Effects of low dose pre-irradiation on the toxicity of cyclophosphamide

Objective:The aim of the study was to investigate the effects as well as the possible mechanisms of low dose γ-ray pre-irradiation on hepatic damage,DNA damage of peripheral lymphocytes and genetic material damage caused by high dosage of cyclophosphamide(CTX).Methods:Kunming strain male mice were randomly divided into five groups:control group,sham-irradiated group,low dose irradiation group(LDR group),cyclophosphamide chemotherapy group(CTX group) and low dose irradiation combined with chemotherapy group(LDR + CTX group).Having being raised for one week,all the mice were implanted subcutaneously with S180 cells in the left inguen(control group excluded).On days 8 and 11,mice of LDR and LDR + CTX groups were given 75 mGy whole-body γ-irradiation,30 h later mice of CTX and LDR + CTX groups were injected i.p.3.0 mg cyclophosphamide.All the mice were sacrificed on day 13.DNA damage of the peripheral lymphocytes was analyzed using single cell gel electrophoresis(SCGE);ALT activity,total protein(TP) and albumin(ALB) of the plasma were analyzed using automatic biochemistry analyzer;MDA content,SOD and GSH-PX activity of the hepatic homogenate were analyzed using chromometry;genetic material damage was analyzed using micronucleus frequency(MNF) of polychromatoerythrocytes(PCE) in bone marrow.Results:1.Differences of MDA contents,SOD and GSH-PX activity of hepatic homogenate between 5 groups had notable statistical significance(P < 0.01);in control group MDA content was the lowest,SOD and GSH-PX activity were the highest,while in CTX group MDA content was the highest,SOD and GSH-PX activity were the lowest;compared with CTX group MDA content decreased significantly(P < 0.01) and SOD and GSH-PX activity increased significantly(P < 0.05) in LDR + CTX group.2.Differences of ALT activity of plasma between 5 groups had no statistical significance(F = 1.262,P > 0.05).Differences of TP and ALB of plasma between 5 groups had statistical significance(F = 12.879 and 6.336 respectively,P < 0.01);TP and ALB in control group were higher than those of other groups and compared with sham-irradiated group,TP and ALB in LDR group elevated significantly(P < 0.05).3.Differences of DNA damage of peripheral lymphocytes had notable statistical significance(F = 6.383,P < 0.01);DNA damage in control group was the lightest,while DNA damage in CTX group was the severest;compared with CTX group,DNA damage in LDR + CTX group was much lighter(P < 0.05).4.MNF of PCE between 5 groups had remarkable significance(F = 179.652,P < 0.01);compared with control group and sham-irradiated group,MNF in CTX group increased significantly(P < 0.01);compared with CTX group,MNF in LDR + CTX group had a tendency of decline,which had no statistical significance(P > 0.05).Conclusion:1.CTX can damage the hepatic tissue through oxidative stress;75 mGy γ-irradiation before CTX chemotherapy can induce activities of anti-oxidative enzymes,promote elimination of free radicals,so as to alleviate the damaging effects of oxidative stress to hepatic tissue caused by high-dose chemotherapy.2.A 75 mGy γ-irradiation before CTX chemotherapy has no obvious effect on ALT activity of plasma,but may have protective effect on the protein synthesis function of liver.3.High-dose CTX chemotherapy can cause DNA damage of peripheral lymphocytes;75 mGy γ-irradiation before chemotherapy may have certain protective effect on DNA damage.4.CTX has potent mutagenic effect,can cause significant increase of MNF of PCE;75 mGy γ-ray pre-irradiation did not show obvious protection against genetic toxicity of high-dose CTX chemotherapy.

