Pediatric Hepatoblastoma After Neoadjuvant Chemotherapy: Diagnostic Performance of MR in Staging POSTTEXT and Vascular Involvement.

BACKGROUND: The assessment of resectability after neoadjuvant chemotherapy of hepatoblastoma is dependent on Post-Treatment EXTENT of Disease (POSTTEXT) staging and its annotation factors P (portal venous involvement) and V (hepatic venous/inferior vena cava [IVC] involvement), but MR performance in assessing them remains unclear. PURPOSE: To assess the diagnostic performance of contrast-enhanced MR imaging for preoperative POSTTEXT staging and diagnosing vascular involvement in terms of annotation factors P and V in pediatric hepatoblastoma following neoadjuvant chemotherapy. STUDY TYPE: Retrospective. SUBJECTS: Thirty-five consecutive patients (17 males, median age, 24 months; age range, 6-98 months) with proven hepatoblastoma underwent preoperative MR imaging following neoadjuvant chemotherapy. FIELD STRENGTH/SEQUENCE: 3.0 T; T2-weighted imaging (T2WI), T2WI with fat suppression, diffusion weighted imaging, radial stack-of-the-star/Cartesian 3D Dixon T1-weighted gradient echo imaging. ASSESSMENT: Three radiologists independently assessed the POSTTEXT stages and annotation factors P and V based on the 2017 PRE/POSTTEXT system. The sensitivities and specificities were calculated for 1) diagnosing each POSTTEXT stage; 2) discrimination of stages III and IV (advanced) from those stages I and II (non-advanced) hepatoblastomas; and 3) annotation factors P and V. The combination of pathologic findings and surgical records served as the reference standard. STATISTICAL TESTS: Sensitivity, specificity, Fleiss kappa test. RESULTS: The sensitivity and specificity ranges for discriminating advanced from non-advanced hepatoblastomas were 73.3%-80.0% and 80.0%-90.0%, respectively. For annotation factor P, they were 66.7%-100.0% and 90.6%, respectively. For factor V, they were 75.0% and 67.7%-83.9%, respectively. There was excellent, substantial, and moderate agreement on POSTTEXT staging (Fleiss kappa = 0.82), factors P (Fleiss kappa = 0.64), and factors V (Fleiss kappa = 0.60), respectively. DATA CONCLUSION: MR POSTTEXT provides reliable discrimination between advanced and non-advanced tumors, and MR has moderate to excellent specificity at identifying portal venous and hepatic venous/IVC involvement. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 3.

Prognostic value of right ventricular trabecular complexity in patients with arrhythmogenic cardiomyopathy.

OBJECTIVES: The present study aimed to investigate the incremental prognostic value of the right ventricular fractal dimension (FD), a novel marker of myocardial trabecular complexity by cardiac magnetic resonance (CMR) in patients with arrhythmogenic cardiomyopathy (ACM). METHODS: Consecutive patients with ACM undergoing CMR were followed up for major cardiac events, including sudden cardiac death, aborted cardiac arrest, and appropriate implantable cardioverter defibrillator intervention. Prognosis prediction was compared by Cox regression analysis. We established a multivariable model supplemented with RV FD and evaluated its discrimination by Harrell's C-statistic. We compared the category-free, continuous net reclassification improvement (cNRI) and integrated discrimination index (IDI) before and after the addition of FD. RESULTS: A total of 105 patients were prospectively included from three centers and followed up for a median of 60 (48, 66) months; experienced 36 major cardiac events were recorded. Trabecular FD displayed a strong unadjusted association with major cardiac events (p < 0.05). In the multivariable Cox regression analysis, RV maximal apical FD maintained an independent association with major cardiac events (hazard ratio, 1.31 (1.11-1.55), p < 0.002). The Hosmer-Lemeshow goodness of fit test displayed good fit (X2 = 0.68, p = 0.99). Diagnostic performance was significantly improved after the addition of RV maximal apical FD to the multivariable baseline model, and the continuous net reclassification improvement increased 21% (p = 0.001), and the integrated discrimination index improved 16% (p = 0.045). CONCLUSIONS: In patients with ACM, CMR-assessed myocardial trabecular complexity was independently correlated with adverse cardiovascular events and provided incremental prognostic value. CLINICAL RELEVANCE STATEMENT: The application of FD values for assessing RV myocardial trabeculae may become an accessible and promising parameter in monitoring and early diagnosis of risk factors for adverse cardiovascular events in patients with ACM. KEY POINTS: • Ventricular trabecular morphology, a novel quantitative marker by CMR, has been explored for the first time to determine the severity of ACM. • Patients with higher maximal apical fractal dimension of RV displayed significantly higher cumulative incidence of major cardiac events. • RV maximal apical FD was independently associated with major cardiac events and provided incremental prognostic value in patients with ACM.

Discovery of the covalent SARS-CoV-2 Mpro inhibitors from antiviral herbs via integrating target-based high-throughput screening and chemoproteomic approaches.

