Publications by authors named "Keon Wook Kang"

356 Publications

Head to head comparison of Ga-NGUL and Ga-PSMA-11 in patients with metastatic prostate cancer: a prospective study.

J Nucl Med 2021 Feb 26. Epub 2021 Feb 26.

Seoul National University College of Medicine, Korea, Republic of.

Ga-NOTA Glu-Urea-Lys (NGUL) is a novel prostate-specific membrane antigen (PSMA) targeting tracer used for positron emission tomography/computed tomography (PET/CT) imaging. This study aims to compare the performance in the detection of primary and metastatic lesions, and to compare biodistribution between Ga-NGUL and Ga-PSMA-11 in the same patients with metastatic prostate cancer. Eleven patients with histologically proven, metastatic prostate cancer were prospectively recruited. Each patient underwent Ga-NGUL and Ga-PSMA-11 PET/CT within 4 days. The PET/CT scans were performed at 60 minutes after tracer injection. The quantitative tracer uptakes were obtained in normal organs including salivary glands, liver, spleen, and kidney and blood pool activity was measured in the inferior vena cava. The normal organ distribution of both tracers was quantified as SUVmean. In addition, three patients underwent dynamic PET/CT scanning (60 min) of the pelvic region to evaluate the urinary clearance. Any focal accumulation of Ga-NGUL and Ga-PSMA-11 not explained by physiologic uptake were defined as pathologic lesions. Lesion numbers and lesion uptake, as SUV, were compared. Quantitative uptakes in the kidneys, salivary glands, spleen, and liver were significantly lower on Ga-NGUL compared with Ga-PSMA-11. The blood pool activity showed no significant difference between the two tracers. The bladder time activity curve revealed a more rapid urinary clearance of Ga-NGUL. The number and sites of detected PSMA positive primary ( = 11) and metastatic lesions ( = 220) were identical between both tracers. Quantitative uptakes of primary tumors, lymph node, and bone metastases were well correlated (R2 = 0.869, 0.845, and 0.624, respectively) without significant difference ( = 0.675, 0.175, and 0.102, respectively) between Ga-NGUL and Ga-PSMA-11. Ga-NGUL showed a relatively lower tumor-to-background (gluteal muscle) ratio than Ga-PSMA-11, especially for bone metastasis. In head to head comparison with Ga-PSMA-11, Ga-NGUL showed lower uptake in normal organs and a trend of relatively low tumor-to-background ratio compared to Ga-PSMA-11. However, both tracers showed similar performance to detect PSMA avid primary and metastatic lesions without significant difference in the absolute lesion uptake. Ga-NGUL could be a valuable option for PSMA imaging and, furthermore, applied in theranostics.
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http://dx.doi.org/10.2967/jnumed.120.258434DOI Listing
February 2021

Discovery and Structure-Activity Relationships of Novel Template, Truncated 1'-Homologated Adenosine Derivatives as Pure Dual PPARγ/δ Modulators.

J Med Chem 2020 12 16;63(24):16012-16027. Epub 2020 Dec 16.

Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Korea.

Following our report that A adenosine receptor (AR) antagonist exhibited a polypharmacological profile as a dual modulator of peroxisome proliferator-activated receptor (PPAR)γ/δ, we discovered a new template, 1'-homologated adenosine analogues , as dual PPARγ/δ modulators without AR binding. Removal of binding affinity to AAR was achieved by 1'-homologation, and PPARγ/δ dual modulation was derived from the structural similarity between the target nucleosides and PPAR modulator drug, rosiglitazone. All the final nucleosides were devoid of AR-binding affinity and exhibited high binding affinities to PPARγ/δ but lacked PPARα binding. 2-Cl derivatives exhibited dual receptor-binding affinity to PPARγ/δ, which was absent for the corresponding 2-H derivatives. 2-Propynyl substitution prevented PPARδ-binding affinity but preserved PPARγ affinity, indicating that the C2 position defines a pharmacophore for selective PPARγ ligand designs. PPARγ/δ dual modulators functioning as both PPARγ partial agonists and PPARδ antagonists promoted adiponectin production, suggesting their therapeutic potential against hypoadiponectinemia-associated cancer and metabolic diseases.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01874DOI Listing
December 2020

Spatial Normalization Using Early-Phase [F]FP-CIT PET for Quantification of Striatal Dopamine Transporter Binding.

Nucl Med Mol Imaging 2020 Dec 13;54(6):305-314. Epub 2020 Oct 13.

Department of Nuclear Medicine, Seoul National University Hospital, 101, Daehak-ro, Jongno-gu, Seoul, 03080 Republic of Korea.

Purpose: The precise quantification of dopamine transporter (DAT) density on -(3-[F]Fluoropropyl)-2β-carbomethoxy-3β-(4-iodophenyl) nortropane positron emission tomography ([F]FP-CIT PET) imaging is crucial to measure the degree of striatal DAT loss in patients with parkinsonism. The quantitative analysis requires a spatial normalization process based on a template brain. Since the spatial normalization method based on a delayed-phase PET has limited performance, we suggest an early-phase PET-based method and compared its accuracy, referring to the MRI-based approach as a gold standard.

Methods: A total of 39 referred patients from the movement disorder clinic who underwent dual-phase [F]FP-CIT PET and took MRI within 1 year were retrospectively analyzed. The three spatial normalization methods were applied for quantification of [F]FP-CIT PET-MRI-based anatomical normalization, PET template-based method based on delayed PET, and that based on early PET. The striatal binding ratios (BRs) were compared, and voxelwise paired tests were implemented between different methods.

Results: The early image-based normalization showed concordant patterns of putaminal [F]FP-CIT binding with an MRI-based method. The BRs of the putamen from the MRI-based approach showed higher agreement with early image- than delayed image-based method as presented by Bland-Altman plots and intraclass correlation coefficients (early image-based, 0.980; delayed image-based, 0.895). The voxelwise test exhibited a smaller volume of significantly different counts in putamen between brains processed by early image and MRI compared to that between delayed image and MRI.

Conclusion: The early-phase [F]FP-CIT PET can be utilized for spatial normalization of delayed PET image when the MRI image is unavailable and presents better performance than the delayed template-based method in quantitation of putaminal binding ratio.
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http://dx.doi.org/10.1007/s13139-020-00669-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704859PMC
December 2020

Efficacy and Safety of Human Serum Albumin-Cisplatin Complex in U87MG Xenograft Mouse Models.

Int J Mol Sci 2020 Oct 26;21(21). Epub 2020 Oct 26.

Department of Nuclear Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea.

Cisplatin (cis-diamminedichloroplatinum (II), CDDP) is a chemotherapeutic drug widely used against many solid tumors. A pharmacokinetics study found that CDDP can bind to human serum albumin (HSA), which is the most abundant plasma protein in serum. HSA has the advantage of being a nanocarrier and can accumulate in tumors by passive targeting and active targeting mediated by the secreted protein acidic and rich in cysteine (SPARC). In this study, we investigated the possibility of using a CDDP-HSA complex (HSA-CDDP) as a SPARC-mediated therapeutic agent. To investigate the HSA-dependent therapeutic effect of HSA-CDDP, we used two types of U87MG glioma cells that express SPARC differently. HSA-CDDP was highly taken up in SPARC expressing cells and this uptake was enhanced with exogenous SPARC treatment in cells with low expression of SPARC. The cytotoxicity of HSA-CDDP was also higher in SPARC-expressing cells. In the tumor model, HSA-CDDP showed a similar tumor growth and survival rate to CDDP only in SPARC-expressing tumor models. The biosafety test indicated that HSA-CDDP was less nephrotoxic than CDDP, based on blood markers and histopathology examination. Our findings show that HSA-CDDP has the potential to be a novel therapeutic agent for SPARC-expressing tumors, enhancing the tumor targeting effect by HSA and reducing the nephrotoxicity of CDDP.
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http://dx.doi.org/10.3390/ijms21217932DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7663476PMC
October 2020

Visual interpretation of [F]Florbetaben PET supported by deep learning-based estimation of amyloid burden.

