The clinical research of 5 steps sequential method for whole treatment of hemorrhagic radiation cystitis in china.

Background: Curing hemorrhagic cystitis remains a challenge. We explore a continuous and effective treatment for hemorrhagic radiation cystitis. Methods: The data of patients in 6 provincial cancer hospital urology departments between April 2015 and December 2019 was reviewed retrospectively. Patients were classified as moderate and severe groups. The 5-steps sequential method was adopted. Two groups were initiated with step 1 and step 3 respectively. Step 1 was symptomatic treatment. Thrombin solution or sodium hyaluronate was administrated for bladder irrigation in step 2. Step 3 was transurethral electrocoagulation. Step 4 was interventional embolization. Step 5 was HBO therapy. OABSS was used to assess the improvement of patients' symptoms. The outcome was evaluated after at least 6 months of follow-up. Results: A total of 650 patients (56 men and 594 women), mean age 71.2 years, were enrolled in the 5 steps sequential method. 582 patients were classified as moderate and 68 severe group. In moderate group, the cure rate of step 1 was 61.2% (356/582), 80.4% (468/582) after step 2, 93.1% (542/582) after step 3, 96.2% (560/582) after step 4, and 99.8% (581/582) after step 5. In severe group, the cure rate was 54.4% (37/68) after step 3, 76.5% (52/68) after step 4, and 94.1% (64/68) after the step 5 respectively. The mean OABSS scores of both groups significantly decreased after 5 steps sequential method treatment (P<0.01). Conclusions: Our results show hemorrhagic radiation cystitis can be cured in 5 steps, and the 5 steps sequential method is welcomed and effective. Therapy efficacy depends on the number of steps adopted and the severity of hematuria.

Urinary 8-Hydroxy-2'-Deoxyguanosine: A Biomarker for Radiation-Induced Oxidative DNA Damage in Pediatric Cardiac Catheterization.

OBJECTIVE: To determine the utility of urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) as a sensitive biomarker for radiation-induced cellular DNA damage in children undergoing cardiac catheterization. STUDY DESIGN: We enrolled pediatric patients with congenital heart diseases requiring cardiac catheterization in conjunction with healthy children and children under sedation as control. Demographic, clinical, laboratory and invasive hemodynamic data, urinary 8-OHdG levels, and radiation exposure measurements were collected prospectively. RESULTS: Nineteen patients, 10 healthy children and 9 children under sedation, were studied. In 19 patients who underwent cardiac catheterization, the median level of 8-OHdG in urine obtained at 24-48 hours after the procedure was significantly higher than at baseline (44.0 vs 17.3 ng/mg creatinine, P = .0001). Furthermore, the urinary 8-OHdG level after the procedure increased in 18 of the 19 study subjects. In contrast, there was no significant difference in 8-OHdG levels between the 2 spot urine samples obtained at arbitrary intervals of 24-48 hours in 10 healthy children (P = .7213), and at baseline and 24-48 hours following echocardiography in 9 children under sedation (P = .1097). Stepwise multiple regression analysis revealed that the cumulative air kerma during the cardiac catheterization was the variable which was strongly and significantly associated with the ratio of post- to precardiac catheterization urinary 8-OHdG levels among the evaluated variables (R(2) = 0.7179, F = 11.0256, P = .0007). CONCLUSIONS: Urinary 8-OHdG could be a useful biomarker for radiation-induced cellular DNA damage in children undergoing diagnostic cardiac catheterization.

The urine proteome as a radiation biodosimeter.

