Radiation-induced bystander effect and its clinical implications.

For many years, targeted DNA damage caused by radiation has been considered the main cause of various biological effects. Based on this paradigm, any small amount of radiation is harmful to the organism. Epidemiological studies of Japanese atomic bomb survivors have proposed the linear-non-threshold model as the dominant standard in the field of radiation protection. However, there is increasing evidence that the linear-non-threshold model is not fully applicable to the biological effects caused by low dose radiation, and theories related to low dose radiation require further investigation. In addition to the cell damage caused by direct exposure, non-targeted effects, which are sometimes referred to as bystander effects, abscopal effects, genetic instability, etc., are another kind of significant effect related to low dose radiation. An understanding of this phenomenon is crucial for both basic biomedical research and clinical application. This article reviews recent studies on the bystander effect and summarizes the key findings in the field. Additionally, it offers a cross-sectional comparison of bystander effects caused by various radiation sources in different cell types, as well as an in-depth analysis of studies on the potential biological mechanisms of bystander effects. This review aims to present valuable information and provide new insights on the bystander effect to enlighten both radiobiologists and clinical radiologists searching for new ways to improve clinical treatments.

Novel Method for Detection of PIK3CA Mutations in Circulating Tumor DNA of Patients with Colorectal Cancer.

The PIK3CA mutation is considered a potential target for treatment of colorectal cancer. We evaluated a PIK3CA mutation assay on plasma cell-free DNA (cfDNA) using a newly developed PCR with restriction digestion integrated and followed by Sanger's sequencing. We analyzed PIK3CA mutation in plasma with our newly developed assays and in matching tumor tissues by routine methods. We detected the PIK3CA gene mutation status by both methods in samples from 40 colorectal cancer patients. Three H1047R mutations of PIK3CA gene were detected in the cfDNA of the 40 patients by restriction digestion PCR. Neither E545K nor H1047R mutations were detected in the cfDNA by routine PCR/sequencing. The PIK3CA H1047R and E545K mutations in cfDNA can be sensitively detected with our newly developed assays. The colorectal cancer has been used as a clinical example in testing our new assays, which indicates that the new assays may have wider applications in detecting mutations in precision oncology. Trial registration: Current Controlled Trials ChiCTR-DDT-12002848, 8 October 2012.

Heavy Ion-Responsive lncRNA EBLN3P Functions in the Radiosensitization of Non-Small Cell Lung Cancer Cells Mediated by TNPO1.

In recent decades, the rapid development of radiotherapy has dramatically increased the cure rate of malignant tumors. Heavy-ion radiotherapy, which is characterized by the "Bragg Peak" because of its excellent physical properties, induces extensive unrepairable DNA damage in tumor tissues, while normal tissues in the path of ion beams suffer less damage. However, there are few prognostic molecular biomarkers that can be used to assess the efficacy of heavy ion radiotherapy. In this study, we focus on non-small cell lung cancer (NSCLC) radiotherapy and use RNA sequencing and bioinformatic analysis to investigate the gene expression profiles of A549 cells exposed to X-ray or carbon ion irradiation to screen the key genes involved in the stronger tumor-killing effect induced by carbon ions. The potential ceRNA network was predicted and verified by polymerase chain amplification, western blotting analysis, colony formation assay, and apoptosis assay. The results of the experiments indicated that lncRNA EBLN3P plays a critical role in inhibiting carbon ion-induced cell proliferation and inducing apoptosis of NSCLC cells. These functions were achieved by the EBLN3P/miR-144-3p/TNPO1 (transportin-1) ceRNA network. In summary, the lncRNA EBLN3P functions as a ceRNA to mediate lung cancer inhibition induced by carbon ion irradiation by sponging miR-144-3p to regulate TNPO1 expression, indicating that EBLN3P may be a promising target for increasing the treatment efficacy of conventional radiotherapy for NSCLC.

