Black tea is more effective than green tea in prevention of radiation-induced oxidative stress in the aorta of rats.

In the work, the effect of black tea on oxidative stress induced in the aorta by irradiation was studied. The efficiency of black and green tea types was compared, and the effect of the main green tea components (-)-epigallocatechin galate (EGCG) and (-)-epigallocatechin (EGC) on the aorta was studied. The activity of ACE in rat aorta segments was determined by measuring the hydrolysis of hippuryl-L-histidyl-L-leucine, and the production of ROS was estimated from the oxidation of dichlorodihydrofluorescein. Black tea prevented the radiation-induced activation of the ACE and suppressed increased ROS production in the aorta of irradiated rats. The IC50 value for the suppression of the irradiation-induced increase in ACE activity is 1 ml of black tea brewed at a rate of 0.17 g/100 ml. Black tea is 12 times more effective than green tea. The administration of both catechin derivatives from green tea to rats leads to an increase in the activity of ACE and the formation of ROS in the aorta. The dose that provided half maximum activation of ACE (EC50) on intraperitoneal (i. p.) injection of galloylated catechins was found to be the same, 0.06-0.07 µg/kg of body weight. Upon intragastric gavage of EGCG, the EC50 value was by one order of magnitude higher, 0.8 µg/kg. Black tea was more effective than green tea in prevention a radiation-induced increase of ACE activity and oxidative stress in the aorta. This difference was explained by a low content of galloylated catechins in black tea.

Radiation-induced lipoprotein-associated phospholipase A2 increases lysophosphatidylcholine and induces endothelial cell damage.

The cardiotoxicity of various anticancer therapies, including radiotherapy, can lead to cardiovascular complications. These complications can range from damaging cardiac tissues within the irradiation field to increasing the long-term risks of developing heart failure, coronary artery disease, and myocardial infarction. We analyzed radiation-induced metabolites capable of mediating critical biological processes, such as inflammation, senescence, and apoptosis. Previously, by applying QTOF-MASS analysis to irradiated human fibroblasts, we identified that metabolite sets of lysophosphatidylcholine (LPC) were increased in these cells. In this study, radiation-induced LPC accumulation in human aortic endothelial cells (HAECs) increased reactive oxygen species (ROS) production and senescence-associated-beta-galactosidase staining, in addition to decreasing their tube-forming ability. Knockdown of lipoprotein-associated phospholipase A2 (Lp-PLA2) with small interfering RNA (siRNA) inhibited the increased LPC production induced by radiation, and reduced the radiation-induced cell damage produced by ROS and oxidized low-density lipoprotein (LDL). Lp-PLA2 depletion abolished the induction of proinflammatory factors, such as interleukin 1ß, tumor necrosis factor-alpha, matrix metalloproteinase 2, and matrix metalloproteinase 9, as well as adhesion molecules, such as intercellular adhesion molecule 1 (ICAM-1) and E-selection. Likewise, we showed that Lp-PLA2 expression was upregulated in the vasculature of irradiated rat, resulting in increased LPC production and LDL oxidation. Our data demonstrate that radiation-induced LPC production is a potential risk factor for cardiotoxicity that is mediated by Lp-PLA2 activity, suggesting that LPC and Lp-PLA2 offer potential diagnostic and therapeutic approaches to cardiovascular damage during radiotherapy.

Radiation Impacts Early Atherosclerosis by Suppressing Intimal LDL Accumulation.