The main proteases (Mpro ) are highly conserved cysteine-rich proteins that can be covalently modified by numerous natural and synthetic compounds. Herein, we constructed an integrative approach to efficiently discover covalent inhibitors of Mpro from complex herbal matrices. This work begins with biological screening of 60 clinically used antiviral herbal medicines, among which Lonicera japonica Flos (LJF) demonstrated the strongest anti-Mpro effect (IC50 = 37.82 µg/mL). Mass spectrometry (MS)-based chemical analysis and chemoproteomic profiling revealed that LJF extract contains at least 50 constituents, of which 22 exhibited the capability to covalently modify Mpro . We subsequently verified the anti-Mpro effects of these covalent binders. Gallic acid and quercetin were found to potently inhibit severe acute respiratory syndrome coronavirus 2 Mpro in dose- and time- dependent manners, with the IC50 values below 10 µM. The inactivation kinetics, binding affinity and binding mode of gallic acid and quercetin were further characterized by fluorescence resonance energy transfer, surface plasmon resonance, and covalent docking simulations. Overall, this study established a practical approach for efficiently discovering the covalent inhibitors of Mpro from herbal medicines by integrating target-based high-throughput screening and MS-based assays, which would greatly facilitate the discovery of key antiviral constituents from medicinal plants.

Myocardial extracellular volume quantified by cardiac magnetic resonance predicts left ventricular aneurysm following acute myocardial infarction.

OBJECTIVE: This study aimed to investigate the correlation between increased extracellular matrix estimated by cardiac magnetic resonance (CMR) and left ventricular aneurysm after acute myocardial infarction. METHODS: A total of 175 patients from 3 centers with an isolated left anterior descending culprit vessel underwent CMR examinations within 1 week and at a 6-month follow-up. Of these, 92 were identified to have left ventricular aneurysms (LVAs): 74 with functional aneurysm and 18 with anatomical aneurysm. The predictive significance of acute extracellular volume (ECV), left gadolinium enhancement (LGE), and other characteristics were analyzed using binary logistic regression analysis. RESULTS: Patients with LVA were more likely to present with left ventricular adverse remodeling (LVAR) than those without (p = 0.009). With optimal cutoff values of 30.90% for LGE and 33% for ECV to discriminate LVA from non-LVA, the area under the curve (AUC) by receiver operator characteristic curve (ROC) analysis was 0.92 (95% CI: 0.87-0.96; p < 0.001) and 0.93 (95% CI: 0.88-0.96; p < 0.001), respectively. ECV was significantly better than LGE at discriminating between functional and anatomical LVA (p < 0.001). Both acute LGE and ECV were predictors of LVA, with an odds ratio of 1.35 (95% CI: 1.21-1.52, p < 0.001) and 1.23 (95% CI: 1.13-1.33, p < 0.001), respectively, by multivariable logistic regression analysis. CONCLUSIONS: Acute LGE and ECV of the myocardium provided predictive significance for LVA. The discriminative significance of ECV for functional versus anatomical LVA was better than the discriminative significance of LGE. KEY POINTS: • Patients with LVA were more likely to present with LVAR. • Acute LGE and ECV of the myocardium provided the strongest predictive significance for LVA. • The discriminative significance of ECV for functional versus anatomical LVA was better than that of LGE.

A deep learning method for the automated assessment of paradoxical pulsation after myocardial infarction using multicenter cardiac MRI data.

OBJECTIVE: The current study aimed to explore a deep convolutional neural network (DCNN) model that integrates multidimensional CMR data to accurately identify LV paradoxical pulsation after reperfusion by primary percutaneous coronary intervention with isolated anterior infarction. METHODS: A total of 401 participants (311 patients and 90 age-matched volunteers) were recruited for this prospective study. The two-dimensional UNet segmentation model of the LV and classification model for identifying paradoxical pulsation were established using the DCNN model. Features of 2- and 3-chamber images were extracted with 2-dimensional (2D) and 3D ResNets with masks generated by a segmentation model. Next, the accuracy of the segmentation model was evaluated using the Dice score and classification model by receiver operating characteristic (ROC) curve and confusion matrix. The areas under the ROC curve (AUCs) of the physicians in training and DCNN models were compared using the DeLong method. RESULTS: The DCNN model showed that the AUCs for the detection of paradoxical pulsation were 0.97, 0.91, and 0.83 in the training, internal, and external testing cohorts, respectively (p < 0.001). The 2.5-dimensional model established using the end-systolic and end-diastolic images combined with 2-chamber and 3-chamber images was more efficient than the 3D model. The discrimination performance of the DCNN model was better than that of physicians in training (p < 0.05). CONCLUSIONS: Compared to the model trained by 2-chamber or 3-chamber images alone or 3D multiview, our 2.5D multiview model can combine the information of 2-chamber and 3-chamber more efficiently and obtain the highest diagnostic sensitivity. CLINICAL RELEVANCE STATEMENT: A deep convolutional neural network model that integrates 2-chamber and 3-chamber CMR images can identify LV paradoxical pulsation which correlates with LV thrombosis, heart failure, ventricular tachycardia after reperfusion by primary percutaneous coronary intervention with isolated anterior infarction. KEY POINTS: • The epicardial segmentation model was established using the 2D UNet based on end-diastole 2- and 3-chamber cine images. • The DCNN model proposed in this study had better performance for discriminating LV paradoxical pulsation accurately and objectively using CMR cine images after anterior AMI compared to the diagnosis of physicians in training. • The 2.5-dimensional multiview model combined the information of 2- and 3-chamber efficiently and obtained the highest diagnostic sensitivity.

A Radiomic MRI based Nomogram for Prediction of Heart Failure with Preserved Ejection Fraction in Systemic Lupus Erythematosus Patients: Insights From a Three-Center Prospective Study.

