体内组织分泌的一种具有生物活性的物质,可促进细胞生长、增殖、迁移和分化.软骨发育过程中有许多生长因子参与,如成纤维细胞生长因子(FGF)、骨形态发生蛋白(BMP)、胰岛素样生长因子(IGF)等.研究显示,在关节软骨修复过程中加入外源性生长因子可有效促进关节软骨损伤的修复.对目前应用于关节软骨损伤修复研究中的生长因子进行综述,讨论这些生长因子在关节软骨发育及其在关节软骨修复中的作用,分析生长因子在关节软骨修复应用中存在的问题.     

A nanodosimetry-based linear-quadratic model of cell survival for mixed-LET radiations

A new nanodosimetry-based linear-quadratic (LQ) model of cell survival for mixed-LET radiations has been developed. The new model employs three physical quantities and three biological quantities. The three physical quantities are related to energy depositions at two nanometre scales, 5 nm and 25 nm. The three biological quantities are related to the lesion production and interaction probabilities and the lesion repair rate. The coefficients alpha and beta of the LQ formula (alpha D + beta D(2)) are explicitly expressed in terms of the three physical quantities and the three biological quantities. The new model is shown to be consistent with the previously published cell survival curves of V-79 cells. The advantage of this new model is that it can be conveniently adopted to estimate the iso-effect for radiotherapies that involve ionizing radiation of mixed LET. An example is given to estimate the cell survival fractions for a high-dose-rate mixed neutron and gamma-ray field from a (252)Cf source.     

高频率微波信号对微波消融效果影响的仿真研究

生物体的介电常数能反映其对微波频率的响应程度,相同微波频率下,不同生物组织的介电常数存在差异,在不同频率的微波消融过程中,微波对消融对象的材料选择性也存在差异性。参照乳腺癌结构建立肿瘤、脂肪相接的生物模型,对比研究高频率微波(6、12、18 GHz)和传统微波(915、2 450 MHz)的消融特性,讨论高频率微波信号在微波消融领域应用的可行性。模拟结果显示,当消融时间达到600 s时,微波频率为12 GHz对正常组织损伤最少,相比正常组织误杀范围最大的2 450 MHz小61.6%;当肿瘤区域达到100%消融时,微波频率为6 GHz对正常组织损伤最少,相比正常组织误杀范围最大的2 450 MHz小71.4%;当肿瘤边缘温度达到52℃时,微波频率为18 GHz时肿瘤边缘两侧温差最大,6 mm区域内最大温差达111.2℃,相同区域内2 450 MHz温差仅为40.1℃。模拟结果表明,高频率微波对介电常数较高的肿瘤组织材料选择性较强,相对于传统的915和2 450 MHz的微波消融,高频率微波具有对周围正常组织的损伤低、消融范围集中的优点。     

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).     

In vivo study of human skin using pulsed terahertz radiation

Studies in terahertz (THz) imaging have revealed a significant difference between skin cancer (basal cell carcinoma) and healthy tissue. Since water has strong absorptions at THz frequencies and tumours tend to have different water content from normal tissue, a likely contrast mechanism is variation in water content. Thus, we have previously devised a finite difference time-domain (FDTD) model which is able to closely simulate the interaction of THz radiation with water. In this work we investigate the interaction of THz radiation with normal human skin on the forearm and palm of the hand in vivo. We conduct the first ever systematic in vivo study of the response of THz radiation to normal skin. We take in vivo reflection measurements of normal skin on the forearm and palm of the hand of 20 volunteers. We compare individual examples of THz responses with the mean response for the areas of skin under investigation. Using the in vivo data, we demonstrate that the FDTD model can be applied to biological tissue. In particular, we successfully simulate the interaction of THz radiation with the volar forearm. Understanding the interaction of THz radiation with normal skin will form a step towards developing improved imaging algorithms for diagnostic detection of skin cancer and other tissue disorders using THz radiation.