The global rise in terrorism has increased the risk of radiological events aimed at creating chaos and destabilization, although they may cause relatively limited number of immediate casualties. We have proposed that a self-administered test would be valuable for initial triage following terrorist use of nuclear/radiological devices. The urine proteome may be a useful source of the biomarkers required for developing such a test. We have developed and extensively used a rat model to study the acute and late effect of total body (TBI) and partial body irradiation on critical organ systems. This model has proven valuable for correlating the structural and functional effects of radiation with molecular changes. Results show that nephron segments differ with regard to their sensitivity and response to ionizing radiation. The urine proteome was analyzed using LC-MS/MS at 24 h after TBI or local kidney irradiation using a 10 Gy single dose of X rays. LC-MS/MS data were analyzed and grouped under Gene Ontology categories Cellular Localization, Molecular Function and Biological Process. We observed a decrease in urine protein/creatinine ratio that corroborated with decreased spectral counts for urinary albumin and other major serum proteins. Interestingly, TBI caused greater decline in urinary albumin than local kidney irradiation. Analysis of acute-phase response proteins and markers of acute kidney injury showed increased urinary levels of cystatin superfamily proteins and alpha-1-acid glycoprotein. Among proteases and protease inhibitors, levels of Kallikrein 1-related peptidase b24, precursor and products of chymotrypsin-like activity, were noticeably increased. Among the amino acids that are susceptible to oxidation by free radicals, oxidized histidine levels were increased following irradiation. Our results suggest that proteomic analysis of early changes in urinary proteins will identify biomarkers for developing a self-administered test for radiation biodosimetry.

The international follow-up of individuals potentially exposed to polonium-210 in London 2006.

OBJECTIVES: Following a death from polonium-210 ((210)Po), contamination was found at several sites in London. This paper describes the UK Health Protection Agency's follow-up and assessment of individuals resident overseas who were potentially exposed to (210)Po. STUDY DESIGN: Descriptive follow-up study. METHODS: Individuals were classified into three exposure groups (higher, lower and unknown). Presence and degree of internal contamination were measured by 24-h urinary (210)Po activity (mBq/day). Results over 30mBq/day were taken to indicate probable contact with (210)Po in this incident. Dose assessments were conducted to determine degree of exposure and to identify individuals requiring further follow-up. RESULTS: Overall, 664 potentially exposed persons from 52 countries and territories were identified. Of these, 157 (24%) were in the higher exposure category, and urinary measurements were reported for 31% (48/157). Results for 19% (9/48) of those at higher exposure were more than 30mBq/day. For those at lower exposure, the percentage was 4% (3/68). Results above 30mBq/day were significantly more likely to be reported for the higher exposure category than the lower exposure category (Fisher's exact test P=0.010). Reported dose assessments suggested that identified individuals were not at increased health risk in the long term. Challenges and practical lessons were identified during the investigation. CONCLUSION: The results suggest that it is unlikely that any overseas resident had significant internal contamination with (210)Po. However, this incident clearly demonstrated the scale of international involvement likely to be necessary in other public health emergencies in large cities. The lessons identified have implications for the international health community, particularly with regard to the follow-up of individuals exposed to radiation in one country who then travel to another.

Assessing public health risk in the London polonium-210 incident, 2006.

OBJECTIVES: Mr Alexander Litvinenko died in a London hospital on 23 November 2006, allegedly from poisoning with the radionuclide polonium-210 ((210)Po). Associated circumstances required an integrated response to investigate the potential risk of internal contamination for individuals exposed to contaminated environments. STUDY DESIGN: Descriptive study. METHODS: Contaminated locations presenting a potential risk to health were identified through environmental assessment by radiation protection specialists. Individuals connected with these locations were identified and assessed for internal contamination with (210)Po. RESULTS: In total, 1029 UK residents were identified, associated with the 11 most contaminated locations. Of these, 974 were personally interviewed and 787 were offered urine tests for (210)Po excretion. Overall, 139 individuals (18%) showed evidence of probable internal contamination with (210)Po arising from the incident, but only 53 (7%) had assessed radiation doses of 1mSv or more. The highest assessed radiation dose was approximately 100mSv. CONCLUSIONS: Although internal contamination with (210)Po was relatively frequent and was most extensive among individuals associated with locations judged a priori to pose the greatest risk, a high degree of assurance could be given to UK and international communities that the level of health risk from exposure to the radionuclide in this incident was low.

Dose Assessment Following a 238Pu-contaminated Wound Case with Chelation and Excision.

