Assessment of Microvascular Invasion of Hepatocellular Carcinoma with Diffusion Kurtosis Imaging.

Purpose To evaluate the potential role of diffusion kurtosis imaging and conventional magnetic resonance (MR) imaging findings including standard monoexponential model of diffusion-weighted imaging and morphologic features for preoperative prediction of microvascular invasion (MVI) of hepatocellular carcinoma (HCC). Materials and Methods Institutional review board approval and written informed consent were obtained. Between September 2015 and November 2016, 84 patients (median age, 54 years; range, 29-79 years) with 92 histopathologically confirmed HCCs (40 MVI-positive lesions and 52 MVI-negative lesions) were analyzed. Preoperative MR imaging examinations including diffusion kurtosis imaging (b values: 0, 200, 500, 1000, 1500, and 2000 sec/mm2) were performed and kurtosis, diffusivity, and apparent diffusion coefficient maps were calculated. Morphologic features of conventional MR images were also evaluated. Univariate and multivariate logistic regression analyses were used to evaluate the relative value of these parameters as potential predictors of MVI. Results Features significantly related to MVI of HCC at univariate analysis were increased mean kurtosis value (P < .001), decreased mean diffusivity value (P = .033) and apparent diffusion coefficient value (P = .011), and presence of infiltrative border with irregular shape (P = .005) and irregular circumferential enhancement (P = .026). At multivariate analysis, mean kurtosis value (odds ratio, 6.25; P = .001), as well as irregular circumferential enhancement (odds ratio, 6.92; P = .046), were independent risk factors for MVI of HCC. The mean kurtosis value for MVI of HCC showed an area under the receiver operating characteristic curve of 0.784 (optimal cutoff value was 0.917). Conclusion Higher mean kurtosis values in combination with irregular circumferential enhancement are potential predictive biomarkers for MVI of HCC. © RSNA, 2017.

Whole-tumor MRI histogram analyses of hepatocellular carcinoma: Correlations with Ki-67 labeling index.

PURPOSE: To evaluate whether whole-tumor histogram-derived parameters for an apparent diffusion coefficient (ADC) map and contrast-enhanced magnetic resonance imaging (MRI) could aid in assessing Ki-67 labeling index (LI) of hepatocellular carcinoma (HCC). MATERIALS AND METHODS: In all, 57 patients with HCC who underwent pretreatment MRI with a 3T MR scanner were included retrospectively. Histogram parameters including mean, median, standard deviation, skewness, kurtosis, and percentiles (5th , 25th , 75th , 95th ) were derived from the ADC map and MR enhancement. Correlations between histogram parameters and Ki-67 LI were evaluated and differences between low Ki-67 (≤10%) and high Ki-67 (>10%) groups were assessed. RESULTS: Mean, median, 5th , 25th , 75th percentiles of ADC, and mean, median, 25th , 75th , 95th percentiles of enhancement of arterial phase (AP) demonstrated significant inverse correlations with Ki-67 LI (rho up to -0.48 for ADC, -0.43 for AP) and showed significant differences between low and high Ki-67 groups (P < 0.001-0.04). Areas under the receiver operator characteristics (ROC) curve for identification of high Ki-67 were 0.78, 0.77, 0.79, 0.82, and 0.76 for mean, median, 5th , 25th , 75th percentiles of ADC, respectively, and 0.74, 0.81, 0.76, 0.82, 0.69 for mean, median, 25th , 75th , 95th percentiles of AP, respectively. CONCLUSION: Histogram-derived parameters of ADC and AP were potentially helpful for predicting Ki-67 LI of HCC. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 3 J. MAGN. RESON. IMAGING 2017;46:383-392.

Potential of MR histogram analyses for prediction of response to chemotherapy in patients with colorectal hepatic metastases.