BACKGROUND: Myocardial T1 and extracellular volume (ECV) fraction values have important roles in the prognostication of heart failure with preserved ejection fraction (HFpEF). However, the traditional mean quantification of intensity levels is not sufficient. PURPOSE: To evaluate a T1 map-based radiomic nomogram as a long-term prognosticator for HFpEF in systemic lupus erythematosus (SLE) patients. STUDY TYPE: Prospective. POPULATION: A total of 115 SLE patients and 50 age- and gender-matched controls. FIELD STRENGTH/SEQUENCE: A 3.0 T scanner; cine imaging, precontrast and post-contrast T1 mapping and T2 mapping sequences. ASSESSMENT: A radiomic nomogram was developed based on precontrast T1 mapping. Three independent readers assessed and compared the ECV value and the value of the radiomic nomogram for predicting HFpEF in SLE patients. STATISTICAL TEST: Cox proportional hazard models, Youden index for determining cut-off values for high HFpEF risk vs. low HFpEF risk classification, Kaplan-Meier analysis, intraclass correlation (ICC), and Uno C statistic test. RESULTS: During a median follow-up of 27 (interquartile range, 19-37) months, 31 SLE patients developed HFpEF. Patients with elevated ECV (≥31%) and a higher output (≥42.7) from the radiomic feature "S_33_sum average" of the precontrast T1 map had a significantly higher risk of developing HFpEF than those who had lower ECV (<31%) and an output <42.7. Patients with a higher "S_33_sum average" value on precontrast T1 map had a significantly increased risk for HFpEF (hazard ratio, 1.363, 95% CI, 1.130-1.645), after adjusting for covariates including ECV and LVEF. Finally, "S_33_sum average" from precontrast T1 mapping had modest but significantly incremental prognostic value over the mean ECV value (Uno C statistic comparing models, 0.860 vs. 0.835). DATA CONCLUSION: The precontrast T1 map-based radiomic nomogram, as a measure of diffuse myocardial fibrosis was associated with HFpEF and provided modest prognostic value for predicting HFpEF in SLE patients. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 2.

Discovery of SARS-CoV-2-E channel inhibitors as antiviral candidates.

Lack of efficiency has been a major problem shared by all currently developed anti-SARS-CoV-2 therapies. Our previous study shows that SARS-CoV-2 structural envelope (2-E) protein forms a type of cation channel, and heterogeneously expression of 2-E channels causes host cell death. In this study we developed a cell-based high throughput screening (HTS) assay and used it to discover inhibitors against 2-E channels. Among 4376 compounds tested, 34 hits with cell protection activity were found. Followed by an anti-viral analysis, 15 compounds which could inhibit SARS-CoV-2 replication were identified. In electrophysiological experiments, three representatives showing inhibitory effect on 2-E channels were chosen for further characterization. Among them, proanthocyanidins directly bound to 2-E channel with binding affinity (KD) of 22.14 µM in surface plasmon resonance assay. Molecular modeling and docking analysis revealed that proanthocyanidins inserted into the pore of 2-E N-terminal vestibule acting as a channel blocker. Consistently, mutations of Glu 8 and Asn 15, two residues lining the proposed binding pocket, abolished the inhibitory effects of proanthocyanidins. The natural product proanthocyanidins are widely used as cosmetic, suggesting a potential of proanthocyanidins as disinfectant for external use. This study further demonstrates that 2-E channel is an effective antiviral drug target and provides a potential antiviral candidate against SARS-CoV-2.

Diagnostic Utility of the Simplified Perfusion Fraction for Identifying Myocardial Injury in Patients With Reperfused ST-segment Elevation Myocardial Infarction.

BACKGROUND: Acute myocardial infarction (AMI) is a disease with high morbidity and mortality worldwide and the evaluation of myocardial injury and perfusion status following myocardial ischemia and reperfusion is of clinical value. PURPOSE: To assess the diagnostic utility of simplified perfusion fraction (SPF) in differentiating salvage and infarcted myocardium and its predictive value for left ventricular remodeling in patients with reperfusion ST-segment elevation myocardial infarction (STEMI). STUDY TYPE: Prospective. POPULATION: Forty-one reperfused STEMI patients and 20 healthy volunteers. FIELD STRENGTH/SEQUENCE: 3.0T MRI. The MR examination included cine, T2 -short tau inversion recovery (T2 -STIR), first pass perfusiong (FPP)，phase sensitive inversion recovery (PSIR), and diffusion-weighted imaging (DWI). ASSESSMENT: SPF values among different myocardium regions (infarcted, salvaged, remote, and MVO) and stages of reperfused STEMI patients as well as normal controls were measured. The diagnostic utility of SPF values in differentiating salvaged and infarcted myocardium was assessed. STATISTICAL ANALYSIS: Independent t-test and the Mann-Whitney U-test. Logistic regression. RESULTS: SPF values in healthy controls were not significantly different than SPF values in the remote myocardium of patients (40.09 ± 1.47% vs. 40.28 ± 1.93%, P = 0.698). In reperfusion STEMI patients, SPF values were lower in infarcted myocardium compared to remote and salvaged myocardium (32.15 ± 2.36% vs. 40.28 ± 1.93%, P < 0.001; 32.15 ± 2.36% vs. 36.68 ± 2.71%, P < 0.001). SPF values of infarcted myocardium showed a rebound increase from acute to convalescent stages (32.15 ± 2.36% vs. 34.69 ± 3.69%, P < 0.001). When differentiating infarcted and salvaged myocardium, SPF values demonstrated an area under the curve (AUC) of 0.89 (sensitivity 85.4%, specificity 80.5%, cutoff 34.42%). Lower SPF values were associated with lower odds ratio (OR = 0.304) of left ventricular remodeling after adjusting for potential confounders with a confidence interval (CI) of 0.129-0.717, P = 0.007. DATA CONCLUSION: SPF might be able to differentiate salvaged and infarcted myocardium and is a strong predictor of left ventricular remodeling in reperfused STEMI patients. Level of Evidence 2 Technical Efficacy Stage 2.