Eur J Nucl Med Mol Imaging 2020 Sep 29. Epub 2020 Sep 29.

Department of Nuclear Medicine, Seoul National University Hospital, Seoul, Republic of Korea.

Purpose: Amyloid PET which has been widely used for noninvasive assessment of cortical amyloid burden is visually interpreted in the clinical setting. As a fast and easy-to-use visual interpretation support system, we analyze whether the deep learning-based end-to-end estimation of amyloid burden improves inter-reader agreement as well as the confidence of the visual reading.

Methods: A total of 121 clinical routines [F]Florbetaben PET images were collected for the randomized blind-reader study. The amyloid PET images were visually interpreted by three experts independently blind to other information. The readers qualitatively interpreted images without quantification at the first reading session. After more than 2-week interval, the readers additionally interpreted images with the quantification results provided by the deep learning system. The qualitative assessment was based on a 3-point BAPL score (1: no amyloid load, 2: minor amyloid load, and 3: significant amyloid load). The confidence score for each session was evaluated by a 3-point score (0: ambiguous, 1: probably, and 2: definite to decide).

Results: Inter-reader agreements for the visual reading based on a 3-point scale (BAPL score) calculated by Fleiss kappa coefficients were 0.46 and 0.76 for the visual reading without and with the deep learning system, respectively. For the two reading sessions, the confidence score of visual reading was improved at the visual reading session with the output (1.27 ± 0.078 for visual reading-only session vs. 1.66 ± 0.63 for a visual reading session with the deep learning system).

Conclusion: Our results highlight the impact of deep learning-based one-step amyloid burden estimation system on inter-reader agreement and confidence of reading when applied to clinical routine amyloid PET reading.
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http://dx.doi.org/10.1007/s00259-020-05044-xDOI Listing
September 2020

Tumor immune profiles noninvasively estimated by FDG PET with deep learning correlate with immunotherapy response in lung adenocarcinoma.

Theranostics 2020 29;10(23):10838-10848. Epub 2020 Aug 29.

Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea.

The clinical application of biomarkers reflecting tumor immune microenvironment is hurdled by the invasiveness of obtaining tissues despite its importance in immunotherapy. We developed a deep learning-based biomarker which noninvasively estimates a tumor immune profile with fluorodeoxyglucose positron emission tomography (FDG-PET) in lung adenocarcinoma (LUAD). A deep learning model to predict cytolytic activity score (CytAct) using semi-automatically segmented tumors on FDG-PET trained by a publicly available dataset paired with tissue RNA sequencing (n = 93). This model was validated in two independent cohorts of LUAD: SNUH (n = 43) and The Cancer Genome Atlas (TCGA) cohort (n = 16). The model was applied to the immune checkpoint blockade (ICB) cohort, which consists of patients with metastatic LUAD who underwent ICB treatment (n = 29). The predicted CytAct showed a positive correlation with CytAct of RNA sequencing in validation cohorts (Spearman rho = 0.32, 0.04 in SNUH cohort; spearman rho = 0.47, 0.07 in TCGA cohort). In ICB cohort, the higher predicted CytAct of individual lesion was associated with more decrement in tumor size after ICB treatment (Spearman rho = -0.54, 0.001). Higher minimum predicted CytAct in each patient associated with significantly prolonged progression free survival and overall survival (Hazard ratio 0.25, 0.001 and 0.18, 0.004, respectively). In patients with multiple lesions, ICB responders had significantly lower variance of predicted CytActs ( 0.005). The deep learning model that predicts CytAct using FDG-PET of LUAD was validated in independent cohorts. Our approach may be used to noninvasively assess an immune profile and predict outcomes of LUAD patients treated with ICB.
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http://dx.doi.org/10.7150/thno.50283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7482798PMC
August 2020

Reciprocal change in Glucose metabolism of Cancer and Immune Cells mediated by different Glucose Transporters predicts Immunotherapy response.

Theranostics 2020 25;10(21):9579-9590. Epub 2020 Jul 25.

Department of Thoracic and Cardiovascular Surgery, Seoul National University Hospital, Seoul, Republic of Korea.

The metabolic properties of tumor microenvironment (TME) are dynamically dysregulated to achieve immune escape and promote cancer cell survival. However, properties of glucose metabolism in cancer and immune cells are poorly understood and their clinical application to development of a biomarker reflecting immune functionality is still lacking. We analyzed RNA-seq and fluorodeoxyglucose (FDG) positron emission tomography profiles of 63 lung squamous cell carcinoma (LUSC) specimens to correlate FDG uptake, expression of glucose transporters (GLUT) by RNA-seq and immune cell enrichment score (ImmuneScore). Single cell RNA-seq analysis in five lung cancer specimens was performed. We tested the GLUT3/GLUT1 ratio, the GLUT-ratio, as a surrogate representing immune metabolic functionality by investigating the association with immunotherapy response in two melanoma cohorts. ImmuneScore showed a negative correlation with GLUT1 ( = -0.70, < 0.01) and a positive correlation with GLUT3 ( = 0.39, < 0.01) in LUSC. Single-cell RNA-seq showed GLUT1 and GLUT3 were mostly expressed in cancer and immune cells, respectively. In immune-poor LUSC, FDG uptake was positively correlated with GLUT1 ( = 0.27, = 0.04) and negatively correlated with ImmuneScore ( = -0.28, = 0.04). In immune-rich LUSC, FDG uptake was positively correlated with both GLUT3 ( = 0.78, = 0.01) and ImmuneScore ( = 0.58, = 0.10). The GLUT-ratio was higher in anti-PD1 responders than nonresponders ( = 0.08 for baseline; = 0.02 for on-treatment) and associated with a progression-free survival in melanoma patients who treated with anti-CTLA4 ( = 0.04). Competitive uptake of glucose by cancer and immune cells in TME could be mediated by differential GLUT expression in these cells.
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http://dx.doi.org/10.7150/thno.48954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449929PMC
July 2020

Relationship of EGFR Mutation to Glucose Metabolic Activity and Asphericity of Metabolic Tumor Volume in Lung Adenocarcinoma.

Nucl Med Mol Imaging 2020 Aug 14;54(4):175-182. Epub 2020 Jun 14.

Department of Nuclear Medicine, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080 South Korea.

Purpose: EGFR-mutation (EGFR-mt) is a major oncogenic driver mutation in lung adenocarcinoma (ADC) and is more often observed in Asian population. In lung ADC, some radiomics parameters of FDG PET have been reported to be associated with EGFR-mt. Here, the associations between EGFR-mt and PET parameters, particularly asphericity (ASP), were evaluated in Asian population.

Methods: Lung ADC patients who underwent curative surgical resection as the first treatment were retrospectively enrolled. EGFR mutation was defined as exon 19 deletion and exon 21 point mutation and was evaluated using surgical specimens. On FDG PET, image parameters of maximal standardized uptake value (SUVmax), metabolic tumor volume (MTV), total lesion glycolysis (TLG), and ASP were obtained. The parameters were compared between EGFR-mt and wild type (EGFR-wt) groups, and the relationships between these PET parameters and EGFR-mt were evaluated.