TIPE2 Suppresses Malignancy of Pancreatic Cancer Through Inhibiting TGFß1 Mediated Signaling Pathway.

Pancreatic cancer is one of the major reasons of cancer-associated deaths due to poor diagnosis, high metastasis and drug resistance. Therefore, it is important to understand the cellular and molecular mechanisms of pancreatic cancer to identify new targets for the treatment. TIPE2 is an essential regulator of tumor apoptosis, inflammation and immune homeostasis. However, the role of TIPE2 is still not fully understood in pancreatic cancer. In this study, we found the expression of TIPE2 was decreased in pancreatic cancer tissues compare to paracancerous tissues, which was negatively correlated with tumor size in patients. Overexpression of TIPE2 significantly decreased cell proliferation, metastasis and increased apoptotic events in pancreatic cancer cell lines. Moreover, the results obtained from real time PCR and western blot revealed that TIPE2 was also involved in inhibiting MMPs and N-Cadherin expression while increasing Bax expression in pancreatic cancer cells. Similarly, TIPE2 could inhibit tumor growth in vivo, decrease the expression of Ki-67 and N-Cadherin, and increase the expression of Bax by IHC analysis in tumor tissues isolated from tumor-bearing mice. Mechanistic studies exhibited that TIPE2 might suppress pancreatic cancer development through inhibiting PI3K/AKT and Raf/MEK/ERK signaling pathways triggered by TGFß1. Moreover, the tumor-infiltrating lymphocytes from tumor-bearing mice were analyzed by flow cytometry, and showed that TIPE2 could promote T cell activation to exert an anti-tumor effect possibly through activation of DCs in a TGFß1 dependent manner. In general, we described the multiple regulatory mechanisms of TIPE2 in pancreatic tumorigenesis and tumor microenvironment, which suggested TIPE2 may act as a potential therapeutic target in pancreatic cancer.

Cancer stage-dependent alterations in cell-free DNA in patients with colorectal cancer.

PURPOSE: Cell-free DNA (cfDNA) in plasma is a useful resource for liquid biopsy. The concentration and integrity of cfDNA may be clinical informative for detecting and predicting cancer progression. METHODS: Plasma from 40 healthy controls and 90 colorectal cancer patients was assessed. qPCR targeting the arithmetic-logic unit (Alu) repeats were performed using two different sets of primers amplifying the long and short segments. DNA integrity was calculated by the ratio of the long to the short fragments of amplified Alu repeats. RESULTS: cfDNA concentration was significantly higher in the patients than that in healthy controls. Patients with stage III colorectal cancer showed no significant difference in their cfDNA levels as compared with the healthy controls. In colorectal cancer, cfDNA level of stage IV patients was higher than that of stage 0-III (p=0.049). The DNA integrity was significantly lower in patients with stage I and II cancer than that in normal controls (p=0.007, 0.029 respectively). The receiver operating characteristic (ROC) curve for discriminating patients with colorectal cancer from normal controls had an area under the curve of 0.672 (95%CI, 0.572 to 0.772) and cfDNA concentration increased within 21 days following surgery and dropped by 3 months after surgery. CONCLUSION: Concentration of cfDNA is a promising molecular marker for assessing colorectal cancer progression. Both the cfDNA concentration and its integrity are highly variable. Some cancer stage dependent changes were observed, which warrants further investigation with more patients included.

Monitoring of Tritium Internal Exposure Doses of Heavy-Water Reactor Workers in Third Qinshan Nuclear Power Plant.

