Tumor-intrinsic role of ICAM-1 in driving metastatic progression of triple-negative breast cancer through direct interaction with EGFR.

Triple-negative breast cancer (TNBC), the most aggressive subtype, presents a critical challenge due to the absence of approved targeted therapies. Hence, there is an urgent need to identify effective therapeutic targets for this condition. While epidermal growth factor receptor (EGFR) is prominently expressed in TNBC and recognized as a therapeutic target, anti-EGFR therapies have yet to gain approval for breast cancer treatment due to their associated side effects and limited efficacy. Here, we discovered that intercellular adhesion molecule-1 (ICAM-1) exhibits elevated expression levels in metastatic breast cancer and serves as a pivotal binding adaptor for EGFR activation, playing a crucial role in malignant progression. The activation of EGFR by tumor-expressed ICAM-1 initiates biased signaling within the JAK1/STAT3 pathway, consequently driving epithelial-to-mesenchymal transition and facilitating heightened metastasis without influencing tumor growth. Remarkably, ICAM-1-neutralizing antibody treatment significantly suppressed cancer metastasis in a breast cancer orthotopic xenograft mouse model. In conclusion, our identification of ICAM-1 as a novel tumor intrinsic regulator of EGFR activation offers valuable insights for the development of TNBC-specific anti-EGFR therapies.

Improving radiation dosimetry with an automated micronucleus scoring system: correction of automated scoring errors.

Radiation dose estimations performed by automated counting of micronuclei (MN) have been studied for their utility for triage following large-scale radiological incidents; although speed is essential, it also is essential to estimate radiation doses as accurately as possible for long-term epidemiological follow-up. Our goal in this study was to evaluate and improve the performance of automated MN counting for biodosimetry using the cytokinesis-block micronucleus (CBMN) assay. We measured false detection rates and used them to improve the accuracy of dosimetry. The average false-positive rate for binucleated cells was 1.14%; average false-positive and -negative MN rates were 1.03% and 3.50%, respectively. Detection errors seemed to be correlated with radiation dose. Correction of errors by visual inspection of images used for automated counting, called the semi-automated and manual scoring method, increased accuracy of dose estimation. Our findings suggest that dose assessment of the automated MN scoring system can be improved by subsequent error correction, which could be useful for performing biodosimetry on large numbers of people rapidly, accurately, and efficiently.

Interventional radiologists have a higher rate of chromosomal damage due to occupational radiation exposure: a dicentric chromosome assay.

OBJECTIVES: There are growing concerns regarding radiation exposure in medical workers who perform interventional fluoroscopy procedures. Owing to the nature of certain interventional procedures, workers may be subjected to partial-body radiation exposure that is high enough to cause local damage. We aimed to investigate the level of radiation exposure in interventional radiologists in South Korea by performing cytogenetic biodosimetry, particularly focusing on partial-body exposure. METHODS: Interventional radiologists (n = 52) completed a questionnaire, providing information about their work history and practices. Blood samples were collected and processed for a dicentric chromosome assay. We determined Papworth's U-value to assess the conformity of dicentrics with the Poisson distribution to estimate the partial-body exposures of the radiologists. RESULTS: Radiologists had a higher number of dicentrics than the normal population and industrial radiographers. Indeed, subjects with a U-value of > 1.96, an indicator of heterogeneous exposure, were observed more frequently; 4.67 ± 0.81% of their body was irradiated at an average dose of 4.64 ± 0.67 Gy. Logistic regression analysis revealed that the total duration of all interventional procedures per week was associated with partial-body exposure levels. CONCLUSIONS: Our findings suggest that interventional radiologists had greater chromosomal damages than those in other occupational groups, and their partial-body exposure levels might be high enough to cause local damage. Use of special dosimeters to monitor partial-body exposure, as well as restricting the time and frequency of interventional procedures, could help reduce occupational radiation exposure. KEY POINTS: • Interventional radiologists had a higher number of dicentrics than the normal population and industrial radiographers. • The level of partial-body exposure of interventional radiologists might be high enough to cause occupational local damage such as a skin cancer in fingers. • Restricting the duration and frequency of interventional procedures might be helpful in reducing occupational radiation exposure.