Estimation of enhanced low dose rate sensitivity mechanisms using temperature switching irradiation on gate-controlled lateral PNP transistor

The mechanisms occurring when the switched temperature technique is applied,as an accelerated enhanced low dose rate sensitivity(ELDRS)test technique,are investigated in terms of a specially designed gate-controlled lateral PNP transistor(GLPNP)that used to extract the interface traps(Nit)and oxide trapped charges(Not).Electrical characteristics in GLPNP transistors induced by ^(60)Co gamma irradiation are measured in situ as a function of total dose,showing that generation of Nit in the oxide is the primary cause of base current variations for the GLPNP.Based on the analysis of the variations of Nit and Not,with switching the temperature,the properties of accelerated protons release and suppressed protons loss play critical roles in determining the increased Nit formation leading to the base current degradation with dose accumulation.Simultaneously the hydrogen cracking mechanisms responsible for additional protons release are related to the neutralization of Not extending enhanced Nit buildup.In this study the switched temperature irradiation has been employed to conservatively estimate the ELDRS of GLPNP,which provides us with a new insight into the test technique for ELDRS.

Low Dose Total Body Irradiation for Relapsed Low Grade Non-Hodgkin’s Lymphoma: Experience of National Cancer Institute, Cairo

Background and Purpose: The relapsed low grade non-Hodgkin’s lymphoma (LG-NHL) is currently?incurable disease and the optimal treatment regimen has not determined yet. Low dose total body irradiation (LTBI) provides an alternative mechanism of action against cancer cells rather than direct cell kill. The mode of action of LTBI is immune-modulatory effect, induction of apoptosis and?hypersensitivity to low radiation doses. The aim of our study is to evaluate the effect of LTBI on relapsed?LG-NHL and reporting our experience at National Cancer Institute, Cairo (NCI, Cairo). Material and Methods: Fifty eight patients with relapsed LG-NHL and received LTBI studied retrospectively.?LTBI dose was 1.6 Gy/8 fractions divided on 2 courses;each course 4 fractions treated over 4 days with 2 weeks rest between the 2 courses. Results: The median age is 54 years;65% of the patients are men. Forty (69%) patients had performance status of 2 or more. Twenty seven patients were stage II/III and 31 patients (53%) had stage IV disease. Twenty six (45%) patients had bulky disease more than 10 cm and 22 (38%) patients had B symptoms at the time of relapse. The?extranodal disease was present in 17 patients (29%) and 78% of the patients received?>3 regimens of chemotherapy before referral to LTBI. Twenty three patients received IFRT (mean dose 32 ± 4 Gy) to initially bulky sites after LTBI. Fourteen patients (24%) achieved complete remission (CR) while 45%, 21% and 10% had partial remission (PR), stable disease (SD) and progressive disease (PD) respectively. The median PFS duration was 14 months and the median OS duration?was 39 months. Stage VI,?>3 regimen of chemotherapy and bad response to LTBI (SD) affected?progression duration adversely (0.03, 0.05 and 0.01 respectively). The response to LTBI is the only factor affected the OS duration significantly. The 3-year PFS was 19% ± 9%, and 3-year OS was 45% ± 8%. Stage IV was the only factor affected the 3-year PFS significantly with p value 0.03. The hematological toxicity was the main side effect of LTBI. Eleven patients developed G3/4 anemia while 8 patients only developed G3/4 thrombocytopenia and 13 patients developed G3/4 leucopenia. Conclusion: The use of LTBI in patients with relapsed low grade NHL is a feasible, effective and tolerable treatment that is worthy of testing in a future with chemotherapy and Rituximab maintenance.

Establishment of NaLuF_(4):15%Tb-based low dose X-PDT agent and its application on efficient antitumor therapy