Results: A total of 64 patients (median age 66 years, M:F = 34:30) were included in the analysis, and 29 (45%) patients showed EGFR-mt. In EGFR-mt group, all the image parameters of SUVmax, MTV, TLG, and ASP were significantly lower than in EGFR-wt group (all adjusted  < 0.050). In univariable logistic regression, SUVmax ( = 0.003) and ASP ( = 0.010) were significant determinants for EGFR-mt, whereas MTV was not ( = 0.690). Multivariate analysis revealed that SUVmax and ASP are independent determinants for EGFR-mt, regardless of inclusion of MTV in the analysis ( < 0.05).

Conclusion: In Asian NSCLC/ADC patients, SUVmax, MTV, and ASP on FDG PET are significantly related to EGFR mutation status. Particularly, low SUVmax and ASP are independent determinants for EGFR-mt.
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http://dx.doi.org/10.1007/s13139-020-00646-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429575PMC
August 2020

[F]CB251 PET/MR imaging probe targeting translocator protein (TSPO) independent of its Polymorphism in a Neuroinflammation Model.

Theranostics 2020 23;10(20):9315-9331. Epub 2020 Jul 23.

Department of Nuclear Medicine, Seoul National University Hospital, Republic of Korea.

The 18 kDa translocator protein (TSPO) has been proposed as a biomarker for the detection of neuroinflammation. Although various PET probes targeting TSPO have been developed, a highly selective probe for detecting TSPO is still needed because single nucleotide polymorphisms in the human TSPO gene greatly affect the binding affinity of TSPO ligands. Here, we describe the visualization of neuroinflammation with a multimodality imaging system using our recently developed TSPO-targeting radionuclide PET probe [F]CB251, which is less affected by TSPO polymorphisms. To test the selectivity of [F]CB251 for TSPO polymorphisms, 293FT cells expressing polymorphic TSPO were generated by introducing the coding sequences of wild-type (WT) and mutant (Alanine → Threonine at 147 Amino Acid; A147T) forms. Competitive inhibition assay was conducted with [H]PK11195 and various TSPO ligands using membrane proteins isolated from 293FT cells expressing TSPO WT or mutant-A147T, representing high-affinity binder (HAB) or low-affinity binder (LAB), respectively. IC values of each ligand to [H]PK11195 in HAB or LAB were measured and the ratio of IC values of each ligand to [H]PK11195 in HAB to LAB was calculated, indicating the sensitivity of TSPO polymorphism. Cellular uptake of [F]CB251 was measured with different TSPO polymorphisms, and phantom studies of [F]CB251-PET using 293FT cells were performed. To test TSPO-specific cellular uptake of [F]CB251, TSPO expression was regulated with pCMV-TSPO (or shTSPO)/eGFP vector. Intracranial lipopolysaccharide (LPS) treatment was used to induce regional inflammation in the mouse brain. Gadolinium (Gd)-DOTA MRI was used to monitor the disruption of the blood-brain barrier (BBB) and infiltration by immune cells. Infiltration of peripheral immune cells across the BBB, which exacerbates neuroinflammation to produce higher levels of neurotoxicity, was also monitored with bioluminescence imaging (BLI). Peripheral immune cells isolated from luciferase-expressing transgenic mice were transferred to syngeneic inflamed mice. Neuroinflammation was monitored with [F]CB251-PET/MR and BLI. To evaluate the effects of anti-inflammatory agents on intracranial inflammation, an inflammatory cytokine inhibitor, 2-cyano-3, 12-dioxooleana-1, 9-dien-28-oic acid methyl ester (CDDO-Me) was administered in intracranial LPS challenged mice. : The ratio of IC values of [F]CB251 in HAB to LAB indicated similar binding affinity to WT and mutant TSPO and was less affected by TSPO polymorphisms. [F]CB251 was specific for TSPO, and its cellular uptake reflected the amount of TSPO. Higher [F]CB251 uptake was also observed in activated immune cells. Simultaneous [F]CB251-PET/MRI showed that [F]CB251 radioactivity was co-registered with the MR signals in the same region of the brain of LPS-injected mice. Luciferase-expressing peripheral immune cells were located at the site of LPS-injected right striatum. Quantitative evaluation of the anti-inflammatory effect of CDDO-Me on neuroinflammation was successfully monitored with TSPO-targeting [F]CB251-PET/MR and BLI. Our results indicate that [F]CB251-PET has great potential for detecting neuroinflammation with higher TSPO selectivity regardless of polymorphisms. Our multimodal imaging system, [F]CB251-PET/MRI, tested for evaluating the efficacy of anti-inflammatory agents in preclinical studies, might be an effective method to assess the severity and therapeutic response of neuroinflammation.
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http://dx.doi.org/10.7150/thno.46875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415805PMC
July 2020

Therapeutic efficacy of modified anti-miR21 in metastatic prostate cancer.

Biochem Biophys Res Commun 2020 08 18;529(3):707-713. Epub 2020 Jul 18.

Department of Nuclear Medicine, Seoul National University Hospital, Seoul, Republic of Korea; Laboratory of Molecular Imaging and Therapy, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea; Cancer Imaging Center, Seoul National University Hospital, Seoul, Republic of Korea. Electronic address:

Despite improved therapeutic efficacy of the locked nucleic acid (LNA)- and peptide nucleic acid (PNA)-modified antisense microRNAs (anti-miRs), their wider application in clinical practice is still not thoroughly investigated. This study aimed to investigate the stability and therapeutic efficacy of the modified LNA- and PNA-type anti-miRs in a murine prostate cancer model under various treatment conditions. After verifying the anti-cancer potential of anti-miR21 by targeting tumor suppressor PTEN, the potential of the modified LNA- and PNA-type anti-miR21s was compared in vitro and in vivo. We found that PNA-type anti-miR21 showed better stability and therapeutic efficacy in the xenografted mouse tumor model than the LNA-type anti-miR21. Furthermore, PNA-type anti-miR21 treatment showed reduced tumor metastasis. This study may serve as a ground for exploring diverse choices in therapeutic oligonucleotide modification techniques to improve cancer treatment.
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http://dx.doi.org/10.1016/j.bbrc.2020.05.215DOI Listing
August 2020

Conjugation of arginylglycylaspartic acid to human serum albumin decreases the tumor-targeting effect of albumin by hindering its secreted protein acidic and rich in cysteine-mediated accumulation in tumors.

Am J Transl Res 2020 15;12(6):2488-2498. Epub 2020 Jun 15.

Department of Nuclear Medicine, Seoul National University College of Medicine Seoul, Korea.

Human serum albumin (HSA) accumulates in tumors by the enhanced permeability and retention (EPR) effect, which is a passive targeting effect in tumors. A recent study showed that secreted protein acidic and rich in cysteine (SPARC), an albumin-binding protein, mediates albumin accumulation in tumors. Arg-Gly-Asp (RGD) is a peptide targeting integrin αβ, which is highly expressed during tumor angiogenesis. We investigated whether conjugation of RGD to HSA could synergistically enhance tumor targeting. Accumulation of cRGDyK-HSA in integrin αβ-expressing SK-OV3 cells was observed by confocal microscopy. In SK-OV3 cells overexpressing the albumin binding protein SPARC, cellular uptake of HSA increased, but uptake of cRGDyK-HSA did not. cRGDyK-HSA showed decreased tumor accumulation compared with HSA by positron emission tomography (PET) scanning and biodistribution studies in an SK-OV3 xenograft mouse model. In SK-OV3 tumors, HSA accumulation colocalized with SPARC expression, while cRGDyK-HSA only accumulated in the outer region of the tumor, even though SPARC and integrin αβ were expressed within the tumor core. We speculate that cRGDyK conjugation to HSA changes the characteristics of HSA and hinders its tumor-targeting effect. Therefore, HSA should be modified to preserve its native characteristics and enhance the tumor-targeting effects of HSA conjugates.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7344055PMC
June 2020

Predicting outcome of repair of medial meniscus posterior root tear with early osteoarthritis using bone single-photon emission computed tomography/computed tomography.