Korean-specific biokinetic model for iodine in radiological protection.

The International Commission on Radiological Protection (ICRP) recently adopted a detailed biokinetic model for systemic iodine with reference transfer coefficients based on typical worldwide dietary intakes of stable iodine. The regional data provided demonstrate that the ICRP reference thyroidal biokinetics may differ substantially across regions with atypically low or high dietary intakes of stable iodine. Importantly, the design of the ICRP model facilitates modifications of reference thyroidal kinetics based on regional dietary iodine intake. The present study extended the ICRP model to the South Korean population, whose dietary iodine intake is much higher than the global mean. The following three transfer coefficients were selected as targets for Korean-specific values: thyroidal uptake rate (λ1), hormonal secretion rate (λ4) and leakage rate of thyroidal organic iodine as inorganic iodide (λ5). The Korean-specific values forλ1,λ4andλ5were determined to be 4.48, 0.0086 and 0.0171 d-1, respectively, to yield the measurements of thyroidal iodine and physiological status of Korean adults. The determinedλ1andλ5values differed noticeably from the ICRP values, whereas theλ4value was comparable to that of the ICRP. Compared with the ICRP reference model, the Korean model, in which the Korean-specific transfer coefficients were adopted, predicted noticeably lower thyroidal uptake and faster decrease of thyroidal iodine. In addition, the predicted cumulative activities of radioiodine in the thyroid were substantially lower (40-80%) than those predicted by the ICRP model. The Korean model developed in this study demonstrates that the iodine biokinetics for Koreans (i.e. a population with a high iodine consumption) obviously differ from the prediction of the ICRP model. Hence, the Korean model may serve to improve the accuracy of thyroid dose estimation for Koreans and will lead to practical changes in matters concerned with radiological protection.

Estimation of the historical radiation dose of Korean radiation workers, 1961-1983.

Accurate dosimetry plays a key role in evaluating the radiation-induced health risks of radiation workers. The National Dose Registry in Korea contains the dose records of radiation workers in nuclear-related occupations since 1984. Thus, radiation doses for workers before 1984 are often sparse or missing. This study aimed to estimate the historical radiation dose before 1984 for radiation workers in Korea based on dose reconstruction models. The dose reconstruction models were derived from the nationwide self-administered questionnaire survey and the personal badge doses for workers in the cohort of the Korean Radiation Worker Study. The mean estimated annual doses between 1984 and 2016 from the dose reconstruction model were 4.67-0.6 mSv, which closely matched the reported doses of 4.51-0.43 mSv. The mean estimated annual doses between 1961 and 1983 based on the exposure scenarios developed by factors associated with radiation doses ranged from 11.08 to 4.82 mSv. The mean estimated annual doses of individuals in the cohort from 1961 to 1983 ranged from 11.15 to 4.88 mSv. Although caution needs to be exercised in the interpretation of these estimations due to uncertainty owed to the nature of extrapolation beyond the range of observed data, this study offers a sense of the radiation doses for workers during Korea's early period of radiation-related activities, which can be a useful piece of information for radiation-induced health risk assessments.

Assessment of working environment and personal dosimeter-wearing compliance of industrial radiographers based on chromosome aberration frequencies.

Industrial radiographers are exposed to relatively higher doses of radiation than other radiation-exposed workers in South Korea. The objective of our study was to investigate the impact of specific occupational conditions on chromosome aberration frequency and evaluate dosimeter-wearing compliance of industrial radiographers in Korea. We studied individual and occupational characteristics of 120 industrial radiographers working in South Korea and evaluated the frequency of dicentrics and translocations in chromosomes to estimate radiation exposure. The association between working conditions and chromosome aberration frequencies was assessed by Poisson regression analysis after adjusting for confounding factors. Legal personal dosimeter-wearing compliance among workers was investigated by correlation analysis between recorded dose and chromosome aberration frequency. Daily average number of radiographic films used in the last six months was associated with dicentrics frequency. Workers performing site radiography showed significantly higher translocation frequency than those working predominantly in shielded enclosures. The correlation between chromosome aberration frequency and recorded dose was higher in workers in the radiography occupation since 2012 (new workers) than other veteran workers. Our study found that site radiography could affect actual radiation exposure to workers. Controlling these working conditions and making an effort to improve personal dosimeter-wearing compliance among veteran workers as well as new workers may be necessary to reduce radiation exposure as much as possible in their workplace.