X-ray excited photodynamic therapy(X-PDT)is the bravo answer of photodynamic therapy(PDT)for deep-seated tumors,as it employs X-ray as the irradiation source to overcome the limitation of light penetration depth.However,high X-ray irradiation dose caused organ lesions and side effects became the major barrier to X-PDT application.To address this issue,this work employed a classic-al co-precipitation reaction to synthesize NaLuF_(4):15%Tb^(3+)(NLF)with an average particle size of(23.48±0.91)nm,which was then coupled with the photosensitizer merocyanine 540(MC540)to form the X-PDT system NLF-MC540 with high production of singlet oxygen.The system could induce antitumor efficacy to about 24%in relative low dose X-ray irradiation range(0.1-0.3 Gy).In vivo,when NLF-MC540 irradiated by 0.1 Gy X-ray,the tumor inhibition percentage reached 89.5%±5.7%.The therapeutic mechanism of low dose X-PDT was found.A significant increase of neutrophils in serum was found on the third day after X-PDT.By immunohistochemical staining of tumor sections,the Ly6G^(+),CD8^(+),and CD11c^(+)cells infiltrated in the tumor microenvironment were studied.Utilizing the bilat-eral tumor model,the NLF-MC540 with 0.1 Gy X-ray irradiation could inhibit both the primary tumor and the distant tumor growth.De-tected by enzyme linked immunosorbent assay(ELISA),two cytokines IFN-γand TNF-αin serum were upregulated 7 and 6 times than negative control,respectively.Detected by enzyme linked immune spot assay(ELISPOT),the number of immune cells attributable to the IFN-γand TNF-αlevels in the group of low dose X-PDT were 14 and 6 times greater than that in the negative control group,respectively.Thus,it conclude that low dose X-PDT system could successfully upregulate the levels of immune cells,stimulate the secretion of cy-tokines(especially IFN-γand TNF-α),activate antitumor immunity,and finally inhibit colon tumor growth.

STIMULATING EFFECT OF LOW DOSE ^(147)Pm ON DNA REPAIR IN SPERMIOGENIC STAGES

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Effects of low-dose heavy ion irradiation on male germ cell adaptation and genetics

The heavy ions with high linear energy transfer and high relative biological effectiveness are much more deleterious on the male germ cells, ones of the most radiosensitive cells of the body,than low-LET ionizing radiation such as X-ray or gamma-ray. The effects of low-dose heavy ion irradiation on male germ cell adaptation and genetics and the possible mechanism of this adaptation are summarized in our laboratory. Our results showed that the heavy ion irradiation significantly increased the frequencies of chromosomal aberrations in spermatogonia and spermato-cytes of mice, the low dose heavy ion irradiation could induce significant adaptative response on mouse testes and human sperm, and pre-exposure of mouse testes with low-dose heavy ion can markedly alleviate damage effects in-duced by subsequent high-dose irradiation. The increase of SOD activity and decrease of lipid peroxidation levels induced by low-dose ionizing radiation may be involved in this adaptative response mechanism. These studies may provide useful theoretical and clinical bases for radioprotection of reproductive potential and assessment of genetic risks for human exposed to heavy ions in radiotherapy and in outer space environment.

Meso-scale Discovery Assay Detects the Changes of Plasma Cytokine Levels in Mice after Low or High LET Ionizing Irradiation

Objective To obtain precise data on the changes in the levels of 29 cytokines in mice after high or low linear energy transfer(LET)irradiation and to develop an accurate model of radiation exposure based on the cytokine levels after irradiation.Methods Plasma samples harvested from mice at different time points after carbon-ion or X-ray irradiation were analyzed using meso-scale discovery(MSD),a high-throughput and sensitive electrochemiluminescence measurement technique.Dose estimation equations were set up using multiple linear regression analysis.Results The relative levels of IL-6 at 1 h,IL-5 and IL-6 at 24 h,and IL-5,IL-6 and IL-15 at 7 d after irradiation with two intensities increased dose-dependently.The minimum measured levels of IL-5,IL-6 and IL-15 were up to 4.0076 pg/mL,16.4538 pg/mL and 0.4150 pg/mL,respectively.In addition,dose estimation models were established and verified.Conclusions The MSD assay can provide more accurate data regarding the changes in the levels of the cytokines IL-5,IL-6 and IL-15.These cytokines could meet the essential criteria for radiosensitive biomarkers and can be used as radiation indicators.Our prediction models can conveniently and accurately estimate the exposure dose in irradiated organism.