Myocardial extracellular volume fraction radiomics analysis for differentiation of reversible versus irreversible myocardial damage and prediction of left ventricular adverse remodeling after ST-elevation myocardial infarction.

OBJECTIVES: Our study sought to explore the prognostic value of radiomic TA (texture analysis) on quantitative ECV (extracellular volume) fraction mapping to differentiate between reversible and irreversible myocardial damage and to predict left ventricular adverse remodeling in patients with reperfused STEMI (ST-elevation myocardial infarction). METHODS: This observational prospective cohort study identified 70 patients (62 ± 9 years, 62 men [85.70%]) with STEMI for TA who consecutively performed native and contrast T1 mapping. Texture features were extracted from each stack of ECV mapping based on ROI (region of interest) analysis. RESULTS: After texture feature selection and dimension reduction, five selected texture features were found to be statistically significant for differentiating the extent of myocardial injury. ROC (receiver operating characteristic) curve analysis for the differentiation of unsalvageable infarction and salvageable myocardium demonstrated a significantly higher AUC (area under the curve) (0.91 [95% CI, 0.86-0.96], p < 0.0001) for horizontal fraction than other texture features (p < 0.05). LVAR (left ventricular adverse remodeling) was predicted by those selected features. The differences in qualitative and quantitative baseline parameters and horizontal fractions were significant between the patients with and without LVAR. LGE (late gadolinium enhancement) and horizontal fraction features of infarcted myocardium in acute STEMI were the only two parameters selected in forming the optimal overall multivariable model for LVAR at 6 months. CONCLUSIONS: Radiomic analysis of ECV could discriminate reversible from irreversible myocardial injury after STEMI. LGE as well as radiomics TA (texture analysis) of ECV may provide an alternative to predict LVAR and functional recovery. KEY POINTS: • ECV quantification was able to differentiate between infarcted myocardium and non-infarcted myocardium. • Radiomics analysis of ECV could discriminate reversible from irreversible myocardial injury. • Radiomics TA analysis shows a promising similarity with LGE findings which could aid the prognosis of myocardial infarction patients.

Crossed cerebellar diaschisis after stroke detected noninvasively by arterial spin-labeling MR imaging.

BACKGROUND: As a noninvasive perfusion-weighted MRI technique, arterial spin-labeling (ASL) was becoming increasingly used to evaluate cerebral hemodynamics in many studies. The relation between ASL-MRI and crossed cerebellar diaschisis (CCD) was rarely discussed. In this study, the aim of our study was to assess the performance of ASL-MRI in the detection of crossed cerebellar diaschisis after stroke in compared with single-photon emission CT (SPECT). RESULTS: 17 of 51(33.3%) patients revealed CCD phenomenon by the SPECT method. In CCD-positive group, CBFASL of ipsilateral cerebellar were significantly increased compared with contralateral cerebellar (p < 0.0001) while no significant differences (p = 0.063, > 0.001) in the CCD-negative group. Positive correlation was detected between admission National institute of health stroke scale (NIHSS) and asymmetry index of SPECT (AISPECT) (r = 0.351, p = 0.011), AIASL (r = 0.372, p = 0.007); infract volume and AISPECT (r = 0.443, p = 0.001), AIASL (r = 0.426, p = 0.002). Significant correlation was also found between cerebral blood flow of SPECT (CBFSPECT) and CBFASL, AISPECT and AIASL (r = 0.204, p = 0.04; r = 0.467, p = 0.001, respectively). Furthermore, the area under the receiver operating characteristic (ROC) curve value of AIASL was 0.829. CONCLUSIONS: CBF derived from ASL-MRI could be valuable for assessment of CCD in supratentorial stroke patients. Additionally, CCD was significantly associated with larger ischemic volume and higher initial NIHSS score.

Prognostic Value of Late Gadolinium Enhancement in Predicting Life-Threatening Arrhythmias in Heart Failure Patients With Implantable Cardioverter-Defibrillators: A Systematic Review and Meta-Analysis.

