Multiparametric MRI-based whole-liver radiomics for predicting early-stage liver fibrosis in rabbits.

OBJECTIVES: To develop and validate a whole-liver radiomic model using multiparametric MRI for predicting early-stage liver fibrosis (LF) in rabbits. METHODS: A total of 134 rabbits (early-stage LF, n = 91; advanced-stage LF, n = 43) who underwent liver magnetic resonance elastography (MRE), hepatobiliary phase, dynamic contrast enhanced (DCE), intravoxel incoherent motion (IVIM), diffusion kurtosis imaging, and T2* scanning were enrolled and randomly allocated to either the training or validation cohort. Whole-liver radiomic features were extracted and selected to develop a radiomic model and generate quantitative Rad-scores. Then, multivariable logistic regression was utilized to determine the Rad-scores associated with early-stage LF, and effective features were integrated to establish a combined model. The predictive performance was assessed by the area under the curve (AUC). RESULTS: The MRE model achieved superior AUCs of 0.95 in the training cohort and 0.86 in the validation cohort, followed by the DCE-MRI model (0.93 and 0.82), while the IVIM model had lower AUC values of 0.91 and 0.82, respectively. The Rad-scores of MRE, DCE-MRI and IVIM were identified as independent predictors associated with early-stage LF. The combined model demonstrated AUC values of 0.96 and 0.88 for predicting early-stage LF in the training and validation cohorts, respectively. CONCLUSIONS: Our study highlights the remarkable performance of a multiparametric MRI-based radiomic model for the individualized diagnosis of early-stage LF. ADVANCES IN KNOWLEDGE: This is the first study to develop a combined model by integrating multiparametric radiomic features to improve the accuracy of LF staging.

Effect of Iron Deposition on Native T1 Mapping and Blood Oxygen Level Dependent for the Assessment of Liver Fibrosis in Rabbits With Carbon Tetrachloride Intoxication.

RATIONALE AND OBJECTIVES: This study aimed to explore the effect of iron deposition on native T1 mapping and blood oxygen level-dependent (BOLD) imaging in detecting liver fibrosis (LF) in a rabbit model. MATERIALS AND METHODS: An LF group (n = 100) was established by subcutaneously injecting 50% carbon tetrachloride (CCl4) oil solution, and 20 normal rabbits composed a control group. Native T1 mapping and BOLD were performed, and the T1native and R2* quantitative parameters were analyzed by receiver operating characteristic (ROC) and multiple logistic regression analyses, with histopathological results and liver iron content (LIC) serving as reference standards. RESULTS: In total, 18, 17, 16, 18, and 15 rabbits were histopathologically diagnosed with LF stages F0, F1, F2, F3, and F4, respectively. T1native (r = 0.47), R2* (r = 0.75) and LIC (r = 0.61) increased with LF stage progression (p < 0.001). Compared to T1native values, R2* performed better in diagnosing the LF stage, especially for distinguishing F1-F2 from F3-F4 (AUC = 0.66 vs. 0.91, p = 0.01). Combined with the LIC, both T1native and R2* showed improved diagnostic value in comparison to the individual imaging techniques, particularly for diagnosing F0 vs. F1-F2 and F0 vs. F1-F4, with AUC values of 0.90 vs. 0.70 (p = 0.01) and 0.93 vs. 0.77 (p = 0.01) for T1native + LIC vs. LIC, respectively. CONCLUSION: BOLD imaging performed better than native T1 mapping in predicting and diagnosing LF stage progression. The decrease in diagnostic accuracy caused by the deposition of liver iron is a potential pitfall in the assessment of LF with BOLD imaging and native T1 mapping.

Staging liver fibrosis on multiparametric MRI in a rabbit model with elastography, susceptibility-weighted imaging and T1ρ imaging: a preliminary study.