Continuous Low-dose-rate Irradiation of Iodine-125 Seeds Inhibiting Perineural Invasion in Pancreatic Cancer

Background：Perineural invasion （PNI） is a histopathological characteristic of pancreatic cancer （PanCa）.The aim of this study was to observe the treatment effect of continuous low-dose-rate （CLDR） irradiation to PNI and assess the PNI-related pain relief caused by iodine-125 （125I） seed implantation.Methods：The in vitro PNI model established by co-culture with dorsal root ganglion （DRG） and cancer cells was interfered under 2 and 4 Gy of 125I seeds CLDR irradiation.The orthotopic models of PNI were established,and 125I seeds were implanted in tumor.The PNI-related molecules were analyzed.In 30 patients with panCa,the pain relief was assessed using a visual analog scale （VAS）.Pain intensity was measured before and 1 week,2 weeks,and 1,3,and 6 months after 125I seed implantation.Results：The co-culture of DRG and PanCa cells could promote the growth of PanCa cells and DRG neurites.In co-culture groups,the increased number of DRG neurites and pancreatic cells in radiation group was significantly less.In orthotopic models,the PNI-positive rate in radiation and control group was 3/11 and 7/11;meanwhile,the degrees of PNI between radiation and control groups was significant difference （P 〈 0.05）.At week 2,the mean VAS pain score in patients decreased by 50% and significantly improved than the score at baseline （P 〈 0.05）.The pain scores were lower in all patients,and the pain-relieving effect was retained about 3 months.Conclusions：The CLDR irradiation could inhibit PNI of PanCa with the value of further study.The CLDR irradiation could do great favor in preventing local recurrence and alleviating pain.

Enhancement of antitumor immunity by low-dose total body irradiation is associated with selectively decreasing the proportion and number of T regulatory cells

Low-dose total body irradiation （LTBI） is used in the treatment of some cancers mainly for immune enhancement rather than cell killing. However, the mechanism underlying LTBI remains unknown. In this study, by analyzing the immune patterns of lymphocytes, we found that the percentage and absolute number of CD4^＋CD25^＋Foxp3^＋ regulatory T cells are markedly decreased in naive mice following treatment with LTBI. On the contrary, the CD4^＋CD44^＋/CD8^＋CD44^＋ effector-memory T cells are greatly increased. Importantly, naive mice treated with dendritic cell-gp100 tumor vaccines under LTBI induced an enhancement of antigen-specific proliferation and cytotoxicity as well as interferon-γ, （IFN-γ） secretion against FIO melanoma tumor challenge, compared to treatment with either the tumor vaccine or LTBI alone. Consequently, the treatment resulted in a reduced tumor burden and prolonged mouse survival. Our data demonstrate that LTBI＇s enhancement of antitumor immunity was mainly associated with selectively decreasing the proportion and number of T regulatory cells, implying the potential application of the combination of LTBI and a tumor vaccine in antitumor therapy.

电子束辐照防治储粮害虫及对小麦品质影响的研究

利用电子束动态辐照的方法对我国南方主要储粮害虫米象、谷蠹、赤拟谷盗等的辐照感应性及致死剂量进行了研究，同时对辐照后小麦的品质进行了分析．研究结果表明，经过0．3kGy和0．6kGy低剂量电子束辐照后能够有效防治储粮害虫，4～5周内，0．3kGy剂量对3种试验虫种的致死率为100％，而0．6kGy剂量辐照后成虫在一周内死亡率达100％，成虫对电子束辐照的敏感性分别为米象〉赤拟谷盗〉谷蠹．辐照后对小麦发芽率和发芽势有所影响，小麦（面粉）品质变化不明显，辐照样品的面团流变学特性、面筋指数和气味色泽没有明显变化．

不同偏置对NPN双极晶体管的低剂量率电离辐照损伤的影响

对NPN双极晶体管进行了低剂量率下不同偏置条件的电离辐射实验。结果表明,不同偏置条件下的低剂量率辐射损伤具有明显差异。基-射结反向偏置时,其过剩基极电流最大,电流增益衰减最为显著。而基-射结正向偏置时,过剩基极电流和电流增益衰减都最小。讨论了出现这种结果的内在机制。