BACKGROUND: The presence of late gadolinium enhanced (LGE), which may enable better evaluation of myocardial impairment, would help predict the occurrence of life-threatening arrhythmias and major adverse cardiovascular events (MACE) in patients suffering from ischemic cardiomyopathy (ICM) and nonischemic cardiomyopathy (NICM) patients and who underwent a process of implantable cardioverter-defibrillator (ICD). PURPOSE: To evaluate the prognostic value of cardiac MR-LGE for ICM and NICM patients with ICD. STUDY TYPE: Systematic review and meta-analysis. POPULATION: A total of 33 studies of 3457 patients were included. FIELD STRENGTH: 1. 5T and 3.0T, LGE. ASSESSMENT: PubMed, Cochrane Library, EMBASE, and Web of Science were systematically searched for studies reporting LGE in ICM or NICM patients with ICD implantation with several kinds of endpoints: MACE, life-threatening arrhythmia, cardiovascular mortality, and all-cause mortality. STATISTICAL TESTS: A meta-analysis was performed using a random-effects model to calculate odds ratios or standard mean differences (SMDs) for binary and continuous data. RESULTS: MR-LGE was positive in 1923 (55.6%) of ICM and NICM patients. LGE-present patients were more likely to have life-threatening arrhythmia (odds ratio [OR]: 5.1; 95% confidence interval [CI]: 3.8-6.8), MACE (OR: 5.2; 95% CI: 3.8-6.9), cardiovascular mortality (OR: 2.4; 95% CI: 1.2-4.6), and all-cause mortality (OR: 2.1; 95% CI: 1.3-3.4) compared with those without LGE. Moreover, ICM and NICM patients with LGE both had increased life-threatening arrhythmia (OR: 4.6; 95% CI: 2.7-8.0; OR: 5.2; 95% CI: 3.6-7.8, respectively) and MACE (OR: 4.7; 95% CI: 2.8-7.9; OR: 4.7; 95% CI: 2.7-8.1, respectively). DATA CONCLUSION: The presence of MR-LGE may worsen the prognosis for adverse cardiovascular events in both ICM and NIMC patients who benefit more from ICDs. LEVEL OF EVIDENCE: 3 Technical Efficacy Stage: 3 J. Magn. Reson. Imaging 2020;51:1422-1439.

Myocardial Extracellular Volume Fraction Allows Differentiation of Reversible Versus Irreversible Myocardial Damage and Prediction of Adverse Left Ventricular Remodeling of ST-Elevation Myocardial Infarction.

BACKGROUND: The relationship between dynamic changes of myocardial injury in ST-elevation myocardial infarction (STEMI) patients and long-term prognosis is still unclear. PURPOSE: To evaluate the extracellular volume fraction (ECV) in the differentiation of reversible from irreversible myocardial injury and the prediction value of left ventricular adverse remodeling in patients with STEMI after reperfusion. STUDY TYPE: Prospective. POPULATION: Twenty-four STEMI patients after reperfusion were included FIELD STRENGTH/SEQUENCE: 3.0 T, T1 mapping, ECV, T2 -STIR, and late gadolinium enhancement (LGE). ASSESSMENT: All the patients underwent cardiac MRI at four timepoints (days 1, 3, and 7, and at 6 months). The regions of interest (ROIs) were selected at the infarcted myocardium (with/without intramyocardial hemorrhage [IMH] and microvascular obstruction [MVO]). STATISTICAL TESTS: One-way analysis of variance and the Kruskal-Wallis test were used for the statistical analysis. RESULTS: Native T1 of MI (without MVO/IMH) gradually decreased after reperfusion (P < 0.05). The ECV of MI increased during the first 3 days and then slowly declined. Native T1 of MI with MVO/IMH was the lowest (1184 msec; 1108.5-1266), while ECV (78%; 65.5-87%) was the highest, P < 0.001. Native T1 and ECV of salvageable myocardium were higher than those of the remote myocardium but lower than those of the MI without MVO or IMH (P < 0.001). ROC analysis revealed an area under the curve (AUC) of ECV (0.85, P < 0.001) for differentiating infarcted and salvageable myocardium was higher than that of native T1 mapping (AUC: 0.63, P < 0.001) in the first week after STEMI (P < 0.0001). T1 and ECV differed significantly between patients with and without left ventricle adverse remodeling (P < 0.05). DATA CONCLUSION: Dynamic temporal changes in reversibly and irreversibly damaged myocardia were differentiated via native T1 and ECV mapping after primary percutaneous coronary intervention in STEMI patients. ECV may better reflect microvascular injury severity and myocardial viability. MI with higher native T1 and ECV or with severe microvascular injury (MVO and IMH) was correlated with adverse LV remodeling. LEVEL OF EVIDENCE: 2 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2020. J. Magn. Reson. Imaging 2020;52:476-487.

M1 muscarinic receptors regulate the phosphorylation of AMPA receptor subunit GluA1 via a signaling pathway linking cAMP-PKA and PI3K-Akt.

M1 muscarinic acetylcholine receptors are highly expressed in key areas that control cognition, such as the cortex and hippocampus, representing one potential therapeutic target for cognitive dysfunctions of Alzheimer's disease and schizophrenia. We have reported that M1 receptors facilitate cognition by promoting membrane insertion of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor AMPA receptor subunit 1 (GluA1) through phosphorylation at Ser845. However, the signaling pathway is still unclear. Here we showed that adenylyl cyclase inhibitor 2',5'-dideoxyadenosine and PKA inhibitor KT5720 inhibited enhancement of phosphorylation of Ser845 and membrane insertion of GluA1 induced by M1 receptor activation. Furthermore, PI3K inhibitor LY294002 and protein kinase B (Akt) inhibitor IV blocked the effects of M1 receptors as well. Remarkably, the increase of the activity of PI3K-Akt signaling induced by M1 receptor activation could be abolished by cAMP-PKA inhibitors. Moreover, inhibiting the mammalian target of rapamycin (mTOR) complex 1, an important downstream effector of PI3K-Akt, by short-term application of rapamycin attenuated the effects of M1 receptors on GluA1. Furthermore, such effect was unrelated to possible protein synthesis promoted by mTOR. Taken together, these data demonstrate that M1 receptor activation induces membrane insertion of GluA1 via a signaling linking cAMP-PKA and PI3K-Akt-mTOR pathways but is irrelevant to protein synthesis.-Zhao, L.-X., Ge, Y.-H., Li, J.-B., Xiong, C.-H., Law, P.-Y., Xu, J.-R., Qiu, Y., Chen, H.-Z. M1 muscarinic receptors regulate the phosphorylation of AMPA receptor subunit GluA1 via a signaling pathway linking cAMP-PKA and PI3K-Akt.