Medicine (Baltimore) 2020 Jul;99(27):e21047

Department of Orthopedic Surgery, Seoul National University Hospital, Seoul, Korea.

Repair of medial meniscus posterior root tear (MMPRT) is considered as an effective early intervention strategy for osteoarthritis. We aimed at evaluating whether or not single-photon emission computed tomography/computed tomography (SPECT/CT) could predict the treatment outcome.Eleven patients with MMPRT who underwent preoperative SPECT/CT were retrospectively enrolled. Clinical symptoms were evaluated based on the knee injury and osteoarthritis outcome score (KOOS) and visual analogue scale (VAS) for pain. The uptake pattern of the medial tibial plateau (MTP) on SPECT/CT was visually assessed. Additionally, the maximum lesion-to-cortical counts ratio (LCRmax) for the anterior and posterior aspects of MTP and anterior-posterior MTP ratio (APR) were quantitatively assessed. Spearman correlation analyses were performed between the change in clinical symptom scores and preoperative SPECT/CT patterns.All patients showed increased radiotracer uptake in MTP. Among them, 8 (73%) showed dominant uptake in the anterior aspect of MTP. The rest 3 (27%) showed posterior-dominant uptake. Patients with anterior-dominant patterns tended to show better outcomes in terms of the postoperative KOOS score (P = .07). Anterior MTP LCRmax showed a negative correlation with the change in VAS (ρ = -0.664, P < .03). APR showed a correlation with the change in the KOOS score (ρ = 0.655, P < .03).Patients with MMPRT with relatively higher uptake in the anterior aspect of MTP could have better clinical outcomes after the repair. The preoperative SPECT/CT pattern may have a predictive value in selecting patients with good postoperative outcomes.
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http://dx.doi.org/10.1097/MD.0000000000021047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7337403PMC
July 2020

Anti-Cancer Effects of CKD-581, a Potent Histone Deacetylase Inhibitor against Diffuse Large B-Cell Lymphoma.

Int J Mol Sci 2020 Jun 19;21(12). Epub 2020 Jun 19.

College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Korea.

Double-hit lymphoma (DHL) and double-expressor lymphoma (DEL) are aggressive forms of lymphoma that require better treatments to improve patient outcomes. CKD-581 is a new histone deacetylase (HDAC) inhibitor that exhibited a better safety profile in clinical trials compared to other HDAC inhibitors. Here, we demonstrate that CKD-581 inhibited the class I-II HDAC family via histone H3 and tubulin acetylation. CKD-581 treatment also up-regulated the phosphorylation of histone H2AX (γH2AX, DNA double-strand break marker), and reduced levels of MYC and anti-apoptotic proteins such as BCL-2, BCL-6, BCL-L, and MCL-1 in DH/DE-diffuse large B cell lymphoma (DLBCL) cell lines. Ultimately, CKD-581 also induced apoptosis via poly(ADP ribose) polymerase 1 (PARP1) cleavage. In a DLBCL SCID mouse xenograft model, CKD-581 exhibited anti-cancer effects comparable with those of rituximab (CD20 mAb). Our findings suggest that CKD-581 could be a good candidate for the treatment of DLBCL.
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http://dx.doi.org/10.3390/ijms21124377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352247PMC
June 2020

A pan-cancer analysis of the clinical and genetic portraits of somatostatin receptor expressing tumor as a potential target of peptide receptor imaging and therapy.

EJNMMI Res 2020 Apr 25;10(1):42. Epub 2020 Apr 25.

Department of Nuclear Medicine, Seoul National University Hospital, Seoul National University College of Medicine, 28 Yongon-Dong, Jongno-Gu, Seoul, 110-744, Republic of Korea.

Purpose: Although somatostatin receptor (SST) is a promising theranostic target and is widely expressed in tumors of various organs, the indication for therapies targeting SST is limited to typical gastroenteropancreatic neuroendocrine tumors (NETs). Thus, broadening the scope of the current clinical application of peptide receptor radiotherapy (PRRT) can be supported by a better understanding of the landscape of SST-expressing tumors.

Methods: SST expression levels were assessed in data from The Cancer Genome Atlas across 10,701 subjects representing 32 cancer types. As the major target of PRRT is SST subtype 2 (SST2), correlation analyses between the pan-cancer profiles, including clinical and genetic features, and SST2 level were conducted. The median SST2 expression level of pheochromocytoma and paraganglioma (PCPG) samples was used as the threshold to define "high-SST2 tumors." The prognostic value of SST2 in each cancer subtype was evaluated by using Cox proportional regression analysis.

Results: We constructed a resource of SST expression patterns associated with clinicopathologic features and genomic alterations. It provides an interactive tool to analyze SST expression patterns in various cancer types. As a result, eight of the 31 cancer subtypes other than PCPG had more than 5% of tumors with high-SST2 expression. Low-grade glioma (LGG) showed the highest proportion of high-SST2 tumors, followed by breast invasive carcinoma (BRCA). LGG showed different SST2 levels according to tumor grade and histology. IDH1 mutation was significantly associated with high-SST2 status. In BRCA, the SST2 level was different according to the hormone receptor status. High-SST2 status was significantly associated with good prognosis in LGG patients. High-SST2 status showed a trend for association with poor prognosis in triple-negative breast cancer subjects.

Conclusion: A broad range of SST2 expression was observed across diverse cancer subtypes. The SST2 expression level showed a significant association with genomic and clinical aspects across cancers, especially in LGG and BRCA. These findings extend our knowledge base to diversify the indications for PRRT as well as SST imaging.
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http://dx.doi.org/10.1186/s13550-020-00632-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7183516PMC
April 2020

Involvement of ER stress and reactive oxygen species generation in anti-cancer effect of CKD-516 for lung cancer.

Cancer Chemother Pharmacol 2020 04 11;85(4):685-697. Epub 2020 Mar 11.

College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea.

Purpose: CKD-516 (Valecobulin), a vascular-disrupting agent, inhibits microtubule elongation. We evaluated the effect of CKD-516 on lung cancer cells and the underlying molecular mechanisms.

Methods: The effects of S516, an active metabolite of CKD-516, were evaluated in HUVECs and three lung cancer cell lines and by a microtubule polymerization assay. Tubulin cross-linking was used to identify the binding site of S516 on tubulin, and Western blotting was performed to identify the intracellular pathways leading to cell death. Subcutaneous lung cancer xenograft models were used to assess the in vivo effect of CKD-516 on tumor growth.

Results: S516 targeted the colchicine binding site on β-tubulin. In lung cancer cells, S516 increased endoplasmic reticulum (ER) stress and induced reactive oxygen species (ROS) generation by mitochondria and the ER. In addition, CKD-516 monotherapy strongly inhibited the growth of lung cancer xenograft tumors and exerted a synergistic effect with carboplatin.

Conclusion: The findings suggest that CKD-516 exerts an anticancer effect in company with inducing ER stress and ROS production via microtubule disruption in lung cancer cells. CKD-516 may thus have therapeutic potential for lung cancer.
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http://dx.doi.org/10.1007/s00280-020-04043-xDOI Listing
April 2020

Risk stratification of symptomatic brain metastases by clinical and FDG PET parameters for selective use of prophylactic cranial irradiation in patients with extensive disease of small cell lung cancer.

