Model incorporating multiple diffusion MRI features: development and validation of a radiomics-based model to predict adult-type diffuse gliomas grade.

OBJECTIVES: To develop and validate a radiomics-based model (ADGGIP) for predicting adult-type diffuse gliomas (ADG) grade by combining multiple diffusion modalities and clinical and imaging morphologic features. METHODS: In this prospective study, we recruited 103 participants diagnosed with ADG and collected their preoperative conventional MRI and multiple diffusion imaging (diffusion tensor imaging, diffusion kurtosis imaging, neurite orientation dispersion and density imaging, and mean apparent propagator diffusion-MRI) data in our hospital, as well as clinical information. Radiomic features of the diffusion images and clinical information and morphological data from the radiological reports were extracted, and multiple pipelines were used to construct the optimal model. Model validation was performed through a time-independent validation cohort. ROC curves were used to evaluate model performance. The clinical benefit was determined by decision curve analysis. RESULTS: From June 2018 to May 2021, 72 participants were recruited for the training cohort. Between June 2021 and February 2022, 31 participants were enrolled in the prospective validation cohort. In the training cohort (AUC 0.958), internal validation cohort (0.942), and prospective validation cohort (0.880), ADGGIP had good accuracy in predicting ADG grade. ADGGIP was also significantly better than the single-modality prediction model (AUC 0.860) and clinical imaging morphology model (0.841) (all p < .01) in the prospective validation cohort. When the threshold probability was greater than 5%, ADGGIP provided the greatest net benefit. CONCLUSION: ADGGIP, which is based on advanced diffusion modalities, can predict the grade of ADG with high accuracy and robustness and can help improve clinical decision-making. CLINICAL RELEVANCE STATEMENT: Integrated multi-modal predictive modeling is beneficial for early detection and treatment planning of adult-type diffuse gliomas, as well as for investigating the genuine clinical significance of biomarkers. KEY POINTS: • Integrated model exhibits the highest performance and stability. • When the threshold is greater than 5%, the integrated model has the greatest net benefit. • The advanced diffusion models do not demonstrate better performance than the simple technology.

Applying MAP-MRI to Identify the WHO Grade and Main Genetic Features of Adult-type Diffuse Gliomas: A Comparison of Three Diffusion-weighted MRI Models.

RATIONALE AND OBJECTIVES: Currently, there is no noninvasive method to effectively judge the genotype of diffuse gliomas. We explored the association between mean apparent propagator-MRI (MAP-MRI) and WHO grade 2/3, IDH 1/2 mutations, and chromosome 1p/19q combined deletion genotypes in adult-type diffuse gliomas and compared it with the diagnostic efficiency of diffusion tensor imaging (DTI) and diffusional kurtosis imaging (DKI). MATERIALS AND METHODS: We prospectively recruited 67 participantshistopathologically diagnosed with adult-type diffuse gliomas. Routine MRI, DKI, and DSI were performed before surgery. The extreme and average partial diffusion indexes of solid tumors were measured. A comprehensive assessment of statistically significant diffusion parameters was performed after Bonferroni correction, including ROC curves, correct classification percentage (CCP), integrated discrimination improvement (IDI), net reclassification improvement (NRI), and k-fold cross validation. RESULTS: For differentiating WHO grade 2/3, q-space inverse variance (QIV), mean kurtosis (MK), non-Gaussianity (NG), and return to the origin probability (RTOP) were different (p' < .05), with the mean QIV exhibiting the best diagnostic efficacy and stability (AUC = 0.973, CCP = 0.906). We observed significant differences in mean diffusivity (MD), mean square displacement, QIV, MK, and RTOP between the IDH wild-type and IDH mutant groups (p' < .001) (AUC, 0.806-0.978) and MAP-MRI showed a higher IDI than DTI and DKI (0.094-0.435, NRI > 0, respectively). For the chromosome 1p/19q combined deletion, the minimum QIV was different between the overall (p' < .05) and no significant differences  in MD and MK was observed. CONCLUSION: MAP-MRI effectively predicts the WHO grade 2/3, IDH 1/2 mutations, and chromosome 1p/19q combined deletion in adult-type diffuse gliomas, and it may perform better than DTI and DKT.

Evaluation of diffuse glioma grade and proliferation activity by different diffusion-weighted-imaging models including diffusion kurtosis imaging (DKI) and mean apparent propagator (MAP) MRI.