Histogram Analysis of Native T1 Mapping and Its Relationship to Left Ventricular Late Gadolinium Enhancement, Hypertrophy, and Segmental Myocardial Mechanics in Patients With Hypertrophic Cardiomyopathy.

BACKGROUND: The use of native T1 mapping for evaluation of hypertrophic cardiomyopathy (HCM) is being explored, and its combination with histogram analysis may benefit the accuracy of such assessments. PURPOSE: To investigate the relationship of segmental left ventricular wall thickness (LVWT), myocardial fibrosis, and strain parameters with segmental histogram parameters of native T1 mapping in HCM patients. STUDY TYPE: Retrospective. SUBJECTS: Ninety-three HCM patients without previous cardiovascular diseases were included. FIELD STRENGTH/SEQUENCE: 3.0T cardiac MR. Steady-state free precession cine imaging, modified Look-Locker inversion recovery, phase-sensitive inversion recovery. ASSESSMENT: Images were assessed by three experienced radiologists. STATISTICAL TESTS: Mann-Whitney U-tests, area under the curve (AUC), Spearman's rank correlation, intraclass correlation coefficient, and Bland-Altman test were used for statistical analysis. RESULTS: A higher LVWT value correlated with higher means, minimums, 10th /25th /50th /75th /90th percentiles, maximums, kurtosis, entropy, and lower SD and energy of T1 mapping (P < 0.05 for all), with the correlation being stronger for entropy and energy (Spearman's rho = 0.439 and -0.413, respectively) than other parameters. Late gadolinium enhancement positive (LGE+) segments exhibited higher mean, minimum, 10th /25th /50th /75th /90th percentiles, maximum, entropy, and lower energy of T1 times than late gadolinium enhancement negative (LGE-) segments (P < 0.001 for all). Impaired strain function parameters (peak thickening and thickening rate in radial, circumferential, and longitudinal directions) demonstrated a weak correlation with higher entropy (P < 0.001 for all) and lower energy (P < 0.001 for all). DATA CONCLUSION: Histogram parameters of native T1 mapping provide more information than mean T1 times alone. Among these parameters, entropy and energy may correlate better with LVWT, myocardial late gadolinium enhancement, and strain parameters than mean T1 times in HCM patients. LEVEL OF EVIDENCE: 2 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2019;49:668-677.

Diffusion kurtosis imaging to assess correlations with clinicopathologic factors for bladder cancer: a comparison between the multi-b value method and the tensor method.

OBJECTIVES: To assess the efficacy of diffusion kurtosis imaging (DKI) in differentiating low-grade from high-grade tumors and evaluating the aggressiveness of bladder cancer. METHODS: From January 2017 to July 2017, 35 patients (28 males, 7 females; mean age 63 ± 9 years) diagnosed with bladder cancer underwent diffusion-weighted imaging (DWI) with two types of DKI protocols: (1) multi-b value ranging from 0 to 2000 s/mm2 to obtain mean diffusivity/kurtosis (MDb/MKb) and (2) the tensor method with 32 directions with 3 b values (0, 1000, and 2000s/mm2) to obtain mean/axial/radial diffusivity (MDt/Da/Dr), mean/axial/radial kurtosis (MKt/Ka/Kr), and fractional anisotropy (FA) before radical cystectomy. Comparisons between the low- and high-grade groups, non-muscle-invasive bladder cancer (NMIBC), and muscle-invasive bladder cancer (MIBC) were performed with the areas under the receiver operating characteristic curves (AUCs). RESULTS: The MKt and Kr values were significantly (p = 0.017 and p = 0.048) higher in patients with high-grade bladder tumors than in those with low-grade tumors. The MKt, Kr, and MKb values were significantly (p = 0.022, p = 0.000, and p = 0.044, respectively) higher in patients with MIBC than in those with NMIBC, while no significant differences (p > 0.05) were found in other values. The AUC of Kr (0.883) was the largest and was significantly higher than those of other metrics (all p < 0.05) for differentiating MIBC from NMIBC, with a sensitivity and specificity of 81.8% and 91.7%, respectively. CONCLUSIONS: Kurtosis metrics performed better than diffusion metrics in differentiating MIBC from NMIBC, and directional kurtosis and Kr metrics may also have great potential in providing additional information regarding bladder cancer invasiveness. KEY POINTS: • Kurtosis metrics performed better than diffusion metrics in differentiating muscle-invasive bladder cancer (MIBC) from non-muscle-invasive bladder cancer (NMIBC). • Directional kurtosis can provide additional directional microstructural information regarding bladder cancer invasiveness.

