alpha6 Integrin Cleavage: Sensitizing human prostate cancer to ionizing radiation

Purpose: The goal was to determine if prostate tumor cells containing a mutant α6 integrin would be defective in tumor re-population following clinically relevant fractionated ionizing radiation (IR) treatments.

Material and methods: Human prostate cancer cells derived from PC3N cells were used which conditionally expressed a cleavable, wild type form of α6 integrin (PC3N-α6-WT) or a mutated non-cleavable form of α6 integrin (PC3N-α6-RR). The resulting tumor growth before, during and after fractionated doses of IR (3 Gy×10 days) was analyzed using the endpoints of tumor growth inhibition (T/C), tumor growth delay (T-C), tumor doubling time (Td) and tumor cell kill (Log₁₀ cell kill).

Results: The T/C values were 36.1% and 39.5%, the T-C values were 20.5 days and 28.5 days and the Td values were 5.5 and 10.5 days for the irradiated PC3N-α6-WT and PC3N-α6-RR cells, respectively. The Log₁₀ was 1.1 for the PC3N-α6-WT cells and 0.8 for the PC3N-α6-RR cells. The tumor response to IR was altered in tumors expressing the mutant α6 integrin as indicated by a significant increase in tumor growth inhibition, an increase in tumor growth delay, an increase in tumor doubling time and an increase in tumor cell kill.

Conclusions: Blocking integrin cleavage in vivo may be efficacious for increasing the IR responsiveness of slow growing, pro-metastatic human prostate cancer.     

AL杂交细胞在放射生物学研究中的应用

AL杂交细胞是近年来研究负荷粒子致突变效应较理想的一种分析体系,可用于直接检测低剂量突变因子的效应。用此体系研究某些人类基因之间的连锁非常方便,体系灵敏度高,具有其他体系细胞所不具备的优势,在放射生物学中可作为研究致突变效应的一种很好的工具。     

不明原因复发性自然流产患者外周血T淋巴细胞亚群和NK细胞特征分析

目的分析不明原因复发性自然流产(URSA)患者外周血T淋巴细胞亚群和NK细胞的特征。方法选取中国医科大学附属第一医院2011年10月至2015年4月确诊的68例URSA患者作为观察组对象,并选取同期诊治的60例健康早期妊娠妇女(自愿要求人工流产者)作为对照组。应用流式细胞术检测患者外周血T细胞亚群和NK细胞数量,并检测NK细胞活性,应用统计学软件分析检测结果。结果 URSA患者外周血中CD4~+细胞比例为(36.14%±3.56%),CD8~+细胞比例为(31.28%±3.53%),CD16~+56~+细胞比例为(17.62%±3.26%),Th/Ts为(3.08%±0.85%),NK细胞比例为(17.38%±2.47%),NK细胞活性为(21.15%±4.82%),均显著高于对照组患者(P<0.05)。结论 URSA患者外周血中T淋巴细胞亚群和NK细胞数目和活性显著升高,连续监测外周血中T细胞亚群和NK的数量和活性有利于临床诊断URSA,了解URSA病情变化。     

Validation of quantitative estimation of tissue oxygen extraction fraction and deoxygenated blood volume fraction in phantom and in vivo experiments by using MRI

The blood oxygenation level dependent signal of cerebral tissue can be theoretically derived using a network model formed by randomly oriented infinitely long cylinders. The validation of this model by phantom and in vivo experiments is still an object of research. A network phantom was constructed of solid polypropylene strings immersed in silicone oil, which essentially eliminated the effect of spin diffusion. The volume fraction and magnetic property of the string network was predetermined by independent methods. Ten healthy volunteers were measured for in vivo demonstration. The gradient echo sampled spin echo signal was evaluated with the cylinder network model. We found a strong interdependency between the two network characterizing parameters deoxygenated blood volume and oxygen extraction fraction. Here, different sets of deoxygenated blood volume/oxygen extraction fraction values were able to describe the measured signal equally well. However, by setting one parameter constant to a predetermined value, reasonable estimates of the other parameter were obtained. The same behavior was found for the in vivo demonstration. The signal theory of the cylinder network was validated by a well‐characterized phantom. However, the found interdependency that was found between deoxygenated blood volume and oxygen extraction fraction requires an independent estimation of one variable to determine reliable values of the other parameter. Magn Reson Med 63:910–921, 2010. © 2010 Wiley‐Liss, Inc.     

Cure, regression and cell survival: a comparison of common radiobiological endpoints using an in vitro tumour model.

