Young Hoon Ji

A Hypoxia-Induced Vascular Endothelial-to-Mesenchymal Transition in Development of Radiation-Induced Pulmonary Fibrosis

Purpose: Radiation-induced pulmonary fibrosis (RIPF) is a late side effect of thoracic radiotherapy. The purpose of our study was to gain further insight into the development of RIPF. Experimental Design/Results: Here, we observed that irradiation of mouse lungs induced collagen deposition, particularly around blood vessels, in the early phase of RIPF. Such deposition subsequently became evident throughout the irradiated tissues. Accompanied by the collagen deposition, vascular EndMT (endothelial-to-mesenchymal transition) began to develop in the early phase of RIPF, before the appearance of EMT (epithelial-to-mesenchymal transition) of alveolar epithelial (AE) II cells in the substantive fibrotic phase. Concomitant with the EndMT, we detected vascular endothelial cell (EC)–specific hypoxic damage in the irradiated lung tissues. In human pulmonary artery endothelial cells (HPAEC), the radiation-induced EndMT via activation of TGFβ-R1/Smad signaling was dependent on HIF1α expression. A novel HIF1α inhibitor, 2-methoxyestradiol (2-ME), inhibited the irradiation-induced EndMT via downregulation of HIF1α-dependent Smad signaling. In vivo, 2-ME inhibited the vascular EndMT, and decreased the collagen deposition associated with RIPF. Furthermore, HIF1α-related EndMT was observed also in human RIPF tissues. Conclusions: We provide the first evidence that an EndMT occurs in RIPF development and that the EndMT may be effectively inhibited by modulating vascular EC-specific hypoxic damage. Clin Cancer Res; 21(16); 3716–26. ©2015 AACR.

The effect of oxidized low-density lipoprotein (ox-LDL) on radiation-induced endothelial-to-mesenchymal transition.

Abstract Purpose: Radiation-induced cardiovascular disease is a potentially severe side-effect of thoracic radiotherapy treatment. Clinically, this delayed side-effect presents as a form of accelerated atherosclerosis several years after irradiation. As general endothelial dysfunction is known to be an initiating event in radiation-induced vascular damage, we examined the effects of radiation on endothelial cells in radiation-induced atherosclerosis. Materials and methods: The effects of radiation on human aortic endothelial cells (HAoEC) were assessed by immunoblotting and immunofluorescence assays. Radiation-induced phenotypic changes of endothelial cells (ECs) were examined using atherosclerotic tissues of irradiated apoprotein E null (ApoE−/−) mice. Results: Radiation induced the HAoEC to undergo phenotypic conversion to form fibroblast-like cells, called the endothelial-to-mesenchymal transition (EndMT), which leads to the upregulation of mesenchymal cell markers such as alpha-smooth muscle actin (α-SMA), fibroblast specific protein-1 (FSP-1), and vimentin, and downregulation of endothelial cell-specific markers such as CD31 and vascular endothelial (VE)-cadherin. Furthermore, compared with low-density lipoprotein (LDL), oxidized low-density lipoprotein (ox-LDL) significantly augmented radiation-induced EndMT in HAoEC. These fibrotic phenotypes of ECs were found in atherosclerotic tissues of irradiated ApoE−/− mice with increased levels of ox-LDL. Conclusions: Taken together, these observations suggest that ox-LDL accelerates radiation-induced EndMT and subsequently contributes to radiation-induced atherosclerosis, providing a novel target for the prevention of radiation-induced atherosclerosis.

HSPB1 Inhibits the Endothelial-to-Mesenchymal Transition to Suppress Pulmonary Fibrosis and Lung Tumorigenesis.

The endothelial-to-mesenchymal transition (EndMT) contributes to cancer, fibrosis, and other pathologic processes. However, the underlying mechanisms are poorly understood. Endothelial HSP1 (HSPB1) protects against cellular stress and has been implicated in cancer progression and pulmonary fibrosis. In this study, we investigated the role of HSPB1 in mediating the EndMT during the development of pulmonary fibrosis and lung cancer. HSPB1 silencing in human pulmonary endothelial cells accelerated emergence of the fibrotic phenotype after treatment with TGFβ or other cytokines linked to pulmonary fibrosis, suggesting that HSPB1 maintains endothelial cell identity. In mice, endothelial-specific overexpression of HSPB1 was sufficient to inhibit pulmonary fibrosis by blocking the EndMT. Conversely, HSPB1 depletion in a mouse model of lung tumorigenesis induced the EndMT. In clinical specimens of non-small cell lung cancer, HSPB1 expression was absent from tumor endothelial cells undergoing the EndMT. Our results showed that HSPB1 regulated the EndMT in lung fibrosis and cancer, suggesting that HSPB1-targeted therapeutic strategies may be applicable for treating an array of fibrotic diseases.