PURPOSE: To determine if magnetic resonance imaging (MRI) histogram analyses can help predict response to chemotherapy in patients with colorectal hepatic metastases by using response evaluation criteria in solid tumours (RECIST1.1) as the reference standard. MATERIALS AND METHODS: Standard MRI including diffusion-weighted imaging (b=0, 500 s/mm(2)) was performed before chemotherapy in 53 patients with colorectal hepatic metastases. Histograms were performed for apparent diffusion coefficient (ADC) maps, arterial, and portal venous phase images; thereafter, mean, percentiles (1st, 10th, 50th, 90th, 99th), skewness, kurtosis, and variance were generated. Quantitative histogram parameters were compared between responders (partial and complete response, n=15) and non-responders (progressive and stable disease, n=38). Receiver operator characteristics (ROC) analyses were further analyzed for the significant parameters. RESULTS: The mean, 1st percentile, 10th percentile, 50th percentile, 90th percentile, 99th percentile of the ADC maps were significantly lower in responding group than that in non-responding group (p=0.000-0.002) with area under the ROC curve (AUCs) of 0.76-0.82. The histogram parameters of arterial and portal venous phase showed no significant difference (p>0.05) between the two groups. CONCLUSION: Histogram-derived parameters for ADC maps seem to be a promising tool for predicting response to chemotherapy in patients with colorectal hepatic metastases. KEY POINTS: • ADC histogram analyses can potentially predict chemotherapy response in colorectal liver metastases. • Lower histogram-derived parameters (mean, percentiles) for ADC tend to have good response. • MR enhancement histogram analyses are not reliable to predict response.

Saturated free fatty acid sodium palmitate-induced lipoapoptosis by targeting glycogen synthase kinase-3ß activation in human liver cells.

BACKGROUND: Elevated serum saturated fatty acid levels and hepatocyte lipoapoptosis are features of nonalcoholic fatty liver disease (NAFLD). AIM: The purpose of this study was to investigate saturated fatty acid induction of lipoapoptosis in human liver cells and the underlying mechanisms. METHODS: Human liver L02 and HepG2 cells were treated with sodium palmitate, a saturated fatty acid, for up to 48 h with or without lithium chloride, a glycogen synthase kinase-3ß (GSK-3ß) inhibitor, or GSK-3ß shRNA transfection. Transmission electron microscopy was used to detect morphological changes, flow cytometry was used to detect apoptosis, a colorimetric assay was used to detect caspase-3 activity, and western blot analysis was used to detect protein expression. RESULTS: The data showed that sodium palmitate was able to induce lipoapoptosis in L02 and HepG2 cells. Western blot analysis showed that sodium palmitate activated GSK-3ß protein, which was indicated by dephosphorylation of GSK-3ß at Ser-9. However, inhibition of GSK-3ß activity with lithium chloride treatment or knockdown of GSK-3ß expression with shRNA suppressed sodium palmitate-induced lipoapoptosis in L02 and HepG2 cells. On a molecular level, inhibition of GSK-3ß expression or activity suppressed sodium palmitate-induced c-Jun-N-terminal kinase (JNK) phosphorylation and Bax upregulation, whereas GSK-3ß inhibition did not affect endoplasmic reticulum stress-induced activation of unfolded protein response. CONCLUSIONS: The present data demonstrated that saturated fatty acid sodium palmitate-induced lipoapoptosis in human liver L02 and HepG2 cells was regulated by GSK-3ß activation, which led to JNK activation and Bax upregulation. This finding indicates that GSK-3ß inhibition may be a potential therapeutic target to control NAFLD.

Saturated fatty acid induction of endoplasmic reticulum stress and apoptosis in human liver cells via the PERK/ATF4/CHOP signaling pathway.

Accumulation of saturated fatty acids in the liver can cause nonalcoholic fatty liver disease (NAFLD). This study investigated saturated fatty acid induction of endoplasmic reticulum (ER) stress and apoptosis in human liver cells and the underlying causal mechanism. Human liver L02 and HepG2 cell lines were exposed to the saturated fatty acid sodium palmitate. MTT assay was used for cell viability, flow cytometry and Hoechst 33258 staining for apoptosis, RT-PCR for mRNA expression, and Western blot for protein expression. Silence of PRK-like ER kinase (PERK) expression in liver cells was through transient transfection of PERK shRNA. Treatment of L02 and HepG2 cells with sodium palmitate reduced cell viability through induction of apoptosis. Sodium palmitate also induced ER stress in the cells, indicated by upregulation of PERK phosphorylation and expression of BiP, ATF4, and CHOP proteins. Sodium palmitate had little effect on activating XBP-1, a common target of the other two canonical sensors of ER stress, ATF6, and IRE1. Knockdown of PERK gene expression suppressed the PERK/ATF4/CHOP signaling pathway during sodium palmitate-induced ER stress and significantly inhibited sodium palmitate-induced apoptosis in L02 and HepG2 cells. Saturated fatty acid-induced ER stress and apoptosis in these human liver cells were enacted through the PERK/ATF4/CHOP signaling pathway. Future study is warranted to investigate the role of these proteins in mediating saturated fatty acid-induced NAFLD in animal models.