Rebamipide alleviates radiation-induced colitis through improvement of goblet cell differentiation in mice.

BACKGROUND AND AIM: Radiation-induced colitis is a common clinical problem associated with radiotherapy and accidental exposure to ionizing radiation. Goblet cells play a pivotal role in the intestinal barrier against pathogenic bacteria. Rebamipide, an anti-gastric ulcer drug, has the effects to promote goblet cell proliferation. The aim of this study was to investigate whether radiation-induced colonic injury could be alleviated by rebamipide. METHODS: This study orally administered rebamipide for 6 days to mice, which were subjected to 13 Gy abdominal irradiation, to evaluate the therapeutic effects of rebamipide against radiation-induced colitis. To confirm the effects of rebamipide on irradiated colonic epithelial cells, this study used the HT29 cell line. RESULTS: Rebamipide clearly alleviated the acute radiation-induced colitis, as reflected by the histopathological data, and significantly increased the number of goblet cells. The drug also inhibited intestinal inflammation and protected from bacterial translocation during acute radiation-induced colitis. Furthermore, rebamipide significantly increased mucin 2 expression in both the irradiated mouse colon and human colonic epithelial cells. Additionally, rebamipide accelerated not only the recovery of defective tight junctions but also the differentiation of impaired goblet cells in an irradiated colonic epithelium, which indicates that rebamipide has beneficial effects on the colon. CONCLUSIONS: Rebamipide is a therapeutic candidate for radiation-induced colitis, owing to its ability to inhibit inflammation and protect the colonic epithelial barrier.

Epithelial cell shape change of Drosophila as a biomonitoring model for the dose assessment of environmental radiation.

Inevitable exposure to ionizing radiation from natural and human-made sources has been increasing over time. After nuclear disasters, such as the Fukushima accident, the public concerns on health risk of radiation exposure because of radioactive contamination of the environment have increased. However, it is very difficult to assess the biological effects of exposure caused by environmental radiation. A reliable and rapid bioassay to monitor the physiological effects of radiation exposure is therefore needed. Here, we quantitatively analyzed the changes in cell shape in Drosophila epidermis after irradiation as a model for biomonitoring of radiation. Interestingly, the number of irregularly shaped epithelial cells was increased by irradiation in a dose-dependent manner. A dose-response curve constructed with the obtained data suggests that the measurement of the number of irregular shaped cell in the epidermis is useful for the assessment of radiation dose. In addition, a comparison of the variation in the different samples and the data scored by different observers showed that our evaluation for cellular morphology was highly reliable and accurate and would, therefore, have immense practical application. Overall, our study suggests that detection of morphological changes in the epithelial cells is one of the efficient ways to quantify the levels of exposure to radioactive radiation from the environment.

Usefulness of cancer-free survival in estimating the lifetime attributable risk of cancer incidence from radiation exposure.

Risk projection models estimating the lifetime cancer risk from radiation exposure are generally based on exposure dose, age at exposure, attained age, gender and study-population-specific factors such as baseline cancer risks and survival rates. Because such models have mostly been based on the Life Span Study cohort of Japanese atomic bomb survivors, the baseline risks and survival rates in the target population should be considered when applying the cancer risk. The survival function used in the risk projection models that are commonly used in the radiological protection field to estimate the cancer risk from medical or occupational exposure is based on all-cause mortality. Thus, it may not be accurate for estimating the lifetime risk of high-incidence but not life-threatening cancer with a long-term survival rate. Herein, we present the lifetime attributable risk (LAR) estimates of all solid cancers except thyroid cancer, thyroid cancer, and leukemia except chronic lymphocytic leukemia in South Korea for lifetime exposure to 1 mGy per year using the cancer-free survival function, as recently applied in the Fukushima health risk assessment by the World Health Organization. Compared with the estimates of LARs using an overall survival function solely based on all-cause mortality, the LARs of all solid cancers except thyroid cancer, and thyroid cancer evaluated using the cancer-free survival function, decreased by approximately 13% and 1% for men and 9% and 5% for women, respectively. The LAR of leukemia except chronic lymphocytic leukemia barely changed for either gender owing to the small absolute difference between its incidence and mortality. Given that many cancers have a high curative rate and low mortality rate, using a survival function solely based on all-cause mortality may cause an overestimation of the lifetime risk of cancer incidence. The lifetime fractional risk was robust against the choice of survival function.