双极电压比较器低剂量率辐照损伤增强效应的变温辐照加速评估方法

对3款同种型号不同公司生产的双极电压比较器进行了高、低剂量率及变温辐照的60 Coγ辐照实验。结果表明:偏置电流和电源电流为双极电压比较器辐射敏感参数,失调电压仅在工作偏置条件下为辐射敏感参数;由于工艺不同,不同公司的双极电压比较器存在辐射响应差异,而同一公司的双极电压比较器在不同偏置条件下的辐照损伤趋势亦不同;变温辐照加速评估方法不仅可鉴别上述不同公司的双极电压比较器在不同偏置条件下的剂量率效应,而且能很好地模拟和保守地评估其低剂量率下的辐照损伤。

改进全脑全脊髓螺旋断层放射治疗计划的研究

目的：通过比较限制与无限制一定照射区域的两种全脑全脊髓螺旋断层放疗方案的剂量学差异．评估通过限制一定照射区域以减少低剂量照射范围的临床可行性。方法：选择8例全脑全脊髓患者分别按照限制与无限制一定照射区域两种方案设计治疗计划，分别比较两个方案的计划靶区和危及器官的剂量分布、剂量体积直方图（DVH）的指标和治疗时间，观察限制一定照射区域后低剂量照射范围的变化及对危及器官的影响。结果：限制一定的照射区域后．靶区的覆盖度、均匀性和适形度与无限制照射区域的治疗方案比较无统计学差异；危及器官的累积剂量除了甲状腺高4％，胸骨柄高5％及肠道高11％以外，其余的危及器官的累积剂量平均降低约26％（8％～75％）。但平均治疗时间增加了1．23倍。结论：两种计划方案均能得到较好的剂量分布，而限制了一定照射区域后在可接受治疗时间范围内能减少低剂量照射区域，更好的保护危及器官。

不同偏置条件下NPN双极晶体管的电离辐照效应

对NPN双极晶体管进行了不同剂量率、不同偏置条件下的电离辐射实验。研究结果表明:同一剂量率辐照时,无论是低剂量率还是高剂量率,辐照损伤均是基-射结反向偏置时最大,零偏置次之,正偏置最小。NPN双极晶体管在3种偏置下均可观察到明显的低剂量率辐照损伤增强(ELDRS)效应,且偏置条件对ELDRS效应很明显,表现为基-射结正向偏置ELDRS效应最为显著,零偏次之,反向偏置最次。对出现这一实验结果的机理进行了探讨。

^(60)Co γ射线低剂量辐照对螟黄赤眼蜂生活力的刺激作用

在卵期用 1 0、70、1 5 0和 30 0mGy60 Coγ射线处理 ,对赤眼蜂的生活力基本没有影响 ;而在蛹后期用 1 5 0mGy和 30 0mGy处理 ,导致了盟黄赤眼蜂F1代的雌雄比例显著提高。扩大范围 ,用 1 0 0～ 30 0mGy的剂量处理对螟黄赤眼蜂当代的平均每寄主的棉铃虫卵产蜂数、雌雄成蜂性比、雌蜂寿命和寄生率无显著影响 ;而这些处理的F1代和F2 代的雌蜂成蜂性比都显著高于对照 ,并且每寄生棉铃虫卵的产蜂数量显著增加 ,到F3 代这些影响消失 ;1 0 0 0和 2 0 0 0mGy的辐射处理对螟黄赤眼蜂当代的生活力有一定的刺激作用 ,表现在雌蜂成蜂性比和寄生率显著提高 ,但每寄生的棉铃虫卵的平均产蜂数和雌成蜂的平均寿命都显著地低于对照 ,但随后连续