Measurement of Cerenkov Radiation Induced by the Gamma-Rays of Co-60 Therapy Units Using Wavelength Shifting Fiber

In this study, a wavelength shifting fiber that shifts ultra-violet and blue light to green light was employed as a sensor probe of a fiber-optic Cerenkov radiation sensor. In order to characterize Cerenkov radiation generated in the developed wavelength shifting fiber and a plastic optical fiber, spectra and intensities of Cerenkov radiation were measured with a spectrometer. The spectral peaks of light outputs from the wavelength shifting fiber and the plastic optical fiber were measured at wavelengths of 500 and 510 nm, respectively, and the intensity of transmitted light output of the wavelength shifting fiber was 22.2 times higher than that of the plastic optical fiber. Also, electron fluxes and total energy depositions of gamma-ray beams generated from a Co-60 therapy unit were calculated according to water depths using the Monte Carlo N-particle transport code. The relationship between the fluxes of electrons over the Cerenkov threshold energy and the energy depositions of gamma-ray beams from the Co-60 unit is a near-identity function. Finally, percentage depth doses for the gamma-ray beams were obtained using the fiber-optic Cerenkov radiation sensor, and the results were compared with those obtained by an ionization chamber. The average dose difference between the results of the fiber-optic Cerenkov radiation sensor and those of the ionization chamber was about 2.09%.

Trends for the Past 10 Years and International Comparisons of the Structure of Korean Radiation Oncology

OBJECTIVE Study aims include determination of nationwide structural characteristics of radiation oncology facilities, types of radiation therapy equipment, availability of human resources and trends and comparisons with previous surveys. METHODS An annual nationwide survey was conducted to collect the statistics of infrastructure since 1997. All requested questionnaires have been identical for 10 years. The questionnaires included status on basic radiation therapy facilities, human resources and radiation therapy equipment. Journal and statistical data reviews were performed to evaluate the structure of other countries. RESULTS Radiation oncology facilities have steadily increased for 10 years and reached 60 sites in 2006. Also a steady increase of 1.5 times for linear accelerators, 5.8 times for computed tomography simulators and 3.0 times for radiation treatment planning systems was noted. Meanwhile, cobalt-60 teletherapy units and hyperthermia equipment had steadily deceased for 10 years. The number of human resources has steadily increased for the past 10 years, especially for radiation therapy technologists. However, radiation therapy equipment and human resources per population are relatively low compared with advanced countries. CONCLUSIONS This study will assist preparation of the administrative planning policy of radiation oncology and should be useful to indicate the direction of future development and educational training programs in Korea and possibly in other countries.

Combination effect of cetuximab with radiation in colorectal cancer cells.

AIMS AND BACKGROUND Colorectal cancer (CRC) is one of the commonest malignant disorders and frequently associated with high expression of epidermal growth factor receptor (EGFR), resulting in advanced disease and a poor prognosis. In this study, we investigated the radiosensitizing effects of the selective EGFR inhibitor cetuximab in human CRC cell lines. METHODS Four human CRC cell lines, CaCo-2, HCT-8, LoVo, and WiDr, were treated with cetuximab and/or radiation. The effects on cell proliferation and viability were measured by MTT and annexin-V staining, and clonogenic survival assay. The in vivo effect on the growth of CRC xenografts was assessed in athymic nude mice. RESULTS Cetuximab in combination with radiation significantly inhibited the in vitro proliferation of CRC cells, with a concomitant increase in cell death, except in WiDr cells. Clonogenic survival assay confirmed that cetuximab worked as a radiosensitizer in three cetuximab-sensitivie CRC cells. However, no correlations were found between the radiosensitivity and EGFR expression level or mutation status of EGFR signaling molecules. In nude mice bearing CRC cell xenografts, cetuximab plus radiation significantly inhibited the tumor growth over either agent alone. Interestingly, the WiDr xenograft was also sensitive to cetuximab and/or radiation in vivo, suggesting host-mediated effects of cetuximab. CONCLUSIONS Cetuximab enhanced the radiosensitivity of CRC cells in vitro and efficiently inhibited xenograft tumor growth. This study provided a rationale for the clinical application of the selective EGFR inhibitor cetuximab in combination with radiation in CRC.