PURPOSE: To evaluate two advanced diffusion models, diffusion kurtosis imaging and the newly proposed mean apparent propagation factor-magnetic resonance imaging, in the grading of gliomas and the assessing of their proliferative activity. METHODS: Fifty-nine patients with clinically diagnosed and pathologically proven gliomas were enrolled in this retrospective study. All patients underwent DKI and MAP-MRI scans. Manually outline the ROI of the tumour parenchyma. After delineation, the imaging parameters were extracted using only the data from within the ROI including mean diffusion kurtosis (MK), return-to-origin probability (RTOP), Q-space inverse variance (QIV) and non-Gaussian index (NG), and the differences in each parameter in the classification of glioma were compared. Receiver operating characteristic (ROC) curve analysis was used to evaluate the diagnostic performance of these parameters. RESULTS: MK, NG, RTOP and QIV were significantly different amongst the different grades of glioma. MK, NG and RTOP had excellent diagnostic value in differentiating high-grade from low-grade glioma, with largest areas under the curve (AUCs; 0.929, 0.933 and 0.819, respectively; P < 0.01). MK and NG had the largest AUCs (0.912 and 0.904) when differentiating grade II tumours from III tumours (P < 0.01) and large AUCs (0.791 and 0.786) when differentiating grade III from grade IV tumours. Correlation analysis of tumour proliferation activity showed that MK, NG and QIV were strongly correlated with the Ki-67 LI (P < 0.001). CONCLUSION: MK, RTOP and NG can effectively represent the microstructure of these altered tumours. Multimodal diffusion-weighted imaging is valuable for the preoperative evaluation of glioma grade and tumour proliferative activity.

Multiparametric MR radiomics in brain glioma: models comparation to predict biomarker status.

BACKGROUND: Genotype status of glioma have important significance to clinical treatment and prognosis. At present, there are few studies on the prediction of multiple genotype status in glioma by method of multi-sequence radiomics. The purpose of the study is to compare the performance of clinical features (age, sex, WHO grade, MRI morphological features etc.), radiomics features from multi MR sequence (T2WI, T1WI, DWI, ADC, CE-MRI (contrast enhancement)), and a combined multiple features model in predicting biomarker status (IDH, MGMT, TERT, 1p/19q of glioma. METHODS: In this retrospective analysis, 81 glioma patients confirmed by histology were enrolled in this study. Five MRI sequences were used for radiomic feature extraction. Finally, 107 features were extracted from each sequence on Pyradiomics software, separately. These included 18 first-order metrics, such as the mean, standard deviation, skewness, and kurtosis etc., 14 shape features and second-order metrics including 24 grey level run length matrix (GLCM), 16 grey level run length matrix (GLRLM), 16 grey level size zone matrix (GLSZM), 5 neighboring gray tone difference matrix (NGTDM), and 14 grey level dependence matrix (GLDM). Then, Univariate analysis and LASSO (Least absolute shrinkage and selection operator regression model were used to data dimension reduction, feature selection, and radiomics signature building. Significant features (p < 0.05 by multivariate logistic regression were retained to establish clinical model, T1WI model, T2WI model, T1 + C (T1WI contrast enhancement model, DWI model and ADC model, multi sequence model. Clinical features were combined with multi sequence model to establish a combined model. The predictive performance was validated by receiver operating characteristic curve (ROC analysis and decision curve analysis (DCA). RESULTS: The combined model showed the better performance in some groups of genotype status among some models (IDH AUC = 0.93, MGMT AUC = 0.88, TERT AUC = 0.76). Multi sequence model performed better than single sequence model in IDH, MGMT, TERT. There was no significant difference among the models in predicting 1p/19q status. Decision curve analysis showed combined model has higher clinical benefit than multi sequence model. CONCLUSION: Multi sequence model is an effective method to identify the genotype status of cerebral glioma. Combined with clinical models can better distinguish genotype status of glioma. KEY POINTS: The combined model showed the higher performance compare with other models in predicting genotype status of IDH, MGMT, TERT. Multi sequence model showed a better predictive model than that of a single sequence model. Compared with other models, the combined model and multi sequence model show no advantage in prediction of 1p/19q status.