RATIONALE: Bone marrow transplantation (BMT) is used frequently to study the role of hematopoietic cells in atherosclerosis, but aortic arch lesions are smaller in mice after BMT. OBJECTIVE: To identify the earliest stage of atherosclerosis inhibited by BMT and elucidate potential mechanisms. METHODS AND RESULTS: Ldlr-/- mice underwent total body γ-irradiation, bone marrow reconstitution, and 6-week recovery. Atherosclerosis was studied in the ascending aortic arch and compared with mice without BMT. In BMT mice, neutral lipid and myeloid cell topography were lower in lesions after feeding a cholesterol-rich diet for 3, 6, and 12 weeks. Lesion coalescence and height were suppressed dramatically in mice post-BMT, whereas lateral growth was inhibited minimally. Targeted radiation to the upper thorax alone reproduced the BMT phenotype. Classical monocyte recruitment, intimal myeloid cell proliferation, and apoptosis did not account for the post-BMT phenotype. Neutral lipid accumulation was reduced in 5-day lesions, thus we developed quantitative assays for LDL (low-density lipoprotein) accumulation and paracellular leakage using DiI-labeled human LDL and rhodamine B-labeled 70 kD dextran. LDL accumulation was dramatically higher in the intima of Ldlr-/- relative to Ldlr+/+ mice, and was inhibited by injection of HDL mimics, suggesting a regulated process. LDL, but not dextran, accumulation was lower in mice post-BMT both at baseline and in 5-day lesions. Since the transcript abundance of molecules implicated in LDL transcytosis was not significantly different in the post-BMT intima, transcriptomics from whole aortic arch intima, and at single-cell resolution, was performed to give insights into pathways modulated by BMT. CONCLUSIONS: Radiation exposure inhibits LDL entry into the aortic intima at baseline and the earliest stages of atherosclerosis. Single-cell transcriptomic analysis suggests that LDL uptake by endothelial cells is diverted to lysosomal degradation and reverse cholesterol transport pathways. This reduces intimal accumulation of lipid and impacts lesion initiation and growth.

Novel Methodology to Investigate the Effect of Radiation Dose to Heart Substructures on Overall Survival.

PURPOSE: For patients with lung cancer treated with radiation therapy, a dose to the heart is associated with excess mortality; however, it is often not feasible to spare the whole heart. Our aim is to define cardiac substructures and dose thresholds that optimally reduce early mortality. METHODS AND MATERIALS: Fourteen cardiac substructures were delineated on 5 template patients with representative anatomies. One thousand one hundred sixty-one patients with non-small cell lung cancer were registered nonrigidly to these 5 template anatomies, and their radiation therapy doses were mapped. Mean and maximum dose to each substructure were extracted, and the means were evaluated as input to prediction models. The cohort was bootstrapped into 2 variable reduction techniques: elastic net least absolute shrinkage and selection operator and the random survival forest model. Each method was optimized to extract variables contributing most to overall survival, and model coefficients were evaluated to select these substructures. The most important variables common to both models were selected and evaluated in multivariable Cox-proportional hazard models. A threshold dose was defined, and Kaplan-Meier survival curves plotted. RESULTS: Nine hundred seventy-eight patients remained after visual quality assurance of the registration. Ranking the model coefficients across the bootstraps selected the maximum dose to the right atrium, right coronary artery, and ascending aorta as the most important factors associated with survival. The maximum dose to the combined cardiac region showed significance in the multivariable model, a hazard ratio of 1.01/Gy, and P = .03 after accounting for tumor volume (P < .001), N stage (P < .01), and performance status (P = .01). The optimal threshold for the maximum dose, equivalent dose in 2-Gy fractions, was 23 Gy. Kaplan-Meier survival curves showed a significant split (log-rank P = .008). CONCLUSIONS: The maximum dose to the combined cardiac region encompassing the right atrium, right coronary artery, and ascending aorta was found to have the greatest effect on patient survival. A maximum equivalent dose in 2-Gy fractions of 23 Gy was identified for consideration as a dose limit in future studies.

Association between Radiation Exposure and Endothelium-Dependent Vasodilation: Results from Clinical and Experimental Studies.