Radiother Oncol 2020 02 7;143:81-87. Epub 2020 Feb 7.

Department of Nuclear Medicine, Seoul National University Hospital, Seoul, South Korea; Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, South Korea; Cancer Research Institute, Seoul National University, Seoul, South Korea. Electronic address:

Purpose: To identify risk factors for developing symptomatic brain metastases and evaluate the impact of prophylactic cranial irradiation (PCI) on brain metastasis-free survival (BMFS) and overall survival (OS) in extensive disease small cell lung cancer (ED-SCLC).

Materials And Methods: Among 190 patients diagnosed with ED-SCLC who underwent FDG PET/CT and brain Magnetic Resonance Imaging (MRI) prior to treatment, 53 (27.9%) received PCI while 137 (72.1%) did not. Prognostic index predicting a high risk of symptomatic brain metastases was calculated for the group without receiving PCI (observation group, n = 137) with Cox regression model.

Results: Median follow-up time was 10.6 months. Multivariate Cox regression showed that the following three factors were associated with a high risk of symptomatic brain metastases: the presence of extrathoracic metastases (p = 0.004), hypermetabolism of bone marrow or spleen on FDG PET (p < 0.001), and high neutrophil-to-lymphocyte ratio (p = 0.018). PCI significantly improved BMFS in high-risk patients (1-year rate: 94.7% vs. 62.1%, p = 0.001), but not in low-risk patients (1-year rate: 100.0% vs. 87.7%, p = 0.943). However, PCI did not improve OS in patients at high risk for symptomatic brain metastases (1-year rate: 65.2% vs. 50.0%, p = 0.123).

Conclusion: Three prognostic factors (the presence of extrathoracic metastases, hypermetabolism of bone marrow or spleen on FDG PET, and high neutrophil-to-lymphocyte ratio) were associated with a high risk of symptomatic brain metastases in ED-SCLC. PCI was beneficial for patients at a high risk of symptomatic brain metastases in terms of BMFS, but not OS. Thus, selective use of PCI in ED-SCLC according to the risk stratification is recommended.
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http://dx.doi.org/10.1016/j.radonc.2020.01.009DOI Listing
February 2020

Induction of E6AP by microRNA-302c dysregulation inhibits TGF-β-dependent fibrogenesis in hepatic stellate cells.

Sci Rep 2020 01 16;10(1):444. Epub 2020 Jan 16.

College of Pharmacy, Chosun University, Gwangju, 61452, Republic of Korea.

Hepatic stellate cells (HSCs) are essential for liver fibrosis. E6 associated protein (E6AP) is one of the E3-ubiquitin-protein ligase and has been studied in proliferation and cellular stress. Currently, no information is available on the role of E6AP on transforming growth factor-β (TGF-β) signaling and hepatic fibrogenesis. This study examined whether E6AP is overexpressed in activated HSCs, and if so, its effect on hepatic fibrogenesis and the molecular mechanism. E6AP was expressed higher in HSCs than hepatocytes, and was up-regulated in activated HSCs, HSCs from the livers of carbon tetrachloride-injected mice, or TGF-β-treated LX-2 cells. The TGF-β-mediated E6AP up-regulation was not due to altered mRNA level nor protein stability. Thus, we performed microRNA (miRNA, miR) analysis and found that miR-302c was dysregulated in TGF-β-treated LX-2 cells or activated primary HSCs. We revealed that miR-302c was a modulator of E6AP. E6AP overexpression inhibited TGF-β-induced expression of plasminogen activator inhibitor-1 in LX-2 cells, albeit it was independent of Smad pathway. Additionally, E6AP inhibited TGF-β-mediated phosphorylation of mitogen-activated protein kinases. To conclude, E6AP overexpression due to decreased miR-302c in HSCs attenuated hepatic fibrogenesis through inhibition of the TGF-β-induced mitogen-activated protein kinase signaling pathway, implying that E6AP and other molecules may contribute to protection against liver fibrosis.
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http://dx.doi.org/10.1038/s41598-019-57322-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6965100PMC
January 2020

Comprehensive gene expression analysis for exploring the association between glucose metabolism and differentiation of thyroid cancer.

BMC Cancer 2019 Dec 30;19(1):1260. Epub 2019 Dec 30.

Department of Nuclear Medicine, Seoul National University Hospital, 28 Yongon-Dong, Jongno-Gu, Seoul, 03080, Republic of Korea.

Background: The principle of loss of iodine uptake and increased glucose metabolism according to dedifferentiation of thyroid cancer is clinically assessed by imaging. Though these biological properties are widely applied to appropriate iodine therapy, the understanding of the genomic background of this principle is still lacking. We investigated the association between glucose metabolism and differentiation in advanced thyroid cancer as well as papillary thyroid cancer (PTC).

Methods: We used RNA sequencing of 505 patients with PTC obtained from the Cancer Genome Archives and microarray data of poorly-differentiated and anaplastic thyroid cancer (PDTC/ATC). The signatures of GLUT and glycolysis were estimated to assess glucose metabolic profiles. The glucose metabolic profiles were associated with tumor differentiation score (TDS) and BRAFV600E mutation status. In addition, survival analysis of glucose metabolic profiles was performed for predicting recurrence-free survival.

Results: In PTC, the glycolysis signature was positively correlated with TDS, while the GLUT signature was inversely correlated with TDS. These correlations were significantly stronger in the BRAFV600E negative group than the positive group. Meanwhile, both GLUT and glycolysis signatures were negatively correlated with TDS in advanced thyroid cancer. The high glycolysis signature was significantly associated with poor prognosis in PTC in spite of high TDS. The glucose metabolic profiles are intricately associated with tumor differentiation in PTC and PDTC/ATC.

Conclusions: As glycolysis was an independent prognostic marker, we suggest that the glucose metabolism features of thyroid cancer could be another biological progression marker different from differentiation and provide clinical implications for risk stratification.

Trial Registration: Not applicable.
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http://dx.doi.org/10.1186/s12885-019-6482-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6937781PMC
December 2019

Inhibition of p90RSK activation sensitizes triple-negative breast cancer cells to cisplatin by inhibiting proliferation, migration and EMT.

BMB Rep 2019 Dec;52(12):706-711

College of Pharmacy and Institute of Drug Research and Development, Chungnam National University, Daejeon 34134, Korea.

Cisplatin (Cis-DDP) is one of the most widely used anti-cancer drugs. It is applicable to many types of cancer, including lung, bladder, and breast cancer. However, its use is now limited because of drug resistance. p90 ribosomal S6 kinase (p90RSK) is one of the downstream effectors in the extracellular signalregulated protein kinases 1 and 2 (ERK1/2) pathway and high expression of p90RSK is observed in human breast cancer tissues. Therefore, we investigated the role of p90RSK in the Cis-DDP resistance-related signaling pathway and epithelialmesenchymal transition (EMT) in breast cancer cells. First, we discovered that MDA-MB-231 cells exhibited more Cis-DDP resistance than other breast cancer cells, including MCF-7 and BT549 cells. Cis-DDP increased p90RSK activation, whereas the inactivation of p90RSK using a small interfering RNA (siRNA) or dominant-negative kinase mutant plasmid overexpression significantly reduced Cis-DDP-induced cell proliferation and migration via the inhibition of matrix metallopeptidase (MMP)2 and MMP9 in MDA-MB-231 cells. In addition, p90RSK activation was involved in EMT via the upregulation of mRNA expression, including that of Snail, Twist, ZEB1, N-cadherin, and vimentin. We also investigated NF-κB, the upstream regulator of EMT markers, and discovered that Cis-DDP treatment led to NF-κB translocation in the nucleus as well as its promoter activity. Our results suggest that targeting p90RSK would be a good strategy to increase Cis-DDP sensitivity in triple-negative breast cancers. [BMB Reports 2019; 52(12): 706-711].
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6941763PMC
December 2019

Differential Expression of Glucose Transporters and Hexokinases in Prostate Cancer with a Neuroendocrine Gene Signature: A Mechanistic Perspective for F-FDG Imaging of PSMA-Suppressed Tumors.