Primary application of mean apparent propagator-MRI diffusion model in the grading of diffuse glioma.

PURPOSE: To evaluate the diagnostic -->performance of mean apparent propagator-magnetic resonance imaging (MAP-MRI) in distinguishing the grades of diffuse gliomas. METHOD: Thirty-six patients with pathologically confirmed diffuse gliomas were enrolled in this study. MAP-MRI parameters were measured in the parenchymal area of the tumour: non-Gaussianity (NG), non-Gaussianity axial (NGAx), non-Gaussianity vertical (NGRad), Q-space inverse variance (QIV), return to the origin probability (RTOP), return to the axis probability (RTAP), return to the plane probability (RTPP), and mean square displacement (MSD). Differences in the parameters between any two grades were compared, the characteristics of the parameters for different diffuse glioma grades were analysed, and receiver operating characteristic (ROC) curves were plotted to analyse the diagnostic value of each parameter. RESULTS: Compared with grade III gliomas, grade II gliomas had lower NG, NGAx and NGRad values. NG, NGAx and NGRad had great area under the ROC curve (AUC) values (0.823, 0.835, and 0.838, P < 0.05). Compared with those of grade IV glioma, the NG, NGAx, NGRad, RTAP and RTOP values for grade II glioma were lower, the QIV values were higher (all P < 0.05). NG, NGAx, NGRad, RTAP, RTOP and QIV had great area under the ROC curve (AUC) values (0.923, 0.929, 0.923,0.793,0.822, and 0.769, P < 0.05). CONCLUSIONS: Quantitative MAP-MRI parameters can distinguish grade II and III and grade II and IV gliomas before surgery but not grade III and IV gliomas. Thus, these parameters have clinical guiding value in the noninvasive preoperative evaluation of tumour pathological grading.

Downregulation of miR-384-5p attenuates rotenone-induced neurotoxicity in dopaminergic SH-SY5Y cells through inhibiting endoplasmic reticulum stress.

Endoplasmic reticulum (ER) stress has been linked to the pathogenesis of Parkinson's disease (PD). However, the role of microRNAs (miRNAs) in this process involved in PD remains poorly understood. Recent studies indicate that miR-384-5p plays an important role for cell survival in response to different insults, but the role of miR-384-5p in PD-associated neurotoxicity remains unknown. In this study, we investigated the role of miR-384-5p in an in vitro model of PD using dopaminergic SH-SY5Y cells treated with rotenone. We found that miR-384-5p was persistently induced by rotenone in neurons. Also, the inhibition of miR-384-5p significantly suppressed rotenone-induced neurotoxicity, while overexpression of miR-384-5p aggravated rotenone-induced neurotoxicity. Through bioinformatics and dual-luciferase reporter assay, miR-384-5p was found to directly target the 3'-untranslated region of glucose-regulated protein 78 (GRP78), the master regulator of ER stress sensors. Quantitative polymerase chain reaction and Western blotting analysis showed that miR-384-5p negatively regulated the expression of GRP78. Inhibition of miR-384-5p remarkably suppressed rotenone-evoked ER stress, which was evident by a reduction in the phosphorylation of activating transcription factor 4 (ATF4) and inositol-requiring enzyme 1 (IRE1α). The downstream target genes of ER stress including CCAAT/enhancer-binding protein-homologous protein (CHOP) and X box-binding protein-1 (XBP-1) were also decreased by the miR-384-5p inhibitor. In contrast, overexpression of miR-384-5p enhanced ER stress signaling. In addition, knockdown of GRP78 significantly abrogated the inhibitory effect of miR-384-5p inhibitors on cell apoptosis and ER stress signaling. Moreover, we observed a significant increase of miR-384-5p expression in primary neurons induced by rotenone. Taken together, our results suggest that miR-384-5p mediated ER stress by negatively regulating GRP78 and that miR-384-5p inhibition might be a novel and promising approach for the treatment of PD.

A highly efficient degradation mechanism of methyl orange using Fe-based metallic glass powders.

