• Korean Journal of Radiology
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• v.21 no.6
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• pp.707-716
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• 2020

Objective: To evaluate pharmacokinetic variables from contrast-enhancing lesions (CELs) and non-enhancing T2 high signal intensity lesions (NE-T2HSILs) on dynamic contrast-enhanced (DCE) magnetic resonance (MR) imaging for predicting progression-free survival (PFS) in glioblastoma (GBM) patients. Materials and Methods: Sixty-four GBM patients who had undergone preoperative DCE MR imaging and received standard treatment were retrospectively included. We analyzed the pharmacokinetic variables of the volume transfer constant (Ktrans) and volume fraction of extravascular extracellular space within the CEL and NE-T2HSIL of the entire tumor. Univariate and multivariate Cox regression analyses were performed using preoperative clinical characteristics, pharmacokinetic variables of DCE MR imaging, and postoperative molecular biomarkers to predict PFS. Results: The increased mean Ktrans of the CEL, increased 95th percentile Ktrans of the CELs, and absence of methylated O⁶-methylguanine-DNA methyltransferase promoter were relevant adverse variables for PFS in the univariate analysis (p = 0.041, p = 0.032, and p = 0.083, respectively). The Kaplan-Meier survival curves demonstrated that PFS was significantly shorter in patients with a mean Ktrans of the CEL > 0.068 and 95th percentile Ktrans of the CEL > 0.223 (log-rank p = 0.038 and p = 0.041, respectively). However, only mean Ktrans of the CEL was significantly associated with PFS (p = 0.024; hazard ratio, 553.08; 95% confidence interval, 2.27-134756.74) in the multivariate Cox proportional hazard analysis. None of the pharmacokinetic variables from NE-T2HSILs were significantly related to PFS. Conclusion: Among the pharmacokinetic variables extracted from CELs and NE-T2HSILs on preoperative DCE MR imaging, the mean Ktrans of CELs exhibits potential as a useful imaging predictor of PFS in GBM patients.

• Korean Journal of Radiology
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• v.21 no.12
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• pp.1294-1304
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• 2020

Objective: To determine whether T1 mapping could monitor the dynamic changes of injury in myocardial infarction (MI) and be histologically validated. Materials and Methods: In 22 pigs, MI was induced by ligating the left anterior descending artery and they underwent serial cardiovascular magnetic resonance examinations with modified Look-Locker inversion T1 mapping and extracellular volume (ECV) computation in acute (within 24 hours, n = 22), subacute (7 days, n = 13), and chronic (3 months, n = 7) phases of MI. Masson's trichrome staining was performed for histological ECV calculation. Myocardial native T1 and ECV were obtained by region of interest measurement in infarcted, peri-infarct, and remote myocardium. Results: Native T1 and ECV in peri-infarct myocardium differed from remote myocardium in acute (1181 ± 62 ms vs. 1113 ± 64 ms, p = 0.002; 24 ± 4% vs. 19 ± 4%, p = 0.031) and subacute phases (1264 ± 41 ms vs. 1171 ± 56 ms, p < 0.001; 27 ± 4% vs. 22 ± 2%, p = 0.009) but not in chronic phase (1157 ± 57 ms vs. 1120 ± 54 ms, p = 0.934; 23 ± 2% vs. 20 ± 1%, p = 0.109). From acute to chronic MI, infarcted native T1 peaked in subacute phase (1275 ± 63 ms vs. 1637 ± 123 ms vs. 1471 ± 98 ms, p < 0.001), while ECV progressively increased with time (35 ± 7% vs. 46 ± 6% vs. 52 ± 4%, p < 0.001). Native T1 correlated well with histological findings (R² = 0.65 to 0.89, all p < 0.001) so did ECV (R² = 0.73 to 0.94, all p < 0.001). Conclusion: T1 mapping allows the quantitative assessment of injury in MI and the noninvasive monitoring of tissue injury evolution, which correlates well with histological findings.