BACKGROUND: Magnetic resonance elastography (MRE), susceptibility-weighted imaging (SWI), and T1ρ are three techniques for staging of liver fibrosis (LF). PURPOSE: To assess the value of MRE, SWI, and T1ρ imaging in staging LF. MATERIAL AND METHODS: Sixty rabbits were injected with 50% CCl4oil solution, whereas 20 rabbits were given normal saline. All rabbits underwent pathological examination to determine LF stages. The liver stiffness (LS), liver-to-muscle signal intensity ratio (SIR), and T1ρ values were measured from MRE, SWI, and T1ρ imaging, respectively. RESULTS: The number of rabbits was 14, 11, 10, 9, and 11 for F0, F1, F2, F3, and F4, respectively. LS (r = 0.91) and T1ρ (r = 0.51) positively correlated with LF stages, while negative correlation was present for SIR (r = -0.81). Among the three parameters, the LS values revealed the best diagnostic efficacy in staging LF, with an AUC value of 0.95 for ≥F1, 0.95 for ≥F2, 0.99 for ≥F3, and 0.98 for ≥F4. The combination of LS and SIR could best predict LF stages ≥F1, ≥F2, ≥F3 and ≥F4, with AUC values of 0.97, 0.98, 0.99, and 0.99, respectively, which were greater than those of the other two-paired parameters. A multiparametric analysis showed that the combination of all three parameters had AUC values of 0.97, 0.98, 1.00, and 1.00 for staging ≥F1, ≥F2, ≥F3, and ≥F4, respectively. CONCLUSION: Multiparametric MR imaging was superior to individual imaging for LF staging.

Collagen deposition in the liver is strongly and positively associated with T1rho elongation while fat deposition is associated with T1rho shortening: an experimental study of methionine and choline-deficient (MCD) diet rat model.

BACKGROUND: A number of questions concerning the histological mechanism of elongated T1rho in liver fibrosis remain unanswered. Using a rat model of non-alcoholic fatty liver disease (NAFLD) induced with methionine and choline-deficient (MCD) diet, the primary aim of this study is to clarify whether collagen deposition per se causes liver T1rho elongation. METHODS: There were 45 rats in the NAFLD model group and 8 rats in the control group. NAFLD model rats were fed MCD diet for 1, 2, 4, 6, 8, or 10 weeks, respectively. At the endpoint, the rats had in vivo MRI at 3.0 T and followed by histology. For T1rho data acquisition, a rotary echo spin-lock pulse was implemented in a three-dimensional fast field echo sequence with frequency selective fat suppression. The spin-lock frequency was set to 500 Hz, and the spin-lock times of 5, 10, 40, and 50 ms were used. Liver specimens were processed with hematoxylin-eosin staining for steatosis and inflammation evaluation, and Masson's trichrome staining for collagen visualization. The semiquantitative histopathological evaluation was based on NASH Clinical Research Network criteria. Histomorphometric analysis calculated percentages of fat and collagen accumulations in the livers. RESULTS: A strong (r=0.82) and significant (P<0.0001) positive correlation between liver collagen content and liver T1rho was observed. Rats with no or minimal inflammation could have very long T1rho value. Among experimental rats without a positive fibrosis grading, five rats did not have an inflammation score (i.e., had minimal inflammation or no inflammation) while four had a positive inflammation score; the difference in liver T1rho between these two types of rats was minimal. Eight control rat livers and 15 stage-1 fibrosis rat livers were separated by liver T1rho completely. When four subgroups of experiment rats were selected where the liver collagen had a very narrow range within these subgroups, all these four subgroups showed a trend of negative correlation between liver fat and liver T1rho. CONCLUSIONS: Collagen deposition in the live strongly contributes to liver T1rho elongation, while fat deposition contributes to T1rho shortening. In a well-controlled experimental setting, T1rho measure alone allows separation of healthy livers and stage-1 liver fibrosis in the MCD rat liver model.

Dynamic contrast-enhanced MRI with Gd-EOB-DTPA for the quantitative assessment of early-stage liver fibrosis induced by carbon tetrachloride in rabbits.

PURPOSE: To explore quantitative parameters obtained by dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) with Gd-EOB-DTPA in discriminating early-stage liver fibrosis (LF) in a rabbit model. MATERIALS AND METHODS: LF was established in 60 rabbits by the injection of 50% CCl4 oil solution, whereas 30 rabbits served as the control group. All rabbits underwent pathological examination to determine the LF stage using the METAVIR classification system. DCE MRI was performed, and quantitative parameters, including Ktrans, Kep, Ve, Vp and Re were measured and evaluated among the different LF stages using spearman correlation coefficients and receiver operating characteristic curve. RESULTS: In all, 24, 25, and 22 rabbits had stage F0, stage F1, and stage F2 LF, respectively. Ktrans (r = 0.803) increased, and Kep (r = -0.495) and Re (r = -0.701) decreased with LF stage progression (P < 0.001), while no significant correlation was found for Ve or Vp. Ktrans and Re were significantly different between all LF stage pairs compared (F0 vs. F1, F0 vs. F2, F1 vs. F2, F0 vs. F1-F2, P < 0.05). With the exception of F0 vs. F1, Kep differed significantly between stages (P < 0.05). The AUC of Ktrans was higher than that of other quantitative parameters, with an AUC of 0.92, 0.99, 0.94 and 0.92 for staging F0 vs. F1, F0 vs. F2, F1 vs. F2, and F0 vs. F1-F2, respectively. CONCLUSION: Among quantitative parameters of Gd-EOB-DTPA DCE MRI, Ktrans was the best predictor for quantitatively differentiating early-stage LF.