低剂量γ射线辐照对斑马鱼胚胎的发育和遗传毒性效应

为研究低剂量γ射线辐照对水生生物的发育和遗传毒性效应,以模式生物斑马鱼为研究对象,采用生物细胞辐照仪对5hpf的斑马鱼胚胎进行不同累积剂量(0.01~1.00Gy)的γ射线辐照处理,分析了胚胎的存活率、孵化率、畸形率和DNA损伤以及发育至150dpf的F1代斑马鱼成鱼的繁殖能力及肝脏、肾脏和脾脏抗氧化酶的活性。结果表明:0.01Gy低剂量γ射线辐照对斑马鱼胚胎存活率和孵化率无显著影响,但畸形率和DNA损伤显著提高;当辐照剂量超过0.10Gy时,存活率和孵化率显著降低。5hpf的斑马鱼胚胎接受0.01Gy低剂量的γ射线辐照后,发育至150dpf的F1代斑马鱼成鱼,产卵量显著降低,且具有剂量依赖性;肝脏的CAT酶的活性显著升高,表明它可能是评价低剂量γ射线辐照毒性效应潜在的生物标记物。

双极运算放大器低剂量率辐照损伤增强效应的变温加速辐照方法

介绍了一种变温辐照加速评估双极电路低剂量率辐照损伤增强效应的新实验方法,并对各种实验现象的潜在机理进行了分析。结果显示,阶跃降低辐照温度的变温辐照法,不仅能较好地模拟双极运放电路实际空间低剂量率的辐照损伤,且比美军标的恒高温辐照法的总剂量评估范围明显增大,还可作为快速鉴别器件是否具有低剂量率辐照损伤增强效应的有效实验方法。

变温辐照加速评估方法在不同工艺的NPN双极晶体管上的应用

对6种不同工艺的NPN双极晶体管进行了高、低剂量率及变温辐照的^(60)Coγ辐照实验。结果显示,6种工艺的NPN双极晶体管均有显著的低剂量率辐照损伤增强效应。而变温辐照损伤不仅明显高于室温高剂量率的辐照损伤,且能很好地模拟并保守地评估不同工艺的NPN双极晶体管低剂量率的辐照损伤。对实验现象的机理进行了分析。

首次低剂量超声辐照对HIFU消融兔肝VX2瘤的影响

目的探讨首次辐照不同低剂量的超声对HIFU消融兔肝VX2瘤的影响。方法 45只荷瘤兔按随机数字表法分为3组:A组首次辐照功率为0W,B组80W,C组100W;均于第2天接受声功率为180W的消融治疗。结果产生相同的凝固性坏死体积B组所用的时间较A组少(P<0.05);B组与C组达到消融坏死的时间无明显差异,但C组所产生的凝固性坏死体积更大(P<0.05);3组比较,A组的能效因子(energy efficiency factor,EEF)值(46.43±13.67)最大,C组最小(7.01±1.33,P<0.05)。结论首次低剂量辐照的功率越大,增效作用越明显。

低剂量辐射对脐血单个核细胞产生IL-2活性的影响

目的 探讨低剂量辐射对脐血单个核细胞产生的白细胞介素 2 (IL - 2 )生物学活性的影响。 方法 新鲜分离的脐血单个核细胞接受 6 2mGy的γ射线照射 ,在照射后不同培养时间 (2 4h ,48h ,72h) ,应用MTT(四甲基偶氮唑盐 )法 ,以CTLL依赖株为靶细胞检测培养上清IL - 2活性。 结果 低剂量照射后 ,脐血单个核细胞上清IL - 2活性随培养时间推移逐渐增幅 ,不同时间点比较均有显著性差异(P <0 .0 5 )。在不同培养时间 (2 4h ,48h ,72h) ,接受低剂量辐射的脐血单个核细胞培养上清IL - 2活性均显著高于未照射组 (P <0 .0 5 )。 结论 低剂量辐射可增强脐血T淋巴细胞释放的IL - 2的生物学活性 ,从而可能在脐血造血干细胞移植时增强移植物抗白血病 (GVL)