• Korean Journal of Radiology
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• v.21 no.6
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• pp.647-659
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• 2020

Objective: The occurrence of intramyocardial hemorrhage (IMH) and microvascular obstruction (MVO) in myocardial infarction (MI), known as severe ischemia/reperfusion injury (IRI), has been associated with adverse remodeling. APT102, a soluble human recombinant ecto-nucleoside triphosphate diphosphohydrolase-1, can hydrolyze extracellular nucleotides to attenuate their prothrombotic and proinflammatory effects. The purpose of this study was to temporally evaluate the therapeutic effect of APT102 on IRI in rats and to elucidate the evolution of IRI in the acute stage using cardiovascular magnetic resonance imaging (CMRI). Materials and Methods: Fifty-four rats with MI, induced by ligation of the origin of the left anterior descending coronary artery for 60 minutes, were randomly divided into the APT102 (n = 27) or control (n = 27) group. Intravenous infusion of APT102 (0.3 mg/kg) or placebo was administered 15 minutes before reperfusion, and then 24 hours, 48 hours, 72 hours, and on day 4 after reperfusion. CMRI was performed at 24 hours, 48 hours, 72 hours, and on day 5 post-reperfusion using a 7T system and the hearts were collected for histopathological examination. Cardiac function was quantified using cine imaging and IMH/edema using T2 mapping, and infarct/MVO using late gadolinium enhancement. Results: The extent of infarction (p < 0.001), edema (p < 0.001), IMH (p = 0.013), and MVO (p = 0.049) was less severe in the APT102 group than in the control group. IMH size at 48 hours was significantly greater than that at 24 hours, 72 hours, and 5 days after reperfusion (all p < 0.001). The left ventricular ejection fraction (LVEF) was significantly greater in the APT102 group than in the control group (p = 0.006). There was a negative correlation between LVEF and IMH (r = -0.294, p = 0.010) and a positive correlation between IMH and MVO (r = 0.392, p < 0.001). Conclusion: APT102 can significantly alleviate damage to the ischemic myocardium and microvasculature. IMH size peaked at 48 hours post reperfusion and IMH is a downstream consequence of MVO. IMH may be a potential therapeutic target to prevent adverse remodeling in MI.

• Korean Journal of Radiology
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• v.24 no.10
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• pp.983-995
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• 2023

Objective: To compare the diagnostic performance and interobserver agreement between contrast-enhanced computed tomography (CECT) and contrast-enhanced magnetic resonance imaging (CE-MRI) with magnetic resonance cholangiopancreatography (MRCP) for evaluating the resectability in patients with extrahepatic cholangiocarcinoma (eCCA). Materials and Methods: This retrospective study included treatment-naïve patients with pathologically confirmed eCCA, who underwent both CECT and CE-MRI with MRCP using extracellular contrast media between January 2015 and December 2020. Among the 214 patients (146 males; mean age ± standard deviation, 68 ± 9 years) included, 121 (56.5%) had perihilar cholangiocarcinoma. R0 resection was achieved in 108 of the 153 (70.6%) patients who underwent curative-intent surgery. Four fellowship-trained radiologists independently reviewed the findings of both CECT and CE-MRI with MRCP to assess the local tumor extent and distant metastasis for determining resectability. The pooled area under the receiver operating characteristic curve (AUC), sensitivity, and specificity of CECT and CE-MRI with MRCP were compared using clinical, surgical, and pathological findings as reference standards. The interobserver agreement of resectability was evaluated using Fleiss kappa (κ). Results: No significant differences were observed between CECT and CE-MRI with MRCP in the pooled AUC (0.753 vs. 0.767), sensitivity (84.7% [366/432] vs. 90.3% [390/432]), and specificity (52.6% [223/424] vs. 51.4% [218/424]) (P > 0.05 for all). The AUC for determining resectability was higher when CECT and CE-MRI with MRCP were reviewed together than when CECT was reviewed alone in patients with discrepancies between the imaging modalities or with indeterminate resectability (0.798 [0.754-0.841] vs. 0.753 [0.697-0.808], P = 0.014). The interobserver agreement for overall resectability was fair for both CECT (κ = 0.323) and CE-MRI with MRCP (κ = 0.320), without a significant difference (P = 0.884). Conclusion: CECT and CE-MRI with MRCP showed no significant differences in the diagnostic performance and interobserver agreement in determining the resectability in patients with eCCA.