J Nucl Med 2020 06 5;61(6):904-910. Epub 2019 Dec 5.

Department of Biomedical Sciences, University of Windsor, Windsor, Ontario, Canada

Although the incidence of de novo neuroendocrine prostate cancer (PC) is rare, recent data suggest that low expression of prostate-specific membrane antigen (PSMA) is associated with a spectrum of neuroendocrine hallmarks and androgen receptor (AR) suppression in PC. Previous clinical reports indicate that PCs with a phenotype similar to neuroendocrine tumors can be more amenable to imaging by F-FDG than by PSMA-targeting radioligands. In this study, we evaluated the association between neuroendocrine gene signature and F-FDG uptake-associated genes including glucose transporters (GLUTs) and hexokinases, with the goal of providing a genomic signature to explain the reported F-FDG avidity of PSMA-suppressed tumors. Data-mining approaches, cell lines, and patient-derived xenograft models were used to study the levels of 14 members of the family (encoding GLUT proteins), 4 members of the hexokinase family (genes - and ), and PSMA ( gene) after AR inhibition and in correlation with neuroendocrine hallmarks. Also, we characterize a neuroendocrine-like PC (NELPC) subset among a cohort of primary and metastatic PC samples with no neuroendocrine histopathology. We measured glucose uptake in a neuroendocrine-induced in vitro model and a zebrafish model by nonradioactive imaging of glucose uptake using a fluorescent glucose bioprobe, GB2-Cy3. This work demonstrated that a neuroendocrine gene signature associates with differential expression of genes encoding GLUT and hexokinase proteins. In NELPC, elevated expression of (encoding glucokinase protein) and decreased expression of correlated with earlier biochemical recurrence. In tumors treated with AR inhibitors, high expression of and low expression of correlated with neuroendocrine histopathology and PSMA gene suppression. GLUT12 suppression and upregulation of glucokinase were observed in neuroendocrine-induced PC cell lines and patient-derived xenograft models. A higher glucose uptake was confirmed in low-PSMA tumors using a GB2-Cy3 probe in a zebrafish model. A neuroendocrine gene signature in neuroendocrine PC and NELPC associates with a distinct transcriptional profile of GLUTs and hexokinases. PSMA suppression correlates with GLUT12 suppression and glucokinase upregulation. Alteration of F-FDG uptake-associated genes correlated positively with higher glucose uptake in AR- and PSMA-suppressed tumors. Zebrafish xenograft tumor models are an accurate and efficient preclinical method for monitoring nonradioactive glucose uptake.
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http://dx.doi.org/10.2967/jnumed.119.231068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7262227PMC
June 2020

Initial M Staging of Rectal Cancer: FDG PET/MRI with a Hepatocyte-specific Contrast Agent versus Contrast-enhanced CT.

Radiology 2020 02 3;294(2):310-319. Epub 2019 Dec 3.

From the Departments of Radiology (J.H.Y., J.M.L., H.J.K.), Nuclear Medicine (S.Y.K., K.W.K.), and Surgery (S.B.R., S.Y.J., K.J.P.), Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 03080, Republic of Korea; Department of Radiology, Seoul National University College of Medicine, Seoul, Republic of Korea (J.H.Y., J.M.L., H.J.K.); Institute of Radiation Medicine, Seoul National University Medical Research Center, Seoul, Republic of Korea (J.M.L.); Department of Radiology, Seoul National University Bundang Hospital, Seongnam, Republic of Korea (W.C.); Department of Biostatistics, University of Pittsburgh, Pittsburgh, Pa (A.B.); and Department of Radiology, National Cancer Center Korea, Goyang, Republic of Korea (H.J.L.).

BackgroundThe performance of PET/MRI in the determination of distant metastases (M stage) in rectal cancer relative to the current practice with contrast material-enhanced CT is largely unknown.PurposeTo compare the staging of clinical M stage rectal cancer with fluorine 18 fluorodeoxyglucose (FDG) PET/MRI (including dedicated liver and rectal MRI) to that of chest and abdominopelvic CT and dedicated rectal MRI.Materials and MethodsFrom January 2016 to August 2017, patients with newly diagnosed advanced mid to low rectal cancers were recruited for this prospective study (clinicaltrials.gov identifier: NCT0265170). Participants underwent both FDG PET/MRI with dedicated liver and rectal MRI and chest and abdominopelvic CT (the standard-of-care protocol) within 3 weeks of each other. Thereafter, M stage assessment performance was determined by using findings from 6-month clinical follow-up or biopsy as the reference standard. Performance was compared between protocols. Agreement in M stage classification was also assessed. Nonparametric statistical analyses were performed, and < .05 indicated a significance difference.ResultsSeventy-one participants (28 women; mean age ± standard deviation, 61 years ± 9; age range, 39-79 years) were enrolled. The M stage could not be determined with the standard-of-care protocol in 22 of the 71 participants (31%; 95% confidence interval [CI]: 20.5%, 43.1%) because of indeterminate lesions. However, among these participants, PET/MRI correctly helped identify all 14 (100%; 95% CI: 76.8%, 100%) without metastases and seven of eight (88%; 95% CI: 47.4%, 99.7%) who were later confirmed to have metastases. PET/MRI showed high specificity for ruling out metastatic disease compared with the standard-of-care protocol (98% [54 of 55 participants] vs 72% [40 of 55 participants], respectively; < .001), without increasing the number of participants with missed metastasis (6% [one of 16 participants] vs 6% [one of 16 participants]; > .99).ConclusionPET/MRI with dedicated rectal and liver MRI can facilitate the staging work-up of newly diagnosed advanced rectal cancers by helping assess indeterminate lesions, metastases, and incidental findings better than contrast-enhanced CT, obviating for additional imaging work-up.© RSNA, 2019Clinical trial registration no. NCT02651701.
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http://dx.doi.org/10.1148/radiol.2019190794DOI Listing
February 2020

Trastuzumab Specific Epitope Evaluation as a Predictive and Prognostic Biomarker in Gastric Cancer Patients.

Biomolecules 2019 11 26;9(12). Epub 2019 Nov 26.

Department of Pathology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam-si 13488, Korea.

While human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC) antibodies bind to the intracellular domain, trastuzumab binds to the extracellular epitope of HER2 receptor: target of drug action. We aimed to evaluate clinical significance of the new IHC method assessing the target of trastuzumab in gastric cancer (GC) patients and compare with conventional methods. Sixty-nine trastuzumab-treated GC patients were enrolled from two different cohorts. Additionally, we enrolled 528 consecutive GC patients to evaluate prognostic implications of HER2 test methods. HER2 status was assessed by trastuzumab IHC, HER2 IHC (4B5), and HER2 silver in situ hybridization (SISH). HER2 IHC showed 3+ in 48/69 trastuzumab-treated patients (69.6%), however, trastuzumab IHC showed 3+ in 25 (36.2%). Patients with trastuzumab IHC ≥2+ had significantly better progression-free survival (PFS) and overall survival (OS) than their counterpart ( = 0.014). In univariate analysis, trastuzumab IHC ≥2+ and HER2 IHC 3+ were only significant predictive factors for OS in trastuzumab-treated patients. Of the 528 consecutive GCs, patients with trastuzumab IHC ≥2+ had shorter disease-free survival (DFS) and OS ( = 0.008 and 0.031, respectively), while conventional methods failed to reveal any significant survival differences. HER2 assessment by trastuzumab IHC was different from conventional HER2 test results. Trastuzumab IHC was suggested to be a significant predictive factor for trastuzumab responsiveness and prognostic factor for consecutive GCs.
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http://dx.doi.org/10.3390/biom9120782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6995606PMC
November 2019

WY-14643 Regulates CYP1B1 Expression through Peroxisome Proliferator-Activated Receptor α-Mediated Signaling in Human Breast Cancer Cells.