PURPOSE: The association between occupational radiation exposure and endothelium-dependent vasodilation (EDV) remains unclear. This study evaluated the association between radiation exposure and EDV among fluoroscopy-guided interventional procedure specialists and explored the possible mechanisms. MATERIALS AND METHODS: Brachial flow-mediated dilation was compared in 21 interventional cardiologists (the radiation group) and 15 noninterventional cardiologists (the nonradiation group). Animal radiation experiments were also performed to observe the impact of radiation on EDV. RESULTS: Flow-mediated dilation in both the left (radiation group, 3.63% vs. nonradiation group, 6.77%; P < .001) and right brachial arteries (5.36% vs. 7.33%, respectively; P = .04) and serum nitric oxide (NO) level (343.69 vs. 427.09 µmol/L, respectively; P = .02) were significantly reduced in the radiation group compared to those in the nonradiation group. EDV was significantly impaired in acetylcholine concentrations of 3 × 10-6 mol/L and 10-5 mol/L (60.09% vs.74.79%, respectively; P = .03; and 62.73% vs. 80.56%, respectively; P = .002), and reactive oxygen species levels in the aorta intima and media layers were significantly increased in mice after a single x-ray exposure, which could be partly rescued by pretreatment with folic acid (P < .05). CONCLUSIONS: Radiation exposure can lead to impairment of flow-mediated vasodilation in human or EDV in mice. In mice acutely exposed to radiation, folic acid alleviated radiation-induced EDV impairment by possible reduction of reactive oxidative species.

Reduction of dose to duodenum with a refined delineation method of Para-aortic region in patients with locally advanced cervical Cancer receiving prophylactic extended-field radiotherapy.

BACKGROUND: To compare irradiation dose to the second and third portions of duodenum (Duo2 and Duo3) with a new refined and old delineation method of para-aortic region for patients with locally advanced cervical cancer (LACC) receiving prophylactic extended-field radiotherapy (EFRT). METHODS: Twenty consecutive patients with LACC were treated with prophylactic EFRT from January 2016 to January 2017 at our institute. Two delineation methods of para-aortic region were designed for each patient, the old delineation method ensured a full coverage of aortic and inferior vena cava, while the right paracaval region above L3 was omitted from CTV in the new delineation method. Patients received a dose of 50.4Gy in 28 fractions for PCTV and a dose of 60.2Gy in 28 fractions for PGTV with volumetric-modulated arc therapy (VMRT). The dose delivered to Duo2 and Duo3 with these two delineation methods were compared. RESULTS: All treatment plans achieved excellent target volume coverage with 95% of PCTV receiving 50.4Gy and 95% of PGTV receiving 60.2Gy. There was no difference between delineation methods in low dose level (V5, V10, V15, V20, V25) for Duo2 and Duo3. The V30, V35, V40, V45, V50, Dmax, Dmean and D2cc for Duo2 with the new and old delineation methods were 55.76% vs 80.54% (P = 0.009), 34.72% vs 70.91% (P < 0.001), 18.69% vs 55.46% (P < 0.001), 8.20% vs 41.49% (P < 0.001), 1.86% vs 21.60% (P < 0.001), 49.58Gy vs 52.91Gy (P = 0.002), 30.38Gy vs 39.22Gy (P = 0.001) and 37.90Gy vs 48.64Gy (P < 0.001) respectively. For Duo3, the new delineation method achieved significant advantages in V30, V35, V40, V45, V50 and Dmean over the old one (96.82% vs 99.25%, P = 0.021; 89.65% vs 97.21%, P = 0.001; 79.50% vs 93.18%, P < 0.001; 65.63% vs 82.93%, P < 0.001; 43.39% vs 65.60%, P < 0.001; 46.09Gy vs 49.24Gy, P < 0.001), no deference was observed regarding D2cc and Dmax with these two delineation methods. CONCLUSION: With the new delineation method of para-aortic area in prophylactic EFRT, significant reduction of irradiation dose to the second and third portions of duodenum in high dose area was obtained. This may further lower the incidence of duodenal toxicity when performing prophylactic EFRT for patients with LACC.

Distinct vascular genomic response of proton and gamma radiation-A pilot investigation.