• Korean Journal of Radiology
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• v.24 no.11
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• pp.1081-1092
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• 2023

Objective: To investigate the incidence of microvascular myocardial ischemia in diabetic patients without obstructive coronary artery disease (CAD) and its relationship with angina. Materials and Methods: Diabetic patients and an intermediate-to-high pretest probability of CAD were prospectively enrolled. Non-diabetic patients but with an intermediate-to-high pretest probability of CAD were retrospectively included as controls. The patients underwent dynamic computed tomography-myocardial perfusion imaging (CT-MPI) and coronary computed tomography angiography (CCTA) to quantify coronary stenosis, myocardial blood flow (MBF), and extracellular volume (ECV). The proportion of patients with microvascular myocardial ischemia, defined as any myocardial segment with a mean MBF ≤ of 100 mL/min/100 mL, in patients without obstructive CAD (Coronary Artery Disease-Reporting and Data System [CAD-RADS] grade 0-2 on CCTA) was determined. Various quantitative parameters of the patients with and without diabetes without obstructive CAD were compared. Multivariable analysis was used to determine the association between microvascular myocardial ischemia and angina symptoms in diabetic patients without obstructive CAD. Results: One hundred and fifty-two diabetic patients (mean age: 59.7 ± 10.7; 77 males) and 266 non-diabetic patients (62.0 ± 12.3; 167 males) were enrolled; CCTA revealed 113 and 155 patients without obstructive CAD, respectively. For patients without obstructive CAD, the mean global MBF was significantly lower for those with diabetes than for those without (152.8 mL/min/100 mL vs. 170.4 mL/min/100 mL, P < 0.001). The mean ECV was significantly higher for diabetic patients (27.2% vs. 25.8%, P = 0.009). Among the patients without obstructive CAD, the incidence of microvascular myocardial ischemia (36.3% [41/113] vs. 10.3% [16/155], P < 0.001) and interstitial fibrosis (69.9% [79/113] vs. 33.3% [8/24], P = 0.001) were significantly higher in diabetic patients than in the controls. The presence of microvascular myocardial ischemia was independently associated with angina symptoms (adjusted odds ratio = 3.439, P = 0.037) in diabetic patients but without obstructive CAD. Conclusion: Dynamic CT-MPI + CCTA revealed a high incidence of microvascular myocardial ischemia in diabetic patients without obstructive CAD. Microvascular myocardial ischemia is strongly associated with angina.

• Korean Journal of Radiology
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• v.24 no.9
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• pp.838-848
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• 2023

Objective: To quantitatively analyze the cardiac magnetic resonance imaging (CMR) characteristics of chemotherapy-related cardiac dysfunction (CTRCD) and explore their prognostic value for major adverse cardiovascular events (MACE). Materials and Methods: A total of 145 patients (male:female = 76:69, mean age = 63.0 years) with cancer and heart failure who underwent CMR between January 2015 and January 2021 were included. CMR was performed using a 3T scanner (Siemens). Biventricular functions, native T1 T2, extracellular volume fraction (ECV) values, and late gadolinium enhancement (LGE) of the left ventricle (LV) were compared between those with and without CTRCD. These were compared between patients with mild-to-moderate CTRCD and those with severe CTRCD. Cox proportional hazard regression analysis was used to evaluate the association between the CMR parameters and MACE occurrence during follow-up in the CTRCD patients. Results: Among 145 patients, 61 had CTRCD and 84 did not have CTRCD. Native T1, ECV, and T2 were significantly higher in the CTRCD group (1336.9 ms, 32.5%, and 44.7 ms, respectively) than those in the non-CTRCD group (1303.4 ms, 30.5%, and 42.0 ms, respectively; P = 0.013, 0.010, and < 0.001, respectively). They were not significantly different between patients with mild-to-moderate and severe CTRCD. Indexed LV mass was significantly smaller in the CTRCD group (65.0 g/m² vs. 78.9 g/mm²; P < 0.001). According to the multivariable Cox regression analysis, T2 (hazard ratio [HR]: 1.14, 95% confidence interval [CI]: 1.01-1.27; P = 0.028) and quantified LGE (HR: 1.07, 95% CI: 1.01-1.13; P = 0.021) were independently associated with MACE in the CTRCD patients. Conclusion: Quantitative parameters from CMR have the potential to evaluate myocardial changes in CTRCD. Increased T2 with reduced LV mass was demonstrated in CTRCD patients even before the development of severe cardiac dysfunction. T2 and quantified LGE may be independent prognostic factors for MACE in patients with CTRCD.