The urinary excretion and wound retention data collected after a Pu-contaminated wound were analyzed using Markov Chain Monte Carlo (MCMC) to obtain the posterior distribution of the intakes and doses. An empirical approach was used to model the effects of medical treatments (chelation and excision) on the reduction of doses. It was calculated that DTPA enhanced the urinary excretion, on average, by a factor of 17. The empirical analysis also allowed calculation of the efficacies of the medical treatments-excision and chelation averted approximately 76% and 5.5%, respectively, of the doses that would have been if there were no medical treatment. All bioassay data are provided in the appendix for independent analysis and to facilitate the compartmental modeling approaches being developed by the health physics community.

Response to a Skin Puncture Contaminated with 238Pu at Los Alamos National Laboratory.

The three principal pathways for intakes of plutonium are ingestion, inhalation, and contaminated wounds. In August 2018, a glovebox worker at Los Alamos National Laboratory (LANL) sustained a puncture from a thread of a braided steel cable contaminated with Pu. The puncture produced no pain, no blood, and little or no visible mark. As a result, the potential for a contaminated wound was not immediately recognized, and a wound count was not conducted until elevated urine bioassay results were received 12 d after the incident. This paper discusses the circumstances of the incident, along with the medical response and dose assessment, and a discussion of the risks and benefits of the medical interventions.

Prostate cancer survivors with symptoms of radiation cystitis have elevated fibrotic and vascular proteins in urine.

Radiation for pelvic cancers can result in severe bladder damage and radiation cystitis (RC), which is characterized by chronic inflammation, fibrosis, and vascular damage. RC development is poorly understood because bladder biopsies are difficult to obtain. The goal of this study is to gain understanding of molecular changes that drive radiation-induced cystitis in cancer survivors using urine samples from prostate cancer survivors with history of radiation therapy. 94 urine samples were collected from prostate cancer survivors with (n = 85) and without (n = 9) history of radiation therapy. 15 patients with radiation history were officially diagnosed with radiation cystitis. Levels of 47 different proteins were measured using Multiplex Luminex. Comparisons were made between non-irradiated and irradiated samples, and within irradiated samples based on radiation cystitis diagnosis, symptom scores or hematuria. Statistical analysis was performed using Welch's t-test. In prostate cancer survivors with history of radiation therapy, elevated levels of PAI 1, TIMP1, TIMP2, HGF and VEGF-A were detected in patients that received a radiation cystitis diagnosis. These proteins were also increased in patients suffering from hematuria or high symptom scores. No inflammatory proteins were detected in the urine, except in patients with gross hematuria and end stage radiation cystitis. Active fibrosis and vascular distress is detectable in the urine through elevated levels of associated proteins. Inflammation is only detected in urine of patients with end-stage radiation cystitis disease. These results suggest that fibrosis and vascular damage drive the development of radiation cystitis and could lead to the development of more targeted treatments.

Development of a New Chelation Model: Bioassay Data Interpretation and Dose Assessment after Plutonium Intake via Wound and Treatment with DTPA.

The administration of chelation therapy to treat significant intakes of actinides, such as plutonium, affects the actinide's normal biokinetics. In particular, it enhances the actinide's rate of excretion, such that the standard biokinetic models cannot be applied directly to the chelation-affected bioassay data in order to estimate the intake and assess the radiation dose. The present study proposes a new chelation model that can be applied to the chelation-affected bioassay data after plutonium intake via wound and treatment with DTPA. In the proposed model, chelation is assumed to occur in the blood, liver, and parts of the skeleton. Ten datasets, consisting of measurements of C-DTPA, Pu, and Pu involving humans given radiolabeled DTPA and humans occupationally exposed to plutonium via wound and treated with chelation therapy, were used for model development. The combined dataset consisted of daily and cumulative excretion (urine and feces), wound counts, measurements of excised tissue, blood, and post-mortem tissue analyses of liver and skeleton. The combined data were simultaneously fit using the chelation model linked with a plutonium systemic model, which was linked to an ad hoc wound model. The proposed chelation model was used for dose assessment of the wound cases used in this study.