BOLD cardiac MRI for differentiating reversible and irreversible myocardial damage in ST segment elevation myocardial infarction.

OBJECTIVES: BOLD imaging is a quantitative MRI technique allowing the evaluation of the balance between supply/demand in myocardial oxygenation and myocardial haemorrhage. We sought to investigate the ability of BOLD imaging to differentiate reversible from irreversible myocardial injury as well as the chronological progression of myocardial oxygenation after reperfusion in patients with ST segment elevation myocardial infarction (STEMI). METHODS: Twenty-two patients (age, 60 ± 11 years; 77.3% male) with STEMI underwent cardiac MRIs on four occasions: on days 1, 3, 7 and 30 after reperfusion. BOLD MRI was obtained with a multi-echo turbo field echo (TFE) sequence on a 3-T scanner to assess myocardial oxygenation in MI. RESULTS: T2* value in MI with intramyocardial haemorrhage (IMH) was the lowest (9.77 ± 3.29 ms), while that of the salvaged zone was the highest (33.97 ± 3.42 ms). T2* values in salvaged myocardium demonstrated a unimodal temporal pattern from days 1 (37.91 ± 2.23 ms) to 30 (30.68 ± 1.59 ms). T2* values in the MI regions were significantly lower than those in remote myocardium, although the trends in both were constant overall. There was a slightly positive correlation between T2* in MI regions and EF (Rho = 0.27, p < 0.05) or SV (Rho = 0.22, p = 0.04) and a slightly negative correlation between T2* in salvaged myocardium and LVEDV (Rho = - 0.23, p < 0.05). CONCLUSIONS: BOLD MRI performed in post-STEMI patients allows accurate evaluation of myocardial damage severity and could differentiate reversible from irreversible myocardial injury. The increased T2* values may imply the pathophysiological mechanism of salvaged myocardium. BOLD MRI could represent a more accurate alternative to the other currently available options. KEY POINTS: • Myocardial oxygenation and haemorrhage after myocardial infarction affect BOLD MRI values • BOLD MRI could be used to differentiate irreversible from reversible myocardial damage • Changed oxygenation implies the pathophysiological mechanism of salvaged myocardium.

Regulation and effects of neurotrophic factors after neural stem cell transplantation in a transgenic mouse model of Alzheimer disease.

According to much research, neurodegeneration and cognitive decline in Alzheimer disease (AD) are correlated with alternations of neurotrophic factors such as nerve growth factor, brain-derived neurotrophic factor, and glial cell-derived neurotrophic factor. The experimental illumination of neural stem cell (NSC) transplantation to eliminate AD symptoms is being explored frequently, and we have acknowledged that neurotrophic factors may play a pivotal role in cognitive improvement. However, the relation between the reversal of cognitive deficits after NSC transplantation and directed alternations of neurotrophic factors is not clearly expounded. Meanwhile, reduced inflammatory response, promoted vessel density, and vascular endothelial growth factor (VEGF) can be reflections of improvement in cerebrovascular function. Three weeks after NSC transplantation, spatial learning and memory function in NSC-injected (Tg-NSC) mice were significantly improved compared with vehicle-injected (Tg-Veh) mice. Meanwhile, results obtained by immunofluorescence and Western blot analyses demonstrated that the levels of neurotrophic factors, VEGF, and vessel density in the cortex of Tg-NSC mice were significantly enhanced compared with Tg-Veh mice, while the levels of proinflammatory cytokines interleukin (IL)-1ß, tumor necrosis factor-α, and IL-6 were significantly decreased. Our results suggest that elevated concentrations of neurotrophic factors probably play a critical role in rescuing cognitive dysfunction in APP/PS1 transgenic mice after NSC transplantation, and neurotrophic factors may improve cerebrovascular function by means such as reducing inflammatory response and promoting angiogenesis.

Intravoxel incoherent motion diffusion-weighted imaging in assessing bladder cancer invasiveness and cell proliferation.

BACKGROUND: Nonmuscle-invasive bladder cancer (NMIBC, Stage T1 or lower) is treated with transurethral resection (TUR), while muscle-invasive bladder cancer (MIBC, Stage T2 or more) requires neoadjuvant chemotherapy before radical cystectomy. Hence, preoperative differentiation is vital. PURPOSE: To investigate whether intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI) can differentiate NMIBC from MIBC and to assess whether there were correlations between IVIM parameters and the Ki-67 labeling index (LI). STUDY TYPE: Retrospective. SUBJECTS: Thirty-six patients diagnosed with bladder cancer confirmed by histopathological findings. FIELD STRENGTH/SEQUENCE: 3.0T magnetic resonance imaging (MRI) DWI with eight b-values ranging from 0 to 1000 s/mm2 . ASSESSMENT: Molecular diffusion coefficient (D), perfusion-related diffusion coefficient (D*), perfusion fraction (f), and apparent diffusion coefficient (ADC) were calculated by biexponential and monoexponential models fits, respectively. STATISTICAL TESTS: Comparisons were made between the MIBC and NMIBC group, and differences were analyzed by comparing the areas under the receiver-operating characteristic curves (AUCs). The correlations between these parameters and Ki-67 LI were assessed by Spearman's rank correlation analysis. RESULTS: The ADC and D value were significantly lower in patients with MIBC compared to those with NMIBC (P < 0.01). No significant (P > 0.05) differences were observed in D* and f. The AUC of D value (0.894) was significantly (P < 0.05) larger than the ADC value (0.786), with sensitivities and specificities of 95% and 87.5% (D) and 80% and 68.7% (ADC), respectively. In addition, the D and ADC values were significantly correlated with Ki-67 LI (r = -0.785, r = -0.643, respectively; both P < 0.01). DATA CONCLUSION: The D value obtained from IVIM exhibited better performance than conventional DWI for distinguishing NMIBC from MIBC and may serve as a potential imaging biomarker for bladder cancer invasion. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018;47:1054-1060.

