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Molecular imaging of atherosclerosis using reporter gene system
Ran Ji Yoo1,Yong Jin Lee 대한방사성의약품학회 2018 Journal of radiopharmaceuticals and molecular prob Vol.4 No.1
Macrophages play a key role in atherosclerotic plaque formation, but their participation has been discerned largely via ex vivo analyses of atherosclerotic lesions. Therefore, we aimed to identify atherosclerosis on noninvasive in vivo imaging using reporter gene system. This study demonstrated that recruitment of macrophages could be detected in atherosclerotic plaques of Apolipoprotein E knockout (ApoE-/-) mice with a sodium iodide symporter (NIS) gene imaging system using 99mTc-SPECT. This novel approach to tracking macrophages to atherosclerotic plaques in vivo could have applications in studies of arteriosclerotic vascular disease.
Glioma‐derived cancer stem cells are hypersensitive to proteasomal inhibition
Yoo, Young Dong,Lee, Dae‐,Hee,Cha‐,Molstad, Hyunjoo,Kim, Hyungsin,Mun, Su Ran,Ji, Changhoon,Park, Seong Hye,Sung, Ki Sa,Choi, Seung Ah,Hwang, Joonsung,Park, Deric M,Kim, Seung‐,Ki,Pa EMBO 2017 EMBO reports Vol.18 No.1
<P>Although proteasome inhibitors (PIs) are used as anticancer drugs to treat various cancers, their relative therapeutic efficacy on stem cells vs. bulk cancers remains unknown. Here, we show that stem cells derived from gliomas, GSCs, are up to 1,000-fold more sensitive to PIs (IC50, 27-70 nM) compared with their differentiated controls (IC50, 47 to >> 100 mu M). The stemness of GSCs correlates to increased ubiquitination, whose misregulation readily triggers apoptosis. PI-induced apoptosis of GSCs is independent of NF-jB but involves the phosphorylation of c-Jun N-terminal kinase as well as the transcriptional activation of endoplasmic reticulum (ER) stress-associated proapoptotic mediators. In contrast to the general notion that ER stress-associated apoptosis is signaled by prolonged unfolded protein response (UPR), GSC-selective apoptosis is instead counteracted by the UPR. ATF3 is a key mediator in GSC-selective apoptosis. Pharmaceutical uncoupling of the UPR from its downstream apoptosis sensitizes GSCs to PIs in vitro and during tumorigenesis in mice. Thus, a combinational treatment of a PI with an inhibitor of UPR-coupled apoptosis may enhance targeting of stem cells in gliomas.</P>
Glioma‐derived cancer stem cells are hypersensitive to proteasomal inhibition
Yoo, Young Dong,Lee, Dae‐,Hee,Cha‐,Molstad, Hyunjoo,Kim, Hyungsin,Mun, Su Ran,Ji, Changhoon,Park, Seong Hye,Sung, Ki Sa,Choi, Seung A,Hwang, Joonsung,Park, Deric M,Kim, Seung Ki,Park, Kyun EMBO 2018 EMBO reports Vol.19 No.9
Yoo, Ji Young,Ryu, Jihoon,Gao, Ran,Yaguchi, Tomoko,Kaul, Sunil C.,Wadhwa, Renu,Yun, Chae-Ok John Wiley Sons, Ltd. 2010 The journal of gene medicine Vol.12 No.7
<B>Background</B><P>Adeno-oncolytic (Adon) viruses offer an effective cancer therapeutic tool with several advantages, including wide host cell permeability, high transduction efficiency, safety, tumor selectivity, non-invasiveness, high genetic modifiability and high level of expression of the integrated transgenes. Armed Adon viruses in which the therapeutic efficacy of virus is enhanced by their coupling with cytotoxic, anti-angiogenic or anti-vascular gene products have gained importance because they engage additional mechanisms for tumor cell killing. In the present study, we selected mortalin, a stress chaperone that is tightly involved in human carcinogenesis, constructed a mortalin-targeting Adon (mot-Adon) virus and examined its therapeutic potential both in vitro and in vivo.</P><B>Methods</B><P>Mortalin-targeting plasmid and viral vectors that harbored mortalin-specific small interfering RNA sequences were constructed. The therapeutic value of these vectors was investigated in vitro and in vivo by cell culture and nude mice tumor models.</P><B>Results</B><P>We demonstrate that the mot-Adon virus has selective cytotoxicity for human cancer cells in vitro. Retrovirus-mediated overexpression of mortalin protected the cells against mot-Adon virus, confirming that mortalin silencing was the real cause of cancer cell death. Although mortalin overexpression enhanced malignant properties of cancer cells in breast xenograft models, mot-Adon virus elicited an enhanced anti-tumor effect. Immunohistochemical examination of the tumors showed that the mot-Adon virus caused enhanced apoptosis (mediated by reactivation of p53) and suppression of microvessel formation.</P><B>Conclusions</B><P>Mortalin is up-regulated in a large variety of tumors and hence mot-Adon virus is proposed as a candidate cancer therapeutic agent. Copyright © 2010 John Wiley & Sons, Ltd.</P>