Prediction of flavor and retention index for compounds in beer depending on molecular structure using a machine learning method.

In order to make a preliminary prediction of flavor and retention index (RI) for compounds in beer, this work applied the machine learning method to modeling depending on molecular structure. Towards this goal, the flavor compounds in beer from existing literature were collected. The database was classified into four groups as aromatic, bitter, sulfury, and others. The RI values on a non-polar SE-30 column and a polar Carbowax 20M column from the National Institute of Standards Technology (NIST) were investigated. The structures were converted to molecular descriptors calculated by molecular operating environment (MOE), ChemoPy and Mordred, respectively. By combining the pretreatment of the descriptors, machine learning models, including support vector machine (SVM), random forest (RF) and k-nearest neighbour (kNN) were utilized for beer flavor models. Principal component regression (PCR), random forest regression (RFR) and partial least squares (PLS) regression were employed to predict the RI. The accuracy of the test set was obtained by SVM, RF, and kNN. Among them, the combination of descriptors calculated by Mordred and RF model afforded the highest accuracy of 0.686. R 2 of the optimal regression model achieved 0.96. The results indicated that the models can be used to predict the flavor of a specific compound in beer and its RI value.

Fully automated magnetically controlled capsule endoscopy for examination of the stomach and small bowel: a prospective, feasibility, two-centre study.

BACKGROUND: The use of magnetically controlled capsules for gastroscopy is in the early stages of clinical adoption. We aimed to evaluate the safety and efficacy of a fully automated magnetically controlled capsule endoscopy (FAMCE) system in clinical practice for gastroscopy and small bowel examination. METHODS: We did a prospective, comparative study to evaluate the safety and efficacy of FAMCE. Patients from two hospitals in Chongqing, China were consecutively enrolled. Eligible participants were aged 18-80 years with suspected gastric pathology and no previous surgery. Participants underwent FAMCE for screening of gastric lesions, then conventional transoral gastroscopy 2 h later, and stomach examination results were compared. The primary outcome was the rate of complete detection of gastric anatomy landmarks (cardia, fundus, body, angulus, antrum, and pylorus) by FAMCE. Secondary outcomes were the time required for gastric completion by FAMCE, the rate of detection of gastric lesions by FAMCE compared with conventional transoral gastroscopy, and the rate of complete small bowel examination. Adverse events were also evaluated. The study was registered in the Chinese Clinical Trial Registry, ChiCTR2000040507. FINDINGS: Between May 12 and Aug 17, 2020, 114 patients (mean age 44·0 years [IQR 34·0-55·0]; 63 [55%] female) were enrolled. The rate of complete detection of gastric anatomical structures by FAMCE was 100% (95% CI 99·3-100·0). The concordance between FAMCE and conventional transoral gastroscopy was 99·61% (99·45-99·78). The mean completion time of a gastroscopy with FAMCE was 19·17 min (SD 1·43; median 19·00, IQR 19·00-20·00), compared with 5·21 min (2·00; 5·18, 3·68-6·45) for conventional transoral gastroscopy. In 114 enrolled patients, 214 lesions were detected by FAMCE and conventional transoral gastroscopy. Of those, 193 were detected by both modalities. FAMCE missed five pathologies (four cases of gastritis and one polyp), whereas conventional transoral gastroscopy missed 16 pathologies (12 cases of gastritis, one polyp, one fundal xanthoma, and two antral erosions). FAMCE was able to provide a complete small bowel examination for all 114 patients and detected intestinal lesions in 50 (44%) patients. During the study, two (2%) patients experienced adverse events. No serious adverse events were recorded, and there was no evidence of capsule retention. INTERPRETATION: The performance of FAMCE is similar to conventional transoral gastroscopy in completion of gastric examination and lesion detection. Furthermore, it can provide a complete small bowel examination. Therefore, FAMCE could be effective method for examination of the gastrointestinal tract. FUNDING: Chinese National Key Research and Development Program.

MR features based on LI-RADS identify cytokeratin 19 status of hepatocellular carcinomas.