• Journal of The Korean Society of Integrative Medicine
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• v.12 no.1
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• pp.1-10
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• 2024

Purpose: Lycopene is abundantly contained in Tomatoes and is known for diverse biological activities such as antioxidant, anti-inflammatory, and anticancer effects. In this study, the antioxidative potential of lycopene was investigated through the induction of hemeoxygenase (HO)-1 by nuclear factor-erythroid 2 p45-related factor2 (Nrf2) and upstream signaling molecules, mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/Aktin RAW 264.7 cells. Methods: The antioxidative potential of lycopene against oxidative stress and its molecular mechanisms were determined by the cell viability assay, intracellular reactive oxygen species (ROS) formation assay, and Western blot analysis in RAW 264.7 cells. Results: Lycopene treatment significantly attenuated tert-butyl hydroperoxide (t-BHP) induced intracellular ROS formation in a dose-dependent manner without any cytotoxicity. In addition, 50 µM of lycopene for 6 h treatment induced potent HO-1 expression and its transcription factor, Nrf2. MAPK and PI3K/Aktwere also analyzed due to their critical roles in the regulation of cellular redox homeostasis against oxidative damage. As a result, phosphorylation of extracellular regulated kinase (ERK) was significantly induced by lycopene treatment while the activated status of c-Jun NH2-terminal kinase (JNK), p38, and Akt, were not given any effect. To confirm the antioxidative mechanism of HO-1 mediated by ERK activation, each selective inhibitor was employed in a protection assay, in which oxidative damage occurred by t-BHP. Lycopene, SnPP, and CoPP treatments reflected accelerated HO-1 expression could be a protective role against oxidative damage-initiated cell death. A selective inhibitor for ERK significantly inhibited the lycopene-induced cytoprotective effect but selective inhibitors for other signaling molecules did not attenuate the rate of t-BHP-induced cell death. Conclusion: In conclusion, lycopene potently scavenged intracellular ROS formation and enhanced the HO-1 mediated antioxidative potential through the modulation of Nrf2, MAPK signaling pathway in RAW 264.7 cells.

• Journal of The Korean Society of Integrative Medicine
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• v.12 no.1
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• pp.63-71
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• 2024

Purpose : Skin is the primary barrier to protect the body from various exogenous factors. Among them, UVB exposure can cause the induction of not only excessive inflammatory responses but also the degradation of extracellular matrix (ECM), including collagen and elastin. This study tried to investigate the ameliorative effect of Persicaria perfoliata ethanol extract (PPEE) on UVB-irradiated photodamage through the regulation of activator protein (AP)-1, phosphoinositide 3-kinase (PI3K)/Akt, and mitogen-activated protein kinase (MAPK) signaling molecules in HaCaT cells. Methods : The cytotoxicity of PPEE on HaCaT cells was evaluated by the WST-1 assay. The 80 mJ/cm² of UVB (312 nm) was irradiated on HaCaT cells to induce the photodamage. Western blot analysis was conducted to investigate the protein expression levels of cyclooxygenase (COX)-2, matrix metalloproteinase (MMP)-9, and heme oxygenase (HO)-1 for ameliorative status by PPEE treatment in UVB-exposed HaCaT cells. In addition, the activated status of the inflammatory transcription factor, AP-1, as well as upstream signaling molecules, PI3K/Akt, and MAPK, were also evaluated by Western blot analysis. Results : Any cytotoxic effect was not induced at the concentration up to 200 ㎍/ml by PPEE treatment. Protein expression levels of COX-2 and MMP-9 were significantly down- and up-regulated by PPEE treatment. The inflammatory transcription factor AP-1, stimulated by UVB irradiation, was also significantly attenuated by PPEE treatment. The phosphorylated status of PI3K/Akt and MAPK were mitigated by PPEE treatment in UVB-exposed HaCaT cells. Moreover, PPEE treatment potently accelerated the expression of HO-1 and its transcription factor, nuclear factor-erythroid 2-related factor (Nrf)2, which is known for its anti-inflammatory activity. Conclusion : Consequently, PPEE treatment significantly regulated COX-2 and MMP-9 expressions in UVB-irradiated HaCaT cells. The inflammatory transcription factor AP-1, along with upstream signaling molecules PI3K/Akt and MAPKs, were also attenuated by PPEE treatment in UVB-exposed HaCaT cells. Additionally, PPEE treatment exaggerated HO-1 expression and Nrf2 activation, which might have contributed to the anti-inflammatory activity of PPEE. These results indicate that PPEE could be a candidate for attenuating UVB-induced photodamage in human skin.