Multicell spheroids of Chinese hamster V79-171 cells grown in suspension culture display many of the characteristics of solid tumours in vivo, and can be used as an in vitro tumour model. Two populations of spheroids differing in age and radiosensitivity were exposed to single doses of gamma-radiation and their response assayed by several techniques: (1) spheroids were reduced to single cells by trypsinization at various times post-irradiation, and viability of the single cells determined by colony formation; (2) entire spheroids were placed in petri dishes and observed for cellular outgrowth; (3)spheroid volume and cell content were monitored as a function of time after irradiation. It was found that spheroid volume changes could not be correlated with either the amount of radiation given or with the relative radiosensitivity. In contrast, the number of cells per spheroid, or cellularity, decreased exponentially with exposure dose at sufficiently long times after irradiation. Radiosensitivity was then quantified by calculating the per cent decrease of cellularity per rad. "Cure" of spheroids as defined by lack of outgrowth when entire spheroids were placed in petri dishes, correlated well with single cell survival, and was achieved 50 per cent of the time after 2,630 rads for the smaller spheroids and 3,750 rads for the larger ones. Since these spheroids contained an average of similar 7,600 and similar 30,700 cells respectively, comparison of cure data with single cell survival data showed that cures were achieved only when every cell was killed. This result may have significant therapeutic implications, since cells of the most radioresistant population of the spheroid, the chronically hypoxic internal cells, were capable of proliferation even when the spheroid was not reduced to single cells after irradiation.     

In vivo bio-distribution and homing of endothelial outgrowth cells in a tumour model

IntroductionEndothelial progenitor cells (EPCs) has been reported to have the potential for advancing revascularization of ischemic tissue. However, the heterogeneous nature of these cells calls for specification of the angiogenic potential of each subtype. The purpose of this study was to gain additional insight on the homing capacity of the EPC subtype, endothelial outgrowth cells (EOCs) in tumours using a well-established tumour model.Methods¹¹¹Indium (¹¹¹In) – and 5-(and-6)-carboxyfluorescein diacetate succinimidyl ester (CFSE) labelled EOCs derived from human umbilical cord blood were injected into mice with a C3H mammary carcinoma foot tumour. The subsequent capture of the EOCs was traced by estimation of activity in individual organs, autoradiography and fluorescence microscopy.Results¹¹¹In activity was found in tumour and other organs. However, varying parts of the activity originated from free ¹¹¹In lost from EOCs. Autoradiography demonstrated accumulation of ¹¹¹In activity in the tumour rim. Microscopy proved that a least part of this radioactivity originated from the presence of human derived EOCs and that those EOCs were not located in the endothelial lining of vessels, in the tumour.ConclusionThe results demonstrated the presence of xenotransplanted EOCs in the rim of a C3H mammary carcinoma. They were, however, not located in the endothelial lining of the vessels, thus indicating that their effect in vasculogenesis might be mediated via paracrine mechanisms rather than differentiating into endothelial cells (ECs) in tumour vessels.     

Correlation of Consecutive Serum Thyroglobulin Levels During Hormone Withdrawal and Failure of Initial Radioiodine Ablation in Thyroid Cancer Patients

Objective

The aim of this study was to evaluate the value of thyroglobulin (Tg) kinetics during preparation of radioiodine ablation for prediction of initial radioiodine ablation failure in thyroid cancer patients.

Methods

Thyroid cancer patients after total thyroidectomy who underwent radioiodine ablation with 3–4 weeks of hormone withdrawal between May 2011 and January 2012 were included. Consecutive serum Tg levels 5–10 days before ablation (Tg1) and on the day of ablation (Tg2) were obtained. The difference between Tg1 and Tg2 (ΔTg), daily change rate of Tg (ΔTg/day) and Tg doubling time (Tg-DT) were calculated. Success of initial ablation was determined by the results of the follow-up ultrasonography, diagnostic radioiodine scan and stimulated Tg level after 6 to 20 months.

Results

A total of 143 patients were included. Failed ablation was reported in 52 patients. Tg2 higher than 5.6 ng/ml and Tg-DT shorter than 4.2 days were significantly related to a high risk of ablation failure. ΔTg and ΔTg/day did not show significant correlation with ablation failure.

Conclusions

Thyroglobulin kinetics on consecutive blood sampling during hormone withdrawal may be helpful in predicting patients with higher risk of treatment failure of initial radioiodine ablation therapy in thyroid cancer patients.     