Diagnostic performance of intravoxel incoherent motion diffusion-weighted imaging in the assessment of the dynamic status of myocardial perfusion.

BACKGROUND: Acute myocardial infarction (AMI) is a major cause of morbidity and mortality worldwide and places a significant financial burden on our society. PURPOSE: To determine the feasibility of cardiac intravoxel incoherent motion (IVIM) in the consecutive evaluation of myocardial perfusion in myocardial infarction patients postpercutaneous coronary intervention (PCI) and to investigate the dynamic biological phenomena in myocardial perfusion after AMI. STUDY TYPE: Prospective observational study. POPULATION: Twenty ST-segment elevation myocardial infarction (STEMI) patients after reperfusion therapy and 12 healthy volunteers served as controls. FIELD STRENGTH/SEQUENCE: Cardiac MRI at 3T, including steady-state free precession (SSFP) cine imaging, T2 -short time inversion recovery (T2 -STIR), late gadolinium enhancement (LGE), T2 mapping, and IVIM diffusion-weighted imaging (DWI) were performed. ASSESSMENT: Myocardial T2 value and IVIM-DWI-associated parameters (ADCfast , ADCslow , and f value) of the infarcted myocardium at different timepoints, remote myocardium, and normal myocardium were analyzed by two experienced radiologists. STATISTICAL TESTS: Independent sample's t-test, Pearson's, and Spearman's correlation and interobserver variability were applied. P ≤ 0.05 was considered significant. RESULTS: The T2 value in ischemic myocardium measured on day 3 (73.58 ± 4.37 msec) was greater than at any other timepoint (24 hours, day 7, day 30; 66.66 ± 4.71 msec, 68.36 ± 4.18 msec, 64.98 ± 5.39 msec, respectively, P < 0.001). ADCfast and f values were significantly lower in ischemic myocardium than in the remote myocardium as well. The f value in ischemic myocardium at day 3 (0.0989 ± 0.02) was lower than at any other timepoint (24 hours, 7 day, 30 day; 0.1203 ± 0.02, 0.1109 ± 0.02, 0.1213 ± 0.02, respectively, P < 0.001. DATA CONCLUSION: This preliminary study demonstrated that a dynamic process exists in the status of myocardial edema and myocardial perfusion in MI patients after PCI. The findings suggest myocardial perfusion would be best evaluated between day 3 and day 7. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;48:1602-1609.

Myocardial fibrosis evaluated by diffusion-weighted imaging and its relationship to 3D contractile function in patients with hypertrophic cardiomyopathy.

BACKGROUND: Previous studies have shown that diffusion-weighted imaging (DWI) is sensitive to myocardial fibrosis in ischemic and nonischemic cardiomyopathy. PURPOSE: To explore the prognostic value of apparent diffusion coefficient (ADC) for detecting myocardial fibrosis and its relationship to the contractile function in hypertrophic cardiomyopathy (HCM). STUDY TYPE: Prospective. POPULATION: A total of 45 HCM patients and 20 controls. FIELD STRENGTH/SEQUENCE: 3.0T cardiac MRI. The cardiac MR sequences included cine, T1 mapping, and DWI. ASSESSMENT: According to the presence of late gadolinium enhancement (LGE) and the extracellular volume (ECV) values (+2 SD of control subjects), respectively, reader W and reader J assessed the value of ADC of each segment for detecting myocardial fibrosis and its relationship to impaired contractile function in HCM patients. STATISTICAL TESTS: Independent sample t-test, Pearson analysis, and intraclass correlation (ICC). RESULTS: The value of ECV was 23.6 ± 3.0% for control. ECV ≥ 29.6% and ECV < 29.6% groups were classified. ADC values in the ECV ≥ 29.6% group were significantly increased compared to the ECV < 29.6% group, (2.41 ± 0.23 µm2 /ms vs. 2.03 ± 0.16 µm2 /ms, P < 0.005). Compared to the LGE - group, ECV (32.1 ± 2.3% vs. 29.0 ± 2.8%, P < 0.005) and ADC (2.60 ± 0.18 µm2 /ms vs. 2.10 ± 0.07 µm2 /ms, P < 0.005) values were significantly increased in the LGE + group. ADC values were linearly associated with ECV values (R2 = 0.65) in HCM patients. ADC values were linearly associated with circumferential and longitudinal strain (R2 = 0.60, R2 = 0.46), as well as circumferential, longitudinal, and radial strain rate (R2 = 0.13, R2 = 0.25, R2 = 0.17, respectively). DATA CONCLUSION: Contractile dysfunction in HCM is predominantly associated with ADC, which is a feasible alternative to ECV and LGE for detecting myocardial fibrosis. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;48:1139-1146.