The cardiovascular biology of proton radiotherapy is not well understood. We aimed to compare the genomic dose-response to proton and gamma radiation of the mouse aorta to assess whether their vascular effects may diverge. We performed comparative RNA sequencing of the aorta following (4 hrs) total-body proton and gamma irradiation (0.5-200 cGy whole body dose, 10 dose levels) of conscious mice. A trend analysis identified genes that showed a dose response. While fewer genes were dose-responsive to proton than gamma radiation (29 vs. 194 genes; q-value ≤ 0.1), the magnitude of the effect was greater. Highly responsive genes were enriched for radiation response pathways (DNA damage, apoptosis, cellular stress and inflammation; p-value ≤ 0.01). Gamma, but not proton radiation induced additionally genes in vasculature specific pathways. Genes responsive to both radiation types showed almost perfectly superimposable dose-response relationships. Despite the activation of canonical radiation response pathways by both radiation types, we detected marked differences in the genomic response of the murine aorta. Models of cardiovascular risk based on photon radiation may not accurately predict the risk associated with proton radiation.

Automated Instead of Manual Treatment Planning? A Plan Comparison Based on Dose-Volume Statistics and Clinical Preference.

PURPOSE: Automated planning aims to speed up treatment planning and improve plan quality. We compared manual planning with automated planning for lung stereotactic body radiation therapy based on dose-volume histogram statistics and clinical preference. METHODS AND MATERIALS: Manual and automated intensity modulated radiation therapy plans were generated for 56 patients by use of software developed in-house and Pinnacle 9.10 Auto-Planning, respectively. Optimization times were measured in 10 patients, and the impact of the automated plan (AP) on the total treatment cost was estimated. For the remaining 46 patients, each plan was checked against our clinical objectives, and a pair-wise dose-volume histogram comparison was performed. Three experienced radiation oncologists evaluated each plan and indicated their preference. RESULTS: APs reduced the average optimization time by 77.3% but only affected the total treatment cost by 3.6%. Three APs and 0 manual plans failed our clinical objectives, and 13 APs and 9 manual plans showed a minor deviation. APs significantly reduced D2% (2% of the volume receives a dose of at least D2%) for the spinal cord, esophagus, heart, aorta, and main stem bronchus (P < .05) while preserving target coverage. The radiation oncologists found >75% of the APs clinically acceptable without any further fine-tuning. CONCLUSIONS: APs may help to create satisfactory treatment plans quickly and effectively. Because critical appraisal by qualified professionals remains necessary, there is no such thing as "fully automated" planning yet.

Flavonoids decrease the radiation-induced increase in the activity of the angiotensin-converting enzyme in rat aorta.

The basic factor of cardiovascular diseases is atherosclerosis, which is due largely to an increase in the activity of the angiotensin-converting enzyme (ACE) in vessels. Flavonoids diminish the risk of cardiovascular diseases and the flavonoid taxifolin normalizes the activity of ACE. We examined the efficiency of seven flavonoids in preventing an increase in ACE activity in aorta of rats exposed to ionizing radiation. It was shown that the activity of flavones and flavonols decreases with an increase in the number of OH groups in the A and B rings, respectively. The reduction in the activity of flavonoids within the classes correlates with a decrease in their lipophilicity. Flavanonols (taxifolin) are more active than flavonols, and flavonols are more active than flavones.

Ionizing Radiation Enhances Activity of Angiotensin-Converting Enzyme in Rat Aorta.

We analyzed changes in angiotensin-converting enzyme activity in rat aorta at the early terms after irradiation in doses equal to one fraction dose used in tumor radiotherapy. Male Wistar rats were exposed to whole body or local (chest) X-ray irradiation (200 kV, 1-7.5 Gy). The activity of the enzyme in aorta segments was measured in 1-48 h after irradiation by hydrolysis of hippuryl-histidine-leucine. Activity of angiotensin-converting enzyme in rat aorta was increased 1-24 h after whole body irradiation in a dose of 2.5 Gy with a peak in 2 h after exposure. After local exposure, enzyme activity also increased in 2 h, but returned to the control level in 24 h. In 2 h after whole-body irradiation in doses >2.5 Gy, the increase in enzyme activity was less pronounced and after exposure to 7.5 Gy, it did not differ from the control. During local exposure, the effect did not decrease with increasing the irradiation dose. The fraction of blood monocytes adherent to plastic in rats subjected to whole body irradiation decreases with increasing the dose. In rats subjected to local irradiation in a dose of 7.5 Gy, monocyte adhesion to plastic did not differ from the control. These data suggest that the increase in activity of angiotensin-converting enzyme in the aorta after irradiation is determined by monocyte adhesion to the endothelium; the decrease in this effects with increasing the dose can be explained by radiation damage of monocytes.