Accurate estimation of global and regional cardiac function by retrospectively gated multidetector row computed tomography

Retrospective reconstruction of ECG-gated images at different parts of the cardiac cycle allows the assessment of cardiac function by multi-detector row CT (MDCT) at the time of non-invasive coronary imaging. We compared the accuracy of such measurements by MDCT to cine magnetic resonance (MR). Forty patients underwent the assessment of global and regional cardiac function by 16-slice MDCT and cine MR. Left ventricular (LV) end-diastolic and end-systolic volumes estimated by MDCT (134±51 and 67±56 ml) were similar to those by MR (137±57 and 70±60 ml, respectively; both P=NS) and strongly correlated (r=0.92 and r=0.95, respectively; both P<0.001). Consequently, LV ejection fractions by MDCT and MR were also similar (55±21 vs. 56±21%; P=NS) and highly correlated (r=0.95; P<0.001). Regional end-diastolic and end-systolic wall thicknesses by MDCT were highly correlated (r=0.84 and r=0.92, respectively; both P<0.001), but significantly lower than by MR (8.3±1.8 vs. 8.8±1.9 mm and 12.7±3.4 vs. 13.3±3.5 mm, respectively; both P<0.001). Values of regional wall thickening by MDCT and MR were similar (54±30 vs. 51±31%; P=NS) and also correlated well (r=0.91; P<0.001). Retrospectively gated MDCT can accurately estimate LV volumes, EF and regional LV wall thickening compared to cine MR. Grant funding: Dr. Belge was supported by a fellowship of the Fondation Nationale de la Recherche Scientifique of the Belgian government. Dr. Gerber was supported by a grant from the Fondation Nationale de la Recherche Scientifique of the Belgian government (FRSM 3.4557.02).     

螺旋CT脑血管造影造影剂注射速度与延迟时间参数研究

目的　探讨正常人螺旋CT脑血管造影造影剂注射速度 (简称流速 )与延迟时间的关系 ,以选择合适流速和相应的延迟时间。方法　对 2 0例CT检查正常的病人进行前瞻性、自身对照研究 ,采用小剂量循环实验 ,分别以 2ml/s、3ml/s、4ml/s的流速进行同层动态CT增强扫描 ,观察动静脉的峰值强化时间、动静脉的强化升高CT值和动静脉峰差时间。结果　动静脉的峰值强化时间、动静脉的强化升高CT值 2ml/s与 3ml/s及 4ml/s流速有显著性差异 (Ρ <0 .0 5 ) ,而 3ml/s与 4ml/s流速无显著性差异 (Ρ >0 .0 5 ) ,2ml/s、3ml/s及 4ml/s流速动静脉峰差时间无显著性差异 (Ρ >0 .0 5 )。结论　 (1)小剂量循环实验可确定SCTA扫描的最佳延迟时间 ;(2 )SCTA检查时 ,采用 3ml/s的流速较为合适 ,其相应的延迟时间为 13 .83 9～ 15 .82 2s ;(3 )采用 2ml/s、3ml/s或 4ml/s的流速扫描 ,动静脉峰差时间无显著性差异。     

In vivo three-dimensional evaluation of tumour hypoxia in nasopharyngeal carcinomas using FMT-CT and MSOT

European Journal of Nuclear Medicine and Molecular Imaging - Accurate evaluation of hypoxia is particularly important in patients with nasopharyngeal carcinoma (NPC) undergoing radiotherapy. The...     

In vivo imaging of extraction fraction of low molecular weight mr contrast agents and perfusion rate in rodent tumors

Tissue uptake of a fully extractable MR detectable tracer, deuterated water (D₂O), was compared with that of a less extractable contrast agent, Gadolinium-DTPA-dimeglumine (Gd-DTPA), in rodent tumor and muscle tissue. This dual tracer method allowed calculation of relative (to muscle) tissue perfusion and extraction fraction of Gd-DTPA in each image pixel in vivo. Solutions of Gd-DTPA and D₂O were injected intravenously into Fisher female rats (n = 9) with R3230 mammary adenocarcinomas implanted in the hind limb. Perfusion rate was approximately two times greater (P < 0.005 by paired t test) in tumor than in muscle. Gd-DTPA extraction fraction at the interface between tumor and muscle was 2.0 times the extraction fraction in normal muscle (P <0.005 by paired t test). Extraction fraction at the tumor center was 1.6 times the extraction fraction in muscle (P <0.01 by paired t test). High extraction fraction of Gd-DTPA correlated with high capillary permeability determined from Evans Blue staining. Low molecular weight Gd-DTPA derivatives are widely used in clinical practice, and their extraction fractions are crucial determinants of image contrast during the first few passes of the contrast agent bolus. Therefore spatially resolved measurements of contrast agent extraction fractions obtained in vivo have significant clinical utility. The data demonstrate that extraction of low molecular weight tracers is sensitive to increased permeability in tumor vasculature and that this increased permeability can be imaged.     