Rebamipide ameliorates radiation-induced intestinal injury in a mouse model.

Radiation-induced enteritis is a major side effect in cancer patients undergoing abdominopelvic radiotherapy. Radiation exposure produces an uncontrolled inflammatory cascade and epithelial cell loss leading to impaired epithelial barrier function. The goal of this study was to determine the effect of rebamipide on regeneration of the intestinal epithelia after radiation injury. The abdomens of C57BL/6 mice were exposed to 13Gy of irradiation (IR) and then the mice were treated with rebamipide. Upon IR, intestinal epithelia were destroyed structurally at the microscopic level and bacterial translocation was increased. The intestinal damage reached a maximum level on day 6 post-IR and intestinal regeneration occurred thereafter. We found that rebamipide significantly ameliorated radiation-induced intestinal injury. In mice treated with rebamipide after IR, intestinal barrier function recovered and expression of the tight junction components of the intestinal barrier were upregulated. Rebamipide administration reduced radiation-induced intestinal mucosal injury. The levels of proinflammatory cytokines and matrix metallopeptidase 9 (MMP9) were significantly reduced upon rebamipide administration. Intestinal cell proliferation and ß-catenin expression also increased upon rebamipide administration. These data demonstrate that rebamipide reverses impairment of the intestinal barrier by increasing intestinal cell proliferation and attenuating the inflammatory response by inhibiting MMP9 and proinflammatory cytokine expression in a murine model of radiation-induced enteritis.

Estimation of counting efficiencies of a portable NaI detector using Monte Carlo simulation for thyroid measurement following nuclear accidents.

Radioiodine can be released in nuclear accidents and can cause internal contamination of the thyroid gland in members of the public. For population monitoring in radiation emergencies, measurement of counting efficiency is very important to accurately determine thyroid activity. Here, we estimate the counting efficiencies of a portable NaI detector using Monte Carlo simulations. Two different types of neck phantoms and a 7.62 cm long by 7.62 cm diameter NaI detector were modeled and the counting efficiencies were calculated depending on the thyroid size and distance from the neck phantom to the detector. We found that distance is a more important parameter than thyroid size. The optimal distance of the NaI detector from the neck surface was determined to be greater than 12 cm, beyond which the counting efficiency was not affected by thyroid size.

Identification of a distinct subpopulation of fibroblasts from murine dermis: CD73(-) CD105(+) as potential marker of dermal fibroblasts subset with multipotency.

Skin dermis includes various types of multipotent stromal cells (MSCs) and a subpopulation of dermal fibroblasts that exhibit the ability to differentiate. However, characterization of this dermal fibroblast subtype remains less understood. In this study, we isolated dermal cells from the skin of newborn C57/B6 mice and investigated their characteristics. Isolated murine dermal cells exhibited a fibroblast phenotype as judged by accepted criteria including a lack of MSC-related antigens and the differentiation potential of MSCs, and the positive expression of fibroblast markers. A comparative analysis demonstrated that CD73(-) CD105(+) but not CD73(-) CD105(-) dermal fibroblasts exhibited some of the functional properties of MSCs. Furthermore, the multipotent phenotype of CD73(-) CD105(+) cells was diminished by treatment of CD105 siRNA and shRNA, indicating that CD105 expression was critical for the retention of differentiation potential of those cells. Overall, these results suggest that CD73(-) CD105(+) cells are a distinct subset of dermal fibroblasts with multipotency and that their surface antigens could help to classify this subpopulation. These cells may contribute to the regeneration of damaged tissue.