Diagnostic Efficacy of Contrast-Enhanced MRI in Detecting Residual or Recurrent Hepatocellular Carcinoma After Transarterial Chemoembolization: A Systematic Review and Meta-analysis.

BACKGROUND: The diagnostic efficacy of contrast-enhanced magnetic resonance imaging (CEMRI) in diagnosing residual or recurrent hepatocellular carcinoma (HCC) after transarterial chemoembolization (TACE) is currently not completely clear. PURPOSE: To investigate the diagnostic efficacy of CEMRI in detecting residual or recurrent HCCs after TACE by meta-analysis. STUDY TYPE: Systematic review and meta-analysis. POPULATION: A systematic literature search was performed in PubMed, Embase, Web of Science, Ovid, and the Cochrane Library database up to June 2019 to find original studies on diagnosing patients suspected of residual or recurrent HCCs after TACE with CEMRI. Thirteen studies comprising 721 nodules were finally included. FIELD STRENGTH/SEQUENCE: 1.5T or 3.0T, CEMRI. ASSESSMENT: Quality assessment of the included studies was performed by applying the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool. STATISTICAL TESTS: Sensitivity and specificity were pooled with a bivariate random-effects model. Heterogeneity was assessed by the chi-square test. The potential sources of heterogeneity were explored by subgroup and publication bias analyses. RESULTS: The pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio, and area under the summary receiver operating characteristic (ROC) curve (AUC) of CEMRI in diagnosing residual or recurrent HCCs after TACE were 91% (95% confidence interval [CI]: 87%-96%), 93% (95% CI: 85%-97%), 12.22 (95% CI: 5.62-26.57), 0.09 (95% CI: 0.05-0.18), 126.99 (95% CI: 34.76-436.99) and 0.97 (95% CI: 0.95-0.98), respectively. Subgroup analysis revealed that CEMRI performed significantly better in prospective studies than in retrospective studies: 0.99 (95% CI: 0.96-1.00) vs. 0.95 (95% CI: 0.92-0.96) with P < 0.05. DATA CONCLUSION: Our meta-analysis suggested that CEMRI had high diagnostic efficacy in detecting residual or recurrent HCCs after TACE and may serve as an alternative method for further evaluation after TACE. LEVEL OF EVIDENCE: 5 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2020;52:1019-1028.

[Key technologies in synthetic biology of natural products].

Natural products with complex and diverse structures are the major sources of new drugs. The biosynthesis of natural products is considered to be one of the best ways to solve the problems of complex and scarce natural products. DNA assembly technology and genome editing technology are two key technologies in the emerging interdisciplinary field of synthetic biology. A number of novel DNA assembly methods developed in the last few years have paved the way for the engineering of high molecular weight DNA molecules, including whole genomes, hence, it can realize the reconstruction of the metabolic pathways and speed up optimization process. A wide variety of new tools for microbial genome editing will be applied widely to modify the chassis genome to increase its adaptation with the exogenetic pathways. This article summarized the latest advance with respect to DNA assembly and genome editing, which aims to provide help for reconstruction and optimization of the synthetic biological systems of natural products.

[Strategies of elucidation of biosynthetic pathways of natural products].

Elucidation of the biosynthetic pathways of natural products is not only the major goal of herb genomics, but also the solid foundation of synthetic biology of natural products. Here, this paper reviewed recent advance in this field and put forward strategies to elucidate the biosynthetic pathway of natural products. Firstly, a proposed biosynthetic pathway should be set up based on well-known knowledge about chemical reactions and information on the identified compounds, as well as studies with isotope tracer. Secondly, candidate genes possibly involved in the biosynthetic pathway were screened out by co-expression analysis and/or gene cluster mining. Lastly, all the candidate genes were heterologously expressed in the host and then the enzyme involved in the biosynthetic pathway was characterized by activity assay. Sometimes, the function of the enzyme in the original plant could be further studied by RNAi or VIGS technology. Understanding the biosynthetic pathways of natural products will contribute to supply of new leading compounds by synthetic biology and provide "functional marker" for herbal molecular breeding, thus but boosting the development of traditional Chinese medicine agriculture.

[Advance in flavonoids biosynthetic pathway and synthetic biology].