A new Fe-based metallic glass with composition Fe76B12Si9Y3 (at. %) is found to have extraordinary degradation efficiency towards methyl orange (MO, C14H14N3SO3) in strong acidic and near neutral environments compared to crystalline zero-valent iron (ZVI) powders and other Fe-based metallic glasses. The influence of temperature (294-328 K) on the degradation reaction rate was measured using ball-milled metallic glass powders revealing a low thermal activation energy barrier of 22.6 kJ/mol. The excellent properties are mainly attributed to the heterogeneous structure consisting of local Fe-rich and Fe-poor atomic clusters, rather than the large specific surface and strong residual stress in the powders. The metallic glass powders can sustain almost unchanged degradation efficiency after 13 cycles at room temperature, while a drop in degradation efficiency with further cycles is attributed to visible surface oxidation. Triple quadrupole mass spectrometry analysis conducted during the reaction was used to elucidate the underlying degradation mechanism. The present findings may provide a new, highly efficient and low cost commercial method for azo dye wastewater treatment.

A novel method for evaluating brain function and microstructural changes in Parkinson's disease.

In this study, microstructural brain damage in Parkinson's disease patients was examined using diffusion tensor imaging and tract-based spatial statistics. The analyses revealed the presence of neuronal damage in the substantia nigra and putamen in the Parkinson's disease patients. Moreover, disease symptoms worsened with increasing damage to the substantia nigra, confirming that the substantia nigra and basal ganglia are the main structures affected in Parkinson's disease. We also found that microstructural damage to the putamen, caudate nucleus and frontal lobe positively correlated with depression. Based on the tract-based spatial statistics, various white matter tracts appeared to have microstructural damage, and this correlated with cognitive disorder and depression. Taken together, our results suggest that diffusion tensor imaging and tract-based spatial statistics can be used to effectively study brain function and microstructural changes in patients with Parkinson's disease. Our novel findings should contribute to our understanding of the histopathological basis of cognitive dysfunction and depression in Parkinson's disease.

Study of binding thermodynamics in the optimization of BH3 mimetics.

The use of small molecule B-cell lymphoma 2 homology domain 3 mimetics to neutralize the B-cell lymphoma 2 protein is an attractive strategy for cancer treatment due to its ability to cause targeted cell apoptosis. We have previously reported the design and optimization of a series of B-cell lymphoma 2 homology domain 3-mimetics, called compounds 1-6. In this study, we evaluated the optimization of B-cell lymphoma 2 homology domain 3-mimetics from a thermodynamic perspective. Understanding the thermodynamic parameters of B-cell lymphoma 2 homology domain 3-mimetics plays a critical role in the development of B-cell lymphoma 2 small-molecule inhibitors. The thermodynamic parameters for the interactions of these compounds with the myeloid cell leukemia sequence 1 protein were obtained using isothermal titration calorimetry. Owing to compounds 1-6 overcoming enthalpy-entropy compensation, the affinities of them improved gradually. Toward binding to the myeloid cell leukemia sequence 1 protein, compound 6 was deemed optimal with an obtained Kd value of 238 nm, which is a 10(4) -fold improvement compared with 1. Analysis of the enthalpy and -TΔS efficiencies showed that ligand efficiencies with respect to molecular size are correlated with the enthalpic efficiencies. Notably, an enthalpy gain of 4.65 kcal/mol identified that an additional hydrogen bond is formed by 2 with myeloid cell leukemia sequence 1 compared with compound 1. For the first time, hydrogen bonding between a small-molecule inhibitor of B-cell lymphoma 2 was demonstrated experimentally.

3-Thiomorpholin-8-oxo-8H-acenaphtho [1,2-b] pyrrole-9-carbonitrile (S1) derivatives as pan-Bcl-2-inhibitors of Bcl-2, Bcl-xL and Mcl-1.

Based on the binding mode of our previously discovered dual inhibitor of Bcl-2 and Mcl-1, 3-thiomorpholin-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile (3, S1), a library of 9-substituted 3 derivatives was synthesized to further probe the p4 pocket of the two targets. By NMR, structure-activity relationship study, and site-directed mutation, compound 6d (3-(4-aminophenylthio)-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-3-phenyl)propylamine) was identified to span p2-p4 pockets of Mcl-1, Bcl-2 and Bcl-x(L), and then exhibited 9- to 35-fold better affinity to the three targets than 3 (IC(50)=10, 20 and 18 nM, respectively), which led to greater activity in induction of apoptosis in multiple cancer cell lines. Different contribution of p4 pocket to binding Bcl-2 and Mcl-1 was also investigated by plotting the potency and the HAC of the derivatives.