To analyze the tritium internal exposure dose of workers in the Third Qinshan Nuclear Power Plant over the past 15 years. Urine samples provided by workers are tested directly to analyze the tritium concentrations and estimate internal exposure dose. Since 2004, an average of approximately 1600 workers have been monitored annually, with an average annual monitoring frequency of approximately 11 000. Since 2004, the average annual collective dose of tritium internal exposure was 149.62 person·mSv, accounting for 19.07% of the total annual collective dose. A total of 18 workers' annual individual internal tritium radiation doses exceeded 2 mSv, of which 5 workers' internal tritium radiation doses in a single intake exceeded 2 mSv. The occupational population with the largest total internal tritium radiation doses consists of maintenance personnel, fuel operators, and radiation protection personnel, whose collective doses of internal exposure account for 75.51% of the total collective doses within the plant. Over 15 years of operation, the internal tritium radiation doses of workers in the Third Qinshan Nuclear Power Plant have been strictly controlled within the national regulatory limit and power plant management target, ensuring the health and safety of the workers.

Medical Treatment and Dose Estimation of a Person Exposed to Tritium.

In this study, we aimed to investigate the damaging effects and clinical therapy of internal contamination with tritium to provide information and gain experience for medical treatments in case of an emergency due to a nuclear accident. Histories were taken by several doctors who observed and recorded the clinical symptoms of the patient described herein. The general health situation was evaluated by laboratory and equipment analyses. Tritium concentrations in the urine were estimated according to relevant standards during the monitoring period using a liquid scintillation counting method. Clinical observation revealed that the patient had symptoms of mild asthenia and sleep disorder with improvement after appropriate treatment. The last committed effective dose was determined through measurement of the urine tritium concentration and dose estimation and was estimated to be 0.123 mSv; the total effective dose was 14.536 mSv. The medical treatment and dose estimation in this patient with tritium contamination were successful and can provide a reference for similar cases in the future.

Rapid and High-Throughput Detection of Peripheral Blood Chromosome Aberrations in Radiation Workers.

There is a pressing need to establish automated solutions for the rapid, high-throughput, and automatic detection of chromosome aberrations (CAs) in the occupational health surveillance of large-scale radiation workers. Here, we described and verified the accuracy of a new measurement system based on the automatic scanning and analysis of dicentric chromosomes (DICs). The effects of cell number on DIC detection by automatic scanning and analysis were studied, and the distribution of DIC values per cell was calculated. In total, 1088 cases were detected by automatic DIC scanning and analysis in 26 663 radiation workers, and 73 cases were further confirmed by a technician, including 5 cases in which radiation exposure lead to harmful medical consequences. Our approach reduces the workload by 96% and increases the speed of assessment approximately 7-fold. Overall, this study validates the utility of a novel rapid and high-throughput CA detection procedure as a means of occupational health surveillance of large-scale radiation workers.

Successful Rescue of the Victim Exposed to a Super High Dose of Iridium-192 during the Nanjing Radiological Accident in 2014.

Here we report on the interventions taken to treat a patient exposed to high-dose radiation and provide a protocol for treating such patients in the future. The patient, Mr. Wang, was a 58-year-old male janitor who was accidentally exposed to a 192Ir source with an activity of 966.4 GBq or 26.1 Ci. The dose estimated to the lower right limb was 4,100 Gy, whereas the whole-body effective dose was 1.51 Gy. The diagnosis was made according to the results of the patient dose estimation and clinical manifestations. Systemic treatment included stimulating bone marrow hematopoietic cells, enhancing immunity, anti-infection and vitamin supplements. The treatment of radiation-induced skin lesions consisted of several debridements, two skin-flap transplantations and application of mesenchymal stem cells (MSCs). Skin-flap transplantations and MSCs play important roles in the recovery of skin wound. A combination of antibiotics and antimycotic was useful in reducing inflammation. The application of vacuum sealing drainage was effective in removing necrotic tissue and bacteria, ameliorating ischemia and hypoxia of wound tissue, providing a fresh wound bed for wound healing and improving skin or flap graft survival rates. The victim survived the accident without amputation, and function of his highly exposed right leg was partially recovered. These results demonstrate the importance of collaboration among members of a multidisciplinary team in the treatment of this patient.

Multiple Organ Lesions in a Case of Contamination With Multiple Radionuclides After 38 Years.