Flavonoids are the valuable components in medicinal plants, which possess a variety of pharmacological activities, including anti-tumor, antioxidant and anti-inflammatory activities. There is an unambiguous understanding about flavonoids biosynthetic pathway, that is,2S-flavanones including naringenin and pinocembrin are the skeleton of other flavonoids and they can transform to other flavonoids through branched metabolic pathway. Elucidation of the flavonoids biosynthetic pathway lays a solid foundation for their synthetic biology. A few flavonoids have been produced in Escherichia coli or yeast with synthetic biological technologies, such as naringenin, pinocembrin and fisetin. Synthetic biology will provide a new way to get valuable flavonoids and promote the research and development of flavonoid drugs and health products, making flavonoids play more important roles in human diet and health.

[Advance in biosynthesis of terpenoid indole alkaloids and its regulation in Catharanthus roseus].

Catharanthus roseus can produce a variety of terpenoid indole alkaloids (TIA), most of which exhibit strong pharmacological activities. Hence, biosynthesis and regulation of TIA have received recent attention. 3α (S)-strictosidine is an important node in TIA biosynthesis, which is a condensation product of secologanin and tryptamine. The former is produced in iridoid pathway, and the latter is produced in indole pathway. Vindoline and catharanthine, which are produced respectively by 3α (S)-strictosidine via multi-step enzymatic reaction, can form α-3, 4-anhydrovinblastine by the condensation reaction. Then, vinblastine and vincristine are generated from α-3, 4-anhydrovinblastine. Many transcription factors are involved in the regulation of TIA synthesis, such as AP2/ERF and WRKY. Illumination of biosynthetic pathway has laid a foundation for the study of synthetic biology. Today, 3α (S)-strictosidine and vindoline have been synthesized in heterologous hosts Saccharomyces cerevisiae.Research about synthetic biology and the regulation mechanisms will provide a guidance for the production and development of TIA drugs in C. roseus.

[Advance in transcriptomic studies of ginseng species].

There are many valuable medicinal plants in Ginseng genus belonging to Araliaceae. Among them, Panax ginseng, P. quinquefolium and P. notoginseng are the most famous species. With the development of next-generation sequencing (NGS) technologies, sequencing and analysis of transcriptomes have become powerful tools for discovery of novel genes, screening molecular markers and elucidation of specific biosynthetic pathway of secondary metabolites. Their transcriptomes provided abundant genes for further study on functional genomics. Here this paper summarized the recent advances in the transcriptomic studies of these three medicinal plants, including discovery of novel genes and elucidation of metabolic regulation, which will contribute to functional genomics in ginseng species.

[Recent advances in biosynthetic pathway and synthetic biology of taxol].

Taxol, a kind of terpenoid secondary metabolite produced by Taxus brevifolia, is an effective anticancer drug that manufacture relies mainly on the extraction form plants. In order to solve the resource shortage, a lot of work has been done to develop the alternative method. Recently, using synthetic biology to realize heterologous biosynthesis of the precursors of taxol has become a hotspot. Now, the basic framework of taxol biosynthetic pathways has been confirmed, and most enzyme genes involved in taxol biosynthesis have been cloned and identified. The two taxol precursors, taxa-4(5),11(12)-diene and taxa-4(20),11(12)-dien-5α-ol, have been synthesized in Escherichia coli and Saccharomyces cerevisiae. Here this paper reviewed the recent advances in the biosynthetic pathway of taxol and the latest developments of synthetic biology, which aims to provide a guidance for the heterologous biosynthesis of taxol.

Complete chloroplast genome sequence of the medicinal plant Gynostemma pentaphyllum.

We report the complete chloroplast genome sequence of Gynostemma pentaphyllum, a well-known traditional Chinese medicine, which produces triterpenoid saponins similar to Panax ginseng. The assembled chloroplast genome (cpDNA) was 157,654 bp in length and structurally divided into four distinct regions, namely, large single copy region (86,794 bp), small single copy region (18,654 bp) and a pair of inverted repeat regions (26,103 bp). A total of 143 genes were annotated, including 87 protein-coding genes, 10 tRNA genes and 46 rRNA genes. Phylogenetic analysis revealed that the chloroplast genome sequence of G. pentaphyllum is most closely related to Cucumis melo.

Comparison of magnetic resonance elastography and diffusion-weighted imaging for staging hepatic fibrosis.