Is the Linear No-Threshold Dose-Response Paradigm Still Necessary for the Assessment of Health Effects of Low Dose Radiation?

Inevitable human exposure to ionizing radiation from man-made sources has been increased with the proceeding of human civilization and consequently public concerns focus on the possible risk to human health. Moreover, Fukushima nuclear power plant accidents after the 2011 East-Japan earthquake and tsunami has brought the great fear and anxiety for the exposure of radiation at low levels, even much lower levels similar to natural background. Health effects of low dose radiation less than 100 mSv have been debated whether they are beneficial or detrimental because sample sizes were not large enough to allow epidemiological detection of excess effects and there was lack of consistency among the available experimental data. We have reviewed an extensive literature on the low dose radiation effects in both radiation biology and epidemiology, and highlighted some of the controversies therein. This article could provide a reasonable view of utilizing radiation for human life and responding to the public questions about radiation risk. In addition, it suggests the necessity of integrated studies of radiobiology and epidemiology at the national level in order to collect more systematic and profound information about health effects of low dose radiation.

Estimates of Radiation Doses and Cancer Risk from Food Intake in Korea.

The aim of this study was to estimate internal radiation doses and lifetime cancer risk from food ingestion. Radiation doses from food intake were calculated using the Korea National Health and Nutrition Examination Survey and the measured radioactivity of (134)Cs, (137)Cs, and (131)I from the Ministry of Food and Drug Safety in Korea. Total number of measured data was 8,496 (3,643 for agricultural products, 644 for livestock products, 43 for milk products, 3,193 for marine products, and 973 for processed food). Cancer risk was calculated by multiplying the estimated committed effective dose and the detriment adjusted nominal risk coefficients recommended by the International Commission on Radiation Protection. The lifetime committed effective doses from the daily diet are ranged 2.957-3.710 mSv. Excess lifetime cancer risks are 14.4-18.1, 0.4-0.5, and 1.8-2.3 per 100,000 for all solid cancers combined, thyroid cancer, and leukemia, respectively.

The radiologic technologists' health study in South Korea: study design and baseline results.

PURPOSE: To describe the study design, methods, and baseline results of a prospective cohort of radiologic technologists which we have initiated in South Korea. METHODS: The cohort participants were enrolled through a self-administered questionnaire survey administered from April 2012 to May 2013. Survey data were linked with radiation dosimetry, a cancer registry, and health insurance data by personal identification numbers. A nationwide representative survey was also conducted using a stratified random sampling design with face-to-face interviews. RESULTS: A total of 12,387 radiologic technologists were enrolled, which accounted for approximately 63% of all diagnostic radiologic technologists working in South Korea. For nationwide survey, 585 workers were interviewed using the detailed questionnaire, and buccal cells were also collected by scraping the inside of the cheek. The majority of study subjects were under 50-year-old and male workers. The average annual effective dose of radiation declined both men (from 2.75 to 1.43 mSv) and women (from 1.34 to 0.95 mSv) over the period of 1996-2011. A total of 99 cancers (66 cancers in men and 33 in women) were reported from 1992 to 2010. The standardized incidence ratio of all cancer combined was significantly lower in men (SIR = 0.75, 95% CI 0.58-0.96) than general population, but the ratios for thyroid cancer were significantly higher than expected among both men and women. CONCLUSIONS: This cohort provides comprehensive information on work activities and health status of diagnostic radiologic technologists. In addition, the nationwide representative sample provides unique opportunities compared with previous radiologic technologist studies.

Effective dose conversion coefficients for health care provider exposed to pediatric and adult victims in radiological dispersal device incident.