Deoxycytidine and radiation response: exceedingly high deoxycytidine aminohydrolase activity in human liver.

The activity of deoxycytidine aminohydrolase in the liver of various species including man was investigated. An enormously high activity was found in human liver. This fact explains the extraordinarily low level of deoxycytidine in human urine in comparison with that of other tested species. The suitability of deoxycitidinuria as a biochemical indicator of postirradiation damage in man remains, therefore, an open question.

Label-free SERS diagnostics of radiation-induced injury via detecting the biomarker Raman signal in the serum and urine bio-samples based on Au-NPs array substrates.

A sensitive approach based on surface enhanced Raman spectroscopy (SERS) has been developed to evaluate the radiation caused biological injury. To achieve the effective SERS substrate, canonical anodic aluminum oxide (AAO) templates with regular array of nanotips were fabricated, and by plasma sputtering the gold nanoparticles (Au-NPs) were distributed on the nanotips to form the Au-NPs array with plenty of hotspots. The SERS substrates were utilized to examine the serum samples taken from the mice with the treatment of total body irradiation (TBI) of X-ray. The impact of TBI on the mice was analyzed and it was found that the SERS peak intensity at 532 cm-1 increased as a function of duration or dose of TBI. We confirmed that this Raman signature belongs to the myoglobin as a biomarker for the muscle damage due to the radiation caused injury. Furthermore, we also tested several blood and urine specimen of cancer patients who received radiotherapy. The results showed that our approach to some extent could distinguish the bio-samples from normal, X-ray treated and untreated individuals. Therefore, the proposed methodology may have the potential for prompt prognosis of radiation injury at early stage.

Small field radiotherapy of head and neck cancer patients is responsible for oxidatively damaged DNA/oxidative stress on the level of a whole organism.

It is possible that oxidatively damaged DNA which arises as a result of radiotherapy may be involved in the therapeutic effect of the ionizing radiation and in the side effects. Therefore, for the first time, the broad spectrum of oxidatively damaged DNA biomarkers: urinary excretion of 8-oxodG (8-oxo-7,8-dihydro-2'-deoxyguanosine), 8-oxoGua (8-oxo-7,8-dihydroguanine) as well as the level of oxidatively damaged DNA in leukocytes, was analyzed in head and neck cancer patients (n = 27) undergoing fractionated radiotherapy using methodologies which involve HPLC (high-performance liquid chromatography) prepurification followed by gas chromatography with isotope dilution mass spectrometry detection and HPLC/EC. Of all the analyzed parameters in the majority of patients, only urinary excretion of the modified nucleoside significantly increased over the initial level in the samples collected 24 hr after the last fraction. However, for the distinct subpopulation of 10 patients, a significant increase in the level of 8-oxodG in cellular DNA and a simultaneous drop in urinary 8-oxoGua (the repair product of oxidative DNA damage) were detected after completion of the therapy. Because 8-oxoGua is a repair product of the DNA damage, there is a possibility that, at least in the case of some patients with the lowest activity of OGG1 (8-oxo-7,8-dihydroguanine glycosylase), the combination of lower OGG1 repair efficacy and irradiation was associated with increased background level of 8-oxoGua in cellular DNA. Apparently reduced DNA repair is unable to cope with the radiation-induced, and the extra amount of 8-oxoGua leading to an increase of potentially mutagenic/carcinogenic lesions.

ANALYSIS OF URINARY EXCRETION DATA FROM THREE PLUTONIUM-CONTAMINATED WOUNDS AT LOS ALAMOS NATIONAL LABORATORY.