Int J Mol Sci 2019 Nov 25;20(23). Epub 2019 Nov 25.

College of Pharmacy, Chungnam National University, Daejeon 34134, Korea.

Human cytochrome P450 1B1 (CYP1B1)-mediated biotransformation of endobiotics and xenobiotics plays an important role in the progression of human breast cancer. In this study, we investigated the effects of WY-14643, a peroxisome proliferator-activated receptor α (PPARα) agonist, on CYP1B1 expression and the related mechanism in MCF7 breast cancer cells. We performed quantitative reverse transcription-polymerase chain reaction, transient transfection, and chromatin immunoprecipitation to evaluate the effects of PPARα on peroxisome proliferator response element (PPRE)-mediated transcription. WY-14643 increased the protein and mRNA levels of CYP1B1, as well as promoter activity, in MCF-7 cells. Moreover, WY-14643 plus GW6471, a PPARα antagonist, significantly inhibited the WY-14643-mediated increase in CYP1B1 expression. PPARα knockdown by a small interfering RNA markedly suppressed the induction of CYP1B1 expression by WY-14643, suggesting that WY-14643 induces CYP1B1 expression via a PPARα-dependent mechanism. Bioinformatics analysis identified putative PPREs (-833/-813) within the promoter region of the CYP1B1 gene. Inactivation of these putative PPREs by deletion mutagenesis suppressed the WY-14643-mediated induction of CYP1B1 promoter activation. Furthermore, WY-14643 induced PPARα to assume a form capable of binding specifically to the PPRE-binding site in the CYP1B1 promoter. Our findings suggest that WY-14643 induces the expression of CYP1B1 through activation of PPARα.
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http://dx.doi.org/10.3390/ijms20235928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6928855PMC
November 2019

Clinical implication of 18F-NaF PET/computed tomography indexes of aortic calcification in coronary artery disease patients: correlations with cardiovascular risk factors.

Nucl Med Commun 2020 Jan;41(1):58-64

Department of Nuclear Medicine, Seoul National University Hospital.

Objective: Vascular calcification is known to be associated with cardiovascular risk factors. Recently, F-NaF PET has been reported to be effective for detecting early and active vascular calcification. In this study, correlations between F-NaF PET/computed tomography (CT) findings and cardiovascular risk factors were investigated in patients with suspected coronary artery disease.

Patients And Methods: Forty patients with suspected coronary artery disease underwent F-NaF PET/CT. The maximum and overall burden of calcifying activity, and the overall burden of calcium deposition in the descending thoracic aorta (DTA) were measured on F-NaF PET/CT and they were compared with cardiovascular risk factors, particularly, with those related to metabolic syndrome.

Results: The maximum and overall burden of calcifying activity in DTA measured on F-NaF PET were significantly correlated with diabetes mellitus (P = 0.030 and 0.049, respectively) and serum HbA1c level (ρ = 0.433 and 0.344, respectively). In contrast, the overall burden of calcium deposition measured on CT was significantly correlated with hypertension (P < 0.001). The overall burden of calcium deposition was also significantly correlated with metabolic syndrome (P = 0.002) and 10-year cardiovascular disease risk score (P = 0.004) CONCLUSION: F-NaF uptake is closely related to diabetes mellitus, whereas aortic calcification on CT is closely related to hypertension. Although F-NaF uptake in DTA can be a potential prognostic factor, aortic calcification on CT is a more significant prognostic factor for overall cardiovascular risk than F-NaF uptake.
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http://dx.doi.org/10.1097/MNM.0000000000001115DOI Listing
January 2020

Amyloid PET Quantification Via End-to-End Training of a Deep Learning.

Nucl Med Mol Imaging 2019 Oct 14;53(5):340-348. Epub 2019 Oct 14.

Department of Nuclear Medicine, Seoul National University Hospital, 010 Daehak-Ro Jongno-Gu, Seoul, 03080 South Korea.

Purpose: Although quantification of amyloid positron emission tomography (PET) is important for evaluating patients with cognitive impairment, its routine clinical use is hampered by complicated preprocessing steps and required MRI. Here, we suggested a one-step quantification based on deep learning using native-space amyloid PET images of different radiotracers acquired from multiple centers.

Methods: Amyloid PET data of the Alzheimer Disease Neuroimaging Initiative (ADNI) were used for this study. A training/validation consists of 850 florbetapir PET images. Three hundred sixty-six florbetapir and 89 florbetaben PET images were used as test sets to evaluate the model. Native-space amyloid PET images were used as inputs, and the outputs were standardized uptake value ratios (SUVRs) calculated by the conventional MR-based method.

Results: The mean absolute errors (MAEs) of the composite SUVR were 0.040, 0.060, and 0.050 of training/validation and test sets for florbetapir PET and a test set for florbetaben PET, respectively. The agreement of amyloid positivity measured by Cohen's kappa for test sets of florbetapir and florbetaben PET were 0.87 and 0.89, respectively.

Conclusion: We suggest a one-step quantification method for amyloid PET via a deep learning model. The model is highly reliable to quantify the amyloid PET regardless of multicenter images and various radiotracers.
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http://dx.doi.org/10.1007/s13139-019-00610-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6821901PMC
October 2019

Secreted protein acidic and rich in cysteine mediates active targeting of human serum albumin in U87MG xenograft mouse models.

Theranostics 2019 11;9(24):7447-7457. Epub 2019 Oct 11.

Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.

Human serum albumin (HSA) is the most abundant plasma protein. The main reason for using HSA as a versatile tool for drug delivery is based on its ability to accumulate in tumors. However, the mechanism of albumin accumulation in tumors is not yet clear. Many researchers using HSA as a drug-carrier have focused on the passive tumor targeting by enhanced permeability and retention (EPR) effect, while other investigators proposed that albumin binding proteins mediate albumin accumulation in tumors. We investigated whether HSA accumulation in tumors is mediated by the EPR effect or by secreted protein acidic and rich in cysteine (SPARC), which is known to be an albumin-binding protein. To investigate the role of SPARC on HSA accumulation in tumors, we compared HSA uptake in U87MG glioblastoma cells with different SPARC expression. U87MG cells generally express high levels of SPARC and were, therefore, used as SPARC-rich cells. SPARC-less U87MG (U87MG-shSPARC) cells were established by viral-shSPARC transduction. We detected cellular uptake of fluorescence-labeled HSA by confocal microscopy in U87MG and U87MG-shSPARC cells. To demonstrate the mechanism of HSA accumulation in tumors, we injected FNR648-labeled HSA and FITC-labeled dextran in U87MG and U87MG-shSPARC tumor-bearing mice and observed their micro-distribution in tumor tissues. HSA was internalized in cells by binding with SPARC . HSA accumulation in U87MG glioma was associated with SPARC expression . FITC-dextran was distributed in U87MG tumors in the vicinity of blood vessels. The distribution of HSA, on the other hand, was observed in the regions remote from blood vessels of U87MG tumor tissues but not in U87MG-shSPARC tumor tissues. Our results demonstrate that the tumor-distribution of HSA is affected not only by the EPR-effect but also by SPARC expression. SPARC enhances HSA accumulation in U87MG glioma and mediates active targeting of HSA in tumors.
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http://dx.doi.org/10.7150/thno.34883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6831305PMC
September 2020

Downregulation of PHGDH expression and hepatic serine level contribute to the development of fatty liver disease.