After an incident of radiological dispersal devices (RDD), health care providers will be exposed to the contaminated patients in the extended medical treatments. Assessment of potential radiation dose to the health care providers will be crucial to minimize their health risk. In this study, we compiled a set of conversion coefficients (mSv MBq(-1) s(-1)) to readily estimate the effective dose from the time-integrated activity for the health care providers while they deal with internally contaminated patients at different ages. We selected Co-60, Ir-192, Am-241, Cs-137, and I-131 as the major radionuclides that may be used for RDD. We obtained the age-specific organ burdens after the inhalation of those radionuclides from the Dose and Risk Calculation Software (DCAL) program. A series of hybrid computational phantoms (1-, 5-, 10-, and 15 year-old, and adult males) were implemented in a general purpose Monte Carlo (MC) transport code, MCNPX v 2.7, to simulate an adult male health care provider exposed to contaminated patients at different ages. Two exposure scenarios were taken into account: a health care provider (a) standing at the side of patients lying in bed and (b) sitting face to face with patients. The conversion coefficients overall depended on radionuclides, the age of the patients, and the orientation of the patients. The conversion coefficient was greatest for Co-60 and smallest for Am-241. The dose from the 1 year-old patient phantom was up to three times greater than that from the adult patient phantom. The conversion coefficients were less dependent on the age of the patients in the scenario of a health care provider sitting face to face with patients. The dose conversion coefficients established in this study will be useful to readily estimate the effective dose to the health care providers in RDD events.

Phosphorylation of ribosomal protein S3 and antiapoptotic TRAF2 protein mediates radioresistance in non-small cell lung cancer cells.

Radioresistance is considered as a main factor restricting efficacy of radiotherapy. However, the exact molecular mechanism of radioresistance has not been explained yet. In this study, to elucidate radioresistance mechanism in lung cancer, we compared radiation responses in two types of non-small cell lung cancer (NSCLC) cells with different radiosensitivity and identified key molecules conferring radioresistance. In radioresistant NSCLC cells, ionizing radiation (IR) led to casein kinase 2α (CK2α)- and PKC-mediated phosphorylation of rpS3 and TRAF2, respectively, which induced dissociation of rpS3-TRAF2 complex and NF-κB activation, resulting in significant up-regulation of prosurvival genes (cIAP1, cIAP2, and survivin). Also, dissociated phospho-rpS3 translocated into nucleus and bound with NF-κB complex (p65 and p50), contributing to p65 DNA binding property and specificity. However, in radiosensitive NSCLC cells, IR-mediated rpS3 phosphorylation was not detected due to the absence of CK2α overexpression. Consequently, IR-induced rpS3-TRAF2 complex dissociation, NF-κB activation, and prosurvival gene expression were not presented. Taken together, our findings revealed a novel radioresistance mechanism through functional orchestration of rpS3, TRAF2, and NF-κB in NSCLC cells. Moreover, we provided the first evidence for the function of rpS3 as a new TRAF2-binding protein and demonstrated that phosphorylation of both rpS3 and TRAF2 is a key control point of radioresistance in NSCLC cells. These results suggest that regulation of rpS3 and TRAF2 in combination with radiotherapy could have high pharmacological therapeutic potency for radioresistance of NSCLC.

The effects of low-dose ionizing radiation in the activated rat basophilic leukemia (RBL-2H3) mast cells.

Mast cells play important roles in many biological responses, such as those during allergic diseases and inflammatory disorders. Although laser and UV irradiation have immunosuppressive effects on inflammatory diseases by suppressing mast cells, little is known about the effects of γ-ionizing radiation on mast cells. In this study, we investigated the effects of γ-ionizing radiation on RBL-2H3 cells, a convenient model system for studying regulated secretion by mast cells. Low-dose radiation (<0.1 gray (Gy)) did not induce cell death, but high-dose radiation (>0.5 Gy) induced apoptosis. Low-dose ionizing radiation significantly suppressed the release of mediators (histamine, ß-hexosaminidase, IL-4, and tumor necrosis factor-α) from immunoglobulin E (IgE)-sensitized RBL-2H3 cells. To determine the mechanism of mediator release inhibition by ionizing radiation, we examined the activation of intracellular signaling molecules such as Lyn, Syk, phospholipase Cγ, PKCs, and MAPK, and intracellular free calcium concentrations ([Ca(2+)](i)). The phosphorylation of signaling molecules following stimulation of high-affinity IgE receptor I (FcεRI) was specifically inhibited by low-dose ionizing radiation (0.01 Gy). These results were due to the suppression of FcεRI expression by the low-dose ionizing radiation. Therefore, low-dose ionizing radiation (0.01 Gy) may function as a novel inhibitor of mast cell activation.