Peculiarities of ultrastructural organization and metabolism of reactive forms of oxygen and nitrogen in a cardiovascular system for permanent effects of ionizing radiation in low doses. / OSOBLYVOSTI UL'TRASTRUKTURNOÏ ORGANIZATsIÏ I METABOLIZMU REAKTYVNYKh FORM KYSNIu TA AZOTU V SERTsEVO SUDYNNIY̆ SYSTEMI ZA POSTIY̆NOÏ DIÏ IONIZUIuChOGO VYPROMINIuVANNIa U NYZ'KYKh DOZAKh.

OBJECTIVE: Determination of the peculiarities of ultrastructural changes and metabolism of reactive forms of oxy gen and nitrogen in the tissues of the myocardium, aorta and portal vein of the radiosensitive BALB/c mice due long term exposure to the complex of radionuclides of Chоrnobyl fallout (ejection) and low intensity low dose γ irradiation. MATERIALS AND METHODS: Experimental studies were performed on 60 mice female radiosensitive lines BALB/c with a body weight of 20-22 g, which were divided into 3 groups: I group (control) animals age 6-9 months which were born and lived their lives in Kyiv vivarium under conditions natural radioactive background; ІІ - animals age 6 months, which were born and lived in the Chornobyl exclusion zone throughout their lives; ІІІ - animals, which from 3 months of age for 6 months were constantly located in cages with flat ionizing radiation sources and exposed to external γ irradiation in a total dose of 0.43 Sv. Animals of II and III groups were kept in the vivarium of the Institute for Safety Problems of Nuclear Power Plants of the National Academy of Sciences of Ukraine (Chornobyl). Mice of the BALB/c lines are sensitive to radiation: for males LD 50/30 < 5.7 Gy, for females - 5.85 Gy. RESULTS AND CONCLUSIONS: The peculiarities of structural and functional changes in the organs of the cardiovascular system (CVS) and mechanisms of the development of oxidative and nitrosatitative stress due long term exposure to the complex of radionuclides of the Chornobyl fallout (ejection) and low intensity low dose γ radiation based on the study of ultrastructural organization and metabolism of reactive oxygen species (ROS) and nitrogen (NRS) of the atri al cardiomyocytes (CMC), the aortic endothelium and portal vein of the BALB/c mice. Found that the permanent expo sure to low doses of radiation changes occur, including the dominant mechanism is to run a CMC apoptosis and endothelial cells of the aorta and portal vein. It is shown that the development of oxidative stress accompanied by increased activity of ROS metabolism that occurs due to activation of nucleotide and lipid superoxide generators. Found that under these conditions the development of nitrosative stress is due to the activation of inducible NO syn thesis enzyme iNOS and inhibit its synthesis constitutive eNOS enzyme. High levels of simultaneous generation of superoxide and NO, bindting, lead to the formation of toxic peroxynitrite, which initiates the process of apoptosis.

Defining the hypoxic target volume based on positron emission tomography for image guided radiotherapy - the influence of the choice of the reference region and conversion function.