Metabolism 2020 01 31;102:154000. Epub 2019 Oct 31.

College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea. Electronic address:

Objective: Supplementation with serine attenuates alcoholic fatty liver by regulating homocysteine metabolism and lipogenesis. However, little is known about serine metabolism in fatty liver disease (FLD). We aimed to investigate the changes in serine biosynthetic pathways in humans and animal models of fatty liver and their contribution to the development of FLD.

Methods: High-fat diet (HFD)-induced steatosis and methionine-choline-deficient diet-induced steatohepatitis animal models were employed. Human serum samples were obtained from patients with FLD whose proton density fat fraction was estimated by magnetic resonance imaging. 3-Phosphoglycerate dehydrogenase (Phgdh)-knockout mouse embryonic fibroblasts (MEF) and transgenic mice overexpressing Phgdh (Tg-phgdh) were used to evaluate the role of serine metabolism in the development of FLD.

Results: Expression of Phgdh was markedly reduced in the animal models. There were significant negative correlations of the serum serine with the liver fat fraction, serum alanine transaminase, and triglyceride levels among patients with FLD. Increased lipid accumulation and reduced NAD and SIRT1 activity were observed in Phgdh-knockout MEF and primary hepatocytes incubated with free fatty acids; these effects were reversed by overexpression of Phgdh. Tg-Phgdh mice showed significantly reduced hepatic triglyceride accumulation compared with wild-type littermates fed a HFD, which was accompanied by increased SIRT1 activity and reduced expression of lipogenic genes and proteins.

Conclusions: Human and experimental data suggest that reduced Phgdh expression and serine levels are closely associated with the development of FLD.
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http://dx.doi.org/10.1016/j.metabol.2019.154000DOI Listing
January 2020

Involvement of the P2X7 receptor in the migration and metastasis of tamoxifen-resistant breast cancer: effects on small extracellular vesicles production.

Sci Rep 2019 08 12;9(1):11587. Epub 2019 Aug 12.

College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea.

Tamoxifen (TAM) is the standard anti-hormonal therapy for estrogen receptor-positive breast cancer. However, long-term TAM therapy can make acquisition of TAM resistance and there are still no solutions to treat TAM-resistant breast cancer. In this study, we found that protein and mRNA expression of the P2X purinoreceptor 7 (P2X7) was higher in tamoxifen resistant MCF-7 (TAMR-MCF-7) cells than in control MCF-7 cells. P2X7 inhibition potently inhibited the migration of TAMR-MCF-7 cells and the liver metastasis burden of TAMR-MCF-7 cells in the spleen-liver metastasis experiment. However, the P2X7 antagonist did not affect protein expression of matrix metalloproteinase (MMP)-2, MMP-9, and epithelial-mesenchymal transition markers. Here our data indicate a link between small extracellular vesicles (sEV) and P2X7, and suggest a new mechanism of metastasis in TAM-resistant breast cancer cells through P2X7 receptors. The migration of TAMR-MCF-7 cells was increased in a concentration-dependent manner by purified sEV treatment. The number of secreted sEVs and the protein levels of CD63 in TAMR-MCF-7 cells were decreased by the P2X7 antagonist, showing that P2X7 influences the production of sEV. Our results suggest that inhibiting the P2X7 could be considered for metastasis prevention in TAM-resistant cancer patients.
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http://dx.doi.org/10.1038/s41598-019-47734-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6690963PMC
August 2019

Compartmental-modelling-based measurement of murine glomerular filtration rate using F-fluoride PET/CT.

Sci Rep 2019 08 2;9(1):11269. Epub 2019 Aug 2.

Department of Nuclear Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam-si, Republic of Korea.

Accurate measurement of glomerular filtration rate (GFR) is essential for optimal decision making in many clinical settings of renal failure. We aimed to show that GFR can be accurately measured using compartmental tracer kinetic analysis of F-fluoride dynamic PET/CT. Twenty-three male Sprague-Dawley rats of three experimental groups (cyclosporine-administered [n = 8], unilaterally nephrectomized [n = 8], and control [n = 7]) underwent simultaneous F-fluoride dynamic PET/CT and reference Cr-EDTA GFR (GFR) test at day 0 and post-intervention day 3. F-fluoride PET GFR (GFR) was calculated by multiplying the influx rate and functional kidney volume in a single-tissue-compartmental kinetic model. Within-test repeatability and between-test agreement were evaluated by intraclass correlation coefficient (ICC) and Bland-Altman analysis. In the control group, repeatability of GFR was excellent (ICC = 0.9901, repeatability coefficient = 12.5%). GFR significantly decreased in the renally impaired rats in accordance with respective GFR changes. In the pooled population, GFR agreed well with GFR with minimal bias (-2.4%) and narrow 95% limits of agreement (-25.0% to 20.1%). These data suggest that the single-compartmental kinetic analysis of F-fluoride dynamic PET/CT is an accurate method for GFR measurement. Further studies in humans are warranted.
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http://dx.doi.org/10.1038/s41598-019-47728-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6677809PMC
August 2019

Estrogen Deficiency Potentiates Thioacetamide-Induced Hepatic Fibrosis in Sprague-Dawley Rats.

Int J Mol Sci 2019 Jul 29;20(15). Epub 2019 Jul 29.

School of Pharmacy, Sungkyunkwan University, Suwon 16419, Korea.

Hepatic fibrosis is characterized by persistent deposition of extracellular matrix proteins and occurs in chronic liver diseases. The aim of the present study is to investigate whether estrogen deficiency (ED) potentiates hepatic fibrosis in a thioacetamide (TAA)-treated rat model. Fibrosis was induced via intraperitoneal injection (i.p.) of TAA (150 mg/kg/day) for four weeks in ovariectomized (OVX) female, sham-operated female, or male rats. In TAA-treated OVX rats, the activities of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and γ-glutamyl transferase (GGT) were significantly increased compared to those in TAA-treated sham-operated OVX rats or TAA-treated male rats. Furthermore, α-smooth muscle actin (α-SMA) expression was significantly increased compared to that in TAA-treated sham-operated rats. This was accompanied by the appearance of fibrosis biomarkers including vimentin, collagen-I, and hydroxyproline, in the liver of TAA-treated OVX rats. In addition, ED markedly reduced total glutathione (GSH) levels, as well as catalase (CAT) and superoxide dismutase (SOD) activity in TAA-treated OVX rats. In contrast, hepatic malondialdehyde (MDA) levels were elevated in TAA-treated OVX rats. Apoptosis significantly increased in TAA-treated OVX rats, as reflected by elevated p53, Bcl-2, and cleaved caspase 3 levels. Significant increases in interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) concentrations were exhibited in TAA-treated OVX rats, and this further aggravated fibrosis through the transforming growth factor-β (TGF-β)/Smad pathway. Our data suggest that ED potentiates TAA-induced oxidative damage in the liver, suggesting that ED may enhance the severity of hepatic fibrosis in menopausal women.
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http://dx.doi.org/10.3390/ijms20153709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6696236PMC
July 2019