The National Council on Radiation Protection (NCRP)-156 Report proposes seven different biokinetic models for wound cases depending on the physicochemistry of the contaminant. Because the models were heavily based on experimental animal data, the authors of the report encouraged application and validation of the models using bioassay data from actual human exposures. Each of the wound models was applied to three plutonium-contaminated wounds, and the models resulted in a good agreement to only one of the cases. We then applied a simpler biokinetic model structure to the bioassay data and showed that fitting the transfer rates from this model structure yielded better agreement with the data than does the best-fitting NCRP-156 model. Because the biokinetics of radioactive material in each wound is different, it is impractical to propose a discrete set of model parameters to describe the biokinetics of radionuclides in all wounds, and thus each wound should be treated empirically.

Rapid Response, Dose Assessment, and Clinical Management of a Plutonium-contaminated Puncture Wound.

Internalization of radionuclides occurs not only by inhalation, ingestion, parenteral injection (i.e., administration of radioactive material for a medical purpose), and direct transdermal absorption, but also by contaminated wounds. In June 2010, a glove-box operator at the U.S. Department of Energy's Savannah River Site sustained a puncture wound while venting canisters containing legacy materials contaminated with Pu. To indicate the canisters had been vented, a flag was inserted into the vent hole. The shaft of the flag penetrated the protective gloves worn by the operator. Initial monitoring performed with a zinc-sulfide alpha detector indicated 300 dpm at the wound site. After being cleared by radiological controls personnel, the patient was taken to the site medical facility where decontamination was attempted and diethylenetriaminepentaacetic acid (DTPA) was administered intravenously within 1.5 h of the incident. The patient was then taken to the Savannah River Site In Vivo Counting Facility where the wound was counted with a Canberra GL 2820 high-purity germanium detector, capable of quantifying contamination by detecting low-energy x rays and gamma rays. In addition to the classic 13, 17, and 20 keV photons associated with Pu, the low-yield (0.04%) 43.5 keV peak was also detected. This indicated a level of wound contamination orders of magnitude above the initial estimate of 300 dpm detected with handheld instrumentation. Trace quantities of Am were also identified via the 59.5 keV peak. A 24 h urine sample collection was begun on day 1 and continued at varying intervals for over a year. The patient underwent a punch biopsy at 3 h postincident (14,000 dpm removed) and excisional biopsies on days 1 and 9 (removal of an additional 3,200 dpm and 3,800 dpm, respectively). The initial post-DTPA urine sample analysis report indicated excretion in excess of 24,000 dpm Pu. Wound mapping was performed in an effort to determine migration from the wound site and indicated minimum local migration. In vivo counts were performed on the liver, axillary lymph nodes, supratrochlear lymph nodes, and skeleton to assess uptake and did not indicate measurable activity. Seventy-one total doses of DTPA were administered at varying frequencies for 317 d post intake. After allowing 100 d for removal of DTPA from the body, five 24 h urine samples were collected and analyzed for dose assessment by using the wound model described in National Council on Radiation Protection and Measurements Report No. 156. The total effective dose averted via physical removal of the contaminant and DTPA administration exceeded 1 Sv, demonstrating that rapid recognition of incident magnitude and prompt medical intervention are critical for dose aversion.

Elevated Urine Levels of Macrophage Migration Inhibitory Factor in Inflammatory Bladder Conditions: A Potential Biomarker for a Subgroup of Interstitial Cystitis/Bladder Pain Syndrome Patients.

OBJECTIVE: To investigate whether urinary levels of macrophage migration inhibitory factor (MIF) are elevated in interstitial cystitis/bladder pain syndrome (IC/BPS) patients with Hunner lesions and also whether urine MIF is elevated in other forms of inflammatory cystitis. METHODS: Urine samples were assayed for MIF by enzyme-linked immunosorbent assay. Urine samples from 3 female groups were examined: IC/BPS patients without (N = 55) and with Hunner lesions (N = 43), and non-IC/BPS patients (N = 100; control group; no history of IC/BPS; cancer or recent bacterial cystitis). Urine samples from 3 male groups were examined: patients with bacterial cystitis (N = 50), radiation cystitis (N = 18) and noncystitis patients (N = 119; control group; negative for bacterial cystitis). RESULTS: Urine MIF (mean MIF pg/mL ± standard error of the mean) was increased in female IC/BPS patients with Hunner lesions (2159 ± 435.3) compared with IC/BPS patients without Hunner lesions (460 ± 114.5) or non-IC/BPS patients (414 ± 47.6). Receiver operating curve analyses showed that urine MIF levels discriminated between the 2 IC groups (area under the curve = 72%; confidence interval 61%-82%). Male patients with bacterial and radiation cystitis had elevated urine MIF levels (2839 ± 757.1 and 4404 ± 1548.1, respectively) compared with noncystitis patients (681 ± 75.2). CONCLUSION: Urine MIF is elevated in IC/BPS patients with Hunner lesions and also in patients with other bladder inflammatory and painful conditions. MIF may also serve as a noninvasive biomarker to select IC/BPS patients more accurately for endoscopic evaluation and possible anti-inflammatory treatment.