BACKGROUND: Hypoxia imaged by positron emission tomography (PET) is a potential target for optimization in radiotherapy. However, the implementation of this approach with respect to the conversion of intensities in the images into oxygenation and radiosensitivity maps is not straightforward. This study investigated the feasibility of applying two conversion approaches previously derived for 18F-labeled fluoromisonidazole (18F-FMISO)-PET images for the hypoxia tracer 18F-flortanidazole (18F-HX4). MATERIAL AND METHODS: Ten non-small-cell lung cancer patients imaged with 18F-HX4 before the start of radiotherapy were considered in this study. PET image uptake was normalized to a well-oxygenated reference region and subsequently linear and non-linear conversions were used to determine tissue oxygenations maps. These were subsequently used to delineate hypoxic volumes based partial oxygen pressure (pO2) thresholds. The results were compared to hypoxic volumes segmented using a tissue-to-background ratio of 1.4 for 18F-HX4 uptake. RESULTS: While the linear conversion function was not found to result in realistic oxygenation maps, the non-linear function resulted in reasonably sized sub-volumes in good agreement with uptake-based segmented volumes for a limited range of pO2 thresholds. However, the pO2 values corresponding to this range were significantly higher than what is normally considered as hypoxia. The similarity in size, shape, and relative location between uptake-based sub-volumes and volumes based on the conversion to pO2 suggests that the relationship between uptake and pO2 is similar for 18F-FMISO and 18F-HX4, but that the model parameters need to be adjusted for the latter. CONCLUSIONS: A non-linear conversion function between uptake and oxygen partial pressure for 18F-FMISO-PET could be applied to 18F-HX4 images to delineate hypoxic sub-volumes of similar size, shape, and relative location as based directly on the uptake. In order to apply the model for e.g., dose-painting, new parameters need to be derived for the accurate calculation of dose-modifying factors for this tracer.

UVB Exposure Prevents Atherosclerosis by Regulating Immunoinflammatory Responses.

OBJECTIVE: UVB irradiation is an established treatment for immunoinflammatory cutaneous disorders and has been shown to suppress cutaneous and systemic inflammatory diseases through modulation of the adaptive immune response. However, it remains unknown whether UVB irradiation prevents an immunoinflammatory disease of arteries such as atherosclerosis. APPROACH AND RESULTS: Here, we show that UVB exposure inhibits the development and progression of atherosclerosis in atherosclerosis-prone mice by expanding and enhancing the functional capacity of CD4+ forkhead box P3+ regulatory T cells and regulating proatherogenic T-cell responses. Experimental studies in Langerhans cell-depleted mice revealed that epidermal Langerhans cells play a critical role in UVB-dependent induction of CD4+ forkhead box P3+ regulatory T cells, suppression of proatherogenic T-cell responses, and prevention of atherosclerotic plaque development. CONCLUSIONS: Our findings suggest the skin immune system as a novel therapeutic target for atherosclerosis and provide a novel strategy for the treatment and prevention of atherosclerosis.

Taxifolin and Fucoidin Abolish the Irradiation-Induced Increase in the Production of Reactive Oxygen Species in Rat Aorta.

We studied changes in ROS content in the aorta of Wistar rats at early terms after irradiation in doses equal to single fraction used in tumor radiotherapy and the effects of taxifolin and fucoidin, blockers of leukocyte adhesion to endothelium, on ROS content. Male rats were exposed to X-rays (200 kW) in doses of 1-7.5 Gy. ROS production in aorta segments was measured in 1-48 h after irradiation by dichlorodihydrofluorescein oxidation. The content of ROS in the aorta of rats exposed to radiation in doses of 1-2.5 Gy increased in 1-24 h after irradiation, the peak ROS content was found in 2 h after irradiation. Taxifolin (100 µg/kg dihydroquercetin once a day with drinking water) and fucoidin (10 mg/kg, i.v.) abolished ROS accumulation. The content of ROS in rat aorta increased in 1-24 h after irradiation in doses used for tumor radiotherapy and this increase can be determined by leukocyte adhesion to the endothelium.

Validity of Current Stereotactic Body Radiation Therapy Dose Constraints for Aorta and Major Vessels.