OBJECTIVE: To retrospectively evaluate the value of MR features based on Liver Imaging Reporting and Data System (LI-RADS ver.2017) for identifying the status of cytokeratin (CK) 19 expression of HCC before surgery. METHODS: A total of 201 patients with 207 HCCs who underwent MR imaging were reviewed retrospectively. MR features based on LI-RADS ver.2017 as well as clinical data were compared between CK19-positive (n = 51) and CK19-negative (n = 156) HCCs groups. Potential predictive parameters were identified by univariate and multivariate logistic regression analysis and diagnostic odds ratios (ORs) were recorded. RESULTS: MR features including targetoid appearance (p = 0.001) was more frequently observed while non-peripheral "washout" (p < 0.0001) and non-rim arterial phase hyper-enhancement (p < 0.0001) were found less frequently in CK19-positive HCCs compared to CK19-negative HCCs. At multivariate analysis, serum alphafetoprotein (AFP)>20 ng/ml (OR = 5.9) and targetoid appearance (OR = 4.2) and non-peripheral "washout" (OR = 0.2) were significant independent predictors of CK19-positive HCCs. CONCLUSION: Targetoid appearance and absence non-peripheral "washout" combined with elevated AFP were useful for differentiating CK19-positive HCCs from CK19-negative HCC.

[Expression and action of hepatic sterol regulatory element-binding protein-1c in patients with nonalcoholic fatty liver disease].

OBJECTIVE: To investigate the hepatic expression of sterol regulatory element-binding proteins-1c (SREBP-1c) in patients with nonalcoholic fatty liver disease (NAFLD). METHODS: NAFLD patients were confirmed using clinical and pathological methods. The expressions of protein and mRNA of SREBP-1 c in the livers were detected by immunohistochemistry, reverse transcription and polymerase chain reactions. The expression of protein of fatty acid synthases (FAS) controlled by SREBP-1c was observed by immunofluorescence. Levels of triglyceride and cholesterol in serum were measured. RESULTS: The serum levels of triglyceride and cholesterol were positively correlated with hepatic adipose degeneration (r=0.71 or 0.70, P less than 0.05). The levels of SREBP-1c protein in the livers of NAFLD patients were significantly higher than those of the control group (2.19+/-0.31 vs 1.15+/-0.20, t=11.06, P less than 0.05), and the more severe the fatty degeneration, the stronger their expression (F=24.54, P less than 0.01). The expressions of the SREBP-1C mRNA in the livers showed the same changes (0.69+/-0.02 vs 0.40+/-0.02, t= -14.63, P less than 0.05). The expression of FAS was enhanced significantly in the livers of the NAFLD patients. CONCLUSION: Enhanced expression of SREBP-1 c and FAS maybe a factor causing hepatic lipopexia in NAFLD patients.

[Fluorescence investigation on interaction between artemisinin (qinghaosu) and hemin and its analytical application].

Hemin-catalytic decomposition of artemisinin (qinghaosu, QHS) was studied using pyronine B (PB) as an indicator. The interaction between hemin and QHS was an enzyme-substrate model, and the action sites were the endoperoxide moiety of QHS and the central metal ion of enzyme respectively. The kinetic catalytic constant depends upon enzyme and substrate concentrations, and the Michaelis-Menten parameters Km, Vmax and Kcat was 8.4 x 10(-5) mol x L(-1), 7.4 x 10(-6) mol x L(-1) s(-1) and 50.23 s(-1) respectively. The catalytic activity of hemin was inhibited in the presence of deactivated agents and at high temperature. Under optimal conditions, the change in fluorescence intensity (Fo-F) of pyronine B was proportional to the QHS concentration from 0.0 to 1.27 x 10(-6) mol x L(-1), and the detection limit (3sigma) was as low as 2.3 x 10(-8) mol x L(-1). The proposed method was applied to detect the concentration of QHS in the media of plasma and urine.

Value of MR histogram analyses for prediction of microvascular invasion of hepatocellular carcinoma.

The objective is to explore the value of preoperative magnetic resonance (MR) histogram analyses in predicting microvascular invasion (MVI) of hepatocellular carcinoma (HCC).Fifty-one patients with histologically confirmed HCC who underwent diffusion-weighted and contrast-enhanced MR imaging were included. Histogram analyses were performed and mean, variance, skewness, kurtosis, 1th, 10th, 50th, 90th, and 99th percentiles were derived. Quantitative histogram parameters were compared between HCCs with and without MVI. Receiver operating characteristics (ROC) analyses were generated to compare the diagnostic performance of tumor size, histogram analyses of apparent diffusion coefficient (ADC) maps, and MR enhancement.The mean, 1th, 10th, and 50th percentiles of ADC maps, and the mean, variance. 1th, 10th, 50th, 90th, and 99th percentiles of the portal venous phase (PVP) images were significantly different between the groups with and without MVI (P <0.05), with area under the ROC curves (AUCs) of 0.66 to 0.74 for ADC and 0.76 to 0.88 for PVP. The largest AUC of PVP (1th percentile) showed significantly higher accuracy compared with that of arterial phase (AP) or tumor size (P <0.001).MR histogram analyses-in particular for 1th percentile for PVP images-held promise for prediction of MVI of HCC.