BACKGROUND: To compare the diagnostic values of magnetic resonance elastography (MRE) and diffusion-weighted imaging (DWI) in staging hepatic fibrosis (HF) in an animal model. METHODS: This study consisted of 44 rabbits served as HF group and 9 normal rabbits. HF group was divided into two subgroups: Group A (n = 32) and Group B (n = 12). Rabbits in Group B were served as a complementary group when rabbits in Group A suddenly died during the study. Rabbits from control and Group A underwent abdominal MR imaging (MRI), MRE, and DWI. In Group A, random eight rabbits underwent MRI examinations at 4, 5, 6, 10 weeks after carbon tetrachloride oil subcutaneous injection. Liver stiffness (LS) and apparent diffusion coefficient (ADC) values of liver parenchyma were measured. The diagnostic performance of MRE and DWI for staging HF was compared using the receiver operating characteristic curve analysis on the basis of the histopathological analysis of HF. RESULTS: Significant differences of LS and DWI values were present among HF stages (P < 0.005). The LS values measured on MRE (r = 0.838, P < 0.001) were more strongly correlated with the HF stages than with ADC values (r = -0.527, P < 0.001). The area under the receiver operating characteristic curve values of LS were significantly larger than those of DWI were for discriminating two stages of HF (0.979 vs. 0.712 for ≥ S1, 0.922 vs. 0.699 for ≥ S2). MRE showed higher specificity for predicting all stages of HF compared to DWI. CONCLUSIONS: MRE more strongly correlated with the HF stages than DWI and is more specific in predicting all HF stages.

Diffusion tensor imaging study of the anterior limb of internal capsules in neuroleptic-naive schizophrenia.

RATIONALE AND OBJECTIVES: Abnormalities in brain structure have been implicated in psychosis. Herein, we investigated the differences in fractional anisotropy (FA) and average diffusion coefficient (ADC) in the bilateral anterior limb of internal capsules between neuroleptic-naive schizophrenic patients and appropriately matched healthy controls. MATERIALS AND METHODS: Magnetic resonance imaging was performed with a 1.5 T superconductive MR scanner, and diffusion tensor imaging was carried out in 21 neuroleptic-naive schizophrenic patients and 18 matched healthy controls. FA and ADC were measured by region of interest analysis. RESULTS: Compared with healthy controls, the neuroleptic-naive schizophrenic patients showed significantly reduced FA in the bilateral anterior limb of the internal capsule. However, the difference in the ADC values between the patients and the controls was not significant. CONCLUSIONS: FA of the bilateral anterior limb of the internal capsule was reduced in neuroleptic-naive schizophrenic patients, indicating that the integrity of the white matter of the bilateral thalamus-frontal connection or the bilateral thalamus-anterior cingulate gyrus connection was destroyed.

[Triple-phase helical CT in the differential diagnosis between small hepatocellular carcinoma and small hepatic cavernous hemangioma].

OBJECTIVE: To scrutinize the enhancement pattern at hepatic arterial phase (HAP), portal venous phase (PVP) and delayed phase (DP) by helical CT examination in order to differentiate small hepatocellular carcinoma (SHCC) from small hepatic cavernous hemangioma (SHCH). METHODS: In 38 patients (41 lesions) with SHCC and 35 patients (45 lesions) with SHCH, the images at HAP, PVP and DP were recorded as to the characteristic of enhancements with the average CT value at the HAP monitored and compared. RESULTS: The enhancement patterns of SHCC at the HAP, PVP, and DP were assessed as hyper-hypo-hypodense in 20 lesions, hyper-iso-hypodense in 6 lesions, hyper-hyper-hypodense in 3 lesions, hyper-iso-isodense in 5 lesions, iso-hypo-hypodense in 3 lesions, and hypo-hypo-hypodense in 4 lesions. The enhancement patterns of the SHCH were assessed as a peripheral hyperdense nodular at HAP, then progressively enlarged at PVP and turned into a isodense or homogeneous hyperdense nodular at DP in 27 lesions, hyper-hyper-iso or hyperdense in 9 lesions, hyper-iso-isodense in 3 lesions, hypo-hypo-hypodense in 6 lesions. The enhancement CT values at the HAP of homogeneous hyperdense SHCC and SHCH were (40.4 +/- 15.5) Hounsfield Unit (HU) and (102.8 +/- 18.9) HU respectively (P < 0.01). CONCLUSION: Most of the small hepatocellular carcinoma and small hepatic cavernous hemangioma have typical appearance by triple-phase helical CT examination, and can easily and properly be diagnosed. But it is difficult to distinguish SHCC from SHCH with atypical appearance in isolated cases. Hence differentiation may be difficult. Therefore, further examinations such as MRI, ultra-sonography or isotope scintigraphy are helpful in the differential diagnosis.