( Ji Won Park ),( Sung Soo Yoo ),( Hyuk Lee ),( Byung Hoon Min ),( Eun Ran Kim ),( Sunghyouk Park ),( Jae Joon Kim ),( Young Ho Kim ) 대한내과학회 2014 대한내과학회 추계학술발표논문집 Vol.2014 No.1
Background/Aims: Current the best screening tool of gastric cancer is endoscopy. However it needs adequate facilities, expensive equipment and skilled staff and it is time-consuming and unpleasant to patients. Serum tumor markers such as CEA, CA 19-9, CA 72-4 can be easily used but they are not satisfactory in making a diagnosis and lack clinical effi cacy. The purpose of this study was to investigate the differences in urine metabolic profi les of gastric cancer patients and healthy volunteers using a NMR-based metabolomic approach and to provide an effective screening tool. Methods: Urine samples were collected from gastric cancer patients (n=139) and healthy volunteers (n=156). Nuclear magnetic resonance (NMR) spectra of these urine samples were analyzed using orthogonal partial least square discriminant analysis (OPLS-DA). Using training set composed of gastric cancer patients (n=93) and healthy volunteers (n=105), prediction model was established. Then, the validity of prediction model was assessed using an external validation set consisting of gastric cancer patients (n=46) and healthy volunteers (n=51). Results: The metabolomic 2-D score plot and OPLS-DA multivariate analysis showed good separation between gastric cancer and normal group (Q2 of 72.4%). The S-TOCSY plot showed multiple identifi ed markers for the separation. The prediction model using validation set exhibited 95.7% sensitivity and 94.1% specifi city. Conclusion: Our findings suggest that the NMR-based metabolomics approach showed an effective and non-invasive way to discriminate healthy person and gastric cancer patients. The established prediction model had high quality of sensitivity and specifi city and it can be a novel screening tool for early gastric cancer. *Funding for this research has been provided by Korean Society of Gastroenterology and SK Chemical.
Yoo, Ran Ji,Lee, Ji Woong,Lee, Kyo Chul,An, Gwang Il,Ko, In Ok,Chung, Wee Sup,Park, Ji Ae,Kim, Kyeong Min,Choi, Yang-Kyu,Kang, Joo Hyun,Lim, Sang Moo,Lee, Yong Jin 대한방사성의약품학회 2015 Journal of radiopharmaceuticals and molecular prob Vol.1 No.2
$^{64}Cu$-labeled diacetyl-bis($N^4$-methylthiosemicarbazone) is a promising agent for internal radiation therapy and imaging of hypoxic tissues. In the study, we confirmed hypoxia regions in VX2 tumor implanted rabbits with injection $^{64}Cu$-ATSM and $^{18}F$-FDG using positron emission tomography (PET)/computed tomography (CT). PET images with $^{18}F$-FDG and $^{64}Cu$-ATSM were obtained for 40 min by dynamic scan and additional delayed PET images of $^{64}Cu$-ATSM the acquired up to 48 hours. Correlation between intratumoral $O_2$ level and $^{64}Cu$-ATSM PET image was analyzed. $^{64}Cu$-ATSM and $^{18}F$-FDG were intravenously co-injected and the tumor was dissected and cut into slices for a dual-tracer autoradiographic analysis. In the PET imaging, $^{64}Cu$-ATSM in VX2 tumors displayed a specific uptake in hypoxic region for48 h. The uptake pattern of $^{64}Cu$-ATSM in VX2 tumor at 24 and 48 h did not match to the $^{18}F$-FDG. Through ROI analysis, in the early phase (dynamic scan), $^{18}F$-FDG has positive correlation with $^{64}Cu$-ATSM but late phase (24 and 48 h) of the $^{64}Cu$-ATSM showed negative correlation with $^{18}F$-FDG. High uptake of $^{64}Cu$-ATSM in hypoxic region was responded with significant decrease of oxygen pressure, which confirmed by $^{64}Cu$-ATSM PET imaging and autoradiographic analysis. In conclusion, $^{64}Cu$-ATSM can utilize for specific targeting of hypoxic region in tumor, and discrimination between necrotic- and viable hypoxic tissue.