Understanding dose constraints for critical structures in stereotactic body radiation therapy (SBRT) is essential to generate a plan for optimal efficacy and safety. Published dose constraints are derived by a variety of methods, including crude statistics, actuarial analysis, modeling, and simple biologically effective dose (BED) conversion. Many dose constraints reported in the literature are not consistent with each other, secondary to differences in clinical and dosimetric parameters. Application of a dose constraint without discriminating the variation of all the factors involved may result in suboptimal treatment. This issue of Seminars in Radiation Oncology validates dose tolerance limits for 10 critical anatomic structures based on dose response modeling of clinical outcomes data to include detailed dose-volume metrics. This article presents a logistic dose-response model for aorta and major vessels based on 238 cases from the literature in addition to 387 cases from MD Anderson Cancer Center at Cooper University Hospital, for a total of 625 cases. The Radiation Therapy Oncology Group (RTOG) 0813 dose-tolerance limit of Dmax = 52.5Gy in 5 fractions was found to have a 1.2% risk of grade 3-5 toxicity, and the Timmerman 2008 limit of Dmax = 45Gy in 3 fractions had 2.3% risk. From the model, the 1% and 2% risk levels for D4cc, D1cc, and D0.5cc are also provided in 1-5 fractions, in the form of a dose-volume histogram (DVH) Risk Map.

Dosimetric Factors and Toxicity in Highly Conformal Thoracic Reirradiation.

PURPOSE: We determined cumulative dose to critical structures, rates of toxicity, and outcomes following thoracic reirradiation. METHODS AND MATERIALS: We retrospectively reviewed our institutional database for patients treated between 2008 and 2014, who received thoracic reirradiation with overlap of 25% prescribed isodose lines. Patients received courses of hyperfractionated (n=5), hypofractionated (n=5), conventionally fractionated (n=21), or stereotactic ablative radiation therapy (n=51). Doses to critical structures were converted to biologically effective dose, expressed as 2 Gy per fraction equivalent dose (EQD2; α/ß = 2 for spinal cord; α/ß = 3 for other critical structures). RESULTS: We identified 82 courses (44 for retreatment) in 38 patients reirradiated at a median 16 months (range: 1-71 months) following initial RT. Median follow-up was 17 months (range: 3-57 months). Twelve- and 24-month overall survival rates were 79.6% and 57.3%, respectively. Eighteen patients received reirradiation for locoregionally recurrent non-small cell lung cancer with 12-month rates of local failure and regional recurrence and distant metastases rates of 13.5%, 8.1%, and 15.6%, respectively. Critical structures receiving ≥75 Gy EQD2 included spinal cord (1 cm(3); n=1), esophagus (1 cm(3); n=10), trachea (1 cm(3); n=11), heart (1 cm(3); n=9), aorta (1 cm(3); n=16), superior vena cava (1 cm(3); n=12), brachial plexus (0.2 cm(3); n=2), vagus nerve (0.2 cm(3); n=7), sympathetic trunk (0.2 cm(3); n=4), chest wall (30 cm(3); n=12), and proximal bronchial tree (1 cm(3); n=17). Cumulative dose-volume (D cm(3)) toxicity following reirradiation data included esophagitis grade ≥2 (n=3, D1 cm(3) range: 41.0-100.6 Gy), chest wall grade ≥2 (n=4; D30 cm(3) range: 35.0-117.2 Gy), lung grade 2 (n=7; V20combined-lung range: 4.7%-21.7%), vocal cord paralysis (n=2; vagus nerve D0.2 cm(3) range: 207.5-302.2 Gy), brachial plexopathy (n=1; D0.2 cm(3) = 242.5 Gy), and Horner's syndrome (n=1; sympathetic trunk D0.2 cm(3) = 130.8 Gy). No grade ≥4 toxicity was observed. CONCLUSIONS: Overlapping courses of reirradiation can be safely delivered with acceptable toxicity. Some toxicities occurred acutely at doses considered safe for a single course of therapy (esophagus). We observed rib fracture, brachial plexopathy, and Horner's syndrome for patients receiving high cumulative doses to corresponding critical structures.

GDF15 contributes to radiation-induced senescence through the ROS-mediated p16 pathway in human endothelial cells.