Candidate protein markers for radiation biodosimetry in the hematopoietically humanized mouse model.

After a radiological incident, there is an urgent need for fast and reliable bioassays to identify radiation-exposed individuals within the first week post exposure. This study aimed to identify candidate radiation-responsive protein biomarkers in human lymphocytes in vivo using humanized NOD scid gamma (Hu-NSG) mouse model. Three days after X-irradiation (0-2 Gy, 88 cGy/min), human CD45+ lymphocytes were collected from the Hu-NSG mouse spleen and quantitative changes in the proteome of the human lymphocytes were analysed by mass spectrometry. Forty-six proteins were differentially expressed in response to radiation exposure. FDXR, BAX, DDB2 and ACTN1 proteins were shown to have dose-dependent response with a fold change greater than 2. When these proteins were used to estimate radiation dose by linear regression, the combination of FDXR, ACTN1 and DDB2 showed the lowest mean absolute errors (≤0.13 Gy) and highest coefficients of determination (R2 = 0.96). Biomarker validation studies were performed in human lymphocytes 3 days after irradiation in vivo and in vitro. In conclusion, this is the first study to identify radiation-induced human protein signatures in vivo using the humanized mouse model and develop a protein panel which could be used for the rapid assessment of absorbed dose 3 days after radiation exposure.

Urinary metabolic signatures and early triage of acute radiation exposure in rat model.

After a large-scale radiological accident, early-response biomarkers to assess radiation exposure over a broad dose range are not only the basis of rapid radiation triage, but are also the key to the rational use of limited medical resources and to the improvement of treatment efficiency. Because of its high throughput, rapid assays and minimally invasive sample collection, metabolomics has been applied to research into radiation exposure biomarkers in recent years. Due to the complexity of radiobiological effects, most of the potential biomarkers are both dose-dependent and time-dependent. In reality, it is very difficult to find a single biomarker that is both sensitive and specific in a given radiation exposure scenario. Therefore, a multi-parameters approach for radiation exposure assessment is more realistic in real nuclear accidents. In this study, untargeted metabolomic profiling based on gas chromatography-mass spectrometry (GC-MS) and targeted amino acid profiling based on LC-MS/MS were combined to investigate early urinary metabolite responses within 48 h post-exposure in a rat model. A few of the key early-response metabolites for radiation exposure were identified, which revealed the most relevant metabolic pathways. Furthermore, a panel of potential urinary biomarkers was selected through a multi-criteria approach and applied to early triage following irradiation. Our study suggests that it is feasible to use a multi-parameters approach to triage radiation damage, and the urinary excretion levels of the relevant metabolites provide insights into radiation damage and repair.

Interpretation of Urinary Excretion Data From Plutonium Wound Cases Treated With DTPA: Application of Different Models and Approaches.