The patient was contaminated with multiple radionuclides 38 years ago due to an accident. To investigate the effects of radionuclide contamination on humans, he has been followed up by examinations for many years. Long-term effects gradually emerge in these years. Lung cancer was diagnosed by medical examinations. Besides, chronic gastritis with intestinal metaplasia was indicated by gastroscopic biopsies, while colorectal polyps found by colonoscopy. All 13 colorectal polyps were removed, and radical surgery for lung cancer was performed. Fortunately, pathological examinations indicated that it was early lung cancer. The ground glass nodule (GGN) in left lung identified during the follow-up will be resected when needed. It is speculated that multiple manifestations of the patient may be related to radiation, and different lesions in the organs may be related to systemic adaptive response. However, longer follow-up is needed due to a lack of effective and direct evidence. This work is expected to provide experiences for similar patients' treatment and follow-up.

Complete Technical Scheme for Automatic Biological Dose Estimation Platform.

To establish a complete technical solution for the automatic radiation biological dose estimation platform for biological dose estimation and classification of the wounded in large-scale radiation accidents, the "dose-effect curve by dicentric chromosome (DIC) automatic analysis" was established and its accuracy was verified. The effects of analyzed cell number and the special treatment of the culture on dose estimation by DIC automatic analysis were studied. Besides, sample processing capabilities of the special equipments were tested. The fitted "dose-effect curve by DIC automatic analysis" was presented as follows: Y = (0.01806 ± 0.00032) D 2 + (0.01279 ± 0.00084) D + (0.0004891 ± 0.0001358) (R 2 = 0.961). Three-gradient scanning method, culture refrigeration method, and interprofessional collaboration under extreme conditions were proposed to improve the detection speed, prolong the sample processing time window, and reduce the equipment investment. In addition, the optimized device allocation ratio for the automatic biological dose estimation laboratory was proposed to eliminate the efficiency bottleneck. The complete set of technical solutions for the high-throughput automatic biological dose estimation laboratory proposed in this study can meet the requirements of early classification and rapid biological dose assessment of the wounded during the large-scale nuclear radiation events, and it is worthy of further promotion.

Pharmacokinetic evaluation of novel oral fluorouracil antitumor drug S-1 in Chinese cancer patients.

AIM: S-1 is an oral anticancer fluoropyrimidine formulation consisting of tegafur, 5-chloro-2,4-dihydroxypyridine and potassium oxonate. The aim of this study was to evaluate the pharmacokinetics and bioequivalence of a newly developed generic formulation of S-1 in Chinese cancer patients in comparison with the branded reference formulation of S-1. METHODS: A single-dose, randomized-sequence, open-label, two-way self-crossover study was conducted in 30 Chinese cancer patients. The subjects alternatively received the two formulations (40 mg/m(2), po) with a 7-d interval. Plasma concentrations of FT, CDHP, Oxo, and 5-Fu were determined using LC-MS/MS. Pharmacokinetic parameters, including Cmax, Tmax, t1/2, AUC0-t, and AUC0-∞ were determined using non-compartmental models with DAS2.0 software. Bioequivalence of the two formulations were to be evaluated according to 90% CIs for the log-transformed ratios of AUC and Cmax of S-1. Adverse events were evaluated through monitoring the symptom, physical and laboratory examinations, ECGs and subject interviews. RESULTS: The mean values of Cmax, AUC0-t, and AUC0-∞ of FT, 5-Fu, CDHP, and Oxo for the two formulations had no significant differences. The 90% CIs for natural log-transformed ratios of Cmax, AUC0-t, and AUC0-∞ were within the predetermined bioequivalence acceptance limits. A total of 11 mild adverse events, including fatigue, nausea and vomiting, anorexia, diarrhea and myelosuppression, were observed, and no serious and special adverse events were found. CONCLUSION: The newly developed generic formulation and reference formulation of S-1 have similar pharmacokinetics with one dose (40 mg/m(2)) in Chinese cancer patients. Both the formulations of S-1 are well tolerated.