Growth differentiation factor 15 (GDF15) is an emerging biomarker of cardiovascular risk and disease. Microarray analyses revealed that GDF15 levels were increased during cellular senescence induced by ionizing radiation (IR) in human aortic endothelial cells (HAECs). However, the role of GDF15 in HAEC cellular senescence remains unclear. This study demonstrated that downregulation of GDF15 in HAECs partially prevented cellular senescence triggered by IR, which was confirmed by recovery of cell proliferation and reverse senescence-associated ß-galactosidase (SA-ß-gal) staining. Conversely, upregulation of GDF15-induced cellular senescence in HAECs, confirmed by G0/G1 cell cycle arrest, decreased during cell proliferation and increased SA-ß-gal staining. GDF15-induced cellular senescence was observed in p16-knockdown cells but not in p53-knockdown cells. GDF15 expression in endothelial cells also generated reactive oxygen species (ROS), which led to activation of extracellular signal-regulated kinases (ERKs) and induction of senescence by oxidative stress. These results suggested that GDF15 might play an important role in cellular senescence through a ROS-mediated p16 pathway and contribute to the pathogenesis of atherosclerosis via pro-senescent activity.

Features of contrast enhancement in different methods of multislice computed tomography.

The purpose of this study was a comparison of the X-ray density in certain organs and anatomical structures and the determination of the radiation exposure during venous-arterial MSCT scanning and classical two-phase CT of organs of the abdominal cavity. It has been established that the technique of venous-arterial MSCT scanning provided a significant reduction of radiation dose during CT of organs of the abdominal cavity and could be used as an alternative to two-phase examination in the process of dynamic monitoring of cancer patients.

Ascending aortic aneurysm caused by Mycobacterium tuberculosis.

BACKGROUND: Tuberculous aortitis is an unusual presentation of a common disease in Sri Lanka. There were no reported cases of tuberculous aortitis from Sri Lanka. Here we report a case of a 40-year-old woman who developed an ascending aortic aneurysm with severe aortic regurgitation caused by Mycobacterium tuberculosis. CASE PRESENTATION: A 40-year-old Sri Lankan female who presented with exertional breathlessness (NYHA II) and weight loss for 4 weeks duration was found to have collapsing pulse and early diastolic murmur at left sternal edge. Transthoracic and transesophageal echocardiogram showed ascending aortic aneurysm with severe aortic regurgitation. Computed tomographic aortography confirmed the diagnosis of aneurysmal dilatation of the ascending aorta. She underwent successful aortic valve replacement and aortic root replacement. The final diagnosis of tuberculous aortitis was made on the basis of macroscopic appearance of inflammation and microscopic confirmation of caseating granuloma. She made a good clinical recovery with category 1 antituberculous chemotherapy. CONCLUSIONS: Although most cases of aortitis are non-infectious in Sri Lanka, an infectious etiology must be considered in the differential diagnosis because therapeutic approaches differ widely. Tuberculous aortitis may be under diagnosed in Sri Lanka, a country with intermediate tuberculosis burden, as the histological or microbiological diagnosis is not possible in most cases. The clinical and radiological diagnostic criteria for tuberculous aortitis need to be set out in case of aneurysmal aortic disease in the absence of apparent etiology.

Influence of irradiation on release of endothelial microparticles (EMP) in vitro.

Survivors of Hodgkin's disease as well as of breast and lung cancer are at risk of radiation-associated cardiovascular disease. Recent studies demonstrated a correlation between cardiovascular risk factors and circulating endothelial microparticles (EMP) and thereby suggest increased EMP levels in circulation to be an early biomarker of endothelial dysfunction and cardiovascular risk. This prompted us to analyze the amount of EMP released by human aortic endothelial cells (HAEC) after exposure to different doses of X-ray (0.4, 2, 4, 6, and 20 Gy) using antibodies against the endothelial cell markers CD31, CD144, and CD146 by flow cytometry. In this pilot experiment only CD146 proved appropriate for quantification of HAEC-derived EMP. Exposure of HAEC to different doses of X-ray did not significantly influence formation of CD146-positive EMP. However, low doses (0.4 Gy) tended to decrease EMP formation, whereas higher doses (2 or 4 Gy) slightly increased release of CD146-positive EMP. By contrast, inflammatory activation of HAEC by TPA significantly increased EMP release about 15-fold (P <  0.01). In conclusion, under the present experimental conditions EMP did not prove a suitable biomarker for radiation-induced endothelial dysfunction in vitro.