Feasibility of histogram analysis of susceptibility-weighted MRI for staging of liver fibrosis.

PURPOSE: We aimed to evaluate whether histogram analysis of susceptibility-weighted imaging (SWI) could quantify liver fibrosis grade in patients with chronic liver disease (CLD). METHODS: Fifty-three patients with CLD who underwent multi-echo SWI (TEs of 2.5, 5, and 10 ms) were included. Histogram analysis of SWI images were performed and mean, variance, skewness, kurtosis, and the 1st, 10th, 50th, 90th, and 99th percentiles were derived. Quantitative histogram parameters were compared. For significant parameters, further receiver operating characteristic (ROC) analyses were performed to evaluate the potential diagnostic performance for differentiating liver fibrosis stages. RESULTS: The number of patients in each pathologic fibrosis grade was 7, 3, 5, 5, and 33 for F0, F1, F2, F3, and F4, respectively. The results of variance (TE: 10 ms), 90th percentile (TE: 10 ms), and 99th percentile (TE: 10 and 5 ms) in F0-F3 group were significantly lower than in F4 group, with areas under the ROC curves (AUCs) of 0.84 for variance and 0.70-0.73 for the 90th and 99th percentiles, respectively. The results of variance (TE: 10 and 5 ms), 99th percentile (TE: 10 ms), and skewness (TE: 2.5 and 5 ms) in F0-F2 group were smaller than those of F3/F4 group, with AUCs of 0.88 and 0.69 for variance (TE: 10 and 5 ms, respectively), 0.68 for 99th percentile (TE: 10 ms), and 0.73 and 0.68 for skewness (TE: 2.5 and 5 ms, respectively). CONCLUSION: Magnetic resonance histogram analysis of SWI, particularly the variance, is promising for predicting advanced liver fibrosis and cirrhosis.

A novel organic-inorganic hybrid constructed from the Nyman-type dititanoniobate [Ti2Nb8O28](8-) and copper-organic cations.

A new organic-inorganic hybrid titaniobate compound, [Cu(en)2][Cu(en)2(H2O)2]3[Ti2Nb8O28]·8H2O (1) (en = ethylenediamine), was successfully synthesized, characterized by single-crystal X-ray diffraction, IR spectroscopy, thermogravimetric analysis (TGA) and UV-Vis diffuse reflectance spectroscopy and its photoluminescence studied.

Effects of nuclear receptor FXR on the regulation of liver lipid metabolism in patients with non-alcoholic fatty liver disease.

OBJECTIVE: The aim of this study was to explore the role of farnesoid X receptor (FXR) in liver lipid metabolism of non-alcoholic fatty liver disease (NAFLD) patients. METHODS: In this study, pathology and clinical criteria confirmed NAFLD in patients. Fatty acid synthetase (FAS)-positive liver cells were visualized by laser scanning confocal microscopy. Levels of FXR, liver X receptor (LXR), sterol regulatory element binding protein 1C (SREBP-1C), and small heterodimer partner (SHP) proteins were detected by Western blot. FXR, LXR, and SHP mRNA levels were measured by real-time PCR. RESULTS: In patients with NAFLD, a significant positive relationship between the degree of hepatic steatosis and serum triglycerides and cholesterol (correlation coefficient > 0.5, P < 0.05) was seen. The NAFLD patients had more FAS protein in liver, which suggests that there could have been more of fatty acid synthesis in hepatic cells (P < 0.05). The levels of FXR protein and mRNA were decreased in patients with NAFLD (P < 0.05), while those of LXR and SREBP-1C were increased (P < 0.05). The levels of SREBP-1C positively correlated with the degree of hepatic steatosis. There were no differences between the levels of SHP protein and mRNA both in NAFLD patients and normal controls (P > 0.05). CONCLUSION: Our data showed that the decreased expression of hepatic FXR is associated with an increased expression of LXR, SREBP-1C, and hepatic triglyceride synthesis; furthermore, increased SREBP-1C is associated with the degree of hepatic steatosis in the NAFLD patients.