双硫仑抗肿瘤活性及在放射生物学中的研究进展

双硫仑（disulfiram,DSF）为临床广泛应用的抗酗酒药物。然而,近年来的一些研究表明,DSF具有极强的抗肿瘤活性,已有临床试验报道其可提高肿瘤患者生存率;并对其抗肿瘤的分子机制进行了深入的阐述。另外,放射生物学研究发现DSF可以减轻射线对机体正常细胞的损伤,并通过其与铜离子形成复合物、抑制肿瘤干细胞、抑制泛素-蛋白酶体活性等机制增强肿瘤细胞的放疗敏感性,极有希望作为放化疗的辅助用药,提高放化疗疗效。本文详细论述了双硫仑抗肿瘤临床研究现状、分子机制,在肿瘤放射生物学中的研究及其应用前景。     

氚标记化合物在放射生物学基础与应用中的研究进展

氚标记化合物被广泛应用于医学领域,特别是氚标记的生物大分子可用于分析生物体内与细胞内各类分子的代谢过程。笔者介绍了氚标记化合物的合成方法,概述了氚标记的生物大分子在放射生物学基础研究与医学应用中的成果及研究进展,重点阐述了氚标记的胸腺嘧啶核苷在测定DNA合成效率中的原理与应用。氚标记化合物对于研究细胞内DNA、RNA、蛋白质等分子的分布、代谢过程具有简便、迅速、直观、准确的优点,进一步研发基于氚标记化合物的分析方法对于深入认识分子生物学机制具有重要意义。     

Influence of thermotolerance on the interaction between hyperthermia and radiation in a solid tumour in vivo

The influence of thermotolerance (i.e. a temporary resistance to a subsequent heat treatment induced by prior heating) on the response of a C3H mouse mammary carcinoma to combined water-bath hyperthermia and radiation was investigated. Prior heating at 43.5 C for 30 min induced thermotolerance which was at a maximum 16 h later and had completely disappeared after 120 h. Prior heating reduced tumour response to simultaneous heat and radiation given 16 h later, as evidenced by a reduction from 5.1 to 3.3 in the thermal enhancement ratio (TER). The effect was lost by 120 h. This indicates that development of thermotolerance reduces the degree of thermal radiosensitisation. However, although the time course was the same, the prior heating effect on the combined treatment was smaller than on the resistance to heat alone. With sequential treatment, the tumours were treated with X rays (28 Gy) followed four hours later by a two-dose heat treatment at 43.5 degrees C, the first for 30 min and the second after an interval of 0, 16 or 120 h. With this treatment thermotolerance fully manifested itself. It was necessary to increase the duration of heating when applied 16 h after prior heating by a factor of 5.4 to cause a TER of 2.0, a value not significantly different from the expected value of 5.2, i.e., the thermotolerance ratio for heat alone.     

Accumulation of technetium-99m glucarate: in vitro cell cultures and in vivo tumour models

99mTc-glucarate is an investigational radiopharmaceutical which has been shown to accumulate in acute cerebral and myocardial injuries and in some tumours. In the present work, a survey of possible factors affecting the cellular accumulation of 99mTc-glucarate was carried out in cell lines and strains in vitro and in murine tumours in vivo. Accumulation was enhanced under hypoxic conditions in 12 of the 16 human and murine cell lines and strains studied, and inhibited in the presence of nitroimidazoles. At temperatures lower than 37 degrees C, accumulation was reduced, but a hypoxic/aerobic differential was maintained. Aerobic accumulation of 99mTc-glucarate was enhanced by cyanide. In transplanted tumours in mice, 99mTc-glucarate showed high tumour/muscle and tumour/blood ratios at early times after injection. Pharmacological enhancement of the extent of hypoxia by the administration of hydralazine or nitro-L-arginine resulted in significantly increased accumulation of 99mTc-glucarate in the tumour. The in vitro and in vivo properties of 99mTc-glucarate suggest that it may be useful for tumour imaging in the clinic, although the exact mechanism(s) by which it localizes in tumours remains unknown.