In vivo monitoring of CD44+ cancer stem-like cells by γ-irradiation in breast cancer

There is increasing evidence that cancer contains cancer stem cells (CSCs) that are capable of regenerating a tumor following chemotherapy or radiotherapy. CD44 and CD133 are used to identify CSCs. This study investigated non-invasive in vivo monitoring of CD44-positive cancer stem-like cells in breast cancer by γ-irradiation using molecular image by fusing the firefly luciferase (fLuc) gene with the CD44 promoter. We generated a breast cancer cell line stably expressing fLuc gene by use of recombinant lentiviral vector controlled by CD44 promoter (MCF7-CL). Irradiated MCF7-CL spheres showed upregulated expression of CD44 and CD133, by immunofluorescence and flow cytometry. Also, gene expression levels of CSCs markers in irradiated spheres were clearly increased. CD44+ CSCs increased fLuc expression and tumor growth in vivo and in vitro. When MCF7-CL was treated with siCD44 and irradiated, CD44 expression was inhibited and cell survival ratio was decreased. MCF7-CL subsets were injected into the mice and irradiated by using a cobalt-60 source. Then, in vivo monitoring was performed to observe the bioluminescence imaging (BLI). When breast cancer was irradiated, relative BLI signal was increased, but tumor volume was decreased compared to non-irradiated tumor. These results indicate that increased CD44 expression, caused by general feature of CSCs by irradiation and sphere formation, can be monitored by using bioluminescence imaging. This system could be useful to evaluate CD44-expressed CSCs in breast cancer by BLI in vivo as well as in vitro for radiotherapy.

Evaluation of premature senescence and senescence biomarkers in carcinoma cells and xenograft mice exposed to single or fractionated irradiation

The purpose of the present study was to elucidate whether premature senescence contributes to the outcome of radiotherapy (RT) and to validate senescence biomarkers in vitro and in vivo. Cultured human cancer cell lines and xenografted mice were exposed to single (SR; 2, 6 or 12 Gy) or fractionated radiation (FR; 3 x 2 Gy or 6 x 2 Gy), and premature senescence was assessed using senescence-associated β-galactosidase (SA-β-Gal) activity, hypophosphorylation of pRb and p21 accumulation. A variety of senescence-associated biomarkers including cathepsin D (CD), the eukaryotic translation elongation factors eEF1A1, eEF1B2, decoy receptor 2 and Dec1 were further validated in vivo or in vitro. We demonstrated the beneficial tumor suppressive role of ionizing radiation (IR)-induced premature senescence in vitro and in vivo. FR inhibited tumor growth via induction of premature senescence as effectively as an equivalent SR dose (≥6 Gy). In addition, CD and eEF1 were valuable biomarkers of cellular senescence in either SR- or RF-exposed carcinoma cells or xenograft mice. Our results suggest that 2 Gy of a conventional RT regime could achieve a better clinical outcome if premature senescence could be increased through an improved understanding of its molecular action mechanism.

Trends of the effective dose distribution of occupational exposures in medical and research departments for KIRAMS in Republic of Korea

This work proposes the basic reference data of occupational dose management and statistical dose distribution with the classification of radiation work groups though analysis of occupational dose distribution. Data on occupational radiation exposure from medical and scientific usage of radiation in Korea Institute of Radiological and Medical Sciences for the years 2002-11 are presented and evaluated with the characteristic tendency of radiation working groups. The results of occupational radiation exposure were measured by personal dosemeters. The monitored occupational exposure dose data were evaluated according to the average effective dose and collective dose. The most annual average effective dose for all occupational radiation workers was under 1 mSv. Considering the dose distribution of each department, most overexposure workers worked in radiopharmaceutical product facilities, nuclear medicine department and radiation oncology department. In addition, no monitored workers were found to have received an occupational exposure over 50 mSv in single year or 100 mSv in this period. Although the trend of occupational exposure was controlled <1 mSv after 2007 and the radiation protection status was sufficient, it was consistently necessary to optimise and reduce the occupational radiation exposure.

Development of the Model for the Subject-oriented Management in Super Tall Building Construction Project

본 연구는 프로젝트 관리, 건축공학, 경영학 및 정보통신기술을 융합하여 건설 프로젝트 관리기술 의 향상을 그 목적으로 한다. 기존의 데이터베이스 활용 프로젝트 관리기술의 한계와 초고층 건물과 같은 초대형 건설공사의 다양한 리스크를 극복하고, 건축 프로젝트 등의 특수성을 감안한 전략적 관 리기술의 개발의 필요성에 부합하기 위하여 본 연구는 주제중심 프로젝트 관리라는 개념을 제안하고, 이를 뒷받침하는 활용 모델을 개발하여 주제지수(Subject Index)라는 개념을 통한 건설 프로젝트 관리 의 효율성 제고 방안을 제시한다. 본 연구를 통하여 제안된 SPM 모델은 초고층 건축 프로젝트 관리기술에서 데이터/정보/지식관리 의 개념을 넘어서는 새로운 관리의 패러다임이 되고, 본 모델의 핵심개념인 주제지수는 실제 현장에 서 활용되어 우리나라의 건설기술과 경영기술의 발전 및 현재 정부가 추진하고 있는 창조경제 정책 실현에도 도움이 되는 중요한 도구가 될 것으로 기대된다.