After a chelation treatment, assessment of intake and doses is the primary concern of an internal dosimetrist. Using the urinary excretion data from two actual wound cases encountered at Los Alamos National Laboratory (LANL), this paper discusses several methods that can be used to interpret intakes from the urinary data collected after one or multiple chelation treatments. One of the methods uses only the data assumed to be unaffected by chelation (data collected beyond 100 d after the last treatment). This method, used by many facilities for official dose records, was implemented by employing maximum likelihood analysis and Bayesian analysis methods. The impacts of an improper assumption about the physicochemical behavior of a radioactive material and the importance of the use of a facility-specific biokinetic model when available have also been demonstrated. Another method analyzed both the affected and unaffected urinary data using an empirical urinary excretion model. This method, although case-specific, was useful in determining the actual intakes and the doses averted or the reduction in body burdens due to chelation treatments. This approach was important in determining the enhancement factors, the behavior of the chelate, and other observations that may be pertinent to several DTPA compartmental modeling approaches being conducted by the health physics community.

Urinary miRNAs as Biomarkers for Noninvasive Evaluation of Radiation-Induced Renal Tubular Injury.

Radiation nephropathy is one of the common late effects in cancer survivors who received radiotherapy as well as in victims of radiation accidents. The clinical manifestations of radiation nephropathy occur months after exposure. To date, there are no known early biomarkers to predict the future development of radiation nephropathy. This study focuses on the development of urinary biomarkers providing readout of acute responses in renal tubular epithelial cells. An amplification-free hybridization-based nCounter assay was used to detect changes in mouse urinary miRNAs after irradiation. After a single LD50 of total-body irradiation (TBI) or clinically relevant fractionated doses (2 Gy twice daily for 3 days), changes in urinary levels of microRNAs followed either an early pattern, peaking at 6-8 h postirradiation and gradually declining, or later pattern, peaking from 24 h to 7 days. Of 600 miRNAs compared, 12 urinary miRNAs showed the acute response and seven showed the late response, common to both irradiation protocols. miR-1224 and miR-21 were of particular interest, since they were the most robust acute and late responders, respectively. The early responding miR-1224 also exhibited good dose response after 2, 4, 6 and 8 Gy TBI, indicating its potential use as a biomarker for radiation exposure. In situ hybridization of irradiated mouse kidney sections and cultured mouse primary renal tubular cells confirmed the tubular origin of miR-1224. A significant upregulation in hsa-miR-1224-3p expression was also observed in human proximal renal tubular cells after irradiation. Consistent with mouse urine data, a similar expression pattern of hsa-miR-1224-3p and hsa-miR-21 were observed in urine samples collected from human leukemia patients preconditioned with TBI. This proof-of-concept study shows the potential translational utility of urinary miRNA biomarkers for radiation damage in renal tubules with possible prediction of late effects.

Increased excretion of collagen crosslinks in irradiated patients indicates destruction of collagen.

PURPOSE: In a recent study we showed an instant radiogenic destruction of collagen in dental tissues. The hypothesis of this analysis was that there is a destruction of collagen directly in bone during irradiation. Our intention was to prove this assumption by the analysis of the intraindividual progression of urinary excretion of bone specific collagen crosslinks before, during and after radiotherapy (RT) of secondary malignant bone tumors. MATERIAL AND METHODS: Forty-six patients were irradiated with a mean dose of 32 Gy (range 30 - 46 Gy). Four urine probes were collected from each patient before, during, at the end and 6 - 8 weeks after RT. Measurement of the mature collagen crosslinks hydroxylysylpyridinoline (HP) and lysylpyridinoline (LP) was performed by high performance liquid chromatography (HPLC). RESULTS: In 43 patients we found increasing HP and LP concentrations by comparing the different chosen time-points. As regards to HP the urine excretion was significantly increased at the end (p = 0.02) and six weeks after RT (p = 0.01) and for LP six weeks after RT (p = 0.01). We observed significantly higher urinary HP levels in patients treated with doses of 35 - 46 Gy as compared to patients treated with 30 Gy (p = 0.05). CONCLUSIONS: The urinary excretion of HP and LP was increased directly after a course of RT. This finding may reflect either destruction of collagen or increased bone remodeling/resorption after radiotherapy. Either way these findings suggest a relation to the mechanical instability of bone directly after radiotherapy. Future investigations of irradiated patients without osseous metastases will further clarify this matter.