• Journal of Life Science
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• v.34 no.2
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• pp.94-104
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• 2024

β-Lapachone is a natural quinone compound originally obtained from the bark of the lapacho tree (Tabebuia vellanedae), which has been used in traditional medicine in several South and Central American countries for treating various diseases. Although β-lapachone has been reported to have potent anticancer activity in many types of cancer cells, its effect on the proliferation of hepatocellular carcinoma (HCC) cells is still unclear. Therefore, in this study, we investigated the effect of β-lapachone on the proliferation of human HCC Hep3B cells. According to our results, the decrease in cell viability of Hep3B cells caused by β-lapachone was closely related to the induction of apoptosis, which was confirmed through changes in nuclear morphology and flow cytometry. In addition, in Hep3B cells treated with β-lapachone, the expression of Bcl-2, an anti-apoptotic factor, was decreased, while the expression of Bax, an apoptosis inducer, was increased, and the activity of the caspase cascade was also increased. However, in the presence of a pan-caspase inhibitor, β-lapachone-induced apoptosis was weakened, indicating that the induction of apoptosis by β-lapachone was caspase-dependent. Moreover, β-lapachone treatment activated extracellular-regulated kinase (ERK) signaling while inhibiting activation of the phosphoinositide 3 kinase (PI3K)/Akt pathway. Furthermore, the effect of the ERK inhibitor on suppressing the induction of apoptosis by β-lapachone was minimal, and the PI3K inhibitor significantly increased β-lapachone-induced apoptosis. The findings from this study will contribute to a better understanding of the anticancer activity of β-lapachone in HCC cells.

• Korean Journal of Radiology
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• v.22 no.9
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• pp.1514-1524
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• 2021

Objective: To develop a radiomics risk score based on dynamic contrast-enhanced (DCE) MRI for prognosis prediction in patients with glioblastoma. Materials and Methods: One hundred and fifty patients (92 male [61.3%]; mean age ± standard deviation, 60.5 ± 13.5 years) with glioblastoma who underwent preoperative MRI were enrolled in the study. Six hundred and forty-two radiomic features were extracted from volume transfer constant (K^trans), fractional volume of vascular plasma space (V_p), and fractional volume of extravascular extracellular space (V_e) maps of DCE MRI, wherein the regions of interest were based on both T1-weighted contrast-enhancing areas and non-enhancing T2 hyperintense areas. Using feature selection algorithms, salient radiomic features were selected from the 642 features. Next, a radiomics risk score was developed using a weighted combination of the selected features in the discovery set (n = 105); the risk score was validated in the validation set (n = 45) by investigating the difference in prognosis between the "radiomics risk score" groups. Finally, multivariable Cox regression analysis for progression-free survival was performed using the radiomics risk score and clinical variables as covariates. Results: 16 radiomic features obtained from non-enhancing T2 hyperintense areas were selected among the 642 features identified. The radiomics risk score was used to stratify high- and low-risk groups in both the discovery and validation sets (both p < 0.001 by the log-rank test). The radiomics risk score and presence of isocitrate dehydrogenase (IDH) mutation showed independent associations with progression-free survival in opposite directions (hazard ratio, 3.56; p = 0.004 and hazard ratio, 0.34; p = 0.022, respectively). Conclusion: We developed and validated the "radiomics risk score" from the features of DCE MRI based on non-enhancing T2 hyperintense areas for risk stratification of patients with glioblastoma. It was associated with progression-